Extracellular Vesicles From Epicardial Fat Facilitate Atrial Fibrillation.

BACKGROUND: The role of epicardial fat (eFat)-derived extracellular vesicles (EVs) in the pathogenesis of atrial fibrillation (AF) has never been studied. We tested the hypothesis that eFat-EVs transmit proinflammatory, profibrotic, and proarrhythmic molecules that induce atrial myopathy and fibrillation. METHODS: We collected eFat specimens from patients with (n=32) and without AF (n=30) during elective heart surgery. eFat samples were grown as organ cultures, and the culture medium was collected every 2 days. We then isolated and purified eFat-EVs from the culture medium, and analyzed the EV number, size, morphology, specific markers, encapsulated cytokines, proteome, and microRNAs. Next, we evaluated the biological effects of unpurified and purified EVs on atrial mesenchymal stromal cells and endothelial cells in vitro. To establish a causal association between eFat-EVs and vulnerability to AF, we modeled AF in vitro using induced pluripotent stem cell-derived cardiomyocytes. RESULTS: Microscopic examination revealed excessive inflammation, fibrosis, and apoptosis in fresh and cultured eFat tissues. Cultured explants from patients with AF secreted more EVs and harbored greater amounts of proinflammatory and profibrotic cytokines, and profibrotic microRNA, as well, than those without AF. The proteomic analysis confirmed the distinctive profile of purified eFat-EVs from patients with AF. In vitro, purified and unpurified eFat-EVs from patients with AF had a greater effect on proliferation and migration of human mesenchymal stromal cells and endothelial cells, compared with eFat-EVs from patients without AF. Last, whereas eFat-EVs from patients with and without AF shortened the action potential duration of induced pluripotent stem cell-derived cardiomyocytes, only eFat-EVs from patients with AF induced sustained reentry (rotor) in induced pluripotent stem cell-derived cardiomyocytes. CONCLUSIONS: We show, for the first time, a distinctive proinflammatory, profibrotic, and proarrhythmic signature of eFat-EVs from patients with AF. Our findings uncover another pathway by which eFat promotes the development of atrial myopathy and fibrillation.

Outcomes of isolated surgical aortic valve replacement in the era of transcatheter aortic valve implantation.

BACKGROUND AND AIMS: Until early into the 21st century, the only therapeutic option for aortic valve (AV) stenosis was surgical aortic valve replacement (AVR), but this changed with the introduction of transcatheter aortic valve implantation (TAVI). Our objective was to present the results of surgical AVR performed in low-risk patients in the era of TAVI, in a large tertiary medical center. METHODS: Data from low surgical risk patients (defined as Euroscore < 5) greater than 60 years of age, who underwent isolated AVR surgery between 2004 and 2018, were obtained from our departmental database. Of the 313 study patients, 110 (35%) underwent isolated AVR before 2010 (early period) and 203 patients (65%) underwent the same procedure from 2010 onward (late period). RESULTS: Mean age was 67 ± 5 years and 182 (58%) were male. Fifty-six patients (18%) had a unicuspid or bicuspid AV. Patient characteristics were similar between the early and late periods. There was no in-hospital or 30-day mortality throughout the entire cohort, with one case (0.3%) of postoperative stroke. Permanent pacemaker implantation was required in 2.2% (N = 7). Patients in the early period required significantly more re-exploration due to bleeding/tamponade (8.2% vs 1.5%; P = .008). Long-term mortality (1, 3, and 5 years) was higher in the early compared with the late period (2.7% vs 1%, 7.3% vs 3%, and 15.5% vs 3.4%, respectively; log-rank P = .005). CONCLUSIONS: Surgical AVR provides excellent short- and long-term results with low morbidity and mortality in low surgical risk patients. While patient characteristics did not change dramatically over the years, the long-term results were encouraging.

Metformin therapy in patients with diabetes mellitus is associated with a reduced risk of vasculopathy and cardiovascular mortality after heart transplantation.

BACKGROUND: Cardiac allograft vasculopathy (CAV) is a major cause of morbidity and mortality following heart transplantation (HT). Reduced cardiovascular mortality and morbidity have been reported in non-HT patients treated with metformin. Given the high prevalence of type 2 diabetes mellitus (T2DM) in HT patients, we investigated the association between metformin therapy and cardiovascular outcomes after HT. METHODS: The study population comprised 103 DM patients who had undergone HT between 1994 and 2018 and were prospectively followed-up. We excluded from the study patients with type 1 diabetes mellitus. Fifty-five HT patients (53%) in the cohort were treated with metformin. Clinical data were recorded on prospectively designed forms. The primary outcomes included CAV, survival, and the combined end-point of CAV or cardiovascular mortality. RESULTS: Kaplan-Meier survival analysis showed that the CAV rate at 20 years of follow-up was lower in DM patients treated with metformin than in those who were not (30 vs. 65%; log-rank p = 0.044). Similarly, the combined risk of CAV or cardiovascular mortality was lower in the metformin-treated patients than in those not receiving metformin (32 vs. 68%; log rank p = 0.01). Consistently, multivariate analysis adjusted for age and comorbidities showed that metformin therapy was independently associated with a significant 90% reduction (95% confidence interval 0.02-0.46, p = 0.003) in the risk for the development of CAV, and a 91% reduction (95% confidence interval 0.02-0.42; p = 0.003) in the risk for CAV or cardiovascular mortality. CONCLUSIONS: In diabetic HT patients, metformin therapy is independently associated with a significant reduction in the long-term risk for CAV and the combined end-point of CAV or cardiovascular mortality after HT.