Genetics of Cardiovascular Diseases

Since the identification of the basis of the human genome, molecular genetics has progressively entered into many fields of medicine. Cardiovascular medicine does not represent an exception to this rule. The unravelling of the molecular determinants of cardiovascular diseases took off from studies of the so-called ‘monogenic’ diseases that provided evidence showing that the genes/proteins involved in genetic diseases of the heart belong to three major functional classes: 1) structural; 2) electrical; 3) regulatory.

It is clear that mutations in structural proteins are associated with structural cardiomyopathies (dilated cardiomyopathy, hypertrophic cardiomyopathy, and arrhythmogenic right ventricular cardiomyopathy, etc.), while proteins underlying cardiac excitability are predominantly associated with inherited arrhythmogenic disorders (long QT syndrome, catecholaminergic tachycardia, Brugada syndrome, etc.). Finally, regulatory proteins (chaperones, second messengers, signal transduction proteins) may be associated either with structural involvement or with arrhythmias in a normal heart. Furthermore it is also clear that, with few exceptions, all monogenic diseases of the heart are characterized by remarkable ‘two-way’ heterogeneity: 1) The same clinical phenotype may be caused by different genes/mutations. 2) The same gene and, in some instances, even the same mutation, can cause different clinical phenotypes.

In parallel with this growing recognition of heterogeneity we are also learning how to get the best from the results of genetic testing to tailor and individualize risk stratification and therapy. Genotype-driven clinical management is therefore progressively entering the clinical practice.

Another major line of research in the field of genetics of cardiovascular diseases is represented by investigations aimed at discovering the genetic determinants of complex traits such as coronary artery disease and hypertension. These conditions recognize both environmental and genetic components. The latter is clearly supported by the evidence of familial predisposition. However, such genetic predisposition is usually polygenic and only rarely results from a single gene mutation. The ‘two ways’ in this case are represented by the ‘initial’ conditions, coded in the genotype, and by the exposure to environmental agents over time.

This chapter will review the current understanding of genetic determinants of cardiovascular diseases spanning monogenic to polygenic disorders, and will highlight the genetic heterogeneity and the mechanisms leading from gene mutation to clinical phenotype.