patho

1. Atherosclerosis
• Although global, it reaches epidemic proportions in
western nations.
• Major consequences are myocardial infarction, CVA,
aortic aneurysms,less important are gangrene of lower
extremities, mesenteric complications, sudden cardiac
death, chronic IHD and ischemic encephalopathy.
• In USA, 50 % of all deaths can be attributed to A.S.
• It is the disease of elastic and muscular arteries.
• Basic lesion is atheroma: raised focal plaque in the intima
composed of lipids along with fibrous covering cap.

2. Atherosclerosis
• At first the atheromas are sparse, which increase in no with
progressive disease and may involve the entire
circumference of the vessel encroaching on the lumen as
well as tunica media of the vessel.
• In the small arteries the plaques are occlusive causing
ischemic injury.
• In large vessels, the plaques are destructive causing
weakening and aneurysms, may also rupture which favours
thrombosis and embolism.

3. Hyperlipidemia
• Patients with familial hyperlipidemia are most prone.
• Higher the cholesterol, higher the risk especially LDL
cholesterol, hypertriglyceridemia with VLDL.
• Treatment with diet and cholesterol lowering drugs
significantly decrease cardiovascular mortality.
• HDL cholesterol reduce the risk.
• High dietary intake of cholesterol raises the plasma levels
of cholesterol.
• Paradoxically in Finland, the Eskimos, in spite of high fat
intake, incidence of IHD is low because of a specific FA in
fish and fish oil, that decreases LDL, increases HDL, and.

4. • And modifies various mediators favoring platelet
aggregates.

5. Hypertension
• Mechanism of role in atherosclerosis in unknown. Higher
the chronic hypertension, higher the risk of IHD and CVA.

6. Smoking
• One of the established risk factor in the incidence and
severity of atherosclerosis.>10-20 cigarettes/day for many
years increases risk to >200%. Cessation of smoking
reverts the risk.
• Diabetes: diabetics have two fold increased risk of dying
from MI, CVA and up to 100 times increased tendency of
lower extremity gangrene.
• Other rare risk factors include elevated homocysteine
levels causing endothelial dysfunction, raised levels of
plasminogen activator inhibitors and inflammation such as
plasma fibrinogen and CRP.

7. Morphological Features
• The key process is intimal thickening and lipid
accumulation. Fatty streaks appear in young children
which are the possible precursors of atheromas.
• Atheromas are the raised focal plaques which consist of
cholesterol and esters surrounded by fibrous cap.
• Grossly appear white to yellow, measuring 0.3-1.5 cm,
encroach on to lumen, may coalesce to form large lesions.
• Superficial part is firm white, deep soft and yellow.
• Distribution: Abdominal aorta, thoracic aorta, more often
near ostia of major branches; coronary, popliteal, circle of
Willis; upper limbs, renal and mesenteric vessels spared.
Usually patchy and part of circumference is involved.

8. • 3 parts of plaque are smooth muscle cells, macrophages
and other inflammatory cells, extracellular matrix e.g.
collagen, elastic tissue and proteoglycans, intracellular and
extracellular lipid deposits.
• Fibrous cap consists of smooth muscle cells, dense
connective tissue, cellular area consists of macrophages
and muscle cells, T lymphocytes, deep necrotic core
contains lipid material, fibrinous material and other plasma
proteins, foamy macrophages which may be transformed
macrophages and smooth muscle cells.
• Around the plaque there is neovascularization.
• Non atheromatous intimal thickening in coronary arteries
may be due to hemodynamic stress in adults having no
significance.
• In late stages, atheromas may get converted to fibrous scar.

9. Complicated Atheromas
• Calcification, vessel may be like a brittle pipe.
• Focal rupture and ulceration causing thrombosis and
cholesterol emboli.
• Hemorrhage in to the atheromas especially in coronaries.
• Superimposed thrombosis and organization.
• May cause atrophy of underlying media, weakening and
aneurysmal dilatation.

10. Fatty Streaks
• Not raised, no flow disturbances, precursors of
atherosclerosis.
• Begin as small yellow spots, may coalesce to form 1 cm
lesions, composed of foamy macrophages, lymphocytes
and minimum amount of lipids.
• Start at 1 year age, most of 10 years aged children have
aortic lesions.
• No relation with sex, geography, race and environment.
• Distribution same as atherosclerosis.
• Not all the streaks develop the ominous disease.
• Types of atheromatous lesions: isolated foam cells, fatty
streaks, small extracellular lipid collections, fibrofatty
atheroma and complicated lesions.

11. Pathogenesis of Atherosclerosis
• Its clinical implications are grave consequences has stimulated the
scientists to explore and discover the cause.
• Hypothesis 1: cellular proliferation in intima as a reaction to
insudation of plasma proteins and lipids. Organization and repetitive
growth of thrombi result in plaque formation.
• Current theory: it is a chronic inflammatory response of the arterial
wall initiated by some form of injury to the endothelium.
• 1- chronic focal endothelial injury- dysfunction- increased
permeability and leukocyte adhesion.
• 2- lipoprotein insudation asp LDL, VLDL, their oxidation.
• 3- adhesion of monocytes, transformation to foamy macrophages
• 4- platelet adhesion
• 5- activated platelets and macrophage release factors that cause
migration of smooth muscle cells from media.

12. • 6- smooth muscle proliferation in intima, elaboration of
extracellular matrix leading to accumulation of collagen
and proteoglycans.
• 7- accumulation of intracellular and extracellular lipids.

13. Endothelial Injury
• Human lesion develop in intact endothelium, so
endothelial dysfunction and activation are more important
in causing permeability, leukocyte adhesion and
alterations, in expression of a number of endothelial gene
products which mediate adhesion of monocyte and
lymphocytes.
• Endothelial dysfunction may be due to endotoxins,
hypoxia, products of cigarette smoking, homocysteine and
viruses.
• Currently it is postulated that hemodynamic disturbances
(ostia and posterior aortic wall, which are adversely
affected by shear stress) and adverse effects of
hypercholesterolemia are the main factors in endothelial
injury.

14. Role of Lipids
• Increased lipids cause endothelial dysfunction through
superoxide and other oxygen free radicals that deactivate
NO.
• Increased lipids result in lipoproteins accumulation in
intima.
• Lipid oxidation yields oxidized LDL ingested readily by
macrophages to form foam cells which is chemotactic for
monocytes and increased their adhesion. It inhibits
macrophage mobility favoring retention. It stimulates
release of growth factors and cytokines. It is cytotoxic to
endothelial cells and smooth muscle cells. It is
immunogenic with formation of antibodies to lipoproteins.

15. Role of Macrophages
• Monocytes adhere to endothelium, proliferate and migrate to
subendothelial tissues, change to macrophages, engulf lipoproteins
esp. oxidized LDL, transform to foamy macrophages.
• Macrophages have secretory and biological functions via IL-1, TNF
which cause adhesion of leukocytes and monocytes, chemoattractant
proteins, produce toxic oxygen species that cause smooth muscle
proliferation, T lymphocytes are also present by unknown mechanism.
• As long as hypercholesterolemia persists, monocyte adhesion,
subendothelial migration of smooth muscle cells and accumulation of
lipids within macrophages and smooth muscle cells continues
eventually leading to form fatty streaks. May regress if
hypercholesterolemia is ameliorated.

16. Role of Smooth Muscle Cell Proliferation
• If hypercholesterolemia persists, smooth muscle
proliferation and extracellular matrix deposition, in intima
continues, which is one of the major factors converting
streaks in to atheromas.
• Growth factors implicated in vascular smooth muscle cell
proliferation are: PDGF (Platelets, macrophages,
endothelial cells, smooth muscle cells), FGF and TGF-
alpha.
• inhibitors are heparin like molecules, TGF-beta.

17. Progression of Lesions
• Initial intimal plaque: central aggregates of foamy
macrophages and foamy smooth muscle cells.
• If progression occurs, cellular fatty atheroma is modified
by further deposition of collagen and proteoglycans. Some
plaques may be fibrous by increased connective tissue.
• Many of the atheromas undergo disruption and thrombosis
which may be associated with catastrophic consequences.

18. Clinical Features and Prevention
• May be due to thrombosis, calcification, aneurysmal
dilatations, distal ischemic events in heart, brain and lower
extremities.
• So measures to prevent the toll are both primary and
secondary.
• Primary are meant to delay the atheroma formation and
regression. Smoking, hypertension, weight, exercise,
alcohol, lowering of LDL and increasing HDL.
• Secondary to prevent recurrences of serious events.
Decreased lipids and anti platelet drugs.

19. Normal Aorta with no Fatty Streaks

20. Fatty Streaks

21. Fatty Streaks, Coronary Artery with Increased
Fat

22. Coronary Artery Atherosclerosis with
Thrombosis and Narrowing

23. Normal Coronary Artery

24. Coronary Artery Atherosclerosis

25. Coronary Atherosclerosis with Thrombosis
and Cholesterol Clefts

26. Atheroma, Showing Foamy Macrophages and
Cholesterol Clefts.

27. Atheroma with Calcification

28. Aortic Atherosclerosis

29. Aortic Atherosclerosis, Mild, Moderate,
Severe

30. Atherosclerosis with Hemorrhage and
Cholesterol Clefts, Aorta

31. Cholesterol Clefts, HP

32. Hypertensive Vascular Disease
• It affects both structure and function of small muscular
arteries and arterioles.
• It has devastating consequences and remains asymptomatic
for long periods.
• One of the major risk factor for heart disease, CVA,
cardiac hypertrophy with failure, aortic dissections and
renal failure esp. if systolic blood pressure is sustained
above 140 mm and diastolic more than 90 mm.
• Prevalence is more with increasing age, blacks are affected
twice more often, more vulnerable to complications.

33. Causes
• In 90% primary.
• Secondary: Renal.
Ac Glomerulonephritis.
Ch Renal Disease.
Renal Artery Stenosis and Vasculitis.
Renin producing Tumours.
Endocrine.
Cushing Syndrome.
Primary Aldosteronism.
Exogenous Hormones.
Sympathomimetic Drugs.
MAO inhibitors.
Phaeochromocytoma.
Acromegaly.

34. Causes
• Cardiovascular.
• Coarctation of Aorta.
• Increased Blood Volume.
• Aortic Rigidity.
• Neurologic.
• Increased Intracranial Pressure.
• Acute Stress, Operative Procedures.

35. • Accelerated Hypertension: >120 mm diastolic, if
untreated, death occurs within 1-2 years.
• Complications include: renal failure, retinal hemorrhage,
exudates and papilloedema.

36. Regulation of Blood Pressure
• Cardiac Out Put x Peripheral Resistance.
• Cardiac Out Put: Blood volume (Na, Mineralocorticoids,
Atrial Natriuretic Peptides, Heart rate, Contractility).
• Peripheral Resistance: Humoral constrictors (Angio II,
Catecholamines, Thromboxane, Leucotrienes, Endothelin).
• Humoral Dilators: Prostaglandins, Kinins, NO/ EDRF.
• Peripheral Resistance: Local Autoregulation by pH and
Hypoxia; Neural Regulation is by alpha adrenergic drugs.

37. Pathogenesis of Hypertension
• Changes that alter the relationship between blood volume
and resistance.
• Mechanism of development: (1)
• Genetic factors: Twins, Family History (Mostly Polygenic
and heterogeneous disorder).
• Environmental: Chinese in China have low BP, Stress,
Obesity, Physical Inactivity, increased salt intake.
• Mechanism of development: (2)
• Renal retention of excess Na, increased volume, increased
cardiac output, vasoconstriction to prevent over perfusion
of tissues. At increased BP, kidneys cab excrete more Na,
called reseting of pressure natriuresis.

38. • Second hypothesis suggests increased resistance as
primary event; factors may be functional vasoconstriction
by increased sensitivity to vasoconstrictors due to genetic
defect in transport of Na and Ca, Neurogenic release of
vasoconstrictors.
• Structural changes in vessel walls causing thickened walls
and narrowed lumina.