Calcium Channel Blockade Ameliorates Cardiac Dysfunction and Failure in Ischemic Cardiomyopathy

To determine whether calcium overload plays a role in the initiation of the cascade of events leading to the thin-walled, decompensated ventricle observed in ischemic heart failure, inhibition of transarcolemmal transport of calcium by nisoldipine was examined in rats in which stenosis of the left main coronary artery (CAN) was utilized to produce global cardiac ischemia. CAN was produced in rats at 2 months of age, and animals were maintained on nisoldipine, 10mg/kg, body weight (CANN) or placebo (CANW) until the time of sacrifice, 1 month later. Surgical intervention resulted in a 50% reduction in coronary artery luminal diameter in both CAN groups, which was associated with an increase in kidney and lung weights in only CANW animals. Heart weights were also increased in the placebo-treated CAN group. In CANW rats, systemic artrial and left ventricular systolic pressures were reduced, whereas left ventricular diastolic pressures were elevated. Peak rates of pressure rise and decay and cardiac output were also reduced in CANW rats. Treatment with nisoldipine reduced the detrimental impact of ischemic heart disease to such an extent that all measured parameters in CANN rats were found to be intermediate between unoperated controls and CANW animals. Thus calcium overload plays a major role in the initiation of cardiac dysfunction and failure seen after the onset of ischemic heart disease in rats. Further, the detrimental impact of ischemic heart disease can be lessened by early and continuous treatment with the calcium channel blocker nisoldipine. Ischemic heart disease is a complex clinical syndrome in which deficiencies in blood supply, tissue oxygen, and metabolic nutrients are created by partial or complete occlusion of a major epicardial coronary artery [1,2]. Moreover, pathologic findings in failing hearts in this setting demonstrate that only moderate quantities of viable tissue have been lost, strongly suggesting that myocyte cell loss does not play a major role in the generation of ventricular failure [3-8]. In this regard, experimentation in small animals has revealed that coronary artery stenosis results not only in a 10-20% loss of myocytes, but also in the appearance of marked ventricular dysfunction and, with time, the occurrence of overt ventricular failure [9-11]. Studies of coronary blood flow hemodynamics have revealed that coronary reserve is altered [12]. Electrocardiographic (ECG) changes, consistent with transmural myocardial ischemia, become apparent shortly after coronary artery narrowing [12]. Hemodynamically these hearts show a progressive deterioration in ventricular pump performance, which is hallmarked by the early appearance of diastolic dysfunction followed by a decline in the systolic indices of pump function and ultimately the appearance of overt cardiac failure [13]. The increase in diastolic stress is greater than that seen in systolic stress and is a result of the marked increase in end-diastolic pressure, impaired diastolic filling, and prolongation of the isovolumic relaxation phase of the cardiac cycle, which are characteristics of this animal model of the human disease. Marked ventricular dilatation occurs during the failing stage as well. Biochemical studies have documented a shift in the pCa-ATPase activity curve following narrowing, with increases in resting and decreases in systolic calcium levels posing a potential mechanism for the observed abnormalities in the diastolic as well as the systolic properties of pump performance [10]. Inhibition of the trans-sarcolemmal flux of calcium has been shown to be beneficial in the prevention of the calcium overload—induced failure seen in the cardiomyopathic Syrian hamster [14]. Thus, on the assumption that calcium overload is the initial trigger in the cascade of events leading to the thin-walled, dilated failing heart in this animal model, the present investigation examines whether inhibition of trans-sarcolemmal transport of calcium by nisoldipine obstructs the initial abnormalities in diastolic cardiac function, maintains cardiac pump performance, and prevents the onset of ventricular failure after coronary narrowing.