Calcium Currents in Chronically Dysfunctional Pig Myocardium

Abstract

Chronic reduction in coronary artery blood flow due to stenosis results in reduced myocardial contractile function, termed “hibernating” myocardium. This change involves electrical remodeling and a propensity for sudden cardiac death in the absence of infarction. We used a pig model of chronic left anterior descending artery stenosis to study calcium currents associated with the hibernating myocardium. We developed a cell isolation technique from punch biopsies of the left ventricle. This yields calcium-tolerant isolated myocytes with brick shaped morphology and clear striation patterns. Myocyte length from hibernating myocardium averaged 145 ± 7.7 (n=15) vs. 124 ± 4.8 μm (n=42) for control, suggesting cellular hypertrophy. The cell shortening of hibernating cells was also reduced compared to the remote region from 6.4 ± 1% (n=21) to 4.45 ± 1% (n=11) suggesting that the reduced contractility seen in the hibernating region was preserved in the isolated myocytes. Furthermore, cells isolated from hibernating myocardium had significantly higher numbers of premature contractions 4/15 for hibernating vs. 0/19 for control suggesting a cellular propensity for arrhythmias. The L-type calcium channel current (ICa,L) in myocytes from hibernating myocardium (1.35 ± 0.08 pA/pF, n=22) was reduced compared to normal myocardium (1.96 ± 0.07 pA/pF, n=33; P<0.01). The voltage dependence of steady state activation and inactivation were nearly identical. Isoproterenol (100 nM) shifted the activation curves nearly identically for both groups, but the ability of isoproterenol to enhance the current was decreased from a 4.1 ± 0.48 fold increase to a 2.64 ± 0.37 (p < 0.05). Finally, the recovery rate for calcium current was reduced by hibernation, reflecting an approximate 20 mV shift. These changes in L-type calcium current and isoproterenol response may explain the reduced contractility of hibernating myocytes and the increased the likelihood of sudden cardiac arrhythmias.