Detecting human coronary inflammation by imaging perivascular fat

Abstract

Early detection of vascular inflammation would allow deployment of targeted strategies for the prevention or treatment of multiple disease states. Because vascular inflammation is not detectable with commonly used imaging modalities, we hypothesized that phenotypic changes in perivascular adipose tissue (PVAT) induced by vascular inflammation could be quantified using a new computerized tomography (CT) angiography methodology. We show that inflamed human vessels release cytokines that prevent lipid accumulation in PVAT-derived preadipocytes in vitro, ex vivo, and in vivo. We developed a three-dimensional PVAT analysis method and studied CT images of human adipose tissue explants from 453 patients undergoing cardiac surgery, relating the ex vivo images with in vivo CT scan information on the biology of the explants. We developed an imaging metric, the CT fat attenuation index (FAI), that describes adipocyte lipid content and size. The FAI has excellent sensitivity and specificity for detecting tissue inflammation as assessed by tissue uptake of 18F-fluorodeoxyglucose in positron emission tomography. In a validation cohort of 273 subjects, the FAI gradient around human coronary arteries identified early subclinical coronary artery disease in vivo, as well as detected dynamic changes of PVAT in response to variations of vascular inflammation, and inflamed, vulnerable atherosclerotic plaques during acute coronary syndromes. Our study revealed that human vessels exert paracrine effects on the surrounding PVAT, affecting local intracellular lipid accumulation in preadipocytes, which can be monitored using a CT imaging approach. This methodology can be implemented in clinical practice to noninvasively detect plaque instability in the human coronary vasculature.

Perivascular adipose tissue and coronary atherosclerosis

“…Nevertheless, the absence of a clear anatomical border has resulted in highly heterogeneous definitions of coronary PVAT in the literature. We have recently proposed a definition of PVAT as any AT within a radial distance from the outer vessel wall equal to the diameter of the adjacent coronary vessel 7. This definition is based on a series of histological and gene expression studies that have revealed changing patterns in AT phenotype with increasing distance from the vascular wall, as a result of complex, paracrine vessel–PVAT interactions 7.…”

“…We have recently proposed a definition of PVAT as any AT within a radial distance from the outer vessel wall equal to the diameter of the adjacent coronary vessel 7. This definition is based on a series of histological and gene expression studies that have revealed changing patterns in AT phenotype with increasing distance from the vascular wall, as a result of complex, paracrine vessel–PVAT interactions 7. In order to better understand these, a review of the physiological functions of PVAT in health and disease is necessary.…”

“…In order to create a standardised CT-based approach to the qualitative analysis of PVAT, we have recently described a novel metric, namely the Fat Attenuation Index (FAI), that provides a numerical index of AT composition 7. FAI was defined as the standardised average attenuation of the AT in a region of interest (within the prespecified window of −190 to −30 Hounsfield Units (HU)) and was inversely associated with adipocyte size and differentiation 7. In the past, several studies have assessed the association of EAT attenuation with the overall cardiovascular risk profile and CAD.…”

“…We have recently developed, for the first time, a detailed analysis method of coronary PVAT as a sensor of coronary inflammation and vascular disease, which can be calculated on routine coronary CT angiograms 7. This followed the observation that in the presence of coronary inflammation, the release of proinflammatory mediators from the vascular wall into the surrounding PVAT blocks the differentiation of perivascular preadipocytes into mature, lipid-laden adipocytes 7.…”

Rational Approaches Targeting the Prevention of Cardiovascular Calcification: The Evolving Field of Osteocardiology

“…Whilst echocardiography and CT were previously capable of detecting only large flakes or nodules of calcium, recent technological advancements have also rendered feasible the imaging of microcalcification. For example, with state-of-the-art coronary CT angiography [9], plaque microcalcification (>215 μm) can be detected, visualized as ‘spotty’ calcification, which is an index of active plaque inflammation and predictive of plaque rupture in clinical studies [2]. Moreover, 18 F-fluoride positron emission tomography (PET) imaging has excellent sensitivity for detecting areas of active microcalcification, where large macroscopic calcium deposits will subsequently accumulate [10].…”