Resistant Hypertension in Adults in the Cardio–Renal–Metabolic Era: A Contemporary Position Statement
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Abstract
Resistant hypertension (RH) remains one of the most challenging clinical scenarios in cardiovascular medicine due to its strong association with target-organ damage, chronic kidney disease (CKD), heart failure, atrial fibrillation, stroke, and premature mortality. Contemporary evidence has transformed the understanding of RH from a simple state of uncontrolled blood pressure into one of a phenotype of a complex cardio–renal–metabolic syndrome characterized by persistent neurohormonal activation, sodium retention, endothelial dysfunction, sympathetic overactivity, obesity, inflammation, and relative aldosterone excess. Importantly, a substantial proportion of apparent resistant hypertension represents pseudoresistance caused by poor adherence, suboptimal pharmacologic regimens, white-coat effect, and inaccurate blood pressure measurement. Recent advances in ambulatory blood pressure monitoring (ABPM), precision phenotyping, and mechanistic therapies have reshaped diagnostic and therapeutic strategies. Spironolactone remains the preferred fourth-line therapy following optimized triple treatment, supported by robust evidence from PATHWAY-2. Chlorthalidone has demonstrated efficacy in advanced CKD, whereas sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RA) provide additional cardio–renal–metabolic benefits. Emerging therapies—including aprocitentan, aldosterone synthase inhibitors such as baxdrostat and lorundrostat, and RNA interference therapies targeting angiotensinogen—represent major advances in difficult-to-control hypertension. Likewise, renal denervation has re-emerged as a promising interventional strategy in carefully selected patients. This Position Statement summarizes current evidence regarding epidemiology, pathophysiology, diagnosis, phenotyping, and treatment of resistant hypertension, proposing a modern management paradigm focused not only on blood pressure control but also on comprehensive cardio–renal–metabolic risk reduction.
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