ABSTRACT NUMBER: ESOC2026A1362 GENETICALLY PROXIED INHIBITION OF ANGIOTENSINOGEN SYNTHESIS AND CARDIO- AND CEREBROVASCULAR OUTCOMES

Abstract Background and aims Angiotensinogen synthesis inhibitors have demonstrated promising results in hypertension trials, but if they could lower the burden of cardiovascular disease remains unknown. Here, we investigate associations between genetic variants mimicking the action of angiotensinogen inhibitors and cardio- and cerebrovascular phenotypes. Methods We performed drug target Mendelian Randomization using minimally correlated variants in the AGT locus associated with circulating angiotensinogen levels (N=47,745) or liver AGT expression (N=1,183). Our primary outcomes included the clinical endpoints of coronary artery disease (CAD, 210,842 cases, 1,167,328 controls), stroke (110,182 cases, 1,503,898 controls) and heart failure (207,306 cases, 2,151,210 controls). We additionally explored associations with ischemic and hemorrhagic stroke subtypes, vascular dementia and imaging features related to carotid atherosclerosis and cerebral small vessel disease. Results Mirroring the effects of angiotensinogen inhibitors in clinical trials, our 40-variant AGT instrument was associated with lower systolic (SBP, beta: -0.597) and diastolic blood pressure (beta: -0.396), as well as increases in renin levels and potassium. Genetically proxied angiotensinogen synthesis lowering was associated with lower odds of CAD (OR per 1mmHg SBP reduction: 0.954, 95% CI: 0.937; 0.972, p=3.8*10-7), stroke (OR: 0.949, 95% CI: 0.928; 0.970, p=2.1*10-6) and heart failure (OR: 0.972, 95% CI: 0.957; 0.987, p=2.4*10-4). Furthermore, we observed associations with ischemic, cardioembolic and small-vessel stroke, subarachnoid hemorrhage, white matter hyperintensities, mean diffusivity and carotid plaque presence. Conclusions Genetically proxied angiotensinogen synthesis inhibition is associated with lower burden of clinical and imaging cardio- and cerebrovascular outcomes, providing a rationale for clinical trials investigating angiotensinogen inhibitors as potential targets for cardiovascular risk reduction. Conflict of interest M.K.G reports consulting fees from Tourmaline bio, Inc., Pheiron GmbH, and GLG, Inc., all unrelated to this work. The other authors have nothing to disclose.