Angiotensinogen (AGT) blood concentrations differ significantly between men and women and between racial/ethnic groups, says a new study that emphasizes the need for new therapies to better treat hypertension and heart failure. The U.S.-based researchers also highlight findings that suggest women have significantly higher median plasma AGT concentrations than men within each race/ethnicity. The team determined the order of plasma AGT concentrations from high to low as white, Black, Hispanic and Chinese, with plasma AGT concentration differences between the sexes most profound in white participants. “We hypothesize that the differences in angiotensinogen levels between ethnicities may have a genetic component,” said the researchers, who reported their findings in a manuscript published Monday online and in the April 4 issue of the Journal of the American College of Cardiology. “Multiple variants in the promoter and enhancer regions of the AGT gene have been shown to be associated with angiotensinogen levels or mRNA expression in humans.” “Furthermore, there may be a relationship between these ethnicity-associated variants and sex-specific regulation of angiotensinogen levels,” added the research team, led by Patrick J. Trainor, PhD, from New Mexico State University. Study methodology Here, researchers also from Ionis Pharmaceuticals in Carlsbad, California, included 5,786 participants in the study from 2000 to 2002 according to prespecified race/ethnicity and age strata. These participants were from four race/ethnicity groups (white, Chinese, Black and Hispanic), and ranged in age from 45 to 84 years from six U.S. communities. The cohort recruitment was sex balanced, with approximately equal numbers of men and women participating. Outcome measures of the study included measured levels of AGT, systolic blood pressure (SBP), diastolic blood pressure (DBP), and prevalent hypertension at baseline (defined as SBP >130 mm Hg, DBP >80 mm Hg, or hypertension medication use). Research findings Results revealed women had significantly higher mean levels of AGT than men within each race/ethnicity. This difference between the sexes was most pronounced in white participants, where the ratio of female to male AGT levels was 1.44 with a 95% simultaneous confidence interval (CI) of 1.40 to 1.48. The difference was least pronounced in Chinese participants, where the ratio of female to male levels was 1.19 with a 95% simultaneous CI of 1.14 to 1.24. Higher AGT levels were also associated with higher BP and odds of prevalent hypertension after adjusting for other risk factors. Further findings revealed equivalent relative differences in AGT were associated with greater differences in BP in males vs females. In men not taking RAAS-blocking medications, a standard deviation increment in log-AGT was associated with 2.61 mm Hg higher systolic BP (95% CI: 1.49 to 3.80). In women, the same increment in AGT was associated with 0.97 mm Hg higher systolic BP (95% CI: 0.30 to 1.65). AGT and BP in muti-ethnic populations “Our results are timely as new therapies targeting the reduction of angiotensinogen are being evaluated in human trials,” the team said, referencing three recent phase I and II trials looking into the effect of antisense oligonucleotide IONIS-AGT-LRx on AGT levels. Two additional phase II/IIb trials are ongoing, with one trial investigating resistant hypertension with a minimum of three medications. The other trial sets out to assess the safety, tolerability and efficacy of IONISAGT-LRx in participants with chronic heart failure with reduced ejection fraction. In an accompanying editorial, Alan Daugherty, PhD, and Hong S. Lu, MD, PhD, from the Saha Aortic Center, University of Kentucky, and George L. Bakris, MD, from University of Chicago Medicine, highlighted the study as one of the first to assess plasma AGT concentrations and blood pressure in a multi-ethnic human population. Theories for higher AGT levels The editorial writers asked why women have higher plasma AGT concentrations, citing evidence that showed the administration of estrogen increased liver AGT mRNA abundance and plasma AGT concentrations in rats. The editorial also cited a report demonstrating the administration of estradiol increased plasma AGT concentrations in postmenopausal women, which is consistent with an estrogen-mediated regulatory effect. The study’s finding that revealed a positive association between plasma AGT concentrations and blood pressure was more significant in men agreed with a cited study that found angiotensin II administration led to greater increases in DBP in men than in women. The authors concluded by saying the development of antisense oligonucleotides and small interfering RNA (siRNA) targeting AGT in hepatocytes “brings new hopes to treat hypertension and its complications.” “It will also provide new insights into understanding the classic vs alternate renin-angiotensin regulation in human health,” they added. Sources: Trainor PJ, Brambatti M, Carlisle SM, et al. Blood Levels of Angiotensinogen and Hypertension in the Multi-Ethnic Study of Atherosclerosis (MESA). J Am Coll Cardiol 2023; 81:1248–1259. Daugherty A, Lu HS, Bakris GL. Angiotensinogen in Sex and Hypertension: New Insights From the Multi-Ethnic Study of Atherosclerosis (MESA). J Am Coll Cardiol 2023; 81:1260–1262 Image Credit: AGPhotography – stock.adobe.com