The molecular genetics of hypertrophic cardiomyopathy: prognostic implications

Hypertrophic cardiomyopathy (HCM) is an inheritable cardiac disorder with heterogeneous clinical features. Sudden cardiac death is a frequent complication, occurring at an annual incidence of 2–3% in young, otherwise healthy individuals with HCM and accounting for nearly 35% of all sudden deaths within this age group. Often, sudden cardiac death is the initial manifestation of HCM, underscoring the need for the precise elucidation of the mechanisms that lead to its occurrence. Over the past decade, modern molecular techniques have greatly increased the understanding of the pathophysiology underlying HCM. Through collaborative efforts, over 100 mutations in eight genes have been found to be responsible for the disease. All presently known aberrations affect the encoding of sarcomeric proteins, whose modification predisposes the heart to myocyte disarray, fibrosis, hypertrophy, and small vessel disease as well as haemodynamic alterations in diastolic and systolic function. Importantly, the natural history of the disease appears to be influenced by the particular protein affected, as well as by the specific changes within the protein encoded by the mutation. This knowledge has provided greater insight into the vulnerability of the myocardial substrate to mechanisms of sudden death. Knowledge of the genetic abnormalities of HCM and their implications will help the clinician to identify HCM patients at high-risk for sudden death, and to make appropriate recommendations in clinical management and prognosis. This article reviews the current understanding of the genetic mutations in HCM with emphasis on prognosis for sudden and disease-related death.