Heart disease is an endemic health problem of great magnitude in the world. In spite of considerable clinical and research effort during the last decade and the development of new drugs and surgical modalities of therapy, the mortality and morbidity rates remain very high. Moreover, many fundamental questions regarding the basic underlying mechanisms and pathophysiology of most cardiovascular diseases (CVDs), including congenital and acquired defects, remain unanswered. Breakthroughs in molecular genetic technology have just begun to be applied in studies of cardiovascular disease, allowing chromosomal mapping and the identification of many genes involved in both the primary etiology and also as significant risk factors in the development of these anomalies. Identification of genes responsible for rare familial forms of cardiovascular disease has proved to be informative in the study of nonsyndromic patients with cardiac pathology.

Common cardiovascular anomalies (e.g., cardiomyopathy, congenital heart disease, atherosclerosis, hypertension, cardiac arrhythmias) seem to be united by association with distinct subsets of genes. These include genes responsible for subcellular structures (e.g., sarcomere, cytoskeleton, channels), metabolic regulatory enzymes (e.g., renin-angiotensin system, cholesterol metabolic pathway), or intracellular signaling pathways (e.g., calcineurin, CaMK, TNFa). At present, the following areas of research appear particularly promising:

(1) With the completion of the Human Genome Project the likely identification of novel genes involved in nonsyndromic cardiac disease, cardiac organogenesis, and vascular development will serve as an important foundation for our understanding of how specific gene defects generate their cardiovascular phenotypes. Bioinformatic methods can be employed to search existing databases with the routine use of reverse genetics techniques, allowing subsequent cloning of novel genes/cDNAs of interest, followed by the characterization of spatial-temporal patterns of specific gene expression. Moreover, post-genomic analysis including both transcriptome and proteomic methodologies can be used to further delineate the functions of the gene products, defining their precise role in pathogenesis, elucidating their interaction with other proteins in the subcellular pathways, and potentially enabling their application as clinical markers of specific CVDs.

(2) The mechanisms governing the early specification of cardiac chambers in the developing heart tube have not yet been precisely delineated but are thought to involve novel cell-to-cell signaling among migrating cells, as well as the triggering of chamber-specific gene expression programs, mediated by specific transcription factors and growth factors such as bone morphogenetic protein (BMP). Future areas of study will focus on elucidating the role of signaling molecules (e.g., WNT) using conditional gene knock-outs (in a variety of genetic backgrounds) and accessing their interaction with critical transcription factors such as dHAND, NKX2.5, GATA4, and TBX. Similar approaches may also prove informative in probing the origins of the cardiac conduction system, and in deciphering the role of signaling systems as participants in vascular formation in endothelial cells, focusing on the interaction of VEGF, angiopoietin, TGF, and the Notch pathway.