(Circulation. 2001;103:787.)
© 2001 American Heart Association, Inc.
Editorial |
Of Phospholamban, Mice, and Humans With Heart Failure
From the Division of Cardiology, University of Colorado Health Sciences Center, Denver.
Correspondence to Michael R. Bristow, MD, PhD, Division of Cardiology, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Campus Box B-139. Denver, CO 80262. E-mail Michael.Bristow{at}UCHSC.edu
Key Words: Editorials • heart failure • norepinephrine • sarcoplasmic reticulum • receptors, adrenergic, beta • cardiomyopathy
Despite recent advances in the medical
treatment of chronic heart
failure,1 this clinical
syndrome remains progressive. For example, in recently completed
clinical trials demonstrating a reduction in mortality by medical
therapy with
-blockade2 3 or
spironolactone,4 the survival
curves of the active treatment groups retained a downward slope, such
that at 20 to 24 months after randomization, only 80% to 85% of
subjects with mild to
moderate2 3 and
70% of subjects with
advanced4 heart failure
remained alive. The progressive nature of heart failure is due to the
inexorable worsening of the underlying disease processes, myocardial
dysfunction, and
remodeling.5 6 What
are the critical factors responsible for progressive contractile
dysfunction and remodeling of the failing heart? Data from clinical
studies implicate both the adrenergic and renin-angiotensin-aldosterone
systems, because treatment with -blocking agents and
renin-angiotensin-aldosterone system inhibitors attenuate the
dysfunction/remodeling
processes.6 Other signaling
pathways are also involved, as shown by studies in animal
models7 and the failure of
inhibiting both the adrenergic and renin-angiotensin-aldosterone
systems to completely prevent progression in dysfunction, remodeling,
and mortality.
Despite the widespread acceptance of this general paradigm, important details remain to be elucidated. For example, the precise nature of the relationship between remodeling and contractile dysfunction is a source of controversy. Some models of chamber dysfunction exhibit remodeling (chamber dilation and cell lengthening) without contractile dysfunction,8 whereas others9 are characterized by contractile dysfunction without structural remodeling. However, most animal models of heart failure10 11 12 and the failing human heart13 14 exhibit both cellular remodeling and dysfunction. Although the phenomena of cellular contractile dysfunction and hypertrophy are inter-related,15 the question of which of these processes typically develops first is an important issue from the standpoint of therapeutic strategies designed to prevent or reverse the vicious cycle of dysfunction and remodeling.
Another unresolved issue in the field of chronic heart
failure is the elucidation of the molecular mechanism(s) responsible
for intrinsic contractile dysfunction. Numerous candidates exist,
including abnormalities of Ca2+ handling,
altered -receptor signal transduction, changes in contractile
protein expression, cytoskeletal or microtubule derangements, and
abnormalities of bioenergetic
mechanisms.16 One of the
first proposed mechanisms for the progression of contractile
dysfunction in the failing human heart was altered -adrenergic
receptor signal
transduction.17 This general
phenomenon, which was first reported as down-regulation of
1-adrenergic receptors in the explanted
failing human
heart,17 18 19
involves multiple other molecular defects; these include upregulation
of the inhibitory G protein
G
i20 21
and of -adrenergic receptor kinase, an enzyme that
phosphorylates/uncouples 1 and
2-adrenergic
receptors.22 The myocardial
1- and 2-adrenergic
receptor pathways terminate on phospholamban, where protein kinase
A–mediated phosphorylation decreases the inhibition of this regulatory
protein on the Ca2+ ATPase of the
sarcoplasmic
reticulum.23 24
In the failing heart, the decrease in -adrenergic signal
transduction capacity means that for any given amount of adrenergic
drive, phospholamban phosphorylation will be
less25 and the contractile
function in response to adrenergic signaling will be
reduced.17 18 26
Although these signal transduction abnormalities are incontrovertible,
the interpretation of their role in the pathophysiology of heart
failure remains somewhat controversial. Some groups interpret this
constellation of signal transduction changes as being
maladaptive,27 whereas the
majority of investigators interpret the changes as being generally
adaptive1 28 29
and serving the purpose of withdrawing the failing heart from harmful
adrenergic stimulation.
In this issue of
Circulation, Dash et
al30 provide evidence
relevant to some of these issues. Using the standard -myosin heavy
chain promoter/transgene cardiac myocyte targeting strategy developed
by Subramaniam et al,31 they
overexpressed phospholamban protein levels 
4 fold in transgenic
mice. The function of unphosphorylated phospholamban is to inhibit the
activity of sarcoplasmic reticulum Ca ATPase; thus, this maneuver
decreased both systolic and diastolic function. When the -myosin
heavy chain promoter began to drive increased phospholamban mRNA and
protein expression in adult mice, intrinsic contractile function was
depressed at the myocyte level at 3 months, without evidence of chamber
and, by inference, cellular
remodeling.30
This model, therefore, mimics certain forms of human
heart failure that usually present with contractile dysfunction without
remodeling, for example, myocarditis and postpartum or anthracycline
cardiomyopathy. In the phospholamban overexpressor mouse, one of the
consequences of this genetically-produced depression of contractile
dysfunction was an increase in myocardial adrenergic activity, which at
3 months tended to normalize myocardial function by increasing
phospholamban
phosphorylation.30 However,
by 15 to 18 months, -adrenergic pathway desensitization had occurred
and phospholamban phosphorylation had been reduced below levels
observed at 3 months.30
Moreover, progressively reduced contractile function was now evident in
vivo, in part because the -adrenergic support mechanism was now
compromised. In addition, the phospholamban knockout mice at 15 to 18
months exhibited hypertrophy and remodeling, which further decreased
intrinsic contractile function by virtue of inducing the expression of
the fetal gene
program16 32 and
through other mechanisms. Thus, the innovative and carefully conducted
study of Dash et al30 nicely
demonstrates that (1) myocyte contractile dysfunction can precede
remodeling by serving as the stimulus for activating signaling pathways
that produce cellular and chamber remodeling and (2) that in the
setting of decreased contractile function, cardiac adrenergic drive is
initially helpful but, ultimately, this compensatory mechanism
contributes to progressive dysfunction and remodeling. Thus, the
"yin-yang" aspect of increased adrenergic drive was systematically
revealed in a carefully investigated genetic model of cardiomyopathy
and myocardial failure.
Finally, Dash et
al30 argue that their data
indicate a feedback loop exists between the proximal and distal ends of
the -adrenergic pathway. According to this idea, if phospholamban
protein expression or function is increased, adrenergic activity will
be increased to phosphorylate/inhibit phospholamban to maintain normal
contractile function, as happened in their study. An extension of this
hypothesis would be that if phospholamban phosphorylation is decreased,
as is the case in explanted failing human
hearts,25 adrenergic
activity would be obligately increased to maintain contractile
function. As was again demonstrated by Dash et
al,30 because sustained
increases in cardiac adrenergic activity are harmful to the heart, this
scenario would logically call for treatment modalities that selectively
increase phospholamban phosphorylation. Such a pharmacological agent
would have both positive inotropic and lusitropic properties, and it
would provide a means of testing the "phospholamban hypothesis" at
the clinical level.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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