Cardiovascular Significance and Genetics of Epicardial and Pericardial Adiposity

Abstract

Importance: Epicardial and pericardial adipose tissue (EPAT) has been associated with cardiovascular diseases such as atrial fibrillation or flutter (AF) and coronary artery disease (CAD), but studies have been limited in sample size or drawn from selected populations. It has been suggested that the association between EPAT and cardiovascular disease could be mediated by local or paracrine effects.

Objective: To evaluate the association of EPAT with prevalent and incident cardiovascular disease and to elucidate the genetic basis of EPAT in a large population cohort.

Design, setting, and participants: A deep learning model was trained to quantify EPAT area from 4-chamber magnetic resonance images using semantic segmentation. Cross-sectional and prospective cardiovascular disease associations were evaluated, controlling for sex and age. Prospective associations were additionally controlled for abdominal visceral adipose tissue (VAT) volumes. A genome-wide association study was performed, and a polygenic score (PGS) for EPAT was examined in independent FinnGen cohort study participants. Data analyses were conducted from March 2022 to December 2023.

Exposures: The primary exposures were magnetic resonance imaging-derived continuous measurements of epicardial and pericardial adipose tissue area and visceral adipose tissue volume.

Main outcomes and measures: Prevalent and incident CAD, AF, heart failure (HF), stroke, and type 2 diabetes (T2D).

Results: After exclusions, this study included 44 475 participants (mean [SD] age, 64.1 [7.7] years; 22 972 female [51.7%]) from the UK Biobank. Cross-sectional and prospective cardiovascular disease associations were evaluated for a mean (SD) of 3.2 (1.5) years of follow-up. Prospective associations were additionally controlled for abdominal VAT volumes for 38 527 participants. A PGS for EPAT was examined in 453 733 independent FinnGen cohort study participants. EPAT was positively associated with male sex (β = +0.78 SD in EPAT; P < 3 × 10-324), age (Pearson r = 0.15; P = 9.3 × 10-229), body mass index (Pearson r = 0.47; P < 3 × 10-324), and VAT (Pearson r = 0.72; P < 3 × 10-324). EPAT was more elevated in prevalent HF (β = +0.46 SD units) and T2D (β = +0.56) than in CAD (β = +0.23) or AF (β = +0.18). EPAT was associated with incident HF (hazard ratio [HR], 1.29 per +1 SD in EPAT; 95% CI, 1.17-1.43), T2D (HR, 1.63; 95% CI, 1.51-1.76), and CAD (HR, 1.19; 95% CI, 1.11-1.28). However, the associations were no longer significant when controlling for VAT. Seven genetic loci were identified for EPAT, implicating transcriptional regulators of adipocyte morphology and brown adipogenesis (EBF1, EBF2, and CEBPA) and regulators of visceral adiposity (WARS2 and TRIB2). The EPAT PGS was associated with T2D (odds ratio [OR], 1.06; 95% CI, 1.05-1.07; P =3.6 × 10-44), HF (OR, 1.05; 95% CI, 1.04-1.06; P =4.8 × 10-15), CAD (OR, 1.04; 95% CI, 1.03-1.05; P =1.4 × 10-17), AF (OR, 1.04; 95% CI, 1.03-1.06; P =7.6 × 10-12), and stroke in FinnGen (OR, 1.02; 95% CI, 1.01-1.03; P =3.5 × 10-3) per 1 SD in PGS.

Conclusions and relevance: Results of this cohort study suggest that epicardial and pericardial adiposity was associated with incident cardiovascular diseases, but this may largely reflect a metabolically unhealthy adiposity phenotype similar to abdominal visceral adiposity.

Figure 1.. Annotation of Epicardial and Pericardial Adipose Tissue Area From 4-Chamber Cardiac Magnetic Resonance (CMR) Images

The combined area of epicardial and pericardial adipose tissue (shaded in yellow) was quantified with deep learning in 44 475 UK Biobank participants. Four-chamber images at random parts of the cardiac cycle from 200 randomly selected participants of the UK Biobank CMR imaging substudy were first manually annotated (middle image). A U-Net–based (University of Freiburg) deep learning model was then constructed using a ResNet50 (Microsoft) encoder and fine-tuned model based on the manual annotations. The resulting model was used to infer segmentation of the combined area of epicardial and pericardial adipose tissue in all remaining images. Magnetic resonance images are reproduced by kind permission of UK Biobank.

Figure 2.. Associations of Epicardial and Pericardial Adipose Tissue (EPAT) With Prevalent and Incident Cardiovascular Diseases

A, The associations of prevalent diseases with the combined area of EPAT were examined with linear regression models, including the respective disease, age, and sex, as predictors and EPAT as the outcome. Each bar corresponds to the difference in EPAT (in SD units) between those with prevalent disease and those without. Error bars correspond to positive 95% CIs. B, Cumulative incidence curves for 3 selected cardiovascular diseases are shown for participants stratified by EPAT deciles at the time of imaging (top 10% vs others). The shaded areas correspond to 95% CIs. Individuals with the corresponding disease at the time of imaging were excluded from the incident disease analyses. P values were estimated using Cox proportional hazards models with age and sex as covariates.

Figure 3.. Manhattan Plot of the Genome-Wide Association Study of Epicardial and Pericardial Adipose Tissue in UK Biobank

A genome-wide association study of the combined area of epicardial and pericardial adipose tissue was performed in 41 494 UK Biobank participants. Each variant is plotted as a data point, with the corresponding −log₁₀(P) shown on the y-axis and the genomic position shown on the x-axis grouped by chromosomes. The genome-wide significance threshold (P = 5 × 10⁻⁸) is shown with a darker dashed line and a suggestive threshold (P = 1 × 10⁻⁵) is shown with a lighter dashed line. Genomic loci with at least 1 variant reaching genome-wide significance are labeled with the name of the nearest gene, and all variants within 500 kilobases of the lead variant are colored in a darker blue for visualization purposes. The y-axis is truncated to only show variants with a P value ≤.1.

Figure 4.. Associations of a Polygenic Score for Epicardial and Pericardial Adipose Tissue (EPAT) With Cardiovascular Diseases in FinnGen

A polygenic score (PGS) for the combined area of EPAT was constructed using the PRS-CS tool, which infers posterior effect sizes for polygenic risk scores (PRS) under continuous shrinkage (CS) priors, based on summary statistics from the genome-wide association study of EPAT in UK Biobank and subsequently applied to 453 733 participants in the FinnGen study. A, The associations of the EPAT PGS with cardiovascular diseases were evaluated using logistic regression models with sex, age at the end of study follow-up or death, genomic principal components 1 to 5, and the genotyping array as basic covariates. B, The associations of the EPAT PGS with cardiovascular diseases were examined including body mass index (BMI) as an additional covariate. Odds ratios (ORs) are shown per SD increment in EPAT PGS.

Figure 5.. Incident Disease Associations of Epicardial and Pericardial Adipose Tissue (EPAT) and Abdominal Visceral Adipose Tissue (VAT) in a Joint Model

The associations of the combined area of EPAT and the volume of abdominal VAT with incident diseases were tested using Cox proportional hazards models with time from imaging to diagnosis or censoring as the outcome and EPAT, VAT, sex, and age as the predictors. A, Hazard ratios (HRs) are shown separately for EPAT (in SD units). B, HRs are shown separately for VAT (in SD units). Participants with the corresponding prevalent disease at the time of imaging were excluded from analyses.