ATHEROSCLEROSIS

Supervisor- Dr. Ndungú

Presenter- Taseer Feroze Din

27/02/2012

OBJECTIVES Introduction

Definition Epidemiology

Risk factors Pathogenesis

Response-to-injury Hypothesis Complications

INTRODUCTION Definition :

Atherosclerosis (arteriosclerotic vascular disease) is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol.

 In Greek, athere means  gruel, and skleros means hard.

EPIDEMIOLOGY- UBIQUITOUS AMONG MOST DEVELOPED NATIONS...’’LIFESTYLE AND DIET DISEASE’’

MAJOR RISKS LESSER OR UNCERTAIN RISKS

Nonmodifiable Obesity

•Increasing age Physical inactivity

•Male gender Stress (type A personality)

•Family History Postmenopausal estrogen def.

•Genetic Abnormalities High Carbohydrate intake

Potentially Controllable

Lipoprotein (a)

•Hyperlipidemia Hardened (trans) unsaturated fat intake

•Hypertension Chlamydia pneumoniae infection

•Cigarette smoking

•Diabetes

•C-reactive protein

Multiplicative effect:•2 risk factors increase risk fourfold•3 risk factors increase the rate of MI seven times!

ATHEROSCLEROSIS IN AFRICA

CVD now the second most common cause of death-accounting for 11% of total deaths (WHO 1999)

 Projections from the Global Burden of Disease Project suggest that from 1990 to 2020, the burden of CVD faced by African countries will double.

In a prospective study among elderly patients in Kenyatta National Hospital, Nairobi, Kenya, in 1991 to 1992: Clinical evidence of CVD was present in 40% of

the patients evaluated; 54% were hypertensive, 53% had arrhythmia, and 49% CCF (Lodenyo, McLigeyo, and Ogola 1997)

PATHOGENESIS

PATHOGENESIS Response-to-injury hypothesis- 4 main stages

to atherogenesis:1. Chronic endothelial injury2. Accumulation of lipoproteins3. Resultant Inflammation & Factor release4. Smooth muscle cell recruitment,

proliferation and ECM production

RESPONSE-TO-INJURY HYPOTHESIS

1) CHRONIC ENDOTHELIAL INJURY : Hyperlipidemia Hypertension Smoking Homocysteine Hemodynamic factors Toxins Viruses Immune Reactions

ENDOTHELIAL INJURY

Intimal thickening; in the presence of high-lipid diets, typical atheromas ensue.

Early human lesions begin at sites of morphologically intact endothelium. 

Endothelial dysfunction underlies human atherosclerosis; in the setting of intact but dysfunctional ECs : increased endothelial permeability enhanced leukocyte adhesion altered gene expression.

2) ACCUMULATION OF LIPOPROTEIN IN VESSEL WALL Dyslipoproteinemia

Other underlying disorder that affects the circulating levels of lipids :• nephrotic

syndrome, alcoholism, hypothyroidism, or diabetes mellitus

(1) increased LDL cholesterol levels,

(2) decreased HDL cholesterol levels, and

(3) increased levels of the abnormal Lp(a)

HYPERLIPIDEMIA-MAJOR RISK FACTOR The mechanisms : Chronic hyperlipidemia, particularly

hypercholesterolemia - increases local production of reactive oxygen species-accelerate nitric oxide decay- local shear stress.

Lipoproteins accumulate within the intima- oxidized through the action of oxygen free radicals (locally generated by macrophages or ECs) Oxidized LDL is ingested by macrophages through a scavenger receptor, resulting in foam-cell formation.

In addition, oxidized LDL stimulates the release of growth factors, cytokines, and chemokines by ECs and macrophages that increase monocyte recruitment into lesions.

Finally, oxidized LDL is cytotoxic to ECs and SMCs- EC dysfunction.

3) MACROPHAGE AS THE INFLAMMATORY MEDIATOR

Monocyte adhesion to the endothelium, followed by migration into the intima and transformation into macrophages and foam cells.

INFLAMMATION Dysfunctional arterial ECs express VCAM-1-

binds monocytes and T cells-migrate- chemokines.

Monocytes transform into macrophages and avidly engulf lipoproteins, including oxidized LDL. –Activated- cytokine production (e.g., TNF)-propel mononuclear inflammatory cell recruitment.

T lymphocytes recruited to the intima- elaborate inflammatory cytokines, (e.g., interferon-γ), which in turn can stimulate macrophages as well as ECs and SMCs.

Activated leukocytes and vascular wall cells release growth factors that promote SMC proliferation and ECM synthesis.

4) SMC PROLIFERATION AND ECM PRODUCTION Intimal SMC proliferation and

ECM deposition convert a fatty streak to a mature atheroma.

Intimal SMC-proliferative, synthetic phenotype

Growth factors: 1. PDGF (platelets,

macrophages, ECs, and SMCs)

2. FGF 3. TGF α.

SMCs synthesize ECM (notably collagen), which stabilizes atherosclerotic plaques.

Inflammatory cells in atheromas can cause intimal SMC apoptosis, and they also increase ECM catabolism, resulting in unstable plaques.

COMPLICATIONS MI Rupture, Ulceration, or Erosion- thrombus

formation-downstream ischaemia Aneurysm-pressure or ischaemic atrophy of

the underlying media, with loss of elastic tissue-weakness

Arrthymias- due to scar formation Mural thrombus Atheroembolism- microemboli Cerebral infarct Renal infarcts Death

NATURAL HISTORY, MAIN PATHOGENIC EVENTS & CLINICAL COMPLICATIONS

THANK YOU ARMY A1