Daily Cardiology Research Analysis

Postoperative atrial fibrillation (poAF) is AF occurring days after surgery, with a prevalence of 33% among patients undergoing open-heart surgery. The degree of postoperative inflammation correlates with poAF risk, but less is known about the cellular and molecular mechanisms driving postoperative atrial arrhythmogenesis. We performed single-cell RNA-seq comparing atrial nonmyocytes from mice with and without poAF, which revealed infiltrating CCR2+ macrophages to be the most altered cell type. Pseudotime trajectory analyses identified Il-6 as a gene of interest driving in macrophages, which we confirmed in pericardial fluid collected from human patients after cardiac surgery. Indeed, macrophage depletion and macrophage-specific Il6ra conditional knockout (cKO) prevented poAF in mice. Downstream STAT3 inhibition with TTI-101 and cardiomyocyte-specific Stat3 cKO rescued poAF, indicating a proarrhythmogenic role of STAT3 in poAF development. Confocal imaging in isolated atrial cardiomyocytes (ACMs) uncovered what we believe to be a novel link between STAT3 and CaMKII-mediated ryanodine receptor-2 (RyR2)-Ser(S)2814 phosphorylation. Indeed, nonphosphorylatable RyR2S2814A mice were protected from poAF, and CaMKII inhibition prevented arrhythmogenic Ca2+ mishandling in ACMs from mice with poAF. Altogether, we provide multiomic, biochemical, and functional evidence from mice and humans that IL-6-STAT3-CaMKII signaling driven by infiltrating atrial macrophages is a pivotal driver of poAF, which portends therapeutic utility for poAF prevention.

BACKGROUND: Longer-term outcomes are especially important for lower-risk patients with severe aortic stenosis undergoing transcatheter aortic valve replacement (TAVR) or surgical aortic valve replacement (SAVR). Additional randomized data comparing TAVR and SAVR have recently become available. OBJECTIVES: The purpose of this study was to perform an updated systematic review with conventional pairwise meta-analyses and pooled survival analyses using reconstructed time-to-event individual participant data (IPD) including the totality of randomized evidence comparing longer-term clinical outcomes after TAVR and SAVR in lower-risk patients. METHODS: The prespecified primary endpoint was all-cause death. Key secondary endpoints included stroke and the composite of death or disabling stroke. Cox proportional hazards frailty regression and restricted mean survival time models were fitted using reconstructed time-to-event IPD. In sensitivity analyses, proportional odds models were fitted with frailty terms. Conventional pairwise meta-analyses were performed under random and fixed effects assumptions. RESULTS: Six trials enrolling 5,341 lower-risk patients were included with 2,717 randomized to TAVR and 2,624 randomized to SAVR (weighted mean follow-up of 35.7 months). At 5 years in the pooled survival analyses of reconstructed time-to-event IPD, TAVR was associated with a 20% reduction in the hazard of all-cause death (HR: 0.80; 95% CI: 0.66-0.97; P = 0.02) and a 19% reduction in the hazard of all-cause death or disabling stroke (HR: 0.81; 95% CI: 0.68-0.96; P = 0.01) compared with SAVR. There was no difference in stroke (HR: 0.97; 95% CI: 0.74-1.26; P = 0.80). CONCLUSIONS: In lower-risk patients, TAVR was associated with a reduced hazard of death and death or disabling stroke compared with SAVR, while rates of stroke were equivalent. Most patients have not yet undergone 5-year follow-up, and so these findings may change as further longer-term data become available. The present data are informative for lower-risk patients and treating clinicians, but further randomized trials and longer-term follow-up are required, particularly in younger patients.

With encouraging early experience, ex vivo machine perfusion (MP) systems are increasingly employed in heart transplantation. In this study, utilizing a national registry database, 2 separate analyses were performed to evaluate the effects of MP on graft preservation time (total n = 22,794; n = 308 with MP) and donor age (total n = 22,581; n = 95 with MP) in donation after brain death (DBD) heart transplantation. The cohort was stratified based on total preservation time (<4 and ≥4 hours) and donor age (<45 and ≥45 years). During the study period, the use of MP in isolated DBD heart transplantation significantly increased. Utilization of MP was associated with improved 90-day post-transplant survival among the recipients with preservation times ≥4 hours or donor age ≥45 years, compared to cases where MP was not utilized. These findings positively highlight the potential utility of ex vivo MP in DBD heart transplantation involving longer graft preservation times and in older donors.