Atherosclerosis Peripheral Arterial Occlusive Disease (PAOD)

AtherosclerosisPeripheral Arterial

Occlusive Disease (PAOD)

AHA Report 2004

• CVD killed 931,108 Americans in 2001.  • Other major causes of death in 2001 were:

•cancer, 553,768; •accidents, 101,537; •Alzheimer’s disease, 53,852; and•HIV 14,175. 

• The report also shows that CVD is the No. 3 cause of death for children under age 15, behind certain conditions originating in the perinatal period and accidents. 

Anatomy of Atherosclerotic Plaque

History

• Atherosclerosis has been recognized in humans for thousands of years. Lesions of atherosclerosis were identified in Egyptian mummies dating from as early as the fifteenth century B.C.

• In the mid–nineteenth century, Virchow proposed the idea that some form of injury to the artery wall associated with an inflammatory response resulted in what was then considered to be the degenerative lesion of atherosclerosis.

History

• This idea was subsequently modified by Antischkow and further included the role of platelets and thrombogenesis in atherosclerosis, as expanded by Duguid in 1948.

History• Many of the modern views of

atherosclerosis stem from the work of John French, who noted that the structural integrity of the endothelial lining of the artery represented a key element in the maintenance of normal arterial function.

• Alterations in endothelial integrity might precede a sequence of events that would lead to the various forms of the lesions of atherosclerosis.

• Thus, over the years, numerous theories concerning the etiology and pathogenesis of atherosclerosis have been developed.

The Response-to-Injury Hypothesis

• One basis for the response-to-injury hypothesis of atherosclerosis lies in the marked similarity observed by many investigators between the ubiquitous fibromusculoelastic lesions noted at autopsy.

• Similar lesions can be induced in a number of animal species, including nonhuman primates, rabbits, ApoE-deficient mice, and swine after different forms of arterial endothelial injury.

The Response-to-Injury Hypothesis

•The hypothesis states that some form of ''injury'' to the endothelium results in structural and/or functional alterations in the endothelial cells.

The Response-to-Injury Hypothesis

• Factors such as chronic hypercholesterolemia; altered shear stress from the flow of blood over the endothelial cells, which may occur at branch points or bifurcations in arteries in hypertension; and dysfunction induced by toxins, viruses, bacteria, chlamydia, genetic factors such as elevated homocysteine.

• These injurious agents may lead to changes in the nature of the protective barrier established by the endothelial cells.

The Response-to-Injury Hypothesis

•With sufficiently severe injury, the endothelial cells might desquamate and be lost into the bloodstream, leading to exposure of the underlying basement membrane.

•Cellular responses include macrophage, lymphocytes, and platelets.

The Response-to-Injury Hypothesis

• Macrophages are converted into foam cells with the uptake of cholesterol.

•The early fatty streak contains principally macrophages and variable numbers of T cells.

•Direct progression of fatty streaks to fibrous plaques probably represents the most common course of atherogenesis in hypercholesterolemia.

The Response-to-Injury Hypothesis

•If the injury at focal sites in the artery wall is either of longstanding or chronically repeated over periods of many years, the lesions could continue to progress, become increasingly complex in terms of their composition, and eventually lead to the principal clinical sequelae of atherosclerosis—myocardial infarction and cerebral infarction.

The Response-to-Injury Hypothesis

• The capacity of the endothelium to regenerate and restore endothelial integrity at sites of injury may be critical in determining whether the lesions of atherosclerosis enlarge, remain relatively constant in size, or regress.

• The superimposition of risk factors that might possibly affect this balance by providing a chronic source of injury or by somehow altering the normal tissue response to injury might change the balance so that lesions would be slowly progressive.

The Response-to-Injury Hypothesis

•The other important factor is understanding why medial hyperplasia occurs in response to injury.

•The primary factory that has been identified is PDGF.

•How every many other factors also have this capacity to stimulate VSM and therefore inhibition of PDGF has not lead to the elimination of PAOD.

RISK FACTORS

UNMODIFIABLE•Family History•Race•Age•Gender

MODIFIABLE•Smoking•Hypertension•Diabetes•Hyperlipidemia•Sedentary Living•Elevated

Cholesterol

The Role of Lipids

• Both lesion initiation and lesion progression in atherosclerosis appear to be associated in many individuals with markedly increased elevations of plasma LDL.

• The presence of elevated levels of LDL suggests that cholesterol internalization and esterification by cells may be accelerated to such a degree that proliferated smooth muscle cells within lesions become filled with cholesterol oleate.

The Role of Lipids

• Many studies have demonstrated that modified or oxidized lipoproteins play a key role in the process of atherogenesis, particularly in hyperlipidemic individuals.

• This role was first appreciated when it was shown that antioxidant therapy, using the lipid-lowering drug probucol, could diminish lesion formation in genetically hyperlipidemic rabbits and that subsequently a similar approach could inhibit the inflammatory response, or fatty streak formation, in hyperlipidemic nonhuman primates.

The Role of Lipids

• The 4S trial demonstrated an approximately 40 percent reduction in the incidence of myocardial infarction as well as a further reduction in the need for procedural intervention in hyperlipidemic individuals.

• The dramatic results in this study pointed to the benefits of reducing plasma LDL cholesterol and elevating high-density lipoprotein (HDL) cholesterol.

The Role of Lipids

• Cholesterol levels below 200 mg/dL are considered normal, levels of 200 to 240 mg/dL are considered borderline and should be treated by diet modification, and levels greater than 240 mg/dL should be treated with drug therapy.

• Similarly, LDL levels less than or equal to 130 mg/dL are considered normal, levels of 130 to 159 borderline, and levels greater than 160 mg/dL require therapy.

HYPERTENSION

•Hypertension has been established unequivocally as an associated risk factor in that individuals with elevated blood pressure show accelerated atherogenesis, an increased incidence of coronary heart disease, and in particular, an increased incidence of cerebro-vascular disease.

HYPERTENSION

•The means by which hypertension induces atherogenesis are not clear, although there are many humoral mediators of blood pressure that may participate in this process.

•For example, renin, angiotensin, -adrenergic substances, and other hypertensive agents may induce cellular changes that lead to atherogenesis.

HYPERTENSION

• The altered flow characteristics, including the eddy currents and backflow of blood, particularly in hypertensive individuals, at selected anatomic sites within the arterial tree may result in focally altered endothelium and in the development of atherosclerotic lesions very much as suggested in the response-to-injury hypothesis discussed earlier.

HOMOCYSTEINE

• Elevated levels of plasma homocysteine (hyperhomocysteinemia) may be important in the population at large not only as a risk factor for atherosclerosis but also as a direct cause of the disease.

• Consistent observations from many studies with over 2000 subjects, including the Framingham Study, have shown that hyperhomocysteinemia together with low concentrations of folates and vitamin B6 in the plasma, are associated with an increased risk of extracranial carotid artery stenosis,

HOMOCYSTEINE

• Levels of homocysteine in the plasma above 14 mm/L appear to be associated with an increased incidence of atherosclerosis.

•Elevated homocysteine appears to be toxic to the endothelium, depresses the capacity of endothelium to make nitric oxide, and induces endothelial dysfunction.

The Matrix Skeleton of Unstable Coronary Artery Plaque

Progression of Vascular Disease

A.NormalB.Endothelial injuryC.Foam cellsD.Plaque rupture

Early Lesion

Mature Plaque

Full Blockage

SMOOTH MUSCLE PROLIFERATION

• Smooth muscle cells have long been recognized to possess a number of features important to normal arterial function, including their capacity to contract, maintain arterial tonus, and synthesize connective tissue proteins.

• Perhaps the most important phenomena associated with the smooth muscle cell are the processes of cell migration, proliferation, and matrix synthesis in atherogenesis.

SMOOTH MUSCLE PROLIFERATION

•

SMOOTH MUSCLE PROLIFERATION

•Growth Factors

•PDGF

•FGF

•Homocysteine

•TGF-•ET

•ATII

SEE: Berk Physiological Reviews, Vol. 81, No. 3, July 2001, pp. 999-1030

SMOOTH MUSCLE PROLIFERATION

•Inhibition of VSM Growth

•Rapamycin (RPM) is a potent and effective immunosuppressant which we have shown previously to inhibit intimal thickening in rat allograft and balloon-injured arteries.

Invasive Treatments for Athersclerosis

•Stenting

•PTCA

•Coronary artery bypass

•Endarterectomy

Coronary Angiography

Coronary Stent

Coronary Stent

Indications for Coronary Artery Bypass Grafting

(CABG) include • unstable angina • Left Main coronary disease • multiple vessel disease with crescendo

angina refractory to medication • high grade proximal LAD disease • post-infarction angina • complication of myocardial infarction

(ventricular wall rupture, ventricular septal defect, papillary muscle dysfunction--acute mitral regurgitation).

• complication of failed PTCA.

Statistics for a patient undergoing CABG surgery

are

•operative mortality 1-3%

•myocardial infarction immediately after surgery 3%

•post-operative wound infection 3%

•post-operative bleeding 3-5%

•post-operative heart arrhythmias 30%

Risks

“Floss or Die”

Gordon Ewy, MDChief, Cardiology

The University of Arizona