Contemporary data have shown a decrease in the ischaemic stroke risk associated with female sex in patients with atrial fibrillation (AF). We evaluated temporal trends in the predictive value of a non-sex CHA₂DS₂-VASc risk score (ie. CHA₂DS₂-VA). The FinACAF study covers all patients with incident AF between 2007 and 2018 in Finland from all levels of care. The CHA₂DS₂-VA score was compared with the CHA₂DS₂-VASc using continuous and category-based net reclassification indices (NRIs), integrated discrimination improvement (IDI), c-statistics and decision curve analyses. We identified 144,879 anticoagulant naïve patients with new-onset AF between 2007 and 2018 (49.9% women; mean age 72.1 years), of whom 3936 (2.7%) experienced ischaemic stroke during one-year follow-up. Based on both continuous and category-based NRIs, the CHA₂DS₂-VA score was inferior to the CHA₂DS₂-VASc in the early years (−0.333 (95% CI −0.411 to −0.261) and −0.118 (95% CI −0.137 to −0.099), respectively). However, the differences attenuated over time, and by the end of the study period, the continuous NRI became non-significant (−0.093 (95% CI −0.165 to 0.032)), whereas the category-based NRI reversed in favor of the CHA₂DS₂-VA (0.070 (95% CI 0.048–0.087)). The IDI was non-significant in early years (0.0009 (95% CI −0.0024 to 0.0037)), but over time became statistically significant in favor of the CHA₂DS₂-VA score (0.0022 (95% CI 0.0001–0.0044)). The Cox models fitted with the CHA₂DS₂-VA and the CHA₂DS₂-VASc scores exhibited comparable discriminative capability in the beginning of the study (p-value 0.63), but over time marginal differences in favor of the CHA₂DS₂-VA score emerged (p-value 0.0002). In 2007–2008 (when females had higher AF-related stroke risks than males), the CHA₂DS₂-VASc score outperformed the CHA₂DS₂-VA score, but the initial differences between the scores attenuated over time. By the end of the study period in 2017–2018 (with limited/no sex differences in AF-related stroke), there was marginal superiority for the CHA₂DS₂-VA score. This work was supported by the 10.13039/100010133 Aarne Koskelo Foundation , The Finnish Foundation for Cardiovascular Research, The Finnish State Research funding, and Helsinki and Uusimaa Hospital District research fund.

Aims : Bone marrow-derived mononuclear cell (BM-MNC) therapy may improve myocardial recovery in patients following acute myocardial infarction (AMI), though existing trial results are inconsistent. Methods and results : Originally an open-label, multicentre Phase III trial, BAMI was designed to demonstrate the safety and efficacy of intracoronary infusion of BM-MNCs in reducing the time to all-cause mortality in patients with reduced left ventricular ejection fraction (LVEF, ≤45%) after primary angioplasty (PPCI) for ST-elevation AMI. Unexpectedly low recruitment means the trial no longer qualifies as a hypothesis-testing trial, but is instead an observational study with no definitive conclusions possible from statistical analysis. In total, 375 patients were recruited: 185 patients were randomized to the treatment arm (intracoronary infusion of BM-MNCs 2–8 days after PPCI) and 190 patients to the control arm (optimal medical therapy). All-cause mortality at 2 years was 3.26% [6 deaths; 95% confidence interval (CI): 1.48–7.12%] in the BM-MNC group and 3.82% (7 deaths; 95% CI: 1.84–7.84%) in the control group. Five patients (2.7%, 95% CI: 1.0–5.9%) in the BM-MNC group and 15 patients (8.1%, CI : 4.7–12.5%) in the control group were hospitalized for heart failure during 2 years of follow-up. Neither adverse events nor serious adverse events differed between the two groups. There were no patients hospitalized for stroke in the control group and 4 (2.2%) patients hospitalized for stroke in the BM-MNC group. Conclusions : Although BAMI is the largest trial of autologous cell-based therapy in the treatment of AMI, unexpectedly low recruitment and event rates preclude any meaningful group comparisons and interpretation of the observed results.

Female sex has been linked with higher risk of ischaemic stroke (IS) in atrial fibrillation (AF), but no prior study has examined temporal trends in the IS risk associated with female sex. The registry-linkage Finnish AntiCoagulation in Atrial Fibrillation (FinACAF) study included all patients with AF in Finland from 2007 to 2018. Ischaemic stroke rates and rate ratios were computed. Overall, 229 565 patients with new-onset AF were identified (50.0% women; mean age 72.7 years). The crude IS incidence was higher in women than in men across the entire study period (21.1 vs. 14.9 events per 1000 patient-years, P < .001), and the incidence decreased both in men and women. In 2007–08, female sex was independently associated with a 20%–30% higher IS rate in the adjusted analyses, but this association attenuated and became statistically non-significant by the end of the observation period. Similar trends were observed when time with and without oral anticoagulant (OAC) treatment was analysed, as well as when only time without OAC use was considered. The decrease in IS rate was driven by patients with high IS risk, whereas in patients with low or moderate IS risk, female sex was not associated with a higher IS rate. The association between female sex and IS rate has decreased and become non-significant over the course of the study period from 2007 to 2018, suggesting that female sex could be omitted as a factor when estimating expected IS rates and the need for OAC therapy in patients with AF. Temporal trends in the association between female sex and ischaemic stroke among patients with atrial fibrillation in Finland from 2007 to 2018.

Atrial fibrillation (AF) is a major cause of ischemic stroke and the number of AF patients is increasing. Thus, up-to-date multifaceted data about the characteristics of AF patients, their treatments, and outcomes are urgently needed. The Finnish anticoagulation in atrial fibrillation (FinACAF) study has collected comprehensive data on all Finnish AF patients from 1st January 2004 to 31st December 2018. The aim of this paper is to describe the study rationale, the process of integrating data from the applied resources and to define the study cohort. Using national unique personal identification number, individual patient data is linked from nationwide health care registries (primary, secondary, and tertiary care), drug purchases, education, and socio-economic status as well as places of domicile, incomes, and taxes. Six regional laboratory databases (~ 282,000, 77% of the patients) are also included. The study cohort comprises of a total of 411,000 patients. Since the introduction of the national primary care register in 2012, 9% of all AF patients were identified outside hospital care registers. The prevalence of AF in Finland—4.1% of whole population—is for the first time now established. The FinACAF study allows a unique possibility to investigate the epidemiology and socio-medico-economic impact of AF as well as the cost effectiveness of different AF management strategies in a completely unselected, nationwide population. This article provides the rationale and design of the study together with a summary of the characteristics of the cohort.

Oxidized phospholipids and microRNAs (miRNAs) are increasingly recognized to play a role in endothelial dysfunction driving atherosclerosis. NRF2 transcription factor is one of the key mediators of the effects of oxidized phospholipids, but the gene regulatory mechanisms underlying the process remain obscure. Here, we investigated the genome-wide effects of oxidized phospholipids on transcriptional gene regulation in human umbilical vein endothelial cells and aortic endothelial cells with a special focus on miRNAs. We integrated data from HiC, ChIP-seq, ATAC-seq, GRO-seq, miRNA-seq, and RNA-seq to provide deeper understanding of the transcriptional mechanisms driven by NRF2 in response to oxidized phospholipids. We demonstrate that presence of NRF2 motif and its binding is more prominent in the vicinity of up-regulated transcripts and transcriptional initiation represents the most likely mechanism of action. We further identified NRF2 as a novel regulator of over 100 endothelial pri-miRNAs. Among these, we characterize two hub miRNAs miR-21-5p and miR-100-5p and demonstrate their opposing roles on mTOR, VEGFA, HIF1A, and MYC expressions. Finally, we provide evidence that the levels of miR-21-5p and miR-100-5p in exosomes are increased upon senescence and exhibit a trend to correlate with the severity of coronary artery disease. Altogether, our analysis provides an integrative view into the regulation of transcription and miRNA function that could mediate the proatherogenic effects of oxidized phospholipids in endothelial cells.