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NONPHARMACOLOGICAL STRATEGIES
Myocardial Repair and Regeneration
As noted in Chap. 22 , HF may develop as a consequence of myocyte loss or dysfunction,
eventually leading to left ventricular remodeling and cardiac decompensation. Replacement
of dead or dysfunctional cardiac myocytes through cell-based therapies represents a logical
and novel option for the treatment of HF. As will be discussed subsequently, cell-based
therapies may achieve true cardiac regeneration by renewing the pool of functionally active
cardiac myocytes, or may lead to cardiac repair by supporting neovascularization,
supplementing and/or augmenting the cytoprotective mechanisms that occur naturally, or by
favorably influencing the remodeling processes. The promise of cellular cardiomyogenesis,
neovascularization, and additional cell-mediated beneficial effects, individually or in
combination, offers altogether novel opportunities for tailored treatment of the underlying
pathobiology.
Stem/Progenitor Cells
In general, two types of stem cells should be discussed separately: embryonic stem cells and
adult stem cells ( Fig. 29-1 ). Whereas embryonic stem (ES) cells clearly have the capacity
to give rise to all cell types of the body and are able to form tissues and organs, most adult
stem cells are more specific (more lineage committed) and the use of adult stem cells for
organogenesis has not yet been explored. Embryonic stem cells are derived from the inner
cell layer of the early embryonic trophoblast and can be propagated in cell culture in an
undifferentiated state infinitely. By changing the cultivation conditions (the so-called
hanging drop technique), embryonic stem cells aggregate and form embryoid bodies, an
early embryonic tissue consisting of all three germ layers. Within an embryoid body,
approximately 5 to 10 percent of embryonic stem cells spontaneously differentiate into
cardiomyocytes. Functionally active cardiomyocytes (ESC-CM) have been generated from
mouse as well as from human ES cells (hESC-CM), although the E-C coupling properties of
hESC-CM differ from the adult myocardium.[1] ES cell-derived cardiomyocytes show
macromolecular sarcomeric organization, calcium sparks, ionic currents, functional and
anatomical integration with surrounding cardiomyocytes, and propagation of electrical
activity as well as pacemaker activity.[1] Collectively, these data demonstrate that ES cells
spontaneously differentiate into fully functionally active, fetal-like cardiomyocytes in vitro.
Although these in vitro data would suggest that ES cells are ideal candidates for in vivo
cardiac repair, animal studies have shown a dose-dependent incidence of tumor formation,
in particular, teratocarcinoma formation, after transplantation of ES cells into mice. Several
strategies aiming to specifically select differentiated cardiomyocytes to exclude highly
proliferating ES cells with a tumor-forming capacity are currently being tested. An
additional question relates to the immunogenic activity of ES cells in an allogenic setting. It
is unclear whether the low immune privilege proposed by experimental studies is
maintained when the ES cells are differentiated and functionally integrated into the human
heart for a long time. Therefore, the safety of ES cell transplantation remains an unsolved
question.[2]
FIGURE 29-1 Cell types and mode of delivery of cells for cardiac repair. A, Cell types used for
cardiovascular repair. B, Delivery strategies used in the clinical setting for cell therapy. MSCs =
mesenchymal stem cells. (From Dimmeler S, Zeiher AM, Schneider MD: Unchain my heart: The
scientific foundations of cardiac repair. J Clin Invest 115:572-583, 2005.)
Adult stem cells comprise at least three different groups: bone marrow-derived stem cells,
the circulating pool of stem or progenitor cells (which at least in part are derived from the
bone marrow), and tissue-resident stem cells (see Fig. 29-1 ). Bone marrow-derived stem
cells are the best studied and were used in most of the clinical trials performed thus far.
Bone marrow contains a complex assortment of progenitor cells, including hematopoietic
stem cells (HSCs), the so-called side population cells (SP cells, defined by the expression
of the Abcg2 transporter allowing export of Hoechst dye),[3] mesenchymal stem cells
(MSCs) or stromal cells,[4] and multipotential adult progenitor cells (MAPCs), a subset of
MSCs.[5]
Circulating blood-derived progenitor cells were initially discovered when searching for proangiogenic cells for therapeutic vasculogenesis. Asahara and Isner isolated endothelial
progenitor cells (EPCs), which were defined by their ability to form new blood vessels and
enhance neovascularization after ischemia (for review see references 6 and 7 [6] [7]). Based
on the assumption that these cells may represent adult hemangioblasts, these cells were
characterized by the expression of hematopoietic markers, such as CD133+ or CD34+, and
endothelial markers for VEGF-receptor 2 (KDR or flk-1). However, it is evident that these
circulating progenitor cells (particularly when cultured in vitro) comprise several different
entities.[6] Individual cells may have clonal potential and stem cell characteristics. Others,
including distinct myeloid subpopulations, may preferentially act as pro-angiogenic cells,[8]
in addition to their capacity to differentiate to endothelial cells. Myeloid cells also have
been shown to contribute to muscle regeneration by fusion, indicating that myeloid
subpopulations may act diversely. An interesting source of endothelial progenitor cells is
placental cord blood, which is enriched in clonally expandable endothelial progenitor cells.
Mesoangioblasts are vessel-associated multipotent progenitors that express the key marker
of angiopoietic progenitors, VEGF-receptor 2, but are distinct from hematopoietic
endothelial progenitor cells. In vitro mesoangioblasts differentiate into many mesoderm cell
types, such as smooth, cardiac and striated muscle, bone and endothelium, and they improve
skeletal muscle dystrophy and heart function. [9] [10] Mesoangioblasts may represent not only
a source of progenitors for therapeutic applications, but also may establish a lineage
relationship between progenitors of vascular and extravascular mesodermal tissues.
The discovery of tissue-resident stem cells in the heart, the cardiac stem cells, offers the
potential to harvest cells, which are primed to acquire a cardiac phenotype and, therefore,
might be optimally suited for cardiac repair. Several different populations have been
identified and characterized: c-Kit+ cells,[11] Sca-1+ cells,[12] SP cells, and cells expressing
the protein Islet-1.[13] Whereas c-Kit+ cells, Sca-1+ cells and cardiac SP cells are isolated
from adult hearts, cells expressing Islet-1 so far have only been detected in the postnatal
stage. Whether c-Kit+, Sca-1+, and cardiac SP cells comprise three different cell
populations is not entirely resolved. At least Sca-1+ cells contain a fraction of SP cells and,
among cardiac SP cells, the greatest potential for cardiomyogenic differentiation is
restricted to cells positive for Sca-1 expression (but negative for CD31)[14]indicating that
the two cell populations may share some common features. Cardiac stem cells also were
obtained by growing self-adherent clusters (termed cardiospheres) from subcultures of
murine or human biopsy specimens. Others have generated cardiac SP cellderived
cardiospheres by adapting a method used for creating a neurosphere and claimed that
functional improvement of the heart was seen even in experimental studies, where no
formation of new cardiomyocytes was detected. Therefore, additional mechanisms initiated
by cell therapy most likely contribute to functional cardiac repair ( Fig. 29-3 ).
FIGURE 29-2 Homing of bone marrow-derived stem cells to the myocardium. The fate of bone
marrow-derived stem cells is determined by the microenvironment that they enter. (From Anversa P,
Leri A: Myocardial rengeneration. In Zipes DP, Libby P, Bonow RO, Braunwald E [eds]:
Braunwald's Heart Disease, 7th ed. Philadelphia, Elsevier, 2004, p 1917.)
Murine BMC
Wnt3a
Wnt11
Human EPC
MSC
Murine ES cells
5-azacytidine MSC
Factor
Cell Type
Citation
BMP
Noggin
Murine ES cells
BMC = bone marrow mononuclear cells; EPC = endothelial progenitor cells; ES cells =
embryonic stem cells; MSC = mesenchymal stem cells.
Tissue Engineering
In contrast to cell therapy, where individual cells are supposed to integrate in the scar tissue,
tissue engineering in its pure sense aims at providing tissue grafts. Larger constructs of
heart muscle can be generated by using heart cell populations to form engineered heart
tissue. So far, it has been challenging to generate tissue in vitro with contractile force and at
a size sufficient to support the failing heart. Several culture conditions have been used in
combination with cell mixtures (e.g., neonatal cardiomyocytes, fibroblasts, skeletal
myoblasts, adult and embryonic stem cells) for creating myocardial tissue in vitro.
Implantation of engineered rat heart tissue from neonatal rat cardiomyocyte in rats after
myocardial infarction improved the contractile function and was shown to be electrically
coupled to the native myocardium.[24] Others have used engineered tissue constructs
containing skeletal muscle derived cells, and the authors claimed that skeletal muscle
cellsin contrast to the results achieved with skeletal muscle cell therapyare electrically
coupled by Gap junctional proteins.[25] Embryonic stem cells are alternative sources for the
generation of heart tissue in vitro.[26] The size of the engineered heart tissue constructs
(unless vascularized and perfused) is limited by oxygen diffusion. Therefore, researchers
have fused several individually cultured single engineered tissue rings.
At the interface between tissue engineering and cell therapy, the development of novel
biomaterials has gained increasing interest. Novel biomaterials have been developed to be
used as ventricular restraints and to provide scaffolds for in vitro tissue engineering. [27] [28] In
addition, the injection of new biomaterial such as self-assembling nanofibers can adapt the
intramyocardial cellular microenvironments to augment homing and functional integration
of cells for in situ tissue engineering and subsequent cardiac regeneration and repair.
ROUTES OF APPLICATION.
Progenitor cells for cardiac repair can be delivered in different ways (see Fig. 29-1 ):
Intracoronary infusion using standard balloon catheters has been used in all clinical trials
treating patients with acute myocardial infarction. This technique offers the advantage
that cells can travel directly only into myocardial regions in which nutrient blood flow
and oxygen supply are preserved, thereby ensuring a favorable environment for cell
survival, a prerequisite for stable engraftment. Conversely, homing of intraarterially
applied progenitor cells requires migration out of the vasculature into the surrounding
tissue, which may mean that unperfused regions of myocardium will be targeted far less
efficiently, if at all. Whereas bone marrow-derived and blood-derived progenitor cells are
known to extravasate and migrate to ischemic areas, other cell types may not, and they
may even obstruct the microcirculation after intraarterial administration, leading to
embolic myocardial damagethus limiting the use of intracoronary delivery.
Injection of cells into the ventricular wall via a percutaneous endocardial or surgical
epicardial approach is an alternative delivery strategy circumventing some of these
limitations: Direct delivery of progenitor cells into scar tissue or areas of hibernating
myocardium by catheter-based needle injection, direct injection during open-heart
surgery, and minimally invasive thoracoscopic procedures are not limited by cell uptake
from the circulation or by embolic risk. An offsetting consideration is the risk for
ventricular perforation, which may limit direct needle injection into freshly infarcted
hearts. In addition, it is hard to envisage that progenitor cells injected into uniformly
necrotic tissuelacking the syncytium of live muscle cells that may furnish instructive
signals, and lacking blood flow for the delivery of oxygen and nutrientswould receive
the necessary cues and environment to engraft and differentiate. Most cells, if injected
directly, simply die. For this reason, electromechanical mapping of viable but
hibernating myocardium may be useful to pinpoint the preferred regions for injection.
Finally, in diffuse disease-like dilated nonischemic cardiomyopathy, focal deposits of
directly injected cells might be poorly matched to the underlying anatomy and
physiology. Thus, it is likely that nature of the patients' cardiomyopathy will ultimately
influence, if not dictate, the source and route chosen among potential progenitor cell
therapies. Additional strategies to augment cell homing and promoting homogeneous
integration of cells may be required, particularly in patients with chronic healed infarcts
or diffuse nonischemic cardiomyopathy lacking active recruitment signals.
N = 10 8
(Nov
03: N =
40)
versus
ctrl.
BMC
40 ml
28
Regional
contractility
(LVA)
Study
Days
Patient after Cell
No.
AMI Type
Cell Number
Cell Preparation (106)
Safety
Myocardial
Function
Ficoll
overnight Teflon
End systolic
volume
(LVA)
Perfusion
(Szinti)
TOPCARE 59
= AMI[30]
4.9
CPC
16
Global
contractility
(LVA/MRI)
BMC
50 ml/Ficoll
same day
213
End systolic
volume
(LVA/MRI)
Viability
(MRI)
Flow reserve
(Doppler)
Fernandez- 20
Aviles[34]
13.5 BMC
50 ml
78
Global
contractility
(MRI)
Ficoll
overnight Teflon
End systolic
volume
Study
Days
Patient after Cell
No.
AMI Type
Cell Number
Cell Preparation (106)
Safety
Myocardial
Function
(MRI)
Ruan, et
al.[56]
10
versus
(rand.)
100
BMC
versus
saline
Global
contractility
(LVA)
Bartunek, et 12
al.[57]
14
Stenosis? Global
contractility
(LVA)
Chen, et
al.[58]
34
versus
35
18
Global
contractility
(LVA)
Randomized Trials
Single/Two Center(s)
BOOST[33]
60
1:1
rand.
4.8
BMC
versus
rand.
6 Months:
Global
contractility
(MRI)
18 Months:
No
significant
difference
(MRI)
18 Months:
Diastolic
Study
Days
Patient after Cell
No.
AMI Type
Cell Number
Cell Preparation (106)
Safety
Myocardial
Function
dysfunction
(Echo)
Janssens, et 67
al.[35]
<24
h
BMC
versus
i.c.
placebo
Ficoll density
gradient
centrifugation
few hours after
acute PCI
304
1:1
rand.
Global
contractility
no change
Infarct size
(MRI)
ASTAMI[36] 100
BMC
versus
rand.
Lymphoprep
controlnext
day infusion
87
Global
contractility
no change
Global
contractility
1:1
rand.
MulticenterPlacebo-Controlled, Double-Blind
REPAIR 1 : 1
204 AMI[37] rand.
BMC
versus
i.c.
placebo
Ficoll density
234
gradient
centrifugation
same or next day
infusion
(QLVA)
AMI = acute myocardial infarction; BMC = bone marrow-derived progenitor cells; CPC =
circulating progenitor cells; i.c. = intracoronary; LVA = left ventricular angiography; MRI
= magnetic resonance imaging; QLVA = quantitative LVA; rand. = randomized trial.
TABLE 29-3 -- Studies with Infusion/Injection of Progenitor Cells in Patients with Old
Myocardial Infarction or Chronic Heart Failure
Status Post
Safety and Functional
Study
N
MI
Cells
Application Assessment
Application with NOGA
Study
Status Post
MI
Cells
Tse, et al.[59]
N=8
Old MI
BMC
Application
IM with
NOGA
thickening
Fuchs, et al.
[50]
N = 10
Old MI
BMC
N = 21
Perin, et al.[49]
Control N = Old MI
7
BMC
IM with
NOGA
Safe
IM with
NOGA
Global contractility
BMC N =
14
Safe
>10 days
after AMI
CD
133+
BMC
IM during
CABG
Safe
Global contractility
Perfusion
Hamano, et
al.[61]
N=5
Galinanes, et
al.[51]
BMC N =
11
Old MI
BMC
IM during
CABG
Safe
Old MI
BMC
IM during
CABG
Safe
N = 34
CABG N =
11
Global contractility
CABG +
BMC: N =
10
Intracoronary Administration
IACT[52]
N = 18
Old MI
BMC
Intracoronary
Safe
Study
Status Post
MI
Cells
Application
5 months to
8.5 years
(LVA/MRI)
Viability
TOPCARE
CHF[53]
N = 92
Old MI
Control N = 3 months23
12 years
BMC
CPC
Intracoronary
(pet)
Safe
Global contractility
Of note, all of the above cited studies used the total population of bone marrow
mononuclear cells, which contain roughly 2 to 3 percent CD34+ cells but also contain SP
cells, mesenchymal cells, and potentially other not yet identified cell populations. However,
patients after acute myo-cardial infarction treated with ex vivo expanded circulating bloodderived EPC in one arm of the TOPCARE-AMI trial showed a similar improvement in heart
function compared to BMCindicating that selected subpopulations might have a similar
capacity for functional repair at least in the acute myocardial infarction setting.[30] Likewise,
the infusion of isolated CD133+ cells, which are enriched for EPC, improved global
ejection fraction in patients with acute myocardial infarction.
The beneficial effects seen in most of the pilot phase I/II studies were confirmed in the
recent so-far-largest double-blind, randomized, multicenter REPAIR-AMI trial.[37] This
study used bone marrow mononuclear cells and demonstrated a significant improvement of
global and regional ejection fraction in the BMC group (+5.5 percentage points) compared
to placebo (+3 percentage points) 4 months after follow-up ( Fig. 29-4 ). End-systolic
volumes significantly increased in the placebo group, but remained unchanged in the BMC
group. Interestingly, although the study was not powered to address a potential benefit on
clinical endpoints, the incidence of the cumulative endpoints death, myocardial infarction,
and rehospitalization for HF was significantly lower in the BMC-treated patients compared
to placebo after 1-year follow up.
FIGURE 29-4 Principal results of the REPAIR-AMI trial. Interaction between baseline left
ventricular ejection fraction and the absolute change in left ventricular ejection fraction (panel A) and
between the timing of intracoronary infusion of BMC or placebo after reperfusion therapy and the
absolute change in left ventricular ejection fraction (panel B). In panel A, the P value for interaction
was determined by analysis of variance. In both panels, the upper and lower edges of each box plot
indicate the 25th and 75th percentiles, the whiskers the 10th and 90th percentiles, the solid
horizontal line the median, and the dashed line the mean. All outliers are shown as individual data
points. In panel B, the P value for interaction was calculated with the use of a general linear model.
The solid line in panel B shows the regression curve for the BMC group, and the dotted line shows the
regression curve for the placebo group. (From Schachinger V, Erbs S, Elsasser A, et al: Intracoronary
bone marrow-derived progenitor cells in acute myocardial infarction. N Engl J Med 355:1210-1221,
2006.)
What variables might influence outcome? The larger number of patients enrolled in the
REPAIR-AMI trial allowed for testing several predefined secondary endpoints to generate
hypotheses for the next generation trials. There was a significant interaction between the
baseline ejection fraction and the improvement seen after BMC therapy. Patients with a
lower ejection fraction (<48.9 percent) showed a significant, threefold higher recovery in
global ejection fraction indicating that patients with more severe myocardial infarction
benefit the most from BMC therapy. Indeed, the beneficial effect on clinical endpoints
was also preferentially observed in those patients with a lower baseline ejection fraction
after myocardial infarction. This observation confirmed the previous results of the
TOPCARE-AMI pilot trial. A second predefined end point addressed the question
whether the timing of BMC delivery affects the outcome. Surprisingly, patients who had
been treated up to 4 days after the myocardial infarction showed no benefit, whereas later
treatment (day 4 to 8) provided an enhanced improvement of ejection fraction during
follow-up. Given that several experimental studies demonstrated that the cells provide a
cytoprotective activity coinciding with a reduction of cardiomyocyte apoptosis, one would
have expected that early timing of cell infusion would have been the most efficient. Based
on the data of the REPAIR-AMI trial, one may speculate that the microenvironment after
acute myocardial infarction changes during the first week after reperfusion, thereby
modulating the homing and/or the subsequent functional activity of the infused cells.[37] It
is well known that ischemia/reperfusion induces a transient change in the expression of
chemoattractive factors such as VEGF and SDF-1, which are known to be essential for
stimulating the recruitment and retention of cells in the tissue. Moreover, the initial edema
formation is followed by a transient invasion of different waves of cells. Therefore, it is
conceivable that cell homing might be best a few days after reperfusion rather than
immediately. Further studies are warranted to prospectively address this question.
Overall, the clinical data available indicate that cell therapy with bone marrow-derived cells
is feasible and safe at least for the follow-up presently available (up to 5 years in the
pioneering studies). None of the studies so far reported an increased incidence of
arrhythmias (as has been seen in myoblast trials). Moreover, restenosis, which was
considered as a potential side effect by progenitor cell-mediated plaque angiogenesis or
plaque inflammation, was increased only in one study using CD133+ cells.[38] Because
CD133+ cells were isolated by using a mouse antibody, one may speculate that the
remaining antibody might have elicited a local proinflammatory reaction, despite the failure
to detect systemic anti-mouse antibodies in the patients. All other studies did not observe an
augmented risk for restenosis; if anything, there was a significantly decreased necessity for
revascularization procedures in the REPAIR-AMI trial.
An important issue is whether the improvement seen during the initial 6 months after cell
therapy is maintained for a prolonged time. Careful evaluation of the 18 months follow-up
data of the BOOST trial indicates that the ejection fraction of the cell therapy group is
maintained from 6 to 18 months of follow-up; however, the difference between the cell
therapy and the control group was no longer statistically significant because of
improvement in ejection fraction in the control group. The small number of patients (30 per
group) may preclude detecting a statistical difference between the two groups. The long
term 2-year follow-up MRI-derived data of the TOPCARE-AMI trial showed that the
ejection fraction is maintained and even further augmented in the treated patients, in parallel
with a sustained reduction in NT-proBNP serum levels, suggesting a beneficial effect of
long term left ventricular remodeling (S. Dimmeler and A. M. Zeiher, unpublished data).
Taken together, these data may provide the rationale to assess the effects of intracoronary
BMC infusion on clinical outcome in a large patient cohort with severe acute myocardial
infarction.
which the initial patients were treated with G-CSF before coronary artery stenting.
However, the reports of an increased incidence of myocardial infarctions and episodes of
angina and arrhythmias during treatment with G-CSF in patients with chronic ischemic
cardiomyopathy should continue to raise some concerns as to whether a G-CSF-induced rise
in leukocyte number may be responsible for plaque growth or destabilization. Accordingly,
in the future, it may be preferable to develop strategies that augment circulating progenitor
cells without the simultaneous induction of massive inflammation.
TABLE 29-4 -- Studies Using Mobilization of Progenitor Cells with Granulocyte ColonyStimulating Factor
Status
Post
Functional
Study
N
MI
Cells
Safety
Assessment
FIRSTLINEAMI[42]
N = 50 1 : 1
rand.
Kuethe, et
al.[43]
STEMMI[44]
G-CSF 10
g/kg, 6 days
safe
Global
contractility
N = 14 versus Acute
MI
N = 9 control
G-CSF 10
g/kg, 7 1
days
safe
Global
contractility
N = 78
Acute
MI
G-CSF 10
g/kg, 6 days
safe
No change
Acute
MI
G-CSF 10
g/kg, 5 days
safe
No change
Rand.,
double-blind,
placebocontrolled
Acute
MI
REVIVAL[45]
N = 114
JAMA 2006
Rand.,
placebo
controlled
Hill, et al.[54]
N = 16
Old MI G-CSF 10
g/kg, 5 days
No change
N = 16
Old MI G-CSF 10
g/kg, 4 times
10 days
DCM
Occasional episodes
of angina
Six minute
walking
JACC 2005
Huttmann, et
al.[55]
ICM: N = 9
DCM: N = 7
Ventricular
fibrillation
distance
Study
MAGIC
N
[47]
N = 10
Status
Post
MI
Cells
Safety
Functional
Assessment
Global
contractility
Restenosis
(methodological
limitations; see text)
Erbs, et al.[31]
N = 26
Rand.,
placebo
controlled
MAGIC cell3-DES[46]
N = 96
AMI control
(N = 25)
safe
Global
contractility
safe
AMI: global
contractility
AMI cell (N =
25)
ICM control
(N = 16)
ICM: no
change
ICM cell (N =
16)
AMI = acute myocardial infarction; CPC = circulating progenitor cells; DCM = dilated
cardiomyopathy; G-CSF = granulocyte colony-stimulating factor; ICM = isolated
cardiovascular malformation; MI = myocardial infarction.
Cell Therapy and Cell Mobilization Strategies in Patients with Chronic Heart
Failure
In patients with chronic ischemic heart disease and a prior myocardial infarction, the results
of the initial attempts at cell-based myocardial repair have been more heterogeneous, and
the number of patients that have been treated has been less when compared to acute
myocardial infarction trials. The first cell-based therapy trial used skeletal muscle-derived
progenitor cells, which were directly injected into the scarred region of the left ventricle
during open heart surgery for coronary artery bypass grafting. Global and regional left
ventricular function were significantly and persistently improved. However, the
concomitant coronary artery revascularization confounded the assessment of true benefit in
these studies. Indeed, in patients not undergoing simultaneous revascularization, the
transcatheter injection of myoblasts into the preexisting (5 to 6 year old) postinfarction scar
tissue led to a reduction in the symptoms of HF without any objective evidence of an
Three published studies addressed the possibility to use intracoronary delivery of BMC by
a balloon catheter. The IACT study tested the feasibility of BMC infusion in patients with
chronic HF and demonstrated a substantial increase in ejection fraction (+15 percent) in
patients with healed (>3 months old) myocardial infarction.[52] Smaller, but significant,
improvements were also seen in the randomized controlled trials by Erbs and colleagues
and the TOPCARE-CHF study. Erbs and colleagues infused G-CSF mobilized, ex vivo
cultivated endothelial progenitor cells in a recanalized coronary artery.[31] Coronary flow
reserve in response to adenosine and global ejection fraction were improved in the celltreated patients compared to recanalization without cell therapy. A smaller, but
significant, improvement was also observed in the TOPCARE-CHF study.[53]
Interestingly, this study was the first to examine a direct side-by-side comparison of two
different cell types in patients with old myocardial infarctions. In this patient cohort,
BMCs were shown to be significantly better as compared to circulating progenitor cells.
This is in contrast to the TOPCARE-AMI trial, wherein BMC and EPC showed a similar
effectiveness in acute myocardial infarction patients.[30] The reason for this discrepancy is
unclear. One may speculate that the number and function of circulating cells is further
impaired in HF patients and that an additional mobilization step is required to yield a
sufficiently high number of functionally active cells (as done by Erbs and colleagues).
Another potential explanation may relate to the combination of a lower number of EPC
applied (22 10[6] compared to 205 10[6] BMC) and/or a reduced homing capacity in the
chronic setting, which might limit the efficiency of EPC.
Finally, as discussed extensively earlier, different cell types may activate different
mechanisms which may be more or less beneficial in acute versus chronic ischemic HF.
Mobilization of progenitor cells with G-CSF without intracoronary reinfusion did not result
in any measurable benefit on left ventricular function, but was associated with adverse
coronary events in two studies. [54] [55]
heightened predisposition to adopt the cardiac muscle fate are on the way for potential
clinical application. However, whether the experimentally suggested promise of
augmented cardiac myogenesis will translate into enhanced contractile function, when
applying cells in patients with chronic HF, is unknown.
More complex and challenging are a series of pathobiological concerns, sending the
scientific community from bedside to bench and back again. As long as a patient's own
cells are used in the autologous setting, certain of those cells may be unsatisfactoryin
their nave and unmanipulated stateprompting systematic dissection of each step in
progenitor cell function. Cell enhancement strategies to improve patient-derived cells by
pretreatment with small molecule or genetic modification may contribute to an augmented
recruitment as well as in the future may enhance differentiation or other beneficial
functions.
Clearly, the use of stem/progenitor cells for cardiac repair is currently not at a stage to be
used in routine clinical practice. Despite a wealth of experimental and clinical data
suggesting feasibility, safety, and even early clinical efficacy in patients with acute
myocardial infarction, progression to widespread clinical application of progenitor cell
administration to promote functional cardiac regeneration must be balanced against the
inherent risk of testing a novel therapy. As such, attempts of regenerative therapeutic
interventions in patients with significant cardiac dysfunction should proceed in controlled
trials with the utmost rigorous scientific and ethical standards, paralleled by further
extensive in vitro and animal studies. Such a strategy will not only maximize patient safety,
which is of paramount interest, but will also generate reciprocal insights into mechanisms
and potential shortcomings of cell-based therapies aiming at functional cardiac
regeneration. Specific attention should be given to the processing of the cells and to
ascertain their functionality for regenerative purposes prior to initiating their clinical
application. The promise of functional cardiac regeneration by cell-based therapies offers
novel opportunities to address the large, unmet clinical need of treating patients with severe
cardiac dysfunction.
Copyright 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com
GENE THERAPY
Gene therapy represents another emerging therapeutic approach for the treatment of HF.
Improvements in gene transfer vectors and gene transfer methodology have enabled
recombinant genes to be expressed at robust levels in cardiac myocytes.[56] Further, recent
advances in the field of RNA interference (RNAi) suggest that it may also be possible to use
gene therapy to silence key pathogenetic genes or pathways that are activated in the
failing heart. [57] [58]
Three elements are necessary for the successful clinical application of any gene therapeutic
approach.[59] First a vector or packaging system is necessary to deliver the genetic material.
Only a few of the currently available viral vectors are able to achieve efficient, high-level
transgene expression in postmitotic cells such as cardiac myocytes. These include
recombinant adenoviruses, adeno-associated viruses, and possibly lentivirus. Recombinant
adenoviruses have been used most commonly because of their ability to package large
DNA constructs, as well as their ability to transduce nonreplicating cells. However, the
robust immune response these vectors evoke suggests that clinical applications will likely
require other vectors or further-refined adenoviral systems. Second, the vector needs to be
adequately delivered to the affected tissue(s). The feasibility of in vivo cardiac gene transfer
by viral vectors has been consistently demonstrated in experimental studies. As illustrated
in Figure 29-5 , a number of mechanical approaches have been used to achieve cardiac gene
transfer. Intracoronary catheter delivery of an adenovirus encoding the reporter gene betagalactosidase achieved transduction of approximately 30 percent of the cardiac myocytes in
the distribution of the injected coronary artery. Direct injection of adenovirus into the
ventricular wall using an epicardial approach has also been shown to induce significant
expression of reporter constructs; however, the expression was focal and the needle
injections within the heart resulted in myocardial damage. Intramyocardial delivery of
adenovirus using an intraventricular approach with retro-infusion of coronary veins has also
been used in larger animals, yielding regional areas of transduction. Injection of an
adenovirus carrying beta-galactosidase into the pericardial sac transduced only the
pericardial cell layers.[59] The third element that is necessary for a successful gene
therapeutic approach is to identify the appropriate gene targets to modulate. Table 29-5
summarizes potential targets for gene therapy in HF based on experimental studies. The
major promising targets for gene transfer have been those genes that regulate the betaadrenergic receptor (AR) signaling pathway and genes that regulate calcium handling in the
heart.[58]
FIGURE 29-5 Different techniques for in vivo cardiac gene transfer. A, Coronary perfusion. B,
Intramyocardial injection. C, Pericardial injection. D, Aortic clamping. E, Cross-clamping of the aorta
and pulmonary artery. IVC = inferior vena cava; SVC = superior vena cava. (Modified from Hajjar
RJ, del Monte F, Matsui T, Rosenzweig A: Prospects for gene therapy for heart failure. Circ Res
86:616-621, 2000.)
TABLE 29-5 -- Potential Therapeutic Targets for Gene Therapy in Heart Failure
Target
Function
Beta-adrenergic receptor Inhibits phosphorylation of -adrenergic receptor thus preventing its
Target
Function
kinase inhibitor
(ARKct)
desensitization
Sarcoplasmic reticulum Responsible for the reuptake of calcium from cytoplasm into the SR
Ca2+ ATPase (SERCA2) lumen. Critical determinant of both relaxation and contractility via
calcium sequestration into SR and via controlling SR calcium
loading, respectively
Phospholamban (PLN)
Parvalbumin (Parv)
S100 protein
As noted in Chap. 21 , the beta-AR signaling pathway is critical for modulating myocardial
contractility. Studies have shown that alterations in the myocardial beta-AR both precede
and accompany the development of HF in humans, including downregulation of the betaARs, functional uncoupling of beta-ARs from second messenger systems, and increased
levels of inhibitory G-proteins that blunt beta-AR signaling (see also Chap. 22 ).[60] Indeed,
transgenic mice with cardiac restricted overexpression of the beta2-AR have enhanced
myocardial contractility.[61] However, as noted in Chap. 22 , excessive and/or sustained
stimulation of the beta-AR signaling can also lead to activation of maladaptive signaling
pathways in the heart (e.g., activation of the fetal gene program), as well as myocyte death
through both necrosis and apoptosis. For example, transgenic mice that overexpress the
beta1-AR develop a dilated cardiomyopathy.[62] Viewed together, these types of
experimental studies have generated considerable interest in using selective genetic
approaches to modulate beta-AR signaling pathways in HF models. Thus far, adenoviralmediated gene transfer of the human beta2-AR resulted in an improvement in contractility in
myocytes isolated from a rabbit model of HF,[59] as well as in myocytes from failing
hearts.[58] Similarly, adenoviral-mediated gene transfer of a peptide inhibitor of beta-AR
kinase (see Chaps. 21 and 22) resulted in restoration of beta-AR signaling, increased cyclic
AMP, and reversal of ventricular dysfunction in rabbit HF models.[59]
PHARMACOLOGICAL STRATEGIES
Pharmacogenetics
Pathway/Gene
Polymorphism
Functional Impact
Impact on
Pharmacological
Therapy
genotypes; II/ID genotype
predicts reverse LV
remodeling in response to
spironolactone
Angiotensinogen Methionine
Increased angiotensinogen
(Met) to
levels with HTN
threonine (Thr)
switch at aa 235
Modest risk of
hypertension in whites;
effect on drug
responsiveness in HF not
known
Aldosterone
synthase
TT genotype associated
with greater impact of
fixed combination of
isosorbide dinitrate and
hydralazine on the eventfree survival in the AHeFT trial
Arg389Arg genotype
greatest improvement in
EF with beta blockers,
and improved mortality
with bucindolol treatment
in BEST
Beta1-AR
Serine (Ser),
glycine (Gly)
switch at aa 49
Ser49Ser genotype
requires higher doses of
beta blocker to achieve a
mortality benefit
Beta2-AR
Pathway/Gene
Polymorphism
Functional Impact
Alpha2C-AR
Impact on
Pharmacological
Therapy
Increased likelihood of
developing HF in patients
with the beta1-AR Arg389
polymorphism; effect on
drug responsiveness in HF
not known
One of the most widely studied genetic variants is the ACE insertion/deletion
polymorphism (I/D) that involves a 287-base pair insertion or deletion within intron 16 of
the ACE gene. Although the clinical significance of this polymorphism remains
controversial, the physiological association with ACE enzymatic activity has consistently
been demonstrated. Studies have shown that individuals with the DD genotype have the
highest ACE activity and angiotensin II levels, heterozygotes (I/D) have intermediate levels,
and individuals who are homozygous for the I allele (I/I) have the lowest levels of ACE
activity. The relationship of ACE I/D has been explored in relation to numerous conditions
including atherosclerosis, myocardial infarction, left ventricular hypertrophy, hypertrophic
cardiomyopathy, and HF. Although the current weight of evidence does not allow for
definitive conclusions to be made with respect to the overall contribution of the ACE I/D
polymorphism to the clinical outcome in these conditions, there is growing evidence that the
ACE I/D polymorphism may predict drug responsiveness to both beta blockers and ACEIs
in HF patients. In one study of patients with chronic HF, the ACE DD polymorphism was
significantly associated with death or the need for transplantation when compared to
patients with II or ID genotypes. Within the ACE DD group, patients treated with beta
blockers had significantly improved transplant-free survival when compared to patients not
receiving beta blocker therapy, whereas beta blocker treatment had no effect in clinical
outcomes in the II or ID groups.[69] In a similar study, patients with the DD genotype had
better clinical outcomes when receiving high-dose ACEI therapy when compared to lowdose ACEI therapy, whereas the ACE dose had no effect on clinical outcomes in patients
with either the II or ID genotypes. In this study, the regimen of high-dose ACE inhibitors
and beta blockers had the greatest impact on transplant-free survival in patients with the DD
variant.[69] Taken together these studies suggest a differential clinical response to standard
HF therapy based on the ACE I/D polymorphism.
Although the impact of genetic heterogeneity on HF outcomes has been extensively studied
in predominantly white cohorts, few studies have investigated the impact of genomic
variation in blacks. In a genetic substudy of the African-Americans in Heart Failure (A-
HeFT) trial (see Chap. 25) , a single nucleotide polymorphism within the promoter region of
the aldosterone synthase gene (C to T transition at position -344) was shown to predict
responsiveness to the fixed combination of hydralazine isosorbide dinitrate (see Chap. 25)
.[70] In A-HeFT treatment with the fixed combination of hydralazine isosorbide dinitrate was
associated with a markedly improved clinical outcome (mortality, HF hospitalization, and
change in quality of life at 6 months) in the TT homozygotes, but had no significant impact
among subjects with the -344C allelesuggesting that genetic variations in aldosterone
production may play an important role in disease progression in blacks with HF.
Polymorphisms that affect the function of beta- or alpha-adrenergic receptors may also
influence the pharmacological response in HF patients (see Table 29-6 ). Patients with a
common polymorphism of the beta1-adrenergic receptor (AR) that results in either an
arginine (Arg) or glycine (Gly) substitution at amino acid position 389 have different
clinical responses to beta blockers. In the Bucindolol Evaluation of Survival Trial (BEST),
bucindolol-treated patients who were homozygous for the Arg389 polymorphism
(Arg389Arg) had improved clinical outcomes when compared to glycine carriers
(Arg389Gly and Gly389Gly) who were treated with bucindolol ( Fig. 29-6 ), suggesting that
the therapeutic response to beta blockers differs by genotype.[71] The Arg389Arg genotype
was also associated with significantly greater reductions in LV end-diastolic and endsystolic diameters following treatment with beta blockers when compared to identically
treated Gly389 carriers.[72] The alpha2c-adrenergic receptor inhibits norepinephrine release at
cardiac presynaptic nerve endings through a negative feedback mechanism. The deletion of
four consecutive amino acids in (aa 322-325) in the alpha2c-adrenergic receptor results in
loss of normal synaptic autoinhibitory feedback mechanism and enhanced presynaptic
release of norepinephrine. There appears to be an increased risk of developing HF ( Fig. 297 ) when the alpha2cDel322-325 and the Arg389 beta1-AR polymorphism are both present
(i.e., a diplotype).[73] Although the impact of the alpha2cDel322-325 and Arg389 beta1-AR
synergism on beta blocker responsiveness is not known, it is likely that patients with this
diplotype may have increased responsiveness to beta blockers, based on what has been
reported for the Arg389 polymorphism. In addition to contributing to the functional
response to beta blockers, genetic polymorphisms that affect drug metabolism may also
influence the therapeutic response to beta blockers. For example, genetic variants in the
cytochrome P450 (CYP) 2D6 gene have a marked effect on plasma concentrations of
metoprolol and carvedilol. In subjects with a nonfunctional CYP2D6 enzyme (poor
metabolizers), the peak plasma concentration of metoprolol is sixfold higher than in
subjects with a normally functioning enzyme.[68]
FIGURE 29-6 Kaplan-Meier analysis of endpoints in BEST trial stratified by treatment (placebo or
bucindolol) and b1AR genotype. A, For survival, Arg homozygotes had an HR = 0.62, 95 percent CI
= 0.40-0.96, p = 0.03. In contrast, for 1-Gly-389 carriers, the HR = 0.90, 95 percent CI = 0.62-1.30, p
= 0.57. B, Graphical representation of HRs and CIs by bucindolol and placebo is shown. Hosp,
hospitalization. (From Liggett SB, Mialet-Perez J, Thaneemit-Chen S, et al: A polymorphism within a
conserved b1-adrenergic receptor motif alters cardiac function and beta blocker response in human
heart failure. Proc Natl Acad Sci U S A 103:11288-11293, 2006.)
FIGURE 29-7 Basis of the hypothesis that the a2cDel322-325 and b1Arg389 receptors act
synergistically as risk factors for heart failure. The a2c-adrenergic receptor (along with the a2aadrenergic receptor) inhibits norepinephrine release at cardiac presynaptic nerve endings through
negative feedback. The presence of the dysfunctional a2cDel322-325 receptor would be expected to
result in enhanced norepinephrine release. The b1-adrenergic receptor is the receptor for
norepinephrine on the cardiomyocyte, and the presence of the hyperfunctional b1Arg389 receptor
would be expected to increase contractile response at the myocytes. The combination of increased
norepinephrine release and increased responsiveness of the receptor was hypothesized to be a risk
factor for heart failure. (From Small KM, Wagoner LE, Levin AM, et al: Synergistic polymorphisms
of b1 and a2c-adrenergic receptors and the risk of congestive heart failure. N Engl J Med 347:1135,
2002.)
Metabolic Modulation
Optimization of myocardial energy utilization represents another unique approach for the
treatment of HF. As noted in Chap. 22 , myocardial high-energy phosphate concentrations
are decreased in experimental and clinical HF, leading to the suggestion that the failing
heart is energy starved. In the normal heart, free fatty acids are the preferred fuel for the
heart, producing roughly 4 times the ATP per mole of substrate utilized when compared to
glucose. However, fatty acid oxidation is less efficient than glucose oxidation, requiring 10
to 12 percent more oxygen consumption to produce equivalent amounts of ATP. In
addition, high rates of fatty acid oxidation are also associated with uncoupling of oxidative
phosphorylation, an oxygen-wasting phenomenon, leading to an even greater consumption
of molecular oxidation. Under conditions wherein oxygen is the limiting substrate, such as
occurs in the failing heart (see Chap. 22) , glycolysis becomes the more efficient pathway,
requiring less oxygen compared with oxidation of free fatty acid. Fatty acid oxidation is
physiologically regulated at several levels, including the concentration of circulating free
fatty acid substrate, at the level of entry into the mitochondrion, and by the activity of
several of the mitochondrial matrix enzymes that comprise the beta-oxidation pathway.[74]
On the other hand, the rate of glucose oxidation is regulated primarily, although not
exclusively, by the rate of fatty acid oxidation which inhibits the pyruvate dehydrogenase
complex (PDH), the activity of which is rate limiting for glucose oxidation ( Fig. 29-8A ).
Inhibition of pyruvate dehydrogenase can lead to increased glucose utilization through
conversion of pyruvate to lactate, resulting in progressive tissue acidosis, and impaired
myocyte contractility (see Fig. 29-8 ). From a theoretical perspective, shifting energy
utilization from free fatty acids to glucose would optimize metabolic efficiency, reverse
abnormalities in the cellular milieu, and improve cardiac function (see Fig. 29-8B ).
FIGURE 29-8 Metabolism of free fatty acids and glucose. A, Metabolic pathway for glucose
metabolism and fatty acid oxidation; B, Effects switching metabolism from fatty acid beta-oxidation
to glucose oxidation (under conditions wherein oxygen supply is rate limiting) using partial inhibitors
of fatty acid oxidation (pFOX).
The prototype partial inhibitors of fatty acid oxidation (pFOX), etomoxir, oxfenicine, and
perhexiline, act by inhibiting carnitine palmitoyltransferase I (CPT I), the gatekeeper of
fatty acid entry to the mitochondrion (see Fig. 29-8A ). These agents shift energy utilization
from free fatty acids to glucose by decreasing oxidation of free fatty acids. However,
because there is no apparent feedback from CPT I activity to sarcolemmal fatty acid import,
CPT I inhibitors can lead to accumulation of unmetabolized lipids in cardiac myocytes,
which may lead to lipotoxicity-induced cardiac myocyte cell death. Etomoxir is an oxirane
carboxylic acid derivative that indirectly promotes increased glucose oxidation through
inhibition of CPT I. In an open-label, uncontrolled trial conducted in 10 patients with
NYHA class II-III HF, treatment with etomoxir for 3 months was associated with a
significant improvement in LVEF, cardiac output at peak exercise, and clinical status.[75]
Subsequent phase II studies with etomoxir were halted because the compound did have the
expected efficacy in the treatment of HF (data obtained from MediGene 2002 Annual
Report [March 26, 2003]). Although oxfenicine was shown to be beneficial in the canine
rapid pacing model of HF, in other animal models treatment with oxfenicine resulted in a
dose-related increase in cardiac mass, as well as an increase in liver and kidney weights.
Perhexiline is currently in use clinically as an anti-anginal agent. Although there were early
reports of hepatotoxicity with this agent, hepatotoxicity occurred in patients with a genetic
variant of a cytochrome P450 enzyme (slow hydroxylation), which resulted in drug
accumulation, as well as accumulation of phospholipids in the liver and nerves. The risk of
toxic effects is virtually eliminated by maintaining plasma concentrations between 150 and
600 ng/ml, at which levels the drug still remains effective.[75] Perhexiline has shown promise
as adjunctive therapy for HF in a small short-term randomized double-blind clinical trial in
patients with ischemic and nonischemic cardiomyopathy. In this study, 8 weeks of treatment
with perhexiline resulted in an increase in the combined primary endpoint of peak oxygen
uptake and LVEF, and an improvement in quality of life (Minnesota Living with Heart
Failure Questionnaire). Importantly, maximum oxygen uptake increased significantly in
both the ischemic and nonischemic groups, suggesting that the benefit of perhexiline was
not entirely anti-ischemic.[76] Although there remains some optimism that CPT I inhibitors
can be used as adjunctive therapy in HF, other pFOX inhibitors may have fewer side
effects.
The pFOX inhibitors trimetazidine and ranolazine were also originally developed as antianginal agents. Trimetazidine is a piperazine compound that has been widely used outside
of the United States as an anti-anginal agent. Trimetazidine has no discernible vasodilator
properties at rest or during dynamic exercise, and has a very favorable side-effect profile.
The exact mechanism of trimetazidine is not known, but it appears to work, at least in part,
through inhibition of long-chain 3-ketoacyl coenzyme A thiolase, a crucial enzyme in the
terminal steps of mitochondrial beta-oxidation. Several small clinical trials have shown
improvements in ejection performance, reverse cardiac remodeling, and improvement in
NYHA functional class with trimetazidine.[75]
Trimetazidine has been evaluated in a number of small clinical trials in patients with both
ischemic and nonischemic cardiomyopathy. [74] [75] Two months of treatment with
trimetazidine resulted in significant improvement in LVEF at rest and enhanced LV wall
motion during a dobutamine stress test compared with placebo in NYHA class II and III
HF patients.[74] In two recent small clinical studies trimetazidine was shown to improve
systolic LV function in patients with diabetes and ischemic cardiomyopathy when
compared with placebo. [74] [77] In contrast, another study, which assessed the effects of
Ranolazine (Ranexa) is a novel anti-ischemic drug that prolongs the QT interval, and is the
first FDA-approved pFOX inhibitor for the treatment of angina. The principal mechanism
of action for this drug as an antianginal remains controversial, although recent studies
suggest that the anti-anginal effects of ranolazine may be related (see Chap. 54) to
decreased sodium entry into cells by inhibiting the rapid component of the delayed rectifier
K+ current (Ikr[BL3] [see Chap. 31 ]). Ranolazine also increases the activity of pyruvate
decarboxylase, a key regulator of glucose metabolism, most likely due to loss of inhibition
of the end-products of the beta-oxidation (NADH, acetyl-CoA). No clinical trials have yet
been reported utilizing ranolazine in patients with cardiomyopathy. However, animal
studies employing a canine model of chronic HF induced by microembolization have shown
that, acutely, ranolazine significantly increased LVEF, peak +dp/dt, stroke volume, and
mechanical efficiency.[79]
Immunomodulation
Experimental and clinical studies suggest that inflammation plays a role in the pathogenesis
of HF ( Chap. 22 ). Over the past decade a variety of different anti-inflammatory strategies
have been tried in small clinical trials in patients with chronic HF ( Fig. 29-9 ; reviewed in
references 80, 81 [80] [81]). Thus far, two different anti-inflammatory approaches have not
favorably impacted morbidity and mortality when examined in phase III clinical trials. The
first trial used a targeted anti-cytokine approach with a tumor necrosis factor (TNF)
antagonist (RENEWAL [Randomized Etanercept Worldwide Evaluation]),[82] whereas the
second trial employed intramuscular injections of autologous blood (ACCLAIM [Advanced
Chronic Heart Failure Clinical Assessment of Immune Modulation Therapy]) that had been
subjected to oxidative stress ex vivo using a proprietary device (Celacade).[83] Despite these
initial disappointing results, there are several emerging antiinflammatory approaches that
are currently being evaluated in HF patients. One of the more promising approaches is the
use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins)
in patients with chronic HF.
FIGURE 29-9 Therapeutic strategies for antagonizing proinflammatory mediators. TNF gene
transcription is mediated, in part, by activation of NF-kB. Agents that increase intracellular levels of
cAMP (1) such as vesnarinone, pentoxifylline, milrinone, thalidomide, and thalidomide analogs
(CelSids) decrease the level of inflammatory mediators through transcriptional blockade of
inflammatory gene expression. Agents such as dexamethasone and prednisone and some p38
inhibitors suppress inflammation by blocking the translation of inflammatory mediators (2). Secreted
TNF can be neutralized (3) by soluble TNF antagonists (etanercept) or by neutralizing antibodies
(infliximab) that prevent TNF from binding to its cognate type 1 (p55) and type 2 (p75) TNF
receptors. In addition to these targeted approaches, broad-based immunomodulatory strategies have
been employed (4) using intravenous immunoglobulin (IVIG), statins, and irradiated (oxidized) whole
blood (Celacade therapy). (Modified from Mann DL: Inflammatory mediators and the failing heart:
Past, present, and the foreseeable future. Circ Res 91:988-998, 2002.)
FIGURE 29-10 The mevalonate pathway leads to the synthesis of cholesterol. Important intermediate
products in the mevalonate pathway include isoprenoids such as farnesyl pyrophosphate (farnesyl-PP)
and geranylgeranyl pyrophosphate (geranylgeranyl-PP), which have been linked to activation Rasand Rho-mediated signaling. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase
inhibitors decrease the synthesis of isoprenoids as well as cholesterol, by blocking HMG-CoA
reductase. PP = pyrophosphate. (From Ramasubbu K, Mann DL: The emerging role of statins in the
treatment of heart failure. J Am Coll Cardiol 47:342-344, 2006.)
FIGURE 29-11 Age- and sex-adjusted rates of death from any cause and hospitalization for heart
failure by incident statin exposure. (From Go AS, Lee WY, Yang J: Statin therapy and risks for death
and hospitalization in chronic heart failure. JAMA 296:2105-2111, 2006.)
There have been five prospective trials that have examined the effects of statins in HF
patients. Node and coworkers demonstrated that patients with symptomatic nonischemic
dilated cardiomyopathy (NYHA class II-III) who were randomized to simvastatin for 14
Thalidomide, known for its sedative and antiemetic properties, has been shown to have
broad immunomodulatory properties, and is currently used to treat diseases such as multiple
myeloma, erythema nodosum leprosum, and rheumatoid arthritis. Three small clinical
studies have shown that thalidomide may be beneficial in HF patients. [93] [94] The largest of
the three studies was a double-blind placebo-controlled study, which showed that treatment
with thalidomide (25 mg once dailyincreasing to 200 mg once daily) resulted in
significant increase in LVEF (7 percent) along with a significant decrease in LV enddiastolic volumes. Although the results of these small studies appear promising, doselimiting toxicity has been observed in some HF patients.[93] Accordingly, it will be important
to determine the safety and efficacy of thalidomide in larger clinical trials before this
therapy can be broadly recommended.
In addition to statin therapy several other immunomodulatory approaches appear to be
promising, albeit in selected HF patients. Previous studies have shown that cardiac
autoantibodies directed against cardiac cell proteins such as mitochondrial and contractile
proteins, cardiac beta1-adrenergic receptors, and muscarinergic receptors may play a
pathogenesis of dilated cardiomyopathy. In small nonrandomized noncontrolled studies,
immunoadsorption has been shown to improve cardiac function and patient outcomes.[95]
However, interpretation of these studies is complicated because patients have also received
concomitant therapy with intravenous immunoglobulin (IVIG), which also has
immunomodulatory properties. Therapy with IVIG has been evaluated in a wide range of
immune-mediated disorders, such as Kawasaki syndrome, idiopathic thrombocytopenic
purpura, and multiple sclerosis. Although IVIG had no effect on LVEF in the IMAC trial
(Intervention in Myocarditis and Acute Cardiomyopathy), 6 months of treatment with IVIG
led to a significant increase in LVEF (5 percent), independent of HF etiology, in a doubleblind placebo-controlled study of NYHA functional Class II to IV HF patients.[81] Although
IVIG was safe and well tolerated, the cost of this therapy may limit broader applicability in
HF patients.