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The Low-Density Lipoprotein Cholesterol Hypothesis: An Update

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Therapeutic Lipidology

Part of the book series: Contemporary Cardiology ((CONCARD))

Abstract

Catabolism of VLDL by lipoprotein lipase creates higher density particles including HDL, IDL, and LDL. Each LDL contains a single apoB and has a core made of esterified cholesterol. The primary transport for cholesterol in the body is via LDL. The main mechanism of clearance of LDL is via hepatic LDL-R.

Numerous studies throughout the 1990s and early 2000s showed an association between reduced LDL-C levels and improved cardiovascular outcomes. Imaging studies in the early twenty-first century showed halting of plaque and even regression with decreased LDL-C concentrations. This led to the LDL hypothesis in which LDL is a causal factor for the development of atherosclerotic disease. However, the pleiotropic effect of statins was a possible confounding factor in the major trials, leading many to discount the LDL hypothesis. With the advent of PCSK9 inhibitors, as well as newer trials and meta-analyses showing improved outcomes with decreased LDL in a statin independent manner, the LDL hypothesis has been vindicated.

The first step LDL takes to worsen disease is oxidization. Once LDL is oxidized, it contributes to atherosclerosis via increasing endothelial dysfunction, foam cell formation, vascular smooth-muscle cell migration and proliferation, and induction of platelet adhesion and aggregation.

The latest guidelines use many factors to risk-stratify patients and recommend maintaining LDL-C levels between 55 and 70 mg/dL for the highest risk individuals. These very low levels may actually be the normal physiologic range for humans, with no harm seen at extremely low levels. Statins are generally considered first-line treatment to reduce LDL, with ezetimibe, bile acid sequestrants, and PCSK9 inhibitors added for increased control.

In this chapter, we delve in detail on the aforementioned topics, present a comprehensive review of LDL, and include the latest information a practicing clinician needs to know.

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Author information

Authors and Affiliations

  1. Department of Internal Medicine, Division of Cardiology, Baylor University Medical Center, Baylor Heart and Vascular Hospital, Dallas, TX, USA

    Ronak Rengarajan

  2. Baylor Heart and Vascular Institute, Baylor Scott and White Research Institute, Dallas, TX, USA

    Kristen M. Tecson

  3. Department of Internal Medicine, Division of Cardiology, Baylor University Medical Center, Baylor Heart and Vascular Hospital, Baylor Heart and Vascular Institute, Dallas, TX, USA

    Peter A. McCullough

Authors
  1. Ronak Rengarajan
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  2. Kristen M. Tecson
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  3. Peter A. McCullough
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Corresponding author

Correspondence to Peter A. McCullough .

Editor information

Editors and Affiliations

  1. The University of Chicago Pritzker School of Medicine, Chicago, IL, USA

    Michael H. Davidson

  2. Cicarrone Center for the Prevention of Cardiovascular Disease, Johns Hopkins Univerity School of Medicine, Baltimore, MD, USA

    Peter P. Toth

  3. Department of Applied Health Science, Indiana University School of Public Health, Bloomington, IN, USA

    Kevin C. Maki

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Rengarajan, R., Tecson, K.M., McCullough, P.A. (2021). The Low-Density Lipoprotein Cholesterol Hypothesis: An Update. In: Davidson, M.H., Toth, P.P., Maki, K.C. (eds) Therapeutic Lipidology. Contemporary Cardiology. Humana, Cham. https://doi.org/10.1007/978-3-030-56514-5_7

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  • DOI: https://doi.org/10.1007/978-3-030-56514-5_7

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  • Publisher Name: Humana, Cham

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  • Online ISBN: 978-3-030-56514-5

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