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

Area of Science:

• Cardiovascular Disease Genetics
• Metabolic Syndrome Research
• Cardiac Structure and Function Analysis

Background:

• Adverse ventricular structure and function are key in heart failure pathogenesis.
• Observational studies link insulin resistance (IR) and glycemic levels to poor cardiac function.
• The causal relationship between IR, glycemic levels, and cardiac structure/function remains unclear.

Purpose of the Study:

• To investigate the causal associations between genetic liability to insulin resistance (IR), glycemic traits (HbA1c, fasting glucose), and left ventricular (LV) parameters.
• To clarify the independent effects of IR and glycemic levels on cardiac structure and function using Mendelian randomization.

Main Methods:

• Utilized genetic variants associated with IR, HbA1c, and fasting glucose from large genome-wide association studies.
• Employed Mendelian randomization (MR) analysis with UK Biobank Cardiovascular Magnetic Resonance data (n=16,923) for LV parameters.
• Performed inverse-variance weighted (IVW) and sensitivity analyses (weighted median, MR-Egger, MR-PRESSO), including multivariable MR.

Main Results:

• Increased genetic liability to IR was significantly associated with adverse LV changes: lower LV end-diastolic volume, lower LV end-systolic volume, and higher LV mass to end-diastolic volume ratio.
• No significant causal associations were found between genetic liability to HbA1c or fasting glucose and any LV parameters.
• Sensitivity and multivariable MR analyses confirmed the independent effect of IR on LV structure and function.

Conclusions:

• Genetic predisposition to insulin resistance, not glycemic levels, is causally linked to adverse left ventricular structure and function.
• Findings provide evidence for a direct impact of IR on cardiac morphology, strengthening its role as a heart failure risk factor.