High-Risk Atherosclerosis and Metabolic Phenotype: The Roles of Ectopic Adiposity, Atherogenic Dyslipidemia, and Inflammation

Abstract

Current algorithms for assessing risk of atherosclerotic cardiovascular disease (ASCVD) and, in particular, the reliance on low-density lipoprotein (LDL) cholesterol in conditions where this measurement is discordant with apoB and LDL-particle concentrations fail to identify a sizeable part of the population at high risk for adverse cardiovascular events. This results in missed opportunities for ASCVD prevention, most notably in those with metabolic syndrome, prediabetes, and diabetes. There is substantial evidence that accumulation of ectopic fat and associated metabolic traits are markers for and pathogenic components of high-risk atherosclerosis. Conceptually, the subset of advanced lesions in high-risk atherosclerosis that triggers vascular complications is closely related to a set of coordinated high-risk traits clustering around a distinct metabolic phenotype. A key feature of this phenotype is accumulation of ectopic fat, which, coupled with age-related muscle loss, creates a milieu conducive for the development of ASCVD: atherogenic dyslipidemia, nonresolving inflammation, endothelial dysfunction, hyperinsulinemia, and impaired fibrinolysis. Sustained vascular inflammation, a hallmark of high-risk atherosclerosis, impairs plaque stabilization in this phenotype. This review describes how metabolic and inflammatory processes that are promoted in large measure by ectopic adiposity, as opposed to subcutaneous adipose tissue, relate to the pathogenesis of high-risk atherosclerosis. Clinical biomarkers indicative of these processes provide incremental information to standard risk factor algorithms and advanced lipid testing identifies atherogenic lipoprotein patterns that are below the discrimination level of standard lipid testing. This has the potential to enable improved identification of high-risk patients who are candidates for therapeutic interventions aimed at prevention of ASCVD.

Keywords: atherosclerosis; dyslipidemia; ectopic adipose tissue; inflammation; lifestyle; metabolic syndrome.

FIG. 1.

The ectopic adiposity phenotype. Ectopic fat accumulation in the abdominal cavity (visceral fat) and in organs like pericardium, liver, and pancreas (A), and muscle wasting/intramuscular fat accumulation (B) are bidirectionally linked to chronic inflammation (C) and insulin resistance (D), both of which have been linked to conventional and novel pathways of cardiometabolic risk. Ectopic fat is a major driver of atherosclerosis and its acute complications: epicardial fat (A1) has been linked to AF, accelerated coronary atherosclerosis, and left ventricular diastolic dysfunction; hepatic fat (NAFLD) (A2) causally contributes to atherogenic dyslipidemia and is closely linked to subclinical atherosclerosis; and pancreatic fat (A3) has been linked to beta-cell dysfunction and concomitant postprandial and fasting hyperglycemia. Chronically elevated serum glucose levels, and postprandial glucose spikes in particular, promote oxidative stress/chronic inflammation, endothelial dysfunction, and sympathetic hyperactivity, and result in the formation of AGEs. Glycation damage has been pathophysiologically linked to numerous chronic disease states such as cardiovascular aging. Down arrows indicate decreased levels, and up arrows indicate increased levels. AF, arrhythmia/atrial fibrillation; AGEs, advanced glycation end products; NAFLD, non-alcoholic fatty liver disease. Color images are available online.

FIG. 2.

Inflammation and plaque phenotype. When LDLs penetrate the intima of the vessel wall from the lumen, the Lp-PLA2 residing there uses oxLDL as a substrate, hydrolyzing it to Lyso-PC and OxFA. Lyso-PC and OxFA act as secondary messengers that stimulate the upregulation of adhesion molecules on the lumen surface, act as chemoattractants for circulating inflammatory cells, and play a role in the activation and transformation of local macrophages within the plaque lesion. As activated local macrophages take up oxidized (phospho)lipids, they transform to foam cells and subsequently express more Lp-PLA2, creating a vicious proinflammatory cycle. The expression of other cytokines like MCP-1 and adhesion molecules creates a feedback loop by attracting more monocytes to the plaque. This feedback loop generates a vicious cycle of attracting more inflammatory cells to the plaque lesion, resulting in an infiltration with an abundance of inflammatory cells, a thinning of the fibrous cap, and a growing necrotic lipid core. Although this process often results in limited luminal narrowing, it leads to the main clinical complications of ASCVD. ASCVD, atherosclerotic cardiovascular disease; LDL, low-density lipoprotein; Lp-PLA2, lipoprotein-associated phospholipase A2; Lyso-PC, lyso-phosphatidylcholine; MCP-1, monocyte chemoattractant protein-1; OxFA, oxidized fatty acids; oxLDL, oxidized LDL. Color images are available online.