Recent analyses from the MESA (Multi-Ethnic Study of Atherosclerosis), a large, community-based cohort of women and men, have turned the spotlight on the pathological influence of pericardial fat depot on the occurrence of newly diagnosed heart failure (HF).^1,2 In this investigation, 6,785 study participants from four different races/ethnicities free of cardiovascular disease at baseline were followed for a median of 15.7 years during which time 385 individuals were newly diagnosed with HF. Multidetector computed tomography (CT) was used to estimate pericardial fat volume (PFV). The key findings of this study were as follows:

1. After adjustment for established risk factors, pericardial fat volume (PFV) was associated with a greater risk of HF in both women and men.
2. A greater amount of PFV was associated with a linear increase in the risk of HF without evidence of a threshold.
3. The amount of PFV was lower in women than in men (69 cm³ vs. 92 cm³; p <0.001). The optimal cutoff of high versus normal PFV for HF prediction was therefore lower in women (≥70 cm³) than in men (≥120 cm³).
4. The relative risk of newly diagnosed HF associated with greater PFV was higher in women than in men. Every one standard deviation (42 cm³) of excess PFV increased the risk of HF by 44% in women and 13% in men. High PFV approximately doubled the risk of HF in women and conferred about a 50% higher risk in men.
5. Major risk factors of HF including hypertension, diabetes mellitus, dyslipidemia, and interim myocardial infarction explained about one-third of the association between elevated PFV and newly diagnosed HF in women and almost one-half in men.
6. The association between PFV and newly diagnosed HF remained robust after accounting for anthropometric indicators of obesity such as body-mass index, waist circumference, hip circumference, and waist-to-hip ratio.
7. CT-based estimates of abdominal subcutaneous fat, abdominal visceral fat, or hepatic fat (non-alcoholic fatty liver disease) did not substantially influence or mediate the association between PFV and HF risk in multivariable statistical models.
8. The effect of PFV on the occurrence of HF was not attenuated by biomarkers of inflammation (C-reactive protein and interleukin-6) and hemodynamic stress (N-terminal pro-B-type natriuretic peptide).
9. The strength of the association between PFV and incident HF was similar in White, Black, Hispanic, and Chinese Americans. Thus, race and/or ethnicity did not alter the association between pericardial fat and the development of HF.
10. High compared with normal PFV was associated with a higher cumulative incidence of HF with preserved, mid-range, and unknown ejection fraction (heart failure with preserved ejection fraction [HFpEF], heart failure with mid-range ejection fraction [HFmrEF], and heart failure with unknown ejection fraction [HFuEF]) but not reduced ejection fraction (HFrEF). Of note, every one standard deviation (42 cm³) increase in PFV was associated with a 42% higher risk of HFpEF. High compared with normal PFV conferred a 2.3-fold greater risk of HFpEF. After adjustment for confounders (not intermediary variables), high PFV was associated with a 40% higher risk of HFrEF that approached near statistical significance. On further adjustment for variables in the causal pathway, the residual 20% elevated risk was not statistically significant.

In a subsample of the Jackson Heart Study (JHS) too, where CT-based estimation of PFV was comparable to that of the MESA cohort, a linear association between PFV and hospitalization for incident worsening HF was evident.³ During a median follow-up of 10.6 years, 77 of 1,386 Black participants were hospitalized for worsening HF. In fully adjusted multivariable models, every 10 cm³ increase in PFV was associated with an 8% increase in the risk of hospitalization for incident worsening HF. Further, in a smaller subset, a statistically significant association was noted between PFV and hospitalization for HFpEF but not HFrEF.

Of note, in both MESA and JHS, CT-based estimate of pericardial fat included a composite of epicardial fat, confined between the myocardium and the visceral pericardium, and paracardial (extrapericardial or mediastinal) fat, located external to the parietal pericardium (Figure 1). These two fat depots were not separately quantified due to difficulty in delineating the pericardium between them, particularly in lean individuals, and because the amount of these two fat depots were highly correlated in a subsample. However, epicardial and paracardial fat depots have inherent differences in their embryological origin, anatomic location, blood supply, and biochemical and biomolecular composition (Table 1).

Figure 1

Table 1: Profiles of Epicardial and Paracardial Fat Depots

	Epicardial fat	Paracardial fat
Embryology
Origin4	Splanchnopleuric mesoderm	Primitive thoracic mesenchyme
Anatomy
Location in relation to the pericardium	Internal to visceral pericardium	External to parietal pericardium
Location in relation to the coronary arteries	Surrounds coronary arteries5	Unrelated
Location in relation to the myocardium	Directly over the myocardium (no intervening fascia separating it from the myocardium)6	Separated from the myocardium by visceral and parietal pericardium
Coverage around normal heart	56% to 100% of the mid-cardiac circumference7	Not well-described
Proportion of normal heart mass	4% to 52% of heart mass7 ~20% of ventricular mass8	Not well-known
Proportion of intrathoracic fat9	~30%	~70%
Blood supply in relation to the myocardium4	Same (branches of coronary arteries)	Unrelated (pericardiocophrenic branch of the internal mammary artery)
Microcirculation with coronary wall (vasa vasora)	Well-known4,8	Not known
Adipocyte size	Smaller1	Relatively larger10
Brown adipose tissue features	5-fold higher expression of Uncoupling Proten-1 (UCP-1) than in substernal fat12	24-fold higher expression of UCP-1 than in subcutaneous fat13; Focal increase in fluorodeoxyglucose (FDG) uptake14
Physiology (Biochemical and Biomolecular)
Fatty acid synthesis (uptake) (lipogenesis)4	Higher	Relatively lower
Fatty acid release (lipolysis)4	Higher (two times that of paracardial fat)	Relatively lower
Energy consumption	High11	Not well-known
Local source of energy for the myocardium	Plausible4,15	Not known
Fatty acid composition	Lower C18:1 to C18:0 ratio10 High in saturated fat16	Higher C18:1 to C18:0 ratio10
Protein content4	Similar (two times that of perirenal and popliteal fat)	Similar
Glucose utilization	Lower (half that of intra-abdominal fat)4	Not well-known
Paracrine and vasocrine function	Well-known source of adipokines;5,6,17 marginally lower adiponectin gene expression than in subcutaneous fat;11 expresses more inflammatory cytokines than subcutaneous fat18	Not well-known

Epicardial fat has been hypothesized to cushion coronary arteries against torsion,¹⁹ generate heat in response to hypothermia,¹² serve as an energy repository for the myocardium,¹⁵ sequester excess fatty acids from the coronary circulation,^15,20 enable positive coronary remodeling,²¹ produce anti-inflammatory adipokines such as adiponectin,²² and harbor intrinsic cardiac ganglia and neuronal plexus that respond to ischemic stress.²³ Notwithstanding these possible cardioprotective functions, excess epicardial fat may induce myocardial dysfunction through myocardial steatosis²⁴ and/or infiltration between myocardial fibers and bundles.²⁵ It may promote oxidative stress,²⁶ inflammation,¹⁸ insulin resistance,²⁷ diabetes mellitus type 2,^28,29 and metabolic syndrome³⁰ and predispose to coronary artery disease and cardiomyopathy.^5,17,31 It is cross-sectionally associated with atrial fibrillation,³² which augments the risk of HF.^33,34 Accompanying factors such as essential hypertension,³⁵ ventricular hypertrophy,⁸ diastolic dysfunction,³⁶ and hemodynamic alteration³⁷ may precipitate the syndrome of HF³⁸ and result in an obese-HFpEF phenotype.³⁹

The cardiovascular implications of paracardial fat are not well-studied. Some studies indicate that paracardial fat is better correlated with cardiometabolic risk factors than epicardial fat.^9,40 Perhaps the accumulating epidemiologic association between pericardial fat (a composite of epicardial and paracardial fat) and coronary atherosclerosis,⁴¹ obstructive coronary artery disease,⁴² incident myocardial infarction,⁴³ and newly diagnosed HF^1-3 will provide the needed impetus for the research community to direct attention toward examining the physio-pathological connotations of paracardial fat on the heart.

References

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Clinical Topics: Arrhythmias and Clinical EP, Cardiovascular Care Team, Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Prevention, Atherosclerotic Disease (CAD/PAD), Atrial Fibrillation/Supraventricular Arrhythmias, Lipid Metabolism, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Interventions and Coronary Artery Disease, Interventions and Imaging, Interventions and Vascular Medicine, Computed Tomography, Nuclear Imaging, Hypertension, Stress, Pericardial Disease

Keywords: Coronary Artery Disease, Heart Failure, Adiponectin, C-Reactive Protein, Interleukin-6, Natriuretic Peptide, Brain, Cardiovascular Diseases, Multidetector Computed Tomography, Waist Circumference, Atrial Fibrillation, Cardiometabolic Risk Factors, Essential Hypertension, Ethnic Groups, Follow-Up Studies, Hypothermia, Insulin Resistance, Intra-Abdominal Fat, Non-alcoholic Fatty Liver Disease, Stroke Volume, Risk, Subcutaneous Fat, Abdominal, Waist-Hip Ratio, Pericardium, Myocardial Infarction, Atherosclerosis, Diabetes Mellitus, Type 2, Hospitalization, Biomarkers, Coronary Circulation, Longitudinal Studies, Models, Statistical, Anti-Inflammatory Agents, Oxidative Stress, Cardiomyopathies, Dyslipidemias, Inflammation, Fatty Acids, Hypertrophy, Myocardium, Phenotype, Ganglia, Obesity

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