EDITORIAL COMMENT
Death or repair of the myocyte in chronic heart failure*
Philip A. Poole-Wilson, MD, FRCP, FACC, FESC*,*
* National Heart and Lung Institute, Imperial College, London, United Kingdom
* Reprint requests and correspondence: Dr. Philip A. Poole-Wilson, Department of Cardiac Medicine, National Heart and Lung Institute, Faculty of Medicine, Imperial College, Dovehouse St., London SW3 6LY, United Kingdom.
p.poole-wilson{at}ic.ac.uk
Perceptions of the fundamental biology of cardiac muscle are undergoing radical change. For many years the accepted mantra was that the cardiac myocyte soon after birth became a terminally differentiated cell that, once destroyed, could not be replaced (1). Many studies by eminent pathologists disputed that view because the increase in the weight of the heart in severe heart failure (HF) could not be accounted for by fibrosis or enlargement of existing myocytes (2,3). In large hearts, hyperplasia (increase in number of cells) rather than hypertrophy (increase in the size of a cardiac myocyte) was necessary to explain the increase in weight. The weakness of that argument was the difficulty in determining the mean size of the myocyte in the heart by conventional two-dimensional pathology methods. There were almost no reports of mitotic bodies having been observed in human myocardium, with one notable exception (4). Certainly the myocardial cell does not have great plasticity, as evidenced by the rarity of cardiac tumors. But several recent reports, albeit from the same laboratory, have provided evidence for the existence of mitotic bodies (5,6) and for the possibility that cardiac cells can be regenerated either from rare cell types within the myocardium or from bone marrow cells migrating to the myocardium before transformation (7). A weakness with this latter argument is that the findings may be due not to transformation of migrant bone marrow cells (8,9) but to fusion of the nucleus of such a cell with an existing myocyte. Several investigators have reported turnover of deoxyribonucleic acid (DNA) under pathological states but rarely in the normal myocardium (10). What might be concluded is that in the normal myocardium cell regeneration is a very rare event indeed. Under pathological conditions there is a small potential for cell division or regeneration, but that this is not usually able to overcome cell destruction associated with disease.
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Progression of pathology
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Concurrent with these findings, a number of studies have reported on the progression of pathology in the myocardium of patients with HF. Extensive pathological changes have been demonstrated in myocytes from the failing heart, including substantial disarray of structural cellular components and loss of contractile material (11–14). Such cells could not possibly be expected to have normal metabolism or normal function. A key question is whether these cells are doomed to eventual destruction. The jargon associated with cell death is extensive, including necrosis, oncosis, autophagy, apoptosis, lethal cell injury, and reversible and irreversible damage. Some of these words such as "irreversible damage" and "lethal cell injury" contain within them predictions for the future and are not useful. Probably the only criteria to determine that a cell is inevitably doomed are gross disruption of the cell membrane or loss or disaggregation of nuclear material. The TUNEL test (terminal deoxynucleotidyltransferase-mediated biotin-dUTP nick-end labeling technique) detects nuclear material that has been damaged in the process of apoptosis (15). The biochemical pathways leading to apoptosis are well defined. Of major importance is the issue as to whether this test detects damaged cells that are potentially recoverable or cells that are destroyed (16). Numerous recent reports on the degree of apoptosis determined by the TUNEL test have detected different degrees of positive cells (17–21). Some of these reports indicate such a high proportion of cells being TUNEL positive that the patient must inevitably die in a short period. Because that does not fit with clinical observation, something is wrong. Possibilities include the fact that TUNEL cells are not destined to destruction (16), cells regenerate to replace the destroyed cells, sampling errors have overestimated the local degree of cell damage, or errors exist in the methods of performing the TUNEL test. There is an argument for those using these methods to exchange tissue so that the reproducibility of the findings between groups of investigators can be determined.
The study by Bartunek et al. (22) in this issue of the Journal adds further information. Importantly, the investigators have made measurements on tissue biopsies from 26 patients with mild to possibly severe HF due to idiopathic dilated cardiomyopathy rather than terminal HF or from hearts removed at the time of transplantation. In contrast to many other investigators, Bartunek et al. (22) were unable, using a "stringent" TUNEL test, to detect positive cells, but they were able to provide evidence of an activated repair process in the myocardium. The activation of repair in patients with lower ejection fractions and thus presumed more severe HF.
Taking the results at face value and putting aside debate concerning methodology and the limitations of the study that the authors declare, these findings would appear to add to our understanding of the progression of HF. The major cause of heart failure is coronary heart disease linked to loss of myocytes. At the edge of a myocardial infarct there may indeed be some temporary regeneration of myocardial cells. The ventricle then remodels and may enter a nascent phase of almost stable heart failure where DNA turnover and destruction and/or regeneration of cells is minimal. Often, patients with HF, once the heart is enlarged and signs of HF develop, deteriorate rapidly. At this stage of disease the clinical picture is somewhat similar regardless of the etiology of HF. The rapid deterioration has been linked to the increased presence of cytokines possibly because the body’s defence mechanisms to infection have been diminished, and to activation of inflammatory and immunological systems (23,24). During this phase the myocardial cells undergo apoptosis and necrosis. The apoptosis is accompanied by futile attempts at cell regeneration.
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Clinical implications
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Were such a hypothesis to be correct, several clinical implications arise. First, restoring circulatory function and reducing the workload of the ventricle with a ventricular assist device should allow much of the myocardium to recover, as has been observed. Second, inhibiting the biological processes activating cell apoptosis and promoting cell regeneration should be clinically effective. Third, the mantra that the myocardial cell cannot regenerate and/or repair is incorrect. The importance of this last point is not that the regeneration is small and futile because the patient’s outlook remains poor, but rather that there is the potential to manipulate cell repair and regeneration. Understanding the biology of that process may lead to new treatments for heart failure, which, despite the many advances in the last few decades, still carries a gloomy prognosis.
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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Progression of pathology
Clinical implications