In human hearts, muscarinic receptors (M-R) are expressed in ventricular and atrial tissue, but the acetylcholine-activated potassium current (I K,ACh ) is expressed mainly in the atrium. M-R activation decreases force and increases electrical stability in human atrium, but the impact of I K,ACh to both effects remains unclear. We used a new selective blocker of I K,ACh to elaborate the contribution of I K,ACh to M-R activation-mediated effects in human atrium. Force and action potentials were measured in rat atria and in human right atrial trabeculae. Cumulative concentration-effect curves for norepinephrine-induced force and arrhythmias were measured in the presence of carbachol (CCh; 1 mM) or CCh together with the I K,ACh -blocker XAF-1407 (1 mM) or in time-matched controls. To investigate the vulnerability to arrhythmias, we performed some experiments also in the presence of cilostamide (0.3 mM) and rolipram (1 mM), inhibiting PDE3 and PDE4. In rat atria and human right atrial trabeculae, CCh shortened the action potential duration persistently. However, the direct negative inotropy of CCh was only transient in human, but stable in rat atria. In rat and human atria, the negative inotropic effect was insensitive to blockage of I K,ACh by XAF-1407. In the presence of cilostamide and rolipram about 40% of trabeculae developed arrhythmias when exposed to norepinephrine. CCh prevented these concentration-dependent norepinephrine-induced arrhythmias, again insensitive to XAF-1407. Maximum catecholamine-induced force was not depressed by CCh. In human atrium, the direct and the indirect negative inotropic effect of CCh are independent of I K,ACh . The same applies to the CCh-mediated suppression of norepinephrine/PDEinhibition-induced arrhythmias.

Objectives We evaluated the potential of cardiac magnetic resonance (CMR)‐derived strain to assess aortic valve (AV) annulus deformation during the cardiac cycle in regurgitant and well‐functioning AVs. Methods Four patients with severe aortic regurgitation and seven healthy controls underwent CMR. Assessment of longitudinal strain was performed by hypothesizing the AV annulus would be the left ventricle in long‐axis orientation. Longitudinal strain of the segments belonging to the muscular and fibrous AV annulus was weighted and averaged to obtain regional values (RLS). Results Comparison of RLS between regurgitant and well‐functioning AVs showed a considerably different deformation of the muscular AV annulus (i.e., median RLS: 4.18 % [patients] vs. −10.41 % [controls], p = .024). The fibrous AV annulus demonstrated comparable deformational changes in both groups. Conclusion CMR‐derived strain allows for quantification of AV annulus deformation during the cardiac cycle and shows an altered RLS in the muscular AV annulus in patients with severe aortic regurgitation.

Objective: At the tissue level, disruption of the extracellular matrix network leads to irreversible cardiac fibrosis, which contributes to myocardial dysfunction. At the myocyte level, downregulation of beta-adrenoceptors (beta-AR) reduces adaptation to increased workload. The aim of our study was to analyse the correlation between myocardial fibrosis and beta-AR sensitivity in patients with aortic valve (AV) disease. Methods: A total of 92 consecutive patients who underwent elective AV surgery between 2017–2019 were included in our study (51 with aortic regurgitation (AR-group); 41 with aortic stenosis (AS-group) and left ventricular (LV) biopsies were obtained intraoperatively. In vitro force contractility testing was performed by measuring beta-AR sensitivity (−log EC50[ISO]). In parallel, a quantitative analysis of myocardial fibrosis burden was performed. Results: Mean age at the time of AV surgery was not statistically different in both groups (AR: 53.3 ± 15.3 years vs. AS: 58.7 ± 17.0 years; p = 0.116). The LV end-diastolic diameter was significantly enlarged in the AR-group when compared to the AS-group (59.4 ± 15.6 vs. 39.7 ± 21.2; p < 0.001). Analysis of beta-AR sensitivity (AR: −6.769 vs. AS: −6.659; p = 0.316) and myocardial fibrosis (AR: 8.9% vs. AS: 11.3%; p = 0.284) showed no significant differences between patients with AS and AR. There was no correlation between myocardial fibrosis and beta-AR sensitivity in the whole study cohort (R = 0.1987; p = 0.100) or in the AS-subgroup (R = 0.009; p = 0.960). However, significant correlation of fibrosis and beta-AR sensitivity was seen in AR-patients (R = 0.363; p = 0.023). Conclusion: More severe myocardial fibrosis was associated with reduced beta-AR sensitivity in patients presenting with AR but not with AS. Therefore, our results suggest that in patients with AR, cellular myocardial dysfunction is present and correlates with the extent of myocardial fibrosis in the myocardium.