Daily Cardiology Research Analysis

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is increasingly acknowledged as a major public health concern due to its complex pathophysiology, which involves neuroinflammation and sympathetic activation. The crosstalk between the heart and hypothalamic microglia in HFpEF, particularly the role of small extracellular vesicles (sEVs), remains insufficiently explored. METHODS AND RESULTS: We constructed an HFpEF model in mice by combining a long-term high-fat diet with the nitric oxide synthase inhibitor l-NAME (N[ω]-nitro-l-arginine methyl ester). These mice exhibited microglial activation and hypothalamic inflammation. Microglial depletion with PLX3397 suppressed sympathetic activity and improved cardiac dysfunction in HFpEF. sEVs derived from the myocardium of HFpEF mice induced a proinflammatory M1 phenotype in microglia, leading to hypothalamic inflammation and sympathetic activation. Intraperitoneal injection of the sEV biogenesis inhibitor GW4869 reversed these changes in HFpEF mice. Similar pathological changes were observed in BV2 microglia treated with sEVs isolated from palmitic acid-treated HL-1 cardiomyocytes. Bioinformatic and RT-qPCR analyses revealed a notable upregulation of miR-200c-3p in sEVs derived from both HFpEF myocardial tissue and palmitic acid-treated HL-1 cardiomyocytes, as well as in microglia. A cardiomyocyte-specific miR-200c-3p sponge inhibited microglial activation, hypothalamic inflammation, and sympathetic activation in HFpEF mice. Conversely, a miR-200c-3p mimic exacerbated proinflammatory responses in BV2 cells, while a miR-200c-3p inhibitor prevented the transition to a proinflammatory phenotype. The antiinflammatory protein DUSP1 (dual-specificity phosphatase 1) was validated as a potential downstream target of miR-200c-3p in microglia. CONCLUSIONS: Our study reveals that HFpEF prompts cardiomyocytes to release sEVs enriched with miR-200c-3p, leading to hypothalamic inflammation and evoking sympathetic outflow, which in turn exacerbates cardiac dysfunction. Focusing on sEV-mediated communication between cardiomyocytes and microglia may offer a new therapeutic approach for HFpEF.

BACKGROUND: Previously developed machine-learning (ML)-based decision support tools for patients presenting with suspected non-ST-segment elevation myocardial infarction (NSTEMI) remain proprietary, limiting public accessibility and clinical adoption. METHODS: To address this limitation, we used two international prospective multicentre diagnostic studies for model derivation and internal validation, and one large prospective European study for external validation, evaluating two open-access ML-based models. The derivation and internal validation cohort comprised 8763 patients (34% women) enrolled across 13 and 12 sites, respectively, in Switzerland, Spain, the Czech Republic, Poland, Belgium, Germany, the UK, Italy and the USA between April 2006 and September 2020, and between August 2011 and June 2013. The external validation cohort included 4882 patients (41% women) from Germany. Patients were excluded if they had a ST-segment elevation myocardial infarction, unclear final diagnosis, renal failure or an absent 12-lead electrocardiogram. A single-high-sensitivity cardiac troponin (hs-cTn) model incorporated information available at emergency department presentation, while a serial-hs-cTn model additionally utilised the second hs-cTn measurement and the time interval between samples. The final diagnosis of NSTEMI was centrally adjudicated by two independent cardiologists in all studies. The diagnostic performance of both models was compared with the European Society of Cardiology (ESC) hs-cTn-0/1 h-algorithm. This study is registered with ClinicalTrials.gov, numbers NCT00470587 and NCT03111862. FINDINGS: The single-hs-cTn- and serial-hs-cTn model demonstrated excellent discrimination in internal validation, and external validation, with an area under the receiver-operating-characteristic curve of 0.94 [0.92-0.95], and 0.91 [0.90-0.92], and 0.96 [0.96-0.97], and 0.96 [0.95-0.97], respectively. Calibration was good across all datasets. Compared to the ESC-0/1 h algorithm, FAST-NSTEMI provided comparable safety metrics while triaging more patients to rule-out or rule-in. Triage efficacy improved substantially with the single-hs-cTn model (internal validation 52.4% versus 29.8%, external validation 32.1% versus 14.9%) and modestly with the serial-hs-cTn model (internal validation 80.8% versus 76.9%, external validation 77.1% versus 72.8%, all p < 0.01). INTERPRETATION: The FAST-NSTEMI ML-models offer excellent discrimination, good calibration, high safety, and improved triage efficacy compared to the ESC 0/1 h-algorithm. Further external validation or prospective implementations are warranted to confirm the generalisability of the findings and the clinical utility of the models. FUNDING: Swiss National Science Foundation and Swiss Heart Foundation.

IMPORTANCE: Efforts to improve heart failure (HF) outcomes have focused on prescribing guideline-directed medical therapy at hospital discharge. Whether new prescriptions translate to sustained medication use after HF hospitalization is largely unknown. OBJECTIVE: To characterize medication-use patterns following HF hospitalizations. DESIGN, SETTING, AND PARTICIPANTS: A cohort study of patients in a regional US health system discharged home after an HF hospitalization between July 1, 2017, and March 30, 2023. Data were analyzed from August 2024 to February 2026. MAIN OUTCOMES AND MEASURES: Medications of interest included β-blockers, renin-angiotensin system inhibitors (RASis), mineralocorticoid receptor antagonists (MRAs), and sodium-glucose co-transporter 2 inhibitors (SGLT2is). New prescriptions were identified by in-hospital administration or discharge medication orders. Using electronic health records linked to pharmacy dispensation records, medication initiation (prescription dispensation) and primary nonadherence (discharge prescriptions that were not filled) were assessed at 7 and 90 days postdischarge. Adherence (proportion of days covered ≥80%) and persistence (continuous days' supply) were assessed over 6 months postdischarge. RESULTS: This cohort study included 6111 patients with HF hospitalizations (mean [SD] age, 69.9 [13.6] years; 37.3% female [2277]) of whom 51% of were prescribed at least 1 new HF medication at discharge. At admission, 58.1% of patients were prescribed β-blockers (3549), 41.4% RASis (2530), 16.3% MRAs (997), and 4.9% SGLT2is (299); and at discharge, use increased to 73.3% (4481), 52.9% (3232), 28.5% (1740), and 9.0% (548), respectively. Primary nonadherence was observed in 51% (972 of 1904) of new prescriptions for β-blockers, 48% (659 of 1361) for RASis, 39% (482 of 1225) for MRAs, and 35% (134 of 383) for SGLT2is. Thus, of 4873 new discharge prescriptions, only 54% (2626) were initiated within 7 days of discharge and an additional 20% (954) had delayed initiation, between 7 and 90 days postdischarge. At 6 months, persistence to β-blockers was 70% (3127 of 4481), for RASis was 60% (1952 of 3232), for MRAs was 55% (961 of 1740), and for SGLT2is was 56% (306 of 548). As a result, at 6 months, only 42% (2188 of 5183) of patients were adherent and 51% (2620 of 5183) were persistent to all HF medications used at discharge. CONCLUSIONS AND RELEVANCE: This cohort study found that following HF hospitalization, most new guideline-directed medical therapy prescriptions went unfilled. Moreover, most newly initiated prescriptions did not persist at 6 months, suggesting a need to develop interventions to support patients' medication use beyond the initial prescription at discharge.