We sought to investigate the role of aldosterone as a mediator of disease and its relationship with the counter-regulatory natriuretic peptide (NP) system. We measured plasma aldosterone (n=1674; age ≥45 years old) in a random sample of the general population from Olmsted County, MN. In a multivariate logistic regression model, aldosterone analyzed as a continuous variable was associated with hypertension (HTN) (OR=1.75, 95%CI= 1.57,1.96; p<0.0001), obesity (OR=1.34, 95%CI= 1.21,1.48; p<0.0001), chronic kidney disease (CKD) (OR=1.39, 95%CI= 1.22,1.60; p<0.0001), central obesity (OR=1.47, 95%CI=1.32,1.63; p<0.0001), metabolic syndrome (MetS) (OR=1.41, 95%CI= 1.26,1.58; p<0.0001), high triglycerides (OR=1.23, 95%CI=1.11,1.36; p<0.0001), concentric left ventricular hypertrophy (cLVH) (OR=1.22, 95%CI= 1.09,1.38; p=0.0007) and atrial fibrillation (OR=1.24, 95%CI= 1.01,1.53; p=0.04), after adjusting for age and sex. The associations with HTN, central obesity, MetS, triglycerides and cLVH remained significant after further adjustment for BMI, NPs, and renal function. Furthermore, aldosterone in the highest tertile correlated with lower NP levels and increased mortality. Importantly, most of these associations remained significant even after excluding subjects with aldosterone levels above the normal range. In conclusion, we report that aldosterone is associated with HTN, CKD, obesity, MetS, cLVH, and lower NPs in the general community. Our data suggests that aldosterone, even within the normal range, may be a biomarker of cardiorenal and metabolic disease. Further studies are warranted to evaluate a therapeutic and preventive strategy to delay the onset and/or progression of disease, using mineralocorticoid antagonists or chronic NP administration in high risk subjects identified by plasma aldosterone.

Objectives We sought to define the cardiometabolic phenotype associated with rs5068, a genetic variant of the atrial natriuretic peptide (ANP) gene. Background ANP and BNP play an important role in cardiorenal homeostasis but also exert metabolic actions. Methods We genotyped 1608 randomly selected residents from Olmsted County, Minnesota, USA. Subjects were well characterized. Results Genotype frequencies were: AA 89.9%, AG 9.7%, and GG 0.4%; all subsequent analyses were AA vs AG+GG. After adjustment for age and gender the G allele was associated with increased plasma levels of N-terminal-proANP (NT-proANP) (p=0.002). The minor allele was also associated with lower BMI (p=0.006), prevalence of obesity (p=0.002), waist circumference (p=0.021), lower levels of C-reactive protein (p=0.027) and higher values of HDL cholesterol (p=0.019). The AG+GG group had a lower systolic blood pressure (p=0.011) and lower prevalence of myocardial infarction (p=0.042). The minor allele was associated with a lower prevalence of metabolic syndrome (p=0.025). After adjusting for BMI the association between the G allele and HDL cholesterol, C – reactive protein values, myocardial infarction and metabolic syndrome was not significant; the association with systolic blood pressure, BMI, obesity, waist circumference remained significant even after adjusting for NT-proANP. Conclusions In a random sample of the general US population the minor allele of rs5068 is associated with a favorable cardiometabolic profile. These findings suggest that rs5068 or genetic loci in linkage disequilibrium may affect susceptibility for cardiometabolic diseases and support the possible protective role of natriuretic peptides by their favorable effects on metabolic function. Replication studies are needed to confirm our findings.