Circulating Proteins Link Obesity With Cardiac Remodeling: Insights From Mendelian Randomization

Area of Science:

• Cardiovascular Medicine
• Genetics
• Metabolic Disease

Background:

• Obesity is a significant risk factor for cardiovascular disease.
• Subclinical cardiac remodeling and heart failure (HF) are potential consequences of obesity.
• Identifying novel therapeutic targets for obesity-related cardiac dysfunction is crucial.

Purpose of the Study:

• To investigate the causal relationship between obesity indicators and cardiac remodeling/HF risk.
• To identify and assess the druggability of plasma proteins mediating obesity's cardiovascular effects.

Main Methods:

• Utilized Mendelian randomization (MR) analyses with obesity indicators (visceral adipose tissue, waist circumference, waist-to-hip ratio adjusted for BMI).
• Assessed causal effects on cardiovascular magnetic resonance (CMR)-derived cardiac traits and HF risk.
• Performed mediation analyses and druggability assessments on identified proteins.

Main Results:

• Genetically determined obesity indicators showed causal links to cardiac remodeling, independent of cardiometabolic risk factors.
• Waist-to-hip ratio adjusted for BMI was the sole independent predictor of HF risk.
• Identified 6 key proteins (SCARA5, CD46, SERPINA3, APOC3, ALDH2, CHRDL2) involved in obesity-driven cardiac remodeling and HF, with existing or investigational drugs.

Conclusions:

• Provided genetic evidence for obesity's direct causal role in cardiac remodeling and HF.
• Highlighted specific druggable proteins as promising therapeutic targets for mitigating obesity-related cardiovascular disease.