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This Article Full Text Full Text (PDF) All Versions of this Article: 297/2/H785    most recent 00310.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Park, M. Articles by Vatner, S. F. PubMed PubMed Citation Articles by Park, M. Articles by Vatner, S. F.

Apoptosis predominates in nonmyocytes in heart failure

¹Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey; ²Cardiovascular Center, Onze-Lieve-Vrouwziekenhuis Clinic, Aalst, Belgium; ³Simian Conservation Breeding and Research, Incorporated, Manila, Philippines; ⁴Saint Luke's Medical Center, Research and Biotechnology Division, Quezon City, Philippines; and ⁵Departments of Medicine and Cell Biology and Einstein-Montefiore Center for Cardiovascular Research, Albert Einstein College of Medicine, Bronx, New York

Submitted 27 March 2009 ; accepted in final form 11 May 2009

The goal of this investigation was to determine the distribution of myocardial apoptosis in myocytes and nonmyocytes in primates and patients with heart failure (HF). Almost all clinical cardiologists and cardiovascular investigators believe that myocyte apoptosis is considered to be a cardinal sign of HF and a major factor in its pathogenesis. However, with the knowledge that 75% of the number of cells in the heart are nonmyocytes, it is important to determine whether the apoptosis in HF is occurring in myocytes or in nonmyocytes. We studied both a nonhuman primate model of chronic HF, induced by rapid pacing 2–6 mo after myocardial infarction (MI), and biopsies from patients with ischemic cardiomyopathy. Dual labeling with a cardiac muscle marker was used to discriminate apoptosis in myocytes versus nonmyocytes. Left ventricular ejection fraction decreased following MI (from 78% to 60%) and further with HF (35%, P < 0.05). As expected, total apoptosis was increased in the myocardium following recovery from MI (0.62 cells/mm²) and increased further with the development of HF (1.91 cells/mm²). Surprisingly, the majority of apoptotic cells in MI and MI + HF, and in both the adjacent and remote areas, were nonmyocytes. This was also observed in myocardial biopsies from patients with ischemic cardiomyopathy. We found that macrophages contributed the largest fraction of apoptotic nonmyocytes (41% vs. 18% neutrophils, 16% fibroblast, and 25% endothelial and other cells). Although HF in the failing human and monkey heart is characterized by significant apoptosis, in contrast to current concepts, the apoptosis in nonmyocytes was eight- to ninefold greater than in myocytes.

myocytes; macrophages; cardiomyopathy; caspase-3