Phenotype-Guided Hypertension Management in the Era of Cardiovascular–Kidney–Metabolic Syndrome: Integrating the CKM and MACARENHA Models for Personalized Dual and Triple Antihypertensive Therapy

Abstract

Background: Hypertension remains the leading modifiable contributor to cardiovascular morbidity and mortality worldwide despite the availability of effective antihypertensive therapies. One of the principal limitations of contemporary management is that treatment strategies continue to focus predominantly on blood pressure values rather than on the biological complexity of the patient. Increasing evidence demonstrates that hypertension rarely exists as an isolated disease; instead, it develops within a complex network of metabolic, vascular, renal, cardiac, hepatic and neurological alterations that interact continuously throughout the lifespan. This systemic interaction has recently been formalized by the American Heart Association through the Cardiovascular–Kidney–Metabolic (CKM) Syndrome, emphasizing that obesity, diabetes, chronic kidney disease and cardiovascular disease represent different manifestations of a common pathophysiological continuum.
Objective: To propose an integrated clinical framework combining CKM staging with the MACARENHA model in order to identify predominant organ phenotypes and personalize antihypertensive therapy through rational selection of dual or triple combination treatment.
Results: CKM staging identifies overall cardiometabolic risk, whereas MACARENHA identifies the predominant target-organ phenotype responsible for disease expression. Together, both models provide complementary information that facilitates precision medicine in hypertension. Patients exhibiting a vascular phenotype characterized by arterial stiffness, endothelial dysfunction, left ventricular hypertrophy or atherosclerotic disease may derive greater benefit from renin–angiotensin system inhibition combined with calcium channel blockade. Conversely, patients presenting with renal dysfunction, albuminuria, fluid retention or heart failure represent a cardiorenal phenotype in which renin–angiotensin inhibition plus thiazide-like diuretics may provide superior cardiorenal protection. Triple therapy should be considered early in patients with advanced CKM stages, persistent uncontrolled hypertension or multiple-organ involvement.
Conclusion: Hypertension should no longer be managed as an isolated hemodynamic disorder. Integrating CKM staging with organ-based phenotyping through the MACARENHA model represents a novel conceptual approach that aligns antihypertensive treatment with the patient’s predominant biological phenotype rather than blood pressure values alone.