PATHOLOGY OF ATHEROSCLEROSIS

Dr. Thuaibah bt HashimDr. Thuaibah bt Hashim

Learning objectives

DefineDefine atherosclerosis atherosclerosis Explain Explain PathogenesisPathogenesis Discuss Discuss Risk factorsRisk factors Describe Describe Gross & microscopyGross & microscopy Discuss Discuss Clinicopathological consequencesClinicopathological consequences DiscussDiscuss Regression of atherosclerosis Regression of atherosclerosis

Definition AtheromaAtheroma: an : an encysted tumourencysted tumour containing containing curdy matter curdy matter

= fibrofatty plaque = fibrofatty plaque

AtherosclerosisAtherosclerosis: disease primarily of : disease primarily of elastic arteries and elastic arteries and large/medium sizedlarge/medium sized muscular arteries. The basic lesion muscular arteries. The basic lesion is atheroma, consisting of a raised focal plaque within is atheroma, consisting of a raised focal plaque within the intima, having a the intima, having a core of lipidcore of lipid (mainly chol. & chol (mainly chol. & chol esters) and a esters) and a covering fibrous capcovering fibrous cap

Greek: athero = gruel / paste / porridgeGreek: athero = gruel / paste / porridge sclerosis = hardnesssclerosis = hardness

Arteriosclerosis = hardening of arteries

1.1. Atherosclerosis Atherosclerosis

2.2. Monckeberg’s medial calcific sclerosisMonckeberg’s medial calcific sclerosis

3.3. ArteriolosclerosisArteriolosclerosis: :

intimalintimal thickening & lipid deposition thickening & lipid depositionelastic arteries and large/medium sizedelastic arteries and large/medium sized muscular arteries muscular arteries

calcification of calcification of mediamedia of muscular arteries of muscular arteries

proliferative or hyaline thickening of the walls ofproliferative or hyaline thickening of the walls ofsmall arteries and arteriolessmall arteries and arterioles

Most common & important

Hyaline arteriolosclerosis

Hyperplastic arteriolosclerosis

Monckeberg’s medial calcific sclerosis

ThrombusThrombus = Structured, solid mass = Structured, solid mass composed composed

of of blood constituentsblood constituents that forms in the that forms in the

cardiovascular system cardiovascular system

(non interupted blood vessels)(non interupted blood vessels)

Embolism :

Occlusion of a vessel by material

(solid, fluid, gasses) travelling in the

blood circulation

Mass of material = embolus

Pathogenesis of atherosclerosis Thrombogenic hypothesisThrombogenic hypothesis Clonal proliferation hypothesisClonal proliferation hypothesis Lipid insudation hypothesisLipid insudation hypothesis

‘‘Response to injury’ hypothesisResponse to injury’ hypothesis(1973, modified 1986 & 1993) Lesions initiated as a response to some form of injury to (1973, modified 1986 & 1993) Lesions initiated as a response to some form of injury to

arterial endothelium.arterial endothelium. Postulated injury : Postulated injury : endothelial dysfnendothelial dysfn without necessary denudation without necessary denudation single or short-lived injurious events single or short-lived injurious events endothelial fn restored, endothelial fn restored,

regression of lesionregression of lesionrepeated / chronic injury repeated / chronic injury plaque development plaque development

Pathogenesis : Endothelial dysfn permeability to plasma constituents including lipidpermeability to plasma constituents including lipid platelet & monocyte adhere to endothelium (VCAM-platelet & monocyte adhere to endothelium (VCAM-

1 & ICAM-1) 1 & ICAM-1) enter intima enter intima monocytes monocytes macrophages ingest lipid & tranform macrophages ingest lipid & tranform

to foam cells.to foam cells. Factors released by platelet stimulate smooth muscle Factors released by platelet stimulate smooth muscle

cells to migrate from media to intima cells to migrate from media to intima proliferate & proliferate & synthesize extra cellular matrixsynthesize extra cellular matrix

macrophages release chemotactic factors for macrophages release chemotactic factors for leukocytesleukocytes

Epidemiology

AS accounts for more deaths & serious AS accounts for more deaths & serious morbidity in Western world than any other morbidity in Western world than any other disorder.disorder.

Global in distributionGlobal in distribution Although not usually clinically evident until Although not usually clinically evident until

middle age, AS is slowly progressive middle age, AS is slowly progressive disease that begins in childhood.disease that begins in childhood.

Distribution

Abd aorta (ostia of major branches)Abd aorta (ostia of major branches) coronary arteries (1st 6 cm)coronary arteries (1st 6 cm) popliteal arteriespopliteal arteries descending thoracic aortadescending thoracic aorta internal carotid arteriesinternal carotid arteries circle of Williscircle of WillisIn an individual case, severity of disease in one artery does not In an individual case, severity of disease in one artery does not

predict the severity in another. Usually eccentric, patchy & predict the severity in another. Usually eccentric, patchy &

variable along the vessel length.variable along the vessel length.

Descendingorder

Major risk factors

Diet & hyperlipidaemia Diet & hyperlipidaemia HypertensionHypertension cigarette smokingcigarette smoking Diabetes mellitusDiabetes mellitus

Framingham study & MRFITFramingham study & MRFIT

Minor risk factors

AgeAge Sex : Sex : female protected by estrogen up to 55 yrsfemale protected by estrogen up to 55 yrs

Family historyFamily history ObesityObesity Stress & type A personalityStress & type A personality physical inactivityphysical inactivity Oral contraceptive pillOral contraceptive pill High carbohydrate intakeHigh carbohydrate intake HyperhomocysteinaemiaHyperhomocysteinaemia

constitutional

Gross appearance

Fatty streaksFatty streaks atheromatous plaques :atheromatous plaques :

fibrolipid fibrolipid fibrous fibrous complicated lesion :complicated lesion :

patchy or massive calcification patchy or massive calcification fissure or gross ulceration fissure or gross ulceration atheroemboli atheroemboli hematoma hematoma superimposed thrombosis superimposed thrombosis aneurysmal dilatationaneurysmal dilatation

Aorta : fatty streaks

Aorta : mild, moderate, severe atherosclerosis

Coronary atherosclerosis with narrowing in proximal part

HistologyLipid core with fibrous cap Lipid core with fibrous cap Cells : macrophages, smooth muscle, leukocyteCells : macrophages, smooth muscle, leukocyte extracellular matrix : collagen, proteoglycanextracellular matrix : collagen, proteoglycan intracellular & extracellular lipidintracellular & extracellular lipid Type I: initial lesionType I: initial lesion II: fatty streakII: fatty streak III: intermediateIII: intermediate IV: atheroma IV: atheroma V: thick layers of fibrous tissueV: thick layers of fibrous tissue VI : fissure, haematoma, thrombusVI : fissure, haematoma, thrombus

Aorta : atheroma

Fatty streaks

Precursors of atheromatous plaquesPrecursors of atheromatous plaques appear in aorta of some children < 1 yr and appear in aorta of some children < 1 yr and

all children > 10 yrsall children > 10 yrs multiple yellow, flat spots < 1mm multiple yellow, flat spots < 1mm

coalesce into elongated streaks 1cm or coalesce into elongated streaks 1cm or longerlonger

composed of lipid-filled foam cells composed of lipid-filled foam cells T-lymphocytes & extracellular lipids in smaller amt than T-lymphocytes & extracellular lipids in smaller amt than in plaques, collagen & proteoglycan in variable amtin plaques, collagen & proteoglycan in variable amt

Clinicopathological consequences of atheroma blood flow : IHDblood flow : IHD

peripheral vascular diseaseperipheral vascular disease

cerebrovascular diseasecerebrovascular disease predisposition to thrombosis / embolismpredisposition to thrombosis / embolism bleeding into plaque bleeding into plaque AMI AMI weakening of wall & aneurysm formationweakening of wall & aneurysm formation

Normal coronary artery

Coronary atheroma

Coronary artery : Thrombosis

Coronary artery : Thrombus recanalisation

Outcomes following occlusive thrombi11. Propagation. Propagation : enlarge along the vessel : enlarge along the vessel2. 2. Lysis Lysis by fibrinolytic system ( assisted by by fibrinolytic system ( assisted by

therapeutic administration of streptokinase)therapeutic administration of streptokinase)3. 3. OrganisationOrganisation : ingrowth of granulation tissue : ingrowth of granulation tissue

from vessel wall from vessel wall 4. 4. RecanalisationRecanalisation : new vascular channels develop : new vascular channels develop

bridging the site of occlusion & reestablishing bridging the site of occlusion & reestablishing flowflow

5. 5. ThromboembolismThromboembolism : fragments may break off to : fragments may break off to impact in other vesselsimpact in other vessels

Atherosclerotic aneurysm

>5cm have high risk of rupture

Clinical conditions

We see AS in terms of its clinical horizon We see AS in terms of its clinical horizon most commonly as ischaemia & infarction.most commonly as ischaemia & infarction.

Previously no means of visualising the Previously no means of visualising the extent & severity of AS exc. at autopsy.extent & severity of AS exc. at autopsy.

B mode ultrasonography to detect intima-B mode ultrasonography to detect intima-media thickness, CT scan. Angiogram is media thickness, CT scan. Angiogram is invasive.invasive.

Ischaemic Heart Disease

Stable anginaStable angina : significant stenosis in 1 or more coronary : significant stenosis in 1 or more coronary arteries arteries > 50% lumenal reduction = >75% reduction in cross-> 50% lumenal reduction = >75% reduction in cross-sectional areasectional area

Unstable anginaUnstable angina AMIAMI Sudden deathSudden death Chronic IHD with CHFChronic IHD with CHF Prinzmetal / variant angina (coronary spasm of lesion free Prinzmetal / variant angina (coronary spasm of lesion free

artery)artery) >90% IHD has stenosing AS>90% IHD has stenosing AS

Plaque with acute changes

Renal artery stenosis

2/3rds are due to atheroma2/3rds are due to atheroma (male, advancing (male, advancing age, DM)age, DM)

1/31/3rdrd due to fibromuscular dysplasia due to fibromuscular dysplasia (female (female 33rdrd-4-4thth decade) decade)

rarely dissecting aneurysm or aortitisrarely dissecting aneurysm or aortitis

Hypertension with high plasma reninHypertension with high plasma renin Malignant hypertensionMalignant hypertension

Intestinal Ischaemia1.1. Arterial occlusion Arterial occlusion (commonest)(commonest)2.2. Non occlusive statesNon occlusive states3.3. Venous occlusion Venous occlusion 4.4. mural vascular pathologymural vascular pathologyIntestine has high metabolic rate & tolerates ischaemia poorly. Intestine has high metabolic rate & tolerates ischaemia poorly.

Many complex pathological entities can be produced Many complex pathological entities can be produced depending on severity, acuteness and duration. Effect depend depending on severity, acuteness and duration. Effect depend on collateral circulation, bacterial flora of the gut and lumenal on collateral circulation, bacterial flora of the gut and lumenal pressure pressure single event not necessarily give identical single event not necessarily give identical outcome.outcome.

Coeliac axis, IMA -- good collateralsCoeliac axis, IMA -- good collateralsSMA -- endarterySMA -- endartery

Chronic intestinal ischaemia:Chronic intestinal ischaemia:

Abdominal angina. Abdominal angina. Abd pain following foodAbd pain following food

Acute intestinal ischaemia:Acute intestinal ischaemia:

Intestinal infarction. Intestinal infarction. Severe abdominal pain, Severe abdominal pain, vomiting, tender abd, absent bowel sound, vomiting, tender abd, absent bowel sound, bloody diarrhoea later.bloody diarrhoea later.

Ischaemia of the legs

Chronic : Male >50 yrs, smokersChronic : Male >50 yrs, smokers Ischaemic cramp-like pain usually in the Ischaemic cramp-like pain usually in the

calves during exercise and relieved by calves during exercise and relieved by rest (intermittent claudication)rest (intermittent claudication)

Rest painRest pain Non-healing leg ulcers or gangreneNon-healing leg ulcers or gangrene

Acute : painful, pale, paralysed, pulseless Acute : painful, pale, paralysed, pulseless limblimb

Cerebrovascular Disease

Transient ischaemic attacks (eg. amaurosis Transient ischaemic attacks (eg. amaurosis fugax, aphasia, hemiparesis, ataxia, drop fugax, aphasia, hemiparesis, ataxia, drop attacks)attacks)

Stroke Stroke 85 % ischaemic85 % ischaemic

15% haemorrhagic15% haemorrhagic

Regression of atherosclerosis In experimentally induced AS, fatty streaks are totally In experimentally induced AS, fatty streaks are totally

reversible (presumed also true for humans)reversible (presumed also true for humans) In hypercholesterolaemic non-human primates In hypercholesterolaemic non-human primates

containing advanced proliferative lesions, it is containing advanced proliferative lesions, it is possible to induce regression of lesions if animals are possible to induce regression of lesions if animals are placed on normocholesterolaemic diet.placed on normocholesterolaemic diet.

Hypercholesterolaemic patients with angiographically Hypercholesterolaemic patients with angiographically demonstrable advanced fibrous plaque demonstrable advanced fibrous plaque plasma plasma cholesterol lowered by combination of diet & drugs cholesterol lowered by combination of diet & drugs over 6 months to several yrs a significant over 6 months to several yrs a significant proportion of indiv. show statistically significant proportion of indiv. show statistically significant reduction in the size of their lesions manifested by reduction in the size of their lesions manifested by increase in lumen of arteries seen on angiogram.increase in lumen of arteries seen on angiogram.

Antioxidant effects of tocotrienols in patients with Antioxidant effects of tocotrienols in patients with hyperlipidemia and carotid stenosis.hyperlipidemia and carotid stenosis.Tomeo AC, Geller M, Watkins TR, Gapor A, Tomeo AC, Geller M, Watkins TR, Gapor A, Bierenbaum ML.Bierenbaum ML.

Lipids 1995 Dec;30(12):1179-83 Lipids 1995 Dec;30(12):1179-83 Tocotrienol gp (n=25) 7 regressed, 2 progressedTocotrienol gp (n=25) 7 regressed, 2 progressedControl gp (n=25) none regressed, 10 progressedControl gp (n=25) none regressed, 10 progressed

A pathomorphological study on atherosclerotic A pathomorphological study on atherosclerotic regression with references between apoptosis and regression with references between apoptosis and atherosclerotic plaque with central depression in atherosclerotic plaque with central depression in rabbit aortarabbit aortaTakashi K, Oinuma T, Yamada T.  

Nippon Ronen Igakkai Zasshi. 1999 May;36(5):328-34. Nippon Ronen Igakkai Zasshi. 1999 May;36(5):328-34.

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