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Publications

Journal Article Ahead of print

PubMed: 42779549 DOI: 10.1161/CIRCGEN.126.005696

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

Circ Genom Precis Med

Authors: Alessia Argirò, Joshua Meisner, Eric Adler, Edoardo Bertero, Niccolò Maurizi, Brian Claggett, Neal K Lakdawala, Anjali Owens, Thomas D Ryan, Erin M Miller, Sara Saberi, Henning Bundgaard, Anna Axelsson Raja, Joseph W Rossano, Kimberly Lin, Francesca Girolami, Michelle Michels, Peter Paul Zwetsloot, Dominic Abrams, Rachel Lampert, John C Stendahl, James Ware, Victoria N Parikh, Euan Ashley, Jodie Ingles, Belinda Gray, Romi L Castillo, Jil Tardiff, Lia Crotti, Alexandre Pereira, Carolyn Y Ho, Sharlene Day, Adam Helms, Iacopo Olivotto

Affiliations

  • Cardiomyopathy Unit, University of Florence, Italy (A.A. N.M. I.O.).
  • Department of Pediatrics (J.M.), University of Michigan, Ann Arbor.
  • UC San Diego Health, CA (E. Adler).
  • Cardiovascular Disease Unit, Cardiac, Thoracic and Vascular Department, IRCCS Ospedale Policlinico San Martino, Genova, Italy (E.B.).
  • Service of Cardiology, University Hospital of Lausanne, Switzerland (N.M.).
  • Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (B.C. N.K.L. C.Y.H.).
  • Perelman School of Medicine (A.O.), University of Pennsylvania, Philadelphia.
  • Heart Institute, Cincinnati Children's Hospital Medical Center, OH (T.D.R.).
  • Department of Pediatrics, University of Cincinnati College of Medicine, OH (E.M.M.).
  • Division of Cardiovascular Medicine, Department of Internal Medicine (S.S.), University of Michigan, Ann Arbor.
  • Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Denmark (H.B. A.A.R.).
  • Division of Cardiology, Children's Hospital of Philadelphia, PA (J.W.R. K.L.).
  • Cardiovascular Medicine (F.G. A.H.), University of Michigan, Ann Arbor.
  • Cardiology Unit (F.G. I.O.) and Cardiogenetics Unit, Meyer Children's Hospital IRCCS, Florence, Italy.
  • Department of Cardiology, Thorax Center, Cardiovascular Institute, Erasmus MC, Rotterdam, the Netherlands (M.M. P.P.Z.).
  • Department of Cardiology, Boston Children's Hospital, MA (D.A.).
  • Section of Cardiovascular Medicine, Yale School of Medicine, New Haven, CT (R.L. J.C.S.).
  • National Heart a Lung Institute, Imperial College London, United Kingdom (J.W.).
  • Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, CA (V.N.P. E. Ashley).
  • Department of Medicine, Center for Undiagnosed Diseases, Stanford University, Stanford University School of Medicine, CA. Garvan Institute of Medical Research and UNSW Sydney, Australia (J.I.).
  • Faculty of Medicine and Health, University of Sydney, New South Wales, Australia (B.G.).
  • Department of Biomedical Engineering, University of Arizona, Tucson (R.L.C. J.T.).
  • Istituto Auxologico Italiano IRCCS, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milano, Italy (L.C.).
  • Department of Medicine and Surgery, University of Milano-Bicocca, Italy (L.C.).
  • Heart Institute (InCor), University of Sao Paulo Medical School, Brazil (A.P.).
  • Division of Cardiovascular Medicine, Department of Medicine, Perelman School of Medicine (S.D.), University of Pennsylvania, Philadelphia.

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.

MeSH

Registries, Genes, Genetics, Amino Acids, Heart, Arrhythmias, Cardiac, Atrial Fibrillation, Cardiomyopathy, Hypertrophic, Odds Ratio, Diagnosis, Transplants, Cardiomyopathies