Abstract
Primary aldosteronism (PA) is associated with a substantially higher cardiovascular risk than essential hypertension, a disparity that cannot be fully explained by blood pressure elevation alone. Clinical studies consistently demonstrate that cardiovascular morbidity and mortality often persist in patients with PA despite adequate blood pressure control and standard therapy, underscoring the existence of residual cardiovascular risk. Accumulating experimental and clinical evidence identifies inflammation as a central mediator of aldosterone-induced cardiovascular injury. Excess aldosterone drives immune-inflammatory remodeling through coordinated activation of innate and adaptive immune responses, including macrophage- and T cell-dependent pathways, as well as downstream signaling cascades such as inflammasome activation and interleukin-6-related trans-signaling. These processes promote myocardial fibrosis, vascular dysfunction, and adverse cardiac remodeling, providing a mechanistic basis for the heightened cardiovascular risk observed in PA. Although mineralocorticoid receptor (MR) antagonists remain the cornerstone of medical therapy for PA, MR blockade alone may be insufficient to fully suppress aldosterone-driven inflammatory and non-hemodynamic effects. Persistent activation of these pathways offers a plausible explanation for the residual cardiovascular risk observed in treated patients. Emerging therapeutic strategies aim to overcome these limitations through combination approaches. Aldosterone synthase inhibitors (ASIs), by targeting aldosterone production upstream, may complement MR antagonism, while interventions directed at inflammatory pathways and non-genomic aldosterone signaling could further enhance cardiovascular protection. This review integrates current mechanistic and clinical evidence on inflammatory drivers and residual risk in PA and discusses emerging combination strategies to optimize cardiovascular risk reduction in this high-risk population.