Gene-specific increase in the energetic cost of contraction in hypertrophic cardiomyopathy caused by thick filament mutations

Witjas-Paalberends, E. Rosalie; Güçlü, Ahmet; Germans, Tjeerd; Knaapen, Paul; Harms, Hendrik J.; Vermeer, Alexa M.C.; Christiaans, Imke; Wilde, Arthur A.M.; Remedios, Cris dos; Lammertsma, Adriaan A.; Rossum, Albert C. van; Stienen, G. J. M.; Slegtenhorst, Marjon van; Schinkel, Arend F. L.; Michels, Michelle; Ho, Carolyn Y.; Poggesi, Corrado; Velden, Jolanda van der

doi:10.1093/cvr/cvu127

Cited by 100 publications

(103 citation statements)

References 49 publications

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“…In FG+/phenotype-negative (Ph−) relatives, the Cox model with grouped jackknife method did not converge because of insufficient number of events. 9 Other triggers, for example, altered Ca 2+ handling and disturbances in myocardial energetics 34 are additionally being investigated. The exact pathways from mutation to disease remain largely unknown.…”

Section: Discussionmentioning

confidence: 99%

Clinical Characteristics and Long-Term Outcome of Hypertrophic Cardiomyopathy in Individuals With a MYBPC3 (Myosin-Binding Protein C) Founder Mutation

Velzen

Schinkel

Oldenburg

et al. 2017

Circ Cardiovasc Genet

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Background— MYBPC3 (Myosin-binding protein C) founder mutations account for 35% of hypertrophic cardiomyopathy (HCM) cases in the Netherlands. We compared clinical characteristics and outcome of MYBPC3 founder mutation (FG+) HCM with nonfounder genotype-positive (G+) and genotype-negative (G−) HCM. Methods and Results— The study included 680 subjects: 271 FG+ carriers, 132 G+ probands with HCM, and 277 G− probands with HCM. FG+ carriers included 134 FG+ probands with HCM, 54 FG+ relatives diagnosed with HCM after family screening, 74 FG+/phenotype-negative relatives, and 9 with noncompaction or dilated cardiomyopathy. The clinical phenotype of FG+ and G+ probands with HCM was similar. FG+ and G+ probands were younger with less left ventricular outflow tract obstruction than G− probands, however, had more hypertrophy, and nonsustained ventricular tachycardia. FG+ relatives with HCM had less hypertrophy, smaller left atria, and less systolic and diastolic dysfunction than FG+ probands with HCM. After 8±6 years, cardiovascular mortality in FG+ probands with HCM was similar to G+ HCM (22% versus 14%; log-rank P =0.14), but higher than G− HCM (22% versus 6%; log-rank P <0.001) and FG+ relatives with HCM (22% versus 4%; P =0.009). Cardiac events were absent in FG+/phenotype-negative relatives; subtle HCM developed in 11% during 6 years of follow-up. Conclusions— Clinical phenotype and outcome of FG+ HCM was similar to G+ HCM but worse than G− HCM and FG+ HCM diagnosed in the context of family screening. These findings indicate the need for more intensive follow-up of FG+ and G+ HCM versus G− HCM and FG+ HCM in relatives.

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Section: Discussionmentioning

confidence: 99%

Clinical Characteristics and Long-Term Outcome of Hypertrophic Cardiomyopathy in Individuals With a MYBPC3 (Myosin-Binding Protein C) Founder Mutation

Velzen

Schinkel

Oldenburg

et al. 2017

Circ Cardiovasc Genet

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“…Increasing evidence suggests that HCM mutations in MYH7 cause increased energy usage due to a less efficient myosin motor and that this energetic mismatch results in perturbed metabolic state (Crilley et al, 2003). As one indication of this energetic mismatch, reduced phospho-creatine levels (PCr) have been observed using 31 P NMR spectroscopy of animal models of HCM and materials from human HCM patients (Ingwall, 2014; Witjas-Paalberends et al, 2014a; Witjas-Paalberends et al, 2014b). Human hearts expressing the MYH7 R403Q mutation generate increased tension and faster actin sliding velocities, but at a higher energetic cost (Alpert et al, 2005).…”

Section: Hypertrophic Cardiomyopathy and Thick Filament Gene Mutationsmentioning

confidence: 99%

The Genetic Landscape of Cardiomyopathy and Its Role in Heart Failure

2015

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Heart failure is highly influenced by heritability, and nearly 100 genes link to familial cardiomyopathy. Despite the marked genetic diversity that underlies these complex cardiovascular phenotypes, several key genes and pathways have emerged. Hypertrophic cardiomyopathy is characterized by increased contractility and a greater energetic cost of cardiac output. Dilated cardiomyopathy is often triggered by mutations that disrupt the giant protein titin. The energetic consequences of these mutations offer molecular targets and opportunities for new drug development and gene correction therapies.

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“…However, myocardial stroke work was reduced to an even greater extent than oxygen consumption; myocardial efficiency (the ratio of stroke work to myocardial oxygen consumption) was, therefore, decreased. A combined in vitro and in vivo study using tissue of genotype-positive patients with HCM, and PET and cardiac MR scans, revealed an increase in energy tension-cost based on an imbalance between force-generating capacity and ATPase activity 9,14 .…”

Section: Energy Depletion Hcm and Diastolementioning

confidence: 99%

“…In this Perspectives article, we focus primarily on the energy depletion hypothesis, but we also summarize the evidence for Ca 2+ sensitization, and discuss how the two theories overlap. Increasing evidence indicates that energy depletion has an important role in the development of hypertrophy and in the wider pathophysiology of HCM [9][10][11][12][13][14][15] . We summarize this evidence, and then discuss the phenotypic manifestations of energy depletion in three realms of cardiac function: diastolic dysfunction, dynamic systolic dysfunction (especially against imposed afterload), and arrhythmogenesis.…”

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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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Gene-specific increase in the energetic cost of contraction in hypertrophic cardiomyopathy caused by thick filament mutations

Cited by 100 publications

References 49 publications

Clinical Characteristics and Long-Term Outcome of Hypertrophic Cardiomyopathy in Individuals With a MYBPC3 (Myosin-Binding Protein C) Founder Mutation

Clinical Characteristics and Long-Term Outcome of Hypertrophic Cardiomyopathy in Individuals With a MYBPC3 (Myosin-Binding Protein C) Founder Mutation

The Genetic Landscape of Cardiomyopathy and Its Role in Heart Failure

Myocardial energy depletion and dynamic systolic dysfunction in hypertrophic cardiomyopathy

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