Long‐term BP control and vascular health in patients with hyperaldosteronism treated with low‐dose, amiloride‐based therapy

Abstract

Whether aldosterone itself contributes directly to macro‐ or microcirculatory disease in man or to adverse cardiovascular outcomes is not fully known. We report our long‐term single‐practice experience in 5 patients with chronic hyperaldosteronism (HA, including 3 with glucocorticoid remediable aldosteronism, GRA) treated with low‐dose amiloride (a specific epithelial sodium channel [ENaC] blocker) 5‐10 (mean 7) mg daily for 14‐28 (mean 20) years. Except for 1 GRA diagnosed in infancy, all had severe resistant hypertension. In each case, BP was normal or near‐normal within 1‐4 weeks after starting amiloride and office BP’s were well controlled for 20 years thereafter. Vascular studies and 24‐hour ambulatory BP monitoring with pulse wave analysis (cardiac output, vascular resistance, augmentation index, and reflection magnitude) were assessed after a mean of 18 years as were regional pulse wave velocities, pulse stiffening ratio, ankle‐brachial index, serum creatinine, estimated glomerular filtration rate, and spot urinary albumin:creatinine ratio. All indicators were completely normal in all patients after 18 years of amiloride, and none had a cardiovascular event during the 20‐year mean follow‐up. We conclude that long‐term ENaC blockade can normalize BP and protect macro‐ and microvascular function in patients with HA. This suggests that (a) any vasculopathic effects of aldosterone are mediated via ENaC, not MR activation itself, and are fully preventable or reversible with ENaC blockade or (b) aldosterone may not play a major BP‐independent role in human macro‐ and microcirculatory diseases. These and other widely divergent results in the literature underscore the need for additional studies regarding aldosterone, ENaC, and vascular disease.

Mineralocorticoid antagonists and ENaC inhibitors in hyperaldosteronism

“…In an article in this journal, Izzo et al report their long‐term results of treatment with low‐dose amiloride 5‐10 mg daily for 14‐28 years in a small group of patients with HA, including 3 with glucocorticoid‐remediable aldosteronism (GRA), with low‐dose amiloride (a relatively specific epithelial sodium channel [ENaC] blocker). Except for one patient, all had severe resistant hypertension.…”

“…Stiffness of the coronary arteries, in turn, leads to cardiac fibrosis, stiffness, and impaired diastolic relaxation leading to heart failure with preserved systolic function. Based on this accumulating body of evidence, one can prevent the CV stiffening effects of excess aldosterone either by blocking vascular MRs with a drug like spironolactone or inhibiting EnNaC activation with amiloride . The renal effects of excess aldosterone, such as tubulointerstitial fibrosis and albuminuria, would likewise be attenuated by either an MR antagonist or by the ENaC/EnNaC inhibitor amiloride …”

“…The article by Izzo et al raises a number of additional questions. For example, the authors also point out that despite inhibiting ENaC with amiloride, plasma aldosterone levels would have remained chronically high .…”

“…In their manuscript, Izzo et al also discuss their observation of rapid changes in arterial stiffness perhaps not being consistent with the reversal of slowly occurring remodeling processes (eg, involving collagen turnover). Rather, they suggest that a rapid decline in stiffness more likely reflects the lowering of BP by amiloride.…”

“…While this may to some extent be the case, it will also be of interest to understand whether more acute/active components of stiffness (eg, vascular cell adhesion, cytoskeletal dynamics, and contractile activity) are affected by amiloride treatment as seen in animal models . In this regard, amiloride may ultimately exert multiple actions through the vascular ENaCs and the renal ENaC that differ in their temporal relationships …”