Cryoinjury: a model of myocardial regeneration.

Abstract

INTRODUCTION: Although traditionally adult cardiomyocytes are thought to be unable to divide, recent observations provide evidence for cardiomyocyte proliferation after myocardial injury. Myocardial cryoinjury has been shown to be followed by neovascularization. We hypothesize that, in addition to neovascularization, cardiomyocyte proliferation after myocardial cryoinjury contributes to regeneration. METHOD: Cryolesions were applied to the left ventricle of mouse hearts. Inflammatory cell infiltration (F4/80, neutrophils), neovascularization (CD31), and cardiomyocyte proliferation (5-bromo-2-deoxyuridine, Ki-67, mitotic spindle) were determined at different time points (2-70 days) after cryoinjury. RESULTS: Between Days 7 and 14 after injury, a 150- and 280-fold increase in number of proliferating cardiomyocytes was observed, as compared to controls. At the same time, numerous proliferating capillaries were found in between the proliferating cardiomyocytes. Presence of high numbers of macrophages in the cryolesion preceded and coincided with this proliferation. The area of cryolesion decreased significantly between Days 7 (23+/-5%) and 14 (8+/-2%) after cryoinjury. Moreover, regeneration of viable, nonhypertrophied myocardium was observed. After 14 days, cardiomyocyte proliferation decreased to numbers observed in controls, and concomitantly, the number of macrophages strongly decreased. CONCLUSION: Our data show that adult cardiomyocytes proliferate in sufficiently high numbers to effectuate myocardial regeneration after left ventricular cryoinjury in mice.