Pathophysiology of right ventricular failure in pulmonary

hypertension
Ronald A. Bronicki, MD; Harris P. Baden, MD

This review focuses on right ventricular anatomy and function ventricular afterload leads to a number of compensatory changes
and the significance of ventricular interdependence in the re- in cardiovascular physiology. These changes are not altogether
sponse of the right ventricle to an increase in afterload. This is intuitive and require an understanding of right ventricular phys-
followed by a discussion of the pathophysiology of right ventric- iology and ventricular interdependence to optimize the care of
ular failure in pulmonary arterial hypertension as well as in other these patients. (Pediatr Crit Care Med 2010; 11[Suppl.]:S15–S22)
clinical syndromes of pulmonary hypertension. Pulmonary hyper- KEY WORDS: right ventricle; ventricular interdependence; cardio-
tension is common in critically ill children and is associated with pulmonary interaction; pulmonary hypertension; heart failure
several conditions. Regardless of the etiology, an increase in right

P
ulmonary hypertension is pears triangular when viewed from the which enables blood to enter the pulmo-
common to a variety of condi- side and crescent-shaped when viewed in nary artery even as the ventricular-
tions occurring in infants and cross section. The left ventricle (LV) is arterial pressure gradient becomes nega-
children presenting to the in- ellipsoidal in shape and the interventric- tive. This interval, from the time RV
tensive care unit. A fundamental under- ular septum (IVS) bows into the RV pressure falls below pulmonary artery
standing of the response of the right ven- throughout the cardiac cycle (Fig. 1). The pressure to the closure of the pulmonary
tricle (RV) to an increase in afterload is, RV is composed of an inlet portion, which valve, is referred to as the hangout inter-
therefore, essential to the medical practi- consists of the tricuspid valve, chordae val. Nearly 60% of RV stroke volume is
tioner caring for patients with pulmonary tendineae, and papillary muscles; the tra- ejected after peak RV systolic pressure
hypertension. In this review, we discuss beculated apical myocardium; and the in- occurs.
normal RV anatomy and physiology as fundibulum, or conus, or outflow region, The RV pumps the same stroke vol-
well as the phenomenon of ventricular which is composed of smooth myocar- ume as the LV but with approximately
interdependence. We then describe the dium. The ventricles are composed of 25% of the stroke work because the im-
compensatory changes that occur in the multiple layers of muscle that encircle pedance in the pulmonary circulation is
face of increased RV afterload. Finally, we both ventricles in a complex interlacing much less than that in the systemic circu-
review the pathophysiology and distin- fashion (1). The RV wall is composed pri- lation. As a result, the muscle mass of the
guishing features of the clinical syn- marily of superficial and deep muscle lay- RV is one sixth that of the LV. Because the
dromes of pulmonary hypertension and ers. The superficial layer is arranged cir- RV is much thinner than the LV, it is also
RV failure. cumferentially and is continuous with more compliant. This accounts for lower
the superficial myofibers of the LV. The filling pressures despite larger operating
Right Ventricular Anatomy and
deep layer of muscle fibers runs longitu- volumes. The difference in ventricular af-
Function
dinally from base to apex and is continu- terload is also responsible for the differ-
When ventricular function and load- ous with those of the IVS. ence in ventricular pressure-volume
ing conditions are normal, the RV ap- Right ventricular contraction occurs loops between the two ventricles. The LV
in a peristalsis-like manner, beginning produces a square-shaped pressure-
with contraction of the inlet portion and volume loop, whereas the RV pressure-
From the Division of Pediatric Critical Care Medi- ending with contraction of the infundib- volume loop is triangular in shape. This
cine (RAB), Children’s Hospital of Orange County, Or-
ange, CA, and the David Geffen School of Medicine, ulum. With contraction of the circumfer- is because RV isovolumic contraction
University of California at Los Angeles, Los Angeles, ential fibers, the RV free wall moves in- time is shorter than that for the LV as RV
CA; and the Division of Pediatric Critical Care Medicine ward, causing the short axis to shorten, systolic pressure rapidly exceeds pulmo-
(HPB), Children’s Hospital and Regional Medical Cen- whereas contraction of longitudinal fi- nary artery diastolic pressure. As RV af-
ter, and the University of Washington School of Med-
icine, Seattle, WA. bers causes the long axis to shorten. In terload increases, the RV pressure-
The authors have not disclosed any potential con- addition, the continuity of muscle fibers volume loop becomes more rounded,
flicts of interest. between the RV free wall and the IVS resembling the pressure-volume loop for
For information regarding this article, E-mail: serves as a contractile strut that, with LV the LV. Similarly, as RV afterload in-
rbronicki@choc.org
Copyright © 2010 by the Society of Critical Care contraction, further reduces the septal- creases, RV volumes and pressures in-
Medicine and the World Federation of Pediatric Inten- to-free wall distance (2, 3). Right ventric- crease, altering the orientation of the IVS
sive and Critical Care Societies ular ejection is also enhanced by the low and changing the geometry of the ventri-
DOI: 10.1097/PCC.0b013e3181c7671c impedance of the pulmonary circulation, cles. In cross section, the RV now appears

Pediatr Crit Care Med 2010 Vol. 11, No. 2 (Suppl.) S15

Figure 1. Geometry of the right ventricle (RV),
left ventricle (LV), and position of the interven-
tricular septum under normal loading conditions
(left) and in pulmonary arterial hypertension
(right). RV pressures are elevated throughout the
cardiac cycle and LV cavitary volume is severely
compromised.
spherical in shape whereas the LV be-
comes crescent-shaped in appearance
(Fig. 1).
The RV has much less contractile re-
serve than the LV and is, therefore, much
more sensitive to increases in afterload.
The functional unit of contraction, the
sarcomere, is the same for both ventri-
cles. The difference in ventricular perfor-
mance results from differences in muscle
mass as well as chamber geometry and
orientation of muscle fibers (4 –7). The
RV free wall fibers are oriented trans-
versely and simply squeeze blood by cir-
cumferential compression. In contrast,
the LV free wall and septum have pre-
dominantly obliquely oriented fibers,
which twist and shorten to eject blood
and, in doing so, generate an ejection
fraction much greater than that for the
RV (6 – 8). Ventricular geometry and fiber
orientation are responsible, in part, for
differences in ventricular performance
and contribute to the pathophysiology of
RV failure. When chamber geometry and
the position of the IVS changes, from
either left- or right-sided disease, the
normal orientation of muscle fibers is
altered. When this occurs, the septal
and/or LV free wall fibers become more
transverse than oblique in orientation,
and ventricular ejection decreases (8).
Ventricular Interdependence
The ventricles have an intimate ana-
tomical relationship. Both ventricles are
bound together by spiraling muscle bun-
dles, which encircle both ventricles in a
complex interlacing fashion forming a
functionally single ventricle. Both atria
and ventricles share a common septum,
and all of the chambers are contained
within and constrained by the pericardial
Figure 2. Geometry of the right ventricle (RV), left ventricle (LV), and interventricular septum (IVS)
during diastole and systole in isolated RV diastolic hypertension (left) and in pulmonary arterial
hypertension (right).
membrane. This intimate anatomical re-
lationship sets up a continuous physio-
logic interplay between the two ventricles
throughout the cardiac cycle, leading to
diastolic and systolic ventricular interde-
pendence. These interactions describe
how the change in the volumes and pres-
sures of one ventricle affect the volumes
and pressures of the other. Under normal
conditions, these effects are minimal.
However, ventricular interaction plays a
major role in the pathophysiology of RV
failure.
Under normal conditions, left ventric-
ular pressures are greater than right ven-
tricular pressures throughout the cardiac
cycle. As a result, the IVS bows into the
RV during diastole and systole. However,
as the transseptal pressure gradient is
altered, so too is its position between the
ventricles (Fig. 2) (9, 10). This occurs
under normal conditions. For example,
with inspiration intrathoracic pressure
falls, which enhances venous return and
RV filling. RV diastolic pressure in-
creases, reducing the transseptal pres-
sure gradient. As a result, the IVS as-
sumes a more midline position (Fig. 2).
The LV is now constrained by RV pressure
and the IVS, and as intrapericardial pres-
sure increases, additional constraint is
provided by the pericardium. As the LV
end-diastolic pressure increases, intra-
pericardial pressure rises to a greater ex-
tent and the determinant of LV filling,
the LV diastolic transmural pressure, de-
creases. As a result, LV cavitary volume,
filling, and output decrease. This mecha-
nism is partly responsible for pulsus para-
doxus, the decrease in arterial blood pres-
sure that occurs during normal
inspiration (11). If the volume load was
large, and the RV diastolic pressure rises
above that for the LV, the reversed trans-
septal pressure gradient causes the IVS to
bow into the LV cavity, and LV filling and
output become severely impaired (Fig. 2).
During systole, septal curvature normal-
izes, as LV systolic pressure is much
greater than that for the RV (Fig. 1). This
shift in direction of curvature of the IVS
results in net motion of the septum an-
teriorly or toward the RV, giving the ap-
pearance of paradoxical septal motion
(12). Systolic loading of the RV increases
RV volumes and pressures throughout the
cardiac cycle. As a result, the normal trans-
septal pressure gradient is reduced, perhaps
reversed, during diastole and systole (Fig.
2). Additionally, as impedance to RV ejec-
tion increases, the duration of RV systole
increases, contributing to a reversal of the
diastolic transseptal pressure gradient (13).
The importance of diastolic ventricular
interplay in RV failure was exemplified in a
study by Takagaki and colleagues, in which
they performed a RV exclusion procedure
for the treatment of isolated congestive
RV failure (14). Three adults (2
arrhythmo- genic RV dysplasia, 1
Ebstein’s anomaly) and 5 children (all
Ebstein’s anomaly) with significant
reductions in LV end-diastolic volume,
function and CO, and with signifi- cant
alterations in LV geometry (evaluated by
an eccentricity index) underwent the
procedure. Pulmonary blood flow was ob-
tained by a cavopulmonary connection in 6
of 8 patients while 2 patients received a
systemic to pulmonary artery shunt. Fol-
lowing the procedure, LV end-diastolic vol-
ume, function, CO, and LV eccentricity in-
dex normalized.
In addition to diastolic interaction, LV
contraction contributes to RV ejection
(15). Several studies have demonstrated
double-peaked waveforms for RV pressure
during isovolumic contraction (16, 17).
Damiano and colleagues demonstrated,
using an electrically isolated RV free wall
preparation, that one waveform was due
to RV free wall contraction, whereas the
other component was directly attribut-
able to left and septal ventricular contrac-
tion (16). The means by which RV iso-
volumic developed pressure is altered by
changes in LV performance seems to be
primarily mediated by the IVS (18). The
greater the displacement of the septum
into the RV cavity, the greater the ven-
tricular developed pressure. When RV af-
terload is elevated, LV assistance to RV
ejection is essential. As a result, when the
pressure-generating abilities of the LV
are diminished, due to inadequate pre-
load or decreased ventricular function,
the ability of the RV to generate pressure
and flow is severely compromised.
The pericardium plays a major role in
diseases, such as heart failure, by enhanc-
ing the mechanical interaction between
cardiac chambers (19, 20). An enlarged
and hypertensive atria adversely effects
ventricular compliance and filling just as
an enlarged and hypertensive ventricle
adversely effects the compliance and fill-
ing of the contralateral ventricle. With
removal of the pericardium, diastolic in-
terplay is attenuated, as is LV assistance
to RV ejection. Goldstein and colleagues
evaluated the role of ventricular interac-
tion in the pathogenesis of low cardiac
output (CO) in an experimental model of
RV infarction with and without an intact
pericardium (21). After infarction, RV
end-diastolic size increased to 210% of
control, LV end-diastolic size decreased
to 69% of control, and stroke volume and
CO decreased significantly. After pericar-
diotomy, despite an increase in RV end-
diastolic size from 210% to 298% of con-
trol, the LV diastolic transmural pressure
increased from 2.0 mm Hg to 9.2 mm Hg
(p < .001), LV end-diastolic size in-
creased from 69% to 120% of control,
and stroke volume and CO approached
baseline values. With removal of the peri-
cardium, diastolic interplay was dramat-
ically reduced, allowing for normaliza-
tion of LV filling. Further demonstrating
the importance of the pericardium in
ventricular interdependence, Page and
colleagues used an animal model of
progressive pulmonary artery constric-
tion and found the maximal pressure
the RV could generate to be linearly
related to LV systolic pressure (22). At
any LV systolic pressure, higher maxi-
mal RV pressure could be achieved with
an intact pericardium.
Response of the RV to
Increased Afterload
By and large, it is the ability of the
RV to adapt to the increase in afterload
that determines both the degree of
symptoms and survival in pulmonary
hypertension. Several factors are
important determi- nants of the
response of the RV to in- creased
afterload. The contractile perfor- mance
of the cardiomyocyte is acutely
increased with changes in the rate of
stimulation, i.e., the force-frequency re-
lationship; with changes in the end-
diastolic length of the sarcomere; and with
changes in the systolic pressure load. The
improvement in contractile performance
that occurs with these changes is the result
of alterations in the availability of or the
sensitivity of the myofilaments to calcium.
The force-frequency relationship refers to
the property of the cardiomyocyte to alter
its contractile performance with changes in
the rate of stimulation frequency. As the
stimulation rate of the myocardium in-
creases, the force of contractility increases
up to an optimal heart rate. Beyond this
rate, the force generated decreases. This
response is limited when myocardial per-
formance is impaired. Heterometric au-
toregulation (i.e., the Frank-Starling
principle) is the mechanism by which an
increase in the length of the muscle fiber
at end-diastole leads to increased ventric-
ular ejection. This results from enhanced
sensitivity of the contractile apparatus to
the prevailing cytosolic calcium ion con-
centration. When RV afterload is increased,
a length-independent mechanism termed
homeometric autoregulation results in in-
creased contractile performance (23, 24).
This phenomenon has been demonstrated
in several animal models. The precise
mechanism responsible for the acute in-
crease in myocardial performance is not
entirely clear but may involve the sensing
of an increase in ventricular stress by
mechanosensitive ion channels and alter-
ations in calcium dynamics. Another factor
that acutely enhances RV performance re-
sults from the release of endogenous cat-
echolamines. Catecholamine levels are ele-
vated in RV failure due to pulmonary
hypertension and have been shown to cor-
relate with the overall severity of cardiovas-
cular derangement (25). Data provided by
Wang and associates, however, suggested
that the response of the RV myocardium to
catecholamines seems to be much less than
that of the LV (26).
RV adaptation also depends on the ra-
pidity at which the increase in afterload
occurs and, therefore, the degree to
which the RV has undergone a compen-
satory increase in muscle mass. Several
studies have demonstrated that RV hyper-
trophy begins to take place within several
hours following an acute increase in af-
terload (27). Nonetheless, if the rate and
magnitude of the increase in RV afterload
outpace the development of ventricular
hypertrophy, RV failure will ensue. The
time of onset of disease is important. At
birth, the ventricles have similar muscle
masses as the work required of the ven-
tricles in utero is approximately equal.
After birth, however, pulmonary vascular
resistance (PVR) decreases, systemic vas-
cular resistance increases, and LV hyper-
trophic growth outpaces that for the RV
(28). However, if the RV is continuously
exposed to systemic pressure, its growth
and function parallel those for the LV (29,
30). This occurs in the presence of a non-
restrictive ventricular septal and/or aor-
tic-pulmonary communication. Ulti-
mately, with the development of a severe
elevation in PVR, there is reversal of the
previous left-to-right shunt. This leads to
arterial hypoxemia, polycythemia, and
the development of Eisenmenger syn-
drome. In these patients, LV filling is
maintained as a result of preservation of
RV systolic function and right-sided de-
compression through a ventricular septal
defect, for example, or a patent foramen
ovale (31). This is in marked contrast to
those patients in whom pulmonary hy-
pertension develops later on in life and
the unconditioned RV is unable to main-
tain systolic function. Accordingly, sur-
vival rates are dramatically worse in these
patients than in those with Eisenmenger
syndrome (32).
Another factor that some have hypoth-
esized to be a determinant of RV adapta-
tion in pulmonary hypertension is the
genotypic response of the myocardium
(33). That some patients have dispropor-
tionately less of a hypertrophic response
and develop RV failure earlier than others
with the same degree of pulmonary hy-
pertension illustrates this point. Recent
studies have demonstrated, as in the fail-
ing LV, evidence of changes in gene ex-
pression characterized by recapitulation
of the fetal gene pattern (34).
Pathophysiology of Pulmonary
Hypertension and Right
Ventricular Failure
As RV afterload is acutely increased, the
velocity and the extent to which the myo-
cyte shortens are reduced. This results in
an increase in RV operating volumes and
pressures throughout the cardiac cycle,
leading to tricuspid regurgitation and
worsening of the volume load. When the
mechanisms of contractile reserve are ex-
hausted, RV systolic failure ensues. Varying
degrees of RV diastolic dysfunction are also
present in pulmonary hypertension (35–
37). Diastolic function is related to RV
mus- cle mass and afterload and correlates
with parameters of disease severity. The
com-
 epinephrine or ligation of the aorta, LV
volume and output increased signifi-
cantly. In contrast, LV systolic pressure
was not maintained by isoproterenol. As a
result, leftward displacement of the IVS
remained unchanged and hemodynamic
deterioration ensued.
The significance of these studies is
that they highlight the pathophysiology
of low CO and the utility of and perhaps
adverse effects of conventional therapies
in the treatment of these patients. Vol-
ume loading may increase RV output or it
may lead to further increases in RV dia-
stolic volume and pressure and greater
encroachment of the IVS on the LV (41,
42). An increase in the LV filling pressure
may be interpreted as an indication of
enhanced LV filling. However, the deter-
minant of LV filling, the LV diastolic
transmural pressure, falls as intrapericar-
dial pressure has increased to a greater
extent. The hemodynamic effects of vaso-
dilators depend on the relative response
of the pulmonary and systemic circula-
tions to the agent (43– 46), as exemplified
in a study by Ricciardi and colleagues
(46). They evaluated echocardiographic
predictors of an adverse response to ni-
Figure 3. Pathophysiology of right ventricular failure due to pulmonary arterial hypertension. RV, fedipine in adults with pulmonary arterial
right ventricle; HTN, hypertension; LV, left ventricle; PVR, pulmonary vascular resistance. hypertension. They found several param-
eters, all of which reflected diminished
LV size and leftward septal deviation, to
bination of reduced RV output and dia-
stolic dysfunction enhances diastolic in-
terplay, severely impairing LV filling. As a
result, the degree to which the LV can
generate pressure and thereby assist the
failing RV decreases, setting into motion
a positive feedback mechanism— de-
creasing LV assistance to RV systole re-
duces RV output, which further compro-
mises LV filling and function, thereby
decreasing LV assistance to RV ejection
(Fig. 3). In addition to impaired LV fill-
ing, septal deviation causes the orienta-
tion of septal fibers to change from
oblique to transverse, thereby impairing
septal twisting and shortening and de-
creasing ventricular ejection from either
cavity (8).
Several studies have demonstrated the
importance of ventricular interaction in
the pathophysiology of heart failure due
to pulmonary hypertension. Gan and as-
sociates evaluated the relative contribu-
tion of diastolic interplay to LV filling in
46 adult patients with pulmonary arterial
hypertension (38). They found leftward
interventricular septum curvature to be
correlated to LV filling rate and LV end-
diastolic volume (both parameters, p <
.001), whereas left atrial filling rate was
normal and not correlated to LV end-
diastolic volume. The author concluded
that diastolic ventricular interaction is as
important, if not more important, than
reduced RV output in the pathophysiol-
ogy of the low CO state due to pulmonary
hypertension.
Belenkie and colleagues evaluated the
effects of manipulating LV afterload on
ventricular interdependence in an animal
model of acute pulmonary hypertension
(39). With aortic constriction, LV operat-
ing volumes and pressures increased sig-
nificantly. This resulted in the septum
shifting rightward, allowing for a signifi-
cant increase in LV cavitary volume and
filling. The otherwise uncompromised LV
was able to increase its output, despite
the increase in afterload. In addition, this
produced a significant increase in peak
RV systolic pressure (47 mm Hg to 68
mm Hg, p < .05), and RV output doubled
(p < .05) as a result of systolic ventricu-
lar interplay. Yamashita and associates
demonstrated similar findings in an ani-
mal model of pulmonary embolic shock
(40). In those animals where an elevated
systemic pressure was maintained by nor-
be significantly associated with nifedip-
ine-induced hypotension. With intact LV
systolic function, vasopressors increase
systemic blood pressure and, in doing so,
increase LV filling and LV assistance to
RV ejection.
Clinical Syndromes of
Pulmonary Hypertension and RV
Failure
The revised clinical classification
scheme of pulmonary hypertension (Ta-
ble 1) provides a framework for reviewing
the important distinguishing features of
the different clinical syndromes of pul-
monary hypertension and RV failure (47).
Pulmonary Venous Hypertension
Left Ventricular Heart Failure. Left
ventricular systolic and diastolic heart
failure is the most common cause of pul-
monary hypertension (48). Chronic ele-
vation of pulmonary arterial pressure due
to pulmonary venous hypertension leads
to pulmonary endothelial injury and dys-
function. In addition to the passive in-
crease in pulmonary artery pressure, en-
Table 1. Adapted from the World Health Organi-
zation classification of pulmonary hypertension
1. Pulmonary arterial hypertension
1.1 Idiopathic pulmonary hypertension
1.2 Familial
1.3 Associated with
1.3.1 Collagen vascular disease
1.3.2 Congenital systemic-to-pulmonary
shunts
1.3.3 Portal hypertension
1.3.4 Human immunodeficiency virus
infection
1.3.5 Drugs and toxins
1.3.6 Other
1.4 Persistent pulmonary hypertension of
the newborn
1.5 Pulmonary veno-occlusive disease
2. Pulmonary hypertension with left heart
disease
2.1 Left-sided atrial or ventricular heart
disease
2.2 Left-sided valvular heart disease
3. Pulmonary hypertension associated with
disorders of the respiratory system
3.1 Chronic obstructive pulmonary disease
3.2 Interstitial lung disease
3.3 Sleep-disordered breathing
3.4 Alveolar hypoventilation disorders
3.5 Chronic exposure to high altitude
3.6 Neonatal lung disease
3.7 Other
4. Pulmonary hypertension due to chronic
thrombotic and/or embolic disease
4.1 Thromboembolic obstruction of
proximal pulmonary arteries
4.2 Thromboembolic obstruction of distal
pulmonary arteries
5. Miscellaneous
Examples include sarcoidosis, histiocytosis,
compression of pulmonary vessels by tumor
or adenopathy
Adapted from Simonneau G, Galie N, Rubin
LJ, et al: Clinical classification of pulmonary hy-
pertension. J Am Coll Cardiol 2004; 43:5S-12S.
dothelial dysfunction leads to alterations
in the production of nitric oxide and en-
dothelin, increasing vasomotor tone and
further elevating PVR (49, 50). Pathologic
vascular remodeling also takes place, in
part, due to the effects of endothelin on
smooth muscle cell proliferation and
phenotype. Right ventricular failure may
develop due to increases in RV afterload,
reduced systolic ventricular interplay,
and inadequate coronary perfusion due
to low CO. Several studies in adults
have found the presence of RV failure to
portend a worse outcome (51, 52).
There are several important distin-
guishing features of pulmonary hyperten-
sion resulting from LV failure. First, LV
diastolic volume and pressure are ele-
vated; therefore, diastolic interplay does
not play a significant role in the patho-
physiologic process. The RV diastolic
transmural pressure is greatly reduced
and, as a result, RV compliance and vol-
ume are reduced, impairing RV filling.
Second, the increase in pulmonary ve-
nous pressure is transmitted to the pul-
monary microvasculature and may lead
to cardiogenic pulmonary edema. If the
rise in hydrostatic pressure occurs grad-
ually, adaptive changes take place within
the pulmonary vasculature and lymphat-
ics that minimize the formation of pul-
monary edema (53, 54). If however the
hydrostatic pressure rises rapidly to high
levels, alveolar epithelial and endothelial
ultrastructural changes take place, which
are consistent with those seen in perme-
ability pulmonary edema (55, 56). This
results in alveolar edema, impaired oxy-
genation, and may contribute to further
increases in PVR. Third, the isolated re-
duction of RV afterload exacerbates LV
congestive heart failure without improv-
ing CO (57, 58). Semigran and associates
evaluated the hemodynamic effects of in-
haled nitric oxide (iNO) in 16 adult pa-
tient with New York Heart Association
class III or IV heart failure (57). The iNO
led to a significant decrease in PVR and a
marked increase in left ventricular filling
pressures without a change in CO. How-
ever, biventricular afterload reduction
with nitroprusside produced significant
decreases in PVR, systemic vascular resis-
tance, and left ventricular filling pres-
sures and significant increases in CO.
Similar findings have been demonstrated
recently with the use of sildenafil in pa-
tients with LV heart failure and pulmo-
nary hypertension (59, 60). Sildenafil
produces similar reductions in PVR and
systemic vascular resistance and, as a
result, left ventricular filling pressures
decrease and CO increases significantly.
Argenziano and colleagues demon-
strated the utility of iNO in patients
with severe LV heart failure whose LV
was unloaded with placement of a left
ventricular assist device but whose flow
rate was limited by elevated PVR (61).
The use of iNO in this setting allowed
for a significant increase in left ventric-
ular assist device flow (1.9 L/min/m2 to
2.6 L/min/m2, p = .005).
Left-Sided Obstructive Lesions. Total
anomalous pulmonary venous return
(TAPVR) is associated in a majority of
cases with varying degrees of obstructed
pulmonary venous return and pulmonary
hypertension. Obligatory right-to-left
shunting occurs through an atrial septal
defect and maintains systemic output. In
“obstructed” TAPVR, pulmonary artery
pressures may be suprasystemic, whereas
“unobstructed” TAPVR is typically associ-
ated with at least modest pulmonary hy-
pertension (62). The most common pre-
sentation of TAPVR is a combination of
pulmonary venous obstruction and in-
creased pulmonary blood flow. As a re-
sult, the RV is volume- and pressure-
loaded, producing s i g n i ficant
RV enlargement. This leads to marked
sep- tal deviation throughout the cardiac
cy- cle and impaired LV filling (63).
Thera- pies that decrease PVR
increase pulmonary blood flow and
pulmonary edema, and do not improve
systemic output. Postoperatively, iNO
reduces PVR and improves CO (64). As
RV load- ing conditions and size
normalize, so too does the position of
the IVS and LV dimensions (63).
Mitral stenosis leads to pulmonary hy-
pertension and may over time lead to RV
dysfunction. As with obstructed TAPVR,
therapies that decrease PVR increase pul-
monary blood flow and may precipitate
pulmonary edema without improving
CO. Atz and colleagues evaluated the use
of iNO in 15 children with pulmonary
hypertension due to congenital mitral
stenosis (65). The iNO produced signifi-
cant reductions in PVR and pulmonary
artery pressures without appreciable
changes in left atrial pressure. Cardiac
output, however, remained unchanged.
Similar findings were demonstrated by
Mahoney and associates in their study of
iNO in adults with mitral stenosis (66).
Hess and colleagues evaluated the effects
of amrinone in 12 adult patients with
mitral stenosis and RV dysfunction (67).
The combined inotropic and vasodilating
properties of amrinone produced signifi-
cant reductions in PVR and pulmonary
arterial pressures as well as significant
increases in CO without an appreciable
change in left atrial pressure.
Aortic stenosis and coarctation of the
aorta cause pulmonary hypertension.
There is considerable variation in the
clinical presentation of these lesions.
Those presenting in the neonatal period
are critically ill with severe elevations in
pulmonary artery pressures. This is due,
in part, to elevated left atrial pressure
and, in part, to excessive pulmonary
blood flow, resulting from left-to-right
shunting through a patent foramen
ovale. Left-sided decompression and pul-
monary overcirculation, as well as pul-
monary hypertension, lead to right heart
enlargement and deviation of the IVS.
Pulmonary Hypertension With
Disorders of the Respiratory
System
A wide range of pediatric respiratory
disorders are associated with pulmonary
hypertension. These include dysfunction
of the respiratory center, diseases of the
airway, parenchymal lung injury, and de-
formities of the chest wall. The common
denominator for these diseases and the
primary mechanism responsible for pul-
monary hypertension is alveolar hypoxia
(PO2 <60 mm Hg), leading to hypoxic
pulmonary vasoconstriction (HPV). The
hypoxia sensing mechanisms are largely
unknown but include alterations in nitric
oxide metabolism. Regional HPV due to
localized lung disease improves ventila-
tion-perfusion matching by redistribut-
ing pulmonary blood flow to better ven-
tilated areas without significant changes
in pulmonary arterial pressure. However,
diffuse alveolar hypoxia produces diffuse va-
soconstriction and leads to pulmonary hy-
pertension. Chronic alveolar hypoxia leads
to vascular remodeling and further in-
creases in pulmonary arterial pressures.
Acute lung injury/acute respiratory
distress syndrome are commonly associ-
ated with at least a moderate degree of
pulmonary hypertension. This is due to
alveolar hypoxia and pulmonary endothe-
lial injury and dysfunction, resulting
from activation and adhesion of platelets,
neutrophils, and monocytes. Selective
pulmonary vasodilation with iNO im-
proves oxygenation acutely in a majority
of patients with acute lung injury. The
iNO is delivered preferentially to areas of
the lung that are well ventilated, redis-
tributing blood from poorly ventilated to
well-ventilated areas of the lung, thereby
optimizing gas exchange (68). The use of
nonselective intravenous vasodilators in
patients with ventilation-perfusion mis-
match reduces pulmonary arterial pres-
sures but will also release HPV and lead
to worsening arterial hypoxemia. In pa-
tients with RV dysfunction, iNO has also
been shown to reduce pulmonary arterial
pressures and improve CO (69, 70).
In patients with pulmonary hyperten-
sion and respiratory failure, the use of
positive-pressure ventilation may con-
tribute to additional increases in pulmo-
nary arterial pressure (71–73). The use of
large tidal volumes or tidal volumes su-
perimposed on an elevated functional re-
sidual capacity significantly increases
PVR. This primarily results from com-
pression of interalveolar vessels. This is
an important consideration when using
positive-pressure ventilation, particularly
in patients with underlying pulmonary
vascular disease and/or RV dysfunction.
Jardin and colleagues demonstrated in
patients with acute respiratory failure
and normal RV function that CO fell with
progressive increases in positive end-
expiratory pressure (72). This resulted
from progressive increases in PVR and
gradual impairment in RV systolic perfor-
mance; i.e., the decrease in systemic out-
put was the result of a decrease in RV
output and diastolic interplay, rather
than a decrease in venous return.
Pulmonary Arterial Hypertension
Congenital Heart Disease. A nonre-
strictive aorta-pulmonary communica-
tion or ventricular septal defect allows for
the complete transmission of systemic
pressures to the pulmonary vasculature.
By definition, these patients have pulmo-
nary hypertension. The primary determi-
nant of flow is the relative resistance of
the two circulations. Over time, this he-
modynamic state leads to progressive
structural and functional abnormalities
of the pulmonary vasculature. These
changes involve abnormal extension of
smooth muscle into the peripheral arter-
ies and medial hypertrophy and alter-
ations in the release of vasoactive sub-
stances, such as nitric oxide and
endothelin (74 –77). Endothelin plays a
major role in the pathologic remodeling
that occurs in the pulmonary vascula-
ture. From birth, the RV is exposed to
systemic pressures, resulting in ventric-
ular hypertrophy and maintained systolic
performance. As PVR increases, the
shunting of blood changes from purely
left to right to bidirectional in nature.
Whereas oxygen content decreases, sys-
temic output and systemic oxygen deliv-
ery is maintained. As PVR increases fur-
ther and approaches that of the systemic
circulation, the patient becomes increas-
ingly more cyanotic. Additional vascular
remodeling leads to obliteration of the
pulmonary vasculature and precludes
corrective surgery. The effects of vasodi-
lators depend on the degree to which the
pulmonary circulation is reactive and the
relative resistance in the pulmonary and
systemic circulation before initiation of
therapy (78).
For those patients undergoing correc-
tive surgery, the use of cardiopulmonary
bypass contributes to postoperative in-
creases in PVR and pulmonary artery
pressures (79). Ischemia-reperfusion in-
jury and the attendant inflammatory re-
sponse resulting from the use of cardio-
pulmonary bypass lead to pulmonary
endothelial dysfunction, including de-
creased production of nitric oxide (80).
Nitric oxide production is also impaired
due to decreased availability of nitric ox-
ide precursors, such as L-arginine after
cardiopulmonary bypass (81). iNO or ni-
tric oxide donors, such as nitroprusside
or nitroglycerin, reduce PVR and pulmo-
nary arterial pressures as pulmonary vas-
cular smooth muscle cell function is in-
tact. After corrective surgery, vasodilators
reduce PVR and improve CO. Nonselec-
tive vasodilators as well as iNO are effec-
tive at reducing postoperative elevations
in PVR (82, 83). The adverse hemody-
namic effects of an increase in RV after-
load are compounded by the presence of
RV dysfunction, which may result from
the effects of cardiopulmonary bypass on
the myocardium, for example, as well as
from the surgery itself (such as right ven-
triculotomy).
Conclusion
Pulmonary hypertension is common
in pediatrics, usually as a secondary phe-
nomenon associated with a myriad of
conditions. Regardless of the etiology, in-
creases in RV afterload lead to a number
of compensatory changes in cardiac phys-
iology. The complex interplay between
the pulmonary and systemic circulations
means that increased demand on the RV
is not isolated to the right side of the
heart. As we have shown, these relation-
ships are not altogether intuitive. An un-
derstanding of RV physiology and ventric-
ular interdependence is essential to
optimizing the care of these patients.
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