Neal K Lakdawala1, Iacopo Olivotto1, Sharlene M Day2, Larry Han3, Euan A Ashley4, Michelle Michels5, Jodie Ingles6, Christopher Semsarian6, Daniel Jacoby7, John L Jefferies8, Steven D Colan9, Alexandre C Pereira10, Joseph W Rossano11, Sam Wittekind12, James S Ware13, Sara Saberi14, Adam S Helms14, Allison L Cirino1, Leslie A Leinwand15, Christine E Seidman1,16, Carolyn Y Ho1. 1. Brigham and Women's Hospital (N.K.L., A.L.C., C.E.S., C.Y.H.), Harvard Medical School, MA. 2. Department of Internal Medicine, University of Pennsylvania, Philadelphia (S.M.D.). 3. Harvard University, Biostatistics, Boston, MA (L.H.). 4. Stanford Center for Inherited Heart Disease, CA (E.A.A.). 5. Department of Cardiology, Thoraxcenter, Erasmus MC Rotterdam, the Netherlands (M.M.). 6. Department of Cardiology, Royal Prince Alfred Hospital, Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, University of Sydney, NSW, Australia (J.I., C.S.). 7. Yale University, New Haven, CT (D.J.). 8. University of Tennessee Health Science Centre, Memphis (J.L.J.). 9. Boston Children's Hospital (S.D.C.), Harvard Medical School, MA. 10. Heart Institute (InCor), University of Sao Paulo Medical School, Brazil (A.C.P.). 11. Children's Hospital of Philadelphia, PA (J.W.R.). 12. Cincinnati Children's Hospital Medical Center, Heart Institute, OH (S.W.). 13. National Heart & Lung Institute, Royal Brompton Cardiovascular Research Centre, Imperial College London, United Kingdom (J.S.W.). 14. Department of Internal Medicine-Cardiology, University of Michigan, Ann Arbor (S.S., A.S.H.). 15. MCDB & BioFrontiers Institute, University of Colorado, Boulder (L.A.L.). 16. Howard Hughes Medical Institute, Chevy Chase, MD (C.E.S.).
Abstract
BACKGROUND: The impact of sex on phenotypic expression in hypertrophic cardiomyopathy (HCM) has not been well characterized in genotyped cohorts. METHODS: Retrospective cohort study from an international registry of patients receiving care at experienced HCM centers. Sex-based differences in baseline characteristics and clinical outcomes were assessed. RESULTS: Of 5873 patients (3788 genotyped), 2226 (37.9%) were women. At baseline, women were older (49.0±19.9 versus 42.9±18.4 years, P<0.001) and more likely to have pathogenic/likely pathogenic sarcomeric variants (HCM patients with a sarcomere mutation; 51% versus 43%, P<0.001) despite equivalent utilization of genetic testing. Age at diagnosis varied by sex and genotype despite similar distribution of causal genes. Women were 3.6 to 7.1 years older at diagnosis (P<0.02) except for patients with MYH7 variants where age at diagnosis was comparable for women and men (n=492; 34.8±19.2 versus 33.3±16.8 years, P=0.39). Over 7.7 median years of follow-up, New York Heart Association III-IV heart failure was more common in women (hazard ratio, 1.87 [CI, 1.48-2.36], P<0.001), after controlling for their higher burden of symptoms and outflow tract obstruction at baseline, reduced ejection fraction, HCM patients with a sarcomere mutation, age, and hypertension. All-cause mortality was increased in women (hazard ratio, 1.50 [CI, 1.13-1.99], P<0.01) but neither implantable cardioverter-defibrillator utilization nor ventricular arrhythmia varied by sex. CONCLUSIONS: In HCM, women are older at diagnosis, partly modified by genetic substrate. Regardless of genotype, women were at higher risk of mortality and developing severe heart failure symptoms. This points to a sex-effect on long-term myocardial performance in HCM, which should be investigated further.
BACKGROUND: The impact of sex on phenotypic expression in hypertrophic cardiomyopathy (HCM) has not been well characterized in genotyped cohorts. METHODS: Retrospective cohort study from an international registry of patients receiving care at experienced HCM centers. Sex-based differences in baseline characteristics and clinical outcomes were assessed. RESULTS: Of 5873 patients (3788 genotyped), 2226 (37.9%) were women. At baseline, women were older (49.0±19.9 versus 42.9±18.4 years, P<0.001) and more likely to have pathogenic/likely pathogenic sarcomeric variants (HCM patients with a sarcomere mutation; 51% versus 43%, P<0.001) despite equivalent utilization of genetic testing. Age at diagnosis varied by sex and genotype despite similar distribution of causal genes. Women were 3.6 to 7.1 years older at diagnosis (P<0.02) except for patients with MYH7 variants where age at diagnosis was comparable for women and men (n=492; 34.8±19.2 versus 33.3±16.8 years, P=0.39). Over 7.7 median years of follow-up, New York Heart Association III-IV heart failure was more common in women (hazard ratio, 1.87 [CI, 1.48-2.36], P<0.001), after controlling for their higher burden of symptoms and outflow tract obstruction at baseline, reduced ejection fraction, HCM patients with a sarcomere mutation, age, and hypertension. All-cause mortality was increased in women (hazard ratio, 1.50 [CI, 1.13-1.99], P<0.01) but neither implantable cardioverter-defibrillator utilization nor ventricular arrhythmia varied by sex. CONCLUSIONS: In HCM, women are older at diagnosis, partly modified by genetic substrate. Regardless of genotype, women were at higher risk of mortality and developing severe heart failure symptoms. This points to a sex-effect on long-term myocardial performance in HCM, which should be investigated further.
Entities:
Keywords:
cardiomyopathy, hypertrophic; genetics; heart failure; sarcomeres; women
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