No impact of sex and age on beta‐adrenoceptor‐mediated inotropy in human right atrial trabeculae

Abstract

Aim There is an increasing awareness of the impact of age and sex on cardiovascular diseases (CVDs). Differences in physiology are suspected. Beta‐adrenoceptors (beta‐ARs) are an important drug target in CVD and potential differences might have significant impact on the treatment of many patients. To investigate whether age and sex affects beta‐AR function, we analysed a large data set on beta‐AR‐induced inotropy in human atrial trabeculae. Methods We performed multivariable analysis of individual atrial contractility data from trabeculae obtained during heart surgery of patients in sinus rhythm (535 trabeculae from 165 patients). Noradrenaline or adrenaline were used in the presence of the beta2‐selective antagonist (ICI 118 551, 50 nmol/L) or the beta1‐selective antagonist (CGP 20712A, 300 nmol/L) to stimulate beta1‐AR or beta2‐AR respectively. Agonist concentration required to achieve half‐maximum inotropic effects (EC50) was taken as a measure of beta‐AR sensitivity. Results Impact of clinical variables was modelled using multivariable mixed model regression. As previously reported, chronic treatment with beta‐blockers sensitized beta‐AR. However, there was no significant interaction between basal force, maximum force and beta‐AR sensitivity when age and sex were modelled continuously. In addition, there was no statistically significant effect of body mass index or diabetes on atrial contractility. Conclusion Our large, multivariable analysis shows that neither age nor sex affects beta‐AR‐mediated inotropy or catecholamine sensitivity in human atrial trabeculae. These findings may have important clinical implications because beta‐ARs, as a common drug target in CVD and heart failure, do not behave differently in women and men across age decades.

Muscarinic Receptor Activation Reduces Force and Arrhythmias in Human Atria Independent of IK,ACh

“…Sample sizes were chosen based on previous experience with experiments with positive inotropic substances and concomitant availability of myocardial preparations. 13 The trabeculae were distributed randomly in 4 organ baths, usually 2 per bath. The assignment of experimental groups to the baths was randomized by drawing lots.…”

“…Therefore, we would not expect large impact of sex in this pharmacologic model. 13 To detect antiarrhythmic effects of CCh in muscle strips exposed to norepinephrine in the absence of PDE-inhibitors, a significantly higher number of experiments would be needed. In addition, we measured APD and force in independent experiments.…”

Beneficial and harmful effects of CB1 and CB2 receptor antagonists on chronotropic and inotropic effects related to atrial β‐adrenoceptor activation in humans and in rats with primary hypertension

“…Human atrial trabeculae were obtained from patients differing in sex and age (Table 1); however, both these parameters can be excluded as confounding factors because they do not affect β‐AR‒mediated inotropy or catecholamine sensitivity 32 . CB‐R antagonists showed concentration‐dependent effects on isoprenaline‐induced increase in contractile force.…”

“…The trabeculae (diameter, 1‐3 mm; length, 4‐8 mm) were connected to isometric force transducers. Like in the study by Pecha et al 32 they were pre‐stretched to ~50% of the resting tension associated with maximum developed force and then stimulated electrically with rectangular impulses at 1 Hz (5 ms duration, just over threshold) via bipolar platinum electrodes. Experiments were conducted when steady basal values were obtained.…”

Exercise‐mediated autophagy in cardiovascular diseases

“…3,4 Here, the impact of age and sex on CVDs is becoming increasingly clear, yet important intracellular processes remain poorly understood. 5 Autophagy is a degradation system regulated by autophagy-related genes where intracellular proteins and organelles that are damaged, denatured, or aged are transported into lysosomes for digestion and degradation. 6 Autophagy can provide substrates and energy for the regeneration and repair of cells, and thus regulate a broad spectrum of key life processes such as cell growth, development, and the maintenance of the organism's metabolism and balance.…”