ARTERIOSCLEROSIS

HARDENING OF ARTERIES WITH LOSS OF ELASTICITY TYPES OF ARTERIOSCLEROSIS 1. MONCKEBERG MEDIAL CALCIFIC SCLEROSIS 2. ATHEROSCLEROSIS 3. ARTERIOLOSCLEROSIS MONCKEBERG MEDIAL CALCIFIC SCLEROSIS THIS USUALLY INVOLVES MEDIUM SIZED ARTERIES FOR EG. RADIAL/ULNAR ARTERIES. IT AFFECTS THE TUNICA MEDIA , WHERE PATCHES OF CALCIFICATION ARE SEEN THESE CALCIFICATIONS ARE AGE RELATED (>50Y) AND HAVE A MALE PREDOMINANCE (IE M>F) NOTE THAT THESE CALCIFICATIONS DO NOT OBSTRUCT THE LUMEN IN ANY WAY AND THIS CONDITION IS VERY BENIGN. THE PATHOLOGY IS IN THE FORM OF VERY PALPABLE ARTERIES DUE TO THE CALCIFICATION. THIS IS MORE COMMON IN THE ARTERIES OF THE UPPER LIMB. THIS CONDITION HAS NO SIGNIFICANT MORBIDITY OR MORTALITY.

ATHEROSCLEROSIS THE COMPLICATIONS OF THIS DISEASE ARE THE LEADING CAUSES OF DEATH IN THE WESTERN WORLD. IE IHD AND STROKE. THIS A DISEASE OF THE INTIMA WHERE THERE IS FORMATION OF FIBROFATTY PLAQUES THE ARTERIES AFFECTED ARE: 1. ELASTIC ARTERIES; AORTIC, CAROTID, ILEAC 2. MEDIUM SIZED ARTERIES; CIRCLE OF WILLIS, POPLITEAL ETC

THE FIBROFATTY PLAQUE THAT IS DEPOSITED WITHIN THE INTIMA MAY OBSTRCT THE LUMEN OF THE VESSEL. IT MAY ALSO CAUSE SECONDARY DEGENERATIVE CHANGES IN THE MEDIA USUALLY WHEN THIS CONDITION INVOLVES SMALLER VESSELS IT CAUSES OBSTRUCTION, HOWEVER WHEN IT INVOLVES LARGER VESSELS LIKE THE AORTA IT HAS A BALLOONING EFFECT CAUSING ANUERYSMS. IT MOST COMMONLY INVOLVES; ABD AORTA>CORONARY ARTERY>POPLITEAL ARTERY> CAROTID ARTERY> CIRCLE OF WILLIS BUSHRA IRSHADALI SUMRA Page 1

ARTERIOLOSCLEROSIS HARDENING OF SMALLER VESSELS THERE ARE 2 TYPES: 1. HYALINE ARTERIOLOSCLEROSIS 2. HYPERPLASTIC ARTERIOLOSCLEROSIS HYALINE ARTERIOLOSCLEROSIS IN MEDIA THERE IS DEPOSITION OF AMORPHOUS HYALINE MATERIAL, DUE TO ACCUMULATION OF PLASMA PROTEINS. THIS DEPOSTION OF EOSINOPHILLIC SMUDGY MATERIAL HARDENS AND NARROWS ARTERIOLES. THEY OCCUR DUE TO 1. NORMAL SENILE CHANGES (OLD AGE) 2. ESSENTIAL HYPERTENSION 3. DIABETES MELLITUS NOTE: IN KIDNEYS THIS IS CALLED BENIGN NEPHROSCLEROSIS; WHEN DUE TO 1 OR 2 ONLY THE AFFERENT ARTERIOLE IS AFFECTED. HOWEVER IN DM BOTH AFFERENT AND EFFERENT ARTERIOLES ARE AFFECTED. HYPERPLASTIC ARTERIOLOSCLEROSIS THIS IS CHARACTERISTIC IN MALIGNANT HTN. WHERE DIASTOLIC PA IS >120mmHg. IT PRESENTS WITH HEMORHAGIC LESIONS IN THE INTIMA AND IN THE MEDIA THE SMOOTH MUSCLE UNDERGOES HYPERTROPHY AND HYPERPLASIA FORMING CONCENTRIC RINGS. HENCE THE ONION RING APPEARANCE. THE INTIMA MAY HAVE AREAS OF NECROSIS

THERE IS A CHARACTERISTIC DUPLICATION OF THE BASEMENT MEMBRANE.

ATHEROSCEROSIS AS MENTIONED THIS IS A DISEASE OF THE INTIMA WHERE THERE IS DEPOSITION OF FIBROFATTY PLAQUES. THESE PLAQUES MAY EITHER OBSTRUCT THE LUMEN OR CAUSE SECONDARY DEGENERATIVE CHANGES. THREE THEORIES TRY TO EXPLAIN ATHEROSCLEROSIS 1. THE RESPONSE TO INJURY HYPOTHESIS 2. OLIGOCLONALITY HYPOTHESIS 3. INFECTIONS BY CHLAMYIA AND CMV CAUSING ATHEROMA FORMATIONS THE RESPONSE TO INJURY HYPOTHESIS: THIS THEORY SAYS THAT ATHEROMA FORMATION HAPPENS AS A RESULT OF CHRONIC OR REPEATED INJURY TO THE ENDOTHELIUM.

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THE INJURIOUS AGENTS INCLUDE 1. HEMODYNAMIC STRESSES EG HTN, NATURAL STRESS ON POSTERIOR WALL OF ABDOMINAL AORTA,BRANCHING/BIFURCATIONS OF VESSELS,MOUTH OF MESENTERIC ARTERIES 2. DYSLIPIDIMIAS/ HYPERLIPIDIMIAS- HIGH CHOLESTROL, LIPID ABN EG H LDL, H LIPOPROTEIN A, L HDL. HIGH LDL IS CAUSED BY: 1. 2. 3. 4. 5. CONGENITAL FAMILIAL HYPERCHOLESTRINEMIA DM NEPHROTIC SYNDROME HYPOTHYROIDISM ALCOHOLISM

WHAT DOES LDL DO? 1. BRINGS CHOLESTROL TO THE PERIPHERY 2. DAMAGES ENDOTHELIAL CELLS HENCE CAUSING DYSFUNCTION >BECOMES MORE PERMEABLE >NEUTRALIZES NITRIC OXIDE IN PRESENCE OF FREE RADICALS >LDL GETS OXIDIZED HENCE PROGRESSES ATHEROMA FORMATION HOW CAN WE INCR HDL? 1. EXCERSIZE 2. MODERATE CONSUMPTION OF ALCOHOL (RED WINE) HOW TO DECR HDL? 1. OBESITY-H BP, H DM, H TGs, L HDL 2. SMOKING DAMAGE TO THE ENDOTHELIUM IS CAUSED BY: 1. 2. 3. 4. 5. 6. 7. HEMODYNAMIC STRESSES- HTN LIPID ABNORMALITIES..DYSLIPIDIMIAS SMOKING HOMOCYSTINEMIA TOXINS-ENDOTOXINS-REPEATED INFECTIONS DIRECT MICROBES-CMV AND CHLAMYDIA HAVE BEEN LINKED TO A.S. HIGH IMMUNE CONDITIONS H C-REACTIVE PROTEIN

THE BIG FOUR:

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ENDOTHELIAL CELLS BECOME ABNORMAL: 1. THEY BECOME MORE PERMEABLE 2. DEVELOP MORE ADHESION MOLECULES->VCAM-1 THESE ENABLE STICKING OF MONOCYTES AND LYMPHOCYTES 3. INCREASED THROMBOGENIC CAPACITY LDL WILL INFLUX INTO THE INTIMA DUE TO THE INCR PERMEABILITY OF ENDOTHELIAL CELLS. THE IRREGULAR INJURED ENDOTHELIUM ATTRACTS MONOCYTES, LYMPHOCYTES AND PLATELETS THERE. THESE CELLS MOVE INTO THE INTIMA IE MONOCYTES WHICH CONVERT TO MACROPHAGES AND TLYMPHOCYTES. BOTH THE MACROPHAGES AND LYMPHOCYTES PRODUCE CHEMICAL MEDIATORS AND GROWTH FACTORS. MACROPHAGES- IL-1, TNFa, MCP-1 WHICH FURTHER IRRITATE THE ENDOTHELIAL CELLS HENCE SIGNIFICANTLY INCR PERMEABILITY AND ADHESION FACTORS. LYMPHOCYTES- g-IFN, LYMPHOTOXINS WHICH DO AS ABOVE. PLATELETS- PDGF ALL THESE GROWTH FACTORS STIMULATE THE SMC IN THE MEDIA TO COME INTO THE INTIMA. WHEN IN THE INTIMA THE SMC LOSE THE CAPACITY TO CONTRACT & RELAX AND GAIN THE PRIMITIVE PROLIFERATING CAPACITY. WHO ARE THE KEY PLAYERS IN ATHEROMA FORMATION? 1. 2. 3. 4. 5. ENDOTHELIAL CELLS MONOCYTESMACROPHAGES T-LYMPHOCYTES PLATELETS SMOOTH MUSCLE CELLS

THE CELLS IN THE INTIMA NAMELY THE MACROPHAGES, T-LYMPHOCYTES AND NOW SMC. FROM THESE MACROPHAGES AND SMC BECOME SUPERACTIVE. MACROPHAGES START PRODUCING FREE OXYGEN RADICALS WHICH COMBINE WITH LDL AND OXIDIZE IT. THIS OXIDIZED FORM OF LDL IS MORE DANGEROUS. THE MACROPHAGES AND SMC START FEEDING ON THE OXIDIZED LDL FORMING FOAM CELLS. MACROPHAGES HAVE SPECIAL RECEPTORS FOR LDL KNOWN AS SCAVENGER RECEPTORS. SO BASICALLY UNDER THE DISRUPTED ENDOTHELIUM WE NOW HAVE MACROPHAGES THAT RELEASE OXIDISING AGENTS, LDL WHICH IS GETTING OXIDIZED, LYMPHOCYTES, SMC AND NOW FOAM CELLS. WHY IS OXIDIZED LDL MORE DANGEROUS YOU ASK? 1. IT IS MORE EFFECTIVLEY TAKEN UP BY THE MACROPHAGES AND SMC..MORE PALATABLE..MORE DELICIOUS? BUSHRA IRSHADALI SUMRA Page 4

2. IT IS HIGHLY CHEMOTACTIC- IT INCREASINGLY CALLS MORE MACROPHAGES AND SMC..INCR NUMBER OF FOAM CELLS MADE 3. IT SUPER STIMULATES THE MACROPHAGES AND SMC, MACROPHAGES HAVE AN INCR CYTOKINE PRODUCTION. 4. LDL IS CYTOTOXIC-IT CAN KILL THE ENDOTHELIAL CELLS. SMCS AND MACROPHAGES THAT ARE GREEDILY ENGULFING LDL MAY RUPTURE. HENCE THERE IS FORMATION OF NECROTIC CELLS THE FAT AND INTRA-CELLULAR CONTENTS LEAKED OUT. THESE FORM A LIPID CORE THE SMCS; HAVE LOST THEIR ABILITY TO CONTRACT AND RELAX THEY HAVE INCR PROLIFERATION THEY ENGULF LDL THEY SECRETE EXTRA-CELLULAR MATRIX AND COLLAGEN

PLATELETS AND ENDOTHELIAL CELLS GIVE A CONSTANT SUPPLY OF GROWTH FACTORS CAUSING THE SMC THAT ARE JUST UNDER THE ENDOTHELIAL CELLS TO PROLIFERATE AND PRODUCE MORE COLLAGEN AND ECM

THE SMC AND ECM TOWARDS THE INTIMA FORM A FIBROUS CAP. FIBROUS CAP= SMC + COLLAGEN +PROTEOGLYCANS + SOME MACROPHAGES + SOME LYMPHOCYTES UNDER THE FIBROUS CAP WILL BE THE LIPID CORE, FOAM CELLS, ECM, SMC. =>SOME GROWTH FACTORS GO TO THE SIDES/SHOULDERS OF THE LESION (GFS PRODUCED BY; ENDOTHELIAL CELLS, PLTS,SMC,) AND STIMULATE THE Vasa Vasorum TO DEVELOP NEW BLOOD VESSELS. A PROCESS CALLED NEOVASCULARIZATION (THIS HAS A ROLE IN INTRA-PLAQUE HEMORRHAGE) RISK FACTORS FOR ATHEROSCLEROSIS(AGAIN): MODIFIABLE HTN DM DIETARY HABITS DYSLIPIDIMIAS SMOKING HOMOCYSTINEMIAS OBESITY SEDENTARY LIFESTYLE NON-MODIFIABLE AGE SEX GENETIC PREDISPOSITION

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AMERICAN HEART ASSOCIATION CLASSIFICATION OF ATHEROSCLEROSIS TYPE-I LESIONS/INITIAL LESIONS/FATTY DOTS- THEY APPEAR IN EARLY AGE, MAY APPEAR AS SOON AS 1ST YEAR OF LIFE.THEY ARE YELLOW COLOURED LESIONS ABOUT 1mm IN SIZE. MOST CHILDREN HAVE THESE BY THE AGE OF 10Y

TYPE II LESIONS/FATTY STREAKS- THEY ARE LIKE TYPE-I LESIONS EXCEPT ELONGATED. THEY ARE FORMED BY FUSION OF FATTY DOTS. UPTO 1cm IN LENGTH. MOST CHILDREN HAVE THESE LESIONS BY ADOLESCENCE

TYPE-III LESIONS /INTERMEDIATE LESIONS- MORE ADVANCED THEN TYPE-II LESIONS. MACROPHAGES WITH LIPID AND EXTRA-CELLULAR LDL

TYPE-IV LESIONS/TRUE ATHEROMAS-IN THIS LESIONS THERE IS A CENTRAL CORE OF LIPID...( A LIPID CORE)

TYPE-V LESIONS/FIBROATHEROMAS- PRESENCE OF A FIBROUS CAP WITH A DISRUPTED ENDOTHELIUM. AND SIGNS OF NEOVASCULARIZATION.

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TYPE-VI LESIONS/COMPLICATED ATHEROMAS-THESE ARE VERY ADVANCED LESIONS, WHICH HAVE PLATELET ADHESION MAKING PLATELET PLAQUES WHICH MAY OCCLUDE VESSELS. FIBRINOGEN MAY ADHERE TO PLAQUE FORMING A THROMBI. THE PLAQUE MAY HAVE FISSURES.

PLATELETS + FIBRIN= THROMBUS HEMORRHAGE MAY OCCUR IN THE PLAQUE (INTRA-PLAQUE HEMORRHAGE) MAY CAUSE THE PLAQUE TO ENLARGE CAUSING OCCLUSION OF THE LUMEN.

NOTE: GROWTH OF TYPES I-IV IS DUE TO FAT ACCUMULATION GROWTH OF TYPE V IS DUE TO ACCELERATED ACCUMULATION OF SMC AND COLLAGEN DEPOSITION. GROWTH OF TYPE VI IS DUE TO FIBROSIS AND THROMBI FORMATION AND ALSO INTRAPLAQUE HEMATOMA FORMATION.

CLINICAL CONSEQUENCES TYPE I-IIISILENT LESIONS TYPE IV-VICLINICALLY OVERT LESIONS FIBROSIS AND DYSTROPHIC CALCIFICATION SURFACE DEFECTS: EROSION, ULCERATION AND RUPTUREMAY LEAD TO; PLATELET PLUG FORMATION WHICH MAY LEAD TO THROMUS FORMATION ATHERO-EMBOLISM INTRAPLAQUE HEMORRHAGE CAUSING OBSTRUCTION...MAY BE EITHER DUE TO NEW VESSELS RUPTURING OR A FISSURE LEADING TO VESSEL BLOOD ACC IN THE PLAQUE ANUERYSMS

ABDOMINAL AORTA 1. LOWER LIMB ISCHEMIA 2. ANEURYSMS- WHICH MAY RUPTURE LEADING TO DEATH BUSHRA IRSHADALI SUMRA Page 7

CORONARY ARTERY IHD: 1. 2. 3. 4. POPLITEAL ARTERY THROMBUS FORMATION COULD BE OCCLUSIVE OR ANUERYSMAL LEADING TO LOWER LIMB ISCHEMIA CAROTID ARTERY/ CIRCLE OF WILLIS 1. TIA~ Neurological defecits caused by CVS that last <24h and are reversible 2. STROKE 3. ISCHEMIC ENCEPHALOPATHY MESENTERIC ARTERY USUALLY AT THE OSTIA(MOUTH ) OF ARTERY ATHEROMA FORMATION. CAUSES ISHEMIA OF GIT ESP SMALL BOWEL ISCHEMIA RENAL ARTERY OSTIUM LESIONS CAUSING INCR RAAS. HENCE ALDOSTERONE INCR WATER ABSN AND HYPERTENSION. LERICHE SYNDROME ADV LESIONS IN ABD AORTA AND ILEAC ARTERIES MALE-IMPOTENCE ANGINA PECTORIS MI SUDDEN CARDIAC DEATH CHRONIC IHD LEADING TO CONGESTIVE CARDIAC FAILURE

CLAUDICATION

ATROPHY OF CALF MUSCLES

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