Programmed death of myocytes occurs in the decompensated human heart in spite of the enhanced expression of BCL2; this phenomenon may contribute to the progression of cardiac dysfunction.

Introduced several decades ago, the dogma persists that cardiac myocytes are terminally differentiated cells and that division of muscle cells is impossible in the adult heart. More recently, nuclear mitotic divisions in myocytes occasionally were seen, but those observations were challenged on the assumption that the rate of cell proliferation was inconsequential for actual tissue regeneration. Moreover, mitoses were never detected in normal myocardium. However, the analysis of routine histologic preparations constituted the basis for the belief that myocytes were unable to reenter the cell cycle and divide, ignoring the limitations of these techniques. We report here by confocal microscopy that 14 myocytes per million were in mitosis in control human hearts. A nearly 10-fold increase in this parameter was measured in end-stage ischemic heart disease (152 myocytes per million) and in idiopathic dilated cardiomyopathy (131 myocytes per million). Because the left ventricle contains 5.8 ؋ 10 9 myocytes, these mitotic indices imply that 81.2 ؋ 10 3 , 882 ؋ 10 3 , and 760 ؋ 10 3 myocytes were in mitosis in the entire ventricular myocardium of control hearts and hearts affected by ischemic and idiopathic dilated cardiomyopathy, respectively. Additionally, mitosis lasts less than 1 hr, suggesting that large numbers of myocytes can be formed in the nonpathologic and pathologic heart with time. Evidence of cytokinesis in myocytes was obtained, providing unequivocal proof of myocyte proliferation.

Abstract-Cardiovascular disease is delayed and less common in women than in men. Myocyte death occurs in heart failure, but only apoptosis has been documented; the role of myocyte necrosis is unknown. Therefore, we tested whether necrosis is as important as apoptosis and whether myocyte death is lower in women than in men with heart failure. Molecular probes were used to measure the magnitude of myocyte necrosis and apoptosis in 7 women and 12 men undergoing transplantation for cardiac failure. Myocyte necrosis was evaluated by detection of DNA damage with blunt end fragments, whereas apoptosis was assessed by the identification of double-strand DNA cleavage with single base or longer 3Ј overhangs. An identical analysis of these forms of cell death was performed in control myocardium. Heart failure showed levels of myocyte necrosis 7-fold greater than apoptosis in patients of both sexes. However, cell death was 2-fold higher in men than in women. Heart failure resulted in a 13-fold and 27-fold increase in necrosis in women and men, respectively. Apoptosis increased 35-fold in women and 85-fold in men. The differences in cell death between women and men were confirmed by the electrophoretic pattern of DNA diffusion and laddering of isolated myocytes.The lower degree of cell death in women was associated with a longer duration of the myopathy, a later onset of cardiac decompensation, and a longer interval between heart failure and transplantation. In conclusion, myocyte necrosis and apoptosis affect the decompensated human heart; each contributes to the evolution of cardiac failure. However, the female heart is protected, at least in part, from necrotic and apoptotic death signals. (Circ Res. 1999;85:856-866.)Key Words: apoptosis Ⅲ necrosis Ⅲ heart failure Ⅲ sex Ⅲ cardiomyopathy C ardiac diseases are delayed and less frequent in women than in men. 1,2 The hormonal profile differs between women and men, and estrogens may exert their protective effects on the heart at multiple levels. Estrogen replacement in postmenopausal women reduces the risk of cardiovascular events, 3 and hypertension affects a more limited number of premenopausal women than men of a comparable age. 4 Similarly, heart failure of ischemic and nonischemic origin is predominantly a male disease. 1,2 Although the pathogenesis of heart failure remains unclear, myocyte apoptosis may be 1 of the critical factors involved. 5,6 Experimentally, myocyte apoptosis has been implicated in the transition from compensated to decompensated hypertensive hypertrophy 7 and in the acute restructuring of the wall and chamber dilation of the postinfarcted heart. 8 Prevention of cell death attenuates the impact of ischemic damage on ventricular anatomy and performance. 9,10 A relevant question is whether the myocardium in women is less susceptible to death signals and possesses an inherent ability to counteract the activation of the endogenous cell death pathway. Cell death occurs by apoptosis, necrosis, and the combination of both. 11,12 The possibility that myocyte ...

SUMMARYPTX3 is a secreted molecule which consists of a C-terminal domain similar to classical pentraxins (e.g. C-reactive protein (CRP)) and of an unrelated N-terminal domain. Unlike the classical pentraxins, the long pentraxin PTX3 is expressed in response to IL-1b and tumour necrosis factor-alpha (TNF-a), but not to IL-6, in various cell types. The present study was designed to investigate the expression of PTX3 in RA. Dissociated RA and osteoarthritis (OA) type B synoviocytes were cultured in the presence and in the absence of inflammatory cytokines. PTX3 mRNA expression in synoviocytes was evaluated by Northern analysis. PTX3 protein levels in synovial cell cultures and synovial fluid were estimated by ELISA, and PTX3 distribution in synovial tissues by immunohistochemical techniques. OA synoviocytes were induced to express high levels of PTX3 mRNA by TNF-a, but not by other cytokines including IL-1b and IL-6. RA synoviocytes, unlike OA synoviocytes, constitutively expressed high levels of PTX3 in the absence of deliberate stimulation. The constitutive expression of PTX3 in RA synoviocytes was not modified by anti-TNF-a antibodies, IL-1 receptor antagonist or a combination of the two agents. In contrast, interferon-gamma and transforming growth factor-beta inhibited PTX3 constitutive expression in RA synoviocytes. The joint fluid from RA patients contained higher levels of immunoreactive PTX3 than controls and the synovial tissue contained endothelial cells and synoviocytes positive for PTX3 by immunohistochemistry. In conclusion, PTX3 may play a role in inflammatory circuits of RA, and its relevance as a marker of disease activity deserves further study.