Shaoheng Zhang(a,b), Jingxuan Guo(a), Ping Zhang(a,b), Yonggang Liu(a), Zhuqing Jia(b,c), Kangtao Ma(c), Weihong Li(a), Linsong Li(b), Chunyan Zhou(b,c)*

a: Department of Cardiology, the Third Hospital of Peking University
b: Peking University Stem Cell Research Center
c: Department of Biochemistry and Molecular Biology, the School of Basic Medical Sciences, Peking University

Received 2 June 2003; Accepted 6 October 2003

Source: http://www.sciencedirect.com

Abstract

This study was performed to evaluate the long-term effect on left ventricular function and remodeling in a rat model of bone marrow cell transplantation (BMT) into acute infarcted myocardium. After myocardial infarction was induced in inbred Lewis rats by left anterior descending artery ligation, the ischemic area was directly injected with saline, peripheral blood mononuclear cells (PB-MNCs) or bone marrow mononuclear cells (BM-MNCs). Cardiac function and structure were evaluated by echocardiography before the operation, and on day 1 and 2 months post-infarct. The collagen content, the number of vessels and the asculogenesis were examined by histology and immunohistochemistry. We found at 2 months post-infarct, BMT significantly improved cardiac systolic function and recovered diastolic function. Transplantation of BM-MNCs, but not PB-MNCs, reversed remodeling and reduced collagen density. Vessel counts showed greater angiogenesis occurred in the animals transplanted with BM-MNCs. Furthermore, a vascular endothelial cell-specific marker was detected in the transplanted bone marrow cells.

Introduction

Despite advances in the treatment of myocardial infarction (MI), reduced cardiac function resulting from ventricular remodeling is still a major problem. Left ventricular (LV) remodeling after myocardial infarction is associated with fibrosis, dilatation and dysfunction. Post-infarction remodeling consists of an early phase (within 72 hours) and a late phase (after 72 hours) (Sutton and Sharpe, 2000). The early phase involves expansion of the infarct zone, which may result in early ventricular rupture or aneurysm formation. Late remodeling consists of progressive expansion of the initial infarct area, dilation of the left ventricle, replacement of cardiomyocytes by fibrous tissue and formation of a collagen scar in the ventricular wall (Erlebacher et al., 1984). Left ventricular remodeling can be considered a primary target for treatment and a reliable surrogate for long-term outcomes. Recently, it has been suggested that cell therapy with bone marrow cells may be effective in the treatment of MI (Orlic et al., 2001). There is now compelling evidence that bone marrow cell transplantation reduces infarct area and improves cardiac function via angiogenesis and differentiation in an ischemic heart model (Kocher et al., 2001). Several different fractions of bone marrow mononuclear cells (BM-MNCs), such as mesenchymal cells and hematopoietic cells, may contribute to the regeneration of vessels and necrotic myocardium (Kocher et al., 2001; Goodell et al., 2001). Clinical data have revealed that autologuous BM-MNCs have been identified as a progenitor population readily accessible from an adult patient’s own tissue that can be adapted to clinical therapy (Hamano et al., 2001; Strauer et al., 2002). Peripheral blood mononuclear cells (PBMNCs) transplantation has been also reported to enhance angiogenic actions and improve cardiac function in ischemic hearts in an animal model (Kamihata et al., 2002). However, those studies laid emphasis on cardiac systolic function and angiogenesis. Little is known about the long-term effects of those procedures on cardiac diastolic function and remodeling. Diastolic heart ailure in particular, which is caused by left ventricular diastolic dysfunction without systolic dysfunction and constitutes 30–50% of heart failure (Redfield et al., 2003), has a poor prognosis (Bella et al., 2002). A specific therapeutic strategy for diastolic heart failure has not yet been established.

The current study aimed to evaluate the long-term effects of BM-MNC transplantation on systolic and diastolic cardiac function, and on left ventricular remodeling in direct comparison of the therapeutic effects with PB-MNCs after myocardial infarction.

Conclusion

Transplantation of BM-MNCs resulted in long-term improvement in left ventricular functionespecially diastolic function- and remodeling. These improvements appeared to be due to reduction in collagen density and enhancement of neovascularization.