Commentary by Athina Markou, MD
“We have shown that mild, daily stress may be involved in the elevation of blood pressure (not only through the known catecholamine pathway) but also through the ACTH-aldosterone pathway,” said lead author Athina Markou, MD, who is a Consultant Endocrinologist in the Department of Endocrinology and Diabetes Center, G. Gennimatas General Hospital, Athens, Greece. “Therefore, aldosterone is a new target for treating hypertension not only in patients with primary aldosteronism, but also in a cohort of patients without PA who were thought to have essential hypertension up to now,” Dr. Markou said.
The researchers examined 113 people with hypertension and without primary aldosteronism, and 61 normotensive controls. All the participants underwent an ultralow-dose (0.03-mcg) ACTH stimulation that simulates low-grade chronic physical and/or psychological stress, and a treadmill test that simulates acute physical stress. The researchers also investigated the effects of mineralocorticoid receptor antagonists (MRAs) in patients with aldosterone (ALD) hypersecretion following the ACTH stimulation test.
More Than One-Quarter of Patients With Hypertension Showed ALD Hyperresponse to Stress
During the ACTH stimulation test, 30 of the 113 patients with hypertension (27%) showed ALD hyperresponse. Basal ACTH/renin concentrations were not significantly different between the 30 patients with ALD hyperresponse and patients without ALD hyperresponse or control patients. During the treadmill test, the 30 patients with ALD hyperresponse showed significantly higher ALD concentrations, ALD-to-renin ratio, and ALD/ACTH ratio.
In addition, treatment with MRAs significantly lowered blood pressure in the 30 patients with ALD hyper-response (19% and 16% reduction in systolic and diastolic blood pressure, respectively; P<0.0001 for both). In contrast, no reduction in blood pressure was found among patients without ALD hyperresponse or in control patients.
Furthermore, the researchers identified 2 novel germline heterozygous KCNJ5 mutations in 2 of 26 patients with ALD hyperresponse who underwent genetic testing.
Possible Explanations for the Findings
One possible explanation for the findings is that “glomerulosa cells are primed by stress-induced ACTH secretion, which makes them more sensitive to any increase in either ACTH or renin/angiotensin II levels, as it happens with chronic physical or psychological stressful events. Another explanation may be the finding of germline mutations such as KCNJ5 gene mutations that could have sensitized the glomerulosa cells to either ACTH or angiotensin stimulation, also leading to an ALD hyper-response,” Dr. Markou explained.
“I would like to emphasize that physicians should not expect potassium levels to be low in order to think about ALD hypersecretion,” Dr. Markou noted. “They should check for ALD hypersecretion in young patients with hypertension or in cases in which blood pressure is not well controlled on treatment with 1, 2 or 3 anti-hypertensives. If testing for ALD hypersecretion is not possible, they could try MRAs as a blind treatment and then assess their effect,” Dr. Markou said.
October 6, 2015
Markou A, Sertedaki A, Kaltsas G, et al. Stress-induced aldosterone hyper-secretion in a substantial subset of patients with essential hypertension. J Clin Endocrinol Metab. 2015;100(8):2857-2864.