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...