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.

NAFLD and cardiovascular diseases: a clinical review

“…Disorders of glucose metabolism in NAFLD patients can be attributed to the underlying systemic inflammation, visceral obesity in conjunction with commonly increased body weight, but also to an increased accumulation of dysfunctional ectopic fatty tissue [12,44]. In addition to an increased liver fat content, accumulation of pancreatic ectopic dysfunctional adipose tissue plays an important role in this context, which [12,28,29]). SFA saturated fatty acids, OSAS obstructive sleep apnea syndrome, carb.…”

“…Insulin resistance and impaired insulin signaling affects various processes that are associated with atherogenesis, enhanced progression of atherosclerotic lesions and plaque vulnerability. Persistent hyperglycemia and postprandial glucose spikes promote oxidative stress with concomitant activation of inflammatory signaling pathways, inflammasome activation, and vascular inflammation via advanced glycation end products (AEG), as well as dysregulation of lipoprotein metabolism or continuing ectopic fat accumulation [12,45,47]. Furthermore, insulin resistance is associated with dysregulated neurohumoral activation of the renin-angiotensin-aldosterone system, fibrinolytic dysfunction via increased plasminogen activator inhibitor-1 (PAI-1) levels, the development of cardiac autonomic neuropathy, which may promote the development of systolic and diastolic dysfunction or cardiac arrhythmias, and endothelial dysfunction [12,[47][48][49][50].…”

“…While most patients have mild steatosis, approximately 20-30% of cases develop NASH with progressive fibrosis, and of those, approximately 20% will progress to cirrhosis with an increased risk of hepatocellular carcinoma [10,11]. Risk factors associated with NAFLD progression include genetic alterations, increasing age, inflammation, gut dysbiosis and metabolic abnormalities such as insulin resistance and hyperinsulinemia [10][11][12][13].…”

Nonalcoholic Fatty Liver Disease and Cardiovascular Diseases: The Heart of the Matter

“…Abnormal glucose metabolism and hepatic IR are the major hallmarks of NAFLD, and they are the main elements in NAFLD and CVD pathogenesis [ 11 – 13 ]. The glucose metabolism disorders in NAFLD are secondary to the underlying systemic inflammation, visceral adiposity, and ectopic fatty tissue [ 14 , 15 ]. The IR is associated with hyperinsulinemia that determines increase in hepatic glucose production and chronic hyperglycemia.…”

“…Persistent hyperglycemia and IR promote oxidative stress, activation of inflammation, and dysregulation of lipoprotein metabolism [ 14 , 16 , 17 ]. IR promotes oxidative stress and activation of inflammatory signaling pathways, vascular inflammation, and dysregulation of lipids metabolism contributing to ectopic fat accumulation [ 14 , 18 , 19 ]. Pancreatic ectopic adipose tissue is also associated with IR and beta cell dysfunction, hyperinsulinemia, and secondary increase of free fatty acid level.…”