Cardiovascular Effects of Aldosterone

Abstract

A ldosterone (aldo) plays a key role in the control of sodium and potassium balance in the distal tubule of the kidney, thus regulating water body content and blood pressure (BP). Aldo acts through the mineralocorticoid receptor (MR), which is a ligandactivated transcription factor. Alteration of the aldo and MR signaling cascade leads to salt-wasting syndromes or hypertension. Clinical Perspective p 390In addition to their role in fluid and electrolyte homeostasis, aldo and MR are important factors for organ damage in cardiovascular (CV) and chronic kidney disease. [2][3][4] This is supported by the beneficial effects of MR antagonism in acute myocardial infarction and heart failure, [5][6][7] although mechanisms underlying the CV effects of aldo are still under debate. Chronic activation of the renin-angiotensin-aldo system (RAAS) is associated with progressive cardiac, vascular, and kidney injury, and aldo per se has deleterious CV effects that are independent of BP levels. In familial hyperaldosteronism type 1 (also known as glucocorticoid remediable aldosteronism), increased aldo levels lead to cardiac and vascular damage in young patients, before the onset of hypertension. 8 In common forms of primary aldosteronism, patients display more CV complications (stroke, nonfatal myocardial infarction, atrial fibrillation) than hypertensive subjects.9,10 MR signaling has been shown to be directly involved in macrophage-dependent cardiac remodeling and fibrosis, 11,12 salt-induced hypertension, 3 vascular remodeling,Background-High plasma aldosterone has deleterious cardiovascular effects that are independent of blood pressure, but the role of the mineralocorticoid receptor remains unclear. Renal pseudohypoaldosteronism type 1 is a rare autosomaldominant disease caused by NR3C2 loss-of-function mutations, which is characterized by renal salt loss and compensatory high renin and aldo secretion. We aimed to assess the cardiovascular outcomes in adults carrying NR3C2 mutations. Methods and Results-In this case-control study, 39 NR3C2 mutation carriers were compared with sex-and age-paired noncarriers. Patients underwent cardiac and vascular ultrasound, cardiac MRI with gadolinium injection, measurement of pulse wave velocity, extracellular water, 24-hour ambulatory blood pressure, and autonomous nervous system activity. Mutation carriers showed increased aldo and renin plasma levels (4. and stroke. 13 In most clinical situations, the respective contributions of renin, angiotensin II (Ang II), aldo, and MR are difficult to assess because of their simultaneous involvement and interaction.14,15 Indeed, experimental models have illustrated a crosstalk between Ang II and aldo signaling in cardiac remodeling and progression of kidney damage. [15][16][17][18] Type 1 pseudohypoaldosteronism (PHA1) is a rare disease of mineralocorticoid resistance.19-21 Despite extremely high plasma renin and aldo levels, patients present with neonatal salt wasting and failure to thrive, hyponatremia, hyperkalemia, and metabolic acidosis...

Mineralocorticoid Receptor, the Main Player in Aldosterone-Induced Large Artery Stiffness

“…Despite high aldosterone levels, cardiac and vascular remodeling, evaluated by gold standard approaches (cardiac MRI, ultrasound, and aortic pulse wave velocity) were not significantly different between MR mutation carriers and noncarriers. 6 These observations support the hypothesis that, in humans, MR is the main receptor involved in aldosterone effect. However, the renal loss of sodium associated with this disease could, per se, explain the observed defect in cardiovascular remodeling.…”

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor mutations

“…Older children are generally clinically asymptomatic. Nevertheless, a recent case-control study investigating 39 adult patients with renal PHA1 carriers of NR3C2 mutations showed that they show lifelong increased plasma renin and aldosterone levels as well as increased salt appetite, with normal blood pressure and potassium levels (Escoubet et al 2013), confirming evidence from earlier case reports suggesting persistence of hormonal abnormalities in adulthood (Kuhnle et al 1990, Zennaro et al 1992, Geller et al 2006. Remarkably, high aldosterone levels and salt intake in the context of low MR activity are not associated with adverse cardiovascular outcome in these patients, but rather with improved diastolic left ventricular function (Escoubet et al 2013).…”

“…These and other studies suggest that common functional MR haplotypes are important determinants of inter-individual variability in basal and stress-induced HPA axis activity and stressrelated appraisal and learning, by differentially mediating cortisol effects on different systems (ter Heegde et al 2015). Remarkably, in adult PHA1 patients carrying MR loss-of-function mutations, personal history revealed an increase in depression compared to paired non-carriers (Escoubet et al 2013).…”

“…In a study performed on a subset of patients from the cohort described in Escoubet and coworkers (Escoubet et al 2013), patients with MR mutations had higher morning plasma cortisol and increased 24-h urinary excretion of cortisol, independent of gender. Higher plasma cortisol was associated with higher plasma renin, lower serum high-density lipoprotein cholesterol and higher waist circumference but not with blood pressure, carotid intima-media thickness or echocardiographic parameters.…”

“…Familial genetic screening for the Ser166X mutation revealed that the mutation was transmitted from the father to the index case and was also present in one sibling, patient K096_4 (Table 1), but absent in the other affected sibling. The parents of the family subsequently participated in the clinical trial 'PHACARV -Cardiovascular Evaluation of Adult PHA 1 Patients' (Escoubet et al 2013); both father and mother had a similar phenotype suggesting PHA1 with increased plasma aldosterone levels. This unexpected result prompted us to sequence the entire NR3C2 coding sequence and intronexon junctions in the asymptomatic mother.…”