Moving beyond simple answers to complex disorders in sarcomeric cardiomyopathies: the role of integrated systems

Abstract

The classic clinical definition of hypertrophic cardiomyopathy (HCM) as originally described by Teare is deceptively simple, "left ventricular hypertrophy in the absence of any identifiable cause." Longitudinal studies, however, including a seminal study performed by Frank and Braunwald in 1968, clearly described the disorder much as we know it today, a complex, progressive, and highly variable cardiomyopathy affecting ~ 1/500 individuals worldwide. Subsequent genetic linkage studies in the early 1990s identified mutations in virtually all of the protein components of the cardiac sarcomere as the primary molecular cause of HCM. In addition, a substantial proportion of inherited dilated cardiomyopathy (DCM) has also been linked to sarcomeric protein mutations. Despite our deep understanding of the overall function of the sarcomere as the primary driver of cardiac contractility, the ability to use genotype in patient management remains elusive. A persistent challenge in the field from both the biophysical and clinical standpoints is how to rigorously link high-resolution protein dynamics and mechanics to the long-term cardiovascular remodeling process that characterizes these complex disorders. In this review, we will explore the depth of the problem from both the standpoint of a multi-subunit, highly conserved and dynamic "machine" to the resultant clinical and structural human phenotype with an emphasis on new, integrative approaches that can be widely applied to identify both novel disease mechanisms and new therapeutic targets for these primary biophysical disorders of the cardiac sarcomere.

Keywords: Dilated cardiomyopathy; Hypertrophic cardiomyopathy; Thin filament; Tropomyosin; Troponin.

Fig. 1

Pathogenesis of sarcomeric cardiomyopathies. Timecourse and proposed trajectory of cardiac remodeling caused by pathogenic sarcomere gene mutations. G+P− refers to genotype-positive patients without evidence of pathogenic remodeling and G+P+ refers to genotype-positive patients with more advanced disease and overt ventricular remodeling.

Fig. 2

Full atomistic model of the human cardiac thin filament. Actin is represented in gray. Tropomyosin dimers are represented in green and orange. Cardiac TnT is depicted in yellow, cTnI is shown in blue, and cTnC is represented in red.

Fig. 3

C-terminal TNT1 extended linker domain. Left panel (box) refers to position of extended linker in the context of the thin filament. Right panel shows the locations of the 160E (HCM) and R173W (DCM) mutations within the extended linker domain. cTnT is shown in yellow and Tropomyosin (orange) is shaded for clarity

Fig. 4

Tropomyosin overlap domain. Left panel (box) shows the position of the overlap domain in the context of the thin filament. Right panel depicts the position of the R92L substitution (HCM) in cTnT (yellow) and the D230N substitution (DCM) in Tropomyosin (orange)