Effects Of Glycemic Traits On Left Ventricular Structure And Function ——A Two-sample Mendelian Randomization Study

BackgroundAdverse ventricular structure and function is a key pathogenic mechanism of heart failure.Observational studies have shown that both insulin resistance（IR）and glycemic level are associated with adverse ventricular structure and function.However,whether IR and glycemic level are causally associated with cardiac structure and function remains unclear.Mendelian randomization（MR）research uses genetic variants as instruments for exposure of interest,which is not easily impacted by confounding factors and reverse causality,can be used to provide less confounded results,and has been proved to be a powerful method to infer causality.ObjectivesIn this study,we conducted a two-sample MR study to examine the potential causal effects of genetic liability to glycemic traits,such as IR,fasting insulin,hemoglobin A1c（Hb A1c）,and fasting glucose,with left ventricular（LV）parameters,so as to infer the potential causal relationship between glycemic traits and LV structure and function.MethodsGenetic variants for glycemic traits were selected based on published genome-wide association studies.Conducting two-sample Mendelian randomization（MR）analyses,outcome datasets for LV parameters were obtained from the UK Biobank CMR sub-study（n=16,923）.The inverse-variance weighted（IVW）method was used for the primary analyses and weighted median,MR-Egger,and MR-PRESSO for sensitivity analyses.ResultsIn the primary IVW MR analyses,per 1-standard deviation（SD）higher IR was significantly associated with lower LV end-diastolic volume(β=-0.31 ml,95%CI:-0.48 to-0.14 ml;P=4.20×10^-4),lower LV end-systolic volume(β=-0.34 ml,95%CI:-0.51 to-0.16 ml;P=1.43×10^-4),and higher LV mass to end-diastolic volume ratio(β=0.50 g/ml,95%CI:0.32 to 0.67 g/ml;P=6.24×10^-8)after Bonferroni adjustment.IR was also associated with higher LV ejection fraction by suggestive evidence（β=0.20%,95%CI:0.05 to 0.36%;P=0.011）.Moreover,per 1-SD higher fasting insulin levels was marginally significantly associated with higher LV mass（β=0.49 g,95%CI:0.14 to 0.84 g;P=0.006）and higher LV mass to end-diastolic volume ratio（β=0.47 g/ml,95%CI:0.02 to 0.92 g/ml;P=0.039）.However,no associations of Hb A1c and fasting glucose were observed with any LV parameters.Results from sensitivity analyses were consistent with the main findings,but with a slightly attenuated estimate.ConclusionsIR is associated with adverse changes in LV structure and function,and glycemic level is not associated with significant changes in any LV parameter.Our findings may strengthen our understanding of IR as a risk factor for heart failure by providing evidence of direct impact on cardiac morphology.