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.

While patients with type 2 diabetes mellitus (T2DM) and heart failure (HF) are frequently prescribed dipeptidyl peptidase-4 inhibitors (DPP-4is), emerging evidence suggests glucagon-like peptide-1 receptor agonists may offer improved outcomes. This study compared the effectiveness of tirzepatide versus DPP-4i in patients with T2DM and HF. Adults with T2DM and HF treated between 2022 and 2025 were included. Cohort A comprised patients receiving tirzepatide, and Cohort B comprised patients receiving DPP-4is. Prespecified subgroup analyses were conducted for HF with reduced ejection fraction (HFrEF) and HF with non-reduced ejection fraction (HFnonrEF). Propensity score matching was performed across demographic, clinical, medication, and laboratory covariates. Outcomes included all-cause mortality, hospitalization, HF exacerbation, and major adverse cardiovascular events (MACE). After matching, 8,956 patients were included in each group. Tirzepatide therapy was associated with a lower hazard of all-cause mortality (HR 0.32, 95% CI 0.25-0.42), hospitalizations (HR 0.53, 95% CI 0.48-0.57), HF exacerbation (HR 0.37, 95% CI 0.33-0.42) and MACE (HR 0.79, 95% CI 0.73-0.84). Sub-group analyses for HFrEF and HFnonrEF demonstrated similar trends. In conclusion, among patients with T2DM and HF, treatment with tirzepatide was associated with markedly lower hazards of mortality, hospitalization, HF exacerbation, and MACE compared to DPP-4 inhibitors.