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(Circulation. 2001;103:787.)
© 2001 American Heart Association, Inc.

Editorial

Of Phospholamban, Mice, and Humans With Heart Failure

Michael R. Bristow, MD, PhD

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@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 -blockade^{2 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 moderate^{2 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 failure^{10 11 12} and the failing human heart^{13 14} exhibit both cellular remodeling and dysfunction. Although the phenomena of cellular . . . [Full Text of this Article]

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