Chapters authored
Inherited Cardiomyopathies: From Genotype to Phenotype
The heart undergoes extensive morphological, metabolic, and energetic remodeling in response to inherited, or familial, hypertrophic cardiomyopathies (FHC). Myocyte contractile perturbations downstream of Ca2+, the so-called sarcomere-controlled mechanisms, may represent the earliest indicators of this remodeling. We can now state that the dynamics of cardiac contraction and relaxation during the progression of FHC are governed by downstream mechanisms, particularly the kinetics and energetics of actin and myosin interaction to drive the trajectory of pathological cardiac remodeling. This notion is unambiguously supported by elegant studies above linking inheritable FHC-causing mutations to cardiomyopathies, known to disturb contractile function and alter the energy landscape of the heart. Although studies examining the biophysical properties of cardiac myocytes with FHC-causing mutations have yielded a cellular and molecular understanding of myofilament function, this knowledge has had limited translational success. This is driven by a critical failure in elucidating an integrated and sequential link among the changing energy landscape, myofilament function, and initiated signaling pathways in response to FHC. Similarly, there continues to be a major gap in understanding the cellular and molecular mechanisms contributing to sex differences in FHC development and progression. The primary reason for this gap is a lack of a “unifying” or “central” hypothesis that integrates signaling cascades, energetics, sex and FHC.
Part of the book: Cardiomyopathies