Atherosclerosis is an inflammatory disease. Because high plasma concentrations of cholesterol, in particular those of low-density lipoprotein (LDL) cholesterol, are one of the principal risk factors for atherosclerosis,1 the process of atherogenesis has been considered by many to consist largely of the accumulation of lipids within the artery wall; however, it is much more than that. Despite changes in lifestyle and the use of new pharmacologic approaches to lower plasma cholesterol concentrations,2,3 cardiovascular disease continues to be the principal cause of death in the United States, Europe, and much of Asia.4,5 In fact, the lesions of atherosclerosis represent . . .

https://www.nejm.org/doi/pdf/10.1056/NEJM199901143400207

Atherosclerosis — An Inflammatory Disease

Detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III)

Atherosclerosis is an Inflammatory Disease

ecent research has shown that inflammation plays a key role in coronary artery disease (CAD) and other manifestations of atherosclerosis. Immune cells dominate early atherosclerotic lesions, their effector molecules accelerate progression of the lesions, and activation of inflammation can elicit acute coronary syndromes. This review highlights the role of inflammation in the pathogenesis of atherosclerotic CAD. It will recount the evidence that atherosclerosis, the main cause of CAD, is an inflammatory disease in which immune mechanisms interact with metabolic risk factors to initiate, propagate, and activate lesions in the arterial tree. A decade ago, the treatment of hypercholesterolemia and hypertension was expected to eliminate CAD by the end of the 20th century. Lately, however, that optimistic prediction has needed revision. Cardiovascular diseases are expected to be the main cause of death globally within the next 15 years owing to a rapidly increasing prevalence in developing countries and eastern Europe and the rising incidence of obesity and diabetes in the Western world. 1 Cardiovascular diseases cause 38 percent of all deaths in North America and are the most common cause of death in European men under 65 years of age and the second most common cause in women. These facts force us to revisit cardiovascular disease and consider new strategies for prediction, prevention, and treatment.

/pdf/inflammation-atherosclerosis-and-coronary-artery-disease-23ryhxhuc2.pdf

Inflammation, Atherosclerosis, and Coronary Artery Disease

The primary purpose of this narrative review was to evaluate the current literature and to provide further insight into the role physical inactivity plays in the development of chronic disease and premature death. We confirm that there is irrefutable evidence of the effectiveness of regular physical activity in the primary and secondary prevention of several chronic diseases (e.g., cardiovascular disease, diabetes, cancer, hypertension, obesity, depression and osteoporosis) and premature death. We also reveal that the current Health Canada physical activity guidelines are sufficient to elicit health benefits, especially in previously sedentary people. There appears to be a linear relation between physical activity and health status, such that a further increase in physical activity and fitness will lead to additional improvements in health status.

/pdf/health-benefits-of-physical-activity-the-evidence-17tsp10zcy.pdf

Health benefits of physical activity: the evidence

The cholesteryl ester transfer protein (CETP) is a hydrophobic M, 70,000 glycoprotein that mediates the transfer and exchange of neutral lipids and phospholipids between the plasma lipoproteins.] The CETP mediates the exchange of HDL CE with the triglycerides of triglyeride-rich lipoproteins (TRL), and thereby enhances the overall catabolism of HDL CE.’ In human genetic CETP deficiency, HDL CE and apoA-I levels are Two common CETP gene mutations have been described in the

Cholesteryl Ester Transfer Protein and Atherogenesis

Metabolic Determinants of Low HDL-C Levels

### Effect of a Monoclonal Antibody to PCSK9 on LDL Cholesterol Stein et al New Eng J Med . 2012;366:1108–1118.

Lowering of LDL cholesterol, predominantly accomplished clinically by statins, is one of the key components of both the prevention and medical management of coronary atherosclerosis; however, additional or alternative cholesterol lowering agents are needed for patients who fail to achieve goals or have adverse effects on statins. Owing to relatively rapid translation of basic science research on a novel regulatory pathway of the LDL receptor by PCSK9, a new class of such drugs with a different mode of action, and potentially better tolerance and less off-target effects may be just over the horizon. 

Proprotein convertase subtilisin/kexin 9 (PCSK9) binds to LDL receptors, resulting in their accelerated degradation and increased LDL cholesterol levels. In a recent New England Journal of Medicine article, Stein et al reported the use of a monoclonal antibody (REGN727) to PCSK9 with the goal of lowering LDL cholesterol levels in 3 randomized double-blind placebo controlled phase I studies.1 The first 2 studies were single-dose escalation studies performed in healthy volunteers, 1 by the intravenous and the other by the subcutaneous route, and each led to dose-dependent reductions in LDL cholesterol levels (28%–65% and 32%–46%, respectively) that were rapid and prolonged. The third study was a multiple-dose escalation study, with drug delivered subcutaneously on days 1, 29, and 43, performed in patients with familial hypercholesterolemia (FH) and non-FH receiving atorvastatin and a small group of 10 patients with non-FH on a modified diet alone (baseline LDL cholesterol, >130 mg per deciliter [3.4 mmol per liter]). In statin-treated FH and non-FH patients, subcutaneous REGN727 lowered LDL cholesterol levels an additional 40% to 60%, depending on dose. Interestingly, REGN727 lowered LDL cholesterol levels by a similar degree in non-FH patients not taking a statin compared to those taking a statin. These studies strongly suggest PCSK9 inhibition as a promising …

Antibodies to PCSK9: a superior way to lower LDL cholesterol?

This chapter outlined the methods used to study intra- and extracellular modifications of apolipoproteins. These and other related studies have shown that several of the apolipoproteins undergo a series of intra- and extracellular modifications as follows: 1. 1. All apolipoproteins studied contain an 18–26 long signal peptide which is cleaved contranslationally by the signal peptidase of the rough endoplasmic reticulum. 2. 2. ApoE is further modified intracellularly with carbohydrate chains containing sialic acid and is secreted in the modified form designated apoEs. The modified apoE is subsequently desialated in plasma. 3. 3. ApoA-I is secreted in a proapoA-I form, which consists of 249 amino acids. The N-terminal hexapeptide of proapoA-I is cleaved extracellularly by a proapoA-I to plasma apoA-I converting protease. This cleavage generates the plasma apoA-I form which consists of 243 amino acids. 4. 4. Other known apolipoprotein modifications include the modification of apoB, apoC-III, and apoD with carbohydrate chains that contain sialic acid and the proteolytic cleavage of the proapoA-II segment. At the present time we are able to distinguish several isoprotein forms for a particular apolipoprotein. In addition, we began to understand the biochemical changes which lead to a few of these isoproteins.

[40] Intra- and extracellular modifications of apolipoproteins

The architecture of natural variation present in a contemporary population is a result of multiple population genetic forces, including population bottleneck and expansion, selection, drift, and admixture. We seek to untangle the contribution of admixture to genetic diversity on the Micronesian island of Kosrae. Toward this goal, we used a complete genetic approach by combining a dense genome-wide map of 100 000 single-nucleotide polymorphisms (SNPs) with data from uniparental markers from the mitochondrial genome and the nonrecombining portion of the Y chromosome. These markers were typed in ∼3200 individuals from Kosrae, representing 80% of the adult population of the island. We developed novel software that uses SNP data to delineate ancestry for individual segments of the genome. Through this analysis, we determined that 39% of Kosraens have some European ancestry. However, the vast majority of admixed individuals (77%) have European alleles spanning less than 10% of their genomes. Data from uniparental markers show most of this admixture to be male, introduced in the late nineteenth century. Furthermore, pedigree analysis shows that the majority of European admixture on Kosrae is because of the contribution of one individual. This approach shows the benefit of combining information from autosomal and uniparental polymorphisms and provides new methodology for determining ancestry in a population.

/pdf/european-admixture-on-the-micronesian-island-of-kosrae-17ci87dppx.pdf

Jan L. Breslow

Papers

Cholesteryl Ester Transfer Protein and Atherogenesis

Metabolic Determinants of Low HDL-C Levels

Antibodies to PCSK9: a superior way to lower LDL cholesterol?

[40] Intra- and extracellular modifications of apolipoproteins

European admixture on the Micronesian island of Kosrae: lessons from complete genetic information