Validation of cardiovascular magnetic resonance assessment of pericardial adipose tissue volume

Pericardial adipose tissue (PAT) is the layer of fat that surrounds the heart. It covers 80% of the heart and constitutes between 20 and 50% of its mass[1]. Historically, this adipose layer has largely been regarded as an inert layer that, at most, may provide some mechanical protection to the coronary arteries[2]. More recently however, the benign nature of this fatty tissue is being re-evaluated.

Pericardial adipose tissue is largely brown adipose tissue[3] and is divided into two layers. The visceral, epicardial fat layer is mainly located within the interventricular and atrioventricular grooves, with lesser amounts located around the atria and right ventricle. This visceral pericardial layer (or epicardial layer) originates embryologically from mesothelial cells that migrate from the septum transversum and hence obtains its vascular supply from the coronary arteries[4, 5]. The paracardial fat (or mediastinal fat) is situated external to the parietal layer of the pericardium. This layer originates from the primitive thoracic mesenchymal cells and thus derives its blood supply from non-coronary sources such as the pericardiacophrenic branch of the internal mammary artery[5].

Although the pathophysiological significance of PAT remains uncertain, it has recently become the subject of increasing attention, with emerging evidence that it may be an independent predictor of obstructive coronary artery disease [6‐8] and possibly acute coronary syndrome[6]. Therefore the characterisation of PAT by non-invasive imaging looms as a potentially valuable adjunct in evaluating cardiovascular risk. There are several candidate modalities for non-invasive imaging of pericardial fat with an ideal methodology providing robust and reproducible data with high accuracy when validated against ex vivo fat mass measurement. Transthoracic echocardiography has traditionally been used to measure epicardial adipose thickness[9], however variable image quality remains a significant limitation particularly in obese subjects: a patient cohort in whom quantification of adipose tissue may be especially relevant. More recently, cardiac computed tomography (CT)[8, 10, 11] and cardiovascular magnetic resonance (CMR)[12] have been applied with encouraging results. Although magnetic resonance imaging is recognised as the "gold standard" modality for imaging adipose tissue[13, 14], CMR has only recently evolved to assess adiposity around the heart[12]. The accuracy of this methodology, however, is yet to be verified against actual measurement of ex vivo mass. In this paper we describe a novel method of assessing complete PAT by volume, and additionally, validate ovine paracardial adipose mass collected at necropsy with its corresponding CMR derived volume. Furthermore we show that volumetric assessment of adipose tissue is a more accurate measure of adipose tissue mass compared with surrogates such as adipose tissue thickness at the RV free wall.

An ovine model was chosen to allow direct comparison between CMR-derived measurement of paracardial tissue volume and paracardial tissue mass at necropsy. In addition, a secondary analysis was performed to determine whether single thickness measurement of adipose tissue over the right ventricular (RV) free wall (a parameter routinely used in echocardiographic studies) reflects an accurate surrogate assessment compared to the corresponding adipose tissue mass measured at necropsy.

Eleven Merino sheep (49 ± 7 kg) were evaluated. CMR imaging was successfully performed in all animals and all images were of acceptable quality for subsequent analysis. CMR imaging acquisition time was approximately 45 minutes per animal. There were no adverse outcomes as a result of the CMR imaging process.

This is the first study to describe an accurate and reproducible CMR technique that is capable of measuring not only total PAT by volume but also its constituents, epicardial and paracardial adipose tissue. In addition, we have shown that CMR assessment of adipose tissue volume displays a strong correlation with its corresponding ex vivo adipose mass, validating its use as a robust measure of cardiac adipose tissue. Further, we have shown that conventional RV free wall adipose thickness measurements do not accurately quantify total PAT. Finally, we have described a method for assessing PAT which intentionally utilises image sequences that would normally be acquired during a standard CMR protocol for myocardial structure and function assessment. The images used were not dedicated adipose-specific sequences as is the case in other studies[9, 12] and hence our methodology may be applied to a number of clinically indicated human scans without the need for additional imaging time.

There is growing evidence to support an important role for PAT in the pathophysiology of cardiovascular disease. Although there has recently been a resurgence of interest in this area, the initial descriptions of pericardial adiposity date back hundreds of years. Its initial association with adverse events was described by Senac in 1783 who described "a case of sudden death in which fat spread over the heart extinguishing its movement"[18]. Furthermore the diagnosis of 'adipositas cordis' was a fashionable diagnosis in Victorian times, although the continued association with sudden cardiac death was more than likely related to sudden coronary thrombotic occlusion rather than myocardial fatty infiltration[18]. It was James Herrick's seminal recognition of the clinical syndrome of myocardial infarction in the early 19^th century that led to diminished interest in pericardial adiposity.

Much of the initial work performed to quantify epicardial fat was performed at autopsy[1, 17, 19, 20], with the epicardial adipose tissue weighing on average 50 grams and thus representing approximately 20% of the heart's mass. More recently, echocardiography has been used to evaluate epicardial fat by measuring its thickness over the RV free wall: a prominent site for adipose tissue around the heart[9, 21]. Indeed epicardial fat thickness has been shown to be a predictor of intra-abdominal visceral fat[9, 15], BMI[7, 22], left ventricular mass[23] and insulin resistance[24]. Despite this, our ovine study did not find a correlation between CMR measures of RV free wall epicardial or pericardial adipose thickness and the actual mass of pericardial fat at necropsy. We acknowledge however, that there may still be some utility in using epicardial fat thickness in ongoing research of cardiovascular risk assessment, particularly given the accessibility and affordability of transthoracic echocardiograpy compared to CMR. However, the imperfect relationship between this echocardiographic index and PAT, in addition to its lower reproducibility, mean that much larger numbers of patients will be required in such studies. Our CMR technique allows future studies of PAT to show potential alterations or even changes in PAT in response to various therapeutic interventions without the need for prohibitively large sample sizes.

While echocardiography has obvious benefits it also has limitations: most notably its reliance on optimal imaging windows which are notoriously difficult in obese patients[25]. In one study, evaluating over 900 patients from an outpatient echocardiography service, 14% of obese subjects had poor echocardiographic images[26]. This is relevant given that these high-risk patients may ultimately benefit from cardiovascular risk prediction assessment from non-invasive characterisation of epicardial and/or pericardial fat. By comparison, CMR is heralded for its ability to provide excellent tissue resolution in such patients. Echocardiography is also limited in its ability to measure the complete pericardial adipose layer and in particular, to determine total pericardial volume. Volumetric assessment of PAT by CT has been shown to predict the presence of significant coronary artery disease[8] and also to be associated with left ventricular structure and function[10] in subgroups of the Framingham Heart Study. However unlike CMR, cardiac CT has the limitation of exposing patients to ionising radiation, which becomes an increasingly important consideration if patients are subjected to serial imaging.

An intriguing issue that has remained unresolved in the area of pericardial adipose assessment relates to the importance of differentiating between the epicardial and paracardial layers of adipose. The mechanistic relevance of these two zones of fat appears to be quite distinct. They have different embryological origins and vascular supply[4, 5]. The epicardial fat layer expresses higher levels of pro-inflammatory mediators than subcutaneous fat in patients with established coronary artery disease suggesting a pathophysiological relationship[27, 28]. Pericardial adipose tissue may also have a detrimental effect on the coronary vasculature due to mechanical restriction and impairment to diastolic coronary flow[29]. As such, the paracardial layer may have greater importance because it remains the main component of total PAT, as confirmed by the current study. Further studies are required to evaluate the relative clinical importance of the individual adipose layers.

Although it was necessary for this study to be performed in animals to allow for validation of in vivo CMR against ex vivo tissue assessment, we do not have reason to doubt the applicability of our findings to the human clinical scenario. Furthermore, we deliberately did not use pre-defined, fat-specific imaging sequences in our CMR protocols because it was our intention to utilise the exact images which would otherwise be acquired in a routine clinical investigation. Whilst this CMR protocol did not utilise inter-slice gaps in the short axis stack, unpublished data analysed in other studies[30] suggests it would be unlikely to have a significant effect on our results.

A simple CMR volumetric technique using standard clinical steady state free precession imaging is the most accurate and reproducible tool currently available for the assessment of pericardial adipose tissue. Furthermore this non-invasive modality does not use ionising radiation and therefore is ideally suited for future studies of pericardial adipose tissue and its role in cardiovascular risk prediction and disease in clinical practice.