From the Division of Cardiology, University of Utah Health Sciences
Center, Salt Lake City.
Correspondence to William H. Barry, MD, Division of Cardiology, University of Utah Health Sciences Center, 50 N Medical Dr, Salt Lake City, UT 84132. E-mail whbarry{at}med.utah.edu
The term
"cardiomyopathy of overload" was coined by
Arnold Katz in 1990.1 As he pointed out, it has
been recognized since the time of Osler that in patients with chronic
pressure or volume overload of the heart, a syndrome of progressive
ventricular dysfunction can develop.
Hypertrophy initially normalizes wall
stress,2 but eventually ventricular
dilation occurs, resulting in a secondary increase in wall stress
because of ventricular remodeling and associated increase
in the radius of curvature of the ventricle. This increase in wall
stress is proposed to cause further deterioration of
ventricular function by a progressive sequence of
hypertrophy
The potential causes of ventricular chamber
dysfunction in patients with advanced hypertrophy were well
summarized by Katz1 and include altered
energetics, myocyte "drop out" caused by necrosis and/or
apoptosis, alterations in the ventricular
connective tissue matrix, and hypertrophy-induced changes
in expression of myocyte genes and resulting alterations in myocyte
protein constituents that lead to a decrease in myocyte function. Work
from many laboratories has shown that hypertrophy in
animals is associated with switch to a fetal pattern of gene
expression3 including changes in actin and myosin
isoforms, an increase in atrial natriuretic factor levels,
a decrease in sarcoplasmic reticulum Ca2+ ATPase,
and an increase in Na+/Ca2+
exchanger expression. The latter two effects might be expected to alter
Ca2+ homeostasis in the
myocyte.4 Although it is recognized that
molecular events associated with hypertrophy in animals may
differ from those in humans,5 studies have shown
that hypertrophy and failure in humans can be associated
with similar changes in myocyte expression of genes and/or protein
levels for the sarcoplasmic reticulum Ca2+
ATPase,6 7 the
Na+/Ca2+
exchanger,8 and contractile protein components of
the myofilaments.9 Hypertrophy or
sarcolemmal stress-induced decreases in the L-type
Ca2+ current,10 and/or in
the cellular microdomains involved in coupling of the
Ca2+ current to release of
Ca2+ from the sarcoplasmic
reticulum,11 as well as alteration of the
cytoskeleton12 also may occur. The relative
importance of these myocyte alterations is not clear, but they could
obviously affect Ca2+ homeostasis, myofilament
responsiveness, and internal myocyte load to cause the decreased
myocyte contraction and relaxation and reduced
[Ca2+]i transient that
have been observed in initial studies of human myocytes from failing
myocardium.13 14
It is important to note that factors associated with the
peripheral circulatory derangements occurring in chronic
heart failure other than increased sarcolemmal stress and/or myocyte
hypertrophy may also contribute to a progressive decrease
in myocyte performance. These include long-term increased
exposure to catecholamines, which can induce a myopathic
effect15 and cause downregulation of the
ß1-receptor,16 and
increased circulating levels of cytokines such as tumor
necrosis factor-
The existence and relative importance of factors causing load-dependent
myocyte dysfunction have been investigated largely in animal models of
hypertrophy and failure. The pathophysiology of failure in
animals may differ significantly from that in humans. However,
obtaining high-quality human myocytes for study has been technically
challenging. Although some success has been achieved by dissociating
human myocytes from biopsy specimens,13 14 20 in
general, arterial perfusion of ventricular
tissue with collagenase is necessary to obtain myocytes of
high enough quality to allow studies at physiologic temperature and
contraction rates. In this issue, Dipla et al21
report a method for isolation of human ventricular myocytes
suitable for such studies. They apply it to show that myocytes isolated
from hearts with end-stage dilated failure caused by both
ischemic and idiopathic dilated
cardiomyopathy, in which a left
ventricular assist device (LVAD) was used for an extended
period of time to unload the ventricle, had significantly improved
contraction, relaxation, and catecholamine responsiveness
relative to myocytes isolated from the hearts of patients who did not
undergo a period of ventricular unloading before heart
transplantation. Preliminary data suggest this improvement in function
reflects changes in calcium homeostasis.
This study is significant from several perspectives. In addition to
establishing techniques that will facilitate the further study of the
pathophysiology and pharmacology of failing human
ventricular myocytes, it provides evidence to support the
hypothesis that chronic dilation and failure of the human heart
produces myocyte dysfunction, and, importantly, that the processes
involved are reversible. Whether the improvement in myocyte function
produced by the LVAD is due to effects of a reduction in sarcolemmal
stress and/or associated hypertrophy or to a decrease in
myocyte exposure to depressant agents such as
catecholamines and/or cytokines due to LVAD-induced
improvement in the circulation will require further study. In addition,
myocytes from nonfailing hearts will need to be examined with similar
techniques to establish what is "normal" function and thus to gauge
the extent of reversibility of depressed function. Development of a
large-animal model of ventricular dilation and failure in
which effects of ventricular unloading with an LVAD could
be similarly investigated would be very helpful in this regard. If the
improvement in myocyte function is due at least in part to the
reduction in ventricular wall stress, the clinical
implications are of considerable importance. It is possible that
prolonged load reduction by medical, surgical, or assist device
interventions in patients with dilated
cardiomyopathy of many causes may cause sufficient
improvement in myocyte function to allow reestablishment of cardiac
compensation and thus avoid or retard the progressive deterioration
that complicates the management of this disorder.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
References
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© 1998 American Heart Association, Inc.
Editorial
Load-Dependent Myocyte Dysfunction
Key Words: Editorials • myocytes • ventricles
decreased ventricular
functiondilationincreased wall
stresshypertrophydecreased ventricular
function. This sequence of events may also account for the progressive
nature of the ventricular enlargement and remodeling that
can occur after loss of a significant component of functioning
myocardium, or reduction in the number of myocytes as
caused, for example, by myocardial infarction or myocarditis. Indeed,
the well-recognized influence of depressed ventricular
function and cardiac dilation on prognosis in patients with
valvular disease, cardiomyopathy, and
ischemic heart disease may in part be due to this process. 
,17 which have direct negative
inotropic effects.18 Also, Kagaya et
al19 have shown that treatment of rats with the
ACE-inhibitor fosinopril improves depressed responsiveness
of myocytes to [Ca2+]i in
aortic-banded rats independent of alterations in
ventricular afterload. This finding suggests that effects
of the renin-angiotensin system on myocytes may be
important in the transition from hypertrophy to
failure. -myosin heavy chain
in hypertrophied, failing ventricular
myocardium. J Clin Invest. 1997;100:2315–2324.[Medline]
[Order article via Infotrieve]
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