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

  • Lechner, Katharina1, 2
  • McKenzie, Amy L.3
  • Kränkel, Nicolle4, 5
  • Von Schacky, Clemens6, 7
  • Worm, Nicolai8
  • Nixdorff, Uwe9
  • Lechner, Benjamin10
  • Scherr, Johannes1, 11
  • Weingärtner, Oliver12
  • Krauss, Ronald M.13
  • 1 Department of Prevention, Rehabilitation and Sports Medicine, School of Medicine, Technical University of Munich, Munich, Germany.
  • 2 DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany.
  • 3 Virta Health, San Francisco, California, USA.
  • 4 Klinik Für Kardiologie, Campus Benjamin Steglitz, Charité—Universitätsmedizin Berlin, Berlin, Germany.
  • 5 DZHK (German Center for Cardiovascular Research), Partner Site Berlin, Berlin, Germany.
  • 6 Preventive Cardiology, Ludwig-Maximilians University, Munich, Germany.
  • 7 Omegametrix, Martinsried, Germany.
  • 8 German University for Prevention and Health Care Management, Saarbrücken, Germany.
  • 9 European Prevention Center, Düsseldorf, Germany.
  • 10 Department of Internal Medicine IV, Ludwig-Maximilians University, Munich, Germany.
  • 11 University Center for Prevention and Sports Medicine, Balgrist University Hospital, University of Zurich, Zurich, Switzerland.
  • 12 Klinik Für Innere Medizin I, Universitätsklinikum Jena, Jena, Germany.
  • 13 University of California, San Francisco, San Francisco, California, USA.
Published Article
Metabolic Syndrome and Related Disorders
Mary Ann Liebert
Publication Date
Apr 28, 2020
DOI: 10.1089/met.2019.0115
PMID: 32119801
PMCID: PMC7196362
PubMed Central


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.

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