Is it time to include ion channel diseases among cardiomyopathies?

Abstract

Heart muscle diseases are traditionally classified according to their peculiar pathophysiologic features such as “dilated,” “hypertrophic,” “restrictive,” and “arrhythmogenic right ventricular” cardiomyopathy. The extraordinary advances accomplished in the last two decades in molecular genetics have allowed the identification of the genetic background of most of these conditions. According to the 1995 World Health Organization definition of cardiomyopathies as “diseases of the myocardium associated with cardiac dysfunction,” they should include not only forms with hemodynamic dysfunction, but also conduction and rhythm disturbances. Arrhythmias are per se a sign of cardiac dysfunction and may reflect an underlying myocardial electrical disease with or without structural abnormalities as features. Nonstructural arrhythmogenic heart diseases include long and short QT syndromes, Brugada syndrome, Lènegre disease, and catecholaminergic polymorphic ventricular tachycardia. These conditions are defined as “channelopathies” because they are the consequence of cardiac ion channel gene mutations. Long and short QT syndromes are mostly caused by either sodium or potassium ion channel gene mutations; Brugada syndrome and Lènegre disease are both related to a defective sodium channel gene; and polymorphic ventricular tachycardia is the result of an abnormal ryanodine receptor regulating calcium release from the sarcoplasmic reticulum. These nonstructural inherited arrhythmic conditions should be regarded as cardiomyopathies because the myocyte is abnormal, although the heart is apparently intact. It is time for a new classification of cardiomyopathies taking into account the underlying gene mutations and the cellular level of expression of encoded proteins, thus distinguishing cytoskeleton (cytoskeletalopathies), desmosomal (desmosomalopathies), sarcomeric (sarcomyopathies), and ion channel (channelopathies) cardiomyopathies.