Effects of glycemic traits on left ventricular structure and function: a mendelian randomization study

Background Adverse 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. Methods Genetic variants for IR, fasting insulin, HbA1c, and fasting glucose were selected based on published genome-wide association studies, which included 188,577, 108,557, 123,665, and 133,010 individuals of European ancestry, respectively. Outcome datasets for left ventricular (LV) parameters were obtained from UK Biobank Cardiovascular Magnetic Resonance sub-study (n = 16,923). Mendelian randomization (MR) analyses with the inverse-variance weighted (IVW) method were used for the primary analyses, while weighted median, MR-Egger, and MR-PRESSO were used for sensitivity analyses. Multivariable MR analyses were also conducted to examine the independent effects of glycemic traits on LV parameters. Results In 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% confidence interval [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. However, no associations of HbA1c 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. Multivariable MR analyses provided further evidence for an independent effect of IR on the adverse changes in LV parameters after controlling for HbA1c. Conclusions Our study suggests that genetic liability to IR rather than those of glycemic levels are associated with adverse changes in LV structure and function, which may strengthen our understanding of IR as a risk factor for heart failure by providing evidence of direct impact on cardiac morphology.