Abstract
It is widely held that myocyte apoptosis in left ventricular hypertrophy (LVH) contributes to left ventricle (LV) dysfunction and heart failure. The main goal of this investigation was to determine if there is a statistical relationship among LV hypertrophy, apoptosis and LV function, and importantly whether the apoptosis occurs in myocytes or nonmyocytes in the heart. We used both rat and canine models of severe LVH induced by chronic thoracic aortic banding with resultant LV-aortic pressure gradients 145-155 mmHg and increases in LV/body weight of 58 and 70%. These models also provided the ability to examine transmural apoptosis in LVH. In both models, the overwhelming majority (88%) of apoptotic cells were nonmyocytes. The regressions for apoptosis vs. LVH were stronger for nonmyocytes than myocytes and also stronger in the subendocardium than the subepicardium. Importantly, LV systolic and diastolic wall stresses were normal, indicating that the apoptosis could not be attributed to LV stretch or heart failure. In addition, there was no relationship between the extent of apoptosis and LV ejection fraction, which actually increased (P < 0.05), in the face of elevated LV systolic pressure, indicating that greater apoptosis did not result in a decrease in LV function. Thus, in response to chronic, severe pressure overload, LVH in the absence of LV dilation, and elevated LV wall stress, apoptosis occurred predominantly in nonmyocytes in the myocardial interstitium, more in the subendocardium than the subepicardium. The extent of apoptosis was linearly related to the amount of LV hypertrophy, but not to LV function.
Highlights
Heart failure; left ventricular hypertrophy; programmed cell death; left ventricular wall stress has occurred [3, 5, 13] have shown that apoptosis occurs in nonmyocytes in the heart
IT IS WIDELY RECOGNIZED THAT apoptosis increases with left ventricular hypertrophy (LVH) and that the increased apoptosis is a critical mechanism mediating the transition from compensated hypertrophy to heart failure [1, 2, 4, 10, 12, 16]
The major finding of the present investigation was that apoptosis in the severe but well-compensated hypertrophied heart occurs not in myocytes, as previously thought, but rather predominantly in interstitial nonmyocytes and that it is related to the extent of LVH
Summary
Heart failure; left ventricular hypertrophy; programmed cell death; left ventricular wall stress has occurred [3, 5, 13] have shown that apoptosis occurs in nonmyocytes in the heart. Whether nonmyocyte apoptosis occurs in the compensated hypertrophied heart without an increase in wall stress, in the absence of myocardial infarction and injury, is not known It is not known whether apoptosis relates to the severity of LVH, whether it results in reduced LV function with more severe LVH, and whether there is a transmural distribution of apoptosis. The goal of this investigation was first to determine the relationship between the extent of LVH and apoptosis where LVH was induced by chronic thoracic aortic banding, and whether with more severe LVH, LV function begins to decline. These models permitted evaluation of transmural apoptosis and were characterized by LV-aortic pressure gradients over 140 mmHg, levels not generally achieved in prior studies of thoracic aortic banding, yet LV wall stress and end-diastolic dimensions and pressures remained normal
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