Connecting the dots: Gouty arthritis, clonal haematopoiesis and myeloid activation, in a unified inflammation model for atherosclerosis progression.

Gout, one of the most prevalent inflammatory arthropathies, arises from hyperuricemia and is increasingly recognized as a condition extending beyond the joints. Hyperuricemia, the core risk factor for gout, is also an independent risk factor for cardiovascular disease (CVD), complications, and mortality. Multiple conditions that predispose to gout and hyperuricemia, including obesity, metabolic syndrome, type 2 diabetes, hypertension, and chronic kidney disease (CKD), also elevate the risk of atherosclerosis, the central contributor to CVD and the leading cause of mortality in Western societies. The association between gout and atherosclerosis highlights the need for deeper understanding of causal links between these conditions. Because evidence remains insufficient to support urate-lowering therapies for improving cardiovascular outcomes, attention has shifted to other mechanisms connecting gout and atherosclerosis. Given the lack of convincing data for clinically significant monosodium urate crystal (MSUc) deposition in atherosclerotic plaques, this review focuses on the hypothesis that expansion of local articular to systemic inflammation, driven by macrophage activation by MSUc, is the primary mechanism accelerating atherosclerosis in gout. Mechanistically, we explore how epigenetic regulators normally restrain MSU-induced local inflammation, thereby protecting against atherosclerosis. We further discuss how aging-related somatic mutations in genes involved in clonal hematopoiesis of indeterminate potential (CHIP) disrupt this protection, resulting in heightened systemic inflammation and atherosclerosis in patients with gout.