Cell therapy in myocardial infarction

Abstract

Heart failure is associated with a high rate of morbidity and mortality. In some patients, current treatment modalities may not be adequate to prevent myocardial remodeling, which leads to exacerbation of the disease. Cell therapy is based on the premise of replacing damaged myocardium with functional tissues. Multiple forms of stem cells, including bone marrow-derived stem cells and skeletal myoblasts, have been investigated using several delivery routes of administration. Different mechanisms have been proposed to explain the beneficial effects of cell-based therapy. These include cell transdifferentiation, cell fusion, and release of paracrine growth factors. The beneficial effects of cell therapy may involve multiple mechanisms. The encouraging results of early clinical cell therapy studies have not been sustained by subsequent robust studies. These findings suggest that many unanswered questions need to be addressed before cell therapy becomes an acceptable adjunctive treatment for heart failure.

Introduction

Heart failure is a leading cause of morbidity and mortality worldwide. There are an estimated 5 million Americans with a diagnosis of heart failure [1]. The overall prevalence ranges from 3 to 20 per 1000 people and exceeds 100 per 1000 people over the age of 65. The annual incidence of heart failure ranges from 1 to 5 per 1000 people and doubles each decade over the age of 45 [2]. Heart failure is responsible for roughly 20% of hospital admissions for patients over the age of 65 [1]. In the United States in 1991, the cost of treating heart failure in ambulatory patients was approximately $15 billion and the cost of inpatient treatment was roughly $23 billion. The total health care cost for treatment of heart failure neared 5% of health care expenditures that year [2].

Determining the etiology of heart failure can be complex due to a lack of consistent diagnostic criteria and patients with multiple morbidities who may contribute to the etiology. Despite this challenge, coronary artery disease (CAD) is currently the most common identifiable cause of heart failure. In over 20,000 patients enrolled in multicenter heart failure treatment trials from 1986 to 1997, CAD was the underlying etiology in 68% of cases [3]. In population-based studies, the prevalence of CAD varies from 28% to 36% [4], [5].

Mortality after myocardial infarction (MI) improves with early reperfusion of the infarct-related artery [6]. If this is not accomplished in a timely fashion, necrosis, scar formation, and left ventricular remodeling occur. Remodeling affects left ventricular function and, therefore, prognosis [7]. The best way to prevent this process from occurring is to minimize the initial insult with timely restoration of flow in the infarct-related artery; however, this is not always possible. Current procedures to treat heart failure once the infarct has occurred work toward prevention of further weakening of the myocardium. However, the primary problem of fibrosis is not addressed with these modalities. Cell-based therapy is an adjunctive treatment to improve left ventricular function after myocardial injury.

Traditional belief that the heart contains myocytes that have terminally differentiated has been questioned. Undifferentiated cells have been found in transplanted human hearts, and evidence of myocyte proliferation in the human heart exists as well [8], [9]. This proliferation is not sufficient to compensate for the up to 1 billion cardiomyocytes (CMCs) that are lost after MI [10]. Cellular cardiomyoplasty describes a method of transplanting stem or progenitor cells to damaged myocardium after infarction in order to regenerate myocardial tissue. The theory behind this method involves replacing degenerate myocardium with functional tissue. A number of different cell types, as well as methods of delivery, have been tested in both human and animal models.