The Cardiovascular Impact and Genetics of Pericardial Adiposity

Background While previous studies have reported associations of pericardial adipose tissue (PAT) with cardiovascular diseases such as atrial fibrillation and coronary artery disease, they have been limited in sample size or drawn from selected populations. Additionally, the genetic determinants of PAT remain largely unknown. We aimed to evaluate the association of PAT with prevalent and incident cardiovascular disease and to elucidate the genetic basis of PAT in a large population cohort. Methods A deep learning model was trained to quantify PAT area from four-chamber magnetic resonance images in the UK Biobank using semantic segmentation. Cross-sectional and prospective cardiovascular disease associations were evaluated, controlling for sex and age. A genome-wide association study was performed, and a polygenic score (PGS) for PAT was examined in 453,733 independent FinnGen study participants. Results A total of 44,725 UK Biobank participants (51.7% female, mean [SD] age 64.1 [7.7] years) were included. PAT was positively associated with male sex (β = +0.76 SD in PAT), age ( r = 0.15), body mass index (BMI; r = 0.47) and waist-to-hip ratio ( r = 0.55) (P < 1×10 -230 ). PAT was more elevated in prevalent heart failure (β = +0.46 SD units) and type 2 diabetes (β = +0.56) than in coronary artery disease (β = +0.22) or AF (β = +0.18). PAT was associated with incident heart failure (HR = 1.29 per +1 SD in PAT [95% CI 1.17–1.43]) and type 2 diabetes (HR = 1.63 [1.51–1.76]) during a mean 3.2 (±1.5) years of follow-up; the associations remained significant when controlling for BMI. We identified 5 novel genetic loci for PAT and implicated transcriptional regulators of adipocyte morphology and brown adipogenesis ( EBF1 , EBF2 and CEBPA ) and regulators of visceral adiposity ( WARS2 and TRIB2 ). The PAT PGS was associated with T2D, heart failure, coronary artery disease and atrial fibrillation in FinnGen (ORs 1.03–1.06 per +1 SD in PGS, P < 2×10 -10 ). Conclusions PAT shares genetic determinants with abdominal adiposity and is an independent predictor of incident type 2 diabetes and heart failure. Clinical Perspective What is new? In a large, prospective and uniformly phenotyped cohort, pericardial adipose tissue was independently predictive of incident heart failure and type 2 diabetes when adjusted for body mass index. In contrast, pericardial adipose tissue was not independently predictive of atrial fibrillation. A genome-wide association study of pericardial adipose tissue identified five novel loci, implicating genes influencing adipocyte morphology, brown-like adipose tissue differentiation and abdominal adiposity. What are the clinical implications? Pericardial adipose tissue accumulation may reflect a metabolically unhealthy adiposity phenotype similarly to abdominal visceral adiposity.