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Multicenter Study
. 2024 Dec;12(12):2041-2052.
doi: 10.1016/j.jchf.2024.08.005. Epub 2024 Sep 25.

Association of Multiple Nonhypertrophic Cardiomyopathy-Related Genetic Variants and Outcomes in Patients With Hypertrophic Cardiomyopathy

Takashi Hiruma  1 , Shunsuke Inoue  2 , Zhehao Dai  1 , Seitaro Nomura  3 , Toru Kubo  4 , Kenta Sugiura  4 , Atsushi Suzuki  5 , Takeshi Kashimura  6 , Shouji Matsushima  7 , Takanobu Yamada  1 , Takashige Tobita  5 , Manami Katoh  2 , Toshiyuki Ko  2 , Masamichi Ito  1 , Junichi Ishida  1 , Eisuke Amiya  1 , Masaru Hatano  1 , Norifumi Takeda  1 , Eiki Takimoto  1 , Hiroshi Akazawa  1 , Hiroyuki Morita  1 , Junichi Yamaguchi  5 , Takayuki Inomata  6 , Hiroyuki Tsutsui  8 , Hiroaki Kitaoka  4 , Hiroyuki Aburatani  9 , Norihiko Takeda  1 , Issei Komuro  10
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Free article
Multicenter Study

Association of Multiple Nonhypertrophic Cardiomyopathy-Related Genetic Variants and Outcomes in Patients With Hypertrophic Cardiomyopathy

Takashi Hiruma et al. JACC Heart Fail. 2024 Dec.
Free article

Abstract

Background: Approximately 10% of hypertrophic cardiomyopathy (HCM) patients have left ventricular systolic dysfunction (end-stage HCM) leading to severe heart-failure; however, risk stratification to identify patients at risk of progressing to end-stage HCM remains insufficient.

Objectives: In this study, the authors sought to elucidate whether the coexistence of other cardiovascular disease (CVD)-related variants is associated with progression to end-stage HCM in patients with HCM harboring pathogenic or likely pathogenic (P/LP) sarcomeric variants.

Methods: The authors performed genetic analysis of 83 CVD-related genes in HCM patients from a Japanese multicenter cohort. P/LP variants in 8 major sarcomeric genes (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL2, MYL3, and ACTC1) definitive for HCM were defined as "sarcomeric variants." In addition, P/LP variants associated with other CVDs, such as dilated cardiomyopathy and arrhythmogenic cardiomyopathy, were referred to as "other CVD-related variants."

Results: Among 394 HCM patients, 139 carried P/LP sarcomeric variants: 11 (7.9%) carried other CVD-related variants, 6 (4.3%) multiple sarcomeric variants, and 122 (87.8%) single sarcomeric variants. In a multivariable Cox regression analysis, presence of multiple sarcomeric variants (adjusted HR [aHR]: 3.35 [95% CI: 1.25-8.95]; P = 0.016) and coexistence of other CVD-related variants (aHR: 2.80 [95% CI: 1.16-6.78]; P = 0.022) were independently associated with progression to end-stage HCM. Coexisting other CVD-related variants were also associated with heart failure events (aHR: 2.75 [95% CI: 1.27-5.94]; P = 0.010).

Conclusions: Approximately 8% of sarcomeric HCM patients carried other CVD-related variants, which were associated with progression to end-stage HCM and heart failure events. Comprehensive surveillance of CVD-related variants within sarcomeric HCM patients contributes to risk stratification and understanding of mechanisms underlying end-stage HCM.

Keywords: cardiovascular disease; end-stage; genetic analysis; hypertrophic cardiomyopathy; sarcomere.

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Conflict of interest statement

Funding Support and Author Disclosures This work was supported by grants from SENSHIN Medical Research Foundation (to Drs Ko and Nomura), Japan Foundation for Applied Enzymology (to Drs Ko and Nomura), Kanae Foundation for the Promotion of Medical Science (to Dr Nomura), Merck Sharp & Dohme Life Science Foundation (to Drs Ko and Nomura), Sakakibara Heart Foundation Cardiovascular Research Program 2023 (to Dr Ko), Tokyo Biomedical Research Foundation (to Dr Nomura), Astellas Foundation for Research on Metabolic Disorders (to Dr Nomura), Novartis Foundation (Japan) for the Promotion of Science (to Dr Nomura), Japanese Circulation Society (to Drs Ko and Nomura), Takeda Science Foundation (to Drs Ko and Nomura), Cell Science Research Foundation (to Dr Nomura), Mochida Memorial Foundation for Medical and Pharmaceutical Research (to Dr Nomura), Japan Heart Foundation (to Dr Ko), Daiichi Sankyo Foundation of Life Science (to Dr Nomura), a Grant-in-Aid for Scientific Research (A) (to Dr Nomura), a Grant-in-Aid for Scientific Research (S) (to Dr Komuro), UTEC-UTokyo FSI Research Grant Program (to Dr Nomura), JST FOREST Program (grant number JPMJFR210U) (to Dr Nomura), Japan Agency for Medical Research and Development (AMED) (JP18km0405209, JP21ek0109543, JP21ek0109569, JP22ama121016, JP22ek0210172, JP22ek0210167, JP22bm1123011, JP23tm0724607, JP23gm4010020, JP223fa627011, JP23tm0524009, JP23tm0524004, JP23jf0126003, JP24ek0109755, and JP24ek0210205) (to Drs Nomura and Komuro), and JP23ek0109600h0002 (to Dr Ko). The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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