Causal Relationship Between Circulating Plasma α-Klotho Levels and Myocardial Fractal Dimension

Myocardial fractal dimension (FD), a marker of myocardial microarchitecture, correlates with cardiac remodeling. The molecular mechanisms linking α-Klotho, a circulating anti-aging protein, to myocardial FD remain unclear. This study investigates the causal relationship between circulating α-Klotho levels and left ventricular trabecular FD using Mendelian randomization (MR) and explores the molecular pathways mediating this association. Data for α-Klotho levels were obtained from the IEU Open GWAS database (N = 4,675), and left ventricular trabecular FD from the UK Biobank (N = 18,096). MR analysis was performed using genetic instruments associated with α-Klotho, applying Maximum Likelihood, MR-Egger, Inverse Variance Weighted (IVW), and other methods. Sensitivity analyses (Leave-One-Out and funnel plots) assessed robustness. Functional Mapping and Annotation (FUMA) and Gene Ontology (GO) enrichment analyses were used to identify biological processes and pathways. MR analysis revealed a significant positive causal relationship between α-Klotho levels and left ventricular trabecular FD in mid-myocardial slices (Slices 5) (OR = 1.003, 95% CI: 1.001–1.005, p = 0.012). No associations were observed in other slices. Functional and pathway analyses highlighted key processes such as fibroblast growth factor signaling, glycosylation, and protein stability. This study provides evidence that α-Klotho influences myocardial FD through growth factor signaling and cellular processes, suggesting potential therapeutic targets for cardiovascular Diseases.