Daily Cardiology Research Analysis

BACKGROUND: We aimed to characterize the genetic architecture of resistant hypertension (rHTN), which affects up to 18% of hypertensive individuals and increases cardiovascular disease risk. METHODS: We conducted a genome-wide association study on rHTN, defined as use of 3 or more concomitant antihypertensive drugs for at least 6 months without reaching blood pressure target (in the 3-drug case), comparing it to controlled hypertension (cHTN), in which persons on 1 or 2 antihypertensives for at least 6 months reach target BP after 30 days of therapy initiation. The study included 23 508 rHTN cases and 24 393 cHTN controls, identified through drug prescription and blood pressure data from Iceland (deCODE), the UK (UK Biobank), and the US (eMERGE). Further analyses included comparisons with all hypertensive individuals (diagnosed with RESULTS: We found 24 rHTN variants, 17 of which used published BP variants as prior. Fifteen risk-increasing rHTN alleles are associated with lower serum potassium and increased hyperaldosteronism risk. Individuals with rHTN and cHTN had lower potassium levels before drug therapy than normotensives. All antihypertensive drug classes increased potassium levels in cHTN, while only aldosterone antagonists increased levels in rHTN. Mendelian randomization analysis was consistent with rHTN being a manifestation of hyperaldosteronism. The variant conferring the largest effect on both rHTN and hyperaldosteronism is a stop-gain variant in CONCLUSIONS: We discovered sequence variants that have different effects on rHTN and cHTN. Our study indicates that genetically determined hyperaldosteronism may be largely accountable for rHTN.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) arises from chronic cardiometabolic and vascular stress and is increasingly recognized as an inflammatory syndrome with immune dysregulation. Regulatory T cells (Tregs) are critical modulators of cardiovascular inflammation, yet the mechanisms driving Treg dysfunction in HFpEF remain poorly defined. stromal interaction molecule 1 (STIM1)-dependent calcium signaling is a key stress-responsive pathway in immune cells; however, its role in Treg maladaptation during HFpEF remains unknown. METHODS: Circulating Tregs from patients with and without HFpEF were analyzed for abundance, STIM1 expression, and stress-associated signaling pathways. To establish causality, mice with Treg-specific deletion of STIM1 (Treg RESULTS: Patients with HFpEF exhibited reduced circulating Treg numbers accompanied by increased STIM1 expression and activation of apoptotic, inflammatory, and ER stress pathways, consistent with stress-induced Treg instability. In vivo, control mice developed features of HFpEF, including diastolic dysfunction with preserved ejection fraction, hypertension, metabolic dysregulation, endothelial dysfunction, cardiac fibrosis, and impaired exercise tolerance. In contrast, Treg CONCLUSIONS: STIM1-dependent stress signaling drives maladaptive Treg instability that amplifies cardiovascular inflammation and HFpEF progression. These findings identify Treg STIM1 as a key driver of immune-mediated HFpEF progression and provide mechanistic evidence from humans to mice supporting immune-targeted therapeutic strategies.

BACKGROUND: Testosterone therapy (TT) is increasingly initiated outside classical hypogonadism, but long-term cardiovascular safety in this context remains uncertain. We assessed whether TT initiation without evidence of hypogonadism is associated with higher long-term cardiovascular risk than TT initiation with evidence of hypogonadism. METHODS: In this global retrospective real-world cohort study, men aged 30-75 years initiating TT were identified from secondary, de-identified structured EHR data from 123 healthcare organisations. A prespecified 3-year pre-index washout excluded prior TT and major cardiovascular/thromboembolic events. Men initiating TT without evidence of hypogonadism were compared with those with evidence of hypogonadism using 1:1 propensity-score matching. The primary outcome was major adverse cardiovascular events (MACE); secondary outcomes included separately all-cause mortality, myocardial infarction, ischaemic stroke, cardiac arrest, and heart failure. Acute appendicitis served as a negative-control outcome. FINDINGS: Among 358,957 TT initiators, 127,152 (35.4%) had no evidence of hypogonadism. After matching, 113,554 pairs were followed for up to 10 years. TT without evidence of hypogonadism was associated with higher risk of MACE (16.53% vs 11.83%; HR 1.51, 1.45-1.56) and all-cause mortality (HR 1.90, 1.79-2.00), with higher risks of ischaemic stroke (HR 1.23, 1.14-1.33), cardiac arrest (HR 1.41, 1.23-1.61), and heart failure (HR 1.32, 1.26-1.39). Race-stratified estimates were directionally consistent but varied in magnitude. INTERPRETATION: The cardiovascular safety of TT appears context-dependent and less favourable when treatment is initiated without evidence of hypogonadism, with clinically relevant heterogeneity across race/ethnicity, supporting biologically informed prescribing and cardiovascular risk surveillance. FUNDING: Deutsche Forschungsgemeinschaft, Schleswig-Holstein Excellence-Chair Program, and Region Stockholm.