W. Glen Pyle

ECG recordings obtained from racehorses during competition provide insight into the cardiac physiology of athletes and potentially pathophysiologic mechanisms that underlie the risk of exercise-associated arrhythmias. The QT/RR relationship is uniquely altered during maximal effort compared with other exercise periods, and the response of the QT interval to changes in heart rate (RR interval) is decreased immediately postrace.

Exercise requires a rapid cardiac response to maintain cardiovascular function. CapZ is a critical stress‐response protein in cardiac myocytes. While its role in the pathological stress response has been explored, its part in the physiological response to exercise is unknown. This study examined CapZ regulation during exercise to determine its importance in the cardiac response. Female wildtype or cardiac CapZ‐deficient transgenic mice (“CapZ mice”) were subjected to exhaustive swimming or running protocols and submaximal running. Time to exhaustion was a measurement of exercise capacity. Following submaximal exercise, cardiac myofilaments were isolated and probed for CapZ, its regulatory proteins, and myofilament proteins. Myofilament function was assessed using an actomyosin MgATPase assay, and protein phosphorylation was quantified with ProQ Diamond staining. Total myofilament CapZ was unaffected by exercise, but increased CapZIP and decreased phosphorylated CapZIP indicated weakened CapZ‐actin interaction. Myofilaments from CapZ mice lacked changes in CapZIP. Time to exhaustion was lower in CapZ mice in both swimming and running protocols. Actomyosin MgATPase activity was maintained in wildtype mice and impaired with CapZ deficiency. Exercise increased myofilament protein phosphorylation in wildtype mice but not in transgenic animals. Exercise‐dependent increases in myofilament PKC‐α and ‐ε were mitigated in CapZ mice. Telethonin/Tcap levels decreased significantly in CapZ‐deficient myofilaments with exercise, and leiomodin 2 increased in wildtype myofilaments. These data show Cardiac CapZ is a critical player in the physiological response to exercise and that CapZ‐actin binding is rapidly altered with exercise. Decreased cardiac CapZ limits exercise capacity, impairs myofilament regulation, and leads to a less stable contractile apparatus.

We investigated the effects of chemically-induced ovarian failure on single fibre contractility of the soleus and extensor digitorum longus (EDL) muscles throughout ovarian failure, thereby mimicking the menopausal transition into late-stage menopause: ((D60; peri-menopause), (D120; onset of menopause), (D134; early-onset menopause), and (D176; late-stage menopause)). We used 4-vinylcyclohexene diepoxide (VCD) to induce ovarian failure in sexually-mature female mice. For the soleus at D120 and D176, mice with VCD-induced ovarian failure produced higher force as compared with controls ( p < 0.05). On D134, however, VCD had lower force production compared with controls ( p < 0.05). The cross-sectional area of the soleus fibres from the VCD group was larger at D120 compared with controls ( p < 0.05), but not at any other time point ( p > 0.05). The VCD group showed time-dependent changes in specific force production compared to controls, with a 37% decrease at D134 but a 39% increase at D176 in the soleus muscle ( p < 0.05). No differences in rate of force redevelopment (Ktr) or calcium sensitivity was observed for the soleus ( p > 0.05). For the EDL there were no differences in force, cross-sectional area, stiffness, Ktr, or calcium sensitivity between groups ( p > 0.05). Our results indicate that muscle contractility across the peri-menopausal transition into late-stage menopause is both muscle and phase-dependent, emphasizing the complexity of changing hormones throughout the lifespan on muscle contractile function.

Prevention as a way to decrease cardiovascular disease morbidity and mortality has long been promoted. Cardiovascular societies and organizations have argued that an ounce of prevention is worth a pound of cure, producing significant reductions in cardiovascular disease mortality and prolonging lives.

Risk of cardiovascular disease mortality rises in women after menopause. While increased cardiovascular risk is largely attributed to postmenopausal declines in estrogens, the molecular changes in the heart that contribute to risk are poorly understood. Disruptions in intracellular calcium handling develop in ovariectomized mice and have been implicated in cardiac dysfunction. Using a mouse model of menopause in which ovarian failure occurs over 120 days, we sought to determine if perimenopause impacted calcium removal mechanisms in the heart and identify the molecular mechanisms. Mice were injected with 4-vinylcyclohexene diepoxide (VCD) to induce ovarian failure over 120 days, mimicking perimenopause. Hearts were removed at 60 and 120 days after VCD injections, representing the middle and end of perimenopause. SERCA2a function was significantly diminished at the end of perimenopause. Neither SERCA2a nor phospholamban expression changed at either time point, but phospholamban phosphorylation at S16 and T17 was dynamically altered. Intrinsic SERCA inhibitors sarcolipin and myoregulin increased >4-fold at day 60, as did the native activator DWORF. At the end of perimenopause, sarcolipin and myoregulin returned to baseline levels while DWORF was significantly reduced below controls. Sodium–calcium exchanger expression was significantly increased at the end of perimenopause. These results show that the foundation for increased cardiovascular disease mortality develops in the heart during perimenopause and that regulators of calcium handling exhibit significant fluctuations over time. Understanding the temporal development of cardiovascular risk associated with menopause and the underlying mechanisms is critical to developing interventions that mitigate the rise in cardiovascular mortality that arises after menopause.

In cardiovascular research, sex and gender have not typically been considered in research design and reporting until recently. This has resulted in clinical research findings from which not only all women, but also gender-diverse individuals have been excluded. The resulting dearth of data has led to a lack of sex- and gender-specific clinical guidelines and raises serious questions about evidence-based care. Basic research has also excluded considerations of sex. Including sex and/or gender as research variables not only has the potential to improve the health of society overall now, but it also provides a foundation of knowledge on which to build future advances. The goal of this guidelines article is to provide advice on best practices to include sex and gender considerations in study design, as well as data collection, analysis, and interpretation to optimally establish rigor and reproducibility needed to inform clinical decision-making and improve outcomes. In cardiovascular physiology, incorporating sex and gender is a necessary component when optimally designing and executing research plans. The guidelines serve as the first guidance on how to include sex and gender in cardiovascular research. We provide here a beginning path toward achieving this goal and improve the ability of the research community to interpret results through a sex and gender lens to enable comparison across studies and laboratories, resulting in better health for all.