Introduction
According to the American Heart Association, in US a total of 869,724 people died due to various cardiovascular diseases in 2004, of which coronary artery disease (CAD) caused the death of more than four hundred thousand people. In comparison, total cancer related deaths in the same year add up to little over 550 thousand. CAD is the single leading cause of death in the US currently (Cardiovascular disease statistics, 2008).
CAD is caused by the narrowing of the coronary arteries due fat deposition in them, eventually leading to either complete obstruction of the artery lumen or dislodgment of the plaque embolism. It can lead to complications such as myocardial infarction or stroke. Therefore a sound knowledge of its patho-physiology enables us to understand the disease in better light and leads us to find means of prevention and treatment.
Discussion
The initiation point of atherosclerosis is usually the deposition of fat in blood vessels. Usually, fatty steaks on the vessel lumen appear. These have been seen in children as young as 9 year old. Fatty streaks are lipids are deposited under the damaged endothelium and which have been ingested by macrophages. The macrophages are now called foam cells. Gradual and ongoing deposition of foam cells leads to the formation of yellow white fibrous plaques.
These plaques either grow large in size and occlude the lumen of arteries completely causing ischemia to the organ or can dislodge and rupture from its place causing platelet aggregation and thrombus at the site, and form emboli of the plaque which was dislodged with the potential to get stuck in the narrow arteries (Schoen, F.J. 2004). The arteries most frequently affected are the coronary arteries, carotid arteries and the aorta, where non laminar or turbulent blood flow is present.
The process of atherosclerosis and plaque formation is a dynamic, progressive and ongoing process, which can start at an early age given that the risk factors for the disease are present. These include family history, male gender, and high blood levels of LDLs, sedentary life style, obesity, cigarette smoking, Diabetes mellitus, infection and chronic inflammation infection (The Merck Manual, 2005). And (Mallika V, 2007)
It has been seen that intimal-medial wall thickness (IMT) is particularly relevant, when looking at complications of atherosclerosis. It ha been seen that IMT is a strong predictor of ischemic attacks. Studies of amongst families, siblings etc have shown that there is a hereditary link to IMT which in turn plays a role in determining the risk of atherosclerosis related complications (Humphries SE, 2004).
In atherosclerosis, from the initiation stage of fatty streaks, through the growth stage of deposition of foam cells and even till the occurrence of complications, all are considered to be an inflammatory response to injury. The multiple factors involved in the process include endothelium lining integrity. Nitrous oxide availability, macrophage migration, inflammatory response, smooth muscles and connective tissue deposition. These all have a role to play in the progression of the disease (The Merck Manual).
Endothelium
“According to (Mitchell ME, et al, 1998,) Injury to the endothelial cell of the artery, resulting in endothelial cell dysfunction is the first step in the process.” Endothelium normally provides a neutral and stable environment to keep the blood flowing. It also produces an endothelium protective nitrous oxide, which prevents inflammation. Injury to the endothelial wall can occur due to multiple factors. A person with diabetes has injury prone blood vessels. Diabetics also have high levels of LDLs which are also a risk factor for atherosclerosis. Smokers have high levels of free radicals and toxins including nicotine in their blood which can damage the endothelium. Once the endothelium becomes damaged, the cascade of effects which lead to the eventual fat deposition, clot formation and lumen narrowing can begin.
Nitrous Oxide is vasoprotective
NO has a protective role to play under normal endothelial conditions. It is produced by the endothelium, functioning as a vasodilatory, anti-thrombotic and anti-inflammatory agent. it also prevents platelets from accumulating. It functions by activating guanylate cyclase (cGMP) leading to smooth muscle dilation and relaxation. Once the endothelial lining gets damaged due to any risk factor, the damaged endothelial cells lose their ability to produce NO and increase the oxidized macro molecules Oxidized LDL and cholesterol (Stone PH. 2005).
Once damaged, the endothelial lining becomes a site of inflation and leukocyte aggregation and eventual atheroma formation.
Initial Inflammation and atheroma
Inflammation due to injury leads to monocyte recruitment. Also known as the scavengers, and activated immunologicaly, they move towards the injury site and move underneath the endothelium and into the intima layer where the lipids deposition is present. They transform into macrophages and engulf the lipids. This leads to the eventual formation of a plaque consisting of a cholesterol core with lipid laden macrophages surrounding the core. Possibility of involvement of T-lymphocytes in the activation of the macrophages in an area of research nowadays (Von Baeyer H, 2003).
Smooth muscle
Macrophages release growth factors which stimulate the growth of smooth muscle cells and connective tissue. Activation of the smooth cells and the connective tissue leads to wall thickening and the reduction of lumen in size.
One of many things can now happen to the plaque. It can continue growing and occlude the lumen completely; it can tear off from its anchoring site and get dislodged. In this case, the exposure of the basement membrane underneath leads to attraction of platelets and coagulation cascade activation which leads to thrombus formation. This thrombus too, can grow to obstruct the vessel can tear off and obstruct some other narrower vessel down stream.
Complications
The plaque which continues to grow over time, can one of many complicating events including Myocardial infarction and stroke.
If the coronary arteries get occluded by the plaque it will eventually lead to MI.
Whether a plaque will stable or rupture and causing an MI depends upon a various factors, a major one being its composition. Size has just a small role to play unless the lumen is completely occluded (Reiner Z, 2001).
Conclusion
The appreciation of the role of inflammatory processes in the formation of atheromas provides us with a guide to the direction in which new pharmacological and drug research should take in an attempt to control this ever growing problem in our society. Having an In-depth knowledge of CAD pathogenesis and help in preparing future therapeutic strategies.
The detailed knowledge of the patho-physiology can help the clinical practioners to manage the disease in a better way.
References
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Schoen, J.F. (2004). Blood vessels. Robbins and Cotran (Ed), Pathologic basis of disease: Elsevier.
Humphries,S.E and Morgan, L. (2004). Genetic risk factors for stroke and carotid atherosclerosis: insights into pathophysiology from candidate gene approaches.. Lancet Neurology. 3, 227-235. Web.
Stone, P.H. (2005). Evaluating cardiovascular pathophysiology and anatomy in atherosclerosis. American heart hospital journal. 3,187-192. Web.
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