Inherited Cardiomyopathies

Watkins, Hugh; Ashrafian, Houman; Redwood, Charles

doi:10.1056/nejmra0902923

Cited by 455 publications

(401 citation statements)

References 97 publications

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“…Despite decades of research, heart failure remains a major cause of death and mortality32333435363738. Therefore, improved understanding of the molecular mechanisms underlying heart failure is still urgently needed to develop novel targeted treatment strategies.…”

Section: Discussionmentioning

confidence: 99%

Myoscape controls cardiac calcium cycling and contractility via regulation of L-type calcium channel surface expression

et al. 2016

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Calcium signalling plays a critical role in the pathogenesis of heart failure. Here we describe a cardiac protein named Myoscape/FAM40B/STRIP2, which directly interacts with the L-type calcium channel. Knockdown of Myoscape in cardiomyocytes decreases calcium transients associated with smaller Ca2+ amplitudes and a lower diastolic Ca2+ content. Likewise, L-type calcium channel currents are significantly diminished on Myoscape ablation, and downregulation of Myoscape significantly reduces contractility of cardiomyocytes. Conversely, overexpression of Myoscape increases global Ca2+ transients and enhances L-type Ca2+ channel currents, and is sufficient to restore decreased currents in failing cardiomyocytes. In vivo, both Myoscape-depleted morphant zebrafish and Myoscape knockout (KO) mice display impairment of cardiac function progressing to advanced heart failure. Mechanistically, Myoscape-deficient mice show reduced L-type Ca2+currents, cell capacity and calcium current densities as a result of diminished LTCC surface expression. Finally, Myoscape expression is reduced in hearts from patients suffering of terminal heart failure, implying a role in human disease.

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Section: Discussionmentioning

confidence: 99%

Myoscape controls cardiac calcium cycling and contractility via regulation of L-type calcium channel surface expression

et al. 2016

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“…In this model, therefore, the two proposed pathophysiological effectsincreased myofilament Ca 2+ sensitivity and energy depletion -were linked. Sudden cardiac death in athletes during competition can reasonably be understood as an 'energy crisis' in this context 12,84,83 .…”

Section: [H3] Increased Myofilament Ca 2+ Sensitivitymentioning

confidence: 99%

Myocardial energy depletion and dynamic systolic dysfunction in hypertrophic cardiomyopathy

2016

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Evidence indicates that anatomical and physiological phenotypes of hypertrophic cardiomyopathy (HCM) stem from genetically mediated, inefficient cardiomyocyte energy utilization, and subsequent cellular energy depletion. However, HCM often presents clinically with normal left ventricular (LV) systolic function or hyperkinesia. If energy inefficiency is a feature of HCM, why is it not manifest as resting LV systolic dysfunction? In this Perspectives article, we focus on an idiosyncratic form of reversible systolic dysfunction provoked by LV obstruction that we have previously termed the 'lobster claw abnormality' — a mid-systolic drop in LV Doppler ejection velocities. In obstructive HCM, this drop explains the mid-systolic closure of the aortic valve, the bifid aortic pressure trace, and why patients cannot increase stroke volume with exercise. This phenomenon is characteristic of a broader phenomenon in HCM that we have termed dynamic systolic dysfunction. It underlies the development of apical aneurysms, and rare occurrence of cardiogenic shock after obstruction. We posit that dynamic systolic dysfunction is a manifestation of inefficient cardiomyocyte energy utilization. Systolic dysfunction is clinically inapparent at rest; however, it becomes overt through the mechanism of afterload mismatch when LV outflow obstruction is imposed. Energetic insufficiency is also present in nonobstructive HCM. This paradigm might suggest novel therapies. Other pathways that might be central to HCM, such as myofilament Ca2+ hypersensitivity, and enhanced late Na+ current, are discussed

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“…Epidemiological studies addressing the prevalence of gene mutations in DCM patients have demonstrated that inherited forms account for at least one-third of all DCM cases. [1][2][3][4] Familial cases frequently show a monogenic origin, and transmission indicates autosomal dominant or X-linked inheritance pattern with incomplete and age-dependent penetrance. 3 To date, positional cloning and candidate gene screening have led to the identification of numerous heterozygous mutations in more than 40 different genes, most of which encode proteins important for the structural integrity and function of cardiomyocytes, such as regulatory proteins of the sarcomere, the nuclear envelope or intracellular homeostasis.…”

Section: Introductionmentioning

confidence: 99%

“…3 To date, positional cloning and candidate gene screening have led to the identification of numerous heterozygous mutations in more than 40 different genes, most of which encode proteins important for the structural integrity and function of cardiomyocytes, such as regulatory proteins of the sarcomere, the nuclear envelope or intracellular homeostasis. 1,2,5 In particular, defects in proteins required for force transduction and force transmission of the sarcomeric apparatus seem to promote the development of DCM.…”

Section: Introductionmentioning

confidence: 99%

Novel mutations in the sarcomeric protein myopalladin in patients with dilated cardiomyopathy

et al. 2012

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on behalf of the German Competence Network Heart Failure Recently, missense mutations in titin-associated proteins have been linked to the pathogenesis of dilated cardiomyopathy (DCM). The objective of this study was to search for novel disease-associated mutations in the two human titin-binding proteins myopalladin and its amino-terminal-interacting partner cardiac ankyrin-repeat protein (CARP). In a cohort of 255 cases with familial and sporadic DCM, we analyzed the coding regions and all corresponding intron flanks located in the MYPN and CARPencoding ANKRD1 gene. Two heterozygous missense mutations were detected in the MYPN gene (p.R955W and p.P961L), but neither of these mutations was found in 300 healthy controls. Both mutations were located in the a-actinin-binding region of myopalladin. Endomyocardial biopsies from the p.R955W carrier showed normal subcellular localization of myopalladin and a-actinin in cardiac myocytes, while their regular sarcomeric staining pattern was significantly disrupted in the p.P961L carrier, indicating that disturbed myofibrillogenesis and altered sarcomere assembly are the cause of the disease. In the ANKRD1 gene, we identified synonymous base exchanges (c.108T4C and c.-79C4T, respectively), but no non-synonymous mutations. In summary, we have identified novel missense mutations in the third immunoglobulin-like domain of myopalladin, which have either no or profound effects on the molecular composition of the sarcomere. According to our epidemiological data, the prevalence of ANKRD1 mutations seems to be lower than that of its binding partner myopalladin, indicating the clinical significance of myopalladin for the functional integrity of the sarcomeric apparatus and the protection against DCM.

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Inherited Cardiomyopathies

Cited by 455 publications

References 97 publications

Myoscape controls cardiac calcium cycling and contractility via regulation of L-type calcium channel surface expression

Myoscape controls cardiac calcium cycling and contractility via regulation of L-type calcium channel surface expression

Myocardial energy depletion and dynamic systolic dysfunction in hypertrophic cardiomyopathy

Novel mutations in the sarcomeric protein myopalladin in patients with dilated cardiomyopathy

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