From the Cardiology Division, Department of Medicine, University of
Connecticut, Farmington.
Correspondence to Arnold M. Katz, MD, Cardiology Division, University of Connecticut Health Center, 263 Farmington Ave, Farmington, CT 06030-2249.
Only
a decade ago, end-stage heart failure was viewed as an irreversible
condition for which therapy could offer only transient
symptomatic relief. This led to a sense of hopelessness
that resembled the prevailing attitude toward coronary
occlusive disease 50 years ago, when atherosclerosis
was thought to be an inevitable feature of natural aging. In the case
of heart failure, as recently as the mid-1980s it was believed that
little could be done to improve the natural history in patients with
advanced chronic heart failure and a severely dilated ventricle. Yet
within a few years, work from unexpected directions demonstrated that
the progressive deterioration of the failing heart can be slowed and
prognosis improved.
The first class of drugs shown in large clinical trials to
improve prognosis in these patients was
vasodilators.1 Because unloading the failing
heart has an obvious energy-sparing effect and because virtually all
vasodilators alleviate symptoms over the short term, it came as a
surprise that not all of these drugs improve prognosis and that some
accelerate deterioration of the failing heart2
and shorten survival.3 4 5 6 Equally
counterintuitive was the finding that positive inotropic agents, which,
like vasodilators initially improve symptoms, also increase
mortality.7 8 Perhaps the most surprising finding
of the clinical trials in heart failure was that long-term
administration of ß-adrenergic receptor blockers, although they
initially worsen symptoms, reduce long-term morbidity and improve
survival.9 10 11 Taken together, these clinical
findings have led to a paradigm shift in our understanding of heart
failure, one that by highlighting long-term mortality as a major
problem has redefined the challenge in managing these patients. Today,
it is clear that we can do more than simply relieve symptoms; we must
also improve long-term survival. This, in turn, requires that we
identify the causes of the poor prognosis in our growing population
with left ventricular dysfunction.
An association between cardiac enlargement and shortened survival
was identified by the great clinician-pathologists of the 18th and 19th
centuries, who recognized that different patterns of cardiac
hypertrophy have different prognostic implications (for
review see Reference 1212 ). In 1745, Giovanni Maria Lancisi in Italy
distinguished between dilatation of the cavities of the heart and
thickening of its walls, a distinction that was correlated with
clinical outcome by Jean Nicolas Corvisart in France, who noted in 1801
that hypertrophy ("active aneurism")
strengthens the heart, whereas dilatation ("passive
aneurism") decreases the energy of cardiac contraction. By
the middle of the 19th century, Austin Flint in the United States and
James Hope in England had noted the rapid downhill course in patients
with ventricular dilatation. In the latter third of the
last century, Leopold Schroetter in Germany and Constantin Paul in
France postulated that hypertrophy, although it provides an
adaptive response that increases the ability of an overloaded heart to
pump blood, is also maladaptive, because cardiac enlargement appeared
to shorten survival. These views were elegantly summarized by William
Osler in Canada, who in 1892 noted that the hypertrophic response of
the failing heart, while initially compensatory, is followed by
progressive worsening of symptoms that ends with the death of the
patient. Osler called this "broken compensation," which he stated
is due to "degeneration and weakening of the heart
muscle."13
Our modern understanding of the importance of maladaptive
hypertrophy (Osler's "broken compensation") began in
the early 1960s, when Felix Meerson demonstrated that aortic banding in
experimental animals shortened survival and caused premature myocardial
cell death,14 a process that can be viewed as a
"cardiomyopathy of
overload."15 More recently, progressive
dilatation of the failing heart, now called "remodeling," was again
recognized as playing an important role in determining the poor
prognosis in heart failure (for review see Reference 1616 ). The 18th and
19th century distinction between concentric hypertrophy
(active aneurism) and dilatation (passive aneurism) was given new
meaning by the finding that dilatation is due largely to cell
elongation, whereas concentric hypertrophy results from
cell thickening.17 A molecular basis for these
different growth responses was provided by the demonstration that cell
elongation and cell thickening in isolated cardiac myocytes are
mediated by different signal transduction
pathways.18 Because neither of these changes in
phenotype is accompanied by a change in sarcomere length,
myocyte thickening can be attributed to addition of new sarcomeres in
parallel, whereas elongation occurs when the new sarcomeres are added
at the ends of the fibers. These studies indicate that cardiac myocyte
thickening and elongation, and thus concentric hypertrophy
and dilatation, are mediated by different growth responses that
generate different phenotypes. These fundamental observations
make it likely that inhibition of the signal transduction pathways that
lead to the addition of sarcomeres in series can slow, and perhaps
reverse, the maladaptive growth response that causes progressive
dilatation (remodeling) of the failing heart.
Reversal of abnormal cell elongation in the failing human left
ventricle is documented in this issue of Circulation by
Zafeiridis et al,19 who used a left
ventricular assist device (LVAD) to reduce left
ventricular preload and afterload for an average of 75
days. In the 6 patients for whom echocardiographic data
were obtained before and after unloading, left ventricular
mass decreased almost 45% and left ventricular
end-diastolic diameter decreased by >25%. The most
interesting of these findings is that unloading the failing left
ventricle reduced both myocyte length and width by
Demonstration that cardiac myocyte elongation can be reversed
("reverse remodeling") adds to a growing optimism regarding the
possibility of alleviating at least some of the maladaptive features of
myocardial hypertrophy. Use of the LVAD to achieve this
benefit, however, raises a number of practical issues. The first, and
perhaps the most important clinically, is whether a short course of
therapy that reverses maladaptive changes in cardiac myocyte
phenotype can provide significant and sustained clinical
improvement. This question could not be addressed by Zafeiridis et
al19 because, by design, the LVAD was a
"bridge" to transplant. Much therefore remains to be learned
regarding the durability of this morphological improvement and whether
the benefits of reversion to a more normal cell size provide useful
long-term palliation in end-stage heart failure. If LVAD therapy does
lead to a useful and sustained remission in end-stage heart failure, we
will need to learn whether this invasive approach has a role in less
severely ill patients.
The overarching question raised by the findings of Zafeiridis et
al19 extends beyond the ability of a surgically
implanted device to reverse maladaptive growth and thus alleviate the
cardiomyopathy of overload. This study also
highlights the possibility that medical therapy can accomplish the same
benefits. Here, happily, the future is promising. We already know that
ACE inhibitors slow deterioration of the failing heart, a
benefit that is due in part to inhibition of
remodeling.20 21 The beneficial long-term effects
of ß-adrenergic blockade in heart failure are also accompanied by a
reduction in heart size.22 23 These findings,
which are consistent with growing evidence that
angiotensin II, norepinephrine, and other
neurohumoral mediators evoke a maladaptive growth response, probably
explain how neurohumoral inhibitors slow the progressive
dilatation of the failing heart. It therefore appears likely that the
promising improvement in phenotype obtained with the LVAD can
also be achieved using less invasive, and much less costly, medical
therapy. Efforts now under way to develop new classes of drugs that can
inhibit, and even reverse, maladaptive cardiac myocyte elongation
therefore offer considerable hope for the growing number of patients
with dying hearts.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
References
© 1998 American Heart Association, Inc.
Editorials
Regression of Left Ventricular Hypertrophy
New Hope for Dying Hearts
Key Words: Editorials • hypertrophy • remodeling • heart failure
20%. These
findings, which confirm other recent reports of the benefit of
"resting" the failing heart (see Reference 1919 for review), document
the reversibility of a major cause of maladaptive
hypertrophy. This study also provides an excellent model
for future research, in both animals and humans, that could identify
what is and what is not reversible in dilated (remodeled) hearts. This
model may also prove useful in identifying means to block signal
transduction pathways that, by causing sarcomeres to be added in
series, lead to cell elongation in failing hearts.
This article has been cited by other articles:
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  N. de Jonge, D. F. van Wichen, M. E. I. Schipper, J. R. Lahpor, F. H. J. Gmelig-Meyling, E. O. Robles de Medina, and R. A. de Weger Left ventricular assist device in end-stage heart failure: persistence of structural myocyte damage after unloading: An immunohistochemical analysis of the contractile myofilaments J. Am. Coll. Cardiol., March 20, 2002; 39(6): 963 - 969. [Abstract] [Full Text] [PDF]
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