Dietary flavonoid intake and cardiovascular-kidney-metabolic syndrome

Cardiovascular-kidney-metabolic (CKM) syndrome represents a pathophysiological continuum from metabolic dysregulation to cardiovascular injury. However, whether dietary interventions confer stage-specific benefits remains unknown. We aimed to examine the association between flavonoid intake and CKM stages and to assess baseline intake and mortality across stages. We analyzed 10,754 US adults from National Health and Nutrition Examination Survey (2007–2010, 2017–2018). CKM stages (0–4) were defined at baseline. Flavonoid intake was assessed via two 24-hour recalls. Mortality was ascertained using the National Death Index linkage in December 2019 (median follow-up, 9.6 years). Cross-sectional associations with CKM stages were examined using multinomial logistic regression. Prospective associations with all-cause, cardiovascular, and cancer mortality were examined using survey-weighted Cox models stratified by CKM stage. Restricted cubic splines and weighted quantile sum regression further characterized dose–response relationships and mixture effects. Higher flavonoid intake was associated with lower odds of advanced CKM stage (stage 2 vs 0: Q 4 odds ratio: 0.53; 95% confidence interval [CI]: 0.33–0.83). Stage-specific mortality associations emerged: Q 4 reduced cancer mortality in stages 1 to 2 (hazard ratio [HR] = 0.60; 95% CI: 0.37–0.96) and all-cause mortality in stages 3 to 4 (HR = 0.80; 95% CI: 0.65–0.99). An L-shaped dose–response showed an inflection at 218.8 mg/d; below this, each 50 mg/d increment reduced the risk by 9% (HR = 0.91). The inverse associations were stronger in adults aged P  < .05). Weighted quantile sum regression identified anthocyanidins (50.6%) and flavones (24.8%) as primary contributors to cancer mortality reduction in the early stages, whereas isoflavones contributed 49.7% to all-cause mortality protection. These findings suggest potential stage-specific benefits: anthocyanidin- and flavone-rich diets may warrant further investigation for prevention, whereas isoflavone-focused intake may have relevance for survival in advanced stages. The observed threshold of approximately 219 mg/d provides a potential quantitative target for future research.