AHA Scientific Sessions 2026 Abstract · Nov 2, 2026
Angiotensinogen as a Risk Enhancer for Severe Hypertension: Sex-Specific Thresholds
By Costet P, Li P, Edelberg D et al.
Background: Genetic variation in angiotensinogen (AGT) is associated with an increased risk of prevalent hypertension (HTN), yet the relationship between circulating AGT concentrations and severe elevations in blood pressure (systolic BP ≥180 mmHg) remains poorly understood. We identified AGT concentration thresholds associated with an increased risk of severe HTN. Methods: Plasma AGT levels were measured by ELISA in 271 Caucasian participants from the Genetic Loci and the Burden of Atherosclerotic Lesions (GLOBAL) study (NCT01738828), including both healthy individuals and patients with coronary artery disease selected to represent a wide range of systolic BP. Genotyping for four AGT single nucleotide polymorphisms (SNPs) (rs699, rs4762, rs5051, rs5050) was available in 155 participants. Associations between AGT levels, clinical variables, and BP were evaluated. AGT cutoff values for increased risk of severe HTN were determined using Youden’s J statistic. Values are presented as mean ± SD. Results: Our main finding is that sex-specific thresholds of AGT were associated with severe HTN: AGT levels ≥18.8 μg/mL in males and ≥24.1 μg/mL in females were associated with a 78% and 54% increased risk, respectively, of systolic BP ≥180 mmHg. Mean age was 62 years (range 32-89), 54% were male, and 82% were overweight or obese. Angiotensin-converting enzyme (ACE) inhibitor and angiotensin receptor blocker (ARB) use was reported in 35% and 23% of participants, respectively; 10% of females were receiving estrogen therapy. AGT concentrations were significantly higher in females than males (20.0 ± 7.9 vs 16.6 ± 4.1 μg/mL; p<0.001). No significant associations were observed between AGT levels and BMI, age, or use of ACE inhibitors or ARBs. Estrogen therapy was associated with a 62% increase in AGT levels (p<0.001). Genetic analyses demonstrated strong linkage disequilibrium among AGT SNPs. Variant alleles of rs4762 and rs5050 were associated with significantly lower AGT concentrations, with up to a 36% reduction in homozygous carriers compared with wild-type individuals (p<0.01). Conclusions: In this Caucasian cohort, sex-specific AGT thresholds were associated with severe hypertension, highlighting the potential role of AGT as a risk enhancer for acute, severe elevations in blood pressure. Circulating AGT concentrations were predominantly influenced by sex, estrogen exposure, and genetic variation. Together, these findings support the continued evaluation of AGT as both a biomarker and a therapeutic target for the prevention and management of extreme blood pressure elevations in patients with uncontrolled HTN.