Clinical Characteristics and Outcomes of Hypertrophic Cardiomyopathy Associated With Thin Filament Variants: Insights From the SHaRe Registry

BACKGROUND: Conflicting evidence exists about whether sarcomeric hypertrophic cardiomyopathy (HCM) caused by genes encoding thin filament proteins ( TNNT2, TNNI3, ACTC, TPM1 , TNNC1 ; thin filament HCM) has a distinct clinical presentation and natural history from disease caused by the more commonly involved thick filament genes ( MYH7 , MYBPC3 , MYL2 , MYL3 ; thick filament HCM). METHODS: Retrospective analysis of the Sarcomeric Human Cardiomyopathy Registry. RESULTS: Four hundred eighty-eight patients with thin filament HCM were compared with 3494 patients with thick filament HCM. After controlling for age at diagnosis, sex, and proband status, thin filament HCM was associated with a higher risk of composite ventricular arrhythmias (hazard ratio, 1.48 [95% CI, 1.09–2.01]), cardiac arrest (hazard ratio, 2.02 [95% CI, 1.33–3.06]), and heart transplant or left ventricular assist device implantation (hazard ratio, 2.18 [95% CI, 1.3–3.65]). Younger age at diagnosis was associated with an increased risk for the ventricular arrhythmia composite outcome in thin and thick filament HCM (hazard ratio, 0.93 [95% CI, 0.91–0.94]; hazard ratio, 0.93 [95% CI, 0.93–0.94]; age reported as 5-year increment). Within specific thin filament genes, an increased risk of arrhythmic events or heart transplant/left ventricular assist device implantation was evident for variants in TNNT2 amino acids 92 to 94 (odds ratio versus other TNNT2 variants; odds ratio, 3.02 [95% CI, 1.17–7.49]) and TNNI3 amino acids 191 to 210 (odds ratio versus other TNNI3 variants; odds ratio, 3.5 [95% CI, 1.58–8.02]). CONCLUSIONS: Thin filament HCM seems to carry a higher risk for ventricular arrhythmias and advanced heart failure compared with thick filament HCM. Integrating gene-level and intragene-level information may improve risk stratification in patients with HCM.

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Journal
Circulation Genomic and Precision Medicine
Published
2026-09-24
DOI
https://doi.org/10.1161/circgen.126.005696
Primary Topic
Cardiomyopathy and Myosin Studies
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article
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article

Clinical Characteristics and Outcomes of Hypertrophic Cardiomyopathy Associated With Thin Filament Variants: Insights From the SHaRe Registry

Carolyn Yung Ho, Brian L. Claggett, Anna Axelsson Raja, John C. Stendahl et al.
Circulation Genomic and Precision Medicine
Cardiomyopathy and Myosin Studies
article

Clinical Characteristics and Outcomes of Hypertrophic Cardiomyopathy Associated With Thin Filament Variants: Insights From the SHaRe Registry

Carolyn Yung Ho, Brian L. Claggett, Anna Axelsson Raja, John C. Stendahl, Michelle Michels, James S. Ware, Francesca Girolami, Lia Crotti, Joshua K. Meisner, Sara Saberi, Iacopo Olivotto, Joseph William Rossano, Alexandre C. Pereira, Edoardo Bertero, ANJALI TIKU OWENS, Rachel J. Lampert, Romi L. Castillo, Henning Bundgaard, Neal K. Lakdawala, Victoria Nicole Parikh, Kimberly Y. Lin, Peter-Paul Zwetsloot, Niccolò Maurizi, Jodie Ingles, Jil C. Tardiff, Dominic James Abrams, Adam S. Helms, Euan Angus Ashley, Alessia Argirò, Belinda R. Gray, ERIC D. ADLER, Sharlene M. Day, Thomas D. Ryan, Erin M. Miller
article en

Abstract

BACKGROUND: Conflicting evidence exists about whether sarcomeric hypertrophic cardiomyopathy (HCM) caused by genes encoding thin filament proteins ( TNNT2, TNNI3, ACTC, TPM1 , TNNC1 ; thin filament HCM) has a distinct clinical presentation and natural history from disease caused by the more commonly involved thick filament genes ( MYH7 , MYBPC3 , MYL2 , MYL3 ; thick filament HCM). METHODS: Retrospective analysis of the Sarcomeric Human Cardiomyopathy Registry. RESULTS: Four hundred eighty-eight patients with thin filament HCM were compared with 3494 patients with thick filament HCM. After controlling for age at diagnosis, sex, and proband status, thin filament HCM was associated with a higher risk of composite ventricular arrhythmias (hazard ratio, 1.48 [95% CI, 1.09–2.01]), cardiac arrest (hazard ratio, 2.02 [95% CI, 1.33–3.06]), and heart transplant or left ventricular assist device implantation (hazard ratio, 2.18 [95% CI, 1.3–3.65]). Younger age at diagnosis was associated with an increased risk for the ventricular arrhythmia composite outcome in thin and thick filament HCM (hazard ratio, 0.93 [95% CI, 0.91–0.94]; hazard ratio, 0.93 [95% CI, 0.93–0.94]; age reported as 5-year increment). Within specific thin filament genes, an increased risk of arrhythmic events or heart transplant/left ventricular assist device implantation was evident for variants in TNNT2 amino acids 92 to 94 (odds ratio versus other TNNT2 variants; odds ratio, 3.02 [95% CI, 1.17–7.49]) and TNNI3 amino acids 191 to 210 (odds ratio versus other TNNI3 variants; odds ratio, 3.5 [95% CI, 1.58–8.02]). CONCLUSIONS: Thin filament HCM seems to carry a higher risk for ventricular arrhythmias and advanced heart failure compared with thick filament HCM. Integrating gene-level and intragene-level information may improve risk stratification in patients with HCM.

Circulation Genomic and Precision Medicine
Brigham and Women's Hospital (US), Cincinnati Children's Hospital Medical Center (US), Boston Children's Hospital (US), Children's Hospital of Philadelphia (US), University of Arizona (US), Universidade de São Paulo (BR), University of Michigan (US), UC San Diego Health System (US), Copenhagen University Hospital (DK), Rigshospitalet (DK), UNSW Sydney (AU), Yale University (US), Lung Institute (US), Meyer Children's Hospital (IT), Michigan Medicine (US), IRCCS Istituto Auxologico Italiano (IT), Ospedale Policlinico San Martino (IT), Erasmus MC Cancer Institute (NL), Boston Children's Museum (US), University of Milano-Bicocca (IT), University of Pennsylvania (US), Erasmus University Rotterdam (NL), University of Cincinnati Medical Center (US), University of Lausanne (CH)
Good health and well-being
Openalex Percentile: Top 11%
Cardiomyopathy and Myosin Studies
DOISourceOpenAlex
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