We investigated whether pericardial fat is adversely related to myocardial perfusion in asymptomatic adults with no prior history of cardiovascular disease. The main finding of this study was that pericardial fat is not associated with coronary vasoreactivity. The lack of a significant relationship between pericardial fat and both hyperemic MBF and PR was surprising given that inverse associations have been found with cardiac obesity in symptomatic individuals 
. We did find an association between higher pericardial fat and higher resting MBF in women; however, this association was attenuated after further adjustment for BMI or RPP. Thus, our data fail to support an independent association between pericardial fat and myocardial perfusion in this population.
Previous studies investigating the association between cardiac obesity and myocardial perfusion have predominately included symptomatic individuals. Sade et al. reported that among women with angiographically normal coronary arteries, those with an impaired PR had 38% greater epicardial fat thickness on the free wall of the right ventricle than women with a normal PR 
. However, measurements of epicardial fat thickness at a single point are highly dependent on cardiac anatomy and fat distribution 
and do not correlate well with either epicardial or pericardial fat volume 
. More recently, Bucci et al. found that among patients with obstructive CAD, epicardial fat volume was roughly 20% higher in those with a hyperemic MBF value below vs. above the median (≤1.75 ml/min/g) 
. Additionally, higher epicardial fat was an independent predictor of lower hyperemic MBF and PR in multiple regression analyses. Janik et al. also reported that among patients presenting with angina and no prior cardiovascular disease, individuals with mild-to-severe ischemia had 38% higher epicardial fat volume compared to those with no ischemia 
. In a similar study that included adults with and without symptoms, Tamarappoo et al. reported 22% higher pericardial fat volume and 24% higher epicardial fat volume in patients with ischemia compared to non-ischemic controls 
. Although the proportion of asymptomatic individuals was fairly similar between cases and controls (63% vs. 54%, respectively), the presence of symptoms was one of the strongest predictors of prevalent ischemia in multivariable analyses, second only to epicardial/pericardial fat volume.
In contrast to the study by Tamarappoo et al., we were unable to find a significant association between pericardial fat and myocardial ischemia. In fact, pericardial fat was only 9% and 5% higher in men and women, respectively, with impaired PR compared to those with a normal PR. In addition, although we observed a significant correlation between higher pericardial fat and lower PR (in women only), this association was attenuated after adjusting for other risk factors. As such, these data suggest that pericardial fat does not have independent effects on myocardial perfusion in asymptomatic adults. Moreover, our findings highlight potentially important distinctions between asymptomatic and symptomatic persons with respect to subclinical atherosclerosis. For example, in the study by Tamarappoo et al., approximately 91% of the population had moderate-to-severe atherosclerosis as evidenced by coronary calcium scores ≥100 
. On the other hand, only 26% of our study participants had coronary calcium scores ≥100, with nearly half having no coronary calcium present at all. High coronary calcium scores are associated with a higher likelihood of significant coronary stenosis, whereas the absence of coronary calcium is associated with a very low likelihood of obstructive CAD 
. Moreover, symptomatic CAD patients with elevated coronary calcium scores have more severe stenosis than asymptomatic CAD patients with similar calcium scores 
, suggesting that the presence of symptoms does indeed reflect the underlying pathology, and likely the patient profile. In this regard, the prevalence of impaired coronary vasoreactivity (as defined using a lower cut-off value of PR<2.0) was very low in our women (6%), compared to those in the study by Sade et al. (40%). Furthermore, while the majority of our participants had a low-to-medium 10-year CAD risk (Framingham risk score
8%), Tamarappoo et al. and Janik et al. investigated persons with Framingham risk scores of ~12–14% 
Obesity-related cardiovascular disease may be partially caused by altered adipokine-mediated signaling between local fat depots and the adjacent blood vessels and cardiomyocytes 
. Epicardial fat has a high expression of chemokines and inflammatory cytokines 
, and increased periaortic fat in aging and obesity promotes vascular smooth muscle cell growth 
. Thus, in the presence of excess fat, these pro-inflammatory activities are likely to be increased and thereby promote the development of vascular dysfunction and atherosclerosis. Consistent with this, Bucci et al. reported that among patients with CAD, only those with significant flow-limiting stenosis had increased epicardial fat volume, which suggests that in our population the combination of CAD and increased pericardial fat may promote impaired coronary vascular function, while CAD plus low/normal pericardial fat may not. Although we do not have direct measures of CAD, we did find that the prevalence of a reduced PR was 48% in participants with coronary calcium present and pericardial fat volume in the highest quartile (≥130.5 cm3
in men, ≥91.2 cm3
in women), while the prevalence was only 15% in participants with no coronary calcium and pericardial fat in the lowest quartile (<64.0 cm3
in men, <47.6 cm3
in women). We also found positive associations between pericardial fat and C-reactive protein, age, blood pressure, HDL cholesterol, BMI, waist circumference, and left ventricular mass in this study, which confirms previous findings in the Framingham Heart Study 
. Although a significant univariate association was found between pericardial fat and resting MBF in women, adjusting for BMI attenuated this relationship. Resting RPP (an indicator of cardiac work) also appeared to be an important determinant of resting MBF and accounted for much of the association between pericardial fat and resting MBF. It is important to remember that our measurement of pericardial fat reflects both the direct paracrine effects of epicardial fat on the coronary arteries, as well as the indirect systemic effects of thoracic visceral fat (i.e. paracardial fat) on metabolic risk factors 
. Thus, taken together, these data suggest that in asymptomatic individuals, global obesity may have a greater influence on coronary vasoreactivity than cardiac obesity.
There are a few limitations in this study. The sample size was relatively small, which may have limited our ability to detect associations in men vs. women. Although gender differences in the prevalence and severity of cardiovascular diseases are well-documented, the impact of gender on obesity-related changes in MBF requires further study. In addition, our investigation was limited to cross-sectional analyses, which cannot determine whether increased pericardial fat precedes coronary vascular dysfunction. Similarly, our assessment of abdominal obesity was limited to anthropometric measures that cannot distinguish between visceral and subcutaneous fat. Without direct measures of total and abdominal fat, however, the relative importance of pericardial fat remains to be elucidated. We also cannot rule out the possibility that our participant subset is not completely representative of or generalizable to the larger MESA population, nor can we confirm the absence of obstructive atherosclerotic lesions since our participants did not undergo coronary angiography. Finally, although the myocardial perfusion measurements are fairly reproducible, the variability of the hyperemic MBF response over 1 year (absolute repeatability coefficient
1.19 ml/min/g) has been shown to increase with the length of time between baseline and follow-up measurements 
. This bias may underestimate the true variability in hyperemic MBF over longer periods of time, which is important to know for prospective population-based studies designed to assess the influence of risk factors on disease incidence and progression.
In conclusion, pericardial fat is not independently associated with hyperemic MBF or PR in asymptomatic men and women with no prior history of cardiovascular disease. These results are in contrast to a previous study in predominately symptomatic adults. Despite the present negative findings, our study provides some insight into the relationship among pericardial fat, atherosclerosis, and MBF in asymptomatic vs. symptomatic individuals. In this regard, it seems plausible that individuals with and without ischemic symptoms may have a different subclinical atherosclerotic disease burden, which may influence the effect of pericardial fat on coronary microvascular function. These differences may have important clinical implications for improving risk stratification in asymptomatic populations. Given the growing evidence that pericardial fat may be an important therapeutic target in the prevention of CAD 
, further research in this area is warranted.