17.

Cardiovascular system

E DW A R D G . LA KATTA National lnstitute on Aging, Nations/ lnsfifutes of Health, Balfimore,

Maryland

CHAPTER CONTENTS Cardiac muscle and myocyte changes with adult aging
Similar effects of aging and experimental pressure overload on
Cardiovascular Structure in Younger and Older Humans cardiac regulatory mechanisms and gene expression
Arterial structure and mechanical properties Possible mechanisms of altered cardiac gene regulation
Arterial stiffness and pressure with aging
Peripheral vascular resistance Response of older rat heart to chronic hemodynamic overload
Arterial impedance Coronary blood flow, oxygen consumption, and oxidative
Cardiac structure metabolism
Ventricular-vascular coupling Effect of Chronic Physical Conditioning on Cardiovascular
Myocardial and Cardiac Pump Function at Rest Performance in Older Humans and Animals
Integrated regulation of cardiac function Studies in humans
Cardiac filling (diastolic) properties Studies in rodents
Cardiac volumes and ejection fraction Summary
Myocardial contractile properties
Heart rate and rhythm
Cardiac output
Cardiovascular Reserve DIFFERENCES IN CARDIOVASCULAR FUNCTION between
Postural reflexes older and younger individuals have been extensively
Arterial pressure and peripheral vascular resistance described in the literature. However, confusion often
Heart rate and cardiac volumes
Isometric exercise
arises in the interpretation of these differences because
Dynamic exercise of a failure to acknowledge, or to control for, interac-
Aerobic capacity tions among age, disease, and life-style. Although recent
Arterial pressure, vascular resistance, and impedance studies have used more rigorous screening techniques to
End-diastolic and end-systolic volumes separate older individuals with clinical or occult dis-
Myocardial contractile reserve
Heart rate, stroke volume, and cardiac output
ease-for example, coronary artery disease-from those
Sympathetic Modulation of Cardiovascular Function without disease, the perfect aging study (one that com-
Intact organisms pletely controls for both disease and life-style varia-
P-Adrenergic modulation of cardiac volumes and heart rate tions) has yet to emerge. Even in the absence of the con-
during exercise founding influences of disease and life-style, the rate of
Neurotransmitter elaboration during stress
Cardiovascular target organ response to P-adrenergic
“true” aging of an organ system, such as the cardiovas-
stimulation with aging cular system, may vary from one individual to the next.
P-adrenergic receptor response in the healthy aging heart Thus even when experimental measurements differ
resembles that in chronic heart failure among younger and older individuals, age per se does
Isolated tissue or cells not usually account for all or even most of the total
Vascular responses
Cardiac responses
variance in the data,
P-AR Various aspects of study design also complicate the
G-protein and adenylate cyclase activity interpretation of measurements of the impact of age on
CAMP, protein kinase activation, and intracellular cardiovascular regulatory mechanisms. Cross-sectional
phosphorylation studies (those in which different individuals of varying
Desensitization of the P-adrenoceptor system
Parasympathetic Modulation of Cardiovascular Function
ages are compared) neither quantify nor control for life-
Cardiovascular Structure and Function in Younger and long habits of nutrition, exercise, or other birth cohort
Older Animals effects. While a longitudinal study design (see chapter 2
Cardiac structure for a discussion of the design of aging studies) intuitively
Myocardial stiffness appears to be superior to the cross-sectional approach,
Passive stiffness
Active stiffness the advantage is more often apparent than real: the
Regulation of the cardiac contraction development of occult disease or changes in life-style,
The cardiac excitation-contraction process for example, due to popular education regarding dietary

413
414 HANDBOOK OF PHYSIOLOGY-AGING
lipids, body weight or smoking, still confound the lon-
gitudinal characterization of the results of aging.
Alterations in some cardiovascular regulatory mech-
anisms occurring over certain parts of the age spectrum
(fetal, postpartum, neonatal, maturational, adult, and
senescent periods) may differ from those occurring over
other parts of the spectrum; still other aspects of car-
diovascular function may change progressively across
the entire age span. Furthermore, cellular mechanisms
underlying altered function at one age may not be the
same as those at another period of the life cycle.
“Aging” is a rather nonspecific term that is applied to
the spectrum of life periods. Statements about the effects
of age on a given aspect of cardiovascular structure or
function, without strict qualification as to the specific
range investigated, have caused confusion. The defini-
tion of age-related effects on cardiovascular regulation
also requires that a broad age range be studied. If a
sufficient adult age range is not sampled, erroneous or
incomplete generalizations about an “age effect” may
be made. Extrapolating findings of an age effect to
groups younger or older than those studied is not war-
ranted. Finally, it is noteworthy that very few data are
available regarding cardiovascular regulatory mech-
anisms in individuals older than 80 yr who are
healthy and maintain a reasonable level of physical ac-
tivity.
Because the cardiovascular system at rest functions at
only a fraction of its capacity, studies at rest d o not
adequately characterize this system or its regulatory
mechanisms. Subtle signs of age-associated differences
in cardiovascular function between younger and older
individuals become manifest, in particular, during
stress, for example, during acute exercise. In this regard,
while most older individuals have a lower aerobic
capacity than most younger ones, it has not usually been
emphasized that the amount of physical work per-
formed dictates the level of cardiovascular performance
achieved or vice versa. In older individuals, noncardio-
vascular factors often limit the amount of physical work
that can be achieved. In these individuals, parameters
of cardiovascular performance at termination of exer-
cise will be reduced, but maximum cardiovascular per-
formance will not have been sampled. Finally, whether
age-associated differences in noncardiac or cardiac fac-
tors that may limit aerobic work capacity are due to
aging per se or in part to the sedentary life-style that
accompanies aging cannot easily be sorted out, as aging
and the assumption of a more sedentary behavior are
interdependent covariants with time.
Studies of cardiovascular regulatory mechanisms in
humans are, of necessity, relatively descriptive in nature.
Use of animal models permits mechanistic studies not
achievable in humans. The rat is by far the most popular
animal model employed in studies of cardiovascular
aging. While the problem of coronary artery disease is
obviated in this species, the major issue of physical
deconditioning with age of rats in captivity may be even
more severe than in humans. Additionally, with increas-
ing age senescent rats usually exhibit renal disease,
which may complicate the interpretation of certain mea-
surements. While the applicability of research findings
in animal models to humans is often questioned, this
potential constraint is a relatively minor one since stud-
ies that address the nature of aging in any model,
regardless of direct applicability to humans, have merit
in their own right.
Attempts such as the present one to integrate the
information contained in the literature need to proceed
cautiously. Yet despite the aforementioned problems in
the design and interpretation of studies that have
addressed the issue of how aging affects the cardiovas-
cular system, when the data of many studies are consid-
ered collectively, a pattern of change in cardiovascular
regulatory mechanisms with age does emerge.
CARDIOVASCULAR STRUCTURE IN YOUNGER AND
OLDER HUMANS
Arterial Structure and Mechanical Properties
Arterial Stiffness and Pressure. Table 17.1 summarizes
the changes in arterial structural and functional prop-
erties with aging in humans. Both in vitro and in vivo
studies have indicated that the stiffness of large arteries
increases with age (13, 21, 25, 29, 46, 110, 160, 180,
197, 207, 284, 303, 359, 406, 407, 414, 480, 558).
Vascular stiffness can be quantified in terms of an elastic
modulus. Both in vivo and in vitro studies indicate that
the pressure-strain modules of large arteries increases
with age (29, 180, 304, 407, 411).
Changes in arterial stiffness with aging are accom-
panied by an increase in arterial diameter and wall
thickness in both humans and rats (78,553).In rats the
average number of nuclei in the aortic wall decreases
with aging (78), much like that in the myocardium in
humans (see below, under Cardiac Structure). The mean
systolic internal radius of the ascending aorta in humans
increases 9% per decade over the age range 20-60 yr
(363).It has been estimated that the thoracic aorta pro-
vides about one-half the total blood volume buffering
capacity of the arterial system (29),that is, one-half the
stroke volume (SV) is stored in the aorta. Up to the age
of 60 yr the aortic buffering capacity is not markedly
decreased by the increased aortic wall stiffness because
the concomitant increase in aortic volume accommo-
dates a given volume ejected into it with less change in
radius (480).Thus the volume elasticity (change in pres-
sure for a given volume change) measured in vitro shows

TABLE 17.1. Arterial Changes with Aging*
Changes in arterial geometry and structure with aging
Dilatation of the aorta and large arteries
Increase in arterial wall thickness
Increase in number of collagen fibers in the arterial wall
Decreased glycoprotein content and increased mineralization (Ca,
PO4) of elastin
Functional changes in arteries
Increased arterial stiffness, manifest as an increased elastic modulus
of the arteries and increased arterial pulse wave velocity
Increased arterial wall tension
Increased peripheral resistance
Alterations in arterial pressure and impedance
Increase in systolic pulse pressure
Increased mean arterial pressure
Increase in absolute amplitude of wave reflections
Decreased amplification of the pressure pulse between the ascending
aorta and the peripheral arteries, due in part to reflected pulse
waves
Alteration in aortic input impedance spectra
Increase in characteristic impedance
Increase in maximum-minimum impedance moduli
Shift of impedance modulus minimum and phase crossover to
higher frequencies
Mismatch between aortic input impedance and energy of LV
ejection wave
Increased systolic pressure time index
*Modified from Nichols et al. (365) with permission.
no age-associated changes up to about 60 yr, likely
reflecting the large increases in aortic volume up to that
age (29).However, beyond that age the volume elastic-
ity markedly decreases (29). As the aorta stiffens with
age, less diastolic aortic recoil also occurs, resulting in
a change in the distribution of blood flow throughout
the cardiac cycle.
Age-associated changes also occur in the more periph-
eral vessels (53, 65, 301, 414), though the increase in
diameter of these vessels with age is less and the increase
in wall thickness with age is greater than that of the
aorta (414). In individuals who have no symptoms of
peripheral vascular disease, the pressure-strain elastic
modulus of the femoral artery, measured noninvasively
via an ultrasonic tracking system and auscultatory pres-
sure, increases greater than twofold with aging over sev-
eral decades (351), though considerable variation
occurs within and among age groups.
Age-associated increases in arterial stiffness, wall
thickness, and diameter are thought to result from a
diffuse process in the vessel wall and cannot readily be
explained on the basis of atherosclerosis, a highly prev-
alent vascular disease in older individuals (110, 163,
207, 303, 359). The alterations in stress-strain curves
of aged vessels in vitro have been interpreted to be con-
CHAPTER 17: CARDIOVASCULAR SYSTEM 41 5
sistent with a relative decrease of elastin and an increase
of collagen (414), and chemical analyses indicate that
this is the case (129).A change in the distribution of un-
stretched collagen may also occur with age, and it has
been proposed that age-associated changes involve a
decrease in the coiling and twisting of molecular chains
and a reduction in effective chain length (204, 257).
While the total mucopolysaccharide content (ground
substance of the interstitial matrix) is unaltered with
aging, chondroitin sulfate p and heparin sulfate increase
and the hyaluronate and chondroitin content decrease
(243). With maturation and aging, the glycoprotein
component of elastic fibrils decreases and eventually dis-
appears (415), elastin (in rats) becomes frayed (553),
and Ca2+ content increases (303). The increased min-
eralization ( Ca2+,phosphorus) of elastin with increas-
ing age is associated with an increase in the content of
more polar amino acids (457).
In addition to structural properties, arterial stiffness
in vivo is determined by vascular smooth muscle cell
(VSMC) contractile tonus, which is controlled in part
by neurohumoral factors, for example, catecholamines
and angiotensin (386, 405, 428, 465, 517). Vascular
tonus is regulated in part by VSMC CaZ+balance. That
the increased arterial stiffness in older patients with
heart disease can be reduced by vasodilators and that
this effect is greater than that in younger individuals
(64) suggest that a component of the increased in vivo
arterial stiffening with aging may be due to augmented
VSMC tone.
The age-associated increase in arterial stiffening is
reflected in an increase in the pulse wave velocity (Fig.
17.1A) with aging (24,46, 147, 160,207,528,558). It
has been suggested that an increased aortic pulse wave
velocity with aging (due to increased aortic stiffness)
causes waves reflected from peripheral sites to the
ascending aorta at an earlier time, that is, during the
ventricular ejection period (pulse waves are reflected to
the aorta after closure of the aortic valve in younger
adults). Reflected pulse waves merge (or sum) with the
incident (or forward) waves generated by left ventricu-
lar (LV) ejection and influence the contour of measured
pressure and flow waves (348, 356, 357, 363, 365,
380). Characteristic changes of the pressure pulse con-
tour with age have been widely described (110, 160,
250, 356, 357, 363, 381, 527) and include a large sec-
ondary systolic wave in older individuals (Fig. 17.1B)
and disappearance of the diastolic pressure wave (381 ).
The duration of the dicrotic wave, which is also related
to arterial stiffness and correlated with the pulse wave
velocity, as measured from a piezogram of the carotid
pulse, also decreases with age (284).It has recently been
shown that, in a healthy sedentary study population of
a broad age range, arterial stiffness varies inversely with
aerobic capacity. This inverse relationship occurs over
416 HANDBOOK O F PHYSIOLOGY-AGING

I I
2 0 4 0 6 0 8 0 5 15 25 35 45 55 65 75
AGE (years)
Age (yea-)

lnpedance Spectra
/+m (Aorta) C

0 2 4 6 8 1012
Frequency Frequency (Hz)
1

FIG. 17.1. A: Mean brachial arterial aortic pressure and aortic pulse wave velocity in two Chinese pop-
ulations (25) selected without respect to arterial pressure (clinically hypertensive subjects included) and
in a North American study population, the Baltimore Longitudinal Study of Aging (BLSA), in which
hypertensive subjects (blood pressure greater than 140/90 mm Hg) were excluded from analysis (527). B:
Augmentation index of the carotid artery pressure pulse in healthy individuals, measured in an applanation
tonometry. The augmentation index is defined as the ratio of AP/PP%; AP is the pressure difference from
the shoulder t o peak; PP is pulse pressure. The 0 population included mildly hypertensive subjects. [From
Kelly et al. (250) with permission]; the population (BLSA) excluded clinically hypertensive subjects
(blood pressure greater than 140/90 mm Hg). [From Vaitkevicius et al. (527)with permission.] C: Hypo-
thetical aortic input impedance spectra. Upper tracing, impedance modulus values decline from a high
value at 0 H z (the PVR) to a minimum at approximately 3.5 Hz. This is approximately the same frequency
at which phase crosses zero (lower tracing). Negative phase values indicate that flow harmonics lead
pressure harmonics; positive phase values indicate that flow harmonics lag pressure harmonics. Impedance
moduli oscillate around a characteristic value (Z”average of moduli > 2 Hz) because of wave reflections.
A wave reflection index can be calculated as the difference between maximum and minimum impedance
moduli. [From Nichols et al. (365) with permission.] D: Aortic input impedance spectra and flow modulus
vs. frequency in a young subject and an elderly subject. [From Nichols et al. (363) with permission.] E:
Characteristic aortic impedance increase with age. [From Nichols et al. (363)with permission.]

and above the effects of age to increase the arterial stiff-
ness and to decrease aerobic capacity (527). The Na
dependence of arterial pressure also increases with aging
( 1 86,256,546). The altered features of the central arte-
rial pulse pressure with aging have been attributed to
early reflected pulse waves (380). Thus early reflected
pulse waves are the primary determinant for the long
recognized increase in systolic (Fig. 17.1A) and
pulse pressures with aging (242, 343, 356, 357, 380,
565).

In summary, central arteries increase in diameter and
wall thickness with aging, and these changes are asso-
ciated with an increase in arterial wall stiffness, a reduc-
tion in volume elasticity, and an increase in systolic arte-
rial pressure. The extent to which these changes occur
with aging appears to be modified by diet (NaCl intake)
and aerobic capacity.
Peripheral Vascular Resistance. It has been suggested
that changes in the pressure pulse contour of central
arteries are related not only to the stiffness properties
of the large vessels but apparently to the properties of
the small vessels which determine the total peripheral
vascular resistance (PVR) (140, 251).
The stiffening of the large arteries, with a concomi-
tant increase in pulse wave velocity and a late increase
in systolic pressure due to earlier reflected pulse waves,
ought to lead to a reduction in diastolic pressure. This
is so because the reflected pulse wave usually returns
after aortic valve closure and contributes to the diastolic
pressure (381).As this has not routinely been observed,
it has been suggested that total PVR increases with age.
In individuals with clinical hypertension it has indeed
been well established in both cross-sectional and lon-
gitudinal studies that PVR increases with age (248,326,
344, 345). However, a great deal of heterogeneity in
PVR is observed among normotensive individuals with
aging (47, 147, 238). In healthy, sedentary men PVR,
calculated in the sitting position at rest, does not
increase with age (see Fig. 17.6G).
Mechanisms that underlie the heterogeneity in the
extent to which PVR is increased in older individuals
are not presently well defined but include wide varia-
tions of basal cardiac output (see below, under Arterial
Impedance) and heterogeneities among older individu-
als in the age-associated decreases in skeletal muscle
mass and capillary density. Although renal blood flow
per gram decreases progressively after the fourth decade
(cortical flow decreases to a greater extent that medul-
lary flow) (316), the decline is due to selective renal
vasoconstriction (91).While the nature of this increase
in renal vascular resistance with aging is not completely
understood, there is presently no conclusive evidence
that renal ischemia is a cause of the age-associated
changes in renal structure or of the increase in PVR in
some elderly normotensive subjects. Age-associated dif-
ferences in blood flow to the skin and its regulation dur-
ing heat stress have also been identified (211,253,254,
412,511).
Arterial Impedance. The relationship between the
steady and the pulsatile components of flow and the
resulting pressure wave in the aorta defines the aortic
input impedance. The impedance modulus (the ratio of
oscillatory pressure and flow) is usually considered in
CHAPTER 17: CARDIOVASCULAR SYSTEM 417
the frequency domain, that is, as the power spectrum of
the pressure-flow relationship (Fig. 17.1C). The phase
relationship between flow and pressure waves varies
with frequency. The zero frequency impedance modulus
(total PVR) is the opposition to steady flow, and the
average of impedance moduli of the frequency-depen-
dent terms above those that encompass the heart rate,
referred to as the characteristic aorta impedance (ZC,),
is
the opposition to pulsatile flow (380,381).Fluctuations
of the impedance modulus about mean level (Fig.
17.1 C) are caused by reflected pulse waves. Aging is
associated with an increase in the characteristic aortic
impedance (Fig. 17.1E), greater fluctuations about the
mean value (Fig. 17.10),and a shift of the characteristic
impedance spectrum with the minimum impedance
modulus and the pressure-flow phase crossover occur-
ring at higher frequencies (363, 365, 381). An increase
in the PVR (the zero frequency impedance term) occurs
in some, but not all, study populations with aging (see
Fig. 17.6G). It is noteworthy, in this regard, that
increases in aortic stiffness and characteristic aortic
impedance can exist in the absence of a substantial
increase in PVR (64, 142, 364,421).
Cardiac Structure
Autopsy data from several thousand human hearts,
unselected for health or disease status, showed that in
subjects aged 30-90 yr, the heart increases in mass by
an average of 1 g/yr in men and 1.5 g/yr in women.
During this time the ratio of heart weight to body
weight also increases (317). More recent autopsy anal-
yses of hearts without coronary artery disease have
found an increase with age in heart mass indexed to
body mass only in women (260).In both sexes the inter-
ventricular septa1 thickness increases more with aging
than does the LV free wall thickness (260).Left ventric-
ular mass may decrease in the very old (80-100 yr of
age) (541), perhaps because the extremely sedentary
life-style of individuals surviving to this age is accom-
panied by regression of cardiac mass; alternatively, an
increase in LV mass may never have accompanied aging
in these long-lived individuals.
During the life span, the effect of age on heart size
and mass has been assessed by chest X-ray, echocardi-
ography, and gated blood-pool scans. In cross-sectional
studies the cardiothoracic ratio, assessed from the chest
X-ray, has been found either to increase or not to
change with age (494).An increase in the cardiothoracic
ratio in men is due to an increase in cardiac diameter
and in women to a reduction in thoracic diameter. In
contrast, longitudinal studies consistently report that
heart size on chest X-ray increases with age in men
between 60 and 98 yr (125, 396). Some cross-sectional
studies of sedentary volunteer subjects without disease
41 8 HANDBOOK OF PHYSIOLOGY-AGING
(Fig. 17.2) indicate that both the end-diastolic and the
end-systolic LV wall thicknesses and the estimated LV
mass, measured via M-mode (one-dimensional) echo-
cardiography, increase progressively with age in both
sexes (170,172,471,477,506). Other studies using M-
mode echocardiography have found only a minor
increase in LV mass with age in healthy women and no
change in healthy men (89).It should be noted that M-
mode echocardiography samples only a single small
area of the LV posterior wall or the ventricular septum
and extrapolates this to represent the global LV thick-
ness; LV mass is then estimated, assuming a constant
ventricular geometry at all ages. The LV cavity size at
end-diastole and end-systole, measured in the semisu-
pine position by 2-D echocardiography or in the sitting
position by gated cardiac blood-pool scans of techne-
tium-labeled red cells (see Fig. 17.6), increases moder-
ately with age in healthy, normotensive, sedentary men
but does not vary with age in women (147,421, 528).
A marked reduction in LV cavity volume observed in
a small minority of older individuals, particular wo-
men (244, 522), and likely associated with clinical
arterial hypertension, is thus an exception to the rule
(236).
When an increase in heart mass occurs with aging,
for the most part it is due to an increase in the average
myocyte size (526). In some older, apparently healthy
hospitalized patients in whom LV mass decreased with
age (375),cardiac myocyte enlargement occurred con-
currently with an estimated decrease in myocyte num-
ber. An increase in the amount and a change in the phys-
ical properties of collagen (due to altered cross-linking)
also occurs within the myocardium with aging (for
review see 173). However, the cardiac muscle to colla-
gen ratio either remains constant or increases in the
older heart (375). Myocardial lipofuscin increases with
aging (501), but this is of no known functional signifi-
cance. Additionally, some forms of amyloid protein can
be found in the hearts of about half of individuals over
70 yr of age, the frequency increasing sharply with
increasing age (297). About half the cases have only
minor quantities of amyloid, confined to the atria.
Whether the cardiac form of amyloid can strictly be con-
sidered a feature of “normal” aging is debatable, since
it is not an invariable finding even in centenarians. The
type of amyloid accumulation in primary cardiac amy-
loidosis (that associated with atrophy of the myofibers
and a firm, large, waxy heart) is not a feature of car-
diac amyloid deposition in healthy older individuals
(297).
In summary, aging between 20 and 80 yr appears to
be associated with a modest increase in LV wall thick-
ness, due mainly to an increase in the size of cardiac
myocytes. The resting LV end-diastolic (LVED) diame-
ter increases moderately with age in men but not in
women. Increases in heart mass with aging are exagger-
ated by coexisting diseases (coronary artery or hyper-
tension) and are substantially influenced by life-style
(physical fitness).
Ventricula~VascularCoupling
The interplay of age-associated cardiac and vascular
changes is depicted in Figure 17.3. Age-associated
changes in the structure, size, and reactivity of the arte-
rial bed affect myocardial performance by contributing
to the vascular impedance of LV ejection. Since pulsatile
ascending aortic pressure and flow fluctuate around
mean values, the total arterial load the LV must over-
come to eject blood includes several components: fre-
quency-dependent, dynamic elastic components related
to the characteristic aortic impedance (Fig. 17.10),
reflective components related to reflected pulse waves
(Fig. 17.1B, E ) , and frequency-independent, static resis-
tive components determined by PVR (365). In other
words, the LV load is affected not only by aortic disten-
sibility and arteriolar tone but also by reflected waves
from arterial reflecting sites. Changes in these compo-
nents individually or in any combination affect ventric-
ular ejection and function (123, 362, 366, 503). Prop-
erties intrinsic to the aorta minimize the characteristic
aortic impedance over a range of frequencies (about 3-
7 Hz) (Fig. 17.1C) in which the energy of the flow wave
is greatest, and this favorable matching permits pulsatile
ejection of blood at a minimal energy expenditure, that
is, only about 10% of total ventricular work (381).
Chronic abnormalities in aortic distensibility, such as
those associated with advancing age, as described
above, under Cardiac Structure, create a chronic mis-
match between ventricular ejection and aortic flow ener-
gies (380).It has been suggested that earlier wave reflec-
tion in older individuals, caused by an increase in pulse
wave velocity due to arterial stiffening (381), would
increase the LV hydraulic load more than would an
increase in characteristic impedance alone (365, 379,
381). In any event, increases in arterial stiffness and
PVR, when they occur (363), and the consequent
change in the aortic impedance spectrum result in an
age-associated increase in vascular loading of the heart
(363, 365). The increased vascular loading of the myo-
cardium with aging appears to be a major cause of the
increase in cardiac myocyte size (375, 526) that leads,
in some older individuals, to an increase in LV wall
thickness (170, 172, 471). When measurements from
normotensive and hypertensive subjects of a given age
range are analyzed concurrently, the aortic elastic mod-
ulus and the cardiac mass index are highly correlated
(225). Additionally, the reduction in arterial distensi-
bility in hypertensive subjects correlates with the
increase in LV mass to volume ratio, that is, to an
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420 HANDBOOK OF PHYSIOLOGY-AGING
CARDIAC ADAPTATIONS TO ARTERIAL STIFFENING
DURING AGING
~ I G .17.3. Arterial and cardiac changes that occur with aging in normotensive subjects and a t any age In
hypertensive subjects. One interpretation of the constellation (flow of arrows) is that vascular changes
lead to cardiac structural and functional alterations that maintain cardiac function. [Modified from Lak-
atta (288)with permission.]
increase in ventricular wall thickness (45,428). LV car-
diac mass estimates via ultrasound are more closely
related to arterial pressures recorded in the patient’s nat-
ural setting during normal activity or exercise, whether
measured by portable recorder or home monitor, than
to blood pressures measured by a physician (100). In
pondering the association between arterial pressure and
heart mass, which is influenced by aortic pressure, it is
important to recall that the amplification of arterial
pressure from the aorta to peripheral arterial sites that
normally occurs in younger individuals does not occur,
or is markedly blunted, in older individuals (365, 380).
Hence, identical brachial arterial pressures (Fig. 17.lA,
F) measured in a younger and an older individual
may indicate a higher aortic pressure in the older indi-
vidual.
Theoretically, an acute increase in vascular imped-
ance is accompanied by an acute reduction in SV, and
this has also been observed experimentally (381). A
chronic reduction in SV has also been observed in some
older vs. younger patients in whom aortic impedance
has been quantified (363). In contrast, other studies in
which arterial stiffness, pulse wave velocity, and systolic
p r o l o n lome
~ 4n r l y dlamlollc
bmrlng capmcity nlllng rate
arterial pressure (and presumably aortic impedance)
increase with age (Figs. 17.1A, B, F ) indicate that resting
SV is preserved in healthy older men, as is the ejection
fraction (EF) (Fig. 17.6A, C). Thus a normal SV and EF
(at rest) can be maintained in the presence of aortic stiff-
ening in healthy older men. Preservation of SV is
enabled by chronic myocardial adaptations, which
include a mild augmentation of cardiac size at end-dias-
tole (Fig. 17.6A). It is important to note that an
increased LV size prior to and during the myocardiac
contraction places a greater load on cardiac fibers and
that this constitutes a “cardiac” component of afterload
(Fig. 17.4) via the law of LaPlace. However, modest
myocardial wall thickening (Fig. 17.2) which reduces
wall stress (and the cardiac component of afterload) and
prolonged Ca2+ activation of the myofilaments (see
below, under Regulation of Cardiac Contraction)
occurs with aging. Thus in male members of a healthy,
community-dwelling population (142, 42 l), both the
LV wall thickness (170) and the end-diastolic volume
index (EDVI) increase with age (see below, under Car-
diac Volume and Ejection Fraction), suggesting that the
expected increase in LV wall stress based on both LV

REGULATION OF CARDIAC OUTPUT
lntrlnslc rnyocardlal
cell performance
“contradestate”
coronary flow load durlng
shortenlng
“afterload”
FIG.17.4. Multiple interdependent factors regulate cardiac output.
[From Lakatta (285) with permission.]
dilatation and increased arterial stiffness is minimized.
Still, the stroke work index (SWI) at rest, measured as
the product of arterial pressure and the stroke volume
index (SVI), increases with age in normotensive men
(147,421) due largely to the increase in systolic pressure
but also in part to an increase in SVI (see Figs. 17.6A,
F, 17.7A). In females, neither EDVI, SVI, nor SWI
increase with age (Figs. 17.6A, 17.7B). Since the LV
wall thickness increases with aging in women to the
same extent as in men, the lack of an increase in EDVI
with aging in women suggests that older women may
function at a reduced LV wall tension. This may be a
factor for the age-associated tendency for end-systolic
volume index (ESVI) to decrease and for EF to increase
at rest in women.
While the cardiac changes in the scheme in Figure
17.3 are depicted as resulting from increased vascular
loading of the heart, a decrease in effective P-adrenergic
stimulation of both the heart and the vasculature occurs
with aging and in hypertension (see below, under Sym-
pathetic Modulation of the Cardiovascular System) and
may be implicated in the associated myocardial changes
in part via a reduction in the heart rate at rest in the
sitting position and during stress, for example, routine
activities of daily life or exercise. In addition, possible
age-associated changes in the level or activity of other
growth factors that influence the size and structure of
myocardial or vascular cells or their matrices may have
a role in the schema depicted in Figure 17.3.
CHAPTER 17: CARDIOVASCULAR SYSTEM 421
MYOCARDIALAND CARDIAC PUMP FUNCTION
AT REST
Integrated Regulation of Cardiac Function
An understanding of the mechanisms that regulate car-
diovascular function is tantamount to addressing the
issue of how these mechanisms are affected by age. Car-
diac output is regulated by multiple mechanisms, the
macroscopic descriptors of which include the heart rate
and factors that affect SV, that is, the quantity of blood
that fills the heart prior to excitation (preload), the
mechanical load encountered following the onset of
contraction (afterload), the intrinsic myocardial con-
tractile properties (contractile or inotropic state or level
of effectiveness of excitation-contraction coupling), and
coronary flow (Fig. 17.4).
When physiologists began to discover these factors
they were often described as independent determinants
of cardiovascular function, but, as indicated in Figure
17.4, these factors are highly interdependent. Addition-
ally, each of these factors is subject to autonomic mod-
ulation, which forms the basis of many cardiovascular
reflexes. Each of the factors in Figure 17.4 has deter-
minants at multiple levels (Table 17.2). For example,
determinants of afterload at the cardiovascular system
level are vascular and blood properties; at the ventric-
ular level are cardiac pressures and volumes; at the mus-
cle level are fiber length and load; at the myocyte level
are sarcomere length and load; and at the molecular
level are the conformation of the contractile proteins
and the extent of Ca2+ binding to the myofilaments dur-
ing contraction. Thus the changing face of the categories
in Figure 17.4 must be kept in mind when utilizing these
simplified terms (293).
Cardiac Filling (Diastolic) Propehes
Early LV filling begins as ventricular pressure decreases
below that in the atrium and continues during the car-
diac diastole with a further evolution of the atrioven-
tricular (AV) pressure gradient. The stiffness of the ven-
tricular myocardium is a determinant of the ventricular
pressure and thus of the AV pressure gradient. The ini-
tial ventricular pressure reduction is due to relaxation
of myocardial fibers from the prior systole. While this
relaxation begins prior to ventricular filling, that is, dur-
ing the isovolumic relaxation period, it continues to
occur following opening of the mitral valve (during the
early LV filling period). Thus while ventricular stiffness
(more often referred to as “compliance,” that is, the
inverse of stiffness) is often thought to reflect the passive
(structural) properties of the myocardial during the
early filling period, it is due, in large part, to the extent
of the declining Ca2+-dependent myofilament interac-
422 HANDBOOK OF PHYSIOLOGY-AGING

TABLE 17.2. Some Determinants of Cardiovascular Performance

Cardiovascular system properties Cardiac muscle properties

Ventricular properties Myocyte properties
Pericardial properties Nonmyocyte properties
Arterial properties Nutrient supply and waste removal
Venous properties Cell length and pre- and (postexcitation)
Blood properties (i.e., volume and rheologic properties, including viscosity) Collagen strain
Body position
Intrathoracic pressure
Cardiac myocyte properties
Myofilament properties
Heart rate
Excitation properties
Cardiac ventricular properties Myofilament activation
Myocardial properties, length dependent (i.e., preload- and afterload-dependent Sarcomere length
fiber orientation) Crossbridge number
Activation sequence Crossbridge activation
Coronary vascular properties: preload system, autonomic system, and afterload lntraccllular skeleton
Afterload system properties: arterial properties, ventricular size and blood density Organelle phosphorylation (e.g., protein kinase or
Preload system properties: blood volume, body position, autonomic tone, and calmodulin kinase)
intrathoracic pressure Oxygen and substrate supply
Valves: preload and afterload ATP production
Intrachamber communication: loading, activation, autonomic and fiber orientation

A quantitative description of cardiovascular function would require a polynomial equation with at least as many terms as the number of
factors listed above (293).Simultaneous measurements of these factors would be required to define the contribution of each at a given moment
and under many diverse physiological and pathological conditions. Adapted from Lakatta and Maughan ( 2 9 3 )with permission.

tion. Thus both active, that is, Ca'+-dependent, and
structural mechanisms likely regulate the rates of ven-
tricular pressure decay and early filling. Ventricular
stiffness or compliance is most often measured as the
end-diastolic pressure-volume relation. Despite the
popular notion that LV compliance decreases with
aging, this parameter, in fact, has not been measured in
healthy humans, as simultaneous measurements of pres-
sure and volume have not been made. Whether the atrial
or LV pressure during the early filling period or at end-
diastole differ in healthy younger and older individuals
is also presently unknown.
The time course of isovolumic myocardial relaxation
(the time between aortic valve closure and mitral valve
opening) becomes prolonged (40% increase) with aging
in both men and women (205, 325,484) (Fig. 17.5A).
The LVED is influenced by the pattern of LV filling fol-
lowing the opening of the mitral valve. The peak rate at
which the LV fills with blood during early diastole is
markedly (50%)reduced with aging between 20 and 80
yr in healthy men and women, as shown by multiple
studies utilizing echocardiography, and echo-Doppler
or radionuclide techniques (20, 43, 75, 172, 261, 269,
276,345,478,484,507,536) (Fig. 17.5B). Asynchrony
of relengthening among ventricular segments increases
with aging and contributes to the reduction in filling rate
(42). In hypertensive subjects, the decrease in the early
ventricular filling rate varies directly with the isovol-
umic relaxation time (479). Following Ca2+ channel
blocker treatment in older hypertensive subjects,
increases in LV peak filling rate were accompanied by
reductions in LV mass (449). In a small study sample,
in which neither systolic arterial pressure nor LV wall
thickness increased with age, the pulmonary capillary
wedge pressure, an index of the LVED filling pressure,
still increased with age and a marked reduction of early
filling rate occurred in the older individuals (261). This
suggests that the early LV filling deficit that accompa-
nies aging may not be directly related to an increase in
LV wall thickness. Life-style variables, for example,
physical activity and ethanol, affect the LV filling rate
measured via Doppler techniques in younger individuals
(536). However, the peak LV early filling rate measured
by radionuclide imaging or echo-Doppler techniques
does not differ between older endurance-trained athletes
and age-matched, sedentary controls (151, 157,448).
Regardless of the uncertainties and the likely multi-
factorial nature of the reduction in the LV early diastolic
filling rate with aging, the LVED volume (LVEDV) at
rest is not reduced in healthy older individuals (147,
298,420,421); in fact, it increases with age in men and
is unchanged in women (Figs. 17.6A and 17.8; also see
below under Cardiac Volumes and Ejection Fraction).
The reduction in early filling rate does not result in a
reduced EDV in part because greater filling occurs later
in diastole, particularly during the atrial contraction
(20, 75,279, 352,484, 507). The enhanced atrial con-
tribution to ventricular filling with advancing age is
 CHAPTER 17: CARDIOVASCULAR SYSTEM 423
size and LV wall thickness appear to ameliorate the
A MALES
increase in LV wall tension that would occur due to the
l W 4 increase in LVEDVI, increases in arterial impedance,
E 120
la]
.. and the increase in peak LV systolic pressure with aging.
The resting end-systolic volume index (ESVI) does not

1 1;-
Y

W increase significantly with aging in healthy men (Fig.

I 100- 17.6A) (147). In the absence of hypertension, the SVI at
rest in the sitting position has been found to not
decrease with age in many studies of highly screened
subjects of a broad age range (147,216,398,421,544,
W
569), in contrast to some prior studies (47, 363 and see
= 40-
171 for review). In fact, as noted above, the resting,
a! I sitting SVI increases slightly with aging in men (Fig.
10 20 30 40 50 60 70 80 90100 17.6A) (133),and this is attributable to the increase in
AGE (years) EDVI with age (Fig. 17.6A),as EDVI and SVI are highly
correlated in healthy individuals of any age (408).Thus
B in a study of young and middle-aged men in whom
EDVI was found to not increase with age at rest in the
sitting position (216), no increase in SVI with age was
observed. In contrast to men, in healthy women neither
b the resting EDVI nor the SVI increases with age, the
W
v

k 9
ESVI tends to decrease slightly, and the EF tends to
B increase slightly (Figs. 17.6A, 17.7). The gender differ-
Y 6 ences in cardiac EDVI, ESVI, EF, and SVI among
3 Max. healthy sedentary individuals (Fig. 17.6) may be attrib-
4
L 3 50% Max utable in part to differences in fitness level even between
3 Rest sedentary men and women, as these effects are abol-
01 I
ished when the fitness influence is controlled for in mul-
20 30 40 50 60 70 80 90
tiple regression statistical analyses (147) or by a priori
AGE
matching of younger and older study subjects for a com-
FIG. 17.5. A Isovolumic relaxation time at rest measured from the mon exercise capacity (298).
closure of the aortic valve to the opening of the mitral valve in healthy In contrast to findings in normotensive men, in hyper-
male participants of the BLSA (Lakatta, E. G., and Fleg, J. L., unpub- tensive men SVI has been found to decrease with aging
lished results). B: Relationships between age and peak filling rate
obtained at rest, at 50% of maximal workload, and at maximal work- in both cross-sectional and longitudinal studies ( 130,
load. For each of these workloads, there was a significant inverse cor- 326,345,346). An age-associated reduction in EDVI in
relation between age and peak filling rate, r = -0.64 (rest), -0.53 older hypertensive men would be a plausible mechanism
(50% maximal workload), and -0.64 (maximal workload). The for the decrease in SVI in these individuals, but no data
slopes of the three lines did not differ with a decrease in peak filling are available in this regard. However, in support of this
rate from 6% to 7% per decade (448).
notion, it has been observed that the reduction in SVI
with age in some hypertensive men in the supine posi-
tion is abolished when a sitting position is assumed
associated with left atrial enlargement (170,172) and is (130).
the basis of an audible fourth heart sound in most The overall systolic function of the heart as a pump
healthy older individuals (143). is best judged from measurement of the EF
[ (EDV-ESV)/EDV]. The EF is not altered with aging in
Cardiac Volumes and Fiection Fraction healthy men or women at rest (147, 421) (Fig. 17.6C).

While blood volume in healthy men does not appear to
change with age (493), the EDVI (EDV normalized for
body size) in the sitting position at rest is moderately
increased in healthy older vs. younger sedentary me
(Figs. 17.7A, 17.8) (147). An increase in the resting
heart size with aging has also been observed in the
supine position in some (181, 529), but not all (331),
other studies. As we have seen, the increases in myocyte
Myocardial Contractile Properties
Because of the interaction of factors that regulate car-
diac performance (Fig. 17.4), the intrinsic contractile
behavior of myocardial fibers cannot be determined sat-
isfactorily in situ. Several noninvasive indices that have
been proposed to characterize myocardial contractility
have essentially fallen by the wayside due to their non-
424 HANDBOOK OF PHYSIOLOGY-AGING

-06
2401 -

_..---
160

120
- 0 100
0 2 0 4 0 6 0 8 0

0-
0 2 0 4 0 6 0 8 0
Age (Yeam)
FIG. 17.6. Linear regression on age of cardiac volume indices (A, at rest; B, during exercise)
and ejection fraction ( C ) ,heart rate (D),cardiac index (El, systolic arterial pressure (F), and
peripheral vascular resistance ( G )at rest and during maximal cycle ergometry in the upright
position. Study participants were healthy, sedentary male ( n = 95, closed symbols) and
female ( n = 50, open symbols), community-dwelling volunteers from the BLSA who had
been rigorously screened to exclude clinical hypertension and occult coronary artery disease
( 147).Cardiac volumes were measured via gated blood-pool scans (421). “Linear regression
on age within sex is statistically significant. Age-gender interactions are described in Fleg
et al. (147).

specificity or lack of sensitivity. The index of myocardial
contractility that is presently considered superior to oth-
ers (although under some conditions it is “preload-
dependent”) is the trajectory of ESV vs. mean arterial
pressure, sometimes referred to as “Emax,”derived from
a series of pressure-volume loops measured over a range
of cardiac volumes (428, 429, 430). In noninvasive
studies, a crude index of this trajectory, that is, the ratio
of end-systolic arterial pressure to ESV, is not reduced
at rest with age in either healthy men (Fig. 17.8A) or
women (148).
The relationship of SWI to EDVI is also a measure of
cardiac pump function. Figure 17.7A indicates that both
LV SWI and EDVI at rest shift with age in men, that is,
 CHAPTER 17: CARDIOVASCULAR SYSTEM 425

A
14000 -
12000 -
10000 -
8000 -
6000 -
R

10000

8000

6000

4000 ! 1 I I

60 70 80 90 1 )O

END DIASTOLICVOLUME INDEX (ml/rn2)

FIG. 17.7. Left ventricular SWI measured as the product of SVI and brachial systolic pressure
at rest and during graded exercise in younger (< 4 0 yr) and older (> 60 yr) men (top),and
women (bottom) of the study population depicted in Figure 17.7. [From Fleg et al. (147)
with permission.]

a greater resting SWI is achieved from a greater EDVI.
In contrast, an age-associated shift in resting SWI is not
apparent in women (Fig. 17.7B).
Heart Rate and Rhytftm
Beginning by age 60 yr there is a pronounced decrease
in the number of pacemaker cells in the sinoatrial (SA)
node, and by age 75 yr less than 10% of the cell number
found in the young adult remains (see 145 for review).
With advancing age, there is an increase in elastic and
collagenous tissue in all parts of the conduction system,
as well as of fat around the SA node. A variable degree
of calcification of the left side of the cardiac fibrous skel-
eton, which includes the aortic and mitral annuli, the
central fibrous body, and the summit of the interven-
tricular septum, occurs. Because of their proximity to
these structures, the AV node, the AV bundle, bifurca-
tion, and proximal left and right bundle branches may
be affected by this process, resulting in so-called “pri-
mary” or “idiopathic” heart block. A modest prolon-
gation of the P-R interval within the normal range
(< 20 ms)’occurswith aging in healthy individuals and
is localized to the proximal P-R segment, probably
reflecting delay within the AV junction (144). An
increase in both supraventricular and ventricular pre-
mature beats occurs in older healthy men and women
compared to their younger counterparts, but this does
not appear to be of clinical significance (142, 144).
Most cross-sectional studies have indicated that the
supine basal heart rate does not differ among younger
and older individuals (144, 147, 435, 449). Studies of
a large number of rigorously screened, healthy individ-
uals, however, indicate that in the sitting position, heart
426 HANDBOOK O F PHYSIOLOGY-AGING

40

30

20 - ....
10

20 40 ' 60 80
Age (Years)

Before Propranolol After Propranolol

i
0 '
mild moderate severe
I
EXERCISE LEVEL
FIG. 17.8. A: Left ventricular contractility index (LVCTI) measured as the ratio of end-
systolic arterial pressure and ESVI. Lines are the best fit, linear regressions at rest and during
exercise in the presence and absence of p-adrenergic blockade with propranolol. [From Fleg
et al. (150) with permission.] B: The effect of exercise o n characteristic aortic impedance
during graded treadmill exercise in the presence and absence of P-adrenergic blockade (pro-
pranolol) in healthy adult 0 and senescent m beagle dogs. In the absence of p-adrenergic
blockade, exercise increased impedance in senescent but not in younger dogs. In contrast,
during p-blockade impedance was increased during exercise in dogs of both ages. [From
Yin et al. (567) with permission.]

rate decreases with age in both males and females (147,
451, 466) (Fig. 17.60). In a longitudinal study, a
decrease in resting heart rate (81-60 bpm) occurred
over 30 yr (20).
Resting heart rate is modulated in part by the balance
of sympathetic and parasympathetic tones, with the lat-
ter predominating. The interaction of age and posture
on heart rate as noted above suggests that age-associ-
ated changes occur in mechanisms that regulate heart
rate (see below under Postural Reflexes). The respira-
tory variation of the heart rate, which is also determined
largely by autonomic tone, is diminished with advanc-
ing age (93), as is the spontaneous variation in heart
rate measured over a 24-h period via Holter monitoring
(248,269,389) or spectral analysis (267,451,466). In
the latter studies the decreased variation in heart rate
with aging was thought to result from reduction in both
parasympathetic and sympathetic modulation. The
intrinsic sinus node rate, that is, in the presence of both
sympathetic and parasympathetic blockade, is signifi-
cantly diminished with age: at 20 yr the average intrinsic
heart rate is 104 bpm as compared with 92 bpm in at

45-55 yr (237). No data are presently available for
older individuals. Heart rate may be influenced by levels
of circulatory catecholamines. Plasma levels of norepi-
nephrine and epinephrine at rest have been found to
increase with age in many (128,134,248,424),but not
all (152),studies. Blocking only the sympathetic system
at rest with propranolol does not produce a differential
effect with age on supine heart rate or LV hemodynam-
ics in healthy men at supine rest (561).
Cardiac Output
Resting cardiac output (the product of SV and heart
rate) and cardiac index (CI) (cardiac output normalized
for body surface area) have been found to be markedly
reduced (47, 85), mildly reduced (80, 238, 312, 344,
495, 496), or unchanged (Fig. 17.6E) in older vs.
younger individuals (148,215,420,421).The variabil-
ity of results among these studies can be attributed
largely to differences in the criteria employed for select-
ing individuals for study, number of individuals
selected, body position during study, body composition,
and measurement methods employed. Cardiac output is
influenced by the basal metabolic rate and body com-
position, both of which change substantially with age
(see below, under Dynamic Exercise). Age-associated
declines in basal metabolic rate are abolished when 0 2
consumption is normalized to an index of lean muscle
mass (525). Age range also influenced the outcome of
cardiac function studies at rest. Close inspection of the
data of one study reporting a marked age-associated
decline in resting cardiac output and EF (277)indicates
that most of the age effect occurred between the ages of
6 and 20 yr. In the highly screened population of 95
men depicted in Figure 17.6, the resting CI (Fig. 17.6E)
does not change with age because an increase in SVI,
due to an increase in the EDVI, compensates for the age-
associated reduction in heart rate (Fig. 17.6E). In
women in the same study, however, the resting sitting
CI was found to decrease slightly with age, in part due
to the absence of cardiac dilatation at end-diastole and
its accompanying increase in SVI (Fig. 17.6A).In older
hypertensive men, that is, those in whom arterial pres-
sure exceeds the clinically defined upper limits of normal
(140/90 mm Hg), CI at rest is less than in younger
hypertensive men and is associated with a diminution
of SVI (326, 344, 345). Part of the difference in age-
associated changes, or the lack of change, of CI in nor-
motensive and hypertensive men may be due to a greater
CI in young hypertensive than in young normotensive
individuals.
For simplicity, blood flow from the heart is sometimes
considered a steady rather than a pulsatile phenomenon,
and PVR is derived from cardiac output (flow) and
CHAPTER 17: CARDIOVASCULAR SYSTEM 427
mean arterial pressure (Ohm’s law applied to the cir-
culation). Arterial pressure and PVR in the sitting posi-
tion in healthy, sedentary men and women of a broad
range are depicted in Figure 17.6F and G. Systolic bra-
chial arterial pressure increases with age at rest in both
sexes; mean arterial pressure increases mildly with age.
PVR at rest in the sitting position is not altered by age
in healthy men but increases with age in women in the
same study population.
The age-associated changes, or the lack thereof, in
several aspects of cardiovascular function at rest in men
are integrated in the lower part of Figure 17.3. A pro-
longed myocardial contraction time in older individuals
maintains a normal ejection time in the presence of the
late augmentation of aortic impedance due to early
reflected pulse waves. The prolonged contraction also
contributes to the maintenance of SV, ESV, and EF at
rest. Thus in healthy humans, systolic cardiac function
at rest is not much altered by age, even though the arte-
rial tree stiffens and imposes an increased afterload on
the heart. The down side of prolonged contractile acti-
vation is that myocardial relaxation time is prolonged
in older individuals and at the time of the mitral valve
opening some contractile activation persists. This is one
factor that causes the early LV filling rate to be reduced
in older individuals. Structural changes and functional
heterogeneity occurring within the LV with aging may
also contribute to this reduction in peak LV filling rate.
However, a concomitant adaptation (left atrial enlarge-
ment and an enhanced atrial contribution to ventricular
filling) compensates for the reduced early filling and in
part maintains an increased LVEDV in men and pre-
vents a decrease in LVEDV in women.
In individuals with hypertension, the same vascular
and cardiac changes observed with aging in normoten-
sive individuals occur at a younger age and in some
instances are exaggerated. The similarities between
aging and hypertension are so striking that aging has
been referred to as “muted hypertension” and hyper-
tension has been referred to as “accelerated aging” (390,
553). According to the perspective depicted in Figure
17.3, changes in the large arteries, cardiac mass, myo-
cardial relaxation, and filling parameters in both nor-
motensive and hypertensive individuals at any age form
a continuum. In this regard, a clinical distinction
between normotensive and hypertensive subjects may be
somewhat artificial but clinically useful with regard to
risk for cardiovascular morbidity and mortality (393).
However, some changes occur with aging in hyperten-
sive subjects that are not observed in normotensive sub-
jects. In hypertensive men PVR increases substantially
with aging, in contrast to normotensive men in whom
no change is observed (Fig. 17.7G). Thus in hyperten-
sive subjects an increase in PVR elevated diastolic and
428 HANDBOOK OF PHYSIOLOGY-AGING
mean arterial pressures and plays a greater role in vas-
cular loading of the heart than in normotensive subjects.
Also, in older hypertensive men, resting SVI and CI are
not maintained at the levels measured in younger hyper-
tensive men.
CARDIOVASCULAR RESERVE
Cardiovascular reflex mechanisms become operative in
response to perturbations from the supine basal state
and partially mediate the utilization of cardiovascular
reserve functions. The end result of these reflex mech-
anisms is enhanced blood flow within selected body
organs and preservation of arterial pressure. A change
in blood flow from the heart depends upon the product
of changes in heart rate and SV, the latter being deter-
mined by the changes in EDV and ESV (Fig. 17.4).
Changes in EDV are determined in part by changes in
venous return, which depend upon the ability of the
blood to flow through the vascular system.
Postural Reflexes
Arterial Pressure and Peripheral Vascular Resistance.
Several studies suggest a general tendency toward either
maintenance or augmentation of PVR during ortho-
static stress in subjects (mostly male) up to 60-70 yr. In
general, in healthy, community-dwelling older individ-
uals the arterial pressure change with posture is also
maintained (230, 457, 459, 472), and postural hypo-
tension or acute orthostatic intolerance, that is, dizzi-
ness or fainting when assuming an upright from a
supine position or during a passive tile, thus does not
occur (472). In contrast to healthy, community-dwell-
ing volunteer subjects, orthostatic intolerance is com-
mon in older (>70 yr), debilitated, chronically institu-
tionalized individuals. ( 318). The likelihood for
orthostatic intolerance is increased in individuals who,
prior to orthostatic stress, exhibit marked reductions in
peak LV filling rate, EDV, and SV in the supine position
(319). In studies of this sort, however, the effects of very
advanced age cannot be dissociated from those of a very
sedentary life-style.
Heart Rate and Cardiac Volumes. The acute heart rate
increase caused by orthostatic stress decreases in mag-
nitude with age and takes longer to achieve. The imme-
diate heart rate responses to sudden increments of neck
suction and neck pressure also change with aging: a
lesser tachycardia during decreases in carotid transmu-
ral pressure and lesser bradycardia during increases in
transmural pressure occur with aging in both women
(395) and men (473). During spontaneous breathing,
age-associated differences in heart rate with postural
movements have been attributed in part to decreases in
P-adrenergic responses, while differences during stand-
ing metronome breathing have been attributed to both
reduced parasympathetic withdrawal and P-adrenergic
activation (451).The decreased variability of heart rate
observed in older vs. younger individuals in the upright
vs. the supine position has been attributed to a dimin-
ished recruitment of baroreceptor sensitivity, that is, the
slope of the relationship of the change in heart rate vs.
the change in arterial pressure is negatively correlated
with increasing age and increased resting arterial pres-
sure (116,183,248,400,461,559). In beagle dogs the
baroreflex control of renal sympathetic nerve activity
and arterial pressure, in addition to heart rate, declines
with age (195, 196). The basal sympathetic nerve activ-
ity to muscles in humans increases with age (195,196).
The basal sympathetic nerve activity to muscles in
humans increases with age (116, 559) in both normo-
tensive and hypertensive individuals. However, the
baroreceptor control of sympathetic outflow to skeletal
muscle can be well maintained in healthy individuals
even into the seventh decade (1 16). The low-pressure
baroreceptor, or cardiopulmonary reflex, also decreases
with age in normotensive (77,195) but not in hyperten-
sive individuals (481). The sensitivity of the chemore-
ceptor reflex also appears to decline with aging, as the
increase in heart rate in healthy men (aged 64-73 yr) is
less than that in young men (aged 22-30 yr) following
exposure to hypoxia (11 vs. 34% increase) or to hyper-
carbia (0% vs. 1 5 % ) (275). The apparent age-associ-
ated reduction in the effectiveness of autonomic nervous
system-mediated reflexes during postural maneuvers
occurs in the presence of age-associated increases in
plasma catecholamine levels (see above and below). The
reduction in baroreceptor function and the increase in
muscle sympathetic nerve activity with aging may be
related to the age-associated increase in plasma cate-
cholamines (461, 559).
The SV reduction with postural stress tends to be less
in healthy older than in younger individuals; thus the
postural change in cardiac output does not vary signif-
icantly with age because the lesser increase in heart rate
in older individuals is balanced by a lesser reduction in
SV (420). This leads to the profile of heart rate and SVI
observed in healthy older individuals in the sitting posi-
tion at rest shown in Figure 17.6. Even in studies that
have found cardiac output to be reduced with aging in
the supine position (on the basis of a reduced SV in older
vs. younger men), this age effect was abolished in the
sitting position due to lesser reduction in SV in older
men upon assumption of the upright position (130,
182). As with a change to an upright position in
response to gradual tilt or graded lower-body negative

pressure (LBNP), SV and cardiac output decrease less in
older than in younger individuals (115, 161, 328),
although the heart rate increase is blunted in these older
individuals ( 1 15).A lesser reduction in SV in older vs.
younger individuals following a postural stress implies
either less of a reduction of LVEDV or more of a reduc-
tion in LVESV in older individuals. Cardiac volumes
(measured by equilibrium-gated cardiac blood-pool
scans) and heart rate have been measured in the steady-
state in supine and sitting positions in male volunteer
subjects (aged 25-80 yr) who had been rigorously
screened to exclude cardiovascular disease (420). Fol-
lowing assumption of the sitting position from the
supine, changes in cardiac output with posture in older
vs. younger individuals depend more on changes in
LVEDV and SV and less on changes in heart rate (420).
Although the cardiac filling rate during early diastole
is less in older than in younger individuals and an appar-
ent age-associated decrease in ventricular compliance is
manifest during postural maneuvers (367), filling vol-
ume deficits, in fact, do not occur in healthy older indi-
viduals either at rest or during orthostatic stress. Rather,
LVEDV and SV in the sitting position at rest are pre-
served or even enhanced (Fig. 17.6) in sedentary,
healthy, older vs. younger individuals (331, 420, 421,
445, 458, 569). A reduced venous compliance in older
vs. younger individuals, advanced as a mechanism to
account for less of a peripheral fluid shift during ortho-
static maneuvers (115,513),could be a mechanism that
preserves cardiac filling volume and maintains SV in the
upright position in healthy elderly individuals. A reduc-
tion in the venous response to p-adrenergic stimulation
(relaxation)with preservation of the a-adrenergic (con-
strictor) response (see below, under Sympathetic Mod-
ulation of Cardiovascular Function), resulting in a
greater relative venoconstriction in older individuals,
may contribute to a reduced venous compliance with
aging.
In contrast to the above observations, when old (74
2 2 yr) were compared to young (27 +- 3 yr) individuals,
the SV decline with tilt was found to be greater in the
former than in the latter and was attributed not to dif-
ferences in EDV response but to a relative inability of
older individuals to reduce ESV (458). In this study, a
substantial PVR increase in the older group occurred
with tilt and was sufficient to maintain arterial pressure,
whereas an increase in PVR did not occur in the younger
group. Intriguingly, age-associated differences in the
ESV response to postural stress were lessened after a
Ca2+ channel blocker (458), perhaps associated with a
reduction in Ca2+-dependent determinants of arterial
impedance (see above, under Cardiac Filling (Diastolic
Properties)).
In summary, in response to orthostatic stress, main-
CHAPTER 17: CARDIOVASCULAR SYSTEM 429
tenance of total PVR does not decline with aging. The
heart rate increase is blunted in older vs. younger indi-
viduals. The expected LVEDV reduction is less in older
vs. younger individuals, and SV is better preserved.
Isomeiric Exercise
Sustained isometric handgrip increases both arterial
pressure and heart rate and the response varies in mag-
nitude in proportion to the relative level and duration
of effort (334). After 30 s of maximal handgrip heart
rate was observed to increase 50 bpm in young (aged
23-31 yr) vs. 12 bpm in older (aged 54-78 yr) healthy
men (258).Heart rates prior to handgrip were not age-
related. During sustained isometric handgrip at 40% of
maximum, held to fatigue, the heart rate increase in
healthy men was found to diminish over a narrow (20-
50 yr) age range (387).
Another type of pressor stress, that induced phar-
macologically, has also been used to assess the intrinsic
myocardial reserve capacity. In response to a 30-mmHg
increase in systolic blood pressure induced by phenyl-
ephrine infusion (in the presence of P-adrenergic block-
ade), significant LV dilatation was noted in healthy
older (60-68 yr), but not in younger (18-34 yr), men;
the cardiac dilatation, measured via M-mode echocar-
diography, in older men occurred even in the presence
of a smaller reduction of the heart rate (561). Thus
because of an apparent age-associated decrease in the
intrinsic myocardial contractile reserve response to an
increase in afterload, the senescent heart dilates and
contracts from a greater preload than does the young
heart. The cardiac response to a pressor stress is also
diminished in senescent rats, whereas the response to a
volume stress is unimpaired (308).
Dynamic Exercise
Aerobic Capacity. The maximum oxygen consumption
(V02,,,ax) achieved during exercise is about ninefold
greater than the basal level of 0 2 consumption. In addi-
tion to a four-to-fivefold increase in cardiac output, the
0 2 extraction by working tissues increases and causes
the arteriovenous 0 2 difference, (AV)02,to increase up
to twofold during strenuous exercise. This results in part
from an increase (up to 15-fold) in the relative propor-
tion of cardiac output delivered to working muscles
(76). The cardiopulmonary factors that underlie total
body 0 2 consumption or aerobic capacity have been
traditionally referred to as “central circulatory,” while
local tissue 0 2 delivery, extraction, and utilization are
referred to as “peripheral” factors.
It has been well documented that VoZmax,adjusted
 430 HANDBOOK O F PHYSIOLOGY-AGING
8o r Master athletes
20/
o l0 25 35 45 55 65 75
AGE (years)
FI<.. 17.9. VO~ml,3xas a function of age as measured in males of varying
age, fitness, and body composition. [Modified from Heath et al. (208)
with permission.] Points are average VOIqmax values for groups of men
of different ages from reports in the literature for young athletes, mas-
ter athletes, lean untrained, and overweight untrained men
( 14,23,33,39,52,92,96,102,184,350,392,4 16,4 17).Champion young
.,
athletes, 0,Heath et al. (208) and 0 Dill et al. (102); ex-champion
athletes, A, Dill et al. (102) and Robinson et al. (417);cross-country
runncrs, A, Grimby and Saltin ( 1 84); runners Pollock et al. (392):
groups of untrained men from 9 studies, 0 and X; master athletes 0
and 0. [From Heath et al. (208) and Fleg et al. (149), respectively,
with permission.]
for body weight, declines with age (Fig. 17.9). The
extent of this decline varies among studies, relating in
part to uncontrolled population truncation due to cross-
sectional sampling and changes in body weight, com-
position, and fitness levels among the individuals stud-
ied. Longitudinal studies report a more pronounced
age-associated decline in V0Zmaxthan do cross-sectional
studies (95). Whether or not the same factors that reg-
ulate V02max are limiting the V0lmaxin individuals of
different ages is not known (401). The maximum car-
diac output may be lower in older than in younger indi-
viduals due to the age-associated reduction in maximum
heart rate (see below, under Cardiovascular Reserve).
Whether or not a measured reduction in cardiac out-
put (compared to younger individuals) at exhaustion
actually limits treadmill exercise capacity and therefore
V O ~in~older , ~individuals
~ is difficult ascertain. Tread-
mill exercise is usually limited by dyspnea (shortness of
breath). However, a reduction in respiratory muscle
reserve function in older individuals, due to an age-asso-
ciated reduction in the number of muscle fibers or to a
reduction in the muscle utilization of 0 2 per muscle unit
(due to aging or to a sedentary disposition), might con-
tribute to the age-associated limitation of work capac-
ity, even though arterial Po2 is maintained. A concom-
itant reduction in cardiac output would be expected to
accompany a reduced work capacity. Thus a reduction
in cardiac output measured at exhaustion cannot ips0
facto be implicated as the cause of reduced work capac-
ity and V 0 2 m a x . Indeed, some studies during graded
upright cycle exercise have been interpreted to indicate
that the cardiac response for the work performed
(VoZmaxachieved) in older subjects is as adequate as that
in younger subjects (182, 238). Is is of note, however,
that during cycle ergometry, the peak 0 2 consumption
in a given individual averages about 80% of that during
treadmill exercise (147), and the factor limiting the
duration of the exercise is usually leg fatigue. While this
difference in peak 0 2 consumption between the two
modes of aerobic exercise is not age-related (147),it still
may preclude extrapolation of the maximum cardiac
output and V O ~ ”measurements
,~~ during cycle ergo-
metry to cardiac output and V O achieved
~ ~during
~ ~
maximum treadmill exercise in a given individual.
Other noncardiac factors leading to a reduction in
peak (A-V)02, for example age-associated changes in
body composition and muscle mass (44, 59, 143, 167,
168, 313, 414, 525), also appear to be involved in
V0lmaxreduction with aging. In spite of a decline in
skeletal muscle mass with aging, total body mass
remains constant because of an increase in body fat, not
only subcutaneously but also intraperitoneally and
intramuscularly (44, 167, 168). Normalization of peak
V 0 2 to an index of muscle mass, creatinine excretion,
markedly reduces the magnitude of the apparent age-
related decline in V02 normalized for body mass (kg
wt), that is, the routine normalization procedure utilized
in most studies (143,222). Changed in muscle strength
and work capacity with aging in sedentary individuals
likely reflect changes in the number of functional motor
units and the presence of neuromuscular dysfunction or
loss of muscle fibers in some older individuals (59,314).
The metabolism of skeletal muscle (flexor digitorum
superficialis) in younger and older healthy humans has
been studies in vivo by 31Pnuclear magnetic resonance,
and, in contrast to the morphological changes noted
above, neither at rest nor during exercise were age dif-
ferences noted in intracellular pH or concentrations of
adenosine triphosphate (ATP), phosphocreatine, or
inorganic phosphate (PJ (514). Thus aging does not
affect the metabolic ability of human hand skeletal mus-
cles, at least, to respond to exercise, and morphological
changes found in superficial hand muscles of the elderly
are not accompanied by alterations in energy metabo-
lism (514). Similar conclusions have been reached from
measurements of mitochondria1 volumes and various

enzyme activities in vastus lateralis biopsies from men
22-65 yr of age (378). Still, decreases in total skeletal
muscle mass or in neuromuscular function with aging,
if these do indeed occur, would have severe functional
implications.
Arterial Pressure, Vascular Resistance, and Impedance.
During cycle exercise, unlike treadmill exercise, the dia-
stolic pressure shows a modest increase due, possibly in
part, to some degree of involuntary isometric contrac-
tion and to increased force generation by the legs of the
subject during this procedure. The age-associated
increases in brachial systolic arterial pressure at rest per-
sist at a similar magnitude during cycle exercise (Fig.
17.6F);in some instances systolic pressure at maximum
exercise increases more than it does at rest in older vs.
younger individuals (147, 238, 349). (With respect to
the arterial load on the LV, it is important to recall that
the relationship between brachial and aortic systolic
pressure in young individuals differs from that in older
ones due to the early return of reflected pulse waves in
the later. Specifically, when brachial arterial pressures
are of equal magnitude in younger and older individuals
the aortic pressure is greater in older individuals.)
The extent to which PVR becomes reduced and arte-
rial pressure and impedance increase during exercise
depends on the maximum work capacity, which
depends in part on the physical fitness and other non-
cardiac neuroendocrine and metabolic factors. In some
studies the reduction in PVR during exercise was less in
older than in younger individuals (238),while in others
(Fig. 17.6G) the age effect was minimal in men but sub-
stantial in women (147,421).
During exercise in young humans, aortic input imped-
ance does not appear to increase, probably due to an
increase in the aortic diameter (357).In older individ-
uals, were a further increase in aortic impedance to
occur during exercise than noted at rest, it could
explain, in part at least, the observed age-associated dif-
ferences in the pattern of ventricular ejection during
exercise. The effect of age on vascular impedance during
exercise has not been studied in humans. However, in
the canine model it has been observed that aortic imped-
ance, which does not vary with age at rest (567),
increases over a wide range of exercise stresses in 10-
12-yr-old beagle dogs but not in l-3-yr-old dogs (Fig.
17.8B).Although changes in the passive stiffness char-
acteristics of the aorta in both dogs (563) and humans
are an apparent cause of increased aortic impedance,
age differences in autonomic modulation might also
play a role. Thus in the presence of P-adrenergic block-
ade effected by propranolol, aortic impedance increased
during exercise in younger dogs and the age-associated
differences in impedance seen during exercise in the
absence of propranolol were abolished (567).
CHAPTER 17: CARDIOVASCULAR SYSTEM 431
End-Diastolic and End-Systolic Volumes. Augmentation
of LVEDV during exercise (as in the case of postural
maneuvers) is one mechanism through which SV may
be maintained or augmented during exercise stress. In
instances where cardiac volumes in a sufficient number
of healthy individuals of a sufficiently broad age range
have been measured during upright cycle exercise, the
peak diastolic filling rate increased in both older and
younger individuals (448) and no deficit in LVEDVI
during upright cycle exercise was observed (147, 421).
In these healthy, sedentary older men (147, 421) the
LVEDVI at exhaustion during upright cycle exercise
was increased compared to younger men (Fig. 17.6);
however, an age-associated increase in LVEDVI during
exercise was not present in women (147).The age-gen-
der interaction in LVEDVI regulation during exercise,
largely due to age-gender differences in LVEDVI at rest
(Fig. 17.6),confounds the interpretation of studies that
compare, without respect to age, cardiac volume
responses during exercise in men and women across a
broad age range (215,502).A greater end-diastolic dila-
tation during supine exercise in older vs. younger indi-
viduals has also been observed (182,331,445,529).In
contrast, a study in which the age range of subjects was
truncated (20-50 yr) failed to detect this age-associated
increase in LVEDVI (216, 217); in this latter study,
however, LVEDVI at rest in the sitting position
decreased with age, that is, older men had smaller hearts
(Fig. 17.6).
Enhanced LVEDVI during exercise in some older
men, even in the absence of ventricular compliance
changes, may be accompanied by enhanced filling pres-
sure. This may explain the observation that in older
individuals in whom filling pressure increased the most
during exercise, SV also increased the most (182).How-
ever, an increase in LV diastolic filling pressure is asso-
ciated with an increase in pulmonary venous pressure,
which enhances the likelihood for pulmonary conges-
tion. This may predispose older individuals to a lower
threshold for dyspnea (shortness of breath) during exer-
cise. Additionally, because the generation of a given
ventricular pressure requires a greater ventricular wall
stress (forcehnit cross-sectional area) if the ventricular
radius is increased, a greater level of myocardial con-
tractility and energy consumption per stroke is required
by the dilated aged heart. The age-associated increase
in ventricular wall thickness, as noted above (see Car-
diac Structure), reduces the magnitude of the increased
LV stress due to ventricular dilatation.
While LVEDVI is preserved or enhanced during exer-
cise in healthy, sedentary, older individuals relative to
younger ones, the reduction in LVESVI during exercise
(Fig. 17.6) is blunted in both healthy older men and
women (147, 331,421, 445,448). This may be attrib-
uted in part to an apparent coupling that has been
432 HANDBOOK OF PHYSIOLOGY-AGING
observed between the change in LVEDV and LVESV in
the transition from rest to exercise in individuals of any
age (408). Alternatively, the increase in LVESVI during
exercise in older individuals may exceed that expected
on the basis of the increase in LVEDVI and may reflect
a relative reduction in myocardial contractile reserve or
a relatively greater increase in impedance of LV ejection
with aging during exercise. The failure of SVI at peak
exercise (Fig. 17.6B) to remain higher in older than in
younger men, as it is at rest, appears to be related to the
failure of LVESVI to decrease in older men to the extent
that it does in younger men. Because the augmentation
of EF during exercise depends on the extent to which
the LVESV is reduced (408),EF also increases less dur-
ing exercise in older than in younger men and women
(Fig. 17.6C) (147, 394, 421). As both maximum myo-
cardial contractile reserve and regulation of vascular
impedance during exercise (567) depend in part on the
response to P-adrenergic stimulation, a deficit in the
effectiveness of the latter with aging (see below, under
Cardiovascular Target Organ Response. . . ) could
account for the failure of ESVI to decrease and for EF
to increase during exercise in older individuals to the
extent that it does in younger ones.
As we know interactions of age, disease, and life-style
(for example, fitness) confound the interpretation of
measures of cardiovascular performance, particularly
during stress. Significant occult obstructive coronary
disease can largely be eliminated noninvasively by the
combination of electrocardiogram (ECG) and thallium
imaging during exercise stress (383). In older individu-
als with occult coronary artery disease the age-associ-
ated trends for LVED dilatation, reduced LVESV,
and reduced EF during exercise are exaggerated (146,
148, 394).
Myocardial Contractile Reserve. The LV contractility
index increases to a lesser extent during exercise in older
men (Fig. 17.8A). this age difference is markedly atten-
uated during exercise in the presence of P-adrenergic
blockade, suggesting a diminution in the effectiveness
of P-adrenergic modulation of myocardial contractility
with aging (see below, under Cardiovascular Target
Organ Response . . . ).
Heart Rate, Stroke Volume, and Cardiac Output. It has
long been known that, relative to younger individuals,
a deficit in the increase in heart rate during vigorous
treadmill or upright cycle exercise (Fig. 17.60) occurs
in older individuals (see 171 for review). The decrease
in the maximum heart rate achieved during exercise in
older individuals is not attributable to disease or sed-
entary left-style, as a deficit of similar magnitude occurs
in both healthy, sedentary men and women and in older
athletes (121, 149, 208). It is of interest that during
exercise, extrasystoles, including short runs of ventric-
ular tachycardia, are more commonly observed in
healthy older than in younger individuals but have no
prognostic significance with respect to 5-yr cardiac mor-
bidity or mortality (54, 141).
In some studies, a reduced SVI during vigorous exer-
cise has also been observed in older vs. younger individ-
uals (238, 277), while in other studies, SVI during vig-
orous exercise is equivalent in younger and older
individuals (147, 216, 217, 569) or greater in some
older individuals (181, 331, 421, 495). The heteroge-
neity of the SVI measurements among older individuals
is in part the cause of variable CI results observed during
upright cycle exercise among older individuals in vari-
ous studies (31, 147, 181, 182, 216, 238, 277, 331,
421). This heterogeneity results from differences in the
extent to which occult coronary artery disease was pres-
ent among older study subjects or from differences in
fitness status, heart size, and body composition. A cross-
sectional study of 145 healthy, sedentary individuals of
a broad age range indicates that the maximum CI dur-
ing cycle ergometry declines modestly with age due to a
smaller heart rate increment in older individuals (Fig.
17.6E), whereas SVI during exercise does not decline
with age in either men or women (Fig. 17.6B). It is note-
worthy, however, that during peak exercise, despite per-
sistent end-diastolic dilatation in older men, SVI is not
greater than in younger men as it is at rest. Thus some
age-associated factors limit SV during exercise (see
below, under Dynamic Exercise). In other studies, the
age-associated decline in CI during maximum cycle
exercise in the sitting position has been noted to be more
marked than that reported by older individuals in these
studies vs. the former (147) study. The SVI achieved
during exercise in the healthy, older, sedentary, nor-
motensive men and women in Figure 17.6B is deter-
mined in part by their respective heart volumes at rest
(Fig. 17.6A). The larger hearts at rest (due to an increase
in LVEDVI) in healthy older men deliver larger SVIs at
rest than the smaller hearts of younger men. As we have
seen peak exercise SVI in healthy younger men equals
that in healthy older men in spite of an augmented
LVEDVI in the latter, because the LVESVI decreases to
a greater extent in the former than in the latter. The
relationship between SWI and LVEDVI during exercise
is often used as an index of cardiac reserve pump func-
tion. Figure 17.7 depicts this relationship for the healthy
men and women described in Figure 17.6. During exer-
cise, LVSWI is similar in healthy older and younger men
but in older men occurs from a larger LVEDV. Thus the
LVSWI-LVEDVI relationship for older men is shifted
rightward of that for younger men. This suggests a

decrease in LV pump functional reserve with age in men.
In contrast, there is no evidence for a decrease in exer-
cise LV pump function in women as the relationship of
stroke work to LVEDVI is similar in older and younger
women. In studies in which SVI during dynamic exercise
has been reported to be reduced in older vs. younger
individuals (238,277),LVEDVI and LVESVI have not
been measured and SVI has been calculated from the
measured 0 2 consumption, heart rate, and CI. Thus
from these studies it is not known whether the failure
of SVI to increase in older individuals to the extent that
it did in younger ones is attributable to a relative reduc-
tion in venous return and LVEDVI, perhaps due in part
to a markedly diminished myocardial compliance, or
from failure of the LVESVI to decrease to the same
extent in elderly vs. younger individuals. In contrast to
healthy, normotensive men (Fig. 17.6), both cross-sec-
tional and longitudinal studies in hypertensive men
report that exercise SVI declines with aging (130, 326),
an effect that may be related in part to age-associated
deficits in LVEDVI, LVESV, SVI, and CI at rest in older
hypertensives (326).
Variation in heart rate and cardiac volume during
exercise may relate to differences in fitness among indi-
viduals when comparing study populations. Fitness lev-
els among younger and older individuals can be quan-
tified by measurements of V 0 Z m a x . Although there is a
statistically significant decline of the latter with aging
(see below, under Aerobic Capacity), wide variations
occur in the exercise capacity and VoZmaxamong sed-
entary individuals of a given age. This variability in aer-
obic capacity among sedentary individuals is sometimes
interpreted as a genetic effect, as opposed to a training
effect. When younger and older sedentary men are
matched for maximum work capacity (and therefore for
maximum CI), ( 1 ) the maximum heart rate still
decreases with age; (2) SVI at maximum exercise, due
to substantial end-diastolic dilatation, increases in older
men, offsetting the heart rate deficit; (3) LVESVI still
fails to decrease to the same extent in older men as it
does in younger ones and both the reduction LVESVI
and the increase in EF are reduced in the older individ-
uals to the same extent as observed in a general, healthy,
sedentary population (292). A similar picture with
respect to age-associated differences in LV cardiac vol-
umes emerges when sedentary younger and older indi-
viduals who vary in VoZmax are studied (as in Fig. 17.6)
and fitness is controlled for via statistical multiple
regression techniques (147). Thus these age-associated
changes in heart rate and cardiac volumes during exer-
cise are not solely attributable to the physical decon-
ditioning that may accompany aging in many individ
uals.
CHAPTER 17: CARDIOVASCULAR SYSTEM 433
SYMPATHETIC MODULATIONOF CARDIOVASCULAR
FUNCTION
Intact Organisms
p-Adrenergic Modulation of Cardiac Volumes and Heart
Rate during Exercise. Each of the factors that deter-
mines cardiac output (Fig. 17.4) is influenced by auto-
nomic nervous control. During maximum exercise, and
sympathetic (p-adrenergic) component is the major
autonomic modulator and a marked increase in cate-
cholamine secretion occurs. p-Adrenergic receptor (AR)
stimulation has two modulatory effects on myocardial
contraction: it enhances contractile strength and
decreases the contraction duration. This latter effect is
particularly necessary in the intact circulation, because
the heart rate increases dramatically in response to p-
stimulation and the contraction time must be briefer to
permit myocardial relaxation and proper filling of the
ventricle during a shorter diastole. The precise impact
of P-adrenergic modulation of heart rate and cardiac
volume during exercise can be determined when exer-
cise is performed in the presence of P-adrenergic block-
ade. In young individuals the same cardiac output is
achieved during upright cycle exercise in the presence of
acute P-blockade with propranolol as in the absence of
p-blockade, but the hemodynamic profile differs: the
increment in heart rate and the reduction in ESV are
markedly less in the presence of p-blockade, but during
p-blockade the EDV increases substantially, permitting
a larger SV than in the absence of p-blockade (409).The
rate of early LV filling and the myocardial contractility
index are reduced. This altered hemodynamic pattern
during acute p-blockade is indicative of the interaction
among parameters (Fig. 17.4) which maintain cardiac
output when a deficit in adrenergic modulation is pres-
ent: cardiac dilatation at end-diastole (or the use of the
Frank-Starling mechanism) augments SV, which com-
pensates for a reduction in heart rate.
An age-associated diminution in the effectiveness of
sympathetic modulation of the cardiovascular response
to exercise could contribute to many of the changes
identified in the cardiovascular response to exercise in
healthy older humans (Fig. 17.6, 17.7): the decline in
maximum heart rate, the increases in LVEDVI and
LVESVI, and decreased EF. A recent study, in fact, has
demonstrated that the age-associated changes in
LVEDVI and SVI during upright cycle exercise do not
occur in the presence of propranolol and that the age-
associated reduction in heart rate is markedly attenu-
ated, due to a greater effect of P-adrenergic blockade to
decrease heart rate and increase heart size in younger
than in older subjects (150).Age differences in the early
diastolic filling rate and the LV contractility index (Fig.
434 HANDBOOK OF PHYSIOLOGY-AGING
17.8A) during exercise have also been found to be
reduced or abolished when exercise was performed dur-
ing P-adrenergic blockade (81, 448).
Neurotransmitter Elaboration during Stress. One possi-
ble explanation for an apparent diminution in the effec-
tiveness of P-adrenergic modulation of cardiovascular
performance during exercise in older individuals is that
the secretion of high levels of norepinephrine or epi-
nephrine during exercise stress, as reflected in plasma
levels, may decline with advancing age. However, dur-
ing exercise or under other circumstances that require
an adjustment in the performance of the variables in
Figure 17.4 from their basal levels, plasma concentra-
tions of norepinephrine and epinephrine are increased
rather than decreased in older vs. younger subjects (133,
152,179,389,397,424,425,482). Although clearance
of plasma catecholamines appears to be reduced in older
individuals (128, 134), excessive spillover into the
plasma also occurs, and this, rather than a diminished
clearance rate, best correlates with the increased plasma
levels (134).The lack of evidence for a reduced secretion
of catecholamines during exercise in older individuals
suggests that if a decline in tissue catecholamine content
occurs in humans, as it does with adult aging in animal
models (see below, under Sympathetic Modulation of
Cardiovascular Function), it appears to be of little func-
tional importance, at least for maintenance of neuro-
transmitter levels during short-term stress. It is note-
worthy that older (average 66 yr) endurance-trained
individuals (cyclists) at a given submaximal workload
also appear to have higher adrenaline and noradrena-
line levels than younger (average 25 yr) ones. However,
when expressed at the same relative workload, no
apparent age difference emerges (310). In contrast, in
sedentary subjects, the age-associated increase in plasma
norepinephrine at rest persists at all relative and abso-
lute workloads, including the maximum workload
(152). (In this regard, the observed similarities and dif-
ferences in the hemodynamic pattern between younger
and older individuals at maximum exercise [Fig. 17.51
also pertain to a common exercise workload, for exam-
ple, at 50% maximum [147].) Thus a most obvious
explanation for the apparent age-associated reduction
in adrenergic modulation of cardiovascular function is
that neurotransmitters are not as effective at the level of
the target organs.
Cardiovascular Target Organ Response to p-Adrenergic
Stimulation with Aging.
Cardiovascular response in humans. One method to
assess the postsynaptic response to neurotransmitters is
to infuse these substances at rest. P-Adrenergic modu-
lation of pacemaker cells accounts in part for the
increase in heart rate during exercise. Bolus infusions of
(3-adrenergic agonists in humans (Fig. 17.10A) have
been found to elicit a diminished heart rate response in
older vs. younger individuals (280, 323, 500,533,564,
568). In humans, isoproterenol infusion also elicits a
greater increase in the LVEF (500)and CI (280,500)in
younger vs. older individuals (Fig. 17.10B).
Vascular responsiveness to adrenergic stimuli modu-
lates the redistribution of cardiac output during exer-
cise. Arterial impedance due to dilation of large arteries
may also be affected by adrenergic stimuli. The dilata-
tion of the forearm arteries in response to infusions of
isoproterenol (Fig. 17.10C) is less in elderly than in
younger men (539). [In contrast, the decrease in calf
vascular resistance in response to isoproterenol has been
found to not differ with age (262)l. The vascular
responses to prostaglandin E or to nitroglycerin are not
reduced with aging (218,244). A deficient P-adrenergic
relaxant effect is, in part at least, a cause for the increase
in characteristic aortic impedance during exercise in the
older beagle dog (Fig. 17.6B). The ability of catechol-
amines to modulate venous capacitance is a major cir-
culatory adjustment to exercise. The ability of P-stim-
ulation to relax veins decreases with aging (Fig.
17.100), but the constrictor response to or,-adrenergic
agonists remains intact (383). Increased neural sympa-
thetic discharge has been implicated in a greater con-
striction of forearm resistance vessel (an a-adrenergic
response) in older vs. younger men (515)(c.f. also above
section titled Postural Reflexes).
In summary, there is indeed a large body of convinc-
ing evidence to indicate that the heart rate, vascular
smooth muscle cell (VSMC),and myocardial contractile
response to P-adrenergic stimulation decline with age.
Cardiovascular responses in intact animals. Isoproter-
enol infusions into intact rats, as in humans, also elicit
a diminished increase in heart rate with aging (2, 305,
368, 562). The major age-associated deficit in some
studies, however, has been found with maturation
rather than with senescence. Infusion of epinephrine
and norepinephrine into intact adult and senescent rats,
or into young and adult cats and rabbits, has elicited a
variety of complex changes in other aspects of cardio-
vascular function (164, 165). While the specific adren-
ergic cardiovascular effects cannot be ascertained from
such studies, some data suggest a lower threshold or a
supersensitivity in the total cardiovascular response in
the senescent animal, while the response to high agonist
concentrations is diminished (163). Supersensitivity of
the heart to catecholamines has been described follow-
ing depletion of tissue catecholamine content (83). It is
well documented that myocardial catecholamine con-
centration in the senescent rate is reduced by 25%-50%
compared to that in younger adult rats (175,274,296).
However, it is unlikely that a depletion of cardiac cat-
echolamine content could explain the lower threshold
 7l
-- I

65

- 5 5
0 7 14 21 28 35
ISOPROTERENOL (pg) ISOPROTERENOL (ng/kg/min)
W

350
-- 100
C old
300 -
A

young
250 -
200 -
150 -
100 -
50 -
3 20

n- A
0.12 1.2 4.0 12.0 .1 1 10 100
-
1000
ISOPRENALINE INTRA-ARTERIALLY ISOPROTERENOL (ng/min)
(ng min-1100 m1-1)

FIG. 17.10. A: The effect of a bolus I.V. isoproterenol infusion to

increase heart rate in healthy young and older men at rest. [From Yin
et al. (564) with permission.] B: Isoproterenol increases the LV ejec-
tion fraction in younger and older healthy men in the supine position
prior to (pre)and following (post)chronic endurance training. Endur-
ance training had no effect on this index of cardiac pump function or
on its response to isoproterenol. [From Stratton et al. (500)with per-
mission.] C: Intraarterial isoproterenol (isoprenaline) infusions
decrease the forearm vascular resistance in healthy younger and older
men. [From van Brummelin et al. ( 5 2 8 )with permission.] D: I.V. arte-
rial infusion of isoproterenol relaxes dorsal hand veins previously con-
stricted by phenylephrine in men of varying ages. [From Pan et al.
( 3 8 3 )with permission.] E: Top: Peak LV filling rates at rest and during
exercise for young p-blocked subjects and age-matched non-p-
blocked subjects. Peak filling rate was significantly less in those young
subjects pretreated with propranolol at both relative and absolute
workloads of 50% of maximal and maximal workloads (left) and S O
and 100 watts (right), respectively. Middle: Peak filling rates at rest
and exercise for the older p-blocked subjects and age-matched non-
@-blockedsubjects. Peak filling rates were similar between the two
;I:
35 groups both at relative workloads of 50% of maximal and maximal
workloads (left) and absolute workloads of S O and 100 watts (right).
d o 4
u w Lower: Peak filling rates at rest and exercise for young and old sub-
3-
Lu
2 jects pretreated with propranolol. Age differences noted during exer-
a cise in the absence of p-blockade are no longer seen during exercise
REST 50 100 509c MAXIMUM in the presence of p-blockade. [From Schulman et al. (448) with
WAlT3 WAlTS MAX
permission.]
WORK LOAD

435
436 HANDBOOK OF PHYSIOLOGY-AGING
for the cardiovascular response to infused catechol-
amines in the senscent organism. No comparable evi-
dence for supersensitivity to catecholamines has been
found in isolated cardiac muscle from the senescent rate
(see below) or in humans (499).
While age-associated differences in the extent of para-
sympathetic tone affect the interpretation of most stud-
ies that have infused P-adrenergic agonists into young
and old humans or animals (and vice versa for infusion
of parasympathetic agonists), it has been demonstrated
in senescent vs. younger adult beagle dogs that the max-
imum heart rate increase in response to isoproterenol
infusion in the presence of full vagal blockade with atro-
pine decreases with age (562). In contrast, the maxi-
mum heart rate that could be elicited by external elec-
trical pacing, which was far in excess of that elicited by
isoproterenol infusion, was not age-related. A deficient
6-adrenergic relaxant effect on aortic smooth muscle
during exercise in the senescent beagle dog is, in part at
least, a cause for the increase in characteristic aortic
impedance (Fig. 17.8B). Regarding the a-adrenergic
modulation of arterial tone in the intact organism, a
greater voltage stimulation of the paravertebral sym-
pathetic chain is necessary to evoke a pressor response
in the leg vessels in the senescent, as compared to the
adult, rate (164). Redistribution of blood flow to vari-
ous organs during isoproterenol infusion, including
skeletal muscle, decreases in senescent rats (305).
P-Adrenergic Receptor Response in the Healthy Aging
Heart Resembles That in Chronic Heart Failure. In severe,
chronic heart failure due to a variety of causes, an
increase in the activity of the sympathetic nervous sys-
tem in response to reduced cardiac output is a general
adaptive mechanism to maintain the pressure and flow
requirements of the organism. Studies in patients suf-
fering from heart failure have demonstrated that plasma
norepinephrine levels are elevated and that myocardial
catecholamines become depleted (18, 413, 546).
Although this increased sympathetic activity may be ini-
tially helpful for the chronically failing heart, it can
simultaneously lead to a desensitization of P-ARs. In
experimental models of heart failure, induced by pres-
sure-overloading or pacing-overdrive, it has recently
been reported that the total P-AR number is decreased
(58, 131, 550). In heart failure in humans, the number
of cardiac p-ARs is also decreased, especially that of PI-
AR (48, S O ) , and it has been speculated that this pref-
erential p,-AR decrease might be caused by high levels
of plasma norepinephrine, which is a rather selective PI-
AR agonist. It has also been noted that in failing human
hearts there is a selective decline in the high-affinity p-
ARs, as well as a decrease in the coupling of receptors
with the G,-protein (337).When these changes in the p-
AR system in heart failure patients are compared to the
characteristic of age-associated alterations in p-modu-
lation of cardiac function, the similarities become very
evident. As we know, in old vs. young animals or
humans, the plasma catecholamine concentration is
increased. Although most studies have shown that the
P-AR density does not change with aging, the affinity
of the receptor for agonists and the coupling of the
receptor to the catalytic subunits decrease (see below,
under G-Protein and Adenylate Cyclase Activity). In
both healthy aged humans and those with chronic heart
failure, reductions in the effectiveness of P-adrenergic
modulation of heart rate, vascular relaxation, and myo-
cardial contractility occur. It has been suggested that
age may be the dominant variable in the reduced p-
adrenergic augmentation in cardiac cells isolated from
the failing human heart (204). The kinetics of myocar-
dial Ca2+cycling are also altered in chronic heart failure
(290), and many strikingly similar changes in excita-
tion-contraction mechanisms occur in the healthy aged
and chronically failing heart. Thus the aging heart in
health and the chronically failing heart exhibit many
common biochemical features; nevertheless, in the for-
mer, overall cardiac performance is remarkably pre-
served, while in the latter it is severely reduced.
Isolated Tissue or Cells
Vascular Responses. Adrenergic modulation of isolated
blood vessels, particularly P-adrenergic-mediated vaso-
dilatation, has been found in decrease with age in most
(126, 153-155, 178, 224, 370-372,518, 524), but not
all (12, 329, 476), studies. Some studies report aging
effects that represent changes during development (113,
153). Other studies suggest that different P-AR or a-
adrenergic subtypes are differentially regulated by aging
(107, 372, 373). Stimulation of presynaptic P-AR, the
majority of which are P2, facilitates the release of nor-
adrenaline (302,488), while stimulation of presynaptic
a-receptor, predominantly of the a2 subtype (108,302,
488), has an opposite effect on norepinephrine release
(135, 263, 530). The a2-AR mediated responsiveness
appears to be selectively reduced with age in human
saphenous vein (107, 108), rat vasculature (109), and
human platelets (504, 505). In contrast, no significant
correlation between aging and a1receptor responses has
been observed (114, 329, 453). However, in large and
medium coronary arteries of beagle dogs al-adrenocep-
tor-mediated responses may increase with age (518).
Studies in which the relaxation response of the aged
aorta is more significantly reduced than that of the pul-
monary artery (370-372) have concluded that age
affects p2-AR stimulation responses more than PI-AR,
since the aorta has more p2-AR than the pulmonary
artery, although additional interpretations of the data
are plausible.

In summary, data in tissues isolated from many spe-
cies, including humans, demonstrate that autonomic
modulation of the vasculature changes with age, and in
particular, that the response to 6-adrenoceptor vascular
dilatation is impaired. Additional studies, however, are
required to further characterize age-associated changes
in specific adrenoceptor subtypes and their interactions.
Cardiac Responses. In isolated rat hearts a progressive
age-associated reduction in heart rate response to nor-
epinephrine has been observed (273). Intracellular
mechanisms that mediate the AR stimulation within
cardiovascular cells have been probed with respect to
age-associated changes. Considering that norepineph-
rine is the physiological neurotransmitter and that a-
and P-ARs are stimulated simultaneously, the roles of
both a-and P-adrenergic effects on contractility need to
be discriminated. The direct effect of a-AR stimulation
of the myocardium in response to norepinephrine is
inconsequential relative to the P-adrenergic effect: a-
adrenergic stimulation does not enhance cardiac relax-
ation and its strengthening effect on contraction is
about an order of magnitude less than that of the P-
adrenergic system. The effects of adult aging in the al-
adrenergic-mediated increase in myocardial contractil-
ity have not been studied.
The immediate cause of the increase in cardiac muscle
performance by @receptor stimulation in an increase in
the amplitude of the Cai transient that follows excita-
tion. While the contractile responsiveness of the myo-
filaments to Ca2+ does not change with aging (37, 187,
295), studies in isolated LV muscle (Fig. 17.11A) and
in individual rat ventricular cardiocytes (Fig. 17.11B)
indicate that a reduced contractile response to P-AR
stimulation occurs with aging. This is due, at least in
part, to a failure of the Cai transient to increase in senes-
cent heart cells to the same extent to which it increase
in younger adult heart cells (556) (Fig. 17.11C). The
blunted increase in the Ca2+ transient in cells from the
aged heart is attributed to a decrease in the ability of P-
AR stimulation to increase L-type sarcolemmal Ca2+
channel availability in cells from senescent vs. younger
adult hearts (556) (Fig. 17.110).
P-AR. One possible mechanism for the observed
decrease in the responsiveness of P-AR-mediated action
on the heart and vasculature with aging would be an
age-associated decrease in cellular P-adrenoceptor den-
sity. This possibility has been extensively studied in a
variety of tissues, including myocardium (4, 72, 187,
282, 361, 434), VSMC (524), and lymphocytes (2, 3,
11 1,137) of humans and animals. In humans, lympho-
cytes have been commonly used as a model to study the
effect of aging on AR function because other human
tissues are not readily available. Such studies have found
CHAPTER 17: CARDIOVASCULAR SYSTEM 437
no significant changes in the P-AR density with age.
This may indicate that P-adrenergic responsiveness of
the cardiovascular system is impaired in aging at levels
other than the P-AR per se but may involve distal intra-
cellular steps. However, the P-ARs of lymphocytes are
of the P 2 subtype (32,49) and the aforementioned stud-
ies do not provide information about P-AR subpopu-
lations with age. Additionally, it has not been es-
tablished that changes in P-AR properties and respon-
siveness of lymphocytes with aging reflect similar
changes of P-AR in cardiovascular tissues with aging.
While rat myocardial P-AR density has not been
found to change with aging in most studies, agonist
binding properties of the receptor do appear to change
with aging. The P-AR affinity for agonist binding is
decreased three- to twentyfold with aging (361, 434-
436, 438). A reduction in P-AR affinity has also been
found in rat lung (437). In contrast, there is no corre-
lation between age and P-AR antagonist affinity (4,136,
187). The decreased P-AR agonist affinity correlates
with the decrease in the ability to form the high-affinity
binding complex, that is, the percent of receptors in the
high-affinity state decreases with age (136, 434, 438,
439). In addition, the high-affinity receptor state
become less stable with aging (136, 434, 438, 439).
Recently, an age-associated increase in the extent of P-
AR sequestration in light-density membrane vesicles iso-
lated from lung has been observed (439). Since light-
density membrane particles (vesicles),when isolated, are
devoid of adenylate cyclase activity and G,-protein
(464,495,499). it has been suggested that a functional
receptor down-regulation occurs in the aged rat lung
(439).It has yet to be determined whether with aging
both PI- and PTAR subtypes undergo the same quali-
tative and quantitative changes in affinity or seques-
tration.
G-Protein and Adenylate Cyclase Activity. G-proteins
and the adenylate cyclase catalytic subunit are impor-
tant components of the P-AR-adenylate cyclase enzyme
complex (176). G-proteins act as coupling factors to
transduce the signal from the receptor to the catalytic
subunit of adenylate cyclase. A number of studies sug-
gest that Gs-protein activity is diminished with aging
(271, 272, 282, 369, 434,435, 438). Both the Gs-pro-
tein activity and the adenylate cyclase activity are simul-
taneously altered with aging in the rat myocardium
(282, 361, 369), human lymphocytes (271, 272), and
rat lung (439).In some tissues it has been demonstrated
that the Gs-protein is present in excess of the adenylate
cyclase catalytic subunit (369, 419). While the Gs-pro-
tein activity is unchanged in human lymphocytes of
older donors, the catalytic subunit activity is lower than
that in lymphocytes from younger individuals (3, 4).
Thus a reduction in adenylate cyclase catalytic subunit
438 HANDBOOK OF PHYSIOLOGY-AGING

170
06 m n=ll A
160- A 12mo n=ll
0 2 5 m n=8

150 -

L
-
/
Norepinephrine (M)

3
2
Norepinephrine (M) 5
r
0
300

c
0
0
2mo
8mo
A 24mo cI -9 200

’ 3 0 -30 -20 -10 0 10 20 30 40 !

Membrane Potential (mV)

0 6 m n=7 E
600 - 0 24 mo n-7
500 -
400 -
Norepinephrine (M)

I 1 1 I 1
0-
10-8 10-7 10-8 10-5 10-4
“El

t . 1 ~17.11. A: The effect of norepinephrine on the maximum rate of isometric tension development in
isolated trabeculae from hearts of varying ages. [From Lakatta et al. ( 2 9 5 )with permission.] B: Velocity
of cell shortening and C maximum rate of increase of the Indo-1 fluorescence transient, an index of
sarcoplasmic reticulum CaZ+release into the cytosol, during electrically stimulated twitch in single cardiac
myocytes isolated from the hearts of rats of varying ages and loaded with the fluorescent probe Indo-1.
[From Xiao et al. (557) with permission.] D: Norepinephrine increases the L-type sarcolemmal channel
current ( l c ~ measured
l) via whole-cell patch clamp technique in single cells isolated as in B and C. [From
Xiao et al. (557) with permission.] E: Norepinephrine increases phosphorylation of troponin 1 (TNI) in
suspensions of heart cells isolated from hearts of rats of varying ages as in above panels. [From Sakai et
al. (431) with permission.] In B-E norepinephrine stimulated P-receptors, because prazosin and a l - A R
antagonist had no effect on the results.

activity may play a more important role in the age-asso-
ciated alteration of the P-AR cascade than does a reduc-
tion of Gs-protein activity. However, most studies have
not differentiated changes in Gs-protein with aging from
those in the catalytic subunit of adenylate cyclase.
Cyclic AMP, Protein Kinase Activation, and IntraceIIuIar
Phosphorylation. The increase of adenylate cyclase
activity or cAMP stimulated by catecholamines, NaF,
or forskolin is diminished with aging in human lym-
phocytes (3, 104, 271, 272, 434), rat heart (139, 282,
368,434), and other tissues (131,493). In aortic tissue,
the isoproterenol-induced relaxation and increase in
intracellular cAMP binding decreases with age (between
5 wk and 11 months), accompanied by a reduced acti-
vation of CAMP-dependent protein kinase (PKA) (74,
97). In contrast, these responses to forskolin or to dibu-
tyryl cAMP are not affected by age over this range (74,
97). The deficit in cAMP of the old rat aorta is reduced
by phosphodiesterase inhibition, suggesting that an
increase in phosphodiesterase could be responsible for
the diminished isoproterenol-induced cAMP accumu-

lation and relaxation (446). Other studies in a variety
of tissues have not found that cAMP production is
reduced following P-AR stimulation of these tissues
from older animals (187,240,270,273). An additional
study has observed that neither basal nor stimulated
activities of ventricular muscle PKA are altered during
adult aging (187).Interpretation of how subcellular bio-
chemical measurements relate to the functional effect of
P-AR stimulation is complicated by compartmentation
of increases in cell cAMP and PKA activity (1, 57, 84,
138,206) and by variable contributions of different cell
types in tissue studies. In the heart, PKA has different
distributions between cytosolic and particulate frac-
tions. The amount of cAMP in the particulate fraction
appears to be the important factor for regulation of con-
traction and relaxation of the myocardium (1). While
some aging studies have addressed the compartrnenta-
tion issue per se (187),additional studies controlling for
a shift in the amount of cAMP within compartments
following P-stimulation seem warranted.
There is evidence that steps distal to protein kinase
activation are also affected by aging. The extent of
phosphorylation of the myofilament proteins troponin-
I (TNI) and C-protein effected by P-AR stimulation
induced by norepinephrine in rat myocytes decreases
with age (431) (Fig. 17.11E. This decrease may be
caused by age-associated changes at more than one
locus, for example, less effective P-AR coupling to the
adenylate cyclase complex, increased phosphodiesterase
activity, or acceleration of protein dephosphorylation.
In the above study (431), it was observed that the age-
associated differences in TNI (and C-protein) phos-
phorylation were abolished by the cAMP phosphodi-
esterase inhibitor IBMX (isobutyl methyl xanthine), and
no evidence for increased protein phosphatase activity
was observed, suggesting that the age difference in the
phosphorylation of these two myofilament proteins
resulted from a reduction in the net production of CAMP
in cells of the old rat heart. In sarcoplasmic reticulum
(SR)vesicles isolated from rat hearts, the ability of phos-
pholamban, a protein in the membrane of SR which
modulates the activity of the SR Ca2+pump, to undergo
CAMP-mediated phosphorylation and the relative
responsiveness of SR Ca2+ pump to phospholamban
phosphorylation are not appreciably altered with aging
(235, 239). There are presently no data regarding
whether the sarcolemmal voltage-dependent Ca2+chan-
nel proteins (88, 221) or other contractile proteins (6,
552) are phosphorylated to a different extent following
P-AR stimulation in younger and older cardiac tissues
or cells. However, the relative inability of P-AR stimu-
lation to augment the Ca2+ channel current amplitude
in cells from older rat hearts (Fig. 17.11D) may indicate
that phosphorylation of this channel protein by PKA is
reduced with aging, but this, like the decreased phos-
CHAPTER 17: CARDIOVASCULAR SYSTEM 43 9
phorylation of TNI, could be due to a reduction in the
net increase in cAMP production with aging. Alterna-
tively, age-associated differences in direct Ca2+channel
modulation by G, (51) could be involved and this
requires further study.
Interactions between various aspects of (Y- and P-
receptor modulation of cell Ca2+ homeostasis have
become the focus of recent studies (56, 90), and a+-
AR interactions, which are not completely characterized
at present, may indeed affect the P-adrenergic response
(90). In addition to al-adrenergic agonists, adenosine,
opioid peptides, and cholinergic agonists can modulate
the effects of P-AR stimulation on heart contraction.
The precise role of an interaction among a- and P-
adrenergic and cholinergic agonists and these other pep-
tide-linked modulating effects on the age-associated
decline in the cardiac response to P-AR stimulation are
presently not well understood. However, it has recently
been demonstrated that the negative contractile and
chronotropic responses to exogenous adenosine are
increased with age in guinea pigs (94). Adenosine
release from aged (12-22 months) rat hearts is greater
than that from younger (3-5 months) rat hearts (106).
Since adenosine has an antiadrenergic action-that is,
it reduces the P-adrenoceptor-induced increase in cAMP
and the subsequent increase in PKA, Ca2+ current, and
contractility (105, 137, 300, 418, 447)-enhanced
adenosine levels in aged myocardium may be responsi-
ble in part for the diminished contractile responsiveness
of the older adult heart to P-AR stimulation (106).
However, it is unlikely that age-associated changes in
adenosine metabolism can directly account for the age-
associated differences in the P-AR of isolated cardiocy-
tes (Fig. 17.11B-E).
Desensitization of the P-Adrenoceptor System. It has
long been recognized that prolonged exposure of myo-
cardial tissue to P-AR agonists modifies (3-AR respon-
siveness. As we have seen, in humans and animals
plasma catecholamines, especially plasma norepineph-
rine, are increased in older vs. younger organisms dur-
ing perturbations from the basal state (128, 132, 152,
179, 295, 390, 397, 425, 482). Chronic elevations of
plasma catecholamines in older individuals, due to
excessive neural discharge and/or reduced clearance,
might induce P-AR desensitization. Desensitization of
P-AR stimulation occurs via modifications of both
receptor and postreceptor events (34, 246, 309, 311,
320,403,404,497,498). A comparison of such P-AR
desensitization and the reduced efficacy of P-AR stim-
ulation with aging (Table 17.3) suggests that the age-
associated alterations may be caused, at least in part, by
a desensitization of the P-AR adenylate cyclase system.
The acute elevation in humans of endogenous plasma
catecholamines associated with assumption of the
440 HANDBOOK OF PHYSIOLOGY-AGING
TABLE 17.3. Comparison of 6-AR Desensitization and Alterations in P-Adrenergic Response with Aging
Desensitization
Characteristics Aging Homologous
Plasma catecholamines t t
Receptor density t) I J
(heart and vessels)
J involve arresting-like protein (barrestin).
(liver and brain)
Receptor sequestration t t
Catecholamine or 1 I
NaF-stimulated adenylate I t)
cyclase
Forskolin-stimulated J t)
adenylate cyclase
t Increased; J decreased; * no change.
Reprinted from Xiao and Lakatta (555) with permission.
upright posture decreases the proportion of high-affin-
ity P-AR in lymphocytes (due to desensitization) in
younger, but not in older, individuals (136). A desen-
sitization of P-AR mechanisms in older individuals in
the supine position, prior to the postural change, could
explain in part this result. In this regard, it has been
noted that catecholamine desensitization of the rat myo-
cardium induced by the chronic in vivo administration
of a P-adrenergic agonist, occurs to a lesser extent in
senescent than in younger rat hearts; this has also been
interpreted to indicate that the P-AR system of aged rat
myocardium had been partially desensitized prior to
study (438). Additional studies indicated that, while
NaF-stimulated adenylate cyclase activity is less in
untreated older vs. younger rats, it is unaffected by
chronic P-adrenergic treatment, suggesting that desen-
sitization may not be fully responsible for the diminu-
tion of the P-AR response with age (435,438). Also, in
older humans the impaired augmentation of the heart
rate and venous relaxation by isoproterenol is not
reversed by chronic administration of a P-adrenergic
antagonist. The results of these studies suggest that
impaired stimulation of heart rate by isoproterenol in
older individuals is probably not due to desensitization
of P-receptors since this difference between young and
older subjects could not be reversed by treatment with
a P-adrenergic antagonist (156).
In summary, an age-associated reduction in the post-
synaptic response of the cardiovascular system to P-AR
stimulation in human and animal tissues and cells has
been richly documented and appears to be due to mul-
tiple changes in molecular and biochemical receptor
coupling and post receptor mechanisms rather than to
a major modification of a single rate-limiting step, as
might occur, for example, in a genetic defect. The most
remarkable change within the P-AR system is the
Desensitization
Heterologous Possible Mechanisms
t Spillover t or clearance J or both, good correlation
between spillover and increased plasma
norepinephrine concentration with aging.
Phosphorylation of receptor by PKA and CAMP-
independent P-AR kinase. P-AR kinase effects may
t Unknown, but phosphorylation may not be the trigger.
Residues 222-229 of the pz receptor are important
for sequestration.
I Receptor coupling J , alteration of G,, G,, G,/G,, and
.1 catalytic subunit. Modification of the G-protein may
be induced by PKA or PKC.
I A cyclase catalytic subunit J by PKA.
decrease in the receptor affinity for agonists without
substantial changes in P-AR density. However, there is
little information regarding changes of P-AR subtype
density, affinity, or functional regulation in aging. The
postreceptor changes with aging include decreases in the
activities of &protein and the adenylate cyclase cata-
lytic unit, as well as a decrease in PKA-induced protein
phosphorylation. Quantitative differences in G-protein
or adenylate cyclase catalytic subunit activities with age
have not been measured nor have specific functional
changes resulting from their altered activities been
defined. The striking similarities between the decreased
effectiveness of P-adrenergic stimulation with age and
the phenomenon of desensitization of P-AR by chronic
P-AR agonist exposure at younger age suggest that the
age-associated changes, especially the reduced receptor-
to-catalytic subunit coupling, may occur in part via
desensitization mechanisms.
PARASYMPATHETIC MODULATION OF
CARDIOVASCULAR FUNCTION
There is some evidence that parasympathetic control of
cardiovascular function changes with age, but it is con-
flicting. Some studies in rats suggest a more efficient
cholinergic modulation with aging. The threshold of the
negative chronotropic effects of vagus nerve stimulation
and concentrations of acetylcholine required to cause
changes in myocardial contractility are decreased with
advancing age in rats (164, 165). Additionally, signifi-
cantly greater increases in cyclic GMP in response to
submaximal doses of acetylcholine have been observed
in hearts of 24-26-month-old rats compared to 6-8-
month-old rats. This difference persisted in the presence
of acetyl-cholinesterase blockade, suggesting that the

mechanisms of the age-associated differences are at or
distal to the receptor (278).Other studies have observed
an enhanced sensitivity to the direct chronotropic action
of acetylcholine in right atria isolated from aged vs.
younger Fischer 344 rats but have attributed this to an
age-associated reduction in cholinesterase activity
(252). In contrast, other observations indicate an age-
associated reduction in the response to parasympathetic
agonists. In one such study, a decrease in heart rate
reduction in old rats to both vagal nerve stimulation and
bolus injections of methacholine was observed (249).
More recent studies have indicated that the number of
cholinergic receptors in the LV decreases with age in
rats, as does the response to acetylcholine (72).Finally,
a marked reduction in acetylcholine content of atrial
tissue from senescent rats has been demonstrated (532).
In humans, a decrease in heart rate variability at rest or
in response to a postural stress in older individuals has
been attributed in part to a reduction in parasympa-
thetic tone with aging.
CARDIOVASCULAR STRUCTURE AND FUNCTION IN
YOUNGER AND OLDER ANIMALS
Cardiac Structure
The vast majority of studies of age-related changes in
the myocardium have employed the rat model (294),the
most commonly studied strains being Wistar, Fischer
344, and Sprague-Dawley. Two-year-old rats housed in
cages are commonly referred to as “senescent,” because
at approximately that age 50% colony mortality occurs
(294).Similarities and differences with respect to mor-
phological changes that accompany aging in these
strains have been noted.
The senescent Wistar rat heart exhibits moderate
(25%)LV hypertrophy compared to hearts from young
and middle-aged animals (565,566).This occurs in the
absence of arterial hypertension (423).The increase in
LV mass with aging in the rat differs from that in
humans in that the LV cavity size is enlarged, while the
estimated LV wall thickness does not increase (463).
Fluctuations in body weight and composition with
aging in rats make body weight an unreliable reference
for normalizing heart weight for comparisons across age
(as for V O ~ )An
. alternative index of body size (tibia1
length) appears to be more appropriate for normaliza-
tion of heart mass (565). The majority of the increase
in cardiac mass with aging in the Wistar rat, however,
is due to myocardial cell enlargement (as in humans). In
individual myocytes isolated from Wistar rats of 2, 6-
9, and 24-26 months of age, the average myocyte length
increases from 133 pm at 2 months to 146 pm at 6-9
months to 162 pm at 24-26 months, but the average
CHAPTER 17: CARDIOVASCULAR SYSTEM 441
slack sarcomere length does not change with age (159).
The average volume of individual cells, measured via
Coulter counter techniques, approximately doubles
between 2 and 24 months (Fig. 17.13F). In Wistar-
Kyoto rats, there is some evidence to indicate that a
reduction in the volume fraction of cardiac myocytes in
myocardial tissue decreases with age between 6 and 24
months (124). Myocyte enlargement also occurs with
aging in the Wistar-Kyoto strain. While no prominent
changes in the ultrastructural appearance of the myofi-
bers are observed in the hearts of aging Wistar rats, an
increase in lipofuscin occurs (523),as in humans. In rats
older than 19 months, increased numbers of residual
bodies among the mitochondria in the nuclear pole zone
and in the mitochondrial rows separating the myofila-
ment masses have also been observed, as have signs of
increased lysosomal activity, particularly prominent in
the mitochondrial regions (523).The functional signif-
icance of such changes, however, is unknown.
In hearts of male Fischer 344 rats, LV collagen
increases from 5.5% of total protein at 1 4 months to
approximately 12%-16% at 22 and 26 months (16,
119);in the right ventricle (RV),collagen increases from
7%-8% at 1 month to approximately 19.5%-22% at
22-26 months (16, 119). Collagen accumulates in
intrinsic collagenous structures, including perimysial
weaves, coiled perimysial fibers, and struts, where the
preexisting fibers are thickened and are more extensive.
Regions of fibrosis also increase in size and volume in
older animals, with predominant subendocardial local-
ization (16, 119). Papillary muscles of the LV become
fibrosed to a greater extent than in the RV of Fischer
rats with advancing age (17). In Fischer 344 rats, an
apparent (19Y0) reduction in the number of cardiac
myocytes (reminiscent of the case in some skeletal mus-
cle) has been estimated in both ventricles between 4 and
12 months of age (16).While at 20 months this reduc-
tion in cell number persists in the LV, it is reversed in
the RV. Moreover, from 20 to 29 months, an apparent
59% increase in the number of cells has been inferred
in the RV, with only a 3% increase estimated in the LV
(16).While this has been interpreted to indicate cardiac
myocyte hyperplasia, that is, an increase in the number
of cardiac rnyocytes, more direct evidence of cell hyper-
plasia is required to substantiate this provocative
notion.
In Sprague-Dawley rats, an age-associated increase in
the extent of myocardial fibrosis, involving 60% of rats
at the time of spontaneous death, has been observed
(549).This fibrosis is dispersed rather widely within the
myocardium, with greater concentrations in the suben-
docardial and subepicardial regions. In male Sprague-
Dawley rats between 3 months and 10-12 months of
age, the mean myocyte cell volume per nucleus increases
53% and 26% in the LV and RV, respectively. The total
442 HANDBOOK OF PHYSIOLOGY-AGING
number of myocyte nuclei remains constant in both ven-
tricles. By 19-20 months, a further (39%) cellular
hypertrophy of the LV occurs in association with an
apparent (18%) loss of cell number. LV cell loss is
accompanied by discrete areas of interstitial and
replacement fibrosis in the subendocardium (15). In
contrast to the LV, no focal myocardial damage is
observed in the RV, and the measured additional 35%
enlargemelit of RV myocytes occurs without an appar-
ent change in cell number. Thus the aged LV of this rat
strain, similar to that of the Fischer 344 strain, appears
to be composed of a smaller number of hypertrophied
cells. The cellular changes with aging in this rat strain
occur in the absence of an increase in the ratio of heart
weight to body weight. The Sprague-Dawley strain, like
the Wistar strain, does not become hypertensive with
aging, the stimuli for cell loss and hypertrophy of the
remaining cells with aging being unknown. In the
Sprague-Dawley strain, the myofibers of senescent
hearts appear irregular and often small, with tapering
projections, and foci of dense mitochondrial accumu-
lations are observed (521). This contrasts with other
species and other types of muscle, in which there is an
apparent decrease in mitochondrial density with aging.
Older Sprague-Dawley hearts also contain autophagic
vacuoles that are rarely noted in the myocardium of
young animals.
In summary, in the normotensive rat, cardiac fibrosis
increases with age, the number of myocytes decreases,
and myocyte size increases. Variable degrees of LV
hypertrophy occur, depending upon the strain, and this
is due to ventricular dilatation, with apparent preser-
vation of a normal ventricular wall thickness.
Myocardial Stiffness
Passive Stiffness. Data arising from studies in animal
models are often cited as being indicative of a change in
passive mechanical myocardial properties with advanc-
ing age. Passive mechanical properties of myocardial
cells and tissue, that is, those properties determined by
the amount and composition of matrix (interstitial) pro-
teins (for example, collagen and cytoskeletal proteins),
affect the contraction amplitude and relaxation of car-
diac muscle and the filling properties of the cardiac ven-
tricle. One way of assessing passive muscle properties is
to examine the passive length-tension curve. However,
it is difficult to directly compare the results of different
studies that examined the length-tension relationship as
a function of age (see 294 for review). An estimation of
the elastic or viscoelastic modulus is a more meaningful
method of assessing passive muscle properties than mea-
surement of the passive length-tension curve (349). In
isolated, unstimulated rat trabecular carneae, using
small sinusoidal length perturbations across a range of
muscle lengths, several studies have failed to demon-
strate an age-associated alteration in the passive visco-
elastic stiffness modulus (486, 487, 566). In contrast,
no generalization can be made from studies of the intact,
isolated heart as the passive viscoelastic modulus was
found to increase in the beagle dog (516), to remain
unchanged in the hamster (241), and to decrease in the
rat (232) with age.
In addition to the variable results of different studies,
more fundamental considerations underlie the ambigu-
ity of the effect of age on passive myocardial properties,
among which is the assumption of classic muscle
mechanics that CaZ+ activation of myofilaments (see
below, under Regulation of the Cardiac Contraction)
does not contribute to passive force, that is, force mea-
sured in the absence of electrical stimulation. In isolated
cardiac cells from rats, and from other species as well,
a tonic, Ca2+-dependentmyofilament interaction is also
present at rest and modulates the resting cell length in
the absence of external loading (571). Additionally, in
the rat, the passive force in the isolated heart and car-
diac muscle may indeed be influenced by asynchronous
spontaneous cytosolic Ca2+ oscillations among myo-
cardial cells that occur even when the bathing milieu
contains Ca2+ in the range of 2.5 mM or less, that is,
over the range where most mechanical measurements
have been made (268,293,492).
Active Stiffness. Active dynamic stiffness, that is, the
force change in response to sinusoidal changes in muscle
length made during Caz+ activation of the myofila-
ments, has been experimentally found to increase as
force increases with time during cardiac muscle con-
traction, making active stiffness a linear function of the
force. In muscle from senescent rat hearts, the slope
coefficient of the linear active stiffness vs. the force rela-
tionship during contraction increases, but the intercept
of the relationship does not change, relative to mea-
surements in muscle from younger rats (486,487,566).
The time to peak stiffness and to half-relaxation of peak
stiffness are also prolonged in senescent vs. young adult
cardiac muscle (486, 487, 566). As just noted, age dif-
ferences in passive viscoelastic properties do not affect
stiffness, as measured by this technique (486,487,566),
and thus cannot account for the increased dynamic stiff-
ness during contraction in senescent muscle. Prolonga-
tion of the force transient and the prolonged time course
of active stiffness in senescent muscle appear to result,
in part at least, from the prolonged Ca, transient with
aging.
Regulation of the Cardiac Contraction
The Cardiac Excitation-ContractionProcess. The cardiac
cycle is initiated as Ca2+ influx via voltage-gated sar-

colemmal Ca2+ channels that become activated by
membrane depolarization during an action potential
(AP), triggering Ca2+ release from the SR (Fig. 17.12).
Following its abrupt increase after excitation, the Ca,
concentration is then reduced, in large measure via SR
pumping and in part via Na-Ca exchange. Following
each cycle, some of the excitationxontraction coupling
mechanisms, for example, sarcolemmal ionic conduc-
tances and SR Ca2+recycling, require a restitution time
for optimal operation following a subsequent ex-
citation.
The myofilaments (actin, myosin, troponin, tropo-
myosin) within each myofibril are arranged in serial
units referred to as “sarcomeres,” which can vary in
length from about 1.9 to 2.4 p,m in the unstimulated
state and from about 1.6 to 2.2 prn following excita-
tion. Ca2+ binding to troponin C following excitation
results in actin-myosin interaction (formation of cross-
bridges) followed by stiffening of the myofilament lat-
tice (force production) and displacement of actin rela-
tive to myosin (sarcornere shortening). The extent and
duration of Ca2+binding to troponin C is a major deter-
minant of the velocity and extent of sarcomere short-
ening following excitation. The extent of Ca2+ binding
to troponin C following excitation depends upon the
magnitude of the Ca2+ release from the SR and on the
resting myofilament or sarcomere length (233, 234).
The extent to which Ca2+ remains bound during con-
traction depends in part on the velocity and extent of
sarcomere shortening during a given contraction (283).
Thus the duration of Ca2+ myofilament activation is
regulated by sarcomere length prior to excitation and
by sarcomere shortening during contraction (see 291 for
review).
FIG. 17.12. Simplified schematic of excitation-contraction coupling
mechanisms in cardiac muscle. CaZ+influx (IG) via L-type sarcolem-
ma1 CaZ+ channels, activated by depolarization during an action
potential, triggers the release of Caz+ from the sarcoplasmic reticulum
to increase the cytosolic [Ca’+]. The binding of CaZ+ to troponin
(TROP) enables actomyosin (AM) interaction, resulting in myofila-
rnent force production and shortening. Cytoplasmic [CaZ+]is then
lowered and relaxation ensues (Mito, mitochondria).
CHAPTER 17: CARDIOVASCULAR SYSTEM 443
In addition to the extent of Ca2+ activation of myo-
filaments, the rate and extent of sarcomere shortening
following excitation and the resultant increases in myo-
filament, cellular and myocardial stiffness, and force
production are dependent on the ambient forces within
the tissue, sometimes referred to as the “load” borne by
these structures. The sarcomere load depends in part on
the length of the sarcomeres and other cytoskeletal
structures to which sarcomeres are attached within cells
and in part the fibrous connections of myocytes to
matrix collagen (see above, under Passive Stiffness).
When sarcomeres shorten during contraction, their
myofilament Ca2+ activation, length, and load are each
important determinants of the cardiac contraction;
these factors are highly interdependent and cannot be
considered to be completely independent of each other
(291). Additional factors that determine the sarcomere
dynamics following excitation are the myosin heavy
chain (MHC) isoform composition, the extent of phos-
phorylation of myofilament components (as determined
by receptor-mediated second messengers, for example),
and the local concentrations of ATP, ADP, Pi, H’, and
Mg2+.Sarcomere relengthening and relaxation of force,
in addition to a dependence on the removal of Ca2+
from troponin C, depends on the mechanical loading
factors discussed above.
Cardiac Muscle and Myocyte Changes with Adult Aging.
Cardiac muscle function has been studied with respect
to aging in thin trabeculae, papillary muscles, and iso-
lated cardiac myocytes that have been removed from the
heart and superfused in physiological saline. Several of
the steps in the excitationxontraction cascade discussed
above differ in cardiac muscle or cells isolated from
senescent rat hearts vs. those from younger adult hearts.
In general, the kinetics of many of these steps are
reduced in the senescent vs. the younger adult muscle
(Fig. 17.13).
Action potential and membrane currents. The heart
beat represents the synchronized cellular Ca2+ oscilla-
tions and cyclic contractions of myocardial cells. For an
organized Ca2+ oscillation to occur within and among
myocardial cells, several cellular mechanisms must act
in concert. In isolated muscle preparations, several
aspects of the heart beat can be simulated as a twitch
contraction elicited by an AP that occurs in response to
external electrical stimulation. Representative examples
of AP, contraction, and the Ca, transient in muscle iso-
lated from adult and senescent male rats are illustrated
in Figure 17.13A-C. While the resting membrane poten-
tial is unaltered with adult aging (60, 539, 545, 557),
the repolarization of the membrane potential in senes-
cent muscle is strikingly (about twofold) prolonged (Fig.
17.13A). This has been observed in separate studies
using different rat strains (Wistar and Fischer 344) in
 0 100 200 0 100 200 300 400 500
TIME (msec) TIME (msec)

2000 -
1600 -

1200 -
800 -
0 24 nm

1 1 1 1 1 l I

0 50 100 154 7.0 6.8 6.6 6.4 6.2 6.0 5.8 5.6
TIME (msec)

F
I

" 80 120 160 200 300 400 2 6-9 24-25

COUPLING INTERVAL (ms) AGE (mo)

FIG. 17.13. Action potential (A), isometric twitch (B), and Ca, transient (C) measured via
aequorin luminescence in isometric right ventricular papillar muscles isolated form the
hearts of young adult and senescent Wistar rats. inset in C indicates the time course of the
Ca, transient (trace 1 ) relative to that of the contraction (trace 2). [A and B from Wei et al.
(545);C from Orchard and Lakatta (377)with permission.] D: The force-pCa relationship
in cardiac muscle in which membranes have been destroyed by detergent (Triton X) treat-
ment does not vary with age. [From Bhatnagar et al. (37)with permission.] E: The ability
of left ventricular trabeculae carneae to respond, via a detectable twitch contraction, t o
paired stimulation decreases with age as the coupling interval of the paired stimuli decreases.
[From Lakatta et al. (296) with permission.] F: Left ventricular cell volume (single cells
isolated via collagenase digestion of hearts), measured via Coulter counter technique,
increases with age. [From Fraticelli et al. (159) with permission.]

444

“pseudoisometric” (auxotonic) RV (545) and LV (59)
papillary muscle and in isolated LV myocytes (539).An
age-related increase in the AP duration of isolated
human atrial fibers has been reported (127); however,
the ages compared were 10 months and 55 years. The
AP amplitude above zero millivolts (overshoot) in rat
cardiac muscle is Ca2+-dependent; in the Wistar strain,
the AP amplitude is greater in senescent than in adult
muscle in both high- and low-Ca2+ loading conditions
(545).The dramatic prolongation of the AP observed in
isometric contractions in the senescent heart depicted in
Figure 17.13 has not been observed in nonworking
intact heart preparations (291), suggesting that the age
differences observed in the AP in working myocardial
tissue in part involve an age difference in response to
stretch. However, recent evidence indicates that the AP
is prolonged in unloaded, single (and thus unstretched)
LV myocytes isolated from senescent hearts compared
to that in cells from younger hearts (539).
Recent studies have begun to address the ionic basis
of the AP prolongation with aging. The peak L-type
Ca2+current (measured via the whole-cell patch clamp)
normalized for cell capacitative area does not change
with aging, suggesting that the density of this Ca2+
channel is not markedly altered in myocytes from older
hearts (539). However, a reduction in the inactivation
rate of the Ca2+ current has been observed with aging
(537) and an age-associated decrease in the magnitude
of ITo (an outwardly-directed K current) contributes to
the prolonged AP with aging (540). The magnitude of
the “inward going rectifier” K current does not change
with age (540). Prolongation of the AP duration with
aging may also relate to a prolonged Cai transient (see
the following section), as Ca2+ extrusion via the Na+-
Cap exchanger during the AP repolarization produces
an inward current and prolongs AP duration of rat cells
(112).
Cyfosolic [Ca2*],confracfion, and relaxation. The Ca,
transient that follows sarcolemmal depolarization in
isolated cardiac muscle has been monitored by injecting
the chemiluminescent protein aequorin into multiple
cells of that tissue and measuring the light transient that
ensues following the AP (377). The amplitude of the
aequorin luminescence transient triggered by excitation
is not altered by age when the [Ca2+]in the superfusate
is in the physiological range and the rate of stimulation
is low (Fig. 17.13C).Studies in which cell and organelle
membranes within thin papillary muscle have been sol-
ubilized by detergent (Triton X-100) treatment to per-
mit the buffering of [Ca2+] within the myofilament
space indicate that neither the maximum force nor the
shape of the relationship between force and [Ca’+] dif-
fer with age (38) (Fig. 17.130).
Peak contraction amplitude of isolated, isometric
CHAPTER 17: CARDIOVASCULAR SYSTEM 445
(auxotonic) cardiac muscle at relatively low rates of
stimulation (6-48 min-’) does not differ with age (Fig.
17.13) when measured across a broad range of bathing
[Ca”] or resting lengths, that is, preloads (10,60, 163,
187, 294-296, 545). (It should be noted that the rela-
tively low rates of stimulation, and usually low temper-
atures, required for isolated cardiac muscle (30°C)stud-
ies do not permit assessment of the extent of Ca2+
release at cycling rates approaching those in the rat in
vivo, for example, 5 Hz and above.) More recent studies
show that the twitch contraction amplitude in single
cardiac myocytes (which in some ways is analogous to
the extent of shortening in the isotonic muscle), when
normalized to myocyte length during stimulation at
either 0.5 or 1.0 Hz at either 29” or 37”C,does not differ
with age (159,432, 557).
Increasing the stimulation rate or varying the stimu-
lation pattern places a stress upon excitation-contrac-
tion mechanisms. In rat muscles bathed in physiological
[Ca+] in the absence of drugs, the amplitude of the
twitch force and the Ca, transient decline as the stimu-
lation frequency is increased, but the magnitude of this
decline does not differ with age (377). In contrast, in
higher bathing [Ca2+],which increases the net myocar-
dial cell Ca2+ load, muscles from younger adults are
able to maintain the amplitude of twitch force and of
Ca, transient as the stimulation frequency increases but
senescent muscles cannot (377). The postextrasystolic
potentiation of contraction amplitude during continual
paired stimulation at low rates is also preserved in senes-
cent muscles bathed in a medium of low [Ca2+] and
stimulated at 24 pairs/min (174). However, when the
coupling interval of paired stimuli is decreased from 200
to 100 ms, senescent, but not adult, muscles fail to gen-
erate a twitch response to the second stimulus (Fig.
17.13E). Additionally, muscles from senescent rats
show a greater likelihood to exhibit contractions of
alternating amplitude at high frequencies of stimulation
(166). Thus under the experimental stress of altered
stimulation patterns during which restitution time is
decreased, the reduced kinetics of ionic channel resti-
tution or of Ca2+ cycling in the senescent myocardium
produce contractions of smaller amplitude.
The time courses of both the Ca, transient and the
simultaneously measured isometric contraction are pro-
longed with advancing age (Fig. 17.13B, C). At times
during the contraction when force is still increasing and
Ca, concentration is decreasing (see Fig. 17.13C, inset),
the latter remains higher in senescent than in young
adult muscles. This may result in a relative increase in
the Ca2+-myofilament interaction in senescent muscles
at later times following excitation and would be
expected to prolong the time course of active stiffness
(see below, under Myofilament Proteins) and force-
446 HANDBOOK O F PHYSIOLOGY-AGING

0Adult
senescent

0 0.5 1.0 1.5 2.0

-
Vmax EP Protein
[Ca2+] pM

1-2 8 24 1-2 8 24
AGE (mo) AGE (mo)

FIG.17.14. A: The effect of age on CaZ+accumulation velocity by sarcoplasmic reticulum

(SR) isolated from senescent and adult Wistar rat hearts. [From Froehlich et al. (163)with
permission.] B: The effect of age on SR isolated from adult and senescent Fischer 344 rat
hearts. Left, V,,, for Ca2+-ATPaseactivity in isolated SR vesicles; middle, formation of
phosphoenzyme product; right, concentration of SR Ca” pump protein. [From Tate et al.
(512) with permission.] The effect of age on steady-state mRNA levels for SR calsequestrin
(D) CaZ+-ATPase(C) in adult senescent Wistar rat hearts. [From Lompre et al. (321) with
permission.]

bearing capacity. Stated alternatively, the prolonged Ca,
transient is a cause of the prolonged relaxation of force
of cardiac muscle of the older heart. Recall that the iso-
volumic relaxation period is prolonged in the human
heart with aging; the basis for this could be prolonged
contractile protein activation due to a prolonged Ca,
transient. While the reduction rate of Ca, concentration
decreases with age, there are no data to indicate that the
diastolic Ca, concentration changes with age (the Ca2+
indicator aequorin is not sufficiently sensitive to report
changes in Ca, at the diastolic level).
The load-dependent aspects of relaxation, that is,
those purported to be independent of Ca, concentration
and Ca2+ activation of the myofilaments but dependent
on mechanical displacement of crossbridges by loading
factors, of posterior papillary muscle relaxation from
the LV and rV of Fischer 344 and Sprague-Dawley rats
have been studied at 4, 10, and 20 months of age ( 6 2 ) .
In the Fischer 344 strain, the relaxation of RV muscle
from young animals was found to be completely load-
independent, that is dependent on Ca,, whereas the LV
muscle was fully load-dependent at all physiological
afterloads. With aging, the load dependence of LV mus-
cle relaxation decreased (and thus the Ca, dependence
increased). In contrast, no aging effects on the load
dependence of relaxation were observed in muscles
from Sprague-Dawley rats (62).
SR function. Although any mechanism that can alter
the flux of Ca” into or out of the myoplasmic space
might affect the duration of the Ca, transient, its decay
is thought to largely depend upon the rate of Ca2+
removal by the SR Ca2+ pump (377).The prolongation
of the Ca, transient in senescent muscle may be related
in part to a diminished SR Ca” pumping rate. Early
studies (Fig. 17.14A) have demonstrated that the rate
of Ca2+ uptake into SR vesicles isolated from senescent
Wistar rat hearts is less than that from younger adult
hearts (163). The net Ca2+ uptake in studies of this sort

depends on the Ca2+pumped into vesicles and any Ca2+
efflux that may occur during the experiment. The latter
can result from a passive, nonspecific leak or from an
efflux via Ca2+channels (ryanodine receptors), through
which Ca2+ release is thought to occur following exci-
tation. The passive leaking of Ca2+ of cardiac homog-
enate membrane preparations has been found to not dif-
fer with age (360).The rate of Ca2+ pumping into the
SR depends on the Cai concentrations (or in isolated
vesicles, on the [Ca2+]of the medium bathing the vesi-
cles; Fig. 17.14A).The reduction in the SR Ca2+ uptake
rate with aging applies to the entire range of Cai con-
centrations that occur in cardiac cells from diastole to
systole (Fig. 17.14A).More recent studies in SR isolated
from other rat strains (Fischer 344 and Sprague-Daw-
ley) have produced results very similar (214, 239, 360,
512) to those in the Wistar strain, as depicted in Figure
17.14A. In the Fischer 344 strain, the diminished SR
Ca2+uptake rate persisted in the presence of added cal-
modulin (214).A decrease in constitutive levels of phos-
phorylation of phospholamban, an SR protein mem-
brane that modulates the Ca2+ pump activity, has also
been reported in native cardiac microsomes obtained
from senescent rats (259). As unphosphorylated phos-
pholamban inhibits Ca2+ uptake by the Ca2+ ATPase
pump of the cardiac SR, it is possible that lower levels
of phosphorylated phospholamban factor into the
decreased rate of Ca2+ uptake by cardiac SR from older
animals observed in the absence of CAMP-dependent
stimulation in the above studies (163, 239, 360, 509,
512). In one study in isolated membrane preparations
from senescent Fischer 344 rats, although the Ca2+
uptake rate was found to be depressed, Ca2+-induced
stimulation of SR pump enzyme (that is, the SR Ca2+-
ATPase) was not found to be reduced by aging (360).
Accordingly, it was suggested that there is an age dif-
ference in the efficiency of coupling between ATP split-
ting and Ca2+ pumping (360). In contrast, another
study in SR isolated from Fischer 344 rat hearts (509)
observed about a 25% age-associated reduction in the
maximum rate of SR Ca2+-ATPase activity (Fig.
17.14B),which accompanied reductions of similar mag-
nitude in the formation of acylphosphate and in Ca2+
uptake in SR vesicles from senescent vs. young adult
hearts (509). Thus the reduction in the rate of Ca2+
pumped into the SR is likely due to a reduction in the
total SR pump protein (Ca2+-ATPase) activity. The
diminished Ca2+-ATPaseactivity and the rate at which
SR from senescent hearts pumps Ca2+ may be related
to a reduction in mRNA coding for the SR Ca2+-ATPase
(Fig. 17.14C) observed in some (321, 328), but not all
( 5 5 ) ,studies, possibly reflecting a decrease in the relative
density of SR pump sites with age (Fig. 17.14C). This
conclusion is further supported by the observation that
gel electrophoresis shows a 40% reduction in the SR
CHAPTER 17: CARDIOVASCULAR SYSTEM 447
Ca'+-ATPase protein (Fig. 17.14B) without a con-
comitant reduction in calsequestrin, a Ca2+-binding
protein within SR (509). The mRNA levels for calse-
questrin (Fig. 17.140) do not decline with adult aging
(321).
~pontaneoussarcoplasmic reticulum Ca2+oscillations
and their functional sequelae. As noted, the heartbeat is
essentially an organized cycling of Ca2+from the SR to
the cytosol and back. In a machine of this design, the
potential for spontaneous Ca2+oscillations (S-CaOs) is
ever present. The probability of S-CaOs varies with the
extent to which the cytosol and the SR become Ca2+-
loaded (287). Aggregate alterations in cytosolic Ca2+,
Na+-Ca+ exchanger, Na+/K+-pump, and SR Ca2+
pump, possibly in conjunction with nonspecific changes
in sarcolemmal membrane ionic permeabilities, may
predispose myocardium to altered cell Ca2+ homeosta-
sis. Spontaneous SR Ca2+ release, unlike that triggered
by an AP, occurs focally and sporadically within cardiac
cells and asynchronously among cells comprising myo-
cardial tissue. At a given instant, one or multiple loci of
increases in Cai due to S-CaOs can be present within a
cell. The local increase of cytosolic [Ca2+] due to S-
CaOs can be as high as that triggered by an AP during
systole. Recent experimental results indicate that acute
perturbations that result in S-CaOs occurrence can pro-
duce the triad of manifestations common to chronic
heart failure of various etiologies, that is, abnormal dia-
stolic tonus, limited systolic function, and a high prob-
ability of arrhythmias (287).Intriguingly, the aged myo-
cardium and that chronically exposed to pressure
overload (see below, under Similar Effects of Aging and
Experimental Pressure Overload . . , ) are more suscep-
tible to Ca2+ overload and S-CaOs (200, 289). When
cell Ca2+ loading is enhanced, the myocardium of such
hearts demonstrates diastolic after-depolarization. The
threshold for ventricular fibrillation, which is preceded
by an increase in SCaOs, is reduced during Ca2+ over-
load in the senescent heart (200).
Nu' regulation. The cytosolic "a+] regulates the cell
Ca2+ load by affecting Ca2+flux through the Na+-Ca+
exchanger (Fig. 17.12). It has been suggested that the
Na+-Ca+ exchanger is more active in ejecting Ca2+
from cells of older vs. younger hearts during diastole
(213, 360). Cytosolic "a+] is primarily regulated by
the Na+/K+-pump.While N+a/K+-ATPase activity has
been reported to decrease with age, the cytosolic "a+]
measured via Na+-selective microelectrodes does not
appear to change with age, either at rest or during rapid
stimulation (426).In this regard, it is of interest to note
that an age-associated decline in the contractile response
to digitalis glycosides, which act via Na+/K+-pumpinhi-
bition, occurs in the absence of an age difference in the
relative extent of glycoside-induced Na+-K+-ATPase
inhibition in both rat and beagle dog models (174,188).
448 HANDBOOK OF PHYSIOLOGY-AGING

o a MHC mRNA loo- a MHC protein

0 8 MHC mRNA A p MHC protein

40

20

0 4 8 12 16 20 24
Age (mo)

0 3mO.
06m0.
D
A12m
A24m

% Relative Load
AQe (mo)

FIG. 17.15. A: Average values for cx and p myosin heavy chain (MHC) mRNNmRNA18S
of individual Wistar rat hearts measured by dot blot analysis (n = 11, 6 , 10, and 10 for
ages 6 wk, 6, 18, and 24 months, respectively). [From O’Neill et al. (376)with permission.]
B: The a and p MHC proteins (V, and Vj isoforms) of hearts of the same rat strain. [From
Effron et al. (118) with permission.] C : Ca2+-activatedmyosin ATPase activity of Wistar
rat hearts decreases with age. [From Effron et al. (118) with permission.] D: The velocity
of shortening during lightly loaded isotonic contractions in isolated cardiac muscle from
younger and older rats decreases with aging. [From Capasso et al. (60) with permission.] E:
Left ventricular actin isoforms (cardiac or skeletal) do not change with aging as do the MHC
isoforms in the Wistar rat. [From Carrier et al. (63) with permission.]

Myofilament proteins. In addition to the extent of
Ca2+ binding to troponin C, the ATPase activity of
myofilament proteins is a determinant of contraction.
Myofibrillar ATPase activity, in preparations using
detergents, exhibits the identical Ca2+ dependence
(K,0.6 km and Hill coefficient of approximately 4.5)
as does force (see Fig. 17.130)(37).Although the Ca2+
sensitivity of myofibrillar ATPase activity does not
change with adult age, the maximum ATPase activity
declines during maturation and then remains stable
from 6 months through senescence (37,294). The Ca2+-
activated ATPase activity in actomyosin preparations
(that is, actin plus myosin in the absence of troponin
and tropomyosin) declines during maturation but also
shows a further decline with age (61, 69, 132).
The Ca2+-activated ATPase activity of purified iso-
lated myosin preparations (Fig. 17.15C) declines pro-
gressively in the rat throughout the age range of 1-24
months (36,61,118,512). This ATPase activity is mod-
ulated in part by the muscle MHC isoform composition
(220).The content of the a M H C isoform (often referred
to as the “V1” isoform), which has a rapid ATPase activ-
 CHAPTER 17: CARDIOVASCULAR SYSTEM 449
TABLE 17.4. Myocardial Changes with Adult Aging in Rats
Ionic BiophysicallBiochemical
Structural A Functional A Mechanisms Molecular Mechanisms

t Myocyte size*
J Myocyte number“
t Matrix collagen
* f , increase; J , decrease.
Prolonged contraction duration
Prolonged action
potential duration
Diminished contraction velocity
Diminished P-adrenergic
contractile response
f Myocardial stiffness
Prolonged cytosolic CaZ+transient J. SR Ca2+ pump mRNA
J SR CaZ+pumping rate Calsequestrin mRNA no A
J. Pump site density
J Ic. inactivation
J. I~~density
J aMHC protein J aMHCmRNA
t PMHC protein f PMHCrnRNA
J. Myosin ATPase activity Actin mRNA
Cardiac no A
Skeletal no A
? J. Coupling PAR-acyclase
J. Ca, transient augmentation
J. TNI phosphorylation
t ANFmRNAI
t Proenkephalin mRNA

ity, decreases progressively with age (Fig. 17.15B). The
lower level of the aMHC protein in preparations iso-
lated from senescent hearts (55, 61, 118, 132, 450)
appears to be a major factor underlying the decreased
myosin ATPase activity. The mRNA coding for aMHC
also declines with age in the myocardium of Wistar (Fig.
17.15A) and Fischer 344 rats (55, 376, 450), and the
diminished expression of this gene with aging may
account in large part for the reduction in the aMHC
content with aging (Fig. 17.15B). Conversely, with
aging, the mRNA coding for the PMHC isoform (which
has a lower ATPase activity than the aMHC and is
sometimes referred to as the “V3” isoform) exhibits a
severalfold increase (55,376,450) (Fig. 17.15A) and is
the apparent mechanism for an increase in the PMHC
protein (Fig. 17.15B).
The switching of the MHC genes with advancing
adult age may in part underlie the decline in the velocity
of shortening in lightly loaded isotonic contractions
(Fig. 17.150) (10, 61) and may also be related to the
prolonged time to peak tension in isometric contrac-
tions (Fig. 17.12B) and the prolonged time to peak
shortening in isotonic contractions in cardiac muscle
from adult vs. older animals (60, 61). It is noteworthy
that the PMHC isoform is energy-efficient in that a
given level of tension development in hearts with pre-
dominantly the PMHC (V3) isoform produces less heat
than in hearts with mixed or predominantly the aMHC
(V,) isoform (8). The pattern of expression of MHC
genes in the senescent heart resembles that around the
time of birth (376). In this regard, a marked increase in
mRNA coding for atrial natriuretic factor (ANF) occurs
in the LV with advancing adult age (40). In contrast,
the expression of genes coding for actin isoforms (that
is, cardiac and skeletal) does not shift with aging (Fig.
17.15E) and thus does not resemble the fetal pattern
(63). A marked increase in the expression of the pre-
proenkephalin gene occurs with aging (41), but
the functional significance of this is presently not de-
fined.
A summary of the structural, functional, biophysical/
biochemical, pharmacological, and molecular changes
that occur in the rat heart with aging is presented in
Table 17.4. Coordinated changes in several key steps of
excitation-contraction coupling occur with aging.
These biochemical, biophysical, and molecular changes
result in a prolonged Ca2+ transient and a prolonged
contraction. The resultant altered Ca2+ homeostasis
renders the older heart more prone to S-CaOs and Ca2+-
dependent arrhythmias.
Simi/ar E k t s of Aging and hperimenfol Pressure
Overload on Cardiac Regulatory Mechanisms and
Gene Expression
The multiple changes in cardiac excitation, myofilament
activation, and contraction mechanisms that occur with
aging (Fig. 17.13-15 and Table 17.4) are interrelated.
Many of these changes can be interpreted as adaptive
in nature, since they also occur in the hypertrophied
myocardium of younger animals that have adapted to
experimentally induced chronic hypertension (7, 8, 11,
28,40,55,60,61,67,71,98,105,117,171,187,189,
199, 210, 212, 223, 229, 265, 286, cf289 for review,
294,299,306,307,322,333,338,339,341,358,379,
450 HANDBOOK OF PHYSIOLOGY-AGING
381,427,433,442,452,462,466,470,508,531,551,
554,560).
In addition to these changes, the electrical manifes-
tation of S-CaOs, that is, diastolic after-depolarization,
is observed in cardiac muscle of pressure-loaded hearts
under conditions in which it is not observed in normal
myocardia of younger rats (19, 209). A predisposition
to pacing-induced ventricular arrhythmias in aortic
banded cats has also been reported (460). Hypertro-
phied hearts due to renal hypertension also show an
enhanced likelihood for voltage oscillations on the AP
plateau. In contrast to diastolic membrane potential
oscillations, these early afterdepolarizations on the AP
plateau appear to be due to the removal of inactivation
of Ca2+channels during the long AP plateau (231),and
the resultant cytosolic Ca2+transients are driven by the
oscillations in I ~ ~ ( 4 8 . 5The
) . greater likelihood for pla-
teau oscillations may lead to an enhanced susceptibility
for arrhythmias under some circumstances in the pres-
sure-hypertrophied heart (534).
Because similar reductions in the cellular ribonucleic
acid (RNA)concentration and in the rate of protein syn-
thesis have been observed with aging and chronic myo-
cardial overload in the rat model, it has been suggested
that the latter (which is usually accompanied by myo-
cardial hypertrophy) represents accelerated aging (340).
The initial myocardial hypertrophy in pressure overload
is a manifestation of an enhanced net protein synthesis
due to enlargement of a relatively constant number of
cardiac myocytes and reflects global activation of car-
diac genes a t the translational and posttranslational lev-
els (452).
There is evidence that one signal involved in the trans-
duction enhanced pressure load stress is mechanical,
that is, stretch or tension (30, 82, 255, 264, 332, 354,
467, 543, 560). In this regard, the relationship of an
increase in protein synthesis and force (both systolic and
diastolic) is described by a single linear function (82).
This tension effect may be mediated in part by enhanced
coronary flow (30) or hormonal stimulation (245, 353,
467,468,535,543). Interactions occur between stretch
and cell-surface-receptor-mediated intracellular signal
transduction mechanisms, for example, increases in
CAMP or in PKC activity (245, 353, 468, 535, 543) or
changes in ion flux [for example, Na+ (255) or Ca2+]
possibly related to stretch-induced activation of ionic
channels (85, 86). Reorganization of intracellular
matrix proteins, for example, desmin and tubulin, may
also mediate the stretch response (542). Additionally,
stretch of extracellular matrix and ventricular and car-
diac endothelium may lead to the production of growth
factors which can initiate protein synthesis and regulate
gene expression (442).
The initial events in response to increased aortic pres-
sure occur rapidly (within 30 min) and mimic the nor-
mal stress and growth responses, including the transient
induction of heat shock proteins (99, 198, 199, 468),
protooncogenes (228, 355, 360, 469), and other early
growth response genes (73).There is also an induction
of proteins that are usually present in ventricular myo-
cardium during the fetal period, for example, a skeletal
actin (228) and P-tropomyosin (228), or proteins that
are usually present only in the atria of adult hearts, for
example, ANF (94, 456). Subsequently, shifts in the
expression of genes coding myofilament, ion channel,
or membrane pump proteins occur. Initially at least,
substantial spatio-temporal heterogeneity exists in the
increase in mRNA encoding these various proteins (400,
443). This could be due in part to a heterogeneity of the
specific factors stimulating the initial growth response.
The phenotype of the stable, adapted hypertensive heart
in some cases is due to differential expression of multi-
gene families of contractile proteins, for example, the
shift of the MHC isoform, and in other instances
involves differential activation of single genes, for exam-
ple, the coding for the SR Ca2+-ATPase protein.
A similar pattern of altered gene expression occurs in
both hypertension in young animals and aging in nor-
motensive animals (290) and in neonatal heart cells
exposed to growth factors (444).It is tempting to spec-
ulate that, because a nearly identical pattern of change
in cell mechanisms occurs in both experimental pressure
overload and aging (and after growth factors in neo-
natal heart cells), this pattern may reflect a “logic”
within the genome, that is, that a common set of tran-
scription factors regulates the expression of multiple
genes resulting in cellular adaptation. This particular
constellation of shifts in gene expression appears to be
adaptive in that it allows for an energy-efficient and pro-
longed contraction. In the hypertensive rodent heart it
can be inferred that these changes in gene expression
permit functional adaptations in response to an
increased vascular afterload.
Possible Mechanisms of Altered Cardiac Gene
Regulation with Aging
If the changes depicted in Figures 17.13-15 and Table
17.4 were to occur in normal human myocardium with
aging, they could easily be construed as adaptations to
the stiffer arterial system and to an increase in arterial
pressure and impedance, as discussed earlier, under
Ventricular-Vascular Coupling. However, with aging in
the normotensive rat, whether the similar changes that
occur with hypertension in younger rats are adaptive or
degenerative is uncertain because the stimuli for these
changes with normotensive aging remain to be identi-
fied. There are presently few data to indicate that arte-
rial stiffening or enhanced arterial impedance occurs
with aging in rats up to 24 months of age at least.

Although peripheral resistance increases with age in
rats, it appears to plateau at 10-12 months and cannot
directly be related to the changes shown in Figures
17.13-15, which are progressive with advancing age
(534).Additionally, as noted above (see Similar Effects
of Aging and Experimental Pressure Overload . . . ), the
changes depicted in Figures 17.13-15 and Table 17.4
have been described in two strains of rat that do not
become hypertensive with aging.
Unlike the hypertensive heart, the increased LV mass
with aging in the Wistar rat strain is largely due to an
increase in LV cavity size, that is, the wall thickness
appears to remain normal with aging (463). However,
as in the young hypertensive rat, cardiac myocytes
become enlarged in the senescent heart. It may be
argued that the mechanical or hormonal stimuli that
initiate and maintain the cardiac hypertrophic response
in the hypertensive heart are also present in the aging
heart. It has been hypothesized that the apparent “drop-
out’’ of some myocardial cells with aging (15, 16) leads
to augmented stretch upon the remaining cells, this
being the stimulus of cellular hypertrophy and of the
accompanying changes in gene expression and biophys-
ical mechanisms that lead to a prolonged contraction.
Nevertheless, prolonged contraction in older hearts per-
sists when these hearts are transplanted, mechanically
unloaded, and atrophied (266).Also, prolonged AP, Ca;
transient, and contraction occur with aging in RV mus-
cle (486,545) in which the ventricular myocyte number
may not be reduced in senescence (15). Additionally,
unlike the LV, the RV does not hypertrophy with age
in the Wistar rat strain (565).
Alterations of thyroid status can produce alterations
in the variables depicted in Figures 17.13-15 and Table
17.4. In this regard, the changes observed in the aging
heart mimic to some extent those observed in the hypo-
thyroid state (9, 66, 103,219,220,227,450).Whether
or not a relative hypothyroid state accompanies aging
is uncertain. An age-associated decline in plasma levels
of thyroid hormones (T3 or T4) occurs in at least two
rat strains (55, 66, 118, 328), but the magnitude of the
decline is small. Still, it has been reported that replace-
ment of sufficient thyroxine to restore plasma levels in
older rats to those found in younger rats can abolish the
age-associated decline in myosin ATPase activity (66);
however, complete reversal of the MHC isoform profile
did not occur with small doses of thyroxine (66).Very
high doses of T4 administered for a short period of time
have been noted to increase the myosin a M H C content
of senescent hearts, but they do not fully restore this
level to that in the younger heart (118). Administration
of T3 or T4 to senescent rats also decreases the PMHC
protein content (118,450) and the PMHC and mRNA
levels (449). Still, a failure of myocardial cells to
respond to thyroxine (for example, due to deficits in
CHAPTER 17: CARDIOVASCULAR SYSTEM 451
nuclear thyroid receptors or changes of the binding
properties of thyroid regulatory elements on the MHC
and other genes) may occur with aging and in part
underlie the pattern of change depicted in Figures
17.13-15 and Table 17.4.
Glucose intolerance has been observed in aged rats
(402) and could possibly relate to some of the changes
noted above. In insulin-deficient diabetic rats, marked
shifts occur in the MHC isoform pattern (increases in
PMHC isoform) and in myofilament ATPase activities
(104, 330). Additionally, the SR Ca2+-ATPaseactivity
and the Ca2+ uptake of isolated SR are depressed in
insulin-deficient diabetic hearts (169,324,385),and the
contraction time is prolonged (135). In noninsulin-
dependent diabetes, the type more typically associated
with aging, the SR Ca2+ pumping rate and the ATPase
activity are also reduced (441),and a shift to the PMHC
isoform occurs. A diminished P-adrenergic response
also occurs in this form of diabetes (440).
Finally, a reduction of physical activity occurs with
aging even rats in captivity (384, 570). Because many
of the changes in the cardiac mechanisms depicted in
Figures 17.13-15 and Table 17.4 can be modulated by
physical conditioning, which in older animals has been
shown to modify some of these changes, physical decon-
ditioning with aging (or lifelong residence in cages) may
have a role in effecting some of these changes.
Response of Older Rat Heart to Chronic Hemdynamic
Overioad
The extent to which MHC isoform composition, myo-
sin ATPase activity, and AP and contraction durations
become altered following pressure overload appears to
be correlated with the extent of hypertrophy, regardless
of age (61). The response to mechanical stresses that
evoke substantial myocardial hypertrophy, for example,
pressure or volume overload, appears, in some
instances, to be reduced in the senescent heart. For
example, the extent of ventricular hypertrophy follow-
ing aortic (226) or pulmonary artery banding (281) vol-
ume overload or the creation of renal hypertension (61)
is reduced in senescent vs. younger rats. Although in the
latter study the significance of this is unclear because of
four age groups tested, one younger age group also
showed a reduction in the extent of hypertrophy. Addi-
tionally, a subsequent study utilizing the same pressure
loading model in the same rat strain observed that the
hypertrophic response of the senescent heart was not
decreased (54). The induction of early-response genes
(protooncogenes) following aortic banding becomes
blunted with age (510). The hypertrophic response to
chronic AV block, which causes a 50% reduction in
heart rate, decreases with age and is accompanied by
reduced functional adaptations in isolated cardiac mus-
452 HANDBOOK OF PHYSIOLOGY-AGING
cle (538). Furthermore, the contractile response to
stressful conditions (high pacing rate and high bathing
[Ca2+]) is reduced in senescent hearts that have
responded to mild aortic banding with an appropriate
degree of hypertrophy (42). Thus it may be argued that
the adaptive reserve capacity, that is, an increase in car-
diac mass or cardiac muscle function, may become
diminished with advancing age. This may indicate that
some cardiac adaptations, for example, an increased
myocyte or heart size, become utilized during normal
aging and that a further utilization of these cannot occur
in response to these experimental stresses. In other
words, the reserve capacity of the aged heart to respond
to these stressful situations appears to be diminished.
This could be related in part to cardiac myocyte cell
death and fibrosis that may occur due to, for example,
an excessive increase in myocyte cell size, relative isch-
emia, or inadequacy of cell ionic homeostasis or of
energy balance for reasons not related to blood flow. In
a spontaneously hypertensive rat strain, advanced age
and chronic hypertension are accompanied by deterio-
ration of hemodynamic function (388), evidence for
impaired myocardial force production, increases in
myocardial collagen, and clinical signs of severe con-
gestive heart failure (38).
Coronary Blood Flow, Oxygen Consumption, and
Oxidative Metabolism
Excitation, contraction, and relaxation mechanisms of
cardiac muscle, which determine myocardial perfor-
mance, require ATP to maintain cytosolic "a'] and Ca,
concentrations at levels far removed from their ther-
modynamic equilibria to maintain ionic homeostasis
and to permit Ca, transients and cyclic Ca2+-actomyosin
interactions. Thus an understanding of how aging
affects cardiac contractile regulation requires not only
specific studies of the effects of intrinsic myofilament
function, cell organelles, or ion pumps but also a delin-
eation of whether or not 0 2 delivery (coronary flow)
and energy metabolism change with aging.
Myocardial cell enlargement (Fig. 17.13F), interstitial
fibrosis, and chronic changes in myocardial function
that have been noted in the isolated working heart from
rats of advanced age (5,162,308,489,490) may affect
the adequacy of coronary flow. In senescent vs. adult
hearts in vitro, coronary blood flow per gram heart is
diminished, and the magnitude of this decrement is
approximately 15% (5, 548). In unrestrained, male
Fischer 344 rats of 4, 12, and 20 months of age, max-
imal coronary blood flow per 100 g tissue decreases by
43% in the LV at both 12 and 20 months vs. 4 months
and by 44% and 47% in RV at the same time intervals
(192). Minimal coronary vascular resistance per 100 g
of myocardium (measured after maximal vasodilata-
tion) increased with age by 56% and 36% in the LV
and by 48% and 44% in the RV at 1 2 and 20 months,
respectively. Maximal coronary blood flow to the endo-
cardium was depressed more than epicardial flow at 20
months. In isolated, working Wistar-Kyoto rat hearts,
coronary blood flow varied threefold (depending on the
prevailing afterload); at any given afterload, coronary
flow was 25% less in hearts from 19-month-old vs. 4-
month-old rats (162). In isolated, senescent Wistar rat
hearts, maximum coronary flow, that is, elicited by hyp-
oxia, was found to be approximately 70-80 ml/g dry
weight in the mature adult and approximately 65 ml/g
dry weight in the senescent heart (548). Thus coronary
flow per unit heart mass decreases with age in three dif-
ferent rat strains.
These changes in coronary blood flow associated with
maturation and aging are comparable with those seen
in pressure overload hypertrophy in younger rats and
may predispose to an increased vulnerability of the
myocardium to ischemic episodes during stress, partic-
ularly of the subendocardial region of the LV. Since
macroscopic structural alterations in the large, medium,
or small coronary vessels are not present in these hearts,
the age-associated reduction in coronary flow reserve
and myocardial O2 consumption may result from a
change in vascular reactivity or from a failure of the
coronary bed to enlarge commensurate with the
increase in heart mass that occurs with senescence. Ear-
lier studies have documented a decrease in the number
of capillaries in 26-27-month-old compared with 4-
month-old rat hearts and in increase in fiber to capillary
ratio (399, 519). This diminution in coronary blood
flow and capillary density might indicate that the aged
heart is chronically hypoxic. However, it should be
emphasized that the capillary density in the aged heart
is not fixed but can be enhanced by chronic exercise
(519,520). Thus it appears unlikely that chronic anoxia
has any significant role in whatever anatomical or func-
tional alterations may occur in the senescent rat heart.
In contrast, the reduction in coronary flow with aging,
in conjunction with the marked shift in MHC isoform
toward the PMHC type may down-regulate (hibernate)
myocardial function and thus energy consumption in
aged hearts (see below).
Whereas the most instructive studies of excitation-
contraction mechanisms with aging have been imple-
mented in isolated cardiac muscles or cells, similar stud-
ies of energy metabolism have been conducted in intact
hearts and isolated mitochondria. The maximum myo-
cardial substrate oxidation rates in working heart prep-
arations from Sprague-Dawley rats decline about 20%
from adulthood to senescence (5).However, energy pro-
duction rates are appropriate for the reduced work per-

formed by older hearts (for reviews see 202,294). More
recent studies in isolate, working hearts from Fischer
344 rats found cardiac work and efficiency to decline
with age, particularly at high aortic pressures (489,
490). This latter study, in which the workload on the
heart was twofold greater than in prior studies (5),
clearly shows that the capacity for energy production in
the heart of the Fischer 344 rat does not decline from
adulthood to advanced old age (489).This is indicated
by the lack of an age-associated decline in maximum
activities of rate-limiting enzymes in both the glycolytic
pathway and the Krebs cycle or in the concentration of
cytochromes in the mitochondria1 respiratory chain. In
this study (489), appropriate measurements, which
allowed for the calculation of the free energy of ATP
hydrolysis (AGatp), indicated that AGATP was not
affected by aging under conditions where heart pump-
ing performance had declined, strongly suggesting that
the capacity of the aged heart to pump blood is not
limited by bioenergetic factors. An additional observa-
tion of this study was that, while chronic exercise con-
ditioning did not affect maximum aerobic energy pro-
duction capacity, it did enhance other performance
measurements of the isolated hearts of aged animals
(489, 490). This dissociation of performance and ener-
getics also indicates that nonenergetic mechanisms (per-
haps a primary decrease in coronary blood flow or a
shift in MHC isoform types) determine performance of
the senescent heart by chronic exercise training.
In contrast to the aforementioned studies in intact
hearts, those in isolated mitochondria have observed
that oxidation of certain substrates is diminished in
senescent vs. adult rat hearts (68,201,202).ADP-stim-
ulated (state 3) respiration of myocardial mitochondria
was diminished in Fischer 344 rats aged 20-24 months
vs. 12-16 months when glutamate-pyruvate, gluta-
mate-malate, and palmitylcarnitine were used as sub-
strates. However, no age-associated differences were
observed when succinate and ascorbate were employed
as substrates (68).In mitochondria isolated from hearts
of Wistar rats, a 40% decline in palmitylcarnitine oxi-
dation was also observed between 6 and 24 months of
age (201);further studies showed that the mitochondria
from aged hearts retained less carnitine than that from
young ones and that this limited the rate of transloca-
tion and thus the rate of palmitate oxidation in the
senescent mitochondria. In addition to these findings, it
was observed that, as in the study of the intact working
heart of the Fischer 344 rat (5), tissue concentrations of
both carnitine and acetylcarnitine are reduced in the
senescent vs. the adult myocardium (201). However,
why isolated mitochondria show declines in oxidation
rates with aging, whereas isolated heart preparations do
not, remains an enigma. An explanation usually offered
CHAPTER 17: CARDIOVASCULAR SYSTEM 453
by “mitochondriacs” to explain this enigma is that the
maximum energy demand of isolated cardiac prepara-
tions is insufficient to stress the maximum energy pro-
duction rates in situ.
EFFECT OF CHRONIC PHYSICAL CONDITIONING ON
CARDIOVASCULAR PERFORMANCE IN OLDER
HUMANS AND ANIMALS
Studies in Humans
There is mounting evidence that age-associated
increases in arterial stiffness and pressure can be mod-
ified by life-style and diet. NaCl dependence of arterial
pressure increases with age (186,257,546).The rate at
which the aorta stiffens with age, manifested by the
pulse wave velocity increase, differs in two Chinese pop-
ulations (27) that differ in exercise and dietary habits,
particularly with reference to the amount of NaCl
ingested (Fig. 17.1A). In a study population advised to
ingest low quantities of NaCl (44 mmo1/24 h) for an
average period of 2 yr the expected age-associated
increases in aortic, arm, and leg pulse velocities did not
occur (26). Age-associated increases in pulse wave
velocity or carotid pressure pulse late augmentation are
blunted in exercise-trained, older athletes (191, 527).
Endurance training younger men blunts the barore-
ceptor response, measured as the change in heart rate
over that of arterial pressure during phenylephrine infu-
sion or during lower body negative pressure (LBNP)
(475). In healthy, rigorously screened sedentary, mid-
dle-aged and older men, strenuous and prolonged
endurance training, sufficient to elicit large increases in
maximal exercise capacity and small reductions in heart
rate at rest, appears to increase cardiac vagal tone at
rest and does not alter arterial baroreflex control of
heart rate but does result in a diminished forearm vaso-
constrictor response to reductions in baroreflex sym-
pathoinhibition (454). During LBNP in endurance-
trained, older (60-80 yr) individuals, LVEDV, SV, and
arterial pressure are better preserved compared to age-
matched controls (158).This contrasts with a reduction
in SV during LBNP in young, endurance-trained vs.
young, sedentary individuals (474).
In younger individuals, endurance training enhances
Vo2 by augmentation in both central and peripheral
mechanisms (77, 88). Maximum cardiac output is aug-
mented following endurance training in younger indi-
viduals via cardiac dilatation, increase in cardiac mass
(347),and enhanced circulating blood volume (87,335,
410). Cardiac enlargement occurs at both end-diastole
and end-systole; the former change is greater than the
latter, resulting in an augmentation of SVI (177).Ejec-
454 HANDBOOK OF PHYSIOLOGY-AGING
tion fraction may decrease or remain unchanged.
Increased SVI at rest and during submaximal exercise is
accompanied by a reduced heart rate; cardiac output for
a given external workload may be even less in condi-
tioned vs. sedentary individuals due to concomitant
augmentation of 0 2 delivery-extraction-utilization
induced by training. In healthy, sedentary, older men,
moderate cardiac dilatation, bradycardia, and aug-
mented SVI occur at both end-diastole and end-systole
in the sitting position at rest and during exercise (Fig.
17.8). Thus some of the macroscopic cardiac adapta-
tions induced by endurance training in younger adults
occur with aging in sedentary individuals.
To determine the interaction of physical conditioning
status and age on cardiorespiratory performance,
young, middle-aged (184, 185), and old individuals
who remain competitive in sports (master athletes) have
often been compared to their sedentary counterparts.
Master athletes (149, 208, 247, 391, 422) have a lesser
accumulation of subcutaneous fat, a better preservation
of muscle mass and lean tissue, an increased peripheral
0 2 utilization, a greater work performance at a given
target heart rate, and nearly twice the aerobic capacity
of sedentary older individuals (Fig. 17.9). Master ath-
letes exhibit type I skeletal muscle fiber hypertrophy and
augmentation of glycolytic and oxidative enzymes of
gastrocnemius muscle compared to younger runners
(80). While in highly trained middle-aged (52-59 yr)
men leg blood flow during cycle exercise increased less
than in younger (25-30 yr) men, equivalent 0 2 con-
sumption occurred in the older men due to a greater
increase in (A-V)02 (537).
In cross-sectional studies, cardiac status, measured in
older master athletes, has been compared to that in sed-
entary controls. Maximum heart rate during cycle or
treadmill exercise does not differ between master ath-
letes and sedentary older individuals (149, 193). During
treadmill exercise, it has been estimated that the cardiac
output (assuming that the SV measured at submaximum
exercise is the same as that at maximum exercise) is
increased in master athletes vs. sedentary, age-matched
controls (193). Estimation of the maximum SV during
exercise as the 0 2 pulse, that is, V02/heart rate, also
suggests that SV in master athletes is increased com-
pared to their sedentary counterparts (208). Another
cross-sectional report indicates that about 85% of the
nearly twofold increase in peak V O ~ achieved during
upright cycle exercise in master athletes is due to
increases in both (A-V)o2 and SVI, the latter being due
to an increase in EDVI (150). Results employing the
acetylene rebreathing technique to measure SV during
treadmill exercise suggest that the nearly twofold
greater V O in master
~ ~ athletes
~ (63~ yr of age) than in
sedentary, age-matched controls is accompanied by
both an increase in cardiac output, due to an increase
in estimated SV, and an increase in maximum (A-V)02
(374).
Longitudinal assessment has been made of the factors
underlying changes in V02maxwith aging in endurance-
trained individuals. In 74 habitually physically active
men and women over a 21-yr period during which age
increased from 25-33 to 41-54 yr, a 20% decrease in
V O ~ , ,was
, ~ ~accompanied by a 9 % reduction in heart
rate. There was no correlation between the decline in
maximum heart rate and the decline in Vo2max among
given individuals (22). Thus a decrease in the efficiency
of peripheral factors that underlie 0 2 utilization must
have occurred with aging. However, a decline in train-
ing status during the course of longitudinal and most
other long-term studies confounds the interpretation
regarding longitudinal reductions in aerobic capacity. In
master athletes who continue to train during aging, it
has been observed that the maximum aerobic capacity
and 0 2 pulse can be maintained (391) or can decline
less (422) over an 8-10-year period compared to sed-
entary controls or athletes who decrease their training
intensity (391). During a 10-year follow-up study, in
which the V0Zmaxof master athletes who continued to
train during the test interval did not decline, the
expected age-associated decline in heart rate did occur
despite continued training. This suggests that compen-
satory cardiac or peripheral adaptations maintained the
enhanced aerobic capacity (391).
In another type of longitudinal study design, mea-
surements of factors that determine aerobic capacity
have been made prior to and following endurance train-
ing of sedentary middle-aged and older individuals.
Middle-aging in sedentary individuals is accompanied
by increased body fat, decreased muscle mass, lower
maximal O2 uptake, and lower energy intake. In both
young and middle-aged men who complete a training
program at 65%-80% maximal 0 2 uptake, changes in
body composition and energy requirements, as well as
aerobic capacity, are observed when compared to sed-
entary men (342). A 7-month endurance-training pro-
gram, sufficient to increase V O 18% ~ (from
~ 35.8~ to~
40 ml/kg/min), for sedentary middle-aged (46-51 yr)
men was accompanied by a decrease in cardiac output
at rest and during vigorous exercise for a given 0 2
uptake, indicating more efficient peripheral 0 2 extrac-
tion and utilization (203). This suggests that the physi-
cal deconditioning that accompanies middle-aging, or
the middle-aging process per se, is associated with a
decrease in peripheral 0 2 delivery-transport-utilization
mechanisms, which can be restored by fitness training.
SVI and ventricular ejection rates are also increased by
training during middle age (203). Additionally, swim
training of middle-aged men increased both peripheral
and central factors, which increased V O from ~ 29.2 to
34.7% ( 3 3 6 ) .

Longitudinal studies of the effects of endurance train-
ing have demonstrated that regular exercise condition-
ing also enhances aerobic capacity in older individuals
(101,120,139,191, 194,247,401). The magnitude of
the V0ZmaXaugmentation and the underlying mecha-
nisms vary with relative fitness prior to training, with
intensity and duration of training (120,247, 401), and
with the experimental paradigm in which performance
is measured (401).It is clear that the reduction in max-
imum heart rate in older individuals is not affected by
physical conditioning, regardless of duration or inten-
sity. Changes in both central and peripheral mecha-
nisms have been found with endurance training of older
individuals (121, 374, 444). After high-intensity train-
ing of older (60-69 yr) individuals for 10 months to 1
yr, VoZmaxincreased by about 20% (25.4 to 32.9 ml/
kg/min); this was achieved primarily by an increase in
estimated (A-V)O~, with little increase in estimated max-
imum cardiac output (453). The results of a study
employing the acetylene rebreathing method show that
SV at peak treadmill exercise increases by 15% in older
(64 yr) men following 12 months of endurance training
(483).This was accompanied by a 7% increase in (A-
V)o2. In contrast, a similar training regimen in women
increased V O exclusively
~ ~ via ~an augmentation
~ of (A-
V)02, with no demonstrable changes in cardiac function
(455) as neither peak SV nor maximum heart rate
increased. In another study, similarly aged individuals
(60-70 yr), who increased their V O by about
~ ~25% ~
(29.6-37.2 ml/kg/min) following training, had an 18%
increase in maximum cardiac output during supine cycle
exercise (121).This increase in cardiac output following
chronic endurance training was achieved by an increase
in SV due to an increase in EDV. Following training, a
greater reduction in ESV during exercise augmented the
EF achieved during exercise. Since arterial pressure dur-
ing supine exercise testing was not affected by condi-
tioning, the enhanced EF and reduced ESV after con-
ditioning have been interpreted (121) to reflect an
increase in myocardial contractility induced by condi-
tioning. A peculiarity of this study is that the estimated
(A-V)02did not increase following exercise, in contrast
to other observations using similar training paradigms
(455).This may relate to the supine body position dur-
ing exercise in this more recent study (121).In contrast
to the above study, less intense exercise paradigms in
older individuals do not enhance cardiac performance
(increased EF or reduced ESV) during cycle ergometry
(445; see also Fig. 17.10B).
Marked changes have been observed in skeletal mus-
cle following endurance training of ol.der individuals
(79, 168, 342). Short-term (2 wk), endurance training
at 70% maximum effort, which had no effect on weight
or body composition in either age group, increased
Vozmaxto the same extent (5.5-6 ml/kg/min) in both
CHAPTER 17: CARDIOVASCULAR SYSTEM 455
young (23 yr) and older 65 yr) individuals (338). Prior
to training, older subjects had more adipose tissue and
less muscle mass than younger subjects. Muscle biopsies
taken at rest before training showed that muscle gly-
cogen stores were 61 % higher in younger subjects. Fol-
lowing training, glycogen stores and muscle 0 2 utiliza-
tion increased significantly (by 25% and 28%) in older,
but not in younger, individuals. In another study, a 30%
increase in VoZmaxeffected by intense endurance train-
ing of older (65 yr) men for 9-12 months was accom-
panied by a 50% increase in the number of type IIa
gastrocnemius muscle fibers, a 13% increase in fiber
area, a 25% increase in capillary/fiber ratio, and a
30%-50% increase in succinate dehydrogenase, citrate
synthase, and P-hydroxyacyl CoA-dehydrogenase activ-
ities (79).These skeletal muscle adaptations likely have
a role in augmented peripheral utilization of 0 2 and in
the enhanced work capacity and Vozmaxafter endurance
training in older individuals. Strength training also
enhances muscle structure and function in older indi-
viduals (168). Leg strength (isometric) training of knee
extensors in healthy older (60-73 yr) individuals
increases the V O ~ , , ,of~ ~the exercised muscles and is
accompanied by increases in muscle strength, as with
endurance training (166).It has been observed that, fol-
lowing leg strength training, the mean vastus lateralis
fiber area increased in these older individuals by 28%
(both types I and I1 fibers), the fibedcapillary ratio by
~15%, and citrate synthase by 38%. In contrast, resist-
ance training (one set of 8-12 repetitions on Nautilus
machines) in older individuals had no effect on cardio-
vascular responses to submaximal or maximal treadmill
exercise (194).
In summary, it is quite clear that the aerobic capacity
of both middle-aged and older individuals can increase
following endurance training and that this is mediated
by adaptations in peripheral, and in some cases
(depending on the intensity of exercise and the baseline
V O ~ cardiac,
~ ~ ~mechanisms.
) These adaptations also
explain, in part at least, differences in Vozmaxmeasured
in cross-sectional comparisons in younger and older
sedentary individuals and between master athletes and
their sedentary counterparts.
Studies in Rodenk
Chronic exercise in senescent rats abolishes prolonged
isometric contraction (Fig. 17.16A) in isolated LV tra-
beculae measured across a range of [Ca2+]and reduces
active dynamic stiffness (486).This chronic (5-month),
mild wheel exercise protocol was insufficient to alter the
body or heart weights in adult (6-9 month) and senes-
cent (24-26 month) rats at time of death and did not
alter the twitch amplitude a t any age. In the younger
animals, this exercise protocol was ineffective in altering
456 HANDBOOK OF PHYSIOLOGY-AGING

the duration of contraction (Fig. 17.16A) or dynamic
stiffness measured during contraction in muscles. The
reduction in both the slope stiffness coefficient and the
duration of contraction (Fig. 17.16A) would be consis-
tent with an effect of exercise to reduce the duration of
the Ca, transient. Indeed, subsequent studies show that
the duration of the Ca, transient in senescent cardiac
muscle is reduced following chronic exercise (190). The
AP prolongation in isolated muscle of senescent hearts
is not reversed by exercise, however (190). The reduced
rate of SR Ca2+ sequestration (Fig. 17.16B) and SR
Ca2+ ATPase and mRNA levels in the senescent heart
(509,512)can also be reversed by chronic physical con-
ditioning. The progressive decline in myocardial Ca2+-
activated actomyosin ATPase activity, that begins dur-
ing maturation (after 1 month in the rat) and progresses
with advancing adult age, can be retarded by a chronic
(3-month) period of exercise, but the beneficial effects
of exercise are relatively small throughout 12-1 5
months (70). Moreover, in older animals that began
exercise at 17-22 months and were sacrificed at 20-25
months, a decline in actomyosin ATPase occurred (70).
The altered MHC isoform profile with aging (Fig. 16C)
or myosin or myosin ATPase activities (Fig. 16D) in the
senescent heart are not affected by chronic physical con-
ditioning (35, 132, 512).
A greater relative effect of chronic exercise on aspects
of cardiac biochemistry that relate to metabolism has
also been observed in senescent vs. young adult rat myo-
cardium. Although chronic exercise does not usually
augment cytochrome c oxidase activity in cardiac mus-
cle of younger animals as it does in skeletal muscle
(382), a modest augmentation of this enzyme has been
observed in hearts of senescent animals (382,512). This
is accompanied by exercise-induced increases in rates of
glutamate, palrnitylcarnitine, and succinate oxidation in

t . senescent control
o - - o senescent exercised
)--.adult control

T LB
-
E 200
0 ’
0 @adult control
0senescent control
180 rn senescent exercised

00’ 1’0 do go
160
Time (min)

c - 1

uu
10 24 10 24
a-MHC f3-MHC
AGE (mo)
FIG. 17.16. Chronic exercise training decreases the isometric contraction duration in isolated right ven-
tricular papillary muscles of older Wistar rats (A) and the velocity of Ca2+ accumulation in sarcoplasmic
reticulum isolated from Fischer 344 rats (B). In contrast, chronic exercise alters neither age-associated
decreases in the M H C isoform content (C) nor age-associated changes in myosin ATPase activity (D). [A
from Spurgeon et al. (486); B and D from Tare et al. (512);C from Farrar et al. (132)with permission.]

isolated mitochondria (382).Thus exercise can partially
reverse the declines in oxidation rates of these substrates
and in cytochrome c activity that occur with aging in
rats (490).In mice the marked age-associated declines
in cardiac aldolase and superoxide dismutase activities
between 9 and 27 months are also prevented by chronic
exercise that began at 6 months of age and continued
into old age (491).Finally, the response of senescent
cardiac muscle to reoxygenation following hypoxia
(315, 544) and insulin resistance of the aging rat are
also ameliorated by chronic exercise (402).
In summary, chronic exercise in older animals
reverses some of the alterations in cardiac function (pro-
longed contraction, reduced SR function) that occur
with aging. Other aspects of cardiac function that
change with aging (prolonged AP, altered myosin iso-
form expression) are not affected by chronic exercise.
SUMMARY
Age-associated changes in cardiovascular structure and
function in healthy individuals have been defined. Arter-
ies increase in diameter and wall thickness with aging
and these changes are associated with an increase in
arterial wall stiffness, a reduction in volume elasticity,
and an increase in systolic arterial pressure. The extent
to which these changes occur with aging appears to be
modified by diet (reduced NaCl intake) and aerobic
capacity. PVR, in contrast, does not markedly increase
with aging in healthy, normotensive individuals. Aging
between 20 and 80 yr is associated with a modest
increase in LV wall thickness, due mainly to an increase
in the size of cardiac myocytes. The resting LVED diam-
eter increases moderately with age in men but not in
women. Increases in heart mass with aging are exagger-
ated by coexisting disease (coronary artery disease or
hypertension) and are substantially influenced by life-
style (physical fitness).
A prolonged myocardial contraction time in older
individuals maintains a normal ejection time in the pres-
ence of the late augmentation of aortic impedance due
to early reflected pulse waves. The prolonged contrac-
tion also contributes to the maintenance of LVSV,
LVESV, and LVEF at rest. Thus in healthy humans, sys-
tolic cardiac function at rest is not much altered by age
even though the arterial tree stiffens and imposes an
increased afterload on the heart. The down side of pro-
longed contractile activation in older individuals is that
myocardial relaxation time is prolonged and at the time
of the mitral valve opening some contractile activation
persists. This is one factor that causes the early LV filling
rate to be reduced in older individuals. Structural
changes and functional heterogeneity within the LV
with aging may also contribute to this reduction in peak
CHAPTER 17: CARDIOVASCULAR SYSTEM 457
LV filling rate. However, concomitant adaptation, left
atrial enlargement, and enhanced atrial contribution to
ventricular filling compensate for the reduced early fill-
ing and in part maintain increased LVEDV in men and
prevent a decrease in LVEDV in women.
In response to orthostatic stress, maintenance of PVR
does not decline with aging but the heart rate increase
is blunted in older vs. younger individuals. The expected
LVEDV reduction is less in older vs. younger individuals
and LVSV is better preserved. Although there is a
decrease in the maximum aerobic work capacity in most
healthy older individuals, it has become clear that this
limitation may not be due to solely to limitations of the
central circulation. Rather, the limitations of exercise
ability in the aged individual are, in part at least, related
to peripheral factors that determine 0 2 utilization, par-
ticularly in women. Peripheral factors that appear to be
involved in the age-associated decline in the V 0 Z r n a x
include a decline in skeletal muscle mass with aging. In
spite of this muscle mass decline, body mass may remain
constant due to an increase in body fat, not only
subcutaneously but also intraperitoneally and intra-
muscularly.
During high levels of physical exertion, heart rate is
substantially lower in healthy elderly vs. younger indi-
viduals. The peak rate of LV filling increases in both
younger and older individuals during exercise but a
diminished rate of filling of similar magnitude (about a
50% reduction), is still observed in older individuals
during exercise, as at rest. However, cardiac dilatation
at end-diastole and end-systole still occurs during vig-
orous exercise in older men. Thus healthy older individ-
uals do not exhibit a compromised LVEDV due to a
“stiff heart,” either at rest or during exercise. During
vigorous exercise the LVSV is not reduced in healthy
older individuals. Maximum CI is moderately decreased
with age in healthy men, on the basis of a reduction in
heart rate. In contrast, in older women, LVSV during
exercise is not maintained as well as it is in older men,
due to a relatively smaller LVEDV during exercise in
older women than in men. The inability of healthy older
individuals of both genders to reduce the LVESV during
vigorous exercise accounts for a smaller increase in
LVEF during exercise compared to younger individuals.
This can result from an age-associated decrease in the
myocardial contractile reserve or the failure of ventric-
ular afterload to sufficiently decrease. In this regard,
while the pulsatile determinants of ventricular afterload
during exercise have not been characterized with respect
to age, PVR is mildly increased in older vs. younger men
during vigorous exercise. The slope of the LVESVhys-
tolic blood pressure relationship, an index of myocar-
dial contractility, is not age-associated at rest but
decreases with age during vigorous exercise. In response
to an increase in arterial pressure at rest elicited by infu-
458 HANDBOOK O F PHYSIOLOGY-AGING
sions of a vasopressor, the older heart dilates and con-
tracts from a greater preload than the younger heart.
This also suggests an apparent age-associated decrease
in the intrinsic myocardial contractile reserve.
It is quite clear that the aerobic capacity of both mid-
dle-aged and older individuals can increase following
endurance exercise training and that this is mediated by
adaptations in peripheral, and in some cases (depending
on the intensity of exercise and the baseline \;Tozmax) in
cardiac, mechanisms. These adaptations also explain, in
part at least, differences in Vozmaxmeasured in cross-
sectional comparisons in younger and older sedentary
individuals and between older endurance-trained indi-
viduals and their sedentary counterparts.
An age-associated reduction in the postsynaptic
response of the cardiovascular system to P-AR stimu-
lation in human and in animal tissues and cells has been
richly documented and appears to be due to multiple
changes in molecular and biochemical receptor coupling
and postreceptor mechanisms, rather than to a major
modification of a single rate-limiting step, as might
occur, for example, in a genetic defect. Cellular and
molecular mechanisms that account for age-associated
changes in myocardial performance can be studied in
animal models. The most remarkable change within the
P-AR system is the decrease in the receptor affinity for
agonists, without substantial changes in P-AR density.
Postreceptor changes with aging include decreases in the
activities of G,-protein, the adenylate cyclase catalytic
unit, and PKA-induced protein phosphorylation and a
diminution in the augmentation of the Ca2+current, Ca,
transient, and contraction amplitudes. The striking sim-
ilarities between the decreased effectiveness of p-adren-
ergic stimulation with age and the phenomenon of
desensitization of P-AR by chronic P-AR agonist expo-
sure at younger age suggest that the age-associated
changes may occur in part via desensitization
mechanisms.
In the normotensive rat, cardiac fibrosis increases, the
number of myocytes decreases, and myocyte size
increases with aging. Variable degrees of LV hypertro-
phy occur, depending upon strain, due to ventricular
dilatation with apparent preservation of a normal ven-
tricular wall thickness. Functional, biophysical/bio-
chemical, pharmacological, and molecular changes have
been noted in the rat heart with aging. There are coor-
dinated changes in several key steps of excitation<on-
traction coupling which result in a prolonged Ca, tran-
sient and a prolonged contraction. The transmembrane
AP is prolonged by about twofold in cardiac muscle iso-
lated from senescent (24-month-old compared to
younger adult, (6-8-month-old) rats. The L-type sar-
colemmal Ca2+ current is not substantially increased in
magnitude but inactivates more slowly and could pos-
sibly account in part for the prolonged transmembrane
AP. However, it is likely that changes in outward cur-
rents substantially contribute to the transmembrane AP
prolongation. The cytosolic Ca2+ transient following
excitation is prolonged in senescent rats. The rate of
Ca2+ sequestration by the SR decreases in senescent rats
and can explain in part the prolonged Ca, transient. A
reduction in the mRNA coding for the SR Ca2+ATPase
suggests that the diminished Ca2+ accumulation rate in
senescent rats could in part be secondary to a decrease
in the SR pump site density. The steady myofilament
force response to CaZ+is not altered by age. However,
marked shifts occur in the MHC, that is, the P or Vj
isozyme becomes predominant in senescent rat (85% P
vs. 15% a).Steady-state messenger RNA levels for a-
and a M H C parallel the age-associated changes in the
MHC proteins VI and Vj, and thus the isozyme shift
appears to be transcriptionally regulated. The myosin
CaZ+ ATPase activity declines with the decline in V1
content. The altered cellular profile, which results in a
contraction that exhibits a reduced velocity and a pro-
longed time course, can be considered adaptive rather
than degenerative in nature because the reduced velocity
is energy-efficient and prolonged contraction permits
continued ejection for a prolonged period. A strikingly
similar pattern of phenotypic and molecular changes
that occur with advancing age in normotensive rats is
induced in young animals within weeks following
chronic pressure loading. The resultant altered Ca2+
homeostasis renders the older (and hypertensive
younger) heart more prone to S-CaOs and Ca2+-depen-
dent arrhythmias. Chronic exercise in older animals
reverses some of the alterations in cardiac function (pro-
longed contraction, reduced SR function) that occur
with aging. Other aspects of cardiac function that
change with aging (prolonged AP, altered myosin iso-
form expression) are not affected by chronic exercise.
REFERENCES
1. AASS, H., T. SKOMEDAL, and J.-B. OSNES.Increase of cyclic
AMP in subcellular fractions of heart muscle after P-adrenergic
stimulation: prenalterol and isoprenaline caused different distri-
bution of bound cyclic AMP. J . Mol. Cell. Curdiol. 20: 847-
860,1988.
2. ARRASS,I. B., and P. J. SCARPACE. Human lymphocyte beta-
adrenergic receptors are unaltered with age. J . Gerontol. 36:
298-301,1981,
3. ARRASS,I. B., and P. J. SCARPACE. Catalytic unit of adenylate
cyclase: reduced activity in aged-human lymphocytes. 1. Clin.
Endocrinol. Metab. 5 5 : 1026-1028, 1982.
4. ABRASS,I. B., J. L. DAVIS,and P. J. SCARPACE. Isoproterenol
responsiveness and myocardial P-adrenergic receptors in young
and old rats. J. Gerontol. 37: 156-160, 1982.
5. ABU-ERREISH, G. M., J. R. NEELY,J. T. WHITMER,V. WHIT-
MAN,and D. R. SANADI.Fatty acid oxidation by isolated per-
fused working hearts of aged rats. Am. ]. Physiol. 232 (Endo-
crinol. Metab. Gastrointest. Physiol. 1): E258-E252, 1977.
6. ADEISTEIN, R. S., and E. EISENBERG. Regulation and kinetics of

the actin-myosin-ATP interaction. Annu. Rev. Biochem. 49:
921-956,1980.
7. AFFLITTO,J. J., and M . A. INCHIOSA, JR. Decrease in rat cardiac 25. AVOLIO,A. P., S. G. CHEN,R. P. WANG,C. L. ZHANG,
myosin ATPase with aortic constriction: prevention by thyrox-
ine treatment. Life Sci. 25: 353-364, 1979.
8. ALPERT,N. R., and L. A. MULIERI. Increased myothermal econ-
omy of isometric force generation in compensated cardiac
hypertrophy induced by pulmonary artery constriction in the
rabbit. A characterization of heat liberation in normal and
hypertrophied right ventricular papillary muscles. Circ. Res. 50:
491-500,1982.
9. ALPERT,N. R., E. M. BLANCHARD, and L. A. MULIERI.The
quantity and rate of Ca2+ uptake in normal and hypertrophied
hearts. In: Pathophysiology of Heart Disease, edited by N.
Dhalla, P. Singel, and R. E. Beamish. New York: Raven, 1983.
10. ALPERT,N. R., H. H. GALE,and N. TAYLOR. The effect of age 28. AYOBE,H. M., and R. C. TARAZI.
on contractile protein ATPase activity and the velocity of short-
ening. In: Factors Influencing Myocardial Contractility, edited
by R. D. Tanz, F. Kavaler, and J. Roberts. New York: Academic,
1967, p. 127-133.
11. ALPERT,N. R., L. A. MULIERI, and R. 2. L[TTEN.Functional
significance of altered myosin adenosine triphosphatase activity
in enlarged hearts. Am.]. Cardiol. 44: 946-953, 1979.
12. ALTURA,B. M., and B. T. ALTURA.Some physiological factors
in vascular reactivity. I. Aging in vascular smooth muscle and
its influence o n reactivity. In: Factors Influencing Vascular Reac-
tivity, edited by 0. Carrier, Jr., and S. Shibata. Tokyo: Igaku-
Shoin, 1977, p. 169-188.
13. AMERY,A., H. BOSSAERT,and M . VERSTRAETE. Muscle blood
flow in normal and hypertensive subjects. Influence of age, exer-
cise, and body position. Am. Heart]. 78: 211-216, 1969.
14. ANDERSEN,K. L., and L. HERMANSEN. Aerobic work capacity
in middle-aged Norwegian men. J. Appl. Physiol. 20: 432-436,
1965.
15. ANVERSA,P., B. HILER,R. RICCI,G. GUIDER], and G. OLIVETTI. 34. BENOVIC,J. L., M. BOUVIER,M. G. CARON,and R. J. LEFKOW-
Myocyte cell loss and myocyte hypertrophy in the aging rat
heart.]. Am. Coll. Cardiol. 8: 1441-1448, 1986.
16. ANVERSA,P., T. PALACKAL, E. H. SONNENBLICK, G. OLIVETTI, 35. BHAN, A. K., and J. SCHEUER.Effects of physical training on
L. G. MEGGS,and J. M. CAPASSO. Myocyte cell loss and myocyte
cellular hyperplasia in the hypertrophied aging rat heart. Circ.
Res. 67: 871-885, 1990.
17. ANVERSA,P., E. PUNTILLO, P. NIKITIN,G. OLIVETTI, J. M.
CAPASSO,and E. H. SONNENBLICK. Effects of age on mechanical
and structural properties of myocardium of Fischer 344 rats.
Am. 1.Physiol. 256 (Heart Circ. Physiol. 25): H1440-H1449,
1989.
18. ARMSTRONG,P. W., T. P. STOPPS,S. E. FORD, and A. J. DE
BOLD. Rapid ventricular pacing in the dog: pathophysiologic
studies of heart failure. Circulation 74: 1075-1084, 1986.
19. ARONSON,R. S. Afterpotentials and triggered activity in hyper-
trophied myocardium from rats with renal hypertension. Circ.
Res. 48: 720-727, 1981.
20. ARORA,R. R., J. MACHAC,M. E. GOLDMAN,R. N. BUTLER,R.
GORLIN, and S. F. HOROWITZ.Atrial kinetics and left ventric-
ular diastolic filling in the healthy elderly. I. Am. Coll. Cardiol.
9: 1255-1260,1987.
21. ASCHOFF,L. Lectures in Pathology. New York: Paul Hoeber,
1924, p. 131.
22. ASMUSSEN, E. K. FRUENSGAARD, and S. NORGAARD.A follow-
up longitudinal study of selected physiologic functions in former
physical education students after forty years. J. Am. Geriatr.
SOC. 23: 4421150,1975.
23. ASTRAND,I. Aerobic work capacity in men and women with
special reference to age. Acta Physiol. Scand. Suppl. 169: 1-92,
1960.
24. ASTRAND,I., P. 0. ASTRAND,I. HALLBACK, and A. KILBOM.
CHAPTER 17: CARDIOVASCULAR SYSTEM 459
Reduction in maximal oxygen uptake with age.]. Appl. Physiol.
35: 649-654,1973.
M. F.
LI, and M. F. O’ROURKE.Effects of aging o n changing arterial
compliance and left ventricular load in a northern Chinese urban
community. Circulation 68: 50-58, 1983.
26. AVOLIO,A. P., K. M. CLYDE,T. C. BEARD,H. M . COOKE,K.
K. Ho, and M. F. O’ROURKE. Improved arterial distensibility in
normotensive subjects on a low salt diet. Arteriosclerosis 6: 166-
169,1986.
27. AVOLIO,A. P., F. Q. DENG,W. Q. LI, Y. F. LUO, Z. D. HUANG,
L. F. XING, and M. F. O’ROURKE.Effects of aging o n arterial
distensibility in populations with high and low prevalence of
hypertension: comparison between urban and rural communi-
ties in China. Circulation 71: 202-210, 1985.
Reversal of changes in myo-
cardial P-receptors and inotropic responsiveness with regression
of cardiac hypertrophy in renal hypertensive rats (RHR.). Circ.
Res. 54: 125-134,1984.
29. BADER,H. Dependence of wall stress in the human thoracic
aorta o n age and pressure. Circ. Res. 20: 354-361, 1967.
30. BAUTERS,C., J. M. MOALIC, J. BERCOWCI,C. MOUAS,R. EMA-
NOIL-RAWER, S. SCHIAFFINO, and B. SWYNGHEDAUW. Coronary
flow as a determinant of c-myc and c-fos proto-oncogene expres-
sion in an isolated adult rat heart.]. Mol. Cell. Cardiol. 20: 97-
101,1988.
31. BECKLAKE, M. R., H. FRANK,G. R. DAGENAIS, G. L. OSTIGUY,
and C. A. GUZMAN.Influence of age and sex o n exercise cardiac
output.]. Appl. Physiol. 20: 938-947, 1965.
32. BEER,M., S. HACKER, J. POAT,and S. M. STAHL.Independent
regulation of PI and P2-adrenoceptors. Br. I. Pharmacol. 92:
827-834,1987.
33. BENESTAD,A. M. Trainability of old men. Acta Med. Scand.
178: 321-327,1965.
ITZ. Regulation of adenylyl cyclase-coupled P-adrenergic recep-
tors. Annu. Rev. Cell Biol. 4: 405428, 1988.
cardiac myosin ATPase activity. Am. I. Physiol. 228: 1178-
1182,1975.
36. BHATNAGAR, G. M., M. B. EFFRON,G. RUANO-ARROYO, H. A.
SPURGEON,and E. G. LAKATTA.Dissociation of myosin CaZ+-
ATPase activity from myosin isoenzymes and conctractile func-
tion in rat myocardium [Abstract]. Fed. Proc. 44: 826, 1985.
37. BHATNAGAR, G. M., G . D. WALFORD,E. S. BEARD,S. HUM-
P H R E Y ~ and
, E. G. LAKATTA.ATPase activity and force produc-
tion in myofibrils and twitch characteristics in intact muscle
from neonatal, adult, and senescent rat myocardium. J. Mol.
Coll. Cardiol. 16: 203-218, 1984.
38. BING, 0. H. L., W. W. BROOKS,C. H. CONRAD,S. SEN, C. L.
PERREAULT, and J. P. MORGAN.Intracellular calcium transient
in myocardium from spontaneously hypertensive rats during the
transition to heart failure. Circ. Res. 68: 1390-1400, 1991.
39. BINKHORST, R. A., J. POOL,P. VAN LEEUWEN, and A. BOUHUYS.
Maximum 0 2 uptake in healthy nonathletic males. rat. Z.
Angew. Physiol. Einschl. Arbeitsphysiol. 22: 10-18, 1966.
40. BOLUYT,M. O., L. O’NEILL,E. G. LAKATTA,and M. T. CROW.
Progressive elevation of atrial natriuretic factor mRNAs in rat
heart with advancing age [Abstract]. I. Mol. Cell. Cardiol.
24(Suppl. 111): S.35, 1992.
41. BOLUYT,M . O., A. YOUNES,J. L. CAFFREY,L. O’NEILI.,B. A.
BARRON,M. T. CROW, and E. G. LAKATTA.Age-associated
increase in rat cardiac opioid production. Am. 1.Physiol. 265:
H212-H218,1993.
42. BOLUYT,M. O., J. A. OPITECK, K. A. ESSER,and T. P. WHITE.
Cardiac adaptations to aortic-constriction in adult and aged
460 HANDBOOK O F PHYSIOLOGY-AGING

rats. Am.J. Physiol. 257 (Heart Circ. Physiol. 26): H643-H648, 61. CAPASSO, J. M., A. MALHOTRA, J. SCHEUER,and E. H. SON-
1989. NENBIKK. Myocardial biochemical, contractile and electrical
43. BONOW,R. O., D. F. VITALE,S. L. BACHARACH, B. J. MARON, performance after imposition of hypertension in young and old
and M. V. GREEN.Effects of aging o n asynchronous left ven- rats. Circ. Res. 58: 445-460, 1986.
tricular regional function and global ventricular filling in normal 62. CAPASSO,J. M., E. PUNTILLO,G. OLIVETTI, and P. ANVERSA.
human subjets.]. Am. Coll. Cardiol. 11: 50-58, 1988. Differences in load dependence of relaxation between the left
44. BORKAN,G. A., D. E. HULTS,S. G. GERZOF,A. H. ROBBINS, and right ventricular myocardium as a function of age in rats.
and C. K. SILBERT.Age changes in body composition revealed Circ. Res. 65: 1499-1507,1989.
by computed tomography. J. Gerontol. 38: 673-677, 1983. 63. CARRIER, L., K. R. BOHELER,c. CHASSAGNE, D. DE LA BASTIE,
45. BOUTHIER, J. D., N . DE LUCA,M . E. SAFAR,and A. C. SIMON. C. WISNEWSKY, E. G. LAKATTA,and K. SCHWARTZ.Expression
Cardiac hypertrophy and arterial distensibility in essential of the sarcomeric actin isogenes in the rat heart with develop-
hypertension. Am. Heart 1. 109: 1345-1352, 1985. ment and senescence. Circ. Res. 70: 999-1005, 1992.
46. BRAMWELL, J. C., and A. V. HILL.The velocity of the pulse wave 64. CARROLL, J. D., S. SHROFF,P. WIRTH,M . HALSTED, and S. I.
in man. Proc. R. SOC.Lond. B Biol. Sci. 93: 298-306, 1922. RAJFER.Arterial mechanical properties in dilated cardiomyop-
47. BRANDFONBRENER, M., M. LANDOWNE,and N. W. SHOCK. athy. Aging and the response to nitroprusside. J . Clrn. lnuest.
Changes in cardiac output with age. Circulation 12: 557-566, 87: 1002-1009,1991,
1955. 65. CARTER,S. A. In vivo estimation of elastic characteristics of the
48. BRISTOW,M. R., R. E. HERSHBERGER, J. D. PORT, w. MINOBE, arteries in the lower extremities of man. Can. J. Physiol. Phar-
and R. RASMUSSEN. Beta I - and beta 2-adrenergic receptor- macol. 42: 309-413, 1964.
mediated adenylate cyclase stimulation in nonfailing and failing 66. CARTER,W. J., W. F. KELLY, F. H. FAAS, M. E. LYNCH,and C.
human ventricular myocardium. Mol. Pharmacol. 35: 295-303, A. PERRY.Effect of graded doses of tri-iodothyronine on ven-
1989. tricular myosin ATPase activity and isomyosin profile in young
49. BRODDE,0.-E., A. DAUL, A. WELLSTEIN,D. PALM, M. C. and old rats. Biochem. J. 247: 329-334, 1987.
MICHEL,and J. J. BECKERINGH. Differentiation in PI- and P Z - 67. CHARLEMAGNE, D., J.-M. MAIXENT,M. PRETESEILLE, and L. G.
adrenoceptor-mediated effects in humans. Am. J. Physiol. 254 LELIEVRE. Ouabain binding sites and (Na+,K+)-ATPaseactivity
(Heart Circ. Physiol. 23): H199-H206, 1988. in rat cardiac hypertrophy. Expression of the neonatal forms. J.
SO. BRODDE,0.-E., H-R. ZERKOWSKI, N. DOETSCH,S. MOTO- Biol. Chem. 261: 185-189, 1986.
MURA, M. KHAMSSI,and M. C. MICHEL. Myocardial beta- 6 8 . CHEN,J. C., J. B. WWARSHAW, and D. R. SANADI.Regulation
adrenoceptor changes in heart failure: concomitant reduction in of mitochondria1 respiration in senescence. J . Cell. Physiol. 80:
beta 1- and 2-adrenoceptor function related to the degree of 141-148,1972.
heart failure in patients with mitral valve disease. I . Am. Coll. 69. CHESKY,J. A., and M. ROCKSTEIN. Reduced myocardial acto-
Cardiol. 14: 323-331, 1989. myosin adenosine triphosphatase activity in the ageing male
51. BROWN,A. M. Regulation of heartbeat by G protein-coupled Fischer rat. Cardiovasc. Res. 11: 242-246, 1977.
ion channels. Am. J. Physiol. 259 (Heart Circ. Physiol. 28): 70. CHESKY,J. A., S. LAFOLLETTE,M. TRAVIS, and C. FORTADO.
H1621-H1628,1990. Effects of physical training on myocardial enzyme activities in
52. BRUCE,R. A., and T. R. HORNSTEN.Exercise stress testing in aging rats. J. Appl. Physiol. 55: 1349-1353, 1983.
evaluation of patients with ischemic heart disease. Prog. Car- 71. CHEVALIER, B., P. MANSIER,F. CALLENS-EL AMRANI,and B.
diouasc. Dis.11: 371-390, 1969. SWYNGHEDAUW. p-Adrenergic system is modified in compen-
53. BUSBY,D. E., and A. C. BURTON.The effect of age on the elas- satory pressure cardiac overload in rats: physiological and
ticity of the major brain arteries. Can. 1. PhysEoI. Pharmacol. biochemical evidence. J. Cardiol. Pharmacol. 13: 412-420,
43: 185-202,1965. 1989.
54. BUSBY,M., E. A. SHEFRIN,and J. L. FLEG.Prevalence and long- 72. CHEVALIER, B., P. MANSIER, E. TEIGER, F. CALLENS-EL AMRANI,
term significance of exercise-induced frequent or repetitive ven- and B. SWYNGHEDAUW. Alterations in p adrenergic and mus-
tricular ectopic beats in apparently healthy volunteers. J . Am. carinic receptors in aged rat heart. Effects of chronic adminis-
Coll. Cardiol. 14: 1659-1665, 1989. tration of propranolol and atropine. Mech. Ageing Dev. 60:
55. BUTTRICK, P., A. MALHOTRA, S. FACTOR,D. GREENEN, L. LEIN- 215-224,1991.
WAND, and J. SCHEUER.Effect of aging and hypertension o n 73. CHIEN,K. R., K. U. KNOWLTON,H. ZHU,and S. CHIEN.Reg-
myosin biochemistry and gene expression in the rat heart. Circ. ulation of cardiac gene expression during myocardial growth
Res. 68: 645-652, 1991. and hypertrophy: molecular studies of an adaptative physiologic
56. BUXTON,I. L. O., and L. L. RRUNTON.Action of the cardiac a,- response. FASEB J . 5: 3037-3046, 1991.
adrenergic receptor. Activation of cyclic AMP degradation. J . 74. CHIN,J. H., and B. B. HOFFMAN.Age-related deficit in beta
Biol. Chem. 260: 6733-6737,1985. receptor stimulation of CAMP binding in blood vessels. Mech.
57. BUXTON,I. L. O., and L. L. BRUNTON.Compartments of cyclic Ageing Deu. 53: 111-125,1990.
AMP and protein kinase in mammalian cardiomyoctes. J . Biol. 75. CHOU,H.-T., Y. YOKOTA,and H. FUKUZAKI. Left ventricular
Chem. 258: 10233-10239,1983. reserve of the hypertrophied heart in patients with systemic
58. CALDERONF., A., M. BOUVIE.R, K. Lr, C. JIJNEAU, J. DE CHAM- hypertension and hypertrophic cardiomyopathy-relation to
PLAIN,and J. L. ROUI.EAU. Dysfunction of the beta- and alpha- age and left ventricular relative wall thickness. l a p . Circ. J. 54:
adrenergic systems in a model of congestive heart failure. The 373-382, 1990.
pacing-overdrive dog. Circ. Res. 69: 332-343, 1991. 76. CLAUSEN,J. P. Effects of physical conditioning. A hypothesis
59. CAMPBELL, M. J., A. J. MCCOMAS,and F. PETITO.Physiological concerning circulatory adjustment to exercise. Scand. J. Clin.
changes in ageing muscles. I . Neurol. Neurosurg. Psychiatry 36: Lab. Invest. 24: 305-313, 1969.
174-182,1973. 77. CI.F.ROUX, J., c. GIANNATTASIO, G. BOLLA,c. CUSPIDI, G.
60. CAPASSO, J. M., A. MAIHOTRA, R. M. REMILY, J. SCHEUER, and GRASSI,C. MAZZOLA,L. SAMPIERI, G. SERAVALLE, M . VALSEC-
E. H. SONNENBLICK. Effects of age o n mechanical and electrical CHI, and G. MANCIA. Decreased cardiopulmonary reflexes with
performance of rat myocardium. Am. J . Physiol. 245 (Heart aging in normotensive humans. Am. J. Physiol. 257 (Heart Circ.
Circ. Physiol. 14): H72-H81, 1983. Physiol. 26): H961-H968, 1989.
 CHAPTER 17: CARDIOVASCULARSYSTEM 46 1
78. CLIFF,W. J. The aortic tunica media in aging rats. Exp. Mol. 97. DEISHER, T. A., S. MANKANI, and B. B. HOFFMAN. Role of cyclic
Pathol. 13: 172-189, 1970. AMP-dependent protein kinase in the diminished beta adrener-
79. COGGAN,A., R. J. SPINA,D. S. KING, M. A. ROGERS,M. gic responsiveness of vascular smooth muscle with increasing
BROWN, and P. M. NEMETH.Skeletal muscle adaptations to age. J. Pharmacol. Exp. Ther. 249: 812419,1989.
endurance training in 60 to 70-yr old men and women. J. Appl. 98. DE LA BASTIE,D., D. LEVITSKY, L. RAPPAPORT, J. J. MERCADIER,
Physiol. 72: 1780-1786,1992. F. MARO-I-I’E, C. WISNEWSKY, V. BROVKOVICH,K. SCHWARTZ,
80. COGGAN,A. R., R. J. SPINA,M. A. ROGERS,D. S. KING,M. and A. M. LOMPRE.Function of the sarcoplasmic reticulum and
BROWN, P. M. NEMETH,and J. 0. HOLLOSZY. Histochemical expression of its Ca2+ATPase gene in pressure overload-induced
and enzymatic characteristics of skeletal muscle in master ath- cardiac hypertophy in the rat. Circ. Res. 66: 554-564, 1990.
letes. J. Appl. Physiol. 68: 1896-1901,1990. 99. DELCAYRE, C., J. L. SAMUEL, F. MAROTIT,M. BEST-BELPOMME,
81. CONWAY, J., R. WHEELER, and R. SANNERSTEDT. Sympathetic J. J. MERCADIER, and L. RAPPAPORT. Synthesis of stress proteins
nervous activity during exercise in relation to age. Cardiovasc. in rat cardiac myocytes 2-4 days after imposition of hemody-
Res. 5 : 577-581,1971. namic overload. J. Clin. Invest. 82: 460-468, 1988.
82. COOPER,G., IV., W. E. MERCER, J. K. HOOBER,P. R. GORDON, 100. DEVEREUX, R. B., T. G. PICKERING, M. H. ALDERMAN, S.
R. L. KENT,I. K. LAWA,and T. A. MARINO.Load regulation CHIEN,J. S. BORER,and J. H. LARAGH.Left ventricular hyper-
of the properties of adult feline cardiocytes. Role of substrate trophy in hypertension. Prevalence and relationship to patho-
adhesion. Circ. Res. 58: 692-705, 1986. physiologic variables. Hypertension 9: 11-53-11-60, 1987.
83. COOPER,T. G. Surgical sympathectomy and adrenergic func- 101. DEVRIES,H. A. Physiological effects of an exercise training reg-
tion. Pharmacol. Rev. 18: 611-618,1966. imen upon men aged 52 to 88.1. Gerontol. 25: 325-336,1970.
84. CORBIN,J. D., P. H. SUGDEN, T. M. LINCOLN,and S. L. KEELY. 102. DILL,D. B., S. ROBINSON, and J. C. ROSS.A longitudinal study
Compartmentalization of adenosine 3’5’-monophosphate and of 16 champion runners. J. Sports Med. Phys. Fitness 7: 4-27,
adenosine 3’:5’-monophosphate-dependentprotein kinase in 1967.
heart tissues. J. Biol. Chem. 253: 3854-3861, 1977. 103. DILLMANN, W. Influence of thyroid hormone administration on
85. COURNAND, A., R. L. RILEY,E. S. BREED, and E. BALDWIN. myosin ATPase activity and myosin isoenzyme distribution in
Measurement of cardiac output in man using the technique of the heart of diabetic rats. Metabolism 31: 199-204, 1981.
catheterization of the right auricle or ventricle. J. Clin. Invest. 104. DILLON,N., S. CHUNG,J. KELLY,and K. O’MALLEY. Age and
24: 106-116,1945. beta adrenoceptor-mediated function. Clin. Pharmacol. Ther.
86. CRAELIUS, W., V. CHEN,and N. EL-SHERIF. Stretch activated ion 27: 769-772,1980.
channels in ventricular myocytes. Biosci. Rep. 8: 407-414, 105. DOBSON,J. G., JR. Mechanism of adenosine inhibition of cate-
1988. cholamine-induced responses in heart. Circ. Res. 52: 151-160,
87. CRAWFORD, M. H., M. A. PETRU,and C. RABINOWITZ. Effect 1983.
of isotonic exercise training on left ventricular volume during 106. DOBSON,J. G., JR., R. A. FENTON,and F. D. ROMANO.
upright exercise. Circulation 72: 1237-1243, 1985. Increased myocardial adenosine production and reduction of p-
88. CURTIS,B. M., and W. A. CATTERALL. Phosphorylation of the adrenergic contractile response in aged hearts. Circ. Res. 66:
calcium antagonist receptor of the voltage-sensitive calcium 1381-1390,1990.
channel by CAMP-dependent protein kinase. Proc. Natl. Acad. 107. DOCHERTY, J. R., and L. HYLAND.Aging and a-adrenoceptor
Sci. U.S.A. 82: 2528-2532,1985. function. Trends Pharmacol. Sci. 7: 131-132, 1986.
89. DANNENBERG, A. L., D. LEVY,and R. J. GARRISON. Impact of 108. DOCHERTY, J. R., and L. HYLAND. Evidence for neuro-effector
age on echocardiographic left ventricular mass in a healthy pop- transmission through postjunctional az-adrenoceptors in human
ulation (the Framingham Study). Am. J. Cardiol. 64: 1066- saphenous vein. Br. J. Pharmacol. 84: 573-576, 1985.
1068,1989. 109. DOCHERTY, J. R., A. MACDONALD, and J. C. MCGRATH.Fur-
90. DANZIGER, R. S., M. SAKAI, E. G . LAKATTA, and R. G. HANS- ther subclassification of a-adrenoceptors in the cardiovascular
FORD. Interactive a-and P-adrenergic actions of norepinephrine system, vas deferens and anococcygeus of the rat. Br. J. Phar-
in rat cardiac myocytes. J. Mol. Cell. Cardiol. 22: 111-123, macol. 67: 421422,1979.
1990. 110. DONTAS,A. S., H. C. TAYLOR, and A. KEYS.Carotid pressure
91. DANZIGER, R. S., J. D. TOBIN,L. C. BECKER,E. G. LAKATTA, plethysmograms: effects of age, diastolic pressure, relative body
and J. L. FLEG.The age-associated decline in glomerular filtra- weight, and physical activity. Archiv. Kreislaufforsch. 36: 49-
tion in healthy normotensive volunteers: lack of relationship to 5 8 , 1961.
cardiovascular performance. J. Am. Geriatr. SOC. 38: 1127- 111. DOYLE,V., K. O’MALLEY, and J. G. KELLY.Human lymphocyte
1132,1990. beta-adrenoceptor density in relation to age and hypertension.
92. DAVIES,C. T. M. Limitations to the prediction of maximum 0 2 J. Cardiovasc. Pharmacol. 4: 738-740, 1982.
intake from cardiac frequency measurements. J. Appl. Physiol. 112. DUBELL,W. H., M. R. BOYETT, H. A. SPURGEON, A. TALO,M.
24: 700-706,1968. D. STERN,and E. G. LAKATTA. The cytosolic calcium transient
93. DAVIES,H. E. F. Respiratory change in heart rate, sinus arrhyth- modulates the action potential of rat ventricular myocytes. J.
mia in the elderly. Gerontol. Clin. 17: 96-100, 1975. Physiol. 436: 347-369, 1991.
94. DAY,M. L., D. SCHWARTZ, R. C. WIEGAND, P. T. STOCKMAN, 113. DUCKLES, S. P. Age-related changes in adrenergic neuronal func-
S. R. BRUNNERT, H. E. TOLUNAY, M. G. CURRIE,D. G. STAN- tion of rabbit vascular smooth muscle. Neurobiol. Aging4: 151-
DAERT, and P. NEEDLEMAN. Ventricular atriopeptin. Unmasking 156,1983.
of messenger RNA and peptide synthesis by hypertrophy or 114. DUCKLES, S. P., B. J. CARTER,and C. L. WILLIAMS. Vascular
dexamethasone. Hypertension 9: 485491,1987. adrenergic neuroeffector function does not decline in aged rats.
95. de GARAVILLA, L., H. L. VALENTINE, J. S. SCHENDEN, W. J. Circ. Res. 56: 109-116, 1985.
KINNIER,and R. C. HANSON. Age-related cardiovascular effects 115. EBERT,T. J., C. V. HUGHES, F. E. TRISTANI, J. A. BARNEY,and
of adenosine in guinea pigs. Drug Dev. Res. 28: 496-502,1993. J. J. SMITH.Effect of age and coronary heart disease on the
96. DEHN,M. M., and R. A. BRUCE.Longitudinalvariations in max- circulatory responses to graded lower body negative pressure.
imal oxygen intake with age and activity. J . Appl. Physiol. 33: Cardiovasc. Res. 16: 663-669, 1982.
805407,1972. 116. EBERT,T. J., B. J. MORGAN, J. A. BARNEY,T. DENAHAN, and
462 HANDBOOK O F PHYSIOLOGY-AGING

J. J. SMITH.Effects of aging on baroreflex regulation of sym- 135. FEIN,F. S., L. B. KORNSTEIN, J. E. STROBECK, J. M. CAPASSO,
pathetic activity in humans. Am. /. Physiol. 263 (Heart Circ. and E. H. SONNENBIKK. Altered myocardial mechanics in dia-
Physiol. 32): H798-H803, 1992. betic rats. Circ. Res. 47: 922-933, 1980.
117. EBRECHT,G., H. RUPP,and R. JACOB.Alterations of mechanical 136. FELDMAN, R. D., L. E. LIMBIRD, J. NADEAU,D. ROBERTSON,
parameters in chemically skinned preparations of rat myocar- and A. J. WOOD. Alterations in leukocyte beta-receptor affinity
dium as a function of isoenzyme pattern of myosin. Basrc Res. with aging. A potential explanation for altered beta-adrenergic
Cardiol. 77: 220-234, 1982. sensitivity in the elderly. N. E n g l . ] . Med. 310: 815-819, 1984.
118. EFFRON,M. B., G. M. BHATNAGAR,H. A. SPURGEON,G. 137. FENTON,R. A., and J. G. DOBSON,JR. Adenosine and calcium
RUANO-ARROYO, and E. G. LAKATTA.Changes in myosin iso- alter adrenergic-induced intact heart protein phosphorylation.
enzymes, ATPase activity, and contraction duration in rat car- Am.]. Physiol. 246 (Heart Circ. Physiol. 15):H559-H565,1984.
diac muscle with aging can be modulated by thyroxine. Circ. 138. FILBURN, C. R., and E. G. LAKATTA.Aging alterations in beta-
Res. 60: 238-245, 1987. adrenergic modulation of cardiac cell function. In: Aging and
119. EGHBALI, M., M. EGHBALI, T. F. ROBINSON, S. SEIFTER,and 0 . Cell Function, edited by J. E. Johnson, Jr. New York: Plenum,
0. BLUMENFELD. Collagen accumulation in heart ventricles as a 1984, p. 211-246.
function of growth and aging. Caudiovasc. Res. 23: 723-729, 139. FISCHEK, A., J. PARIZKOVA, and 2. ROTH. The effect of system-
1989. atic physical activity on maximal performance and functional
120. EHSANI,A. A. Cardiovascular adaptations to exercise training capacity in senescent men. Int. Z. Angew. Physiol. Einschl.
in the elderly. Fed. Proc. 46: 1840-1843, 1987. ArbeitsphysioL 21: 269-304, 1965.
121. EHSANI,A. A., T. OGAWA, T. R. MII.I.ER,R. J. SPINA,and S. M. 140. FITCHE-I-I,D. H., G. J. SIMKUS, J. P. BEAUDRY, and D. G. F.
JILKA.Exercise training improves left ventricular systolic func- MARPOLE.Reflected pressure waves in the ascending aorta:
tion in older men. Circulation 83: 96-103, 1991. effect of glyceryl trinitrate. Cardiovasc. Res. 22: 494-500,1988.
122. EICHLER, H. G., A. HIREMATH,T. F. BI.AsCHKE,and B. B. HOFF- 141. FLEG,J. I.. Arrhythmias and conduction disorders. In: The Merck
MAN. Absence of age-related changes in venous responsiveness Manual of Geriatrics, edited by W. B. Abrams and R. Berkow.
to nitroglycerin in vivo in humans. Clin. Pharmacol. Ther. 42: Rahway, NJ: Merck Sharp & Dohme, 1990, p. 370-380.
521-524,1987. 142. FLEG,J. L., and H. L. KENNEDY. Cardiac arrhythmias in healthy
123. ELZINGA, G., and N. WESTERHOF. Pressure and flow generated elderly population: detection by 24-hour ambulatory electrocar-
by the left ventricle against different impedances. Circ. Res. 32: diography. Chest 81: 302-307, 1982.
178-186,1973. 143. FI.EG,J. L., and E. G. LAKATTA.Role of muscle loss in the age-
124. ENGELMANN, G. L., J. C. VITULLO,and R. G. GEKRITY. Mor- associated reduction in VOz,.lx. ]. Appl. Physiol. 65: 1147-
phometric analysis of cardiac hypertrophy during development, 1151,1988.
maturation, and senescence in spontaneously hypertensive rats. 144. FLEG,J. L., D. N. DAS,J. WRIGHT, and E. G. LAKATTA. Age-
Circ. Res. 60: 487494, 1987. associated changes in the components of atrioventricular con-
125. ENSOR,R. E., J. L. FLEG,Y. C. KIM,E. F. DE LEON,and S. M. duction in apparently healthy volunteers. ]. Gerontol. Med. Sci.
GOLDMA&’. Longitudinal chest x-ray changes in normal men. J . 45: M9S-M100,1990.
Gerontol. 38: 307-314, 1983. 145. FI.EG,J. L., G. GEKSTENBLITH, and E. G. LAKATTA.Pathophys-
126. ERICSSON, E., and L. LUNDHOI-M. Adrenergic P-receptor activity iology of the aging heart and circulation. In: Cardiovascular Dis-
and cyclic AMP metabolism in vascular smooth muscle; varia- ease in the Elderly (2nd ed.), edited by F. H. Messerli. Boston:
tions with age. Mech. Ageing Dev. 4: 1-6, 1975. Martinus Nijhoff, 1988, p. 9-35.
127. ESCANDE,D., D. LOISANCE, C. PLANCHE, and E. CORABOEUF. 146. FLEG,J., S. P. SCHULMAN, G. GERSTENBLITH, L. C. B ~ C K E RF.,
Age-related changes of action potential plateau shape in isolated C. O’CONNOR,and E. G. LAKATTA. Additive effects of age and
human atrial fibers. Am. I. Physiol. 249 (Heart Circ. Physiol. silent myocardial ischemia on the left ventricular response to
18): H843-H850, 1985. upright cycle exercise. J . Appl. Physiol. 75: 499-504, 1993.
128. ESLER,M., H. SKEWS,P. LEOKARD,G. JACKMAN, A. BOBOK, 147. FI.EG,J. L., G. GERSTENBLITH, S. P. SCHULMAN, L. C. BECKER,
and P. KORNER.Age-dependence of noradrenaline kinetics in F. C. O’CONNOR,and E. G. LAKATTA.Gender differences in
normal subjects. Clin. Sci. 60: 217-219, 1981. exercise hemodynaniics of older subjects: effects of conditioning
129. FABER,M., and G. MOLLER-HOLI. The human aorta. V. Colla- status [Abstract]. Circulation 82: 111.239, 1990b.
gen and elastin in the normal and hypertensive aorta. Acta 148. FI.EG, J. L., G. GERSTENBLITH, A. B. ZONDERMAN, L. C.
Pathol. Microhiol. Scand. 31: 377-382, 1952. BECKER,M. L. WEISFELDT, P. T. COSTA,JR., and E. G. LAKATTA.
130. FAGARD, R., and J. STAESSEN. Relation of cardiac output at rest Prevalence and prognostic significance of exercise-induced silent
and during exercise to age in essential hypertension. Am. J . Car- myocardial ischemia detected by thallium scintigraphy and elec-
d i d . 67: 585-589, 1991. trocardiography in asymptomatic volunteers. Circulation 8 1:
131. FAN, T. H., C. S. LIANG,S. KAWASHIMA, and S. P. BANERJEE. 423436, 1990c.
Alterations in cardiac beta-adrenoceptor responsiveness and 149. FI.EG,J. L., S. P. SCHULMAN, F. C. O’CONNOR, G. GERSTEN-
adenylate cyclase system by congestive heart failure in dogs. Eur. BLITH,L. C. BECKER,S. FORTNEY,A. P. GOLDBERG, and E. G.
I . Pharmacol. 140: 123-132, 1987. LAKATTA.Cardiovascular response to exhaustive upright cycle
132. FARRAR, R. P., J. W. STARNES, G. D. CARTEE,P. Y. OH,and H. exercise in highly trained older men.]. Appl. Physiol. 77: 1500-
L. SWEENEY. Effects of exercise on cardiac myosin isozyme com- 1506,1994.
position during the aging process.]. Appl. Physiol. 64: 880-883, 150. FLEG,J. L., S. SCHULMAN, F. O’CONNOR,G. Gerstenblith, J. F.
1988. CLULOW,D. G. RFNLUND,and E. G. LAKATTA.Effect of pro-
133. FEATHERSTONE, J. A., R. c. Vt,ITH, D. FLATNESS, M. M. MUR- pranolol on age-associated changes in left ventricular perfor-
BURG,E. C. VII.I.ACRES, and J. 8. HALTER.Age and alpha-2 mance during exercise [Abstract]. Circulation 84: 11-187, 1991.
adrenergic regulation of plasma norepinephrine kinetics in 151. FLEG,J. L., E. SHAPIRO, F. O’CONNOR’,L. LAKATTA, and E. L.
humans.]. Gerontol. 42: 271-276, 1987. LAKATTA. Failure of intensive aerobic conditioning to alter the
134. FEATHERSTONE, J. A., R. C. VF.lTH, and J. B. HAI.TF.R.Effect of age-associated decline in diastolic left ventricular performance
age and alpha-2 adrenergic stimulation on plasma norepineph- [Abstract]. Circulation 8 (suppl. I): 1-377, 1992.
rine kinetics in man [Abstract]. Clin. Res. 32: 69A, 1984. 152. FI.EG,J. L., S. P. TZANKOFF, and E. G. LAKATTA.Age-related
 CHAPTER 17: CARDIOVASCULAR SYSTEM 463
augmentation of plasma catecholamines during dynamic exer- 170. GARDIN, J. M., W. L. HENRY,D. D. SAVAGE, J. H. WARE,C.
cise in healthy males.]. Appl. Physiol. 59: 1033-1039, 1985. BURN,and J. S. BORER.Echocardiographic measurements in
153. FLEISCH, J. H. Age-related decrease in beta adrenoreceptor activ- normal subjects: evaluation of an adult population without clin-
ity of the cardiovascular system. Trends Pharmacol. Sci. 2: 337- ically apparent heart disease. J . Clin. Ultrasound 7: 439447,
339,1981. 1979.
154. FLEISCH, J. H., and C. S. HOOKER. The relationship between age 171. GENDE,0. A., A. MATTIAZZI,M. C. CAMILLION, P. PEDRONI,
and relaxation of vascular smooth muscle in the rabbit and rat. C. TAQUINI, H. GOMEZ-LLAMI, and H. E. CINGOLANI. Renal
Circ. Res. 38: 243-249, 1976. hypertension impairs inotropic isoproterenol effect without p-
155. FLEISCH, J. H., H. M. MALING,and B. B. BRODIE.Beta-receptor receptor changes. Am. J. Physiol. 249 (Heart Circ. Physiol. 18):
activity in aorta; variations with age and species. Circ. Res. 26: H814-H819,1985.
151-162,1970. 172. GERSTENBLITH, G., J. FREDERIKSEN, F. C. P.YIN, N. J. FORTUIN,
156. FORD,G. A., B. B. HOFFMAN,and T. F. BLASCHKE. Cardiac E. G. LAKATTA,and M. L. WEISFELDT.Echocardiographic
chronotropic and vascular smooth muscle beta adrenergic assessment of a normal adult aging population. Circulation 56:
responses during propranolol therapy and withdrawal in young 273-278,1977.
and elderly persons. 1. Gerontol.: Med. Sci. 47: M22-M26, 173. GERSTENBLITH, G., E. G. LAKATTA, and M. L. WEISFELDT. Age
1992. changes in myocardial function and exercise response. Prog.
157. FORMAN,D. E., W. J. MANNING, R. HAUSER, E. V. GERVINO, Cardiovasc. Dis. 19: 1-21, 1976.
W. J. EVANS,and J. Y. WEI. Enhanced left ventricular diastolic 174. GERSTENBLITH, G., H. A. SPURGEON, J. P. FROEHLICH, M. L.
filling associated with long-term endurance training. J , Geron- WEISEFELDT, and E. G. LAKATTA. Diminished inotropic respon-
tol.: Med. Sci. 47: M56-MS8, 1992. siveness to ouabain in aged rat myocardium. Circ. Res. 44: 517-
158. FORTNEY, S., C. TANKERSLEY, J. T. LIGHTFOOT,D. DRINKWA- 523,1979.
TER, J. CLULOW, F. O'CONNOR,L. BECKER,E. LAKATTA,and J. 175. GEY,K. P., W. P. BURKARD,and A. PLETSCHER. Variation of the
FLEG.Cardiovascular responses to lower body negative pressure norepinephrine metabolism of the rat heart with age. In: Struc-
in trained and untrained older men. ]. Appl. Physiol. 73: 2693- ture and Chemistry of the Aging Heart, edited by K. F. Gey, W.
2700,1992. P. Burkard, V. V. Frolkis, et al. New York: MSS Information,
159. FRATICELLI, A,, R. JOSEPHSON, R. DANZIGER, E. LAKATTA, and 1974, p. 10-19.
H. SPURGEON. Morphological and contractile characteristics of 176. GILMAN,A. G. G-proteins: transducers of receptor-generated
rat cardiac myocytes from maturation to senescence. Am. 1. signals. Annu. Rev. Biochem. 56: 615-649, 1987.
Physiol. 257 (Heart Circ. Physiol. 26): H259-H265, 1989. 177. GINZTON,L. E., R. CONANT,M. BRIZENDINE, and M. M. LAKS.
160. FREIS,E. D., W. C. HEATH,P. C. LUCHSINGER, and R. E. SNELL. Effect of long-term high intensity aerobic training on left ven-
Changes in the carotid pulse which occur with age and hyper- tricular volume during maximal upright exercise. J . Am. Coll.
tension. Am. Heart]. 71: 757-765, 1966. Cardiol. 14: 364-371, 1989.
161. FREY,M. A. B., and G. W. HOFFLER. Association of sex and age 178. GODFRAIND, T. Alternative mechanisms for the potentiation of
with responses to lower-body negative pressure. J . Appl. Phys- the relaxation evoked by isoprenaline in aortae from young and
iol. 65: 1752-1756, 1988. aged rats. Eur. J. Pharmacol. 53: 273-279,1979.
162. FRIBERG, P., M. NORDLANDER, S. LUNDIN,and B. FOLKOW. 179. GOLDSTEIN, D. S., C. R. LAKE,B. CHERNOW, M. G. ZIEGLER,
Effects of ageing on cardiac performance and coronary flow in M. D. COLEMAN, A. A. TAYLOR, J. R. MITCHELL, I. J. KOPIN,
spontaneously hypertensive and normotensive rats. Acta Phys- and H. R. KEISER.Age-dependence of hypertensive-normoten-
iol. Scand. 125: 1-11, 1985. sive differences in plasma norepinephrine. Hypertension 5 : 100-
163. FROEHLICH, J. P., E. G. LAKATTA, E. BEARD,H. A. SPURGEON, 104,1983.
M. L. WEISFELDT, and G. GERSTENBLITH. Studies of sarcoplas- 180. GOZNA,E. R., A. E. MARBLE, A. SHAW,and J. G. HOLLAND.
mic reticulum function and contraction duration in young adult Age-related changes in the mechanics of the aorta and pulmo-
and aged rat myocardium. J. Mol. Cell Cardiol. 10: 427438, nary artery of man.]. Appl. Physiol. 36: 407411, 1974.
1978. 181. GRANATH, A., and T. STRANDELL. Relationships between car-
164. FROLKIS, V. V., V. V. BEZRUKOV, L. N. BOGATSKAYA, N. S. diac output, stroke volume and intracardiac pressures at rest and
VERKHRATSKY, V. P. ZAMOSTIAN, V. G. SHEVTCHUK, and I. V. during exercise in supine position and some anthropometric
SHTCHEGOLVA. Catecholamines in the metabolism and function data in healthy old men. Acta Med. Scand. 176: 447466,1964.
regulation in aging. Gerontologia 16: 129-140, 1979. 182. GRANATH, A., B. JONSSON,and T. STRANDELL. Circulation in
165. FROLKIS,V. V., V. V. BEZRUKOV, and V. G. SCHEVTCHUK. healthy old men studied by right heart catheterization at rest
Hemodynamics and its regulation in old age. E x p . Gerontol. 10: and during exercise in supine and sitting position. Acta Med.
251-271,1975. Scand. 176: 425446,1964.
166. FROLKIS, V. V., R. A. FROLKIS, L. S. MKHITARIAN, V. G. SCHEV- 183. GRIBBIN, B., T. G. PICKERING, P. SLEIGHT,and R. PETO. Effect
CHUK, V. E. FRAIFELD, L. G. VAKULENKO, and I. SYROVY. Con- of age and high blood pressure on baroreflex sensitivity in man.
tractile function and Caz+ transport system of myocardium in Circ. Res. 297: 424431, 1971.
ageing. Gerontology 34: 64-74, 1988. 184. GRIMBY, G., and B. SALTIN. Physiological analysis of physically
167. FRONTERA, W. R., C. N. MEREDITH, K. P. O'REILLY,and W. J. well-trained middle-aged and old athletes. Acta Med. Scand.
EVANS.Strength training and determinants of VOzmax in older 179: 513426,1966.
men.]. Appl. Physiol. 68: 329-333, 1990. 185. GRIMBY, G., N. J. NILSSON, and B. SALTIN. Cardiac output dur-
168. FRONTERA, W. R., C. N. MEREDITH, K. P. O'REILLY,H. G. ing submaximal and maximal exercise in active middle-aged ath-
KNUTTGEN, and W. J. EVANS.Strength conditioning in older letes.]. Appl. Physiol. 21: 1150-1156, 1966.
men: skeletal muscle hypertrophy and improved function. J . 186. GROBBEE, D. E., and A. HOFMAN. Does sodium restriction lower
Appl. Physiol. 64: 1038-1044, 1988. blood pressure? Br. Med. J. Clin. Res. 293: 27-29, 1986.
169. GANGULY, P. K., G. N. PIERCE,K. S. DHALLA,and N. S. 187. GUARNIERI, T., C. R. FILBURN, G. ZITNIK,G. S. ROTH, and E.
DHALLA. Defective sarcoplasmic reticulum calcium transport in G. LAKAITA.Contractile and biochemical correlates of P-adren-
diabetic cardiomyopathy. Am. J. Physiol. 244 (Endocrinol. ergic stimulation of the aged heart. Am. J . Physiol. 239 (Heart
Metab. 7): E528-ES35, 1983. Circ. Physiol. 10):H501-HS08, 1980.
464 HANDBOOK O F PHYSIOLOGY-AGING

188. GUARNIERI, T., H. SPURGEON, J. P. FROEHLICH, M. L. WEIS- contraction, ejection, and relaxation of the normal human heart.
FELDT, and E. G. LAKATTA.Diminished inotropic response but Am. HeartJ. 67: 189-199,1964.
unaltered toxicity to acetylstrophanthidin in the senescent bea- 206. HAYES, J. S., L. L. BRUNTON, and S. E. MAYER.Selective acti-
gle. Circulation 60: 1548-1554, 1979. vation of particulate CAMP-dependent protein kinase by isopro-
189. GWATHMEY, J. K., and J. P. MORGAN. Altered calcium handling terenol and prostaglandin E l . 1. Biol. Chem. 255: 5 113-5 119,
in experimental pressure-overload hypertrophy in the ferret. 1980.
Circ. Res. 57: 836-843, 1985. 207. HAYNES, F. W., L. B. ELLIS,and S. WEISS.Pulse wave velocity
190. GWATHMEY, J. K., M. T. SLAWSKY, C. L. Perreault, G. M. and arterial elasticity in arterial hypertension, arteriosclerosis
BRIGGS, J. P. MORGAN,and J. Y. WEI. The effect of exercise and related conditions. Am. Heart]. 11: 385-401, 1936.
conditioning on excitation-contraction coupling in aged rats. 1. 208. HEATH,G. W., J. M. HAGBERC, A. A. EHSANI, and J. 0. HOL-
Appl. Physiol. 69: 1366-1371, 1990. LOSZY. A physiological comparison of young and older endur-
191. HABER, P., B. HONIGER, M. KLICPERA, and M. NIEDERBERGER. ance athletes. J. Appl. Physiol. 51: 634-640, 1981.
Effects in elderly people 67-76 years of age of three-month 209. HELLER, L. J. Augmented aftercontractions in papillary muscles
endurance training o n a bicycle ergometer. Eur. Heart 1. from rats with cardiac hypertrophy. Am. 1.Physiol. 237 (Heart
~ ( S U P P I . E): 37-39, 1984. Circ. Physiol. 8): H649-H654, 1979.
192. HACHAMOVITCH, R., P. WICKER,J. M. CAPASSO,and P. 210. HELLER, L. J., and W. V. WHITEHORN. Age-associated altera-
ANVERSA.Alterations of coronary blood flow and reserve with tions in myocardial contractile properties. Am. J . Physiol. 222:
aging in Fischer 344 rats. A m . ] . Physiol. 256 (Heart Circ. Phys- 1613-1619,1972,
iol. 27): H66-H73, 1989. 21 1. HELLON, R. F., and A. R. LIND.The influence of age on periph-
193. HAGBERC, J. M., W. K. ALLEN,D. R. SEALS,B. F. HURLEY, A. eral vasodilatation in a hot environment.]. Physiol. (Lond.) 141:
A. EHSANI, and J. 0. HOLLOSZY. A hemodynamic comparison 262-272, 1958.
of young and older endurance athletes during exercise. J . Appl. 212. HENRY,P. D., G. G. AHUMADA, W. F. FRIEDMAN, and B. E.
Physiol. 58: 2041-2046, 1985. SOBEL.Simultaneously measured isometric tension and ATP
194. HAGBERC, J. M., J. E. GRAVES, M. LIMACHER, D. R. Woons, hydrolysis in glycerinated fibers from normal and hypertrophied
S. H. LECGETT,C. CONONIF,, J. J. GRUBER, and M. L. POL- rabbit heart. Circ. Res. 31: 740-749, 1972.
LOCK. Cardiovascular responses of 70- to 79-yr-old men and 213. HEYLIGER, C. E., A. R. PRAKASH, and J. H. MCNEILL. An assess-
women to exercise training. J. Appl. Physiol. 66: 2589-2594, ment of phospholipid methylation in sarcolemma and sarco-
1989. plasmic reticulum of the aging myocardium. Biocbim. Biophys.
195. HAJDUCZOK, G., M. W. CHAPLEAU, and F. M. ABBOUD. Increase Acta 960: 462465, 1988.
in sympathetic activity with age. 11. Role of impairment of car- 214. HEYLIGER, C. E., A. R. PRAKASH, and J. H. MCNEILL. Effect of
diopulmonary baroreflexes. Am. /. Physiol. 260 (Heart Circ. calmodulin on sarcoplasmic reticular Caz+-transport in the
Physiol. 31): H1121LH1127, 1991. aging heart. Mol. Cell. Biochem. 85: 75-79, 1989.
196. HAJDUCZOK, G., M. W. CHAPLEAU, S. L. JOHNSON, and F. M. 215. HIGGINBOTHAM, M. B., K. G. MORRIS, R. E. COLEMAN, and F.
ABBOUD. Increase in sympathetic activity with age. I. Role of R. COBB.Sex-related differences in the normal cardiac response
impairment of arterial baroreflexes. Am. J. Physiol. 260 (Heart to upright exercise. Circulation 70: 357-366, 1984.
Circ. Physiol. 31): H1113-H1120, 1991. 216. HIGGINBOTHAM, M. B., K. G. MORRIS, R. s. WILLIAMS, and F.
197. HALLOCK, P. and I. C. BENSON. Studies on the elastic properties R. COBB.Physiologic basis for the age-related decline in aerobic
of human isolated aorta.]. Clin. Invest. 16: 595-602, 1937. work capacity. Am. I. Cardiol. 57: 1374-1379, 1986.
198. HAMMON, G. L., Y. K. LAI,and C. L. MARKERT. Diverse forms 217. HIGGINBOTHAM, M. B., K. G. MORRIS,R. S. WILLIAMS, P. A.
of stress lead to new patterns of gene expression through a com- MCHALE, R. E. COLEMAN, and F. R. COBB.Regulation of stroke
mon and essential metabolic pathway. Proc. Natl. Acad. Sci. volume during submaximal and maximal upright exercise in
U.S.A. 79: 3485-3488, 1982. normal man. Circ. Res. 58: 281-291, 1986.
199. HANF,R., I. DRURAIX, F. MARO'ITE,and L. G. LELIEVRE. Rat 218. HIREMATH, A. M., R. A. PERSHE,B. B. HOFFMAN, and T. F.
cardiac hypertrophy. Altered sodium-calcium exchange activity BLASCHKE. Comparison of age-related changes in prostaglandin
in sarcolemma vesicles. FEBS Lett. 236: 145-149, 1988. E l and beta-adrenergic responsiveness of vascular smooth mus-
200. HANO,O., K. Y. BOGDANOV, and E. G. LAKATTA. Enhanced cle in adult males.]. Gerontol. Med. Scr. 44: M13-Ml7, 1989.
calcium intolerance manifest as aftercontractions and ventricu- 219. HOH,J. F. Y., and G. H. ROSSMANITH. Ventricular isomyosins
lar fibrillation in hearts of aged rats [Abstract]. J . Moll. Cell. and the tonic regulation of cardiac contractility. In: Pathobiol-
Cardiol. 22: S.24, 1990. ogy of Cardiovascular Injury, edited by H. L. Stone and W. B.
201. HANSFORD, R. G. Lipid oxidation by heart mitochondria from Weglicki. Boston: Martinus Nijhoff, 1985.
young adult and senescent rats. Blochem. J. 170: 285-295, 220. HOH,J. F. Y., P. A. MCGRATH, and P. T. HALE.Electrophoretic
1978. analysis of multiple forms of rat cardiac myosin: effects of
202. HANSFORD, R. G. Metabolism and energy production. In: hypophysectomy and thyroxine replacement. J. Mol. Cell. Car-
Aging: The Aging Heart: Its Function and Response to Stress, drol. 10: 1053-1076, 1978.
edited by M. L. Weisfeldt. New York: Raven, 1980, vol. 12, p. 221. HOSF,Y,M. M., M. BORSOTTO, and M. LAZDUNSKI. Phosphor-
25-76. ylation and dephosphorylation of dihydropyridine-sensitive
203. HANSON, J. S., B. S. TABAKIN, and A. M. LEVY.Long-term phys- voltage-dependent CaZ+channel in skeletal muscle membranes
ical training and cardiovascular dynamics in middle-aged men. by CAMP-and CAZ+-dependentprocesses. Proc. Natl. Acad. Sci.
Circulation 38: 783-799, 1968. U.S.A. 83: 3733-3737,1986.
204. HARDING, S. E., S. M. JONES,P. O'GARA,F. DELMONTE,G. 222. HOSSACK, K. F., and R. A. BRUCE. Maximal cardiac function in
VESCOVO, and P. A. POOLE-WILSON. Isolated ventricular sedentary normal men and women: comparison of age-related
myocytes from failing and non failing human heart: the relation changes. I. Appl. Physiol. 53: 799-804, 1982.
of age and clinical status of patients to isoproterenol response. 223. HOUSER, S. R., A. R. FREEMAN, J. M. JAEGER,E. A. BREISCH,
1. Mol. Cell. Cardiol. 24: 549-564, 1992. R. L. COULSON, R. CAREY, and J. F. SPANN. Resting potential
205. HARRISON, T. R., K. DIXON,P. 0. RUSSELL, JR., P. S. BIDWAI, changes associated with Na-K pump in failing heart muscle. Am.
and H. N. COLEMAN. The relation of age to the duration of J . Physiol. 240 (Heart Circ. Physiol. 11): H168-H176, 1981.
 CHAPTER 17: CARDIOVASCULAR SYSTEM 465
224. IKEZONO,K., H. R. ZERKOWSKI, J. J. BECKERINGH, M. C. 243. KAPLAN, D., and K. MEYER.Mucopolysaccharides of aorta at
MICHEL,and 0. E. BRODDE. Beta-2 adrenoceptor-mediated various ages. Proc. SOC.Exp. Biol. Med. 105: 78-81, 1960.
relaxation of the isolated human saphenous vein. J . Pharmacol. 244. KARAM, R., H. M. LEVER,and B. P. HEALY. Hypertensive hyper-
Exp. Ther. 241: 294-299,1987. trophic cardiomyopathy or hypertrophic cardiomyopathy with
225. ISNARD, R. N., B. M. PANNIER, S. LAUREN,G. M. LONDON, hypertension? A study of 78 patients. J. Am. Coll. Cardiol. 13:
B. DIEBOLD,and M. E. SAFAR.Pulsatile diameter and elastic 580-584,1989.
modulus of the aortic arch in essential hypertension: a nonin- 245. KARIYA,K., L. R. KARNS,and P. C. SIMPSON.Expression of a
vasive study. J. Am. Coll. Curdiol. 13: 399-405, 1989. constitutively activated mutant of the P-isozyme of protein
226. ISOYAMA, S., W. GROSSMAN, and J. Y. WEI. Effect of age on kinase C in cardiac myocytes stimulates the promoter of the p-
myocardial adaptation to volume overload in the rat. J . Clin. myosin heavy chain isogene. J . Biol. Chem. 266: 10023-10026,
Invest. 81: 1850-1857,1988. 1991.
227. IZUMO,S., B. NADAL-GINARD, and V. MAHDAVI. All members 246. KASSIS,S., and P. H. FISHMAN.Functional alteration of the p-
of the MHC multigene family respond to thyroid hormone in a adrenergic receptor during desensitization of mammalian aden-
highly tissue-specific manner. Science 231: 597-600, 1986. ylyl cyclase by P-agonists. Proc. Natl. Acad. Sci. U.S.A. 81:
228. IZUMO,S., B. NADAL-GINARD, and V. MAHDAVI.Protoonco- 6686-6690,1984.
gene induction and reprogramming of cardiac gene expression 247. KAVANAGH, T., and R. J. SHEPHARD. The effects of continued
produced by pressure overload. Proc. Natl. Acad. Sci. U.S.A. training on the aging process. Ann. N.Y. Acad. Sci. 301: 656-
85: 339-343,1988. 670,1977.
229. JACOB,R., G. KISSLING, G. EBRECHT, C. HOLUBARSCH,~. MEDU- 248. KAWAMOTO,A., K. SHIMADA, K. Matsubayashi, T. CHIKAMORI,
GORAC, and H. RUPP.Adaptive and pathological alterations in 0. KUZUME,H. OGURA,and T. OZAWA. Cardiovascular regu-
experimental cardiac hypertrophy. In: Advunces in Myocardiol- latory functions in elderly patients with hypertension. Hyper-
ogy, edited by E. Chazov, V. Saks, and G. Rona. New York: tension 13: 401-407, 1989.
Plenum, 1983, vol. 4., p. 55-77. 249. KELLIHER,G. J., and J. CONAHAN. Changes in vagal activity and
230. JANSEN,R. W., J. W. M. LENDERS,T. THIEN,and W. H. L. response to muscarinic receptor agonists with age. J. Gerontol.
HOEFNAGELS. The influence of age and blood pressure on the 35: 842-849,1980.
hemodynamic and humoral response to head-up tilt. J. Am. Ger- 250. KELLY,R., C. HAYWARD, A. AVOLIO,and M. O'ROURKE. Non-
iatr. SOC. 37: 528-532, 1989. invasive determination of age-related changes in the human arte-
231. JANUARY, C. T., J. M. RIDDLE,and J. J. SALATA. A model for rial pulse. Circulation 80: 1652-1659, 1989.
early after-depolarizations: induction with the CaZ+ channel 251. KELLY,R. P., H. H. GIBBS,M. F. O'ROURKE,J. E. DALEY,K.
agonist Bay K 8644. Circ. Res. 62: 563-571, 1988. MANG,J. J. MORGAN,and A. P. AVOLIO.Nitroglycerin has
232. JANZ,R. F., B. R. KUBERT, I. MIRSKY, B. KORECKY,and G. C. more favourable effects on left ventricular afterload than appar-
TAICHMAN. Effect of age on passive elastic stiffness of rat heart ent from measurement of pressure in a peripheral artery. Eur.
muscle. Biophys. J . 16: 281-290, 1976. Heart J. 11: 138-144,1990.
233. JEWELL, B. R. A reexamination of the influence of muscle length 252. KENNEDY, R. H., and E. SEIFEN.Aging: effects of chronotropic
on myocardial performance. Circ. Res. 40: 221-230, 1977. actions of muscarinic agonists in isolated rat atria. Mech. Ageing
234. JEWELL, B. R. Activation of contration in cardiac muscle. Mayo Dev. 51: 81-87,1990.
Clin. Proc. 57: 6-13, 1982. 253. KENNEY,W. L. Control of heat-induced cutaneous vasodilata-
235. JIANG,M. T., and N. NARYANAN. Effects of aging on phospho- tion in relation to age. Eur. J. Appl. Physiol. 57: 120-125,1988.
lamban phosphorylation and calcium transport in rat cardiac 254. KENNEY, W. L., C. G. TANKERSLEY, D. L. NEWSWANGER, D. E.
sarcoplasmic reticulum. Mech. Ageing Dev. 54: 87-101, 1990. HYDE,S. M. PUHL,and N. L. TURNER. Age and hypohydration
236. JOINT NATIONALCOMMITTEE. The 1984 report of the Joint independently influence the peripheral vascular response to heat
National Committee on the Detection, Evaluation and Treat- stress. J . Appl. Physiol. 68: 1902-1908, 1990.
ment of High Blood Pressure. Arch. Intern. Med. 144: 1045- 255. KENT,R. L., J. K. HOOBER,and G. COOPER,IV. Load respon-
1057,1984. siveness of protein synthesis in adult mammalian myocardium:
237. JOSE, A. D. Effect of combined sympathetic and parasympa- role of cardiac deformation linked to sodium influx. Circ. Res.
thetic blockade on heart rate and cardiac function in man. Am. 64: 74-85,1989.
J. Curdiol. 18: 476-478, 1966. 256. KHAW, K. T., and E. BARRETT-CONONR. The association
238. JULIUS,S., A. AMERY,L. S. WHITLOCK, and J. CONWAY.Influ- between blood pressure, age, and dietary sodium and potassium:
ence of age on the hemodynamic response to exercise. Circula- a population study. Circulation 77: 53-61, 1988.
tion 36: 222-230, 1967. 257. KING,A. L. Pressure-volume relation for cylindrical tubes with
239. KADOMA,M., B. SACKTOR, and J. P. FROEHLICH. Stimulation elastomeric walls: the human aorta. J . Appl. Physics 17: 501-
by CAMPand protein kinase of calcium transport in sarcoplas- 505,1946.
rnic reticulum from senescent rat myocardium [Abstract]. Fed. 258. KINO,M., V. Q. LANCE,A. SHAHAMATPOUR, and D. H. SPOD-
Proc. 39: 2040,1980. ICK. Effects of age on responses to isometric exercise. Isometric
240. KALISH, M. I., M. S. KATZ,M. A. PINEYRO,and R. I. GREGER- handgrip in noninvasive screening for cardiovascular disease.
MAN. Epinephrine- and glucogon-sensitive adenylate cyclases of Am. Heart J . 90: 575-581,1975.
rat liver during aging. Evidence for membrane instability asso- 259. KIRCHBERGER, M. A., E. ZHEN, C. KASINATHAN, and M. A.
ciated with increased enzymatic activity. Biochim. Biophys. KIRCHBERGER. Altered phospholamban phosphorylation in car-
Acta 483: 452-466, 1977. diac microsomes obtained from senescent rats [Abstract]. Bio-
241. KANE,R. L., T. A. MCMAHON,R. L. WAGNER,and W. H. phys. J. 57: 504a, 1990.
ABELMANN. Ventricular elastic modulus as a function of age in 260. KITZMAN, D.W., D. G. SCHOLZ,P. T. HAGEN,D. M. ILSTRUP,
the Syrian golden hamster. Circ. Res. 38: 74-80, 1976. and W. D. EDWARDS. Age-related changes in normal human
242. KANNEL, W. B., P. A. WOLF,D. L. MCGEE,T. R. DAWBER, P. hearts during the first ten decades. Part I1 (Maturity): a quanti-
MCNAMARA, and W. P. CASTELLI. Systolic blood pressure, arte- tative anatomic study of 765 specimens from subjects 20 to 99
rial rigidity, and risk of stroke. The Framingham study. JAMA years old. Mayo Clin. Proc. 63: 137-146, 1988.
245: 1225-1229,1981. 261. KITZMAN,D. W., K. H. SHEIKH,P. A. BEERE, J. L. PHILIPS,and
466 HANDBOOK O F PHYSIOLOGY-AGING
M. B. HIGGINBOTHAM. Age-related alterations of Doppler left
ventricular filling indexes in normal subjects are independent of
left ventricular mass, heart rate, contractility and loading con-
ditions.]. Am. Coll. Cardiol. 18: 1243-1250, 1991.
262. KLEIN, C., W. R. HIATT,J. G. GERBER, and A. S. NIES.Age does
not alter human vascular and nonvascular PI-adrenergic
responses to isoproterenol. Clin. Pharmacol. Ther. 44: 573-578,
1988.
263. KOBINC.ER,W. a-Adrenoceptors in cardiovascular regulation.
In: Norepinephrine, edited by M. G. Ziegler and C. R. Lake.
Baltimore: Williams and Wilkins, 1984, p. 307-326.
264. KOMURO,I., Y. KATOH,T. KAIDA, Y. SIIIHAZAKI,M. KURARAY-
ASHI, E. HOH, TAKAKU, and Y. YAZAKI. Mechanical loading
stimulates cell hypertrophy and specific gene expression in cul-
tured rat cardiac myocytes. Possible role of protein kinase C
activation.]. Biol. Chem. 266: 1265-1268, 1991.
265. KOMURO, I., M. KURABAYASHI, Y. SHIHAZAKI, F. TAKAKU, and
Y. YAZAKI.Molecular cloning and characterization of a CaZ+
+ Mg2+-dependentadenosine triphosphatase from rat cardiac
sarcoplasmic reticulum. Regulation of its expression by pressure
overload and developmental stage. 1. Clin. Invest. 83: 1102-
1108, 1989.
266. KORCKY,B. The effects of load, internal environment and age
on cardiac mechanics [Abstract].]. Mol. Cell. Cardiol. 1l(supp1.
1): 33, 1979.
267. KORKUSHKO, 0. V., V. B. SIiATILO, and J. K. KAUKENAS.
Changes in heart rhythm power spectrum during human aging.
Aging 3: 177-179, 1991.
268. KORT, A. .A, and E. G. LAKATTA. Calcium-dependent mechan-
ical oscillations occur spontaneously in unstimulated mamma-
lian cardiac tissues. Circ. Res. 54: 396404, 1984.
269. KOSTIS, J. B., A. E. MOREYRA,M. T. AMENDO,J. Dr P r k ~ ~ o ,
N. COSCROVE,and P. T. Kuo. The effect of age o n heart rate
in subjects free of heart disease. Studies by ambulatory electro-
cardiography and maximal exercise stress test. Circulation 65:
141-145, 1982.
270. KRAFT,C. A., and C. M. CAsn EDEN. The effect of aging on p-
adrenoceptor-stimulated cyclic AMP formation in human lym-
phocytes. Clin. Sci. 60: 587-589,1981.
271. KRALL,J. F., M. CONNEI.I.Y, and M. L. TUCK.Evidence for
reversibility of age-related decrease in human lymphocyte ade-
nylate cyclase activity. Biochem. Biophys. Res. Commun. 99:
1028-1034,1981.
272. KRAIL,J. F., M. CONNELI.Y, R. WHSHART,and M. I.. TUCK.
Age-related elevation of plasma catecholamine concentration
and reduced responsiveness of lymphocyte adenylate cyclase. J.
Clin. Endocrinol. Metab. 52: 863-867, 1981.
273. KRANZ,D., and A. WOLLENHERGER. Age dependence of ade-
nylate cyclase activity and CAMPgeneration in aortas and fem-
oral arteries of rats. Z. Alternsforsch. 32: 461-466, 1976.
274. KREIDER, M. S., P. B. GOLDBERG, and J. ROBERT\.Effect of age
on adrenergic neuronal uptake in rat heart. J . Pharmacol. Exp.
Ther. 231: 367-372,1984.
275. KRONENRFRG, R. S., and C. W. DRAGE.Attenuation of the ven-
tilatory and heart rat responses to hypoxia and hypercap-
nia with aging in normal men.]. Clin. invest. 52: 1812-1819,
1973.
276. KUECHEKER, H., K. RUFFMANN, and W. KUF,HI.EK. Effect of
aging on Doppler echocardiographic filling parameters in nor-
mal subjects and in patients with coronary artery disease. Clin.
Cardiol. 11: 303-306, 1988.
277. KUICKKA,J. T., and E. LANSIMIES. Effect of age on cardiac index,
stroke index and left ventricular ejection fraction at rest and
during exercise as studied by radiocardiography. Actu Physiol.
Scand. 114: 339-343, 1982.
278. KULCHITSKII, 0. K. Effect of acetylcholine on the cyclic GMP
level in the rat heart at different ages. Bull. Exp. Biol. Med. 90:
1237-1239,1980.
279. Kuo, L. C., M. A. QUINONES, R. ROKEY,M. SARTORI, E. G.
AHINADEK, and W. A. ZOGHRI.Quantification of atrial contri-
bution to left ventricular filling by pulsed Doppler echocardi-
ography and the effect of age in normal and diseased hearts.
A m . ] . Cardiol. 59: 1174-1178, 1987.
280. KURAMOTO, K., S. MATSUSHITA, J. MIFUNE,M. SAKAI,and M .
MURAKAMI. Electrocardiographic and hemodynamic evalua-
tions of isoproterenol test in elderly ischemic heart disease. Jpn.
Circ. 1.42: 955-960, 1978.
281. KUROHA,M., s. ISOYAMA, N . ITO, and T. TAKISHIMA. Effects
of age on right ventricular hypertrophic response to pressure-
overload in rats. ]. Mol. Cell. Cardiol. 23: 1177-1 190, 199 1.
282. KUSIAK, J. W., and J. PITHA.Decreased response with age of the
cardiac catecholamine sensitive adenylate cyclase system. Life
Sci. 33: 1679-1686,1983.
283. LAB, M . J. Contraction-excitation feedback in myocardium.
Physiological basis and clinical relevance. Circ. Res. 40: 757-
766,1982.
284. LAGRUE,G., J. C. ANSQUEK,and A. MEYEK-HEINE. Peripheral
action of spironolactone: improvement in arterial elasticity. Am.
/. Cardiol. 65: 9K-llK, 1990.
285. LAKATTA,E. G. Determinants of cardiovascular performance:
modification due to aging.]. Chron. Dis. 36: 15-30, 1983.
286. LAKAJTA,E. G. Do hypertension and aging have a similar effect
on the myocardium? Circulation 75(suppl. I): 169-177, 1987.
287. LAKATTA, E. G. Chaotic behavior of myocardial cells: possible
implications regarding the pathophysiology of heart failure. Per-
spect. B i d . Med. 32: 421-433, 1989.
288. LAKAITA,E. G. Normal changes of aging. In: Merck Manual of
Geriatrics, edited by W. B. Abrams and R. Berkow. Rahway,
NJ: Merck Sharp & Dohme, 1990, p. 310-325.
289. LAKATTA,E. G. Regulation of cardiac muscle function in the
hypertensive heart. In: Cellular and Molecular Mechanisms of
Hypertension, edited by R. H. Cox. New York: Plenum, 1991,
p. 149-173.
290. LAKATTA, E. G. Excitation-contration coupling in heart failure.
Hosp. Pract. 26: 85-88, 1991.
291. LAKATTA,E. G. Length modulation of muscle performance:
Frank-Starling law of the heart. In: The Heart and Cardiovas-
cular System (2nd ed.), edited by H . M. Fozzard, E. Haber, R.
B. Jennings, A. M. Katz, and H. E. Morgan. New York: Raven,
1992, VOI.2, p. 1325-1351.
292. LAKA-I’TA, E. G., and D. L. LAPPE.Diastolic scattered light fluc-
tuation, resting force and twitch force in mammalian cardiac
muscle.]. Physiol. (1,ond.) 315: 369-394, 1981.
293. LAKATTA, E. G., and W. I,. MAUGHAN. Cardiovascular function.
In: Current Concepts in Cardiovascular Physiology, edited
by 0. B. Garfein. New York: Academic Press, 1990, p. 351-
464.
294. LAKATTA, E. G., and F. C. P. YIN.Myocardial aging: functional
alterations and related cellular mechanisms. Am. I . Physiol. 242
(Heart Circ. Physiol. 13): H927-H941, 1982.
295. LAKATTA,E. G., G. GERSTENHl.ITH, c . s. ANGELL,N. w.
SHOCK,and M. L. WEISFELDT. Diminished inotropic response
of aged myocardium to catecholamines. Circ. Res. 36: 262-269,
1975a.
296. LAKATTA, E. G., G. GERSTENHI.ITH, C. S. ANGELL,N. W.
SHOCK,and M. L. WEISFELDT. Prolonged contraction duration
in aged myocardium.]. Clin. Invest. 55: 61-68, 1975b.
297. LAKATTA,E. G., H. J. MITCHEI.I., A. POMERANCE, and G. G.
ROWE.Human aging: changes in structure and function.]. Am.
Coll. Cardiol. 10: 42A47A, 1987.
298. LAKATTA,E. G., F. O’CONNOR, s. SCHUIMAN, G. GFRSTEN-
HLITH,L. BECKER,and J. L. FLEG.Cardiac volumes at rest and

during cycle exercise in healthy men of a broad age range: effect
of fitness matching [Abstract]. FASEBJ. 5 : A766, 1991.
299. LAMERS,J. M. J., and J. T. STINIS.Defective calcium pump in
the sarcoplasmic reticulum of the hypertrophied rabbit heart.
Life Sci. 24: 2313-2319, 1979.
300. LAMONICA,D. A,, N. FROHLOFF,and J. G. DOBSON,JR. Aden-
osine inhibition of catecholamine-stimulated cardiac membrane
adenylate cyclase. Am.]. Physiol. 248 (Heart Circ. Physiol. 19):
H737-H744,1985.
301. LANDOWNE,M. The relation between intra-arterial pressure and
impact pulse wave velocity with regard to age and arterioscle-
rosis.]. Gerontol. 13: 153-161,1958.
302. LANCER,S. 2. The role of a- and P-presynaptic receptors in the
regulation of noradrenaline release elicited by nerve stimulation.
Clin.Sci. Mol. Med. 5l(suppl. 3): 423~-426s,1976.
303. LANSING,A. I. The Arterial Wall: Aging, Structure, and Chem-
istry. Baltimore: Williams and Wilkins, 1959, p. 136-160.
304. LEAROYD,B. M., and M. G. TAYLOR.Alterations with age in
the viscoelastic properties of human arterial walls. Circ. Res. 18:
278-292,1966.
305. LE BLAC,P. R., and K. RAKUSAN. Effects of age and isoproter-
enol on the cardiac output and regional blood flow in the rat.
Can.]. Cardiol. 3: 246-250, 1987.
306. LECARPENTIER, Y., L. B. BUGAISKY, D. CHEMLA,J. J. MERCA-
DIER, K. SCHWARTZ,R. G. WHALEN,and J. L. MARTIN.Coor-
dinated changes in contractility, energetics, and isomyosins after
aortic stenosis. Am. I. Physiol. 252 (Heart Circ. Physiol. 23):
H275-H282,1987.
307. LECARPENTIER, Y., A. WALDENSTROM,M. CLERQUE,D.
CHEMLA,P. OLIVIERO, J. L. MARTIN,and B. SWYNGHEDAUW.
Major alterations in relaxation during cardiac hypertrophy
induced by aortic stenosis in guinea pig. Circ. Res. 61: 107-116,
1987.
308. LEE, J. C., L. M . KARPELES, and S. E. DOWNING. Age-related
changes of cardiac performance in male rats. Am. I. Physiol.
222: 432438,1972,
309. LEFKOWITZ,R. J., W. P. HAUSDORFF, and M. G. CARON.Role
of phosphorylation in desensitization of the P-adrenoceptor.
Trends Pharmacol. Sci. 11: 190-194,1990.
310. LEHMANN,M., P. SCHMID,and J. KEUL. Age- and exercise-
related sympathetic activity in untrained volunteers, trained ath-
letes and patients with impaired left-ventricular contractility.
Eur. Heart]. 5(suppl. E): 1-7, 1984.
31 1. LEVITZKI, A. Regu!ation of hormone-sensitive adenylate cyclase.
Trends Pharmacol. Sci. 8: 299-303, 1987.
312. LEWIS,W. H. Changes with age in the cardiac output of adult
men. Am.]. Physiol. 121: 517-527,1938.
313. LEXELL,J., K. HENRIKSSON-LARSEN, B. WINBLAD, and M. Sjo-
STROM. Distribution of different fiber types in human skeletal
muscles: effects of aging studied in whole muscle cross sections.
Muscle Nerve 6: 588-595, 1983.
314. LEXELL,J., C. C. TAYLOR, and M. SJOSTROM.What is the cause
of the ageing atrophy? Total number, size and proportion of
different fiber types studied in whole vastus lateralis muscle from
15- to 83-year-old men. J. Neurol. Sci. 84: 275-294, 1988.
315. LI, Y. X., T. LINCOLN,D. MENDELOWITZ, W. GROSSMAN,and
J. Y. WEI. Age-related differences in effect of exercise training
o n cardiac muscle function in rats. Am.]. Physiol. 251 (Heart
Circ. Physiol. 22): H12-Hl8, 1986.
316. LINDEMAN, R. D., and R. GOLDMAN.Anatomic and physiologic
age changes in the kidney. Exp. Gerontol. 21: 379406, 1986.
317. LINZBACH,A. J., and E. AKUAMOA-BOATENG. Die alternsver-
anderungen des menschlichen herzens I. Das herzgewicht in
alter. Klin. Wochenschr. 51: 156-163, 1973.
318. LIPSITZ,L. A. Orthostatic hypotension in the elderly. N. Engl.
1.Med. 321: 952-957,1989.
CHAPTER 17: CARDIOVASCULAR SYSTEM 467
319. LITSITZ,L. A., P. V. JONSSON,B. L. MARKS,J. A. PARKER, J. D.
ROYAL,and J. Y. WEI. Reduced supine cardiac volumes and
diastolic filling rates in elderly patients with chronic medical
conditions.]. Am. Geriatr. SOL. 38: 103-107, 1990.
320. LOHSE,M. J., J. L. BENovlc, J. CODINA,M. G. CARON,and R.
J. LEFKOWITZ.Barrestin-a novel protein that regulates p-
adrenergic-receptor function [Abstract]. Circulation 82(suppl.
111): 111-L, 1990.
321. LOMPRES,A. M., F. LAMBERT, E. G. LAKATTA, and K.
SCHWARTZ. Expression of sarcoplasmic reticulum CaZ+-ATPase
and calsequestrin genes in rat heart during ontogenic develop-
ment and aging. Circ. Res. 69: 1380-1388, 1991.
322. LOMPRE,A. M., K. SCHWARTZ,A. D’ALBIS,G. LACOMBE,N.
VAN THIEM, and B. SWYNGHEDAW. Myosin isozyme redistri-
bution in chronic heart overload. Nature 282: 105-107,1979.
323. LONDON,G. M., M. E. SAFAR,Y. A. WElss, and P. L. MILLIEZ.
Isoproterenol sensitivity and total body clearance of propranolol
in hypertensive patients.]. Clin.Pharmacol. 16: 174-183,1976.
324. LOPASCHUK, G. D., A. G. TAHILIANI, R. V. S. V. VADLAMUDI,
S. KATZ, and J. H. MCNEILL.Cardiac sarcoplasmic reticulum
function in insulin- or carnitine-treated diabetic rats. Am. 1.
Physiol. 245 (Heart Circ. Physiol. 16):H969-H976, 1983.
325. LUISADA, A. A., K. WATANABE, P. K. BHAT,D. B. RAO, and V.
KNIGHTEN.Correlates of the echocardiographic waves of the
mitral valve in normal subjects of various ages. J. Am. Geriatr.
SOC.23: 216-223,1975.
326. LUND-JOHANSEN, L. Twenty-year follow-up of hemodynamics
in essential hypertension during rest and exercise. Hypertension
18: 11154-11161, 1991.
327. LYE, M., nad E. VARGAS.An analysis of impedance cardiogra-
phy in the elderly. J. Med. Eng. Tecbnol. 5: 289-292, 1981.
328. MACIEL,L. M. Z., R. POLIKAR,D. ROHRER,B. K. POPOVICH,
and W. V. DILLMANN. Age-induced decreases in the messenger
RNA coding for the sarcoplasmic reticulum CaZ+-ATPaseof the
rat heart. Circ. Res. 67: 230-234, 1990.
329. MACLENNAN W. J., M . R. P. HALL,and J. I. TIMOTHY. Postural
hypotension in old age: is it a disorder of the nervous system or
of blood vessels? Age Ageing 9: 25-32, 1980.
330. MALHOTRA, A., S. PENPARGKUL, F. S. FEIN,E. H. SONNENBLICK,
and J. SCHEUER.The effect of streptozotocin-induced diabetes
in rats o n cardiac contractile proteins. Circ. Res. 49: 1243-1250,
1981.
331. MANN,D. L., B. S. DENENBERG, A. K. GASH,P. T. MAKLER,
and A. A. BOVE.Effects of age o n ventricular performance dur-
ing graded supine exercise. Am. Heart]. 111: 108-1 15,1986.
332. MANS, D. L., R. L. KENT, and G. COOPER,IV. Load regulation
of the properties of adult feline cardiocytes: growth induction
by cellular deformation. Circ. Res. 64: 1079-1090, 1989.
333. MANSIER,P., B. CHEVALIER, and B. SWYNGHEDAUW. Charac-
terization of the beta adrenergic system in adult rat hypertro-
phied hearts [Abstract].]. Mol. Cell. Cardiol. 21: S.17, 1989.
334. MARTIN,C. E., J. A. SHAVER,D. F. LEON, M. E. THOMPSON,
P. S. REDDY,and J. J. LEONARD.Autonomic mechanisms in
hemodynamic responses to isometric exercise.]. Clin. Invest. 54:
104-115,1974.
335. MARTIN w. H., III., E. F. COYLE, s. A. BLOOMFIELD, and A. A.
EHSANI.Effects of physical deconditioning after intense endur-
ance training on left ventricular dimensions and stroke volume.
1.Am. Coil. Cardiol. 7: 982-989, 1986.
336. MARTIN,W. H., 111, J. MONTGOMERY, P. G. SNELL,J. R. COR-
BETT, J. J. SOKOLOV,J. C. BUCKEY, D. A. MALONEY, and C. G.
BLOMQVIST.Cardiovascular adaptations to intense swimming
training in sedentary middle-aged men and women. Circulation
75: 323-330,1987,
337. MARZO,K. P., M. J. FRFY,J. R. WILSON,B. T. LIANG,D. R.
MANNING,V. LANOCE,and P. B. MOLINOFF.Beta-adrenergic
468 HANDBOOK OF PHYSIOLOGY-AGING

receptor-(; protein-adenylate cyclase complex in experimental Mechanical, neural, and endocrine dependence. Circulation 83:
canine congestive heart failure produced by rapid ventricular 13-25, 1991.
pacing. Circ. Res. 69: 1546-1556, 1991. 355. MULVAGH, S. L., L. H. MICHAEL, M. B. PERRYMAN, R. ROB-
338. MAUGHAN, D., E. LOW, R. LITTEN,111, J. BRAYDLN, and N. ERTS, and M. D. SCHNEIDER. A hemodynamic load in vivo
ALPERT.Calcium-activated muscle from hypertophied rabbit induces cardiac expression of the cellular oncogene, c-myc. Bio-
hearts. Mechanical and correlated biochemical changes. Circ. chem. Biophys. Res. Commun. 147: 627-636,1987.
Res. 44: 279-287, 1979. 356. MURGO,J. P., N . WESTERHOF, J. P. GIOLMA,and S. A. ALTO-
339. MAYOUX,E., F. CALLENS,B. SWYNGHEDAW, and D. CHAR- BELLI. Aortic input impedance in normal man: relationship to
LEMAGNE. Adaptational process of the cardiac Ca” channels to pressure wave forms. Circulation 62: 105-1 16, 1980.
pressure overload: biochemical and physiological properties of 357. MURGO,J. P., N. WESTERHOF, J. P. GIOLMA,and S. A. ALTO-
the dihydrophyridine receptors in normal and hypertrophied rat BELLI. Effects of exercise on aortic input impedance and pres-
hearts. J. Cardiovasc. Pharmacol. 12: 390-396, 1988. sure wave forms in normal humans. Circ. Res. 48: 334-343,
340. MEERSON, F. Z., M. P. JAVICH,and M. I. LEWRMAN. Decrease 1981.
in the rate of RNA and protein synthesis and degradation in the 358. NAGAI,R., A. ZARAIN-HERZBERG, C. J. BRANDL, J. FUJI[, M.
myocardium under long-term compensatory hyperfunction and TADA,D. H. MACLENNAN, N. R. ALPERT,and M. PERIASAMY.
on aging. J. Mol. Cell. Cardiol. 10: 145-159, 1978. Regulation of myocardial Ca2+-ATPase and phospholamban
341. MERCADIER, J-J., A.-M. LOMPRF, c . WISNEWSKY, J:L. SAMUPI., mRNA expression in response to pressure overload and thy-
J. BERcOvlCl, B. SWYNGHEDAW, and K. SCHWARTZ. Myosin roid hormone. Proc. Natl. Acad. Sci. U.S.A. 86: 2966-2970,
isoenzyme changes in several models of rat cardiac hypertrophy. 1989.
Circ. Res. 49: 525-5.32, 1981. 359. NAKASHIMA, T., and J. TANIKAWA. A study of human aortic
342. MEREDITH, C. N., M. J. ZACKIN, W. R. FRONTERA, and W. J. distensibility with relations to atherosclerosis and aging. Angi-
EVANS.Body composition and aerobic capacity in young and ology 22: 477490, 1971.
middle-aged endurance-trained men. Med. Sci. Sports Exerc. 19: 360. NARAYANAN, N. Differential alterations in ATP-supported cal-
557-563,1987. cium transport activities of sarcoplasmic reticulum and sarco-
343. MERILLON, J. P., G. MOTTE, C. MASQUET,I. AZANCOT,A. lemma of aging myocardium. Biochim. Biophys. Acta. 678:
GUIOMARD, and R. GOURGON.Relationship between physical 442459,1981.
properties of the arterial system and left ventricular performance 361. NARAYANAN, N., and J. A. DERBY.Alterations in the properties
in the course of aging and arterial hypertension. Eur. Heart J . of beta-adrenergic receptors of myocardial membranes in aging:
~ ( S U P P I . A): 95-102, 1982. impairment of agonist-receptor interactions and guanine nucle-
344. MESSERLI, F. H., E. D. FROHLICH, D. H. SUAREZ, E. RFISIN,G. otide regulation accompany diminished catecholamine-respon-
R. DRESLINSKY, F. G. DUNN,and F. E. COLE.Borderline hyper- siveness of adenylate cyclase. Mech. Ageing Dev. 19: 127-139,
tension: relationship between age, hemodynamics and circulat- 1982.
ing catecholamines. Circulation 64: 760-764, 1981. 362. NICHOLS, W. W., and C. J. PEPINE.Left ventricular afterload
345. MESSERLI,F. H., SUNDGAARD-RIISE, H. 0. VENTURA,F. G. and aortic input impedance: implications of pulsatile blood flow.
DUNN,W. OIGMAN, and E. D. FROHLICH. Clinical and hemo- Prog. Cardiovasc. Dis. 24: 293-306, 1982.
dynamic determinants of left ventricular dimensions. Arch. 363. NICHOLS, W. W., M. F. O’ROURKE,A. P. AVOLIO,T. YAGIN-
Intern. Med. 144: 4 7 7 4 8 1 1984. UMA, J. P. MURGO,C. J. PEPINE,and C. R. CONTI.Effects of
346. MILLER,T. R., S. J. GROSSMAN, K. B. SCHECTMAN, D. R. age on ventricular-vascular coupling. Am. J. Cardiol. 55: 1179-
BIELLO, P. A. LUDBROOK, and A. A. EHSANI.Left ventricular 1184,1985.
diastolic filling and its association with age. Am. J. Cardiol. 58: 364. NICHOLS, W. W., M. F. O’ROURKE,A. P. AVOLIO,T. YAGIN-
531-535,1986. UMA, C. J. PEPINE, and C. R. CONTI.Ventriculadvascular inter-
347. MILLIKEN, M. C., J. STRAY-GUNDERSEN, R. M. PESHOCK,J. action in patients with mild systemic hypertension and normal
KATZ,and J. H. MITCHELL. Left ventricular mass as determined peripheral resistance. Circulation 74: 455462, 1986.
by magnetic resonance imaging in male endurance athletes. Am. 365. NICHOLS, W. W., M. F. O’ROURKE,A. P. AVOLIO,T. YAGIN-
I . Cardiol. 62: 301-305, 1988. UMA, J. P. MURGO,C. J. PEPINE,and C. R. CONTI. Age-related
348. MILNOR,W. R. Hemodynamics. Baltimore: Williams and Wil- changes in left ventricular/arterial coupling. In: Ventricular Vas-
kins, 1982. cular Coupling: Clinical Physiology, and Engineering Aspects,
349. MIRSKY,I., and M. M. LAKS.Time course of changes in the edited by F. C. P. Yin. New York: Springer-Verlag, 1987, p. 79-
mechanical properties of the canine right and left ventricles dur- 114.
ing hypertrophy caused by pressure overload. Circ. Res. 46: 366. NICHOLS,W. W., C. J. PEPINE,R. L. FELDMAN, J. WHITTLE,J.
530-542, 1980. H. SELBY,T. KELLY,and C. R. CONTI.Influence of changes in
350. MITCHELL, J. H., B. J. SPROULF,nad C. B. CHAPMAN. The phys- pulsatile components of vascular load on left ventricular func-
iological meaning of the maximal oxygen intake test. J. Clin. tion: power-load relations in patients without heart failure
Intest. 37: 538-547, 1958. [Abstract]. Circulation 59/60: 11-94, 1979.
351. MITHOEFER, J. C., and M. S. KARETZKY. Surgery o f t h e Aged 367. NIXON,J. V., H. HALLMARK, K. PAGE,P. R. RAVEN,and J. H.
and Debilrtated Patient. Philadelphia: J. H. Powers, 1968, p. MITCHELL. Ventricular performance in human hearts aged 61
765-779. to 73 years. Am. J. Cardiol. 56: 932-937, 1985.
352. MIYATAKE, K., M. OKAMOTO,N. KINOSHITA, M. OWA, I. 368. O’CONNOR,S. W., P. J. SCARPACE, and I. B. ABRASS.Age-asso-
NAKASONE, H. SAKAKIBARA, and Y. NIMURA. Augmentation of ciated decrease of adenylate cyclase activity in rat myocardium.
atrial contribution to left ventricular inflow with aging as Mech. Ageing Dev. 16: 91-95, 1981.
assessed by intracardiac Doppler flowmetry. Am. J . Cardiol. 53: 369. O’CONNOR,S. W., P. J. SCARPACE, and I. B. ABRASS.Age-asso-
586-589,1984. ciated decrease in the catalytic unit activity of rat myocardial
353. MOCHLY-ROSEN, D., C. J. HENRICH, L. CHEEVER, H. KHANER, adenylate cyclase. Mech. Ageing Dev. 21: 357-363, 1983.
and P. C. SIMPSON. A protein kinase C isozyme is translocated 370. O’DONNELL,S. R., and J. C. WANSTALL. Demonstration of both
to cytoskeletal elements on activation. Cell Reg. 1: 693-706, p1- and pz-adrenoceptor mediating relaxation of isolated ring
1990. preparations of rat pulmonary artery. Br. J. Pharmacol. 74:
354. MORGAN,H. E., and K. M. BAKER. Cardiac hypertrophy. S47-552,1981.

371. O'DONNELL,S. R., and J. C. WANSTALL. Beta-1 and beta-2
adrenoceptor-mediated responses in preparations of pulmonary
artery and aorta from young and aged rats. J. Pharmacol. Exp.
Tber. 228: 733-738,1984.
372. O'DONNELL,S. R., and J. C. WANSTALL. Thyroxine treatment
of aged or young rats demonstrates that vascular responses
mediated by p-adrenoceptor sybtypes can be differentially reg-
ulated. Br. J. Pharmacol. 88: 41-49, 1986.
373. O'DONNELL,S. R., and J. C. WANSTALL. Functional evidence
for differential regulation of p-adrenoceptor subtypes. Trends
Pharmacol. Sci. 8: 265-268,1987.
374. OGAWA, T., R. J. SPINA,W. H. MARTIN, 111, W. M. HOHRT,K.
B. SCHECHTMAN, J. 0. HOLLOSZY, and A. A. EHSANI.Effects of
aging, sex, and physical training on cardiovascular responses to
exercise. Circulation 86: 494-503, 1992.
375. OLIVETIT,G., M. MELISSARI, J. M. CMASSO,and P. ANVERSA.
Cardiomyopathy of the aging human heart. Myocyte loss and
reactive cellular hypertrophy. Circ. Res. 68: 1560-1568, 1991.
376. O'NEILL,L., N. J. HOLBROOK, J. FARGNOLI, and E. G. LAKATTA.
Progressive changes from young adult age to senescence in
mRNA for rat cardiac myosin heavy chain genes. Cardioscience
2: 1-5, 1991.
377. ORCHARD, C. H., and E. G. LAKATTA. Intracellular calcium
transients and developed tensions in rat heart muscle. A mech-
anism for the negative interval-strength relationship. I. Gen.
Physiol. 86: 637-651, 1985.
378. ORLANDER, J., K. H. KIESSLING, L. LARSSON, J. KARLSSON, and
A. ANIANSSON. Skeletal muscle metabolism and ultrastructure
in relation to age in sedentary men. Acta. Physiol. Scand. 104:
249-261,1978.
379. ORLOWSKI, J., and J. B. LINGREL. Differential expression of the
Na,K-ATPase a1 and a2 subunit genes in murine myogenic cell
line. Induction of the a2 isozyme during myocyte differentiation.
J . Biol. Chem. 263: 17817-17821,1988.
380. O'ROURKE,M. F. Arterial Function in Health and Disease. New
York: Churchill Livingstone, 1982, p. 275.
381. O'ROURKE,M. F. Vascular impedance in studies of arterial and
cardiac function. Physiol. Rev. 62: 570-623, 1982.
382. OSCAI,L. B., P. A. MOLE,and J. 0. HOLLOSZY. Effects of exer-
cise on cardiac weight and mitochondria in male and female rats.
Am. J. Physiol. 220: 1944-1948, 1971.
383. PAN,H. Y., B. B. HOFFMAN,R. A. PERSHE, and T. F. BLASCHKE.
Decline in beta adrenergic receptor-mediated vascular relax-
ation with aging in man. J. Pharmacol. Exp. Ther. 239: 802-
807,1986.
384. PENG,M. T., and M. KANG.Circadian rhythms and patterns of
running-wheel activity, feeding and drinking behaviors of old
rats. Physiol. Behav. 33: 615-620, 1984.
385. PENPARGKUL, S., F. FEIN,E. H. SONNENBLICK, and J. SCHEUER.
Depressed cardiac sarcoplasmic reticular function from diabetic
rats. J. Mol. Cell. Cardiol. 13: 303-309, 1981.
386. PETERSON, L. H., R. E. JENSEN,and J. PARNELL.Mechanical
properties of arteries in vivo. Circ. Res. 8: 622-639, 1960.
387. PETROFSKY, J. S., and A. R. LIND.Isometric strength, endurance,
and the blood pressure and heart rate responses during isometric
exercise in healthy men and women, with special reference to
age and body fat content. Pflugers Arch. 360: 49-61, 1975.
388. PFEIFFER, J. M., M. A. PFEIFFER, M. C. FISHBEIN,and E. D.
FROHLICH. Cardiac function and morphology with aging in the
spontaneously hypertensive rat. Am. J. Physiol. 237 (Heart Circ.
Physiol. 8 ) : H461-H468, 1979.
389. PFEIFER,M. A., C. R. WEINBERG,D. COOK,J. D. BEST, A.
REENAN,and J. B. HALTER. Differential changes of autonomic
nervous system function with age in man. Am. J . Med. 75: 249-
258,1983.
390. PICKERING, G. W. High Blood Pressure. London: Churchill,
1955, p. 154-183.
CHAPTER 17: CARDIOVASCULAR SYSTEM 469
391. POLLOCK, M. L., C. FOSTER,D. 0. KNAPP,J. L. ROD, and D.
H. SCHMIDT. Effect of age and training on aerobic capacity and
body composition of master athletes. J. Appl. Physiol. 62: 725-
731,1987.
392. POLLOCK, M. L., H. S. MILLER,JR., and J. WILMORE.Physio-
logical characteristics of champion American track athletes 40
to 75 years of age.]. Gerontol. 29: 645-649, 1974.
393. POOLINGPROJECTRESEARCH GROUP.Relationship of blood
pressure, serum cholesterol, smoking, relative weight and ECG
abnormalities to incidence of major coronary events: final report
of the pooling project.]. Chron. Dis. 31: 201-306, 1978.
394. PORT,S., F. R. COBB,R. E. COLEMAN, and R. H. JONES.Effect
of age on the response of the left ventricular ejection fraction to
exercise. N. Engl. J. Med. 303: 1113-1117, 1980.
395. PORTH,C. J., L. GROBAN,and J. J. SMITH.Carotid-cardiac bar-
oreflex rseponses decrease with early aging in women [Abstract].
Physiologist 28: 350, 1985.
396. POTTER,J. F., D. ELAHI,J. D. TOBIN,and R. ANDRES.Effect of
aging on the cardiothoracic ratio of men. /. Am. Geriatr. SOC.
30: 404-409,1982.
397. PRINZ,P. N., J. HALTER,C. BENEDETII, and M. RASKIND. Cir-
cadian variation of plasma catecholamines in young and old
men: relation to rapid eye movement and slow wave sleep. J.
Clin. Endocrinol. Metab. 49: 300-304, 1979.
398. PROPER,R., and F. WALL.Left ventricular stroke volume mea-
surements not affected by chronologic aging. Am. Heart J. 83:
843445,1972.
399. RAKUSAN, K., and 0. POUPA.Capillaries and muscle fibers in
the heart of old rats. Gerontologia 9: 107-112,1964.
400. RANDALL, O., M. ESLER,B. CULP,S. JULIUS,and A. ZWIFLER.
Determinants of baroreflex sensitivity in man. Lab. Clin. Med.
91: 514-519,1978.
401. RAVEN,P. B., and J. MITCHELL. The effect of aging on the car-
diovascular response to dynamic and static exercise. In: The
Aging Heart, edited by M. L. Weisfeldt. New York: Raven Press,
1980, p. 269-296.
402. REAVEN,E. P., and G. M. REAVEN.Structure and function
changes in the endocrine pancreas of aging rats with reference
to the modulating effects of exercise and caloric restriction. J .
Clin. Invest. 68: 75-84, 1981.
403. REITHMANN, C., P. GIERSCHIK, U. MULLER,K. WERDAN,and
K. H. JAKOBS.Pseudomonas exotoxin A prevents p-adrenocep-
tor-induced upregulation of Gi protein a-subunits and adenylyl
cyclase desensitization in rat heart muscle cells. Mol. Pharmacol.
37: 631-638,1990.
404. REITHMANN, C., P. GIERSCHIK, D. SIDIROPOULOS, K. WERDAN,
and K. H. JAKOBS. Mechanism of noradrenaline-induced heter-
ologous desensitization of adenylate cyclase stimulation in rat
heart muscle cells: increase in the level of inhibitory G-protein
a-subunits. Eur. J. Pharmacol. 172: 211-221,1989.
405. REMINGTON, J. W. The physiology of the aorta and major arter-
ies. In: Handbook of Physiology. Circulation 11, edited by W. F.
Hamilton and P. Dow. Washington, DC: American Physiologi-
cal Society, 1963, p. 808.
406. RENEMAN, R. S., T. VAN MERODE,P. HICK,and A. P. G. HOEKS.
Flow velocity patterns in and distensibility of the carotid artery
bulb in subjects of various ages. Circulation 71: 500-509,1985.
407. RENEMAN, R. S., T. VANMERODE,and A. P. G. HOEKS.Non-
invasive assessment of arterial flow patterns and wall properties
in humans. News Physiol. Sci. 4: 185-190,1989.
408. RENLUND, D. G., G. GERSTENBLITH, J. L. FLEG,L. C. BECKER,
and E. G. LAKATTA. Interaction between left ventricular end-
diastolic and end-systolic volumes in normal humans. Am. ].
Physiol. 258 (Heart Circ. Physiol. 29): H473-H481, 1990.
409. RENLUND, D. G., G. GERSTENBLITH, R. J. RODEHEFFER, J. L.
FLEG,and E. K. LAKATTA. Potency of the Frank Starling reverse
in normal man [Abstract].]. Am. Coll. Cardiol. 5: 514, 1985.
470 HANDBOOK O F PHYSIOLOGY-AGING
410. RERYCH,S. K., P. M. SCHOLZ,D. C. SABISTON, JR., and R. H.
JONF.S. Effects of exercise training on left ventricular function in
normal subjects: a longitudinal study by radionuclide angiog- 429.
raphy. Am. 1.Cardiol. 45: 244-252, 1990.
411. RICH, K. A,, J. CODINA,G. FLOYD,R. SEKURA, J. D. HILDE- 430.
BRANDT, and R. IYENGAR.Glucagon-induced heterologous
desensitization of MDCK cell adenylyl cyclase. Increase in the
apparent levels of the inhibitory regulator (Ni). I. Btol. Chem. 431.
259: 7893-7901,1984.
412. RICHARDSON, D. Effects of age on cutaneous circulatory
response to direct heat on the forearm. J . Gerontol.: Med. Sci.
44: M189-M194,1989.
413. RIEGGER, G. A., D. ELSNER,E. P. KROMER, C. DAFFNER, W. G. 432.
FORSSMANN, F. MUDERS,E. W. PASCHER,and K. KOCHSIEK.
Atrial natriuretic peptide in congestive heart failure in the dog:
plasma levels, cyclic guanosine monophosphate, ultrastructure
of atrial myoendocrine cells, and hemodynamic, hormonal, and 433.
renal effects. Circulation 77: 398406, 1988.
414. ROACH,M. R., and A. C. BURTON.The effect of age on the
elasticity of human iliac arteries. Can. I. Biochem. Physiol. 37:
557-570,1959. 434.
415. ROBERT,L., B. ROBERT,and A. M. ROBERT.Molecular biology
of elastin as related to aging and atherosclerosis. Exp. Gerontol. 435.
5: 339-356,1970.
416. ROBINSON, S. Experimental studies of physical fitness in relation
to age. Arbeitsphysiologie 10: 251:323, 1938. 436.
417. ROBINSON, S., D. B. DILL,R. D. ROBINSON,S. P. TZANKOFF,
and J. A. WAGNER.Physiological aging of champion runners. 1.
Appl. Physiol. 41: 46-51, 1976. 437.
418. ROCKOFF,J. B., and J. G. DOBSON,JR. Inhibition by adenosine
of catecholamine-induced increase in rat atrial contractility.
Am. I. Physiol. 239 (Heart Circ. Physiol. 10): H365-H370, 438.
1980.
419. RODBELL,M. The role of hormone receptors and GTP-regula-
tory proteins in membrane transduction. Nature 284: 17-22, 439.
1980.
420. RODEHEFFER, R. J., G. GERSTENBLITH, E. BEARD,J. L. FLEG,L.
C. BECKER,M. L. WEISFELDT, and E. G. LAKATTA.Postural 440.
changes in cardiac volumes in men in relation to adult age. Exp.
Gerontol. 21: 367-378, 1986.
421. RODEHEFFER, R. J., G. GERSTENBLITH, L. C. BECKER, J. L. FLEG,
M. L. WEISFELDT, and E. G. LAKAITA. Exercise cardiac output 441.
is maintained with advancing age in healthy human subjects:
cardiac dilatation and increased stroke volume compensate for
a diminished heart rate. Circulation 69: 203-213, 1984.
422. ROGERS,M . A,, J. M. HAGBERG,W. H. MARTIN,111, A. A. 442.
EHSANI,and J. 0. Hol.l.oszu. Decline in V02,,,ax with aging in
master athletes and sedentary men.]. Appl. Physiol. 68: 2195-
2199,1990.
423. ROTHBAUM,D. A., D. J. SHAW, C. S. ANGELL,and N. W. 443.
SHOCK.Cardiac performance in the unanesthetized senescent
male rat.]. Gerontol. 28: 287-292, 1973.
424. ROWE,J. W., and B. R. TROEN.Sympathetic nervous system
and aging in man. Endocr. Rev. 1: 167-179, 1980.
425. RUBIN,P. C., P. J. SCOTT, K. M c L ~ A Nand , J. L. REID. Nor-
adrenaline release and clearance in relation to age and blood 444.
pressure in man. Eur. /. Clin. Invest. 12: 121-125, 1982.
426. RUCH,S., W.-B. IM, R. H. KENNEDY,E. SEIFEN,and T. AKERA.
Aging: stimulation rate of cardiac intracellular Na' activity and 445.
developed tension. Mech. Ageing Dev. 60: 303-313, 1991.
427. RUPP,H. The adaptive changes in the isoenzyme pattern of myo-
sin from hypertrophied rat myocardium as a result of pressure
overload and physical training. Basic Res. Cardiol. 76: 79-88, 446.
1981.
428. SAFAR,M. E., J. J. TOTO-MOUKOUO, J. A. BOUTHIER,R. E.
ASMAR, J. A. LEVENSON,A. C. SIMON, and G. M . LONDON.
Arterial dynamics, cardiac hypertrophy, and antihypertensive
treatment. Circulation 75: 1156-1161, 1987.
SAGAWA, K. The ventricular pressure-volume diagram revisited.
Circ. Res. 43: 678-687, 1978.
SAGAWA, K. Editorial: The pressure-volume relation of the ven-
tricle: definition, modifications and clinical use. Circulation 63:
1223-1227,1981.
SAKAI,M., R. S. DANZIGER, J. M. STADDON,E. G. LAKATTA,
and R. G. HANSFOKD.Decrease with senescence in the norepi-
nephrine-induced phosphorylation of myofilament proteins in
isolated rat cardiac myocytes.]. Mol. Cell. Cardiol. 21: 1327-
1336,1989.
SAKAI,M., R. S. DANZIGER, R:P. XIAO, H. A. SPURGEON, and
E. G. LAKATTA.Contractile response of individual cardiac
myocytes to norepinephrine declines with senescence. Am. 1.
Physiol. 262 (Heart Circ. Physiol. 33): H184-Hl89, 1992.
SCAMPS,F., E. M A Y O ~ JD. X , CHARLEMAGNE, and G. VASSORT.
Calcium current in single cells isolated from normal and hyper-
trophied rat heart. Effect of beta-adrenergic stimulation. Circ.
Res. 67: 199-208, 1990.
SCARPACE, P. J. Decreased P-adrenergic responsiveness during
senescence. Fed. Proc. 45: 51-54, 1986.
SCARPACE, P. J. Decreased receptor activation with age. Can it
be explained by desensitization?]. Am. Geriatr. Soc. 36: 1067-
1071,1988.
SCARPACE, P. J. Forskolin activation of adenylate cyclase in rat
myocardium with age: effects of guanine nucleotide analogs.
Mech. Ageing Dev. 52: 169-178, 1990.
SCARPACE, P. J., and I. B. ABRASS.Decreased beta-adrenergic
agonist affinity and adenylate cyclase activity in senescent rat
lung.]. Gerontol. 38: 143-147, 1983.
SCARPACE, P. J., and I. B. ABRASS.Beta-adrenergic agonist-medi-
ated desensitization in senescent rats. Mech. Ageing Dev. 35:
255-264,1986.
SCARPACE, P. J., and L. A. BARESI.Increased beta-adrenergic
receptors in the light-density membrane fraction in lungs from
senescent rats. I. Gerontol. 43: B163-B167, 1988.
SCHAFFER, S. W., S. AI.LO, S. PUMMA,and T. WHITE.Defective
response to CAMP-dependent protein kinase in non-insulin-
dependent diabetic heart. Am. I. Physiol. 261 (Endocrinol.
Metab. 24): E369-E376, 1991.
SCHAFFER, S. W., M. S. MOZAFFARI, M . ARTMAN,and G. L.
WILSON.Basis for myocardial mechanical defects associated
with non-insulin-dependent diabetes. A m . I. Physiol. 256
(Endocrinol. Metah. 19): E25-E30, 1989.
SCHEUER, J., A. MALHOTRA, C. HIRSCH,J. CAPASSO, and T. F.
SCHAIBLE. Physiologic cardiac hypertrophy corrects contractile
protein abnormalities associated with pathologic hypertrophy in
rats.]. Clin. Invest. 70: 1300-1305, 1982.
SCHIAFFINO, s., J. L. SAMUEL, D. SASSOON,A. M. LOMPRE,I.
GARNER,F. MAROTT, M. BUCKINGHAM, L. RAPPAPORT, and K.
SCHWARTZ. Non-synchronous accumulation of a ,skeletal actin
and P-myosin heavy chain mRNAs during early stages of pres-
sure-overload-induced cardiac hypertrophy demonstrated by in
situ hybridization. Circ. Res. 64: 937-948, 1989.
SCHNEIDER, M. D., and T. G. PARKER.Cardiac myocytes as
targets for the action of peptide growth factors. Circulation 81:
1443-1456,1990.
SCHOCKEN, D. D., J. A. BLUMENTHAL, S. PORT,P. HINDLE, and
R. E. COLEMAN. Physical conditioning and left ventricular per-
formance in the elderly: assessment by radionuclide angiocar-
diography. Am. I. Cardiol. 52: 359-364, 1983.
SCHOEFFTER, P., and J.X. STOCLET.Age-related differences in
cyclic AMP metabolism and their consequences on relaxation
induced by isoproterenol and phosphodiesterase inhibitors in rat
isolated aorta. Mech. Ageing Dev. 54: 197-205, 1990.
 CHAPTER 17: CARDIOVASCULAR SYSTEM 471
447. SCHRADER, J., G. BAUMANN,and E. GERLACH. Adenosine as 466. SIMPSON, D. M., and R. WICKS.Spectral analysis of heart rate
inhibitor of myocardial effects of catecholamines. Pflugers Arch. indicated reduced baroreceptor-related heart rate variability in
372: 29-35,1977. elderly persons. 1.Gerontol.: Med. Sci. 43: M21-M24, 1988.
448. SCHULMAN, S., E. G. LAKATTA, J. L. FLEG,L. LAKATTA, L. C. 467. SIMPSON, P. Stimulation of hypertrophy of cultured neonatal rat
BECKER,and G. GERSTENBLITH. Age-related decline in left ven- heart cells through an a,-adrenergic receptor interaction. Evi-
tricular filling at rest and exercise. Am. J. Physiol. 263 (Heart dence for independent regulation of growth beating. Circ. Res.
Circ. Physiol. 34): H1932-H1938, 1992. 56: 884-894,1985.
449. SCHULMAN, S. P., J. L. WEISS, L. c. BECKER,S. 0. GOTTLIEB, 468. SIMPSON, P. C., Molecular mechanisms in myocardial hypertro-
K. M. WOODRUFF, M. L. WEISFELDT, and G. GERSTENBLITH. phy. Heart Failure 5: 113-129, 1989a.
The effects of antihypertensive therapy on left ventricular mass 469. SIMPSON, P. C. Proto-oncogenes and cardiac hypertrophy. Ann.
in elderly patients. N. Engl. J. Med. 322: 1350-1356, 1990. Rev. Physiol. 51: 189-202, 1989b.
450. SCHUYLER, G. T., and L. R. YARBROUGH. Comparison of myo- 470. SIRI,F. M., J. KUREGER, C. NORDIN,Z. MING,and R. S. ARON-
sin and creatine kinase isoforms in left ventricles of young and SON. Depressed intracellular calcium transients and contraction
senescent Fischer 344 rats after treatment with triiodothyronine. in myocytes from hypertrophied and failing guinea pig hearts.
Mech. Ageing Dev. 56: 39-48, 1990. Am. J . Physiol. 261 (Heart Circ. Physiol. 32): H514-H530,
451. SCHWARTZ, J. B., W. J. GIBB,and T. TRAN.Aging effects on 1991.
heart rate variation. 1.Gerontol.: Med. Sci. 46: M99-M106, 471. SJOGREN,A. L. Left ventricular wall thickness determined by
1991. ultrasound in 100 subjects without heart disease. Chest 60: 341-
452. SCHWARTZ, K., A. M. LOMPRE,D. DE LA BASTIE,and J. J. MER- 346,1971.
CADIER. Mechanogenic transduction in the hypertrophied heart 472. SMITH,J. J., and C. J. M. PORTH.Age and response to ortho-
[Abstract]. J. Mol. Cell. Cardiol. 2l(suppl. 111): S.24, 1989. static stress. In: Circulatory Response to the Upright Posture,
453. SCOTT,P. J., and J. L. REID.The effect of age on the responses edited by J. J. Smith. Boca Raton: FL: CRC Press, 1990, p. 1-
of human isolated arteries to noradrenaline. BY. J . Clin. Phar- 46.
macol. 13: 237-239,1982. 473. SMITH,J. J., J. A. BARNEY,L. GROBAN, A. STADNICKS, and T.
454. SEALS,D. R., and P. B. CHASE.Influence of physical training on J. EBERT.Carotid-cardiac baroreflex responses decrease with
heart rate variability and baroreflex circulatory control.]. Appl. early aging in man [Abstract]. Fed. Proc. 44: 1887, 1985.
Physiol. 66: 1886-1895, 1989. 474. SMITH,M. L., and P. B. RAVEN.Cardiovascular responses to
455. SEALS,D. R., J. M. HABERG,B. F. HURLEY, A. A. EHSANI,and lower body negative pressure in endurance and static exercise-
J. 0. HOLLOSZY. Endurance training in older men and women. trained men. Med. Sci. Sports Exerc. 18: 545-550, 1986.
I. Cardiovascular responses to exercise. J. Appl. Physiol. 57: 475. SMITH,M. L., H. M. GRAITZER,D. L. HUDSON,and P. B.
1024-1029,1984. RAVEN.Baroreflex function in endurance- and static exercise-
456. SEIDMAN, C. E. Expression of atrial natriuretic factor in the nor- trained men.]. Appl. Physiol. 64: 585-591, 1988.
mal and hypertrophied heart. Heart Failure 5: 130-134, 1989. 476. SMITH,S. A., and J. J. FASLER. Age-related changes in autonomic
457. SELIGMAN, M., R. F. EILBERG, and L. FISHMAN. Mineralization function: relationship with postural hypotension. Age Ageing
of elastin extracted from human aortic tissues. Calcif. Tiss. Res. 12: 206-210,1983.
17: 229-234,1975. 477. SMITH,V. E., G. H. RUTAN,and L. H. KULLER. LV mass is best
458. SHANNON, R. P., K. A. MAHER,J. T. SANTINGA, H. D. ROYAL, predicted by systolic ambulatory blood pressure in the elderly
and J. Y. WEI. Comparison of differences in the hemodynamic [Abstract]. J. Am. Coll. Cardiol. 17: 269A.
response to passive postural stress in healthy subjects > 70 years 478. SMITH,V. E., P. SCHULMAN, M. K. KARIMEDDINI, W. B. WHITE,
and < 30 years of age. Am. J. Cardiol. 67: 1110-1116,1991. M. K. MEERAN,and A. M. KATZ. Rapid ventricular filling in
459. SHANNON, R. P., J. Y. WEI, R. M. ROSA,F. H. EPSTEIN,and J. left ventricular hypertrophy 11. Pathologic hypertrophy. J. Am.
W. Rowe. The effect of age and sodium depletion on cardio- CON. Cardiol. 5: 869-874, 1985.
vascular response to orthostasis. Hypertension 8: 438-443, 479. SMITH,V. E., W. B. WHITE,and M. K. KARMEDDINI. Echocar-
1986. diographic assessment of left ventricular diastolic performance
460. SHECHTER, J. A., T. D. FRIEHLINC, C. UBOH,G. J. KELLIHER, in hypertensive subjects: correlation with changes in left ven-
K. M. O'CONNOR,and P. R. KOWEY.The effect of left ventric- tricular mass. Hypertension 9(suppl. 2): 1181-1184, 1987.
ular hypertrophy on inducible ventricular arrhythmias 480. SMULYAN, H., T. J. CSERMELY, S. MOOKHERJEE, and R. A.
[Abstract]. Circulation 70: 11-234, 1984. WARNER. Effect of age on arterial distensibility in asymptomatic
461. SHIMADA, K., T. KITAZUMI,N. SADAKANE, H. OGURA,and T. humans. Arteriosclerosis 3: 199-205, 1983.
OZAWA.Age-related changes of baroreflex function, plasma 481. SOWERS, J. R., and P. K. MOHANTY.Effect of advancing age on
norepinephrine, and blood pressure. Hypertension 7: 113-1 17, cardiopulmonary baroreceptor function in hypertensive men.
1985. Hypertension 1 0 274-279, 1987.
462. SHIVERICK, C. T., B. B. HAMRELL, and N. R. ALPERT.Structural 482. SOWERS, J. R., L Z. RUBENSTEIN, and N. STERN.Plasma nor-
and functional properties of myosin associated with the com- epinephrine responses to posture and isometric exercise increase
pensatory cardiac hypertrophy in the rabbit.]. Mol. Cell. Car- with age in the absence of obesity. J. Gerontol. 38: 315-317,
diol. 8: 837-851, 1976. 1983.
463. SHREINER, D. P., M. L. WEISFELDT, and N. W. SHOCK.Effects 483. SPINA,R. J., R. OGAWA,W. M. KOHRT,W. H. MARTIN,111, J.
of age, sex, and breeding status on the rat heart. Am. J. Physiol. 0. HOLLOSZY, and A. A. EHSANI.Differences in cardiovascular
217: 176-180,1969. adaptations to endurance exercise training between older men
464. SIBLEY, D. R., and R. J. LEFKOWITZ. Molecular mechanisms of and women.]. Appl. Physiol. 75: 849-855.
receptor desensitization using the P-adrenergic receptor-coupled 484. SPIRITO,P., and B. J. MARON.Influence of aging on Doppler
adenylate cyclase system as a model. Nature 317: 124-129, echocardiographic indices on left ventricular diastolic function.
1985. Br. Heart]. 59: 672-679,1988.
465. SIMON,A. C., J. A. LEVENSON, J. L. BOUTHIER,and M. E. SAFAR. 485. SPURGEON,H. A., duBell, M. BOYETI-, A. TALO,M. C. CAPO-
Captopril-induced changes in large arteries in essential hyper- GROSS], and E. G. LAKATTA. Cytosolic CaZ+ modulation of
tension. Am. ]. Med. 76: 71-75, 1984. membrane potential during a heart beat: perspectives from the
472 HANDBOOK O F PHYSIOLOGY-AGING

single cardiac cell [Abstract]. J. Mol. Cell. Cardiol. 21: S.19, in normal men and women. Am. 1. Cardiol. 67: 1405-1412,
1989. 1991.
486. SPURGEON, H. A., M. F. STEINBACH, and E. G. LAKATTA. 503. SUNAGAWA, K., W. L. MAUGHAN, and K. SAGAWA. Optimal
Chronic exercise prevents characteristic age-related changed in arterial resistance for the maximal stroke work studied in iso-
rat cardiac contraction. Am. 1. Physiol. 244 (Heart Circ. Phys- lated canine left ventricle. Circ. Res. 56: 586-595, 1985.
iol. 15): H513-HS18, 1983. 504. SUPIANO, M. A., 0. A. LINARES, J. B. HALTER,K. M. RENO,
487. SPURGEON, H. A., P. R. THORNE, F. C. P. YIN, N. W. SHOCK, and S. G. ROSEN.Functional uncoupling of the platelet c12-
and M. F. WEISFELDT. Increased dynamic stiffness of trabeculae adrenergic receptor-adenylate cyclase complex in the elderly. 1.
carneae from senescent rats. Am. 1. Physiol. 232 (Heart Circ. Clin. Endocrinol. Metab. 64: 1160-1 164, 1987.
Physiol. 3): H373-380, 1977. 505. SUPIANO, M. A., R. R. NEUBIG, 0. A. LINARES, J. B. HALTER,
488. STARKE, K. Regulation of noradrenaline release by presynaptic and S. G. ROSEN.Effects of low-sodium diet o n regulation of
receptor systems. Rev. Physiol. Biochem. Pharmacol. 77: 1-124, platelet nz-adrenergic receptors in young and elderly humans.
1977. Am.]. Physiol. 256 (Endocrinol. Metab. 19):E399-E344,1989.
489. STARNES, J. W., and W. L. RUMSEY. Cardiac energetics and per- 506. SUITON,M. S., S. N. REICHEK, J. LOVETT,J. A. KASTOR,and
formance of exercised and food-restricted rats during aging. Am. E. GUILIANI. Effects of age, body size and blood pressure o n the
J. Physrol. 254 (Heart Circ. Physiol. 25): H599-H608, 1988. normal human left ventricle [Abstract]. Circulation 62: 111-305,
490. STARNES, J. W., R. E. BEYER, and D. W. EDINGTON. Myocardial 1980.
adaptations to endurance exercise in aged rats. Am. /. Physiol. 507. SWINNE, C. J., E. P. SHAPIRO, S. D. LIMA,and J. L. FLEG.Age-
245 (Heart Circ. Physiol. 16): H560-H566,1983. associated changes in left ventricular diastolic performance dur-
491. STEINNHAGEN-THEISSEN, E., A. Z. REZNICK, and J. D. RINGE. ing isometric exercise in normal subjects. Am. I. Cardiol. 69:
Age dependent variations in cardiac and skeletal muscle during 823-826,1992.
short and long term transmill-running of mice. Eur. Heart 1. 508. SWYNGHEDAUW, B. Remodelling of the heart in response to
5(suppl. E): 37-30,1984. chronic mechanical overload. Eur. Heart J. 10: 935-943,1989.
492. STERN,M. D., A. A. KORT,G. M. BHATNAGER,and E. G. LAK- 509. TAFFET,G. E., and C. A. TATE.The sarcoplasmic reticulum cal-
ATTA. Scattered-light intensity fluctuations in diastolic rat car- cium ATPase from rat heart is decreased in senescence
diac muscle caused by spontaneous Ca+ +-dependent cellular [Abstract]. Gerontologist 30: l l l A , 1990.
mechanical oscillations. J. Gen. Physiol. 82: 119-153, 1983. 510. TAKAHASHI, T., H. SCHUNKERT, S. ISOYAMA, J. Y. WEI, B.
493. STESSMAN, J., R. ELIAKIM, C. CAHAN,and R. P. EBSTEIN. Dete- NADAL-GINARD, W. GROSSMAN, and S. IZUMO.Age-related dif-
rioration of beta-receptor-adenylate cyclase function in elderly, ferences in the expression of proto-oncogene and contractile
hospitalized patients. I. Gerontol. 39: 667-672, 1984. protein genes in response to pressure overload in the rat myo-
494. STRANDELL, T. Heart volume and its relation to anthropometric cardium. 1. Clm. Invest. 89: 939-946, 1992.
data in old men compared with young men. Acta Med. Scand. 511. TANKERSLEY, C. G., J. SMOLANDER, W. L. KENNEDY, and S. M.
176: 205-218,1964a. FORTNEY. Sweating and skin blood flow during exercise: effects
495. STRANDELL, T. Total haemoglobin, blood volume and haemo- of age and maximal oxygen uptake.]. Appl. Physiol. 71: 236-
globin concentration at rest and circulatory adaptation during 242,1991.
exercise in relation to some anthropometric data in old men 512. TATE,C. A., G. E. TAFFET,E. K. HUDSON,S. L. BLAYLOCK, R.
compared with young men. Acta Med. Scand. 176: 219-232, P. MCBRIDE, and L. H. MICHAEL. Enhanced calcium uptake of
1964b. cardiac sarcoplasmic reticulum in exercise-trained old rats. Am.
496. STRANDELL, T. Circulatory studies on healthy old men. With J . Physiol. 258 (Heart Circ. Physiol. 29): H431-H435, 1990.
special reference to the limitation of the maximal physical work- 513. TAWNEY, K. W., E. C. JOHNSON, and E. R. GREENE. Age-related
ing capacity. Acta Med. Scand. 175(414):1-44, 1964c. differences in reactivity of the central circulation to head-up tilt
497. STRASSER, R. H., R. A. CERIONE, J. COD[NA,M.G. CARON,and [Abstract]. Physiologist 31: A130, 1988.
R. J. LEFKOWITZ. Homologous desensitization of the beta- 514. TAYLOR, D. J., M. C R O W E ,J.~ BoRE,P.
. STYLES,D. L. ARNOLD,
adrenergic receptor. Functional integrity of the desensitized and G. K. RADDA.Examination of the energetics of aging skel-
receptor from mammalian lung. Mol. Pharmacol. 28: 237-245, etal muscle using nuclear magnetic resonance. Gerontology 30:
1985. 2-7,1984.
498. STRASSER, R. H., D. R. SIBIIY,and R. J. LEFKOWITZ. A novel 515. TAYLOR, J. A., G. A. HAND,D. G. JOHNSON,and D. R. SEALS.
catecholamine-activated adenosine cyclic 3',5'-phosphate inde- Augmented forearm vasoconstriction during dynamic exercise
pendent pathway for P-adrenergic receptor phosphorylation in in healthy older men. Circulation 86: 1789-1799, 1992.
wild-type and mutant S49 lymphoma cells: mechanism of homol- 516. TEMPLETON, G. H., M. R. PLATT,J. T. WILLERSON, and M.L.
ogous desensitization of adenylate cyclase. Biochemistry 25: WEISFELDT. Influence of aging o n left ventricular hemodynamics
1371-1377,1986. and stiffness in beagles. Circ. Res. 44: 189-194, 1979.
499. STRASSER, R. H., G. L. STILES,and R. J LEFKOWITZ. Translo- 517. TING,C. T., K. P. BRIN,S. J. LIN, S. P. WANG,M. S. CHANG,
cation and uncoupling of the beta-adrenergic receptor in rat lung B. N. CHIANG, and F. C. YIN. Arterial hemodynamics in human
after catecholamine promoted desensitization in vivo. Endocri- hypertension. I. Clin. Invest. 78: 1462-1471,1986.
nology 115: 1392-1400,1984. 518. TODA,N., and M. MIYAZAKI. Senescent beagle coronary arteries
500. STRATTON, J. R., M. D. CERQUERIRA, R. S. SCHWARTZ, W. C. in response to catecholamines and adrenergic nerve stimulation.
LEVY,R. C. VEITH,S. E. KAHN,and I. B. ABRASS.Differences I. Gerontol. 42: 210-218,1987.
in cardiovascular responses to isoproterenol in relation t o age 519. TOMANEK, R. J. Effects of age and exercise on the extent of the
and exercise training in healthy men. Circulation 86: 504-512, myocardial capillary bed. Anat. Rec. 167: 55-62, 1970.
1992. 520. TOMANEK, R. J., and J. M. HOVANEC. The effects of long-term
501. STREHLER,B. L., D. D. MARK,A. S. MILDVAN, and M. V. GEE. pressure-overload and aging on the myocardium. I. Mol. Cell.
Rate and magnitude of age pigment accumulation in the human Cardiol. 13: 471488, 1981.
myocardium.]. Gerontol. 14: 430439, 1959. 521. TOMANEK, R. J., and U. L. KARLSSON.Myocardial ultrastruc-
502. SULLIVAN, M. J., F. R. COBB,and M. B. HIGGINBOTHAM. Stroke ture of young and senescent rats. J. Ultrastruc. Res. 42: 201-
volume increases by similar mechanisms during upright exercise 220,1973.
 CHAPTER 17: CARDIOVASCULAR SYSTEM 473
522. TOPOL,E. J., T. A. TRAILL, and N. J. FORTUIN.Hypertensive 542. WATKINS, S. C., J. L. SAMUEL, F. MAROTTE,B. BERTIER-SAV-
hypertrophic cardiomyopathy of the elderly. N . Engl. I. Med. ALLE, and L. RAPPAPORT. Microtubules and desmin filaments
312: 277-183,1985. during onset of heart hypertrophy in rat: a double immunoelec-
523. TRAVIS,D. F., and A. TRAVIS.Ultrasound changes in the left tron microscope study. Circ. Res. 60: 327-336,1987.
ventricular rat myocardial cells with age. J. Ultrastruct. Res. 39: 543. WATSON,P. A., T. HANEDA,and H. E. MORGAN.Effect of
124-148,1972. higher aortic pressure on ribosome formation and CAMP con-
524. TSUJIMOTO, G., C.-H. LEE, and B. B HOFFMAN.Age-related tent in rat heart. Am.]. Physiol. 256 (CellPhysiol. 25): C1257-
decrease in beta adrenergic receptor-mediated vascular smooth C1261,1989.
muscle relaxation. I. Pharmacol. Exp. Ther. 239: 411-415, 544. WEI,J. Y., Y. X. LI, T. LINCOLN, W. GROSSMAN, and D. MEN-
1986. DELOWITZ. Chronic exercise training protects aged cardiac mus-
525. TZANKOFF, S. P., and A. H. NORRIS.Effect of muscle mass cle against hypoxia. 1. Clin. Invest. 83: 778-784, 1989.
decrease on age-related BMR changes. 1. Appl. Physiol. 43: 545. WEI,J. Y., H. A. SPURGEON, and E. G. LAKATTA. Excitation-
1001-1006,1977. contraction in rat myocardium: alterations with adult aging.
526. UNVERFERTH, D. V., J. K. FETTERS, B. J. UNVERFERTH, C. V. Am. I. Physiol. (Heart Circ. Physiol. 17): H784-H791, 1984.
LEIER,R. D. MAGORIEN, A. R. ARN, and P. B. BAKER.Human 546. WEINBERGER, M. H., and N. S. FINEBERG. Sodium and volume
myocardial histologic characteristics in congestive heart failure. sensitivity of blood pressure. Age and pressure change over time.
Circulation 68: 1194-1200, 1983. Hypertension 18: 67-71, 1991.
527. VAITKEVICIUS, P. V., J. L. FLEG,J. H. ENGEL,F. C. O'CONNOR, 547. WEISFELDT, M. L., W. A. LOEVEN,and N. W. SHOCK.Resting
J. G. WRIGHT,L. E. LAKATTA, F. C.-P. YIN, and E. G. LAKATTA. and active mechanical properties of trabeculae carneae from
Efects of age and aerobic capacity on arterial stiffness in healthy aged male rats Am.]. Physiol. 220: 1921-1927, 1971.
adults. Circulation 88: 1456-1462, 1993. 548. WEISFELDT, M. L., J. R. WRIGHT,D. P. SHREINER, E. LAKATTA,
528. VAN BRUMMELEN,P., F. R. BUHLER, W. KIOWSKI,and F. W. and N. W. SHOCK.Coronary flow and oxygen extraction in the
AMANN.Age-related decrease in cardiac and peripheral vascular perfused heart of senescent male rats. 1.Appl. Physiol. 30: 44-
responsiveness to isoprenaline: studies in normal subjects. Clin. 49, 1971.
Sci. 60: 571-577,1981. 549. WILENS,S. L., and E. E. SPROUL.Spontaneous cardiovascular
529. VANTOSH,A., E. G. LAKATTA, J. L. FLEG,J. WEISS,C. KALLMAN, disease in the rat. Am. J. Pathol. 14: 177-216, 1938.
M. WEISFELDT, and G. GERSTENBLITH. Ventricular dimensional 550. WILSON,J. R., P. DOUGLAS, W. F. HICKEY,V. LANOCOE,N.
changes during submaximal exercise: effect of aging in normal FERRARO, A. MUHAMMAD, and N. REICHEK. Experimental con-
man [Abstract]. Circulation 62: 111-129, 1980. gestive heart failure produced by rapid ventricular pacing in the
530. VEITH,R. C., J. D. BEST, and J. B. HALTER. Dose-dependent dog: cardiac effects. Circulation 75: 857-867, 1987.
suppression of norepinephrine appearance rate in plasma by clo- 551. WISENBAUGH, T., P. ALLEN,G. COOPER,IV, W. N. O'CONNOR,
nidine in man.]. Clin. Endocrinol. Metab. 59: 151-155, 1984. L. MEZAROS, R. STRETER, A. BAHINSKI, S. HOUSER,and J. F.
531. VENTURA-CLAPIER, R., H. MEKHFI,P. OLIVIERO,and B. SPANN.Hypertrophy without contractile dysfunction after
SWYNGHEDAUW. Pressure overload changes cardiac skinned- reversal of pressure overload in the cat. Am. 1. Physiol. 247
fiber mechanics in rats, not in guinea pigs. Am. /. Physiol. 254 (Heart Circ. Physiol. 18): H146-Hl54, 1984.
(Heart Circ. Physiol. 25): H517-524, 1988. 552. WOLF,H., and F. HOFMANN. Purification of myosin light chain
532. VERKHRATSKY, N. S. Acetylcholine metabolism peculiarities in kinase from bovine cardiac muscle. Proc. Natl. Acad. Sci. U.S.A.
aging. Exp. Gerontol. 5: 49-56, 1970. 77: 5852-5855,1980.
533. VESTAL, R. E., A. J. H. WOOD,and D. G. SHAND.Reduced beta- 553. WOLINSKY, H. Long-term effects of hypertension on the rat aor-
adrenoreceptor sensitivity in the elderly. Clin. Pharmacol. Ther. tic wall and their relation to concurrent aging changes. Mor-
26: 181-186,1979. phological and chemical studies. Circ. Res. 3 0 301-309, 1972.
534. VIZEK,M., and I. ALBRECHT.Development of cardiac output in 554. WOODCOCK,E. A., J. W. FUNDER,and C. I. JOHNSTON.
male rats. Physiol. Bohemoslov. 22: 573-580, 1973. Decreased cardiac p-adrenergic receptors in deoxycorticoste-
535. VON HARSDORF, R., R. E. LANG,M. FULLERTON, and E. A. rone-salt and renal hypertensive rats. Circ. Res. 45: 560-565,
WOODCOCK. Myocardial stretch stimulates phosphatidylinosi- 1979.
to1 turnover. Circ. Res. 65: 494-501, 1989. 555. XIAO,R.-P., and E. G. LAKATTA. Mechanisms of altered p-
536. VOUTILAINEN, S., M. KUPARI,M. HIPPELAINEN, K. KARPPINEN, adrenergic modulation of the cardiovascular system with aging.
M. VENTILA,and J. HEIKKILA. Factors influencing Doppler Rev. Clin. Gerontol. 1: 309-322, 1991.
indexes of left ventricular filling in healthy persons. Am. J. Car- 556. XIAO,R.-P., M. C. CAPOGROSSI, H. A. SPURGEON, and E. G.
diol. 68: 653-659, 1991. LAKATTA. Stimulation of 8 opioid receptors in single heart cells
537. WAHREN, J., B. SALTIN, L. JORFELDT, and B. PERNOW. Influence blocks p-adrenergic receptor mediated increase in calcium and
of age on the local circulatory adaptation to leg exercise. Scand. contraction [Abstract]. J. Mol. Cell. Cardiol. 23(suppl. 111): S83,
1. Clin. Lab. Invest. 33: 79-86, 1974. 1991.
538. WALFORD, G. D., H. A. SPURGEON, and E. G. LAKATTA. Dimin- 557. XIAO,P.-P., H. A. SPURGEON, F. O'CONNOR,and E. G. LAK-
ished cardiac hypertrophy and muscle performance in older ATTA. Age-associated changes in beta-adrenergic modulation on
compared to younger adult rats with chronic atrioventricular rat cardiac excitation-contraction coupling.]. Clin.Invest. 1994
block. Circ. Res. 63: 502-511,1988. (in press).
539. WALKER K. E., and S. R. HOUSER. Intracellular calcium buffers 558. YAKOVLEV, V. M. Some data on the functional state of the arte-
affect age-related calcium current decay [Abstract]. Circulation rial system in aged persons. Kardiologiia 11: 99-103, 1971.
82: 111-746, 1990. 559. YAMADA,Y., E. MIYAJIMA, 0. TOCHIKUBO, T. MATSUKAWA,
540. WALKER, K. E., E. G. LAKATTA, and S. R. HOUSER.Age asso- and M. ISHII.Age-related changes in muscle sympathetic nerve
ciated changes in membrane currents in rat ventricular myo- activity in essential hypertension. Hypertension 13: 870-877,
cytes. Cardiovasc. Res. 27: 1968-1977, 1993. 1989.
541. WALLER, B. F., and W. C . ROBERTS. Cardiovascular disease in 560. YAZAKI,Y., and I. KOMURO. Molecular analysis of cardiac
the very elderly. Analysis of 40 necropsy patients ages 90 years hypertrophy due to overload [Abstract]. J. Mol. Cell. Cardiol.
or over. Am. J. Cardiol. 51: 403-421, 1983. 2l(suppl. 111): S.29, 1989.
474 HANDBOOK OF PHYSIOLOGY-AGING
561. YIN, F. C. P., G. S. RAIZES,T. GUARNIERI, H. A. SPURGEON, E.
G. LAKATTA, N. J. FORTUIN,and M. L. WEISFELDT. Age-asso-
ciated decrease in ventricular response to haemodynamic stress
during beta-adrenergic blockade. Br. Heart I. 40: 1349-1355,
1978.
562. YIN, F. C. P., H. A. SPURGF,ON, H. L. GREENE, E. G. LAKATTA,
and M. L. WEISFELDT. Age-associated decrease in heart rate
response to isoproterenol in dogs. Mech. Ageing Dew. 10: 17-
25, 1979.
563. YIN,F. C. P., H. A. SPURGEON,and C. H. KALLMAN.Age-asso-
ciated alterations in viscoelastic properties of canine aortic
strips. Circ. Res. 53: 464-472, 1983.
564. YIN, F. C. P., H. A. SPURGEON,G. S. RAIZES,H. L. GREENE, M.
L. WEISFELDT, and N. W. SHOCK.Age-associated decrease in
chrontropic response to isoproterenol [Abstract]. Circulation
~ ( S U P P ~2):
. 11-167, 1976.
565. YIN, F. C. P., H. A. SPURGEON,K. RAKUSAN, M. L. WEISFELDT,
and E. G. LAKATTA. Use of tibia1 length to quantify cardiac
hypertrophy: application in the aging rat. Am. 1. Pbysiol. 243
(Heart Circ. Physiol. 14): H941-H947, 1982.
566. YIN, F. C. P., H. A. SPURGEON, M. L. WEISFELDT, and E. G.
LAKATTA. Mechanical properties of myocardium from hyper-
trophied rat hearts. A comparison between hypertrophy induced
by senescence and by aortic banding. Circ. Res. 46: 292-300,
1980.
567. YIN, F. C. P., M. L. WEISFELDT, and W. R. MILNOR.Role of
aortic input impedance in the decreased cardiovascular response
to exercise with aging in dogs.]. Clin. Invest. 68: 28-38, 1981.
568. YOUNG, J. B., J. W. ROWE,J. A. PALLOTTA, D. SPARROW, and
L. LANDSBERG.Enhanced plasma norepinephrine response to
upright posture and oral glucose administration in elderly
human subjects. Metabolism 29: 532-539, 1980.
569. YOUNIS,L. T., J. A. MELIN,A. R. ROBERT,and J. M. R. DETRY.
Influence of age and sex on left ventricular volumes and ejection
fraction during upright exercise in normal subjects. Eur. Heart
1. 11: 916-924,1990.
570. Yu, B. P., E. J. MASORO,and C. A. MCMAHAN.Nutritional
influences on aging of Fischer 344 rats: I. Physical, metabolic,
and longevitiy characteristics. 1. Cerontol. 40: 657-670, 1985.
571. ZIMAN, B., H. A. SPURGEON,M. D. STERN,and E. G. LAKATTA.
A Ca2+myofilament interaction modulates resting length of sin-
gle rat ventricular myocytes [Abstract]. Circulation 82: 111-214,
1990.