Search

Males and females exhibit intrinsic differences in the structure and function of the heart, while the prevalence and severity of cardiovascular disease vary in the two sexes. However, the mechanisms of this sex-based dimorphism are yet to be elucidated. Sex chromosomes and sex hormones are the main contributors to sex-based differences in cardiac physiology and pathophysiology. In recent years, the advances in induced pluripotent stem cell-derived cardiac models and multi-omic approaches have enabled a more comprehensive understanding of the sex-specific differences in the human heart. Here, we provide an overview of the roles of these two factors throughout cardiac development and explore the sex hormone signaling pathways involved. We will also discuss how the employment of stem cell-based cardiac models and single-cell RNA sequencing help us further investigate sex differences in healthy and diseased hearts. [ABSTRACT FROM AUTHOR]

Male sex is one of the most important risk factors of atrial fibrillation (AF), with the incidence in men being almost double that in women. However, the reasons for this sex difference are unknown. Accordingly, in this study, we sought to determine whether there are sex differences in intracellular Ca2+ homeostasis in mouse atrial myocytes that might help explain male predisposition to AF. AF susceptibility was assessed in male (M) and female (F) mice (4–5 months old) using programmed electrical stimulation (EPS) protocols. Males were 50% more likely to develop AF. The Ca2+ transient amplitude was 28% higher in male atrial myocytes. Spontaneous systolic and diastolic Ca2+ releases, which are known sources of triggered activity, were significantly more frequent in males than females. The time to 90% decay of Ca2+ transient was faster in males. Males had 54% higher Na+-Ca2+ exchanger (NCX1) current density, and its expression was also more abundant. L-type Ca2+ current (ICaL) was recorded with and without BAPTA, a Ca2+ chelator. ICaL density was lower in males only in the absence of BAPTA, suggesting stronger Ca2+-dependent inactivation in males. CaV1.2 expression was similar between sexes. This study reports major sex differences in Ca2+ homeostasis in mouse atria, with larger Ca2+ transients and enhanced NCX1 function and expression in males resulting in more spontaneous Ca2+ releases. These sex differences may contribute to male susceptibility to AF by promoting triggered activity. [ABSTRACT FROM AUTHOR]

Aims During pregnancy, there is a significant increase in heart rate (HR) potentially associated with an increased risk of arrhythmias or exacerbation of pre-existing cardiac conditions endangering both mother and foetus. Calcium homeostasis plays an important role in regulating automaticity of the sinoatrial node (SAN); however, its contribution to the accelerated HR during pregnancy remains unknown. Methods and results Using murine SAN cells, we showed that pregnancy increased L-type Ca2+ current (I CaL) and CaV1.3 mRNA expression, whereas T-type Ca2+ current (I CaT) and its underlying channel were unchanged. Analysis of SAN intra-cellular Ca2+ oscillations showed that the rate of spontaneous Ca2+ transients was significantly higher in pregnant mice along with a higher mRNA expression of ryanodine receptor. Assessment of supra-ventricular arrhythmias using programmed electrical stimulation protocols on anaesthetized mice revealed higher susceptibility in pregnancy. Of note, the modifications associated with pregnancy were reversible following delivery. Furthermore, chronic administration of 17β-estradiol (E2) to nodal-like human-induced pluripotent stem cell-derived cardiomyocytes (N-hiPSC-CM), control mice, oestrogen-receptor-β knockout (ERKOβ) but not ERKOα mice, accelerated cardiac automaticity, recapitulating the pregnancy phenotype in both mouse and human SAN cell models. Conclusion Together, these results indicate that pregnancy considerably alters intra-cellular Ca2+ homeostasis sustaining faster HR during pregnancy. Importantly, these changes were dependent on an oestrogen receptor α (ERα) mechanism that resulted in increased I CaL and spontaneous Ca2+ release from the sarcoplasmic reticulum, highlighting a novel role for oestrogen in regulating HR. [ABSTRACT FROM AUTHOR]

Cardiac-specific overexpression of wild-type a w-adrenergic receptors (α1B-AR) in mice predisposes to dilated cardiomyopathy and sudden death. Although α-adrenergic stimulation is thought to contribute to induction of α1-rhythmias in heart failure, the electrophysiological consequences of chronic at-adrenergic activation have not been clearly defined. Thus we characterized ventricular repolarization and monitored incidence of spontaneous arrhythmias in end-stage heart failure α1B-AR mice (9-12 mo) and younger α1B-AR mice (2-3 mo) that do not present signs of heart failure. Compared with agedmatched controls, the corrected QT interval was 34% longer in the 9to 12-mo α1B-AR mice, and the action potential durations were also significantly prolonged in these mice. These changes were associated with a decrease in the density of the outward K+ currents, Ca2+-independent transient, ultrarapid delayed rectifier, and steady state (at +30 mV, reduction of 68, 64, and 41%, respectively), and underlying K+ channel expression. Electrocardiogram (ECG) recordings revealed that older α1B-AR mice exhibited spontaneous ventricular arrhythmias. The alterations in repolarization can contribute to these rhythm abnormalities and are likely caused by chronic α1B-AR activity. Additional data obtained in 2- to 3-mo α1B-AR mice clearly showed that electrical remodeling was already observed in younger transgenic animals. However, it appeared to be slightly less pronounced than in older mice. These results suggest that there are two waves of remodeling: one due to chronic α1B-AR activity, and a second due to heart failure. Taken together, these data provide strong evidence for a pathological role of chronic α1B-AR activity in the development of repolarization defects and ventricular arrhythmias. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Gender differences in mouse cardiac repolarization have been reported to be due to the stimulatory action of androgens on the ultrarapid delayed rectifier K+ current (IKur) and its underlying Kv1.5 channel. To confirm the regulation of ventricular repolarization by androgens, the present study compared two strains of mice (CD-1 and C57BL/6) that present different androgen levels. Methods and results: Measurement of testosterone levels in different strains of mice (CD-1, C57BL/6, C3H and FVB) revealed that male C57BL/6 mice had very low levels of testosterone, whereas males of the other strains displayed normal testosterone levels. Furthermore, whole-cell voltage clamp recordings in isolated ventricular myocytes showed that the current density of IKur in male C57BL/6 mice was similar to that in female mice but smaller with respect to male CD-1 mice. Androgen replacement in male C57BL/6 mice as well as in castrated male CD-1 mice shortened ventricular repolarization, increased IKur current density, and increased expression of Kv1.5 channels. Conclusion: Strain and gender differences observed in mouse cardiac repolarization can be explained by different androgen levels. As a consequence, androgens are major regulatory factors in cardiac repolarization and special attention should be paid to the hormonal status of the animal when studying hormonal regulation of cardiac repolarization. [Copyright &y& Elsevier]

Objectives and methods: This study examines postnatal development of action potential duration (APD) and voltage-dependent K+ currents in mouse atrial myocytes and compares the expression levels of corresponding K+ channels between adult and neonatal mouse atrial tissues. APD and K+ currents were compared between atrial myocytes isolated from postnatal Day-1, Day-7, Day-20, and adult mice. Results: All K+ currents examined underwent significant up-regulation during postnatal life in mouse atrium, resulting in a dramatic shortening of the APD. The ultrarapid delayed rectifier (IKur) was absent in the developing mouse heart and only contributed to repolarization in the adult mouse atrium, whereas the density of the other K+ currents increased earlier during the developmental period. Indeed, the major changes in the expression of the inward rectifier current (IK1) occurred within the first week of life, the density of the Ca2+-independent transient outward K+ current (Ito) gradually increased while the development of the steady-state outward K+ current (Iss) was completed within the first 3 weeks of life. Results of RNase protection assay and Western blot analysis confirmed that the postnatal development of the mouse atrial K+ currents correlates with an increase in expression levels of underlying K+ channel isoforms. Conclusion: These findings indicate that in mouse atrium, each K+ current exhibits a specific postnatal development, suggesting that regulatory factors taking place during development are major determinants of the functional role of K+ channels in cardiac repolarization. The mouse atrium is, therefore, a very interesting model to gain information on the mechanisms regulating K+ channel activity. [Copyright &y& Elsevier]

Although the K+ currents expressed in hearts of adult mice have been studied extensively, detailed information concerning their relative sizes and biophysical properties in ventricle and atrium is lacking. Here we describe and validate pharmacological and biophysical methods that can be used to isolate the three main time- and voltage-dependent outward K+ currents which modulate action potential repolarization. A a2+-independent transient outward K+ current, Ito, can be separated from total outward current using an 'inactivating prepulse'. The rapidly activating, slowly inactivating delayed rectifier K+ current, IKur, can be isolated using submillimolar concentrations of 4-aminopyridine (4-AP). The remaining K+ current, Iss, can be obtained by combining these two procedures: (i) inactivating Ito and (ii) eliminating IKur by application of low concentration of 4-AP. Iss activates relatively slowly and shows very little inactivation, even during depolarizations lasting several seconds. Our findings also show that the rate of reactivation of Ito is more than 20-fold faster than that of IKur. These results demonstrate that the outward K+ currents in mouse ventricles can be separated based on their distinct time and voltage dependence, and different sensitivities to 4-AP. Data obtained at both 22 and 32°C demonstrate that although the duration of the inactivating prepulse has to be adapted for the recording temperature, this approach for separation of K+ current components is also valid at more physiological temperatures. To demonstrate that these methods also allow separation of these K+ currents in other cell types, we have applied this same approach to myocytes from mouse atria. Molecular approaches have been used to compare the expression levels of different K +... [ABSTRACT FROM AUTHOR]