Sex differences in cardiomyopathies

Meyer, Sven; Meer, Peter van der; Tintelen, J. Peter van; Berg, Maarten P. van den

doi:10.1002/ejhf.15

Cited by 80 publications

(53 citation statements)

References 120 publications

(192 reference statements)

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“…34 Reduced estradiol levels in female patients may therefore lead to an aggravation of ARVC/D after the onset of menopause, and likely explain the late disease onset in females as compared to males. 5,9,12 To investigate the pathogenic role of our clinical findings, it was important to use an in vitro model to fully recapitulate a pathological phenotype. For this reason, an established human iPSC-CM based ARVC/D model was used to show that sex hormones were directly involved in the disease process.…”

Section: Discussionmentioning

confidence: 99%

“…Male patients with ARVC/D have been reported to develop life-threatening ventricular arrhythmias at an earlier age as compared to females, although the disease is usually transmitted as an autosomal dominant trait. 4,9,12,13 Thus, sex hormones have been suggested to influence the onset and progression of ARVC/D, but this hypothesis has not been thoroughly investigated.…”

Section: Introductionmentioning

confidence: 99%

“…20 In terms of cardiac arrhythmias and gender differences, males are at greater risk for atrial fibrillation, ventricular arrhythmias in Brugada syndrome, and SCD after myocardial infarction. 12,21 Females have longer QT intervals with a higher risk of drug-induced torsades de pointes as compared to males. Estrogens suppress ischaemia-related arrhythmias and have been associated with fewer idiopathic ventricular arrhythmias originating from the RV outflow tract.…”

Section: Introductionmentioning

confidence: 99%

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Sex hormones affect outcome in arrhythmogenic right ventricular cardiomyopathy/dysplasia: from a stem cell derived cardiomyocyte-based model to clinical biomarkers of disease outcome

Akdiş¹,

Saguner²,

Shah

et al. 2017

European Heart Journal

126

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Aims Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is characterized by fibrofatty infiltration of the myocardium and ventricular arrhythmias that may lead to sudden cardiac death. It has been observed that male patients develop the disease earlier and present with more severe phenotypes as compared to females. Thus, we hypothesized that serum levels of sex hormones may contribute to major arrhythmic cardiovascular events (MACE) in patients with ARVC/D. Methods and results The serum levels of five sex hormones, sex hormone-binding globulin, high sensitivity troponin T, pro-brain natriuretic peptide, cholesterol, triglycerides, insulin, and glucose were measured in 54 ARVC/D patients (72% male). Twenty-six patients (48%) experienced MACE. Total and free testosterone levels were significantly increased in males with MACE as compared to males with a favourable outcome, whereas estradiol was significantly lower in females with MACE as compared to females with a favourable outcome. Increased testosterone levels remained independently associated with MACE in males after adjusting for age, body mass index, Task Force criteria, ventricular function, and desmosomal mutation status. Furthermore, an induced pluripotent stem cell-derived ARVC/D cardiomyocyte model was used to investigate the effects of sex hormones. In this model, testosterone worsened and estradiol improved ARVC/D-related pathologies such as cardiomyocyte apoptosis and lipogenesis, strongly supporting our clinical findings. Conclusions Elevated serum testosterone levels in males and decreased estradiol levels in females are independently associated with MACE in ARVC/D, and directly influence disease pathology. Therefore, determining the levels of sex hormones may be useful for risk stratification and may open a new window for preventive interventions.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Sex hormones affect outcome in arrhythmogenic right ventricular cardiomyopathy/dysplasia: from a stem cell derived cardiomyocyte-based model to clinical biomarkers of disease outcome

Akdiş¹,

Saguner²,

Shah

et al. 2017

European Heart Journal

126

View full text Add to dashboard Cite

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“…cardiovascular diseases associated with pregnancy, erectile dysfunction) and sex-different in etiology, pathophysiology, symptom presentation, severity and progression [3, 29, 30]. The concept that there are sex by trait interactions is not new [31] and several methods are used to examine genetic components of complex traits including GWAS, linkage analysis, association studies, and candidate-gene association studies.…”

Section: Genetics Of Cardiovascular Diseasementioning

confidence: 99%

Genetics of cardiovascular disease: Importance of sex and ethnicity

2015

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Sex differences in incidence and prevalence of and morbidity and mortality from cardiovascular disease are well documented. However, many studies examining the genetic basis for cardiovascular disease fail to consider sex as a variable in the study design, in part, because there is an inherent difficulty in studying the contribution of the sex chromosomes in women due to X chromosome inactivation. This paper will provide general background on the X and Y chromosomes (including gene content, the pseudoautosomal regions, and X chromosome inactivation), discuss how sex chromosomes have been ignored in Genome-wide Association Studies (GWAS) of cardiovascular diseases, and discuss genetics influencing development of cardiovascular risk factors and atherosclerosis with particular attention to carotid intima-medial thickness, and coronary arterial calcification based on sex-specific studies. In addition, a brief discussion of how ethnicity and hormonal status act as confounding variables in sex-based analysis will be considered along with methods for statistical analysis to account for sex in cardiovascular disease.

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“…33,34 In TMEM43 p.S358L ARVC, SCD occurred earlier in males, ICDs were inserted at a younger age (mean age 31years), and the survival benefit of the ICD was substantially larger.…”

Section: Discussionmentioning

confidence: 99%

Long-Term Clinical Outcome of Arrhythmogenic Right Ventricular Cardiomyopathy in Individuals With a p.S358L Mutation in TMEM43 Following Implantable Cardioverter Defibrillator Therapy

Hodgkinson

Howes

Boland

et al. 2016

Circ: Arrhythmia and Electrophysiology

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Background— We previously showed a survival benefit of the implantable cardioverter defibrillator (ICD) in males with arrhythmogenic right ventricular cardiomyopathy caused by a p.S358L mutation in TMEM43 . We present long-term data (median follow-up 8.5years) after ICD for primary (PP) and secondary prophylaxis in males and females, determine whether ICD discharges for ventricular tachycardia/ventricular fibrillation were equivalent to an aborted death, and assess relevant clinical predictors. Methods and Results— We studied 24 multiplex families segregating an autosomal dominant p.S358L mutation in TMEM43 . We compared survival in 148 mutation carriers with an ICD to 148 controls matched for age, sex, disease status, and family. Of 80 male mutation carriers with ICDs (median age at implantation 31 years), 61 (76%) were for PP; of 68 females (median age at implantation 43 years), 66 (97%) were for PP. In males, irrespective of indication, survival was better in the ICD groups compared with control groups (relative risk 9.3 [95% confidence interval 3.3–26] for PP and 9.7 [95% confidence interval 3.2–29.6] for secondary prophylaxis). For PP females, the relative risk was 3.6 (95% confidence interval 1.3–9.5). ICD discharge-free survival for ventricular tachycardia/ventricular fibrillation ≥240 beats per minute was equivalent to the control survival rate. Ectopy (≥1000 premature ventricular complexes/24 hours) was the only independent clinical predictor of ICD discharge in males, and no predictor was identified in females. Conclusions— ICD therapy is indicated for PP in postpubertal males and in females ≥30 years with the p.S358L TMEM43 mutation. ICD termination of rapid ventricular tachycardia/ventricular fibrillation can reasonably be considered an aborted death.

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Sex differences in cardiomyopathies

Cited by 80 publications

References 120 publications

Sex hormones affect outcome in arrhythmogenic right ventricular cardiomyopathy/dysplasia: from a stem cell derived cardiomyocyte-based model to clinical biomarkers of disease outcome

Sex hormones affect outcome in arrhythmogenic right ventricular cardiomyopathy/dysplasia: from a stem cell derived cardiomyocyte-based model to clinical biomarkers of disease outcome

Genetics of cardiovascular disease: Importance of sex and ethnicity

Long-Term Clinical Outcome of Arrhythmogenic Right Ventricular Cardiomyopathy in Individuals With a p.S358L Mutation in TMEM43 Following Implantable Cardioverter Defibrillator Therapy

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