Cellular Cardiomyoplasty Improves Survival After Myocardial Injury

Abstract

Background-Cellular cardiomyoplasty is discussed as an alternative therapeutic approach to heart failure. To date, however, the functional characteristics of the transplanted cells, their contribution to heart function, and most importantly, the potential therapeutic benefit of this treatment remain unclear. Methods and Results-Murine ventricular cardiomyocytes (E12.5-E15.5) labeled with enhanced green fluorescent protein (EGFP) were transplanted into the cryoinjured left ventricular walls of 2-month-old male mice. Ultrastructural analysis of the cryoinfarction showed a complete loss of cardiomyocytes within 2 days and fibrotic healing within 7 days after injury. Two weeks after operation, EGFP-positive cardiomyocytes were engrafted throughout the wall of the lesioned myocardium. Morphological studies showed differentiation and formation of intercellular contacts. Furthermore, electrophysiological experiments on isolated EGFP-positive cardiomyocytes showed time-dependent differentiation with postnatal ventricular action potentials and intact ␤-adrenergic modulation. These findings were corroborated by Western blotting, in which accelerated differentiation of the transplanted cells was detected on the basis of a switch in troponin I isoforms. When contractility was tested in muscle strips and heart function was assessed by use of echocardiography, a significant improvement of force generation and heart function was seen. These findings were supported by a clear improvement of survival of mice in the cardiomyoplasty group when a large group of animals was analyzed (nϭ153). Conclusions-Transplanted embryonic cardiomyocytes engraft and display accelerated differentiation and intact cellular excitability. The present study demonstrates, as a proof of principle, that cellular cardiomyoplasty improves heart function and increases survival on myocardial injury. (Circulation. 2002;105:2435-2441.)

A novel model of cryoinjury-induced myocardial infarction in the mouse: a comparison with coronary artery ligation

“…Although cryoinjury has been previously described in mice (1,14,15), this is the first study to directly compare both models using echocardiography and LV catheterization and to evaluate different sizes of cryoinjury. The principal findings of this study were 1) cryoinfarction in the mouse is a feasible and highly standardized method to create MI with low peri-and postoperative mortality; 2) cryoinfarction results in macrovascular reperfusion with microvascular reperfusion occurring selectively along the endocardial borders; and 3) cryoinfarction results in loss of contractility and in diastolic dysfunction to a similar degree as LAD ligation after 8 wk with, however, more modest LV remodeling and no signs of overt backward LV failure.…”

“…In the last years, cryoinjury has been mainly applied in studies on intracardiac cell transplantation (9,14,15,21). However, to date, no study has been performed to elucidate the effects of cryoinjury on infarct size, heart function, and left ventricular (LV) remodeling in the mouse.…”

Cardiac Repair by Embryonic Stem-Derived Cells

“…Although improvement in left ventricular function was observed in several studies where fetal cardiomyocytes were transplanted into injured hearts, the mechanism underlying the improvement was not obvious (Muller-Ehmsen et al 2002;Roell et al 2002). This was particularly true in instances where donor cell density was low, suggesting that the donor cells might have exerted a beneficial effect on the myocardium independent of participation in a functional syncytium.…”

Embryonic Stem Cells: New Possible Therapy for Degenerative Diseases That Affect Elderly People

“…Several animal models of MI using coronary ligation in rats or cryoinjury in mice have been used to test the implantation of fetal-, embryo-, or ES-derived cardiomyocytes by direct injection into heart muscle (78)(79)(80)(81) (81).…”