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).

Many processes have been implicated in early atherogenesis. These include endothelial denudation, injury, or activation, including shear stress–related events; local adherence of platelets; lipoprotein oxidation; lipoprotein aggregation; macrophage chemotaxis and foam cell formation; and smooth muscle cell alterations. Which process, if any, could be regarded as the key event in early atherogenesis, ie, absolutely required, yet also sufficient as the sole pathological stimulus in an otherwise normal artery to provoke a cascade of events leading to lesion formation? The work of many investigators, which we summarize here, strongly supports subendothelial retention of atherogenic lipoproteins as the central pathogenic process in atherogenesis (for prior reviews, see References 1 through 61 2 3 4 5 6 ). Our thesis is that other contributory processes are either not individually necessary or are not sufficient. Most often, they are merely normal, expected responses of otherwise-healthy tissue to the presence of retained lipoproteins.

It is instructive to catalog other processes that have been argued to be central to the initiation of atherogenesis. The first is endothelial denudation,7 8 9 injury,10 or activation,11 12 as outlined in the “response-to-injury” hypothesis of Ross, Glomset, and coworkers. Although this important hypothesis has stimulated much of the work that we cite here, there is no definitive evidence in vivo that endothelial injury is either necessary or sufficient for lesion formation.

The response-to-injury hypothesis originally presupposed endothelial desquamation as the key event in atherogenesis.7 8 9 It is now clear, however, that developing atheromata are covered by an intact endothelial layer throughout most stages of lesion progression: lipoprotein retention, fatty streak formation, and formation of advanced lesions.5 6 12 13 14 15 In humans, only the most complicated, ulcerated lesions lose their endothelial layer. Furthermore, in some experimental models, an intact endothelium is required …

The Response-to-Retention Hypothesis of Early Atherogenesis

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)

American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus.

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.

Endothelial cells play a critical role in thromboregulation by virtue of a surface-connected fibrinolytic system. Cultured endothelial cells synthesize and secrete tissue-type plasminogen activator (t-PA) which can bind to at least two discrete sites on the cell surface. These binding sites preserve the catalytic activity of t-PA and protect it from its physiological inhibitor (PAI-1). N-terminal glutamic acid plasminogen (Glu-PLG), the main circulating fibrinolytic zymogen, also interacts specifically with the endothelial cell surface. Binding is associated with a 12-fold increase in catalytic efficiency of plasmin generation by t-PA which may reflect conversion of Glu-PLG to its plasmin-modified form, N-terminal lysine plasminogen (Lys-PLG). Lipoprotein(a) is an atherogenic lipoprotein particle which contains the plasminogen-like apolipoprotein(a) bound to low density lipoprotein. We report here that lipoprotein(a) interferes with endothelial cell fibrinolysis by inhibiting plasminogen binding and hence plasmin generation. In addition, we demonstrate lipoprotein(a) accumulation in atherosclerotic lesions. These findings may provide a link between impaired cell surface fibrinolysis and progressive atherosclerosis.

D Gavish

Papers

Lipoprotein(a) modulation of endothelial cell surface fibrinolysis and its potential role in atherosclerosis.