Chapter 68: Cell Therapy for Cardiovascular Diseases

INTRODUCTION

Ischemic heart disease and heart failure continue to be the predominant causes of morbidity and mortality worldwide. Acute myocardial infarction is the most common cause of heart failure and triggers a series of cellular and molecular changes leading to apoptosis, necrosis, hypertrophy of cardiomyocytes, impaired neovascularization, interstitial fibrosis, inflammation, reduced contractility, and pathologic remodeling.¹ Despite advances in medical and device therapy, hospitalization rates and mortality for heart failure continue to remain high, with 1 in 5 patients dying within 12 months of diagnosis.² Medical therapy has centered on the treatment of underlying risk factors and on the initiation of antiplatelet, lipid-lowering, β-adrenergic receptor, and angiotensin antagonist therapy. Interventions designed to facilitate cardiovascular regeneration were not initially pursued because it was assumed that the adult heart is a terminally differentiated postmitotic organ where the number of cardiomyocytes are established at birth, with no potential for regeneration after damage.³

Over the last 2 decades, irrefutable evidence has emerged that challenges these concepts due to the discovery of a population of bone marrow–derived and resident progenitor/stem cells that promote cardiomyocyte and vascular renewal and proliferation. It is now clear that human cardiomyocytes renew throughout a person’s lifespan at a rate that decreases from 1% annual turnover at age 25 to 0.45% at age 75 years.⁴ Regeneration of infarcted myocardium requires massive cell replenishment, possibly in the order of a billion cardiomyocytes together with functional integration with supporting cell types.⁵ The adult heart, however, has a relatively low number of cardiac progenitor cells with a low proliferation rate that cannot compensate for the large losses of cardiomyocytes seen after an acute myocardial infarction. Cell-based therapies offer a novel strategy to repair and regenerate injured and nonviable cardiac and vascular tissue.

In the past decade, there has been an influx of clinical trials investigating the safety and efficacy of both autologous and allogeneic stem/progenitor cells for cardiovascular repair and regeneration. To date, phase I and phase II cell therapy trials have been conducted in patients with refractory angina pectoris, acute myocardial infarction, ischemic and nonischemic heart failure, and peripheral vascular disease. While a variety of cell types and delivery techniques have been used, the majority of clinical trials have used a catheter-based approach to target delivery of cells to areas of ischemia or dysfunction. Herein we will review potential mechanisms of action of stem cells, mechanisms of cellular delivery, and cell types currently being studied for cardiovascular regeneration, and review ongoing clinical trials. Characteristics of stem cells being investigated in cardiovascular cell therapy are summarized in Table 68-1.