A condition that afflicts the large and medium-sized arteries of almost every human, at least in societies in which cholesterol-rich foodstuffs are abundant and cheap, is atherosclerosis. This condition begins in childhood and, in the absence of acelerating factors, develops slowly until it is widespread in old age. However, it is accelerated by a wide variety of genetic and environmental factors.

Atherosclerosis is characterized by localized fibrous thickenings of the arterial wall associated with lipid-infiltrated plagques that may eventually calcify. Old plaques are also prone to ulceration and rupture, triggering the formation of thrombi that obstruct flow.

Risk Factors Accelerating Atherosclerosis

First let see the risk factors that accelerate the progression of atherosclerosis, since treating the accelerating conditions that are treatable and avoiding those that are avoidable should reduce the incidence of myocardial infarctions, strokes, and other complications of atherosclerosis.

Detail mechanisms of lipid metabolism can be found here


Estrogen increases cholesterol removal by the liver, and the progression of atherosclerosis is less rapid in premenopausal women than in men. In addition, epidemiologic evidence shows that estrogen replacement therapy protects the cardiovascular system in postmenopausal women. But, in several studies, estrogen treatment of postmenopausal women failed to prevent second heart attacks (note here, it was secondary prevention, not primary prevention).

Homocysteine and related molecules

The effect of increased plasma levels of homocysteine and related molecules such as homocystine and homocysteine thiolactone, a condition sometimes called hyperhomocystinemia, deserves emphasis. These increases are assoicated with accelerated atherosclerosis, and the magnitude of the plasma elevation is positively correlated with the severity of the atherosclerosis. Markedly elevated levels resulting from documented mutations of relevant genes are rare, but mild elevations occur in 7% of the general population.

The mechanism responsible for the accelerated vascular damage is unsettled, but homocysteine is a significant source of H2O2 and other reactive forms of oxygen, and this may accelerate the oxidation of LDL.

Cholesterol and triglyceride

Evidence is now overwhelming that lowering plasma cholesterol and triglyceride levels and increasing plasma HDL levels slows, and in some cases reverses, the atherosclerotic process. For the ways to lowering serum cholesterol and triglyceride (including how to elevate HDL) please refer the thread describing the management of dyslipidemia.


Men who smoke a pack of cigarettes a day have a 70% increase in death rate from ischemic heart disease compared with nonsomokers, and there is also an increase in women. The deleterious effects of smoking include endothelial damage caused by carbon monoxide-induced hypoxia. Other factors may also be involved. In general, these deleterious increase the risk of atherosclerosis.

Blood pressure

Because of the increased shear stress imposed on the endothelium by an elevated blood pressure, hypertension is another important modifiable risk factor for atherosclerosis.


In diabetes, there are microvascular complications and macrovascular complications. These complications are shown below:


The nephrotic syndrome and hypothyroidism also accelerate the progression of atherosclerosis.

Pathogenesis of Atherosclerosis

The initial event in atherosclerosis is infiltration of LDLs into the subendothelial region. The endothelium is subject to shear stress, the tendency to be pulled along or deformed by flowing blood. This is most marked at points where the arteries brach, and this is where the lipids accumulate to the greatest degree.

The LDLs are oxidized or altered in other ways. Thus, altered LDLs activate various components of innate immune system including macrophages, natural antibodies, and innate effector proteins such as C-reactive protein and complement. Altered LDLs are recognized by a family of scavenger receptors expressed on macrophages. These scavenger receptors mediate uptake of the oxidized LDL into macrophages and the formation of foam cells. The foam cells form fatty streaks.

The streaks appear in the aorta in the first decade of life, in the coronary arteries in the second decade, and in the cerebral arteries in the third and fourth decades.

Oxidized LDLs have a number of deleterious effects, including stimulation of the release of cytokines and inhibition of NO production. Vascular smooth muscle cells in the vicinity of foam cells are stimulated and move from the media to the intima, where they proliferate, lay down collagen and other matrix molecules, and contribute to the bulk of the lesion. Smooth muscle cells also take up oxidized LDL and become foam cells.

Lipids accumulate both intracellularly and extracellularly.Screen Shot 2015-10-18 at 1.31.03 PM

As the atherosclerotic lesions age, T cells of the immune system as well as macrophages are attracted to them. The intercellular “soup” in the plaques contains a variety of cell-damaging substances, including ozone. Overally, the lesions have been shown to have many of the characteristics of a low-grade infection.

Growth factors and cytokines involved in cell migration and proliferation are also produced by smooth muscle cells and endothelial cells, and there is evidence for shear stress response elements in the flanking DNA of relevant genes in the endothelial cells. Major investigations found bacteria in plaques – Chlamydophila pneumoniae, whereas other organisms have also been found.

As plaques mature, a fibrous cap forms over them. The plaques with defective or broken caps are most prone to rupture. The lesions alone may distort vessels to the point that they are occluded, but it is usually rupture or ulceration of plaques that triggers thrombosis, blocking blood flow.

A characteristic of atherosclerosis that is currently receiving considerable attention is its association with deficient release of NO and defective vasodilation. As noted, oxidized LDLs inhibit NO production. If acetylcholine is infused via catheter into normal coronary arteries, the vessels dialte; however, if it is infused when atherosclerosis is present, the vessels constrict. This indicates that endothelial secretion of NO is defective.

PS: Acetylcholine (ACh) can effect vasodilation by several mechanisms, including activation of endothelial nitric oxide (NO) synthase and prostaglandin (PG) production[1].


1.Kellogg DL Jr1, Zhao JL, Coey U, Green JV. Acetylcholine-induced vasodilation is mediated by nitric oxide and prostaglandins in human skin. J Appl Physiol (1985). 2005 Feb;98(2):629-32. [PMID: 15649880]


Current guidelines of Joint Natinal Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure define normal blood pressure as systolic pressure of <120 mm Hg and diastolic pressure of <80 mm Hg. Hypertension is defined as an arterial pressure greater than 140/90 mm Hg in adults on at least three consecutive visits to the doctor’s office.

The most common cause of hypertension is increased peripheral vascular resistance. However, because blood pressure equals total peripheral resistance times cardiac output, prolonged increase in cardiac output can also cause hypertension. These are seen, for example, in hyperthyroidism and beriberi.

In addition, increased blood volume causes hypertension (see below), especially in individuals with mineralocorticoid excess or renal failure; and increased blood viscosity (blood resistance increases with viscosity), if it is marked, can increase arterial pressure.

PS: Cardiac output is a function of stroke volume, heart rate, and venous capacitance. Increased blood volume increase cardiac preload, which causes increase in stroke volume, and finally the cardiac output and arterial pressure.

Pathogenesis of Hypertension