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Original Articles

Multiple Defects in Intracellular Calcium Cycling in Whole Failing Rat Heart

J. Andrew Wasserstrom, PhD; Rohan Sharma, BS; Sunil Kapur, MD; James E. Kelly, BS; Alan H. Kadish, MD; C. William Balke, MD and Gary L. Aistrup, PhD

From the Departments of Medicine (Cardiology) (J.A.W., R.S., S.K., J.E.K., A.H.K., G.L.A.) and Molecular Pharmacology and Biological Chemistry (J.A.W., G.L.A.) and the Feinberg Cardiovascular Research Institute (J.A.W., A.H.K.), Northwestern University Feinberg School of Medicine, Chicago, Ill; and Departments of Physiology and Medicine (C.W.B.), University of Kentucky College of Medicine, Lexington, Ky.

Correspondence to J. Andrew Wasserstrom, PhD, Northwestern University Feinberg School of Medicine, Chicago, IL 60611. E-mail ja-wasserstrom{at}northwestern.edu

Received July 31, 2008; accepted March 4, 2009.

Background— A number of defects in excitation-contraction coupling have been identified in failing mammalian hearts. The goal of this study was to measure the defects in intracellular Ca²⁺ cycling in left ventricular epicardial myocytes of the whole heart in an animal model of congestive heart failure (CHF).

Methods and Results— Intracellular Ca²⁺ transients were measured using confocal microscopy in whole rat hearts from age-matched Wistar-Kyoto control rats and spontaneously hypertensive rats at 23 months of age. Basal Ca²⁺ transients in myocytes in spontaneously hypertensive rats were smaller in amplitude and longer in duration than Wistar-Kyoto control rats. There was also greater variability in transient characteristics associated with duration between myocytes of CHF than Wistar-Kyoto controls. Approximately 21% of CHF myocytes demonstrated spontaneous Ca²⁺ waves compared with very little of this activity in Wistar-Kyoto control rats. A separate population of spontaneously hypertensive rat myocytes showed Ca²⁺ waves that were triggered during pacing and were absent at rest (triggered waves). Rapid pacing protocols caused Ca²⁺ alternans to develop at slower heart rates in CHF.

Conclusions— Epicardial cells demonstrate both serious defects and greater cell-to-cell variability in Ca²⁺ cycling in CHF. The defects in Ca²⁺ cycling include both spontaneous and triggered waves of Ca²⁺ release, which promote triggered activity. The slowing of Ca²⁺ repriming in the sarcoplasmic reticulum is probably responsible for the increased vulnerability to Ca²⁺ alternans in CHF. Our results suggest that defective Ca²⁺ cycling could contribute both to reduced cardiac output in CHF and to the establishment of repolarization gradients, thus creating the substrate for reentrant arrhythmias.

Key Words: arrhythmia • calcium • heart failure • sarcoplasmic reticulum

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