- H.J. Houtgraa // Cell-based Therapies for Cardiovascular Repair: How small things matter
Celtherapie voor ziekten van hart en bloedvaten
Cardiovascular disease accounts for almost half of the deaths in the Western world and 25% in developing countries, despite significant therapeutic and interventional advances. It is estimated that by the year 2020, cardiovascular disease will surpass infectious disease, to become the world’s leading cause of mortality and morbidity. Approximately half of the cardiovascular mortality is due to acute myocardial infarction, whereas subsequent heart failure and stable coronary artery disease account for the majority of morbidity. Stem cell therapy to reduce the burden of cardiovascular disease has been the topic of extensive research over the past decade. The assumption that multipotent cells can graft to the injured heart and incorporate into the host’s myocardium, thereby contributing to contractility and improving cardiac function, is considered to be the holy grail for cardiac cell therapy. Hence, the first attempt of cardiac cell therapy more than a decade ago was with skeletal myoblasts (SkM) in end-stage heart failure patients. These progenitor cells are derived from striated skeletal muscle, and are destined to become contracting myofibers. It was hypothesized that, once injected into myocardial scars, these SkM would differentiate into contractile units in vivo, and actually contribute to the contractile apparatus. Unfortunately, clinical reality turned out to be less manipulable, and subsequent research has indicated that the road towards the holy grail is still long and comprises many obstacles on the way. More specifically, injected SkM did not actually incorporate into scars, but rather formed re-entry circuits for ventricular arrhythmias, whereas cardiac function was not enhanced following SkM injection. In the clinical arena, these disappointing results were rather generalized into the notion that cardiovascular cell therapy did not work. However, as there are several different cardiovascular pathologies and even more different stem cell types, cell therapy is not a single entity. Therefore, the last decade has been devoted to unraveling numerous questions, as 1) what is the ideal stem cell type and dose; 2) what cardiovascular disease types qualify for stem cell therapy; 3) when should stem cell therapy be initiated; 4) how should cells be administered; 5) what is the best surrogate end point to evaluate the effect of cell therapy; etcetera. This thesis aims to clarify some of these questions, and summarizes our current knowledge about cardiovascular cell therapy.
