IN the 19th century there were two major hypotheses to explain the pathogenesis of atherosclerosis: the "incrustation" hypothesis and the "lipid" hypothesis. The incrustation hypothesis of von Rokitansky,1 proposed in 1852 and modified by Duguid,2 suggested that intimal thickening resulted from fibrin deposition, with subsequent organization by fibroblasts and secondary lipid accumulation. The lipid hypothesis, proposed by Virchow3 in 1856, suggested that lipid in the arterial wall represented a transduction of blood lipid, which subsequently formed complexes with acid mucopolysaccharides; lipid accumulated in arterial walls because mechanisms of lipid deposition predominated over those of removal. The two hypotheses are now . . .

https://www.nejm.org/doi/pdf/10.1056/NEJM199201233260406?articleTools=true

The pathogenesis of coronary artery disease and the acute coronary syndromes (1).

Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma protein cofactor

Lipoprotein(a) [Lp(a)] is a macromolecular complex found in human plasma that combines structural elements from the lipoprotein and blood clotting systems and that is associated with premature coronary heart disease and stroke. It is assembled from low-density lipoprotein (LDL) and a large hydrophilic glycoprotein called apolipoprotein(a) [apo(a)], which is homologous to the protease zymogen plasminogen. Plasma Lp(a) concentrations vary 1000-fold between individuals and represent a continuous quantitative genetic trait with a skewed distribution in Caucasian populations. Variation in the hypervariable apo(a) gene on chromosome 6q2.6-q2.7 and interaction of apo(a) alleles with defective LDL-receptor genes explain a large fraction of the variability of plasma Lp(a) concentrations. Though of high theoretical and practical interest, many aspects of the metabolism, function, evolution, and regulation of plasma concentrations of Lp(a) are presently unknown, controversial, or mysterious.

http://science.sciencemag.org/content/sci/246/4932/904.full.pdf

The mysteries of lipoprotein(a)

Much more is known about the APLS than 15 yr ago, but more needs to be done. Clinically, major characteristics of the disorder have been defined, but the course of the disease and its relationship to other disorders, such as systemic lupus erythematosus (SLE), need to be defined. Good progress has been made in standardizing anticardiolipin and, to a lesser extent, LA. However, problems with interlaboratory and inter-assay variation need to be addressed. Doctors are getting a better idea of how to manage these patients with a view to preventing recurrences of thrombosis or pregnancy losses, but prospective studies are still desirable to give more definitive answers. Attention has turned to the pathogenesis of the disorder. It seems likely that antibodies mediate the clinical disorders with which they are associated, but the mechanisms by which this occurs still require further study.

The antiphospholipid syndrome. Diagnosis, management, and pathogenesis.

Atherosclerotic diseases and their thrombotic complications remain the leading causes of mortality and morbidity in Western society In the United States, cardiovascular disease is responsible for one in every 24 (414%) deaths and is the leading single cause of mortality Furthermore, the presence of atherosclerotic disease (defined as thickening of the arterial wall through the accumulation of lipids, macrophages, T-lymphocytes, smooth muscle cells, extracellular matrix, calcium and necrotic debris) is more prevalent, but by itself rarely fatal The crucial, final common process for the conversion of a nonocclusive, often clinically silent atherosclerotic lesion to a potentially fatal condition is often plaque disruption The mortality associated with atherosclerotic disease relates to the acute coronary syndromes, including acute myocardial infarction, unstable angina pectoris and sudden cardiac death Substantial clinical, experimental and postmortem evidence demonstrates the central role that a superimposed acute thrombosis on a disrupted atherosclerotic plaque plays in the onset of acute coronary syndromes Therefore, therapeutic approaches to date have focused on reducing such thrombotic complications of atherosclerotic plaques (ie, antiplatelet, anticoagulant and thrombolytic therapies) to reduce the resulting morbidity and mortality In this review, we will focus on the current theories of atherogenesis and how they impact on our understanding of acute coronary syndromes

Coronary artery disease: pathogenesis and acute coronary syndromes.

Prothrombinase activity of human platelets is inhibited by β2-glycoprotein-I

β2-glycoprotein-I (apo-H) inhibits the release reaction of human platelets during ADP-induced aggregation

Lipoprotein (a) and plasminogen are immunochemically related

The interaction of beta 2-glycoprotein-I (beta 2-G-I), a plasma constituent of unknown function, with blood platelets was studied. The following results were obtained: 1) beta 2-G-I binds to washed human platelets isolated by centrifugation (WP) at one kind of specific, saturable binding sites. The dissociation constant was found to be approx. 1 X 10(-6) M. In the presence of physiological concentrations of Ca++ (2.5 mM), this specific binding is markedly reduced. Unspecific binding of beta 2-G-I to platelets, however, is not influenced by Ca++. Platelets prepared by gel filtration (GFP), differing in their in vitro aggregability from WP, exhibit no specific binding of beta 2-G-I. Binding to GFP is also not induced by activation with thrombin, collagen or ADP. beta 2-G-I causes significant alteration of the ADP-induced aggregation of GFP. Aggregation induced by thrombin, collagen, arachidonic acid or PAF-acether, however is not altered by beta 2-G-I. It is suggested, that pelleting during centrifugation causes irreversible rearrangements in the membrane of platelets.

J. Nimpf

Papers

Prothrombinase activity of human platelets is inhibited by β2-glycoprotein-I

β2-glycoprotein-I (apo-H) inhibits the release reaction of human platelets during ADP-induced aggregation

Lipoprotein (a) and plasminogen are immunochemically related

Interaction of beta 2-glycoprotein-I with human blood platelets: influence upon the ADP-induced aggregation.

Free and Apo B-associated Lpa-specific protein in human serum