The Genetic and Molecular Bases for Hypertrophic Cardiomyopathy: The Role for Calcium Sensitization

Ren, Xin; Hensley, Nadia B.; Brady, Mary Beth; Gao, Wei Dong

doi:10.1053/j.jvca.2017.05.035

Cited by 22 publications

(15 citation statements)

References 90 publications

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“…Patients with double mutations generally show an earlier disease presentation, more severe LV hypertrophy, higher prevalence of advanced heart failure, and an increased risk of sudden cardiac death than patients with single heterozygous mutations (Maron et al., 2012; Biagini et al., 2014; Fazeli Dehkordy et al., 2018). A differential Ca 2+ sensitivity has also been observed in other studies with different HCM disease genes (Ren et al., 2018; Mamidi et al., 2019). It therefore seems that the direction and magnitude of the change not only depends on the affected gene ( MYBPC3 vs. MYH7 ) but also on the genetic status (single vs. double heterozygous), but not on the mutation type (missense vs. truncating).…”

Section: Discussionsupporting

confidence: 77%

“…The observation of an increased myofilament Ca 2+ sensitivity has mainly been made in HCM transgenic mouse models, reconstituted myofilament systems, and isolated cardiomyocytes, but data from multicellular tissues from HCM patients with mutations in different HCM genes have not been reported before (Morimoto et al., 1998; Tardiff et al., 1999; Cazorla et al., 2006; Pohlmann et al., 2007; Robinson et al., 2007; Jacques et al., 2008; Morimoto, 2008; van Dijk et al., 2009, 2012; Vignier et al., 2009; Huke and Knollmann, 2010; Kimura, 2010; Fraysse et al., 2012; Moore et al., 2012; Barefield et al., 2014; Flenner et al., 2016; Wijnker et al., 2016; Stucker et al., 2017; Ren et al., 2018). We therefore investigated force development and myofilament Ca 2+ sensitivity in multicellular cardiac muscle strips derived from septal myectomies of patients with different HCM gene mutations and evaluated the potential use of epigallocatechin-3-gallate (EGCg), a known Ca 2+ -desensitizer, for myofilament Ca 2+ desensitization.…”

Section: Discussionmentioning

confidence: 99%

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Analysis of Contractile Function of Permeabilized Human Hypertrophic Cardiomyopathy Multicellular Heart Tissue

et al. 2019

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Background : Many forms of hypertrophic cardiomyopathy (HCM) show an increased myofilament Ca 2+ sensitivity. This observation has been mainly made in HCM mouse models, myofilament systems, and cardiomyocytes. Studies of multicellular tissues from patients with different HCM-associated gene mutations are scarce. We investigated Ca 2+ sensitivity in multicellular cardiac muscle strips of HCM patients. We furthermore evaluated the use of epigallocatechin-3-gallate (EGCg), a Ca 2+ desensitizer. Methods : After strip isolation from cardiac tissues with single ( MYBPC3 , MYH7) or double heterozygous mutations ( MYBPC3/FLNC, MYH7/LAMP2, MYBPC3/MYH7 ) and permeabilization, we performed contractility measurements ±EGCg. We furthermore evaluated gene expression with a customized heart failure gene panel using the NanoString technology. Results : F max tended to be higher in HCM than in non-failing (NF) control strips and in single than in double heterozygous strips. Ca 2+ sensitivity was higher by trend in most HCM vs. NF strips and by trend in tissues with double vs. single heterozygous mutations. EGCg desensitized myofilaments to Ca 2+ in most of the strips and tended to induce a more pronounced shift in strips with truncating than missense or single than double heterozygous mutations. Gene expression analysis revealed lower ATP2A2 , PPP1R1A, and FHL2 and higher NPPA , NPPB, COL1A1, CTGF, and POSTN marker levels in HCM than in NF tissues . NPPA , NPPB , ACTA1 , CTGF , COL1A1 , and POSTN levels were higher in tissues with missense than truncating mutations. Conclusion : We report an increased myofilament Ca 2+ sensitivity in native multicellular cardiac HCM strips, which by trend was more pronounced in samples with double heterozygous mutations. EGCg could have differential effects depending on the underlying genetic status (single vs. double heterozygous) and type (missense vs. truncating).

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Analysis of Contractile Function of Permeabilized Human Hypertrophic Cardiomyopathy Multicellular Heart Tissue

et al. 2019

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“…Interestingly, recent reports using cytoplasmic R-GECO1.0 to study the p.R92Q-cTnT and p.R145G-cTnI HCM-associated mutations found systolic peak amplitude changes in the latter model but not the in the former [ 50 ]. Thus, genetically-encoded calcium reporter cell lines are increasingly useful tools to investigate discrepancies of calcium transient abnormalities in HCM patients bearing different mutations [ 51 ]. Finally, both HCM models did not reveal differences in SR Ca 2+ storage as sarcomeric mutant hiPSC-CMs showed similar responses to caffeine as healthy lines.…”

Section: Discussionmentioning

confidence: 99%

Isogenic models of hypertrophic cardiomyopathy unveil differential phenotypes and mechanism-driven therapeutics

Bhagwan

Mosqueira

Chairez‐Cantu

et al. 2020

Journal of Molecular and Cellular Cardiology

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Background Hypertrophic cardiomyopathy (HCM) is a prevalent and complex cardiovascular condition. Despite being strongly associated with genetic alterations, wide variation of disease penetrance, expressivity and hallmarks of progression complicate treatment. We aimed to characterize different human isogenic cellular models of HCM bearing patient-relevant mutations to clarify genetic causation and disease mechanisms, hence facilitating the development of effective therapeutics. Methods We directly compared the p.β-MHC-R453C and p.ACTC1-E99K HCM-associated mutations in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and their healthy isogenic counterparts, generated using CRISPR/Cas9 genome editing technology. By harnessing several state-of-the-art HCM phenotyping techniques, these mutations were investigated to identify similarities and differences in disease progression and hypertrophic signaling pathways, towards establishing potential targets for pharmacological treatment. CRISPR/Cas9 knock-in of the genetically-encoded calcium indicator R-GECO1.0 to the AAVS1 locus into these disease models resulted in calcium reporter lines. Results Confocal line scan analysis identified calcium transient arrhythmias and intracellular calcium overload in both models. The use of optogenetics and 2D/3D contractility assays revealed opposing phenotypes in the two mutations. Gene expression analysis highlighted upregulation of CALM1, CASQ2 and CAMK2D, and downregulation of IRF8 in p.β-MHC-R453C mutants, whereas the opposite changes were detected in p.ACTC1-E99K mutants. Contrasting profiles of nuclear translocation of NFATc1 and MEF2 between the two HCM models suggest differential hypertrophic signaling pathway activation. Calcium transient abnormalities were rescued with combination of dantrolene and ranolazine, whilst mavacamten reduced the hyper-contractile phenotype of p.ACTC1-E99K hiPSC-CMs. Conclusions Our data show that hypercontractility and molecular signaling within HCM are not uniform between different gene mutations, suggesting that a ‘one-size fits all’ treatment underestimates the complexity of the disease. Understanding where the similarities (arrhythmogenesis, bioenergetics) and differences (contractility, molecular profile) lie will allow development of therapeutics that are directed towards common mechanisms or tailored to each disease variant, hence providing effective patient-specific therapy.

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“…The mutations decrease ATP production and regulate contraction force [40,41,42]. In HCM, these sarcomeric or adenosine triphosphate (ATP) kinase protein mutations may induce increased contraction force via calcium signaling in mechanotransduction pathways and decreased ATP production, leading to LV diastolic dysfunction [43,44,45]. Several mechanisms associated with pathogenesis include mechanotransduction, Ras-Raf-mitogen-activated protein kinase (MEK)-extracellular signal-activated kinase (ERK) pathway, protein kinase C (PKC) signaling, mothers against decapentaplegic homolog (SMAD), and mitogen-activated protein kinase (MAPK) pathways.…”

Section: Hcmmentioning

confidence: 99%

Advanced Evolution of Pathogenesis Concepts in Cardiomyopathies

Chen

Yiang

et al. 2019

JCM

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Cardiomyopathy is a group of heterogeneous cardiac diseases that impair systolic and diastolic function, and can induce chronic heart failure and sudden cardiac death. Cardiomyopathy is prevalent in the general population, with high morbidity and mortality rates, and contributes to nearly 20% of sudden cardiac deaths in younger individuals. Genetic mutations associated with cardiomyopathy play a key role in disease formation, especially the mutation of sarcomere encoding genes and ATP kinase genes, such as titin, lamin A/C, myosin heavy chain 7, and troponin T1. Pathogenesis of cardiomyopathy occurs by multiple complex steps involving several pathways, including the Ras-Raf-mitogen-activated protein kinase-extracellular signal-activated kinase pathway, G-protein signaling, mechanotransduction pathway, and protein kinase B/phosphoinositide 3-kinase signaling. Excess biomechanical stress induces apoptosis signaling in cardiomyocytes, leading to cell loss, which can induce myocardial fibrosis and remodeling. The clinical features and pathophysiology of cardiomyopathy are discussed. Although several basic and clinical studies have investigated the mechanism of cardiomyopathy, the detailed pathophysiology remains unclear. This review summarizes current concepts and focuses on the molecular mechanisms of cardiomyopathy, especially in the signaling from mutation to clinical phenotype, with the aim of informing the development of therapeutic interventions.

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The Genetic and Molecular Bases for Hypertrophic Cardiomyopathy: The Role for Calcium Sensitization

Cited by 22 publications

References 90 publications

Analysis of Contractile Function of Permeabilized Human Hypertrophic Cardiomyopathy Multicellular Heart Tissue

Analysis of Contractile Function of Permeabilized Human Hypertrophic Cardiomyopathy Multicellular Heart Tissue

Isogenic models of hypertrophic cardiomyopathy unveil differential phenotypes and mechanism-driven therapeutics

Advanced Evolution of Pathogenesis Concepts in Cardiomyopathies

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