Medical conception of a disease begins with in vivo observation and develops with recognition of cognate findings on gross anatomy, histology, and cellular pathology. It was histopathology that established myocyte disarray as the cardinal feature of hypertrophic cardiomyopathy, present even in cases where left ventricular (LV) hypertrophy is subtle or absent. To this day, clinical-pathological association retains its historical value as the primary means of gaining insight into underlying disease processes. Enhancing its appeal is its accessibility to physicians, most of whom are familiar with histopathology from medical school and attuned to visual diagnosis. Article see p 632 With the advent of molecular genetics, however, the limitations of clinical-pathological association have become apparent and nowhere more so than in the inherited arrhythmia syndromes. In the long-QT and Brugada syndromes and catecholaminergic polymorphic ventricular tachycardia, a structurally normal heart belies the propensity to ventricular arrhythmia and sudden cardiac death (SCD). How this might be possible began to unravel with the isolation of mutations in genes encoding ion channels, transporters, and binding proteins. Genetic studies also have provided fresh insights into diseases with an obvious pathological substrate, such as hypertrophic cardiomyopathy, in which sarcomeric mutations predominate. Families with a high incidence of SCD and myocyte disarray but minimal LV hypertrophy were found to have mutations in troponin T,1 lending further support to the inclusion of this phenotype within the spectrum of hypertrophic cardiomyopathy. Redefining diseases according to their genetic etiology, while attractive, is less straightforward than immediately obvious. Defects in sarcomeric components, for example, have been implicated in both hypertrophic cardiomyopathy and dilated cardiomyopathy. In some heritable disorders, such as dilated cardiomyopathy, marked locus heterogeneity precludes delineation of a single genetic determinant. The ultimate solution to disease classification involves going 1 step further and identifying a unifying molecular mechanism, which may …
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