Pathophysiology of aldosterone dysregulation in difficult-to-control hypertension

Aldosterone, a key component of the renin-angiotensin-aldosterone system (RAAS), plays a central role in sodium balance, vascular tone, blood pressure control, and cardiovascular remodeling. Dysregulation of aldosterone mechanism, including excessive production, deficiency, and inappropriate receptor activation, represents a significant contributor to cardiovascular and renal disease which is often underrecognized. Aldosterone dysregulation may manifest as primary aldosteronism that is increasingly identified as a common cause of secondary hypertension, or by secondary hyperaldosteronism that reflects maladaptive responses in common clinical conditions such as heart failure and liver cirrhosis. Conversely, hypoaldosteronism, particularly in diabetic nephropathy, predisposes to hyperkalemia and metabolic acidosis. Furthermore, aldosterone dysregulation can be observed in many clinically important and common patient phenotypes such as older patients, obese, and patients with diabetes where the elevated levels of aldosterone can contribute to poor blood pressure control and development of target organ damage particularly at the cardiac, vascular, and renal level. Beyond circulating levels of aldosterone itself, mineralocorticoid receptor (MR) overactivation in the absence of elevated aldosterone highlights the complexity of tissue-specific signaling. This review summarizes the spectrum of aldosterone dysregulation, delineates key patient phenotypes, and discusses diagnostic and therapeutic implications with a focus on cardiovascular outcomes. Recognizing aldosterone dysregulation as a systemic cardio-renal-metabolic disorder has important implications for risk stratification and targeted therapies.