Molecular Medicine for the Cardiac Surgeon

Over the last decade, the insight into the etiology and pathogenesis of cardiovascular disease has expanded dramatically. This has been made possible thanks to the development of advanced techniques in molecular biology. The powerful tool of gene therapy will become available for clinical use in the future, and studies have already shown bene cial effects of gene therapy in cardiovascular disease related to cardiac surgery. Ischemic heart disease with subsequent development of heart failure is a leading killer in the western world and a daily challenge to the cardiac surgeon. Therefore, in this review we will focus on some of the existing literature concerning molecular medicine and cardiac disease relevant to the cardiac surgeon. We believe that, in short, the cardiac surgeon might play a key role in performing gene therapy in patients with ischemic heart disease and heart failure, since such treatment often takes place in the operating theatre. Professor Dzau and colleagues have also pointed out the importance for cardiovascular surgeons to acquire knowledge in the  eld of molecular medicine and gene therapy (1). They have summarized this as follows: “We believe that integration of the disciplines of gene therapy and genomics and cardiovascular surgery should result in the emergence of a new  eld of therapy that we term surgiomics”. There are still numerous challenges in molecular medicine. Since the human genome is now characterized, research is increasingly aimed at revealing how the genes govern the function of the cell. This  eld of research, which makes use of various approaches, for instance microarray techniques, bioinformatics, proteomics, gene modi ed animals, cell biology among others, is called functional genomics. Several important aspects of cell function have recently become clear. First, there are probably many more different proteins than genes. This means that the cell performs important processing of the message from the nucleus to achieve greater variability and  exibility. This makes it important to know more than merely the gene sequences to be able to predict the effect that activation or modi cation of a gene will have on cell function. Second, the role of genes in disease pathogenesis is much more important and complex than previously recognized. Advancing from the simple concept of mono-gene inherited diseases, it is now important to unravel the multi-gene background that predisposes individuals to various diseases, for instance cardiovascular disease. It is no longer a matter of single genes, but it is a question of how many and which genes, that together form the predisposing phenotype. Furthermore, once the disease is in progress, a variety of responses occurs, some adaptive or suited to combat disease, some clearly maladaptive. Again, the genotype can be decisive for the outcome. Third, one protein rarely functions independently of other proteins. The proteins interact in many ways, which means that localization and organization of proteins within the cell is very important. We take this for granted with regard to the contractile proteins, but, in principle, all proteins are precisely localized. The cytosol of the cell is not a simple aqueous solution in which proteins and metabolites are dissolved. It is a highly structured gel, and most proteins are anchored to the cytoskeleton. In this way, microdomains are created by protein complexes within the cell. An example of this is the precise localization and cooperation of proteins that translate the electrical signal in the heart into a calcium signal that in turn causes activation of the contractile apparatus. It is possible that a disturbance of this delicate interaction between various ion-channel proteins can explain the defective contraction observed in the failing heart (2–4). Insight into this complex relationship between genotype and phenotype is of course important for the speci c manipulation of relevant genes to treat cardiac disease. Therefore, we will  rst brie y describe, as an example, some changes in gene and protein expression that take place in the failing heart. With this knowledge, dual gene therapy experiments have been performed with the future goal of doing this on patients (5). A comprehensive review on gene therapy for cardiovascular disease has recently been published (6). The route of application and the application form of the therapeutic protein molecules or their encoding genes into the diseased cardiovascular system are both