Sex-dependent alterations of Ca<sup>2+</sup>cycling in human cardiac hypertrophy and heart failure

Fischer, Thomas; Herting, Jonas; Eiringhaus, Jörg; Pabel, Steffen; Hartmann, Nico; Ellenberger, David; Friedrich, Martin; Renner, André; Gummert, Jan; Maier, Lars S.; Zabel, Markus; Hasenfuß, Gerd; Sossalla, Samuel

doi:10.1093/europace/euv313

Cited by 26 publications

(33 citation statements)

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“…Sarcoplasmic reticulum calcium leak is lower in ventricular myocytes isolated from women with heart failure than from men. 7 In association with this finding, a lower ratio of arrhythmic myocytes was observed in the female patients with heart failure. These sex differences may explain, in part, the lower incidence of spontaneous sustained ventricu- lar arrhythmias observed in women with heart failure in comparison with men.…”

Section: Sex Differences In Cardiac Electrophysiologymentioning

confidence: 62%

“…Sex differences in ion channel expression/function, autonomic regulation, and intracellular calcium handling may also influence the substrate and triggers for ventricular arrhythmias. 1,7 Figure 6. Probability of VT/VF or death (A and C) and cumulative incidence of VT/VF (B and C) on the basis of sex and the etiology of heart disease.…”

Section: Arrhythmic Events In Icd Recipientsmentioning

confidence: 99%

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Atrial Fibrillation and Ventricular Arrhythmias

Gillis

2017

Circulation

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ABSRACT: Sex-specific differences in the epidemiology, pathophysiology, clinical presentation, clinical treatment, and clinical outcomes of atrial fibrillation (AF), sustained ventricular arrhythmias, and sudden cardiac death are recognized. Sex hormones cause differences in cardiac electrophysiological parameters between men and women that may affect the risk for arrhythmias. The incidence and prevalence of AF is lower in women than in men. However, because women live longer and AF prevalence increases with age, the absolute number of women with AF exceeds that of men. Women with AF are more symptomatic, present with more atypical symptoms, and report worse quality of life in comparison with men. Female sex is an independent risk factor for death or stroke attributable to AF. Oral anticoagulation therapy for stroke prevention has similar efficacy for men and women, but older women treated with warfarin have a higher residual risk of stroke in comparison with men. Women with AF are less likely to receive rhythm control antiarrhythmic drug therapy, electric cardioversion, or catheter ablation in comparison with men. The incidence and prevalence of sustained ventricular arrhythmias and sudden cardiac death are lower in women than in men. Women receiving implantable cardioverter defibrillators for primary prevention of sudden cardiac death are less likely to experience sustained ventricular arrhythmias in comparison with men. In contrast, women receiving a cardiac resynchronization therapy implantable cardioverter defibrillator for the treatment of heart failure are more likely to benefit than men. Women are less likely to be referred for implantable cardioverter defibrillator therapy despite current guideline recommendations. Women are more likely to experience a significant complication related to implantable cardioverter defibrillator implantation in comparison with men. Whether sex differences in treatment decisions reflect patient preferences or treatment biases requires further study.

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Section: Sex Differences In Cardiac Electrophysiologymentioning

confidence: 62%

Section: Arrhythmic Events In Icd Recipientsmentioning

confidence: 99%

Atrial Fibrillation and Ventricular Arrhythmias

Gillis

2017

Circulation

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“…Previous in vitro and in vivo studies have suggested that high testosterone levels may have pro-arrhythmic effects through modulation of cardiac contraction and calcium homeostasis. [28][29][30][31] Other studies suggested that arrhythmias may occur due to higher adrenergic activity increasing apoptosis, which would worsen ARVC/D pathologies. 32,33 the arrhythmic potential in this specific disease constellation, since in our in vitro model, the healthy CMs did not show increased lipogenesis and apoptosis after 5F pathogenic induction.…”

Section: Discussionmentioning

confidence: 99%

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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“…However, previous work of our group demonstrated that the diastolic SR‐Ca 2+ leak is similar in human ischemic heart disease and dilated cardiomyopathy rendering significant effects of this difference on the outcomes of our study unlikely. The fact that the proportion of male patients is slightly lower in the HF‐Tx group compared with HF‐Im may even lead to an underestimation of this increase as male HF patients were shown to display a higher SR Ca 2+ leak compared with female patients (). Our paper additionally shows that the SR Ca 2+ leak can still be reduced by CaMKII inhibition at the stage of heart transplantation due to insufficient response to LVAD support.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of CaMKII Attenuates Progressing Disruption of Ca²⁺ Homeostasis Upon Left Ventricular Assist Device Implantation in Human Heart Failure

et al. 2016

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In heart failure, left ventricular assist device (LVAD) implantation is performed to ensure sufficient cardiac output. Whereas some patients are subsequently weaned from LVAD support, other patients still need heart transplantation. To elucidate underlying mechanisms, we assessed the arrhythmogenic SR-Ca(2+) leak at the time of LVAD implantation (HF-Im) and heart transplantation (HF-Tx) and evaluated the effects of CaMKII-inhibition. Human left-ventricular cardiomyocytes were isolated, paced at 1 Hz for 10 beats to ensure SR-Ca(2+) loading and scanned for diastolic Ca(2+) sparks (confocal microscopy). In HF-Im, the high diastolic spark frequency (CaSpF) of 0.76 ± 0.12 × 100 μm(-1) × s(-1) could be reduced to 0.48 ± 0.10 × 100 μm(-1) × s(-1) by CaMKII inhibition (AIP, 1 μM). The amplitude of Ca(2+) sparks, width, and length was not significantly altered. In sum, CaMKII inhibition yielded a clear tendency toward a reduction of the SR-Ca(2+) leak (n cells/patients = 76/6 vs. 108/6, P = 0.08). In HF-Tx, we detected an even higher CaSpF of 1.00 ± 0.10 100 μm(-1) × s(-1) and a higher SR-Ca(2+) leak compared with HF-Im (increase by 81 ± 33%, n cells/patients = 156/7 vs. 130/7, P < 0.05), which fits to the further decreased LV function. Here, CaMKII inhibition likewise reduced CaSpF (0.35 ± 0.09 100 μm(-1) × s(-1,) P = 0.06) and significantly reduced spark duration (n sparks/patients = 58/3 vs. 159/3, P < 0.05). Conclusively, the SR-Ca(2+) leak was reduced by 69 ± 12% in HF-Tx upon CaMKII inhibition (n cells/patients = 53/3 vs. 91/3, P < 0.05). These data show that the SR-Ca(2+) leak correlates with the development of LV function after LVAD implantation and may represent an important pathomechanism. The fact that CaMKII inhibition reduces the SR-Ca(2+) leak in HF-Tx suggests that CaMKII inhibition may be a promising option to beneficially influence clinical course after LVAD implantation.

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Sex-dependent alterations of Ca²⁺cycling in human cardiac hypertrophy and heart failure

Cited by 26 publications

References 26 publications

Atrial Fibrillation and Ventricular Arrhythmias

Atrial Fibrillation and Ventricular Arrhythmias

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

Inhibition of CaMKII Attenuates Progressing Disruption of Ca²⁺ Homeostasis Upon Left Ventricular Assist Device Implantation in Human Heart Failure

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Sex-dependent alterations of Ca2+cycling in human cardiac hypertrophy and heart failure

Cited by 26 publications

References 26 publications

Atrial Fibrillation and Ventricular Arrhythmias

Atrial Fibrillation and Ventricular Arrhythmias

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

Inhibition of CaMKII Attenuates Progressing Disruption of Ca2+ Homeostasis Upon Left Ventricular Assist Device Implantation in Human Heart Failure

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Sex-dependent alterations of Ca²⁺cycling in human cardiac hypertrophy and heart failure

Inhibition of CaMKII Attenuates Progressing Disruption of Ca²⁺ Homeostasis Upon Left Ventricular Assist Device Implantation in Human Heart Failure