Resistant Hypertension: Pathophysiology, Diagnostic Approaches, and Emerging Therapeutic Strategies

INTRODUCTION: Resistant Hypertension (RH) is defined as Blood Pressure (BP) that remains uncontrolled despite the concurrent use of three antihypertensive agents from different classes, including a diuretic. This review examines the pathophysiology, diagnostic criteria, and emerging therapeutic strategies in RH management, with an emphasis on current clinical challenges and future directions. METHODS: This article is a narrative (non-systematic) review. PubMed and Scopus were searched for "English language" literature from January 2000 through June 2025, using terms including "resistant hypertension", "apparent treatment resistant hypertension", "renal denervation", "aldosterone", and "secondary hypertension". Guidelines, randomized controlled trials, and systematic reviews/meta-analyses directly relevant to the pathophysiology, diagnosis, and treatment of resistant hypertension were prioritized. Additional landmark observational studies were included when considered clinically informative. RESULTS: RH affects up to 10% of hypertensive patients globally, with higher prevalence in those with chronic kidney disease and obstructive sleep apnea. Misdiagnosis due to pseudo-resistance and poor medication adherence remains prevalent. Pathophysiology involves complex mechanisms, including sympathetic overactivity, dysregulation of the RAAS, and aldosterone excess. Diagnostic confirmation includes excluding pseudo-resistance and evaluating for secondary causes. Lifestyle modifications remain foundational. Mineralocorticoid receptor antagonists, aldosterone synthase inhibitors, renal denervation, and baroreceptor therapies show promise in treating cases resistant to other therapies. DISCUSSION: While conventional pharmacotherapy remains the cornerstone, inadequate BP control in RH necessitates a deeper understanding of underlying mechanisms and adherence assessment. Device-based approaches and emerging agents, such as zilebesiran and aprocitentan, may hold promise in revolutionizing RH management but require further validation. Limitations include a lack of large-scale comparative trials and accessibility concerns in low-resource settings. CONCLUSION: Resistant hypertension represents a multifactorial condition requiring a multidimensional diagnostic and therapeutic approach. Integrating lifestyle changes, optimized pharmacotherapy, and emerging options, including aldosterone synthase inhibition, dual endothelin receptor antagonism, small-interfering RNA strategies, and refined device-based approaches, offers incremental BP reductions in carefully selected patients. The synthesis emphasizes a pragmatic, stepwise strategy that couples adherence and secondary cause assessment with evidence-based pharmacologic intensification (notably mineralocorticoid receptor antagonists) and selective device therapy. This integrated approach may be critical for achieving durable BP control and reducing cardiovascular risk in patients with resistant hypertension.