Unmasking Hormonal Mechanisms of Hypertension in Obesity

Understanding hormonal mechanisms of obesity-related hypertension may inform the optimal approach to targeted therapy.

To interrogate hormonal phenotypes of obesity-related hypertension.

77 participants with obesity and hypertension underwent deep-phenotyping of adrenocortical hormones at baseline and following multiple dynamic maneuvers to suppress and stimulate hormone production, including: the seated saline suppression (SST), oral sodium loading (OSLT) test, dexamethasone suppression test (DST), and ACTH-stimulation (ACTHstim). Participants were classified into 3 aldosteronism phenotypes: (1) primary aldosteronism (PA) phenotype (low renin with non-suppressible aldosterone), low-renin phenotype (low renin and low aldosterone), and renin-dependent aldosteronism (high renin with renin-mediated aldosteronism). The DST was used to evaluate for ACTH-independent hypercortisolism and ACTHstim was used to evaluate ACTH-modulated adrenocortical hormone production.

Participants were 55.4 ± 9.4 years, 66.2% women, and had a BMI of 34.8 ± 5.2 kg/m². At baseline, 37.7% of participants had a PA phenotype. Following sodium loading with SST, a persistent PA phenotype was seen in 28.5% and unmasked in an additional 23.4% of participants (total 51.9%). Participants with an unmasked PA phenotype had renin-dependent aldosteronism prior to SST, and thus were not identified during baseline testing. Persistent renin-dependent aldosteronism following SST was identified in 23.4% of the cohort and was characterized by greater kaliuresis and higher aldosterone levels (at baseline and following dynamic maneuvers to modulate ACTH and angiotensin II). These patterns were all reproduced following sodium loading with the OSLT. The DST identified ACTH-independent hypercortisolism in 9.2% of participants.

Over 80% of participants with obesity-related hypertension reproducibly exhibited pathologic phenotypes of aldosteronism and/or hypercortisolism. These overlapping hormonal mechanisms reveal the multi-factorial nature of obesity-related hypertension and provide evidence to support aldosterone- and cortisol-directed therapies to treat hypertension in people with obesity.