Low Klotho Levels Linked to Greater Coronary Artery Disease Burden on CT Scans

Cardiovascular disease is the world's leading cause of death, and identifying circulating biomarkers that reflect underlying atherosclerotic biology—beyond traditional risk factors—remains a priority. Alpha-Klotho, a protein whose circulating levels decline with age, has shown vasculoprotective properties in preclinical and observational studies, but its relationship to objectively quantified coronary atherosclerosis has rarely been examined using comprehensive CT imaging metrics within the same cohort.

This single-center, prospective cross-sectional study enrolled 86 adults undergoing clinically indicated CCTA at Aydın Adnan Menderes University. Patients on statins, those with renal impairment (eGFR <60), prior revascularization, active inflammatory disease, or malignancy were excluded to limit confounding. Serum alpha-Klotho was measured by ELISA. Coronary atherosclerotic burden was characterized by both the Agatston calcium score (continuous) and CAD-RADS grading (ordinal, 0–5). Cardiometabolic risk was assessed using the TyG index, Atherogenic Index of Plasma (AIP), and METS-IR. Spearman correlations, age-adjusted partial correlations, multivariable linear regression with HC3-robust standard errors, binary and ordinal logistic regression, and bootstrap-validated ROC analysis were applied.

Klotho showed strong negative correlations with age (ρ = −0.598), Agatston score (ρ = −0.540), and CAD-RADS (ρ = −0.549), all p < 0.001. Critically, after adjusting for age, associations with both Agatston score (ρ = −0.348) and CAD-RADS (ρ = −0.352) remained statistically significant, indicating an age-independent relationship. AIP also remained inversely associated with Klotho after age adjustment (ρ = −0.289, p = 0.007), whereas TyG and METS-IR associations were attenuated. Multivariable models explained 50–52% of Klotho variance. In ordinal logistic regression adjusting for age, sex, BMI, and AIP, Klotho remained independently associated with CAD-RADS severity (OR = 0.525, p = 0.033). ROC analysis for the presence of any coronary atherosclerosis yielded an AUC of 0.754 (95% CI: 0.654–0.855); an exploratory cutoff of ≤823 pg/mL provided 72.0% sensitivity and 75.0% specificity (bootstrap-corrected: 69.3% and 72.5%). A significant interaction between diabetes status and the Klotho-TyG association was also identified, replicating a directional pattern previously reported in general-population data.

Mechanistically, Klotho deficiency is thought to promote vascular calcification through osteogenic transdifferentiation of smooth muscle cells and impaired autophagy, consistent with the imaging findings here. The concurrent inverse association with AIP—a log ratio of triglycerides to HDL cholesterol that reflects small dense LDL particle burden—suggests Klotho's vascular protection may partly operate through lipid-related pathways.

The study is limited by its moderate sample size (n = 86), single-center design, cross-sectional nature precluding causal inference, and an exploratory rather than clinically validated biomarker cutoff. The statin exclusion criterion, while controlling confounding, limits generalizability to the broader population typically evaluated by CCTA. These findings are preliminary and support larger longitudinal studies to determine whether Klotho monitoring could augment cardiovascular risk stratification.