Published Online
on February 17, 2003

A more recent version of this article appeared on March 4, 2003

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Submitted on October 8, 2002
Revised on November 7, 2002
Accepted on November 20, 2002

Contractile Reserve and Calcium Regulation Are Depressed in Myocytes From Chronically Unloaded Hearts

Kenta Ito MD, PhD, Masaharu Nakayama MD, PhD, Faisal Hasan MD, Xinhua Yan MD, Michael D. Schneider MD, and Beverly H. Lorell MD^*

From the Department of Medicine (K.I., M.N., F.H., X.Y., B.H.L.), Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, Mass, and the Departments of Medicine, Molecular & Cellular Biology, and Molecular Physiology and Biophysics (M.D.S.), Baylor College of Medicine, Houston, Tex.

^* To whom correspondence should be addressed. E-mail: blorell{at}caregroup.harvard.edu.

Background--Chronic cardiac unloading of the normal heart results in the reduction of left ventricular (LV) mass, but effects on myocyte contractile function are not known.

Methods and Results--Cardiac unloading and reduction in LV mass were induced by heterotopic heart transplantation to the abdominal aorta in isogenic rats. Contractility and [Ca²⁺]_i regulation in LV myocytes were studied at both 2 and 5 weeks after transplantation. Native in situ hearts from recipient animals were used as the controls for all experiments. Contractile function indices in myocytes from 2-week unloaded and native (control) hearts were similar under baseline conditions (0.5 Hz, 1.2 mmol/L [Ca²⁺]_o, and 36°C) and in response to stimulation with high [Ca²⁺]_o (range 2.5 to 4.0 mmol/L). In myocytes from 5-week unloaded hearts, there were no differences in fractional cell shortening and peak-systolic [Ca²⁺]_i at baseline; however, time to 50% relengthening and time to 50% decline in [Ca²⁺]_i were prolonged compared with controls. Severe defects in fractional cell shortening and peak-systolic [Ca²⁺]_i were elicited in myocytes from 5-week unloaded hearts in response to high [Ca²⁺]_o. However, there were no differences in the contractile response to isoproterenol between myocytes from unloaded and native hearts. In 5-week unloaded hearts, but not in 2-week unloaded hearts, LV protein levels of phospholamban were increased (345% of native heart values). Protein levels of sarcoplasmic reticulum Ca²⁺ ATPase and the Na⁺/Ca²⁺ exchanger were not changed.

Conclusions--Chronic unloading of the normal heart caused a time-dependent depression of myocyte contractile function, suggesting the potential for impaired performance in states associated with prolonged cardiac atrophy.

Key words: calcium • myocytes • contractility • transplantation

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