Crystal clear - Part II: the role of uric acid in cardiorenal disease.

Abstract

Building on the foundational mechanistic and epidemiological knowledge from Part I, this second part of the review further unpacks the cardiovascular implications of abnormalities in serum levels of uric acid (UA). With a focus on hypertension, coronary artery disease (CAD), heart failure (HF), stroke, and peripheral artery disease (PAD), we provide a nuanced synthesis of how elevated serum UA influences disease risk and clinical outcomes. We describe mechanistic pathways including endothelial dysfunction, vascular smooth muscle proliferation, oxidative stress, inflammation, and renin-angiotensin system activation. Large cohort studies demonstrate linear or U-shaped relationships between serum UA (SUA) and cardiovascular events, with risk often appearing below conventional hyperuricemia thresholds. We also analyze interventional evidence for UA-lowering treatments such as xanthine oxidase inhibitors, urate transporter 1 (URAT-1) inhibitors and sodium-glucose transport protein 2 (SGLT2), highlighting context-dependent benefits in patients with hypertension or heart failure, both with and without preserved ejection fraction. Importantly, we discuss sex differences, kidney function influence, and the U-shaped association seen in men. Finally, we argue that SUA should be integrated into cardiovascular risk stratification, potentially serving as both a biomarker and a therapeutic target, while recognizing the need for personalized approaches based on comorbidities and biochemical profiles. This completes the two-part series by bridging mechanistic insights with practical clinical implications.