Molecular genetics of card iomyopathies

The first classifications of cardiomyopathies from 1980 and 1996 described them as heart muscle diseases, with dilated (DCM), hypertrophic (HCM), restrictive (RCM), arrhythmogenic right ventricular (ARVC), and nonclassifiable cardiomyopathies. Furthermore, the World Health Organization/International Society and Federation of Cardiology (WHO/ISFC) classification from 1996 listed among the specific cardiomyopathies inflammatory cardiomyopathy as a new and distinct entity, which was defined histologically as myocarditis in association with cardiac dysfunction. Infectious and autoimmune forms of inflammatory cardiomyopathy were recognized. Viral cardiomyopathy was defined as viral persistence in a dilated heart without ongoing inflammation. If it was accompanied by myocardial inflammation, it was termed inflammatory viral cardiomyopathy (or viral myocarditis with cardiomegaly). This entity was further elucidated in a World Heart Federation consensus meeting in 1999 by quantitative immunohistological criteria (< 14 infiltrating cells/mm(2)) and the etiology by molecular biological methods, e.g., polymerase chain reaction, as viral, bacterial, or autoimmune (= nonmicrobial). The development of molecular genetics, with the discovery of a genetic background in several forms of cardiomyopathies previously alluded to as "of unknown origin", was the origin of a debate on a new classification based on genomics. A genomic/postgenomic classification was postulated taking the underlying gene mutations and the cellular level of expression of encoded proteins into account, thus distinguishing cytoskeleton (cytoskeletalopathies, e.g., DCM or ARVC), sarcomeric (sarcomyopathies as in HCM and RCM) and ion channel (channelopathies, e.g., long or short QT syndrome and Brugada's syndrome) cardiomyopathies. Such a classification of cardiomyopathies was proposed in 2006 by the American Heart Association (AHA), which took the rapid evolution of molecular genetics in cardiology into account. It also introduced several recently described diseases, and is unique in that it incorporated ion channelopathies even without hemodynamic dysfunction as a "primary" cardiomyopathy. The ESC (European Society of Cardiology) Working Group on Myocardial and Pericardial Diseases has deliberately taken a different approach based on a clinically oriented classification in which heart muscle disorders were grouped according to morphology and function. This obviously remains the clinically most useful approach for the diagnosis and management of patients and families with heart muscle disease. In the ESC position statement published in 2008, cardiomyopathies were defined as myocardial disorders in which the heart muscle is structurally and functionally abnormal, and in which coronary artery disease, hypertension, valvular and congenital heart disease are absent or do not sufficiently explain the observed myocardial abnormality. The aim was to help clinicians look beyond generic diagnostic labels in order to reach more specific diagnoses. In parallel, a scientific statement on the role of endomyocardial biopsy in the management of cardiovascular disease was published at the end of 2007 making useful recommendations for clinical practice and providing an understanding for the use of endomyocardial biopsy in an individual patient. Taking the classification of cardiomyopathies and the statement on the role of endomyocardial biopsies in different clinical scenarios together, the clinician is now able to identify genetic, autoimmune and viral causative factors by using a thorough and logical approach to reach a diagnosis in patients with familial and nonfamilial forms of the underlying structural heart muscle diseases.