Daily Cardiology Research Analysis

AIMS: A comprehensive understanding of the genome-wide regulatory landscape of the cardiac tissues post-myocardial infarction (MI) is still lacking. We therefore integrated single-cell RNA sequencing (scRNA-seq) and single-cell for transposase-accessible chromatin sequencing (scATAC-seq) to elucidate the epigenetic landscape of the heart post-MI. METHODS AND RESULTS: We established MI mice through ligation of the left anterior descending coronary artery, and obtained cardiac tissues from mice at 1-, 3-, 7-, and 14-days post-MI. Integrative analyses of the scRNA-seq and scATAC-seq data revealed the presence of two novel fibroblast subpopulations in the cardiac tissues of MI mice, termed GATA-binding protein 5/ISL LIM Homeobox 1 (GATA5/ISL1)+ fibroblasts and GLI family zinc finger 3 (Gli3)high fibroblasts. The GATA5/ISL1+ fibroblasts were characterized by fibroblast and cardiomyocyte signatures and were found to play a crucial role in cardiac repair post-MI. Moreover, adenoviral-mediated overexpression of GATA5 and ISL1 ameliorated cardiac function and attenuated myocardial fibrosis in the MI mice.

AIMS: Platelets contain non-coding RNAs (ncRNAs), and their measurement may complement platelet aggregometry. METHODS AND RESULTS: In the community-based Bruneck study (n = 338), we generated platelet-rich plasma (PRP), platelet-poor plasma (PPP), and platelets. PRP was subjected to aggregometry using various agonists and processed to platelet releasates thereafter. Releasates, PPP, and platelets underwent real-time polymerase chain reactions to measure ncRNAs. Platelet ncRNA release appeared agonist-specific, dose-dependent, and inhibited by aspirin. Collagen triggered the strongest release for most ncRNAs, whereas miR-150 was hyperresponsive to ADP, and miR-21 was hyperresponsive to arachidonic acid. Comparing the dynamic range of ncRNA release to aggregation, aggregation reached a maximum at high agonist concentrations, while ncRNAs continued to rise. Cohort-wide associations showed that inflammation parameters like neutrophil counts and C-reactive protein correlated inversely with platelet aggregation and ncRNA release. Similarly, a high leucocyte-derived RNA content in isolated platelets correlated inversely with aggregation. Inverse correlations were absent in aspirin users. Through experiments on plasma-free platelet releasates and platelets, including size-exclusion chromatography, ultracentrifugation, and degradation assays, we discovered that microRNAs and YRNAs are carried by proteins and readily released, while circular-, long non-coding-, and messenger RNAs are carried by vesicles and preferentially retained. Finally, we assessed ncRNA responses to short- and long-term dual anti-platelet therapy (DAPT) in plasma from 265 patients with acute myocardial infarction (AMI) of the PACMAN-AMI trial. Most of the DAPT effect was already achieved by 4 weeks, with a further reduction at 52 weeks, revealing a short- and long-term DAPT effect not captured by aggregometry. CONCLUSION: Inflammation and leucocyte-derived RNAs in isolated platelets are associated with reduced platelet responses ex vivo, potentially reflecting exhaustion through pre-activation in vivo. We show that protein-bound ncRNAs are readily released from platelets, whereas vesicle-bound ncRNAs are preferentially retained. We highlight the potential of ncRNAs as biomarkers complementing aggregometry.

IMPORTANCE: Both myocardial infarction (MI) and anemia have deleterious effects on health-related quality of life (QOL). Red blood cell (RBC) transfusion may improve QOL after MI by relieving symptoms and/or increasing functional capacity. OBJECTIVE: To evaluate whether a liberal transfusion strategy compared with a more restrictive transfusion strategy affects QOL in patients with MI and anemia. DESIGN, SETTING, AND PARTICIPANTS: This analysis of QOL as a prespecified secondary outcome of the Myocardial Ischemia and Transfusion (MINT) trial, a randomized clinical trial comparing a liberal vs restrictive RBC transfusion strategy, included participants from 144 sites across 6 countries. Hospitalized adults with acute MI and anemia (hemoglobin [Hb] less than 10 g/dL). The MINT trial randomized 3504 patients, and this analysis included those who had QOL data collected and those who died before the 30-day follow-up period. Data were collected from April 2017 to April 2023, and data were analyzed from February 2024 to January 2025. INTERVENTIONS: The MINT trial randomized patients to a restrictive (Hb of 7 to 8 g/dL) or a liberal (Hb of less than 10 g/dL) RBC transfusion strategy. MAIN OUTCOMES AND MEASURES: QOL was measured using the EQ-5D-5L 30 days after randomization. RESULTS: Of 2844 included patients, 1551 (54.5%) were male, and the mean (SD) age was 71.9 (11.5) years. A total of 2525 (88.8%; 1254 [49.7%] in the restrictive group and 1271 [50.3%] in the liberal group) had QOL data, and 319 (11.2%) died before 30-day follow-up. Overall, there were no differences in mean or median scores for any EQ-5D-5L QOL outcome between assigned transfusion strategies at 30 days postrandomization. Although a higher percentage of patients in the liberal compared with the restrictive transfusion group reported no problems compared with any problem in usual activities (506 of 1268 [39.9%] vs 473 of 1247 [37.9%]), mobility (474 of 1270 [37.3%] vs 460 of 1254 [36.7%]), and self-care (858 of 1271 [67.5%] vs 803 of 1254 [64.0%]) domains, none of these differences were statistically significant. Adjusted mixed-effects linear regressions showed no association between assigned transfusion strategy and mean differences in any QOL outcome. Adjusted regressions in several prespecified subgroups showed an association between a liberal transfusion strategy and better QOL scores in domains related to functional capacity, but the effects were only statistically significant in patients with a history of heart failure (Health Today rating: β, 2.06 [95% CI, -0.23 to 4.35] vs -1.44 [95% CI, -3.81 to 0.92]; P = .04). CONCLUSIONS AND RELEVANCE: This secondary analysis of the MINT trial found that in patients with MI and anemia, a liberal transfusion strategy compared with a restrictive transfusion strategy did not affect QOL outcomes 30 days after randomization. This suggests that higher Hb levels maintained with RBC transfusion may not offer significant benefits to QOL overall in patients with MI and anemia. Additional studies may be useful for further examining and validating transfusion's effect on QOL in patients with MI and heart failure. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02981407.