Abstract
BACKGROUND: Primary aldosteronism (PA), an overt form of renin-independent aldosterone production, leads to a disproportionately high rate of major adverse cardiovascular events (MACEs). Mounting evidence suggests that milder forms of renin-independent aldosterone production (subclinical PA) are highly prevalent; however, the link between subclinical PA and MACE remains uncertain. METHODS: This prospective study included 2017 Canadian adults 40 to 69 years of age from the randomly sampled, population-based CARTaGENE cohort (Québec, Canada), in which aldosterone and renin concentrations at enrollment (2009-2010) were measured. Follow-up data were obtained via provincial health care administrative database linkage. MACE outcomes consisted of a composite of myocardial infarction, stroke, hospitalization for heart failure, and cardiovascular death. Multivariable linear and nonlinear Cox regression models measured the associations of concentrations of aldosterone, renin, and the aldosterone-to-renin ratio with MACE. Outcome-derived optimal thresholds for these markers were then determined. RESULTS: The mean (SD) age of participants was 56 (8) years, and 45% were women. Mean blood pressure was 129 (15)/76 (10) mm Hg, with hypertension being present in 27%. Over a median follow-up time of 10.8 years, 57 (3%) MACE outcomes occurred. Lower renin concentration (adjusted hazard ratio [aHR], 2.22 [95% CI, 1.02-4.76]) and higher aldosterone-to-renin ratio (aHR, 2.43 [95% CI, 1.15-5.12]) were associated with a higher risk for MACE, whereas no significant association was found with aldosterone concentration (aHR, 1.57 [95% CI, 0.42-5.90]). Renin concentration exhibited a nonlinear relationship with MACE risk. The outcome-derived optimal thresholds to discriminate a higher MACE risk were renin concentration ≤4.0 ng/L (aHR, 2.12 [95% CI, 1.21-3.72]) and aldosterone-to-renin ratio ≥70 pmol/L per ng/L (aHR, 2.03 [95% CI, 1.09-3.80]). All aforementioned associations were independent of blood pressure. CONCLUSIONS: Independent of blood pressure, the subclinical PA biochemical phenotype is associated with an increased risk of MACE. Future studies are necessary to determine whether early identification and targeted treatment of subclinical PA mitigates this risk.