Abstract Body: Introduction: Hypertension, a risk factor for cardiovascular disease and chronic kidney disease, poses a significant burden in the U.S, especially among Black U.S. adults. Higher pro-enkephalin A (PENK-A), a byproduct of endogenous opioid peptide processing and a novel marker for estimation of glomerular filtration rate, is associated with antihypertensive use and greater risk of stroke, heart failure, and renal dysfunction. Whether low PENK-A is a risk factor for incident hypertension is unknown.

Hypotheses: We hypothesized that lower PENK-A will be associated with greater risk of incident hypertension.

Methods: REGARDS cohort study enrolled 30,239 Black and White U.S adults aged ≥45 years, with an initial visit between 2003-2007 and a follow-up visit in 2013-2016. A race-sex stratified sample of 4,400 participants were randomly selected. Hypertension was defined with a blood pressure (BP) threshold of 140/90 mm Hg or use of antihypertensive medications. We excluded those with prevalent hypertension, missing model covariates, or missing PENK-A, resulting in an analytical population of 1,859 participants. Proportion of incident hypertension events were calculated by tertile of PENK-A. Modified Poisson regression estimated unadjusted and adjusted risk ratios (RR) of incident hypertension per 1-SD higher of log-transformed PENK-A.

Results: Among 1,859 participants (mean [SD] age 62 [8] years, 51% female, and 36% Black race), median (IQR) follow up was 9.5 (8.7 to 10.0) years. Median (IQR) PENK-A was 59.7 (49.6-72.4) pmol/L. Hypertension developed in 35.4% of participants overall, (37.7% of tertile 1, 34.9% of tertile 2, and 33.7% of tertile 3 of PENK-A). However, there was no difference in RR of incident hypertension per 1-SD higher of log PENK-A in unadjusted (RR 0.96; 95% CI 0.90-1.02) or fully-adjusted models (RR 1.01; 95% CI 0.94-1.08). Restricted cubic splines depict no difference in RR of incident hypertension across the means of PENK-A levels relative to the median value (Figure).

Conclusions: PENK-A was not associated with greater risk of incident hypertension in a contemporary cohort study. PENK-A does not appear to influence risk for stroke and heart failure through hypertension, but whether PENK-A modifies cardiovascular disease risk among persons with hypertension is unclear given its bidirectional role in the cardiorenal pathway.