Apoptosis predominates in nonmyocytes in heart failure.
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/mm(2)) and increased further with the development of HF (1.91 cells/mm(2)). 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.
Park
Misun
M
Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, University of Medicineand Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey 07103, USA.
Shen
You-Tang
YT
Gaussin
Vinciane
V
Heyndrickx
Guy R
GR
Bartunek
Jozef
J
Resuello
Ranillo R G
RR
Natividad
Filipinas F
FF
Kitsis
Richard N
RN
Vatner
Dorothy E
DE
Vatner
Stephen F
SF
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001706:Biopsy; D009202:Cardiomyopathies / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000473:pathology; D006333:Heart Failure / Q000473:pathology*; D006801:Humans; D020287:In Situ Nick-End Labeling; D008252:Macaca fascicularis; D008264:Macrophages / Q000473:pathology; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology*; D017202:Myocardial Ischemia / Q000473:pathology; D009206:Myocardium / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000473:pathology; D009504:Neutrophils / Q000473:pathology; D010138:Pacemaker, Artificial
C505407:CASP3 protein, human; D053148:Caspase 3