Daily Cardiology Research Analysis

Access to hypertension care remains insufficient, particularly in remote rural areas in resource-limited settings. Community health workers (CHWs), lay providers living in the communities they serve, may help close this gap, but the effectiveness and safety of lay CHW-led hypertension care-including independent initiation and titration of medication-remain uncertain. We conducted a 1:1 cluster-randomized trial nested within the Community-Based Chronic Care Lesotho (ComBaCaL) cohort study in 103 rural villages in Lesotho. Following community-based hypertension screening, 547 nonpregnant adults with blood pressure (BP) ≥140/90 mm Hg were enrolled (274 control and 273 intervention). In intervention clusters, lay CHWs independently prescribed and titrated a fixed-dose combination of amlodipine and hydrochlorothiazide, guided by a mobile clinical decision support system. In control clusters, participants were referred to health facilities for standard care. The primary objective was to assess the effectiveness and safety of lay CHW-led care, with the primary outcome defined as BP <140/90 mm Hg at 12 months. In the intention-to-treat analysis (543 participants with 4 exclusions owing to intercurrent pregnancy), BP control was achieved by 156/271 (58%) versus 130/272 (48%) in intervention and control arms, respectively (adjusted odds ratio 1.52, 95% confidence interval 1.01 to 2.29, P = 0.046). A predefined complete case analysis yielded consistent results. No relevant differences in safety outcomes were observed. Among people with uncontrolled hypertension, lay CHW-led, CDSS-supported care was safe and more effective than referral to facility-based professional care. These findings support expanding first-line hypertension management by lay CHWs in remote, resource-limited settings. Clinicaltrials.gov registration: NCT05684055 .

BACKGROUND AND AIMS: Fulminant myocarditis (FM) is a life-threatening inflammatory cardiomyopathy with high mortality. Soluble ST2 (sST2), traditionally regarded as a decoy receptor for interleukin-33 (IL-33), is markedly elevated in FM, yet its mechanistic and translational roles remain unclear. METHODS: A Coxsackievirus B3-induced FM mouse model was used to define the cellular source and function of sST2 through histological, molecular, and integrated single-cell and single-nucleus transcriptomic analyses. Cardiomyocyte responses were assessed in neonatal murine cardiomyocytes and human engineered heart tissues. The therapeutic efficacy and safety of sST2-neutralizing antibodies were evaluated in vivo, with clinical relevance examined in a cohort of FM patients. RESULTS: sST2 originated predominantly from infiltrating CCR2+ macrophages in FM hearts and aggravated cardiac damage by amplifying inflammation, mitochondrial dysfunction, and contractile failure. Mechanistically, sST2 acted independently of IL-33. It entered cardiomyocytes via IGF2R and bound the transcription factor YY1, preventing its nuclear translocation and repressing mitochondrial electron transport chain gene expression, thereby reducing ATP synthesis. Neutralizing antibodies targeting sST2 effectively restored mitochondrial function, improved hemodynamics, and reduced mortality without evident short-term systemic toxicity. Integrated single-cell and single-nucleus transcriptomic analyses revealed broad therapeutic effects across cardiomyocytes, fibroblasts, endothelial cells, and macrophages. Combined glucocorticoid and anti-sST2 therapy provided additive benefit. Clinically, elevated plasma sST2 independently predicted 30-day mortality or extracorporeal membrane oxygenation requirement in FM patients, outperforming N-terminal pro-B-type natriuretic peptide and cardiac troponin I for prognostic discrimination. CONCLUSIONS: sST2 drives FM by disrupting cardiomyocyte mitochondrial homeostasis independently of IL-33 and represents both a clinically prognostic biomarker and a therapeutic target.

IMPORTANCE: Cardiovascular-kidney-metabolic (CKM) syndrome represents a syndromic continuum encompassing overlapping cardiovascular, kidney, and metabolic dysfunction. Hypertension is a central driver in the pathogenesis of CKM syndrome, promoting both kidney and metabolic deterioration, but little is known about the benefits of intensive blood pressure (BP) control across CKM syndrome stages. OBJECTIVE: To evaluate CKM syndrome stage-specific outcomes, safety, and net clinical benefits associated with a comprehensive intensive BP intervention. DESIGN, SETTING, AND PARTICIPANTS: This is a post hoc, secondary analysis of a cluster randomized clinical trial, the China Rural Hypertension Control Project (CRHCP), which was conducted between May 2018 and March 2023. Participants were adults aged 40 years or older with hypertension and CKM syndrome stages 2 to 4, which were defined using standard criteria. Stage 2 indicates that the patient has a metabolic risk factor; stage 3, subclinical cardiovascular disease or predicted 10-year risk of 20% or greater; and stage 4, clinical cardiovascular disease. In this analysis, participants had a median (IQR) follow-up of 3.02 (2.97-3.06) years. Data analysis was conducted from November 2024 to June 2025. INTERVENTION: The comprehensive BP control strategy targeted a systolic BP less than 130 mm Hg and a diastolic BP less than 80 mm Hg. The intervention was delivered by trained nonphysician practitioners. MAIN OUTCOMES AND MEASURES: The primary clinical outcome was a composite of major adverse cardiovascular events (stroke, myocardial infarction, heart failure, or cardiovascular death). Safety outcomes included hypotension, syncope, injurious falls, and kidney adverse events. A quantitative benefit-harm analysis was conducted to estimate net benefit associated with the intervention. RESULTS: Among 33 736 participants (mean [SD] age, 63.0 [9.2] years; 20 677 [61.3%] women), 18 662 (55.3%) had stage 2 CKM syndrome (of whom 9526 [51.0%] received the intervention), 7984 (23.7%) had stage 3 (of whom 4032 [50.5%] received the intervention), and 7090 (21.0%) had stage 4 (of whom 3713 [52.4%] received the intervention). Treatment outcomes were generally consistent across CKM syndrome stages. Intensive BP control was associated with reduced cardiovascular events across all stages: in stage 2, the hazard ratio (HR) was 0.61 (95% CI, 0.50-0.73); in stage 3, the HR was 0.71 (95% CI, 0.58-0.84); and in stage 4, the HR was 0.67 (95% CI, 0.58-0.76). The risk of all-cause mortality was also lower in stage 2 (HR, 0.73; 95% CI, 0.57-0.90) and stage 3 (HR, 0.82; 95% CI, 0.68-0.96) but not in stage 4 (HR, 1.02; 95% CI, 0.84-1.20). Risk of hypotension increased across all stages (relative risk range, 1.79-2.34), while other adverse events, including kidney events, were similar between groups, despite some numerical variation across stages. Net benefits were favorable: stage 2, 1.58 (95% CI, 1.53-1.62); stage 3, 2.53 (95% CI, 2.42-2.64); and stage 4, 2.15 (95% CI, 2.04-2.26). CONCLUSIONS AND RELEVANCE: In this post hoc analysis of a cluster randomized clinical trial, a comprehensive intervention targeting BP less than 130/80 mm Hg demonstrated a favorable benefit-to-harm profile across CKM syndrome stages, with no clear heterogeneity across CKM syndrome stages. These findings provide the first trial-based evidence to guide CKM syndrome management and support scalable strategies for this high-risk, multimorbid population. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03527719.