(Circulation. 1999;100:999-1008.)
© 1999 American Heart Association, Inc.
Current Perspective |
Mechanisms and Models in Heart Failure
A Combinatorial Approach
From the Winters Center for Heart Failure Research, Department of Medicine, Baylor College of Medicine, and Houston Veterans Administration Medical Center, Houston, Tex.
Correspondence to Douglas L. Mann, MD, Cardiology Research (151C), VA Medical Center, 2002 Holcombe Blvd, Houston, TX 77030. E-mail dmann{at}bcm.tmc.edu
Key Words: heart failure • neurohormone • mechanism remodeling • cytokine
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 Top  References |
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The people who bind themselves to systems are those who are unable to encompass the whole truth and try to catch it by the tail; a system is like the tail of truth, but the truth is like a lizard; it leaves its tail in your fingers and runs away knowing full well that it will grow a new one in a twinkling.
–Ivan Turgenev to Leo Tolstoy
Despite repeated attempts to develop a unifying hypothesis that explains the clinical syndrome of heart failure, no single conceptual paradigm for heart failure has withstood the test of time. One logical explanation for our inability to define the syndrome of heart failure in precise mechanistic and/or clinical terms is that the clinical syndrome of heart failure almost certainly represents the summation of multiple anatomic, functional, and biological alterations that interact together in an exceedingly complex manner and in different genetic and environmental backgrounds over a sustained (but variable) period of time. Thus, it is not surprising that clinicians and investigators have used a variety of increasingly complex model systems in an attempt to describe the syndrome of heart failure. Whereas clinicians initially viewed heart failure as a problem of excessive salt and water retention that was caused by abnormalities of renal blood flow (the "cardiorenal model"1 ), as physicians began to perform careful hemodynamic measurements, it also became apparent that heart failure was associated with a reduced cardiac output and excessive peripheral vasoconstriction. This latter realization led to the development of the cardiocirculatory or hemodynamic model for heart failure,1 wherein heart failure was thought to arise largely as a result of abnormalities of the pumping capacity of the heart and excessive peripheral vasoconstriction. However, although both the cardiorenal and cardiocirculatory models for heart failure explained the excessive salt and water retention that heart failure patients experience, neither of these models explained the relentless disease progression that occurs in this syndrome. That is, although the cardiorenal models provided the rational basis for the use of diuretics to control the volume status of patients with heart failure, and the cardiocirculatory model provided the rational basis for the use of inotropes and intravenous vasodilators to augment cardiac output, these therapeutic strategies have not prevented heart failure from progressing, nor have they led to prolonged life for patients with moderate to severe heart failure.2 3 4
On the basis of the above arguments, it has become increasingly apparent that heart failure can no longer be defined in simple hemodynamic terms. Indeed, what has become increasingly apparent is that at some point in time in the overall pathogenesis of heart failure, the disease will progress independently of the patient's hemodynamic status. Accordingly, the currently accepted working definition that "heart failure occurs when an abnormality of cardiac function causes the heart to fail to pump blood at a rate required by the metabolizing tissues or when the heart can do so only with an elevated pressure," will likely prove to be only partially correct.5 Indeed, the clinical observation that heart failure can progress independently of the hemodynamic status of the patient has focused interest on the potential spectrum of mechanism(s) responsible for disease progression in the failing heart.
Figure 1
provides a general conceptual
framework for discussing the development and progression of heart
failure. As shown, heart failure may be viewed as a progressive
disorder that is initiated after an index event either damages the
heart muscle, with a resultant loss of functioning cardiac myocytes, or
alternatively disrupts the ability of the myocardium to
generate force, thereby preventing the heart from contracting normally.
This index event may have an abrupt onset, as in the case of a
myocardial infarction, it may have a gradual or insidious onset, as in
the case hemodynamic pressure or volume overloading, or
it may be hereditary, as in the case of many of the genetic
cardiomyopathies. Regardless of the nature of the
inciting event, the feature that is common to each of these index
events is that they all, in some manner, produce a decline in pumping
capacity of the heart. In most instances, patients will remain
asymptomatic or minimally symptomatic following
the initial decline in pumping capacity of the heart, or will develop
symptoms only after the dysfunction has been present for some time.
Thus, when viewed within this conceptual framework, left
ventricular (LV) dysfunction is necessary but not
sufficient for the development of the syndrome of heart failure.
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Although the precise reasons why patients with LV dysfunction remain asymptomatic is not certain, one potential explanation is that many compensatory mechanisms become activated in the setting of cardiac injury or depressed cardiac output appear to be able to sustain and modulate LV function for a period of days to months to years. The portfolio of compensatory mechanisms that have been described include early activation of the sympathetic nervous system and salt and water retaining systems in order to preserve cardiac output,6 7 8 as well as activation of a family of vasodilatory molecules, including natriuretic peptides, prostaglandins (PGE2 and PGEI2) and nitric oxide.9 10 However, it bears emphasis that our understanding of the family of molecules that may be involved in this process is far from complete. Moreover, we have very little information with respect to how genetic background, gender, age, or environment impact these compensatory mechanisms.
As shown in Figure 1
, the compensatory mechanisms
activated following the initial decline in the pumping capacity
of the heart are able to modulate LV function within a
physiological/homeostatic range, such that the
functional capacity of the patient is preserved or is depressed only
minimally. Thus, patients may remain asymptomatic or
minimally symptomatic for a period of years. However, at
some point in time patients will become overtly
symptomatic, with a resultant striking increase in
morbidity and mortality. Why this transition to symptomatic
heart failure occurs, and exactly how this transition occurs, and
whether it occurs in all patients with LV dysfunction remains unknown
and represents an important area of discovery in heart failure.
What is known, however, is that the transition to
symptomatic heart failure is accompanied by further
activation of neurohormonal and cytokine systems, as well as a
series of adaptive changes within the myocardium,
collectively referred to as LV remodeling. Although there are further
modest declines in the overall pumping capacity of the heart during the
transition to symptomatic heart failure, the weight of
experimental and clinical evidence suggests that heart failure
progressions occur independently of the hemodynamic
status of the patient. Accordingly, it becomes difficult to ascribe the
transition to symptomatic heart failure to worsening LV
function alone. Thus, one important question that arises from the above
discussion is why heart failure progresses.
Heart Failure as a Progressive Model
Neurohormonal Mechanisms
It has been suggested that heart failure should be viewed as a
neurohormonal model, in which heart failure progresses as a result of
the overexpression of biologically active molecules that are capable of
exerting toxic effects on the heart and circulation.11 12
Thus far, a variety of proteins including norepinephrine,
angiotensin II, endothelin, aldosterone, and
tumor necrosis factor (TNF) have been implicated as some of the
potentially biologically active molecules whose biochemical properties
are sufficient to contribute to disease progression in the failing
heart. It bears emphasis that the term neurohormone is largely an
historical term, reflecting the original observation that many of the
molecules that were elaborated in heart failure were produced by the
neuroendocrine system and thus acted on the heart in an endocrine
manner. However, it has since become apparent that a great many of the
so-called classic neurohormones such as norepinephrine and
angiotensin II are synthesized directly within the
myocardium, and thus act in an autocrine and paracrine
manner. Furthermore, molecules such as angiotensin II,
endothelin, and TNF are peptide growth factors and/or cytokines
produced by a variety of nucleated cell types within the heart,
including cardiac myocytes, and thus do not necessarily have a
neuroendocrine origin. Nonetheless, the important unifying concept that
arises from the neurohormonal model is that the overexpression of
portfolios of biologically active molecules can contribute to disease
progression independently of the hemodynamic status of
the patient, by virtue of the direct toxic effects that these molecules
exert on the heart and circulation. The evidence in support of this
point of view is derived from 2 lines of investigation. First, many
experimental models which have shown that
pathophysiologically relevant concentrations of
neurohormones are sufficient to mimic some aspects of the heart failure
phenotype.12 13 14 Second, clinical studies have
shown that antagonizing neurohormones leads to clinical improvement for
patients with heart failure.15 16 17 18 19 Thus, one logical
explanation for why heart failure progresses is that long-term
activation of a variety of neurohormonal mechanisms produces direct
end-organ damage within the heart and circulation. Accordingly,
progressive activation of neurohormonal mechanisms may explain why
heart failure may develop insidiously many years after an acute
myocardial infarction, despite the absence of ongoing ischemia.
The neurohormonal model also explains why the so-called heart failure
phenotype appears remarkably consistent in patients
with different etiologies for their heart failure, insofar as disease
progression is ultimately driven by very similar portfolios of
biologically active molecules, regardless of the inciting cause.
Is the Neurohormonal Model Adequate to Explain the Progression of
Heart Failure?
Despite the many strengths of the neurohormonal model in terms of
explaining disease progression and the many insights that neurohormonal
models have provided in terms of drug development for heart failure,
there is increasing clinical evidence to suggest that our current
neurohormonal models fail to completely explain disease progression in
heart failure. This concept is illustrated by the differences in the
Kaplan-Meier curves observed in lipid lowering trials for patients with
coronary artery disease and for neurohormonal antagonism for
patients with heart failure. Figure 2A
illustrates a Kaplan-Meier curve for death or nonfatal myocardial
infarction for patients who were randomized to receive placebo or
pravastatin in the West of Scotland Coronary
Prevention Study.20 As shown, the Kaplan-Meier curves
begin to diverge at 1 year and then continue to diverge over the next 5
years. The observation that the event curves continue to diverge over
time implies that pravastatin has in some way altered the
underlying mechanism of the disease process, presumably through lipid
lowering. In contrast, Figure 2B illustrates Kaplan-Meier curves
for death or hospitalization for heart failure for patients who were
randomized to placebo or enalapril in the treatment arm of the Studies
on Left Ventricular Dysfunction (SOLVD).16 As
shown, the curves begin to diverge at 6 months, suggesting that
enalapril has at least initially altered the underlying mechanism of
the disease process, presumably by preventing disease progression.
However, as shown in Figure 2B, the Kaplan-Meier curves for the
placebo and enalapril arms become parallel between 18 and 48 months.
Interestingly, similar patterns can be observed in the Kaplan-Meier
curves for the patients who are randomized to receive both ß-blockers
and ACE inhibitors.19 The observation that the
event curves become parallel following neurohormonal antagonism
suggests that there may be an attenuation or loss of effectiveness of
neurohormonal antagonism as heart failure progresses.
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Although the precise mechanism(s) for this attenuation or loss of effectiveness of neurohormonal antagonism is not known, there are at least 4 potential explanations that warrant a brief discussion. One obvious explanation is that it may not be possible to achieve complete inhibition of the renin angiotensin system or the adrenergic system in heart failure because of dose-limiting side effects of ACE inhibitors and ß-blockers. A second explanation is that there may be alternative metabolic pathways for neurohormones that are not antagonized by conventional treatment strategies. For example, angiotensin converting enzyme inhibitors do not antagonize the conversion of angiotensin I to angiotensin II within the myocardium by tissue chymase.21 22 Therefore, ACE inhibitors do not completely antagonize the renin angiotensin system. Third, the currently available portfolio of neurohormonal antagonists, namely ACE inhibitors and ß-blockers, may not antagonize all of the biologically active systems that become activated in the setting of heart failure (eg, endothelin, aldosterone, and TNF). Indeed, given the inherent biological redundancy of all mammalian systems, it is perhaps predictable that there will be many biologically active molecules that are sufficient to contribute to disease progression by virtue of their toxic effects on the heart and the circulation. Thus, it is likely that with the current technologies for gene expression monitoring, as well as the innovative cloning strategies that are being used, it is only a matter of time before investigators identify new families/classes of biologically active molecules capable of contributing to disease progression. A fourth, albeit speculative explanation for the loss of effectiveness of neurohormonal antagonism is that at some point in time, heart failure may progress independently of the neurohormonal status of the patient. Thus, analogous to the limitations described for hemodynamic models for heart failure, neurohormonal models may be necessary but not sufficient to explain all aspects of disease progression in the failing heart.
LV Remodeling: Cause or Consequence of Heart Failure?
Natural history studies have shown that progressive LV remodeling
is directly related to future deterioration in LV performance
and a less favorable clinical course in patients with heart
failure.23 24 25 Although some investigators currently view
LV remodeling simply as the end-organ response that occurs following
years of exposure to the toxic effects of long-term neurohormonal
stimulation, others have suggested that LV remodeling may contribute
independently to the progression of heart failure.23 Given
the potential central importance of LV remodeling in the progression of
heart failure, the following section will focus on the basic cellular
and molecular mechanisms responsible for this process.
In the context of the present discussion, the term LV remodeling
refers to the changes in LV chamber and volume not related to preload
mediated increases in sarcomere length.23 26 Although the
complex changes that occur in the heart during LV remodeling have
canonically been described in anatomic terms, the process of LV
remodeling also impacts importantly on the biology of the cardiac
myocyte, on changes in the volume of myocyte and nonmyocyte
components of the myocardium, as well as on the geometry
and architecture of the LV chamber (Table 1). Whereas each of these various
components of the remodeling process may contribute importantly to the
overall development and progression of heart failure, it is extremely
unlikely that any single aspect of the remodeling process itself will
satisfactorily explain the progressive cardiac decompensation that
occurs as heart failure advances. Accordingly, the remaining discussion
will focus on the collective changes that occur in the cardiac myocyte,
the myocardium, and the LV chamber, with an emphasis on
those aspects of the remodeling process that might potentially
contribute to disease progression.
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Alterations in the Biology of the Cardiac Myocyte
Numerous studies have suggested that failing human cardiac
myocytes undergo several important changes that might be expected to
lead to a progressive loss of contractile function, including decreased
-myosin heavy chain gene expression with a concomitant increase in
ß-myosin heavy chain expression,27 progressive loss of
myofilaments in cardiac myocytes,28 alterations in
cytoskeletal proteins,28 alterations in excitation
contraction coupling,29 as well as desensitization of
ß-adrenergic signaling.30 Although many of the
aforementioned changes may be thought of as beneficial in terms of
protecting myocytes against the potential deleterious consequences of
excessive neurohormonal activation, collectively these changes would be
expected to lead to a defect in myocyte contractile function as well as
decreased loss of responsiveness to normal adrenergic control
mechanisms, both of which are hallmarks of failing human
myocardium. And indeed, when the contractile
performance of isolated failing human myocytes has been
examined under very simple experimental conditions, investigators have
found that there is an 
50% decrease in cell shortening in failing
human cardiac myocytes when compared with nonfailing human
myocytes.31 Moreover, as noted in the above discussion,
this defect in cell shortening has several important components which
may act combinatorially to produce the observed phenotype of
cellular contractile dysfunction. Thus, the contractile dysfunction
that develops within myocytes during the process of LV remodeling is
likely to involve ensembles of genes, including those that regulate
calcium handling, sarcomerogenesis, ß-adrenergic signaling, and the
cytoskeleton, all of which may interact in an exceedingly complex
manner within the cardiac myocyte to produce contractile
dysfunction.
Are the Defects in Myocyte Function Reversible?
The experimental literature suggests that alterations in the
biology and the contractility of the failing cardiac
myocyte are reversible following ß-adrenergic
blockade.32 Although the mechanism for the improved
contractile performance in isolated myocytes is not known, the
improvement in myocyte contractility has been linked to
an increase in the density of myofilaments within the failing myocytes.
Thus, in this experimental model, ß-adrenergic blockade appeared to
be able to reverse some of the deleterious alterations in the biology
of the myocyte. Whether the improvement in LV ejection fraction that
occurs in heart failure patients placed on ß-adrenergic blocking
agents33 is the result of the reversal on unfavorable
alterations in the biology of the adult myocyte remains speculative for
the present, but it is an attractive explanation.7
Another example of the potential reversibility of myocyte contractile
defects is suggested by the studies in which isolated failing myocytes
obtained from hearts that had been supported with a LV assist device
manifested improved shortening and responsiveness to isoproterenol when
compared with myocytes isolated from hearts that had not been supported
with a LV assist device.34 Although this interesting study
did not directly demonstrate an improvement in myocyte function, it
does suggest that defects at the myocyte level are potentially
reversible.
Alterations in Failing Myocardium
The unfavorable alterations that occur in failing
myocardium may be categorized broadly into those that occur
in the volume of cardiac myocytes and changes that occur in the volume
and composition of the extracellular matrix. With respect to the
changes that occur in cardiac myocyte component of the
myocardium, there is increasing evidence to suggest that
progressive myocyte loss, through both necrotic and apoptotic
cell death, may contribute to progressive cardiac dysfunction and LV
remodeling. For example, it has long been postulated that excessive
adrenergic drive might be overtly deleterious by triggering myocyte
necrosis.35 Indeed, concentrations of
norepinephrine available within myocardial tissue, as well
as in circulating levels in patients with advanced heart failure, are
sufficient to provoke myocyte necrosis in experimental model
systems.13 Moreover, excessive stimulation with either
angiotensin II or endothelin has been shown to provoke
myocyte necrosis in experimental models.12 Until recently,
the clinical evidence which suggested that myonecrosis occurred in
heart failure was confined to histological specimens of
myocardium obtained during implantation of LV assist
devices, which revealed the presence of contraction band necrosis.
However, additional evidence for the existence of ongoing myonecrosis
in patients with heart failure is suggested by a recent study that
showed that levels of circulating troponin I were increased 3- to
4-fold in patients with advanced heart failure.36
Taken together, these clinical studies suggest that myocyte necrosis
may contribute to the progressive myocardial remodeling and LV
dysfunction that occurs as heart failure progresses.
The relatively recent recognition that mammalian cells are capable of
undergoing apoptosis, or programmed cell death, has prompted
the intriguing thought that heart failure might also progress by virtue
of progressive apoptotic cell death. This point of view has
received increasing support with the recognition that DNA damage
characteristic of apoptotic cell death occurs in myocytes from
failing hearts.37 38 Moreover, many of the factors that
have been implicated in the pathogenesis of heart failure, including
myocardial stretch, norepinephrine, TNF, oxidative stress,
and angiotensin II, have been shown to trigger
apoptosis in a variety of simple in vitro and vivo experimental
model systems.39 40 41 Nonetheless, despite the undeniable
intrinsic appeal of programmed cell death as a potentially important
mechanism for disease progression in the failing heart, there are
several caveats that warrant discussion. First, all of the currently
available assessments of myocyte apoptosis in failing hearts
have been performed in explanted hearts obtained from patients awaiting
cardiac transplantation, many of whom were receiving
intravenous inotropic support before cardiac
transplantation. Given that catecholamines can provoke
apoptosis in experimental models,42 the existing
clinical studies may overestimate the true frequency of
apoptosis in the failing heart.37 38 Second, at
present, there are no data with respect to whether myocyte
apoptosis occurs in patients with mild to moderate heart
failure. Thus, it is not clear whether apoptosis contributes to
disease progression in heart failure, or whether instead it is a
phenomenon that is observed only in end-stage heart failure. Third, the
current estimates of myocyte apoptosis in failing
myocardium range from clinically insignificant levels of
0.003%/y (estimated myocytes cell loss 1%/y; [Jutta
Schaper, personal oral communication, June 24, 1998]) to
clinically unrealistic estimates of 5% to 35% (estimated
myocyte loss >100%/y). These striking disparities make it difficult
to know exactly what contribution apoptosis plays in
progressive cardiac dysfunction. Thus, although the general concept
that myocyte cell loss may contribute to the progressive myocardial
dysfunction and myocardial remodeling is likely to have validity,
further clinical studies will be necessary to determine the frequency
of necrosis and apoptosis in patients with mild to moderate
heart failure. These studies will be needed in order to obtain a
clearer understanding of whether cell death occurs early and
continually in heart failure or, instead, only in end-stage hearts.
In addition to alterations in the volume and composition of the cardiac myocytes, there are several important changes that also occur within the extracellular matrix component of the myocardium.43 44 45 46 Perhaps the most widely recognized alteration that occurs in the extracellular matrix is the development of perivascular fibrosis around intramyocardial blood vessels, as well as replacement fibrosis, which is the term that has been used to describe the excessive deposition of fibrillar collagen that occurs following the death of myocytes. Enthusiasm for the idea that progressive fibrosis plays an important role in the progression of heart failure has been engendered by experimental studies; these studies have shown that angiotensin II, endothelin, and aldosterone47 48 49 are sufficient to trigger excessive fibrosis in myocardial tissue, thus providing a potential biochemical explanation for the development of the excessive fibrosis in heart failure.
Although excessive fibrin deposition has been invoked as one logical explanation to explain the progressive contractile dysfunction that occurs in the failing heart, until recently it has been difficult to explain precisely how excessive fibrosis (which would be expected to lead to stiffer and less compliant ventricle) could explain the progressive LV dilation that occurs during the process of LV remodeling. Recently, it has been suggested that a family of collagenolytic enzymes become activated within the failing myocardium.43 44 46 Collectively these collagenolytic enzymes have been referred to as matrix metalloproteinases (MMPs). Conceptually, progressive activation of MMPs might be expected to lead to progressive degradation of the extracellular matrix, which would in turn lead to mural realignment (slippage) of myocyte bundles and/or individual myocytes within the LV wall, and thus account for the LV wall thinning and the dilation that occurs in heart failure. Although the precise biochemical triggers responsible for activation of MMPs are not known, it bears emphasis that TNF, as well as other cytokines and peptide growth factors expressed within the failing myocardium, are capable of activating MMPs. However, the biology of matrix remodeling in heart failure is likely to be much more complex than the simple presence or absence of MMP activation, insofar as degradation of the matrix is also controlled by glycoproteins termed tissue inhibitors of matrix metalloproteinases (TIMPs), capable of regulating the activation of MMPs by binding to and preventing these enzymes from degrading the collagen matrix of the heart. However, the exact role of TIMPs in the failing heart is far from clear, in that it appears that under certain conditions TIMPs may actually stabilize and/or localize MMPs, which in turn may facilitate the activation of MMPs. When viewed together, the above observations suggest that the alterations in the extracellular matrix that occur during LV remodeling are likely to be far more complex than were proposed originally, and that there may be periods of ongoing fibrin degradation and deposition throughout the process of LV remodeling.
Are the Defects in the Failing Myocardium Reversible?
In contrast to the defects that occur in the failing myocyte, many
of the defects that occur within the myocardium, most
notably those affecting myocyte survival, are not reversible and may
therefore directly contribute to disease progression. Furthermore,
whereas changes in the extracellular matrix may be partially reversible
in some situations,50 51 52 there is no current clinical
evidence to suggest that the magnitude of the fibrotic changes that
occur in the myocardium are completely reversible. Thus,
defects that arise at the myocardial level represent an
important and potentially irreversible mechanism for disease
progressive.
Alterations in Ventricular Chamber Geometry
On the basis of the above discussion, it is clear that the changes
that occur in the biology of the failing myocyte and in the biology of
failing myocardium contribute to the development of the LV
dilation and LV dysfunction that occur during the process of LV
remodeling. The importance of this statement is that there are several
lines of evidence to suggest that the deleterious changes that occur in
the geometry of the remodeled LV may promote worsening heart failure.
One of the first observations with respect to the abnormal geometry of
remodeled ventricle was the consistent finding that the
remodeled heart was not only larger but was also more spherical
shape.26 As shown in Table 2, the increase in LV size and resultant
change in LV geometry from the normal prolate ellipse to a more
spherical shape creates several de novo mechanical burdens for the
failing heart. Perhaps the most obvious problem that occurs in the
remodeled ventricle is the increase in LV end-diastolic
volume, and hence end-diastolic wall stress. Insofar as the
load on the ventricle at end-diastole contributes
importantly to the afterload that the ventricle faces at the onset of
systole, it follows that LV dilation itself will increase the work of
the ventricle, and hence the oxygen use as well. In addition to the
increase in LV end-diastolic volume, LV wall thinning also
occurs as the ventricle begins to remodel. The increase in wall
thinning along with the increase in afterload created by LV dilation
leads to a functional afterload mismatch that may further contribute to
a decrease in forward cardiac output.53 54 55 56 Moreover, the
high end-diastolic wall stress might be expected to lead to
episodic hypoperfusion of the subendocardium with resultant worsening
of LV function.57 58 59 60 Finally, increased LV wall stress
might lead to sustained expression of stretch-activated genes
(angiotensin II, endothelin, and TNF)61 62
and/or increased oxidative stress as a result of subendocardial
hypoperfusion, with the resultant activation of families of genes that
are sensitive to free radical generation (eg, TNF and
interleukin-1ß).
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A second important problem that results from increased sphericity of the ventricle is that the papillary muscles are pulled apart, resulting in incompetence of the mitral valve and the development of functional mitral regurgitation.63 Whereas the amount of functional mitral regurgitation was once thought to be mild, the advent of noninvasive imaging modalities has shown that functional mitral regurgitation is clinically significant. Apart from the more obvious problem of loss of forward blood flow, mitral regurgitation presents yet a second problem to the heart, insofar as the mitral regurgitation results in further hemodynamic overloading of the ventricle. Taken together, the mechanical burdens engendered by LV remodeling might be expected to lead to decreased forward cardiac output, increased LV dilation (stretch), and increased hemodynamic overloading, any or all of which are sufficient to contribute to disease progression independently of the neurohormonal status of the patient. Moreover, the aforementioned changes in LV structure and function might be expected to render the cardiovascular system less responsive to normal homeostatic control mechanisms, such as increased adrenergic drive. Thus, alterations in the remodeled ventricle may foster a self-amplifying situation, in which worsening neurohormonal activation occurs in response to the inability of the remodeled LV to respond appropriately to these compensatory mechanisms. Moreover, at some point in time it is predictable that the aggregate end-organ changes that occur within the cardiomyopathic ventricle may progress to the point that no amount of neurohormonal stimulation can maintain cardiovascular homeostasis. At this point, heart failure may progress independently of the neurohormonal statues of the patient.
Are the Defects in the Geometry of the Remodeled LV
Reversible?
The extant clinical experience suggests that it is possible to
retard and possibly regress LV remodeling in some patients. The most
obvious clinical example of reversed LV remodeling is the striking
change that occurs in the dilated cardiomyopathic
ventricle following implantation of a LV assist device. The salutary
changes that have been reported include increased LV wall
thickness,64 decreased LV volume,65 and a
favorable leftward shift in the LV pressure-volume
curve.65 Medical therapy has also been shown to halt
and/or reverse LV remodeling in some patients. For example, therapy
with angiotensin converting enzyme inhibitors
appears to prevent worsening LV dilation and further increases in LV
mass66 67 ; however, it bears emphasis that these agents
will not regress or reverse LV remodeling.66 67 Recently
ß-blockers have been shown to favorably influence LV remodeling,
including improvements in LV function and a decrease in LV
end-diastolic volume.32 33 68 Thus, the
preponderance of experimental and clinical evidence suggests that the
defects in the remodeled LV chamber are at least partially reversible
in some patients.
LV Remodeling as a Therapeutic Target in Heart Failure
The suggestion that LV remodeling may not only be a consequence of
heart failure but may also contribute to the progression of heart
failure raises the interesting possibility that therapeutic strategies
specifically designed to prevent and/or antagonize LV remodeling may
also be beneficial in heart failure. Although it is unclear as of this
writing which of the myriad of cellular and molecular mechanisms that
contribute to LV remodeling should be therapeutic targets, one logical
starting point would be to focus on those aspects of the remodeling
process that contribute to irreversible disease progression. Thus, one
attractive approach would be to develop antiremodeling strategies along
2 mutually complementary lines: preservation of cardiac myocyte cell
number and maintenance of the integrity and composition of the
extracellular matrix. At present, there are several intriguing
possibilities with regard to preserving myocyte cell number, including
strategies designed to prevent necrotic and/or apoptotic cell
death,69 70 or alternatively, strategies designed to
replace lost myocytes through the use of stable myocyte
implants,71 by increasing cardiac myocyte cell number
through increased cell division,72 or perhaps through
genetic programming of nonmyocytes (eg, fibroblasts) to
myocytes. Additional approaches may also include attempts to modulate
cardiac myocyte cell mass through the use of myocardial growth
factors.73 Attempts to maintain the structural integrity
and composition of the extracellular matrix will likely involve
strategies designed to prevent excessive degradation of the
extracellular matrix, as well as strategies designed to modulate
excessive replacement fibrosis.74 Finally, it is important
to emphasize that antiremodeling strategies need not and should not be
confined to those discussed above and will likely also be extended to
include a variety of novel surgical, medical, bioprosthetic,
and biomechanical approaches.
Clinical Implications
In this review, we have described the clinical syndrome of heart
failure in terms of 3 different clinical model systems, including
cardiorenal, hemodynamic, and neurohormonal. We have
also discussed the point of view that strategies designed to
specifically prevent and/or attenuate LV remodeling may eventually play
an important role in the clinical treatment of heart failure. However,
whereas each of the established model systems explains some aspects of
the syndrome of heart failure, as noted throughout this review, none of
these pathophysiological models is sufficient to
explain all aspects of the syndrome of heart failure. That is, each of
these clinical models systems fails to encompass the whole truth about
heart failure. The question that arises from the foregoing discussion
is how should clinicians use these various clinical models to develop
effective therapeutic strategies to treat patients with heart
failure.
Given that no 1 clinical model adequately predicts and/or explains all
aspects the syndrome of heart failure, it follows that clinicians
should not develop therapeutic heart failure strategies based entirely
on cardiorenal, hemodynamic, and neurohormonal model
systems alone. Rather, clinicians should develop therapeutic strategies
that combine useful elements of each of the aforementioned model
systems. Moreover, the optimal choice of treatment models may vary
depending on the patients clinical presentation. For
example, as shown in Figure 3, the
combination of cardiorenal and cardiocirculatory models is extremely
useful for developing short-term strategies to treat patient symptoms
related to volume overload and/or acute cardiac decompensation.
Accordingly, the use of diuretics (cardiorenal model) is
warranted to treat congestive symptoms, whereas the use of short-term
inotropic support an/or intravenous vasodilators
(cardiocirculatory model) is also clearly warranted during periods of
extreme cardiac decompensation. Nonetheless, it bears emphasis that
although short-term changes in cardiac output and filling pressures can
favorably influence cerebral, renal, and pulmonary function,
neither cardiorenal nor hemodynamic models adequately
predict disease progression in heart failure. Indeed, many of the drugs
that produce acute symptomatic relief in heart failure do
not produce long-term benefits in heart failure and may even lead to
untoward long-term clinical outcomes.3 Therefore,
clinicians should not formulate intermediate or long-term treatment
strategies for heart failure based entirely on cardiorenal or
hemodynamic models alone. Clinicians should instead
formulate long-term treatment strategies that include the use of
neurohormonal antagonists known to attenuate disease
progression. Accordingly, as shown in Figure 4, patients with asymptomatic
and symptomatic LV dysfunction should be started and
maintained on both ACE inhibitors and ß-blockers in order
to antagonize the renin-angiotensin and the adrenergic
systems, respectively. The use of diuretic agents in
combination with neurohormonal antagonists is also
suggested if the patients manifest signs and symptoms related to
excessive salt and water retention. Although neurohormonal
antagonists may not produce acute symptomatic
benefits, the overwhelming weight of clinical
evidence15 16 17 19 75 suggests that the combined use of the
appropriate pharmacological agents (Figure 4) will not only lead
to improvements in quality of life, but will decrease the likelihood of
disease progression and thereby decrease the risk of major cardiac
events in patients with heart failure.
|
|
Heart Failure Therapy in the Coming Millennium
Despite the tremendous strides that have been achieved in the
theory and therapy for heart failure over the past 2 decades, heart
failure remains a relentlessly progressive disease process. Thus, our
current therapy for heart failure should be viewed as an ongoing
work in progress. Although the reason why heart failure progresses in
patients receiving optimal therapy with ACE inhibitors and
ß-blockers is not known, one explanation (alluded to above) is that
these agents do not directly and/or sufficiently antagonize all of the
biologically active systems that become activated in the
setting of heart failure. Accordingly, one logical direction for future
heart failure therapies will be to develop therapeutic strategies that
either more effectively antagonize the neurohormonal systems that we
believe are deleterious (eg, renin angiotensin receptor
blockers76 ), or alternatively, to develop therapeutic
strategies designed to antagonize some of the other currently
recognized biologically active systems that appear to play a role in
disease progression in heart failure. And indeed, there are ongoing
heart failure trials designed to examine the effects of antagonizing
molecules such as endothelin, aldosterone, and TNF. As
shown in Figure 5, these new
neurohormonal treatment strategies will likely be adjunctive to
existing neurohormonal strategies. However, we have also alluded to the
possibility that it may not be possible and/or feasible to antagonize
all of the biologically active systems that become activated in
the setting or heart failure. Moreover, there is increasing evidence to
suggest that at some point, heart failure may progress independently of
the neurohormonal status of the patient. Accordingly, as shown in
Figure 5 it is possible that future therapeutic targets in heart
failure will extend beyond antagonizing neurohormonal systems and may
instead begin to address the fundamental cellular and molecular
mechanisms responsible for contributing to the heart failure
phenotype (LV remodeling). Although speculative at present,
it is conceivable that these strategies may target therapies designed
to increase myocyte cell number as well as strategies designed to
prevent deleterious changes from occurring within the extracellular
matrix. In addition, recent advances in the delivery of gene constructs
into the vasculature and/or the myocardium raise the
important possibility that gene therapeutic approaches may one day be
used to attenuate disease progression in heart failure (eg, through the
use of ß-adrenergic receptor kinase
inhibitors77 78 ). Conceivably, these newer
strategies would also be adjunctive to and/or possibly synergistic with
existing therapeutic strategies for treating patients with heart
failure. Whether a combinatorial approach that incorporates
anti-remodeling strategies along with existing heart failure strategies
will ever really encompass the whole truth about heart failure remains
unknown for the present, but represents a potentially
important area of theoretical and therapeutic discovery in the coming
millennium.
|
|
Acknowledgments |
|---|
The author would like to apologize in advance to all of his colleagues whose work he could not cite herein because of imposed space limitations. He would like to thank Dr Michael Bristow and William "Robb" MacLellan for their critical reviews of the manuscript and Dr Andrew I. Schafer for his past and present guidance and support. This work was supported, in part, by research funds from the Department of Veterans Affairs and the N.I.H. (RO1 HL58081-01A1 RO1 HL61543-01 and P50 HL-O6H).
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F. Forini, A. Paolicchi, T. Pizzorusso, G. M. Ratto, M. Saviozzi, V. Vanini, and G. Iervasi 3,5,3'-Triiodothyronine deprivation affects phenotype and intracellular [Ca2+]i of human cardiomyocytes in culture Cardiovasc Res, August 1, 2001; 51(2): 322 - 330. [Abstract] [Full Text] [PDF]
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J. S. Rao and M. Bond Microarrays : Managing the Data Deluge Circ. Res., June 22, 2001; 88(12): 1226 - 1227. [Full Text] [PDF]
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J. L. Abramson, S. A. Williams, H. M. Krumholz, and V. Vaccarino Moderate Alcohol Consumption and Risk of Heart Failure Among Older Persons JAMA, April 18, 2001; 285(15): 1971 - 1977. [Abstract] [Full Text] [PDF]
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J. Huang, J. M. Rogers, C. R. Killingsworth, G. P. Walcott, B. H. KenKnight, W. M. Smith, and R. E. Ideker Improvement of Defibrillation Efficacy and Quantification of Activation Patterns During Ventricular Fibrillation in a Canine Heart Failure Model Circulation, March 13, 2001; 103(10): 1473 - 1478. [Abstract] [Full Text] [PDF]
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B. K. Podesser, D. A. Siwik, F. R. Eberli, F. Sam, S. Ngoy, J. Lambert, K. Ngo, C. S. Apstein, and W. S. Colucci ETA-receptor blockade prevents matrix metalloproteinase activation late postmyocardial infarction in the rat Am J Physiol Heart Circ Physiol, March 1, 2001; 280(3): H984 - H991. [Abstract] [Full Text] [PDF]
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