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Cardiomyocytes from the apex but not the base of the heart increase their contractility in response to β2-adrenoceptor (β2AR) stimulation, which may underlie the development of Takotsubo cardiomyopathy. However, both cell types produce comparable cytosolic amounts of the second messenger cAMP. We investigated this discrepancy using nanoscale imaging techniques and found that, structurally, basal cardiomyocytes have more organized membranes (higher T-tubular and caveolar densities). Local membrane microdomain responses measured in isolated basal cardiomyocytes or in whole hearts revealed significantly smaller and more short-lived β2AR/cAMP signals. Inhibition of PDE4, caveolar disruption by removing cholesterol or genetic deletion of Cav3 eliminated differences in local cAMP production and equilibrated the contractile response toAR. We conclude that basal cells possess tighter control of cAMP because of a higher degree of signaling microdomain organization. This provides varying levels of nanostructural control for cAMPmediated functional effects that orchestrate macroscopic, regional physiological differences within the heart. [ABSTRACT FROM AUTHOR]

Background: It is unclear whether the innate immune response represents a therapeutic target for organ protection strategies in cardiac surgery.Methods: A systematic review of trials of interventions targeting the inflammatory response to cardiac surgery reporting treatment effects on both innate immune system cytokines and organ injury was performed. The protocol was registered at the International Prospective Register of Systematic Reviews: CRD42020187239. Searches of the Cochrane Central Register of Controlled Trials, MEDLINE, and Embase were performed. Random-effects meta-analyses were used for the primary analysis. A separate analysis of individual patient data from six studies (n=785) explored sources of heterogeneity for treatment effects on cytokine levels.Results: Searches to May 2020 identified 251 trials evaluating 24 interventions with 20 582 participants for inclusion. Most trials had important limitations. Methodological limitations of the included trials and heterogeneity of the treatment effects on cytokine levels between trials limited interpretation. The primary analysis demonstrated inconsistency in the direction of the treatment effects on innate immunity and organ failure or death between interventions. Analyses restricted to important subgroups or trials with fewer limitations showed similar results. Meta-regression, pooling available data from all trials, demonstrated no association between the direction of the treatment effects on inflammatory cytokines and organ injury or death. The analysis of individual patient data demonstrated heterogeneity in the association between the cytokine response and organ injury after cardiac surgery for people >75 yr old and those with some chronic diseases.Conclusions: The certainty of the evidence for a causal relationship between innate immune system activation and organ injury after cardiac surgery is low. [ABSTRACT FROM AUTHOR]

Patients with atrial fibrillation (AF) who underwent percutaneous coronary intervention (PCI) are at elevated risk for bleeding and thromboembolic ischemic events. Currently, guidelines on antithrombotic treatment for these patients are based on weak consensus. We describe patterns and determinants of antithrombotic prescriptions in this population. The Antithrombotic Strategy Variability in Atrial Fibrillation and Obstructive Coronary Disease Revascularized with PCI Registry was an international observational study of 859 consecutive patients with AF who underwent PCI from 2009 to 2011. Patients were stratified by treatment at discharge with either dual antiplatelet therapy (DAPT; aspirin plus clopidogrel) or triple therapy (TT; warfarin plus DAPT). Bleeding and thromboembolism risks were assessed by the HAS-BLED and CHADS2 scores, respectively, and predictors of TT prescription at discharge were identified. Major adverse cardiovascular events and clinically relevant bleeding (Bleeding Academic Research Consortium score ≥2) at 1-year follow-up were compared across antithrombotic regimens. Compared with patients on DAPT (n = 488; 57%), those given TT (n = 371; 43%) were older, with higher CHADS2 scores, lower left ventricular ejection fraction, and more often had permanent AF, single-vessel coronary artery disease, and bare-metal stents. In multivariate analysis, increasing thromboembolic risk (CHADS2) was associated with a higher rate of TT prescription at discharge (intermediate vs low CHADS2: odds ratio 2.2, 95% confidence interval [CI] 2.0 to 3.3, p <0.01; high vs low CHADS2: odds ratio 1.6, 95% CI 2.6 to 4.3, p <0.01 for TT). However, there was no significant association between bleeding risk and TT prescription in the overall cohort or within each CHADS2 risk stratum. The rates of major adverse cardiovascular events were similar for patients discharged on TT or DAPT (20% vs 17%, adjusted hazard ratio 0.8, 95% CI 0.5 to 1.1, p = 0.19), whereas the rate of Bleeding Academic Research Consortium ≥2 bleeding was higher in patients discharged on TT (11.5% vs 6.4%, adjusted hazard ratio 1.8, 95% CI 1.1 to 2.9, p = 0.02). In conclusion, the choice of the intensity of antithrombotic therapy correlated more closely with the risk of ischemic rather than bleeding events in this cohort of patients with AF who underwent PCI. [ABSTRACT FROM AUTHOR]