[Gene therapy in heart diseases]

Cardiovascular diseases are the most important cause of death and hospitalisation in industrialised countries. Although pharmacological, interventional and surgical therapy has achieved major progress during the past 25 years, most therapeutic measures are only transiently effective or require life-long medication. Molecular cardiology aims at applying molecular biological methods for both diagnosis and treatment of cardiovascular disease. With respect to diagnosis of cardiac diseases such as hypertrophic cardiomyopathy or the long QT syndrome, it has become possible to characterise mutations in the genome responsible for the disease process. It is interesting that different mutations inducing hypertrophic cardiomyopathy are associated with a different prognosis and survival time. This example demonstrates that molecular biological analysis allows a better estimation of the individual risk in patients with a monogenetic disease. Such diseases are an important target for genetic therapies, as transfection of normal copies of the diseased gene would potentially cure the patient. Clinical experience has so far only been obtained in patients with familial hypercholesterolaemia and mutations in the LDL receptor. Molecular biology also permits a better understanding of the pathogenesis of atherosclerosis, which is responsible for most cardiovascular disease. Atherosclerosis is a disease of conduit arteries such as the aorta and the coronary arteries. In recent years it has become possible to characterise better the molecular and cellular changes leading to endothelial dysfunction, coronary vasospasm, adhesion of monocytes and lymphocytes, proliferation and migration of vascular smooth muscle cells, and formation of extracellular matrix. This improved understanding has led to new therapeutic approaches, although a genetic intervention is not probable for the moment due to the complexity of the disease process. Balloon dilatation of coronary arteries has generated a new disease, namely restenosis. Vascular remodelling and proliferation are of major importance for this disease. Many cellular mechanisms have been characterised, and gene therapeutic strategies including signal transduction and cell cycle regulation have already been investigated experimentally. Coronary bypass graft disease represents another target for gene therapy in the vascular system. Many experimental and a few clinical protocols have been performed with the saphenous vein. Yet another strategy for gene therapy is the endogenous formation of new vessels due to the effect of vascular endothelial growth factor. Molecular cardiology is a new and promising approach to a better understanding of cardiovascular disease. Genetic analysis is already established for the diagnosis of single gene disorders and, in addition, allows a more precise prognostic evaluation. Cardiovascular gene therapy has been focussing mainly on angiogenesis; other strategies, however, are under investigation mainly in an experimental setting.