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Advances in Molecular Genetics and Management of Hypertrophic Cardiomyopathy

Lameh Fananapazir, MD, FRCP
JAMA. 1999;281(18):1746-1752. doi:10.1001/jama.281.18.1746.
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Fananapazir L, Epstein ND.Prevalence of hypertrophic cardiomyopathy and limitations of screening methods. Circulation.1995;92:700-704.
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Rayment I, Holden HM, Sellers J, Fananapazir L, Epstein ND.Structural interpretation of the mutations in the β-cardiac myosin that have been implicated in familial hypertrophic cardiomyopathy. Proc Natl Acad Sci U S A.1995;92:3864-3868.
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Figures

Figure 1. Rare Left Ventricular Morphology in Hypertrophic Cardiomyopathy Caused by Specific Genetic Defects
Graphic Jump Location
A, Left ventricular (LV) angiograph in a patient with midcavity obstructive hypertrophic cardiomyopathy (HCM) caused by Met149Val mutation of the essential light chain of myosin. B, Left ventricular angiogram in patient with midcavity obstructive HCM caused by Glu22Lys mutation of the regulatory light chain of myosin. In both cases, massive LV hypertrophy at the level of the papillary muscles has reduced LV chamber size to a narrow tunnel that connects the proximal LV cavity to a distal aneurysm. Atrial and ventricular pacing leads are also evident. C, Left ventricular angiogram in an HCM patient with Leu908Val β-myosin mutation. The midcavity hypertrophy has caused subtotal obstruction, preventing contrast from filling of a distal aneurysm.
Figure 2. Sarcomere Contractile Proteins
Graphic Jump Location
The sarcomere is made up of contractile proteins organized into thick and thin filaments. The thick filament consists of β-myosin heavy chains (Myosin), essential light chains (ELC), and regulatory light chains (RLC). The thin filament consists of several proteins including actin, tropomyosin (α Tm), troponin C (TnC), troponin I (TnI), and troponin T (TTnT). Myosin has 3 functional domains: a head, a neck, and a tail (or rod). The myosin head contains an adenosine triphosphate–binding pocket (ATP cleft), and an actin binding site. The neck allows extension of the myosin for interaction with actin, and the tail anchors the molecule. Hydrolysis of ATP to adenosin diphosphate and Pi by (ATPase activity of the myosin head) powers translocation of actin by the myosin head. Binding of an ATP to myosin then dissociates myosin from actin. In hypertrophic cardiomyopathy, sarcomeric mutations may affect different stages of this contraction and relaxation process and interfere with the proper functioning of the myosin molecular motor.

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