Arecent editorial published in Circulation Research by Jutta Schaper and collaborators1 has raised several challenging questions concerning the role of myocyte death in myocardial diseases. 2 Numerous studies have documented that myocyte death is an important variable in the development of ventricular dysfunction and failure in ischemic and idiopathic dilated cardiomyopathy, 3–5 long-term systemic hypertension, 6 and during myocardial aging in animals7, 8 and humans. 9, 10 Loss of myocytes leads to wall restructuring, side-to-side slippage of cells, mural thinning, chamber dilation, fibroblast activation, myocardial scarring, and depressed ventricular function. 11–14 Collagen accumulation resulting from focal and scattered myocyte death plays a critical role in both ischemic and idiopathic dilated cardiomyopathy, comprising more than 20% of the ventricles in the late stages of the cardiac disease. 3, 4 Contrary to the notion stated in the editorial, 1 coronary blood flow is impaired in both pathological conditions. 15 The importance of cell death as a mechanism of altered hemodynamics has been well demonstrated following myocardial infarction16 and diffuse cell death associated with limitations in coronary perfusion. 17 Myocyte death by apoptosis and necrosis documented in our human2, 5 and animal (for review, see Reference 11) studies has been interpreted as “an epiphenomenon that is not related to the evolution of heart failure....” 1 This conclusion was reached by the authors of the editorial on the basis that cell death in the decompensated heart was not counteracted by an equivalent amount of myocyte proliferation. 14, 18 Questionably, durations of cell apoptosis were indicated, 1 but no attempt was made to emphasize that mitosis lasts between 30 to 45 minutes. 14, 18 This does not imply that cell regeneration compensates for the extent of myocyte loss in the diseased myocardium. Such an imbalance between cell growth and cell death has been a major hypothesis of our laboratory, which has considered inadequate myocyte division as a critical event in the evolution of the pathological heart to terminal failure. 2, 13, 14 Experimentally, inhibition of myocyte apoptosis and necrosis in models of ischemic cardiomyopathy attenuates ventricular dilation, reactive hypertrophy, and diastolic wall stress, demonstrating unequivocally the crucial role of cell death in ventricular remodeling. 19, 20

Myocyte death is important, but the relevant question is whether it can be recognized and its magnitude actually measured. This technical issue will be addressed first, since according to the editorial,“electron microscopy provides the gold standard for the identification of both apoptosis and necrosis.” We do not share this view; to avoid any possible subjective interpretation of morphological findings, oligonucleotide probes have been developed that allow the recognition of different aspects of DNA damage. 21–24 Double-strand DNA cleavage with staggered ends can be detected by the terminal deoxynucleotidyl transferase (TdT) assay; doublestrand DNA cleavage with single-base 3 overhang can be detected by a polymerase chain reaction (PCR)–generated Taq polymerase probe or hairpin probe with single-base 3 overhang; double-strand DNA cleavage with blunt ends can be detected by a PCR-generated Pfu polymerase probe or hairpin probe with blunt ends; and single-strand DNA cleavage can be detected by the in situ nick translation assay. 21–24 The first two recognize different aspects of cell apoptosis, the third depicts cell necrosis, and the last identifies potentially repairable DNA damage. The specificity of these DNA probes has been questioned …