Marc van Bilsen – författare

The development of the heart and vessels during embryogenesis depends on the complex interplay of various cell types and growth factors. The implementation of molecular tools has enabled us to analyse early steps in cardiogenesis and vasculogenesis. Furthermore the introduction of transgenic and knock-out techniques in mice, and the miniaturization of physiologic measurements to the mouse level has fundamentally changed our knowledge. Pathophysiology can be unravelled at the molecular level. The implications of various stimuli on specific membrane receptors can be analyzed. In response to receptor activation, interacting intracellular signalling pathways can activate or block transcription factors. The changes in gene expression lead to functional changes observed in the cardiovascular systems of animal models and humans. Changes in the level of gene expression and protein function in cardiovascular disease are discussed for the sarcomeric, calcium handling and ion channel genes. Furthermore, different approaches to the design of cell-type-specific gene therapy approaches for the heart and vessels are outlined.

Improving our insights into the genetic predisposition to cardiovascular disease is one of the most important challenges in our field in the next millennium, not only to unravel the cause of disease but also to improve the selection of patients for particular treatments. Nowadays, for example, subjects with a cholesterol above a particular plasma level are exposed to a cholesterol lowering regime based upon the beneficial outcome of epidemiological studies which include subjects not prone to the disease, despite a plasma cholesterol above the accepted level. Identification of the patients who are genetically predisposed to the consequences of this disorder will reduce the number of subjects unnecessarily treated and, hence, the costs of health care. Because in most cardiovascular diseases the genetic component is a consequence of more than one gene defect, only limited progress has as yet been made in identifying subjects genetically at risk. For example, in hypertension only in less than 10% of the patients the genetic defect has been identified. It has been known for quite some time that in heart and blood vessels fetal genes are as high blood pressure and upregulated or induced when they are exposed to such disorders ischemia. Little is known about the function of these genes in the cardiac and vascular adaptation to these disorders; only guesses can be made.