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(Circulation Research. 1999;84:741-743.)
© 1999 American Heart Association, Inc.

Editorial

Calcineurin Inhibition as Therapy for Cardiac Hypertrophy and Heart Failure

Requiescat in Pace?

Richard A. Walsh

From the Department of Medicine, Case Western Reserve University, University Hospitals, Cleveland, Ohio.

Correspondence to Richard A. Walsh, MD, Department of Medicine, Case Western Reserve University, University Hospitals, 11100 Euclid Ave, LKS-5029, Cleveland, OH 44106-5029.

Key Words: signal transduction • cyclosporine therapy • cardiomyopathy

Congestive heart failure is a major public health problem that is increasing, despite a reduced incidence and prevalence of other forms of cardiovascular disease. Initially, the heart responds to diverse pathological stimuli by an increase in mass achieved principally by enlargement of terminally differentiated cardiomyocytes. The resulting augmented chamber mass provides temporary maintenance of wall stress and organ function. If the pathological stimulus is sufficiently intense or prolonged, decompensated hypertrophy characterized by diminished cardiomyocyte and organ function occurs, and the syndrome of congestive heart failure ensues.¹

Over the past decade, the application of molecular and cellular biological techniques to this process has begun to provide mechanistic insights into the subcellular processes responsible for impaired cardiac function in hypertrophy and failure.² Evidence has accumulated to implicate both cell death (necrosis and apoptosis) and chamber remodeling due to alterations in the extracellular matrix in the pathogenesis of heart failure. In addition, multiple laboratories have focused on biochemical alterations intrinsic to the cardiomyocyte, such as abnormalities of calcium homeostasis, altered myofilament activation, and altered abundance or activity of sarcolemmal ion pumps and channels. In particular, a number of laboratories using a variety of in vitro and in vivo approaches have implicated changes in signal transduction pathways in the development of this pathological process. In this context, intense interest was recently evoked by the elucidation of a new cardiomyocyte signal transduction pathway that could initiate cardiac hypertrophy and failure. Molkentin et al³ demonstrated that the calcium calmodulin–dependant protein phosphatase calcineurin can activate hypertrophic signals . . . [Full Text of this Article]

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