ArticleCirculation research2013
Perturbed length-dependent activation in human hypertrophic cardiomyopathy with missense sarcomeric gene mutations.
Article in Circulation research, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 147 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
147 citing papers in PubMed, 1 synthesis or guideline pooled it, 193 citations in OpenAlex.
- Fabry disease cardiomyopathy: A state-of-the-art review.Progress in cardiovascular diseasesPooled it
- Evidence for a role of adverse sarcomere signaling in atrial fibrillation induction.Journal of molecular and cellular cardiology plus · 2026Review
- Myofilament-level effects of aficamten increase diastolic chamber volumes and maintain cardiac output through preserved length-dependent force generation in healthy rat and canine myocardium.Basic research in cardiology · 2026Article
- Immature and mature myocardium in the pathophysiology of hypertrophic cardiomyopathy.Journal of molecular and cellular cardiology plus · 2026Review
- Thin filament interaction and CaJournal of molecular and cellular cardiology · 2026Article
- iPSC-derived cardiac organoids for drug cardiotoxicity evaluation and efficacy prediction in myocardial infarction and cardiac hypertrophy models.Stem cell research & therapy · 2026Article
- Why the septum thickens in hypertrophic cardiomyopathy.Journal of molecular and cellular cardiology plus · 2026Review
- Revisiting the Genetics of Hypertrophic Cardiomyopathy: From Sarcomeres to Polygenic Modulation and Clinical Translation.Journal of clinical medicine · 2026Review
- What can skinned cardiomyocytes teach us about heart disease? Response to letter to the editor: Challenges in assessing myoflament calcium sensitivity and contractile function in HFpEF by Christophe Maack and Vasco Sequeira.Journal of molecular and cellular cardiology · 2025Article
- CaJournal of molecular and cellular cardiology · 2025Article
- Myosin-actin crossbridge independent sarcomere length induced CaJournal of molecular and cellular cardiology · 2025Article
- Reduction in myofilament CaFrontiers in physiology · 2025Article
- Distinct mechanisms drive divergent phenotypes in hypertrophic and dilated cardiomyopathy-associated TPM1 variants.The Journal of clinical investigation · 2024Article
- Definitional Challenges in Understanding Hypertrophic Cardiomyopathy.Diagnostics (Basel, Switzerland) · 2024Review
- Arg92Leu-cTnT Alters the cTnC-cTnI Interface Disrupting PKA-Mediated Relaxation.Circulation research · 2024Article
- Allele-specific dysregulation of lipid and energy metabolism in early-stage hypertrophic cardiomyopathy.Journal of molecular and cellular cardiology plus · 2024Article
- Hypertrophic cardiomyopathy dysfunction mimicked in human engineered heart tissue and improved by sodium-glucose cotransporter 2 inhibitors.Cardiovascular research · 2024Article
- Increased Chamber Resting Tone Is a Key Determinant of Left Ventricular Diastolic Dysfunction.Circulation. Heart failure · 2023Article
- Cardiac troponin T N-domain variant destabilizes the actin interface resulting in disturbed myofilament function.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Mechano-energetic uncoupling in hypertrophic cardiomyopathy: Pathophysiological mechanisms and therapeutic opportunities.Journal of molecular and cellular cardiology plus · 2023Review
87 more citing papers are in PubMed but not listed here.
Corrections and comments
- Commented on by
- Erratum issued
Authors and funding
22 authors at 1 institution in 1 country.
Funding
Abstract
rationaleHigh-myofilament Ca(2+) sensitivity has been proposed as a trigger of disease pathogenesis in familial hypertrophic cardiomyopathy (HCM) on the basis of in vitro and transgenic mice studies. However, myofilament Ca(2+) sensitivity depends on protein phosphorylation and muscle length, and at present, data in humans are scarce.
objectiveTo investigate whether high myofilament Ca(2+) sensitivity and perturbed length-dependent activation are characteristics for human HCM with mutations in thick and thin filament proteins. METHODS AND
resultsCardiac samples from patients with HCM harboring mutations in genes encoding thick (MYH7, MYBPC3) and thin (TNNT2, TNNI3, TPM1) filament proteins were compared with sarcomere mutation-negative HCM and nonfailing donors. Cardiomyocyte force measurements showed higher myofilament Ca(2+) sensitivity in all HCM samples and low phosphorylation of protein kinase A (PKA) targets compared with donors. After exogenous PKA treatment, myofilament Ca(2+) sensitivity was similar (MYBPC3mut, TPM1mut, sarcomere mutation-negative HCM), higher (MYH7mut, TNNT2mut), or even significantly lower (TNNI3mut) compared with donors. Length-dependent activation was significantly smaller in all HCM than in donor samples. PKA treatment increased phosphorylation of PKA-targets in HCM myocardium and normalized length-dependent activation to donor values in sarcomere mutation-negative HCM and HCM with truncating MYBPC3 mutations but not in HCM with missense mutations. Replacement of mutant by wild-type troponin in TNNT2mut and TNNI3mut corrected length-dependent activation to donor values.
conclusionsHigh-myofilament Ca(2+) sensitivity is a common characteristic of human HCM and partly reflects hypophosphorylation of PKA targets compared with donors. Length-dependent sarcomere activation is perturbed by missense mutations, possibly via posttranslational modifications other than PKA hypophosphorylation or altered protein-protein interactions, and represents a common pathomechanism in HCM.
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