© 1999 American Heart Association, Inc.
Point/Counterpoint |
Prevention of Cardiac Hypertrophy by Calcineurin Inhibition
Hope or Hype?
From the Department of Molecular Biology and Oncology (E.N.O.), University of Texas Southwestern Medical Center at Dallas, Texas, and Division of Molecular Cardiovascular Biology (J.D.M.), Children's Hospital Medical Center, Cincinnati, Ohio.
Correspondence to Eric N. Olson, PhD, Department of Molecular Biology and Oncology, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, TX 75235-9148. E-mail eolson@hamon.swmed.edu
Key Words: cardiac hypertrophy • calcineurin • cardiomyocyte • NFAT • cyclosporin
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Introduction |
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Heart failure afflicts about 5 million Americans at an estimated cost to the healthcare system of 40 billion dollars annually.1 2 Despite extensive knowledge of the causes and effects of heart failure, the underlying molecular mechanisms responsible for the disease remain vague. Elucidation of these mechanisms is an essential prerequisite to the development of rational pharmacological approaches to prevent and potentially reverse the pathological changes associated with this catastrophic disease.
Cardiac hypertrophy is an adaptive response of the heart to a wide array of intrinsic and extrinsic stimuli, including hypertension, myocardial infarction, cardiac arrhythmias, valvular disease, endocrine disorders, and contractile abnormalities resulting from mutant sarcomeric proteins. Because cardiomyocytes lose the ability to divide soon after birth, enlargement of the heart during hypertrophy involves an increase in size and mass of individual cardiomyocytes without an increase in cell number. Although initially beneficial, prolonged hypertrophy can become deleterious, resulting in dilated cardiomyopathy, heart failure, and sudden death. Several drugs show efficacy in sustaining cardiac function and prolonging life in heart failure patients, but the 5-year mortality rate for patients with the disease remains nearly 50%, and there is no truly effective pharmacological prevention or cure. The recent creation of several mouse models that mimic aspects of human heart disease represents an auspicious step toward the development of improved drug therapies.
Over the past decade, a multitude of papers have described
various signal-transduction pathways that can induce
hypertrophy in cultured cardiomyocytes and
transgenic mice.3 4 However, although it is apparent that
a host of signals
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Z. Kassiri, C. Zobel, T.-T. T. Nguyen, J. D. Molkentin, and P. H. Backx Reduction of Ito Causes Hypertrophy in Neonatal Rat Ventricular Myocytes Circ. Res., March 22, 2002; 90(5): 578 - 585. [Abstract] [Full Text] [PDF]
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