Cardiovascular pathology

Dr D S O’Briain October 2009

CARDIOVASCULAR SYSTEMWeek 6 Monday 05 October 2009Time Discipline Topic: Hypertension and Ischaemia Venue Lecturer1.00pm Path Pathogenesis of Hypertension WMLT DSOB2.00pm Pharm Modern Management of Hypertension RSLT AM3.00pm Pharm Management of CVS Risk Overview &

Smoking CessationRSLT MB or MH

4.00pm Clinical 1 Non Invasive Cardiology RSLT Vinnie MaherWeek 6 Tuesday 06 October 2009Time Discipline Topic: General Principles of

ManagementVenue Lecturer

9.00am Micro Infections in A&E RSLT PGMTopic: Ischaemic Heart Disease

10.00am Path Pathogenesis of Ischaemic HeartDisease

RSLT DSOB

11.00am Pharm Management of Ischaemic HeartDisease, MI

RSLT JS

12 noon Lunch1.00pm Pharm CVS Risk: Lipid Lowering Therapy/

ObesityRSLT MB

2.00pm Clinical 2 Chest pain: Approach to CardiacIschaemia

RSLT tbc

Topic: Valvular Heart Disease3.00pm Path Pathogenesis of Valvular Heart Disease RSLT DSOB4.00pm Clinical 3 Valvular Heart Disease RSLT Mr Vincent YoungWeek 6 Wednesday 07 October 2009Time Discipline Topic: Peripheral Vascular Disease Venue Lecturer9.00am Path Pathogenesis of Peripheral Vascular

DiseaseRSLT DSOB

10.00am Pharm Anti-platelet Therapies RSLT JSTopic: General Principles ofManagement

11.00am Micro Surgical infections leg ulcers, woundsand dressings

RSLT PGM

12 noon Clinical 4 The Ischaemic Leg: Painful Cold limbs WMLT tbc1.00pm Lunch

Topic: General Principles ofManagement

2.00pm Micro Bacteraemia and line-associatedinfections

WMLT BO’C

Topic: Myocarditis / Endocarditis3.00pm Micro Endocarditis, Myocarditis & Pericarditis:

A microbiological approachWMLT TRR

4.00pm Path Pathogenic basis of Endocarditis,Myocarditis & Pericarditis

WMLT DSOB

Week 6 Thursday 08 October 2009Time Discipline Topic: Myocarditis/Endocarditis Venue Lecturer9.00am Free slot10.00am Micro Myocarditis & Pericarditis - is there a role

for Microbiology?WMLT Dr Jerome Fennell

11.00am Clinical 5 Sudden Death in young people andCardiomyopathy

RSLT Dr Ross Murphy

12 noon LunchTopic: Heart Failure, Cardiac Arrestand Cardiogenic Shock

1.00pm Path Pathogenesis of Cardiac Failure RSLT VC2.00pm Pharm Management of Heart Failure including

Acute Pulmonary OedemaRSLT MB

3.00pm Pharm Management of Cardiac Arrhythmiasand Cardiac Arrest

RSLT MB

4.00pm Free slotWeek 6 Friday 09 October 2009Time Discipline Topic: General Principles of

ManagementVenue Lecturer

9.00am Clinical 6 SOB & Palpitations tbc10.00am Micro Healthcare associated infections 1 RSLT FRF11.00am Clinical 7 Wound care and management tbc12 noon Path CPC 1: Cardiovascular System RSLT JOL/OS1.00pm Lunch

Cardiovascular pathology

Systemic pathology

Topic: 2-5 min discussion, then summary panel

Segments:

1. Hypertension (12 panels)

2. Ischaemic heart disease (23 panels)

3. Valvular heart disease: (14) Rheumatic fever, congenital heart disease

4. Peripheral vascular disease: atherosclerosis (20), aneurysms (4) vasculitis (7), vessels (3)

5. Endocarditis, myocarditis, pericarditis:

6. Pathogenesis of cardiac failure (Dr Crowley)

7. CPC (Prof O’Leary)

QuickTime™ and aTIFF (Uncompressed) decompressor

are needed to see this picture.

Hypertension

• High blood pressure is common and asymptomatic,– 25% of population >140/90

• Incidence increases: age, black, young males, older females– More severe: younger, blacks.

• Consequences: Cardiac, cerebral and renal disease

Hypertension

• Types: Primary 95% Secondary 5% (renal, vascular, endocrine)

• Course: Benign 95% Accelerated (malignant) 5%

• Compensated / decompensated.

BP = Cardiac output X peripheral vascular (arteriolar) resistance.

Factors: Blood volume, ECF volume, total body Na.Regulation: renin-angiotensin-aldosterone system.

Terminology

How to say

"we have some ideas but we're not sure of the cause"

• primary• ideopathic• agnogenic

• cryptogenic• essential

Essential Hypertension

Pathogenesis: Sodium retention and/or vasoconstrictionUpper limit of the continuous variable of blood pressure

• Genetic factors (polygenic) : Twin, sibling, familial, racial (blacks), animal (rat strains)Rarely single gene defects for aldosterone metabolism, sodium resorption

• Environment:Exiled Chinese incidence increased: behavior, stress, obesity, OCTDietary sodium: animal study (rats), remote peoples exposed to salt

a) defect in Na excretionb) defect in cell membrane Na or Ca transport

(Ca - phosphorylation - response to vasoconstrictors)c) sympathetic response (stress, neurogenic factors)

Sodium Homeostasis

Total body sodium regulates blood volume and cardiac output

• Influenced by: Renin angiotensin system.Blood volume -GFR - proximal tubule Na resorption.

Atrial natriuretic factor: inhibits (volume expansion -GFR -distal tubule Na resorption).

• Renal vasodepressors:a) prostaglandins, b) kallikrein-kinin system, c) platelet activating factor.Vasoconstrictors: angiotensin II, catechol amines, thromboxane, leukotriene, endothelin

Hypertension - Morphology

• Adaptive response to pressure or volume overload:

• Myocyte cytoplasm and nucleus enlarged.New myofibrils, filaments, mitochondria, ribosomes(later degeneration, loss of myofibres, cell atrophy, interstitial fibrosis)

• Left ventricle: Concentric hypertrophy (normal LV thickness 1.4 cm); dilates with decompensation

Hypertension - Effects

• Compensation - none.

• Decompensate - CCF

• Thick wall: increases 02 requirement and diffusion distance

• Dilation - eventually overstretches fibres

• Myocyte degeneration and fibrosis - stiffness - impairs diastolic filling (stroke volume)

• Atherosclerosis

Benign nephrosclerosisAssociations: age, diabetes, hypertension.

• a) Arteriole walls thickened, hyaline, and lumen narrowed• Hyaline: plasma protein, lipids, basement membrane, intracellular matrix.

• b) Fibroelastic hyperplasia (interlobular & arcuate arteries) - narrowing. Reduplication of elastic lamina, increased fibromuscular tissue in media.

• Secondary effects but may sustain & aggravate hypertension.

• Effect - loss of tubules, interstitial fibrosis, damaged glomeruli, cortical narrowing, granular kidney surface, mild reduction in size of kidney,

mild reduction in function and reserve.

Accelerated (malignant) hypertension - Clinical

• Medical emergency; effects young, male, blacks• CNS: papilloedema, visual effects, encephalopathy headaches, nausea,

vomiting, coma, fits• CVS: failure• Renal: proteinuria, haematuria (microscopic or gross), altered renal

function, later failure

50% mortality in 3 months untreated - 50% mortality in 5 years treated.Death - uremia (CNS or CVS disease)

Hyperplastic arteriosclerosis - Pathology

• De novo.• On benign hypertension.• On renal disease (GN, reflux, scleroderma )

a) fibrinoid necrosis of arterioles (fibrin ± necrotising inflammation)b) hyperplastic arteriolitis (arterioles and interlobular arteries) onion-skinning

with smooth muscle and collagen.

• Effect: narrowed arterioles, necrotic glomeruli, thrombosed capillaries, ischaemic atrophy, infarction, high renin, endothelial injury (activated platelets, coagulation system - thrombus).

Secondary Hypertension (Mechanisms)

• Renal – a) Renin increase : renovascular – b) Volume excess: acute GN– c) Mixed.

• Other (examples) – Primary hyperaldosteronism ( blood volume)– Phaeochromocytoma (vasoconstriction - (nor)adrenaline– Oral contraceptives (renin angiotensin)– Periarteritis nodosa (renin angiotensin)

Renal Artery Stenosis

Goldblatt. Hypertension proportional to constriction in one renal artery (Dog). Increased renin from JGA; reverse with surgery or angiotension II antagonists. But secondary renal changes may lead to persisting hypertension

• 70% have atheromatous plaque at origin of artery (males, diabetes, age) 2/3 curable• 30% fibromuscular dysplasia (females,young) 90% curable Fibromuscular thickening of

intima, media or adventitia; multiple (or single) artery (or branches) unilateral (or bilateral)

Morphology- In ischaemic kidney: ischaemic changes, JGA hyperplastic, arterioles normal. In other kidney: hypertensive changes.

Clinical: (Bruit) IVP: small kidney, delayed function. Arteriogramvisualise stenosis, segmental beaded effect. Measure renal vein renin.

Ischaemic Heart Disease

Imbalance in the supply and demand for oxygen (also for nutrients and for removal of metabolites) in cardiac muscle.

• Increased demand: Exercise, emotion

• Decreased supply:

Reduced oxygen (anaemia, cyanosis, carbon monoxide, cigarettes).

Reduced coronary flow (atheroma, thrombus, spasm, shock).

Ischaemic Heart Disease Epidemic

• Causes 80% of cardiac mortality• Peaked in US in 1960s, 40% decline since• Different patterns in some Western countries• Cause of decline:

– Changing lifestyle (diet, smoking, exercise)

– Better therapy (CCU, thrombolysis, arrhythmia therapy, CABG, angioplasty)

Atherosclerotic Coronary Artery Disease: Distribution

• Narrowing of greater than 75% is clinically significant

• In 1/3 of patients one vessel is involved, in 1/3, two vessels and in 1/3, three vessels.

• Sites: Proximal 2 cm of LAD and circumflex, proximal 1/3 of right coronary artery.

• Less frequent: Secondary diagonal, obtuse, marginal branches and posterior descending artery.

• Rare: Intramyocardial branches

Atherosclerotic Coronary Artery Disease:

Clinical Syndromes

• Silent Infarct

• Angina Pectoris

• Myocardial Infarct

• Chronic Ischaemic Heart Disease

• Sudden Death

Angina Pectoris• Stable: Pain with exercise, emotion or other increases in demand.

– ST segment depressed—subendocardial ischaemia

• Prinzmetal: Rest pain– ST segment raised —transmural ischaemia. – Due to spasm, (? cause: vasoconstrictive humoral factors, mast cells, nerves– atherosclerosis usually present.

• Unstable: Pain, increasing in duration and severity with less effort or at rest,– (also called preinfarction angina or acute coronary insufficiency). – Caused by: plaque enlarging, fissured, ulcerated, ruptured, vasospasm, platelet

aggregation and activation

Atherosclerotic Coronary Artery DiseaseVascular obstruction

• Plaque ulceration, fissure or rupture – platelets to adhere and become activated– thrombus forms (activated thrombin transforms fibrinogen to fibrin)– release of histamine, other vasoactive factors – microemboli may occur

• Vasospasm: Demonstrated angiographically– rarely causes infarct in absence of atheroma– may rupture plaque, role of nerve supply and vasoactive factors

• Other: Emboli, trauma, arteritis (SLE, PAN, etc), cocaine (arrhythmia, spasm)

Myocardial Infarct - Coronary Artery Lesions

• 90% of infarcts are supplied by an artery which has a thrombus over an ulcerated or fissured plaque

• Platelets activated — aggregate to form thrombus (embolus) — vasospasm, occlude.

• Deaths under 4 hours — 90% have thrombus; over 12 hours — 60% have thrombus (thrombolysis)

• 10% without thrombus: (usually have severe atherosclerosis) Spasm, platelet aggregates, emboli (mural thrombus, endocarditis, paradoxical), arteritis, cocaine, tachycardia or arrhythmia

Evolution of infarct

• 4 hours: No morphological changes (subtle ultrastructural changes).

• 8 hours: Oedema, myocytolysis, contraction band necrosis, wavy fibres.

• 24 hours: Grossly pale, acute inflammatory infiltrate.• Days: Infarct becomes clearly defined grossly, centre

softens, a hyperaemic rim appears, granulation tissue appears.

• Weeks: Organisation proceeds leaving an organised scar by about six weeks.

Myocardial Infarct, Morphology

• Experimentally after 20 minutes of occlusion– ischaemic necrosis begins in the subendocardium (least collaterals and vessels most

compressible)

• Infarct size:– Proportional to extent and duration of ischaemia, collateral supply, metabolic

demands; may be transmural or subendocardial.

• Infarct site: – Left ventricle (If adjacent, right ventricle is involved in 25%, adjacent atrium in 5%)– Isolated right ventricle in 1% (usually following marked right ventricle hypertrophy and

strain).

• Distribution: – LAD (50%) Anterior 2/3 septum, anterior wall, apex. – RCA (35%) Posterior wall and septum. – LCA (15%) Lateral left ventricular wall

• Infarcts are usually single– may extend (retrograde thrombus, vasospasm, arrhythmia), reperfusion injury.

Cardiac Enzymes

• Creatine Kinase – MB isoenzyme specific for

heart

– Rises 4-8h, peaks 18h, falls 2-3d

• Troponin T or I– Similar start, remain for 7-

14d

Myocardial Infarct, Clinical

• Asymptomatic (15%).• Symptomatic (60%).

– Sudden pain, crushing character, retrosternal, radiation (left shoulder, arm, jaw), associated sweating, nausea, vomiting, dyspnoea, indigestion.

• Sudden death (25%).• ECG:

– new Q waves, ST and T wave abnormalities, arrhythmias– evolving pattern, 20% are non-specific or silent.

• Enzymes: – Soluble cytoplasmic enzymes (CK 4h-4d, Troponin I and T 4h-14d

• Image: Echo (mural dyskinesia), Angiography, perfusion scintography, MRI.

Effects of Myocardial Infarction

• Decompensation: – Muscle is dead, injured, stunned, disorganised,

• Infarct dyskinesia: – May cause aneurysm, mural thrombus, embolism.

• Infarct rupture: – tamponade, septal shunt.

• Papillary muscle infarct or rupture – mitral valve dysfunction

• Arrhythmias provoked in injured tissue

• Haemorrhagic pericarditis.

Myocardial infarct — complications

• Uncomplicated (15%)• Sudden death (25%)• Arrhythmia

– (sinus brady-, tachy-cardia, ventricular tachycardia, PVC, V fibrillation, asystole, block)

• Left ventricular failure (60%)• Pump failure (40% of myocardium damaged)• Shock (10%)• Rupture (free wall, septum, papillary muscle)• Thromboembolism• Mortality 35% in one year (50% sudden, 25% in hospital. 10% die

each subsequent year.

Percutaneous Transluminal Coronary Angioplasty

• Mechanisms– Plaque compression—redistribute soft contents (most human plaques are hard)– Plaque fracture—breaking, cracking, splitting; – Stretching of plaque-free wall (70% of all, 24% severe plaques, are eccentric)

• Early closure– Spasm– Thrombus– Dissection with large intimal flap– Relaxation of overstretched wall of eccentric plaque– Subintimal bleed (concurrent thrombolysis)

• Late chronic stenosis (20-50%)– Fibrocellular intimal proliferation– Progression of plaque

Myocardial Infarct, Demography

• Age (only 5% under 40)• Male (risk x 6 under 45, less when older)• Smoker (risk x 5, proportional to number

smoked)• Other: personality (type A: increased risk),

exercise and moderate alcohol protect• Western countries: risk was high, now

falling

Chronic Ischaemic Heart Disease

Insidious congestive cardiac failure (possibly remote myocardial infarct or angina)

• Findings: possibly: left ventricular dilation, murmur, calcification

• Morphology: patchy fibrosis, old infarcts• ECG: Normal, bundle branch block or non -specific

changes

Sudden Cardiac Death

• Ischaemic heart disease (at least 75% stenosis)– occluding thrombus in 1/2, new infarct in 1/4, old infarct in 1/3

• Other coronary artery disease: anatomic anomalies, embolism, arteritis, dissection

• Myocardial disease: hypertrophic obstructive cardiomyopathy, right ventricular dysplasia, myocarditis, amyloid, sarcoid

• Valve disease: aortic valve stenosis, floppy mitral valve infective endocarditis.

• Conduction defects• Electrolyte abnormalities

Congestive Cardiac Failure

State resulting from impaired cardiac function and resulting in insufficient output for the metabolic requirements of tissues and organs

A) Excess Load.B) Decreased pumping ability.

• Muscle fibre – a) death– b) dysfunction.

– Decreased output - Forward failure.– Damming back - Backward failure.

Cardiac Failure - Compensation

• Dilation: produces increased force of contraction and stroke volume (Starling)

• Hypertrophy• Increased blood volume• But increased muscle mass and blood volume require more

work — excess dilation — reduced efficiency

No morphological difference between compensated and non-compensated heart — look for hypoxic and congestive effects remote from the heart

Left Ventricular Failure

• Heart: – Hypertrophy and dilation of left ventricle (except mitral stenosis)

• Lungs: – Congestion, oedema of lung and pleural space

– Dyspnoea, orthopnoea, paroxysmal nocturnal dyspnoea, cough with frothy blood-tinged sputum

• Kidney: – Decreased perfusion (ischaemic tubular changes)

– renin angiotensin aldosterone system (increased NaCl, H20, ECF and blood volume)

• Brain: – Hypoxia — irritable, decreased concentration and attention span, stupor, coma

Right Ventricular FailureSecondary to A) Left ventricular failureB) Other causes: cor pulmonale, cardiomyopathy, constrictive pericarditis, tricuspid and pulmonary valve

disease

• Liver: – Enlarged, chronic passive congestion (nutmeg)– if severe: central necrosis with fibrosis result in cardiac sclerosis (cardiac cirrhosis)

• Spleen: – Enlarged, congested, dilated sinusoids and fibrotic walls

• Kidney: – Congested

• Subcutis: – Oedema, anasarca

• Pleura: – Effusion (especially on right)

• Portal System: – Congestion of GIT, spleen; ascites

Heart Failure

Organ LV Failure

RV Failure Effect

Lung +++ + Oedema, cough, dyspnoea.

Kidney + ++ Fluid retention, decreased perfusion.

Brain ++ + Hypoxia.

Liver - + +++ Enlarged, congested.

Spleen - + +++ Enlarged, congested.

Portal - + ++ Ascites, GIT congestion.

Subcutis - + +++ Oedema.

Cor Pulmonale

Right ventricular enlargement secondary to disordered structure or function of lungs

Causes: • Lung parenchymal disease: COAD, pulmonary fibrosis, cystic fibrosis• Vascular disease: pulmonary embolism, vasculitis• Chest disorders: Kyphoscoliosis, obesity, neuromuscular disorders

Effect: Narrowing of pulmonary vascular bed (hyperviscosity-polycythemia)

• Pulmonary hypertension -> cor pulmonale: acute (due to eg pulmonary embolism) -or chronic). Right ventricular wall hypertrophies then dilates and fails

Rheumatic fever

Acute recurrent inflammation associated with reaction to streptococcal infection.

Occurs 1-5 weeks after Group A, ß haemolytic streptococcal infection, mainly children (5-15 years)

Rheumatic Fever, Jones Criteria

Major criteria of Jones

• Polyarthritis — sequential involvement of large joints• Erythema marginatum • Subcutaneous nodules• Sydenham's chorea — rapid purposeless movements.• Carditis

Also (minor criteria): fever, arthralgia, previous rheumatic fever, prolonged PR interval, acute phase reactants (ESR, CRP or WCC increased)

Jones (AHA): 2 major or 1 major and 2 minor criteria: high probability of rheumatic fever. Recent streptococcal infection increases probability

Rheumatic Fever, Pathogenesis

• 1. Follows streptococcal infection but lesions sterile

• 2. Streptococcal antibodies — anti streptolysin 0 (AS0) & hyaluronidase

• 3. Most frequent after severe streptococcal infections

• 4. Recur with repeated streptococcal infection

• 5. 99.9% decline in incidence—better living conditions, antibiotics, organism has changed.

• 6. Individual susceptibility — genetic.

Rheumatic Fever, Pathogenesis

Aetiology : • Cross reaction • Hyaluronate of humans—streptococcal capsule.• Streptococcal membrane—muscle sarcolemma• Streptococcal M protein—cardiac myosin• Autoimmune - antiheart antibody (but ? cross reaction)

Pathology: • Aschoff Body: Fibrinoid necrosis surrounded by mononuclear cells with Anitschkew

cells (with caterpillar nucleus)• Pericarditis (bread &butter)• Myocarditis• endocarditis (verrucae on lines of closure) & McCallum's patches. • Heal by scarring - distort valve

Rheumatic Fever: Cardiac involvement

Acute - in 2/3 of children, 1/3 of adults.Pericarditis, arrhythmias (atrial fibrillation), prolonged PR interval, auricular

thrombus, cardiac dilation (MI murmur). Valve involvement (MI, AI), (death 1%))

Chronic - if first attack severe or when very young.• MV in 2/3, MV & AV 1/4, TV (Few), PV rare• Valve fibrosis, calcification, fused commissures (fish mouth) &

chordae.• Mitral stenosis: LA dilation, auricular thrombus, pulmonary

congestion, RVH

Congenital Heart Disease - Varieties

a) Shunts: Chamber (or vessel) to chamber (or vessel).

• Right to left - Early cyanosis, clubbing, hypertrophic osteoarthropathy, polycythemia (cerebral thrombosis).

• Left to right - cyanose tardive. Increased pulmonary flow with vascular sclerosis, pulmonary hypertension, reversed flow (right to left).

• Shunt complication. paradoxical embolism, infected embolism, infective endocarditis.

b) Obstruction: Non-cyanotic. Failure to thrive, retarded development, intercurrent diseases of childhood.

c) Malposition: Ectopia, dextrocardia (isolated or other anomalies) situs inversus totalis (Kartagener; sinusitis, bronchiectasis, immotile cilia).

Congenital Heart Disease - Early Cyanosis

1. Tetralogy of Fallot• VSD, overriding aorta, right ventricular outflow obstruction, RVH.• Outflow obstruction (infundibular, valve, supravalve) dictates severity.

2. Transposition (multiple combinations with atria, ventricles, vessels)• Mixing essential: ASD in all, most also have PDA, or VSD.

3. Truncus arteriosus• Common aorta & PA • Usually other cardiac defects

4. Tricuspid Atresia

Congenital Heart Disease Late Cyanosis—septal development

1. Ventricular septal defect• Development of septum (week 5-6): common ventricle divided by muscular &

membranous septum

2. Atrial septal defect• Development of septum (week 4): atrial canal closed by septum primum,

(ostium primum). Valve effect allows RA-LA flow, closes at birth

3. Patent ductus arteriosus• Ductus closes day 1-2 (High 02, low PGE)

Congenital Heart Disease - Late Cyanosis

Ventricular septal defect Size dictates effect:• Small — 5mm: (Roger), well tolerated, 50% close spontaneously,

loud murmurs & thrill, endocarditis • Large: pulmonary hypertension, shunt reverses

Atrial septal defect Ostium primum defect (5%). Often Down's syndromeOstium secundum (90%). Often other defects

Patent ductus arteriosus• 90% PDA isolated (important for survival in other forms of CHD). • Machinery murmur, systolic thrill. LVH, dilated PA

Congenital Heart Disease - Obstructive

1. Coarctation of Aorta - systolic murmur & thrill– Preductal: infants, (PDA) RVH with cyanosis of lower body– Postductal: adults (PDA in 50%)

» hypertension in upper body insufficiency (claudication, cold) in lower body.

» Large collateral vessels: intercostal, axillary, mammary with rib notching

2. Pulmonary stenosis

3. Aortic stenosis

Top 3 (50%) —VSD, PDA, ASD: late cyanosis

Middle 3 — non-cyanotic

Bottom 4 — Fallot etc: early cyanosis

Other Valve Diseases

Calcific aortic stenosis– bicuspid (1% of population)

– rheumatic or normal valve becomes calcified - sclerotic, later stenotic.

• Result: systolic murmur, LVH, CCF; angina, syncope, sudden death

Mitral annular calcification• asymptomatic, seen on imaging (rarely regurgitation, stenosis,

arrhythmias, thrombi, infection)

Mitral valve prolapse

• Ballooned (floppy) valve with myxoid degeneration of valve fibrosa

• 7% of population, peak young females (in Marfan syndrome, abnormal fibrillin gene)

• Asymptomatic - mid systolic click late systolic murmur• Minority: chest pain, dyspnoea, fatigue, psychiatric symptoms• Benign (Rarely: infective endocarditis, mitral insufficiency,

arrhythmias, emboli with infarction, sudden death)

Malignant carcinoid syndrome

Plaques of fibrous tissue on valve and endocardium of right ventricle outflow tract

• Syndrome: – Flushing, cramps, nausea, vomiting, diarrhoea (100%)– Cardiac disease (50%)– Asthma (33%)

• Syndrome occurs in less than 1% of all carcinoids but in 10% of carcinoids with large hepatic metastases (rarely: with ovarian or lung carcinoids)

• Mediators: 5HT, kallikrein, bradykinin, histamine, prostaglandins• Metabolism: in liver, monoamine oxidases of lungs

Prosthetic valves

Types • A) Mechanical occluders• B) porcine or bovine bioprostheses

Complications in 5-10% (emboli 3%, infection 1%) per patient year• Paravalvular leak• Thromboembolism: (anticoagulate mechanical valves) emboli, infection,

obstruct movement of valve• Infections: at tissue interface (ring abscess), also at cusp in bioprosthesis• Deterioration: Bioprostheses, calcification and degeneration in 25% • Also: Haemolysis, fibrous tissue ingrowth effecting function

Atheromatous Plaque, Macroscopic

• Fibrous cap (white), deeper portion (grumous, yellow).• 3 - 15 mm diameter, raised, coalesce.• Scanty to numerous

• Distribution: Abdominal aorta> coronary > popliteal > descending thoracic >internal carotid > circle of Willis.

• Spared: upper extremities, renal, mesenteric (except ostia).

Atheromatous Plaque Histology

• Fibrous cap: Smooth muscle, WBC, connective tissue, collagen, elastic, proteoglycan.

• Core: lipid debris, cholesterol, cholesterol esters, foam cells ( smooth muscle and macrophage), fibrin, plasma proteins, T-cells.

• Periphery: neovascularisation, chronic inflammation.

Effects of Atheromatous Plaque

Different effects in narrow (coronary) and wide (aorta) vessels

Clinically silent Most plaques have no effect. Calcification: Identify on imaging.

Complicated plaques Fissure Ulcerate: atheroemboli. Thrombose: occlude, embolise Haemorrhage: occlude.

Consequences Stenose: Ischaemia, atrophy. Occlude (by thrombus or haemorrhage): Infarct. Aneurysm: pressure effects, leak (rupture)

Fatty streak

Possible precursor of atheroma.

• Spot (1mm), Streak (1x10mm).

• Composition: Macrophages filled with lipid (foam cells) later smooth muscle cells with lipid droplets, extracellular lipid, T-lymphocytes, proteoglycans, collagen, elastin.

• Incidence: More frequent with high milk/fat diet: • 10% first decade, 30% third decade, • May recede, persist or convert to fibrous plaque • Distribution: Aorta - unlike atheroma, Coronary arteries - like

atheroma.

Intimal Cushion

• White areas of diffuse intimal thickening composed of intimal smooth muscle and matrix (little collagen, no lipid), gelatinous lesion.

• Degenerate effect of blood pressure and time.

• But occur at ostia (atheroma sites).

Monckeberg’s Calcific Medial Sclerosis

• Calcification of medium or small arteries

• Both sexes, over 50• Arteries: Femoral, radial, ulnar,

genital.• Cause: vasotonic factors, adrenaline,

nicotine.• Effect: none, visible in imaging

Arteriolosclerosis

• Hyaline change in vessel walls.

• Pathogenesis - plasma leakage, smooth muscle matrix.

• Associations - hypertension, diabetes, age.

• Benign - hyaline narrowing.• Hyperplastic - onion skin (fibrinoid necrosis).• Sites: Kidney, gall bladder, intestine, periadrenal,

pancreatic.

Atherosclerosis Risk FactorsHyperlipidemia. LDL.

Hypertension: 160/95 Vs 140/90,- Risk X 5. Increases: Atheroma, IHD, CVD. Risk decreases with therapy.

Cigarettes: More AS, more sudden death, Risk increased by 70-200%. Decreases after cessation.

Diabetes: More AS, MI x 2, Increased CVD, PVD risk increased x 8-150.

Other: Physical activity, stress, obesity, oral contraceptives, hyperuricemia, high CHO intake, male, age, family history, homocystinemia.

Multiple Factors:More than additive.

Theories of Atherogenesis

• Virchow - imbibation

• Rokitansky - encrustation

Role of lipid in Atherosclerosis

1. Found in plaque

2. Experimentally raised lipid -> AS

3. Hyperlipidemias -> AS

4. Populations with high lipids -> high AS rate

5. Treat hyperlipidemia - decrease AS.

Risk of Atherosclerosis

• High: Raised LDL (70% cholesterol), triglyceride and VLDL.• Low: Raised HDL.

• Risk increases with increased cholesterol level (risk x 5 with cholesterol increase 220 to 265)

• Increased intake cholesterol and triglycerides - increases serum cholesterol.• Omega 3 fatty acids (fish) protective

How Hyperlipidemia may damage intima

More serum LDL, more cellular penetration.• LDL with proteoglycan - avid uptake.

• LDL modified - lysosomal uptake.

• LDL - directly damages endothelial cell.

• Oxidised lipoproteins: Endothelial injury, smooth muscle injury, foam cells - scavenger receptor, chemotactic.

Intimal dysfunction

• Cause: Mechanical, Haemodynamic stress, Immune complex, Radiation, Chemotherapy.

• Association: Hypertension, Stress, Cigarettes.

• Effect: Increased intimal permeability, adhesion, smooth muscle proliferation, atheroma (if hyperlipidemia )

Macrophage

• Family: Monocyte, histiocyte, macrophage, epithelioid cell, giant cell, granuloma

• Monocytes adhere, migrate, phagocytose

• Have scavenger receptor - modified VLDL receptor (Lipid internalised, hydrolysed, esterified -> lipid droplet).

• Monocytes produce: IL-1, TNF (increased adhesion), chemotaxis factors, toxic O2, PDGF, TGF beta -> smooth muscle

Smooth muscle proliferation

• Origin: From media (or myointima)• Stimulus: PDGF (from platelets, macrophages,

endothelial and smooth muscle cells), FGF, EGF, TGF.

• Inhibit: Heparin, TGF-B.

• Result: Smooth muscle cells produce extracellular matrix and foam cells (atheroma)

Arterial Injury

Permeability increases.

Adhesion of platelets, monocytes

Factors released

Smooth muscle migrates to intima, proliferates and produces

extracellular matrix, collagen, elastin, proteoglycans

Monocytes - phagocytose

Lipid deposited

Other Theories of Atherogenesis

• Primary smooth muscle proliferation: monoclonal growth (as a form of leiomyoma)

• Cause: Exogenous (hydrocarbon, virus), endogenous (cholesterol)

• Experimentally: Plaques in Marek chicken virus, anthracycline, herpes mRNA in plaque

Aneurysms

• Localised abnormal dilation of vessel.

• Types: Saccular, fusiform, cylindroid, dissection.

• Complications: Pressure, thrombus, rupture.

• Aetiology: Atherosclerosis, cystic medial necrosis, syphilis, trauma (arteriovenous aneurysm), PAN, infections, (mycotic), congenital (berry).

Atherosclerotic Aneurysm

• Males of 50+, frequently (50%) hypertensive• Abdominal aorta (between renal artery and aortic biforcation).

(Thoracic aorta, renal, mesenteric arteries)

• Complications;• Rupture (if >6 cm, 50% rupture in 10 years)• surgical mortality 50% (unruptured 5%)• Compression - ureter, vertebrae• Occlusion (thrombus, pressure)• Embolism• Abdominal mass

Syphilis

Obliterative endarteritis of vasa vasorum

Medial destruction with fibrosis (causes tree barking or wrinkling of intima and dilation of vessel). Aortic valve dilated with rolled thickened cusps

Secondary atherosclerosis usual

• Complications• Mediastinal encroachment• Respiratory effects in lung and airway• Swallowing impairment• Cough (recurrent laryngeal nerve)• Pain (involvement of vertebrae and ribs)• Cardiac effects

Dissecting Haematoma (Aneurysm)

Males x 3 , aged 40 to 60, Females often young, pregnant and hypertensive.

Haematoma between middle and outer 1/3 of vessel enters through 4-5 cm transverse intimal tear.

Type A - Within 10cm of aortic valve.Type B - Distal to subclavical artery.

Haematoma dissects proximal, distal or reenters lumen. Pain - back, radiates progressively. Rupture into pericardial, pleural or peritoneal cavity. Narrowing of vessels - cerebral or coronary insufficiency.

Dissecting Haematoma (Aneurysm)

Cause: Hypertension - mechanical stress

Cystic medial necrosis: basophlic mucoid pools with fragmented elastic, abnormal collagen, elastin,

proteoglycan

Marfan, abnormal collagen cross links. Structural effects in retina, lens, joint, aorta, abnormal height

Therapy: Surgery, hypotensive therapy.

ArteritisArteritis (vasculitis, angiitis).

Cause: Bacterial, irradiation, toxin, trauma, collagen disease.

Immune pathogenesis:Resemble arthus phenomenon, serum sickness (immune complex disorders)Found in SLE, Mixed cryoglobulinemia(IgG,M,Complement)Virus Ag/Ab complex, IgG+C. HBsAg-antibody complexDrugsCytotoxic Ab to endothelial cells (SLE) to activated endothelial cells (Kawasaki)c-ANCA (PAN, Wegeners), p-ANCA (microscopic PAN, Churg Strauss)T cells + granulomas; cell mediated immunity

Arteritis

• Periarteritis nodosa (PAN)• Leukocytoclastic vasculitis

• Temporal arteritis• Wegener’s granulomatosis

• Allergic granulomatosis• Lymphomatoid granulomatosis

• Raynaud’s• Buerger’s

• Takayasu’s• Kawasaki’s

Periarteritis Nodosa, Pathology

• Classic type involves medium or small vessels (except lung).• Kidney 85%, heart 75%, liver 65%, GI 50% (also pancreas, testes,

skeletal muscle, skin). • Involves sharply localised segments of vessels especially branching

points.

• Stages (may coexist):• Acute - fibrinoid necrosis (of segments), leukocytes, aneurysm

formation, thrombus.• Healing - fibroblastic reaction - nodules, macrophages, plasma cells,

organised thrombus• Healed - fibrotic (elastic stains).

Periarteritis Nodosa, Clinical• Ill young adult, (male x 3), fever, malaise, weak, raised

WCC, PUO, weight loss.• Renal failure, haematuria, hypertension, albuminuria.• Abdominal pain, melaena.• Muscle aches and pains, peripheral neuritis.

• Investigate: Hepatitis B Ag 30%, ANCA, Arteriography - nodules (aneurysms)

• Biopsy: Kidney, skin.• Therapy: Steroid and cyclophosphamide cure 90%.

Temporal arteritis

• Granulomatous inflammation of small and medium sized cranial arteries

• Morphology: giant cell reaction to fragmented elastic in vessel wall with polys and lymphocytes. Later thrombus formation and intimal fibrosis. Segmental involvement; biopsy is negative in 40%.

• Clinical: aged, female, high ESR, headache, local tenderness, facial pain, visual loss (40%). May involve aortic arch, GI tract, myocardium, CNS

• Association; polymyalgia rheumatica (flu-like illness with muscle stiffness.

• Cause: ? Cell mediated immunity to arterial antigen. • Responds to steroids

Wegener’s Granulomatosis

Acute necrotising granulomatous inflammation of upper and lower respiratory tract with focal necrotising vasculitis.

Glomerulonephritis:.• Clinical: males in 5th decade• 95% pneumonitis with nodular or cavitating infiltrate• 90% chronic sinusitis• 75% mucosal ulceration of nasopharnyx• 80% renal disease.

» 80% die in one year,t. 90% respond to cyclophosphamide

Pathogenesis: ANCA, Occasionally immune complexes found, cell mediated immunity role.

Raynaud

Raynaud’s Disease.• Vasospastic disorder of young women, onset: cold, emotion.• Involves fingers, hands, nose and feet which become white, blue and

red.• Benign: Secondary arterial thickening, tropic skin changes (atrophy,

ulcers).

Raynaud’s phenomenon.• Vasospastic changes in extremities due to:• Atherosclerosis, connective tissue diseases, Buerger’s disease,

Buerger’s Disease (Migratory Thrombophlebitis)

• Segmental thrombotic acute & chronic inflammation of intermediate and small vessels (arteries, veins and nerves)

• Involves males, strong association with tobacco smoking

• Pain, vascular insufficiency of lower limbs - gangrene, Raynaud phenomenon

Varicose Veins

• Dilated tortous veins (legs, portal system),female, fat, familial, increase with age

• Aetiology: Posture, pregnancy, tumours, poor support (superficial veins surrounded by fat)

• Pathology: Valves distorted and damaged, vein elastica degeneration and calcification and fibrosis (phlebosclerosis), luminal thrombus

• Effect: Leg congestion, oedema, heavyness, pain, stasis dermatitis, tropic changes, ulcer

Thrombophlebitis (Deep venous thrombosis)

Predisposition: CCF, cancer, pregnancy, bed-rest, immobilisation, post-operative.

Effects: Local: Deep leg veins (periprostatic, pelvis) inflamed - oedema, dilated

surrounding veins, dusky cyanosis, pain on pressure or dorsiflexion. Asymptomatic. Pulmonary embolism.

Lymphatics

– Inflammation: Lymphangitis, lymphadenitis• Obstruction: tumour, surgery, radiation, inflammation,

filiariasis. Results in oedema with fibrosis, brawny induration, peau d’orange, ulceration.

• Leak: chylothorax, chylous ascites.

• Lymphoedema praecox: Females 10-25 years, lower limb. ? cause

• Milroy’s disease: Lymphoedema from birth, mendelian, abnormal lymphatics.

Vascular Tumours

Benign

• Haemangioma; capillary, cavernous

• glomus, telangiectasia, spider naevus, granuloma pyogenicum, naevus flammeus (simple birthmark), port-wine stain (disfiguring birthmark) Lindau von Hipple, Sturge Weber, Osler Weber Rendau

Malignant.

• Haemangioendothelioma, haemangiopericytoma

• Angiosarcoma: High grade malignancy Skin, soft tissue, breast, liver – (arsenic, thorotrast, PVC) .

• Kaposi’s sarcoma: immune deficiency, herpes virus HHV8

Infective endocarditis

Microbiological colonisation of valve. (Similar effect: Colonisation of endocardium, aorta, aneurysms)

Valve lesion– Abnormal valves: Rheumatic (especially: small shunt, jet lesions), congenital

(VSD, PDA, Fallot), mitral prolapse, calcific stenosis (bicuspid), prosthetic valves, catheters

– Normal valves

Risk – In neutropenia, immunodeficiency, immunosuppression, IVDU

Seeding – Infection, surgery, dentist, IVDU. trivial injury, transient gut or mouth seeding

Infective endocarditis

Microbiological colonisation of valve. (Similar effect: Colonise endocardium, aorta, aneurysms)

Valve lesion– Abnormal valves: Rheumatic (especially: small shunt, jet lesions), congenital

(VSD, PDA, Fallot), mitral prolapse, calcific stenosis (bicuspid), prosthetic valves, catheters

– Normal valves

Risk – In neutropenia, immunodeficiency, immunosuppression, IVDU

Seeding – Infection, surgery, dentist, IVDA. trivial injury, transient gut or mouth seeding

Infective Endocarditis: Organisms

Organisms– 65% streptococcal: alpha haemolytic (viridens), bovis, faecalis – 25% staphylococcus aureus.

• Others: S. pneumoniae, GNB (E.Coli, N. gonorrhoea).

– 10% sterile.

Precipitating factors: • agglutinating antibodies, adhesion factors, platelet-fibrin deposits on

valve.

Infective Endocarditis: Clinical

• Systemic: fever, fatigue, weight loss, flu-like illness, chills.• Murmur (changing in acute, absent in 10%).• Emboli: subungual, retina (Roth spots); to brain, spleen, kidney

(lung).• Metastatic abscess (in acute): cerebral, meninges, renal.• Renal: Embolic infarct, focal or diffuse glomerulonephritis.• Cardiac: valve stenosis or incompetence, abscess, graft dehiscence,

pericarditis

Infective endocarditis: course

• Acute (days) : – virulent organism, large invasion, low resistance. On normal or

prosthetic valve, IVDU, catheter. Large ulcerating vegetation, perforate, erode valve.

• Chronic (months) : – low virulence, partial healing.

Endocarditis, other forms

Non-Bacterial thrombotic endocarditis• 1-5mm, fibrin, on leaflet (lines of closure), sterile.• marantic (chronic debilitating disease); or following catheter.• Associated with DVT or pulmonary embolus (hypercoagulable states)• Mucinous carcinomas (may secrete procoagulant)• Complication: (Rare), emboli, infarct, infection.

Libman Sacks —SLE (and antiphospholipid syndrome).• 1-4mm, fibrin & necrotic debris overlying fibrinoid necrosis.• Anywhere in leaflet - MV & TV, may be multiple. Also lesions in

myocardium, pericardium and vessels

Myocarditis.

Pathology: Leucocyte infiltration and myocyte degeneration or necrosis. Heart is normal sized or enlarged. Patchy haemorrhagic foci, pale flabby myocardium. May involve one or several chambers. Normal peri- and endocardium.

Clinical: Asymptomatic. Fatigue, dyspnoea, palpitations, chest discomfort, fever. Arrhythmia. Sudden onset congestive cardiac failure, murmur

(dilated AV valves).

Myocarditis, Aetiology.• Viral: Coxsachie A, B, ECHO, polio, influenza A, B, HIV.

– Occurs days to weeks after a respiratory or neurological infection (is occasionally primary). Cell mediated immunity (activated macrophages, CD8 lymphocytes), cells attack virus- containing myocytes.

• T. Cruzi: South American Trypanosomiasis (Chagas disease). Myocarditis in 80%, 10% die acutely.

• Trichinosis, Lyme disease (borrelia borgdorferi).• Other: other infections, collagen diseases, drugs, transplant, sarcoid,

Cardiomyopathy

Non-inflammatory heart muscle disease of unknown cause.

• Exclude: Inflammatory, hypertensive, congenital, valve and pericardial disease.

• Primary : Dilated (congestive) — more than 90% Hypertrophic Restrictive (obliterative) — rare

• Secondary.

Dilated (Congestive) Cardiomyopathy

Heart – weight increased – 4 chamber dilation – mural thrombi left ventricle (also right ventricle, atria) – valves and coronary arteries normal

Biopsy: Fibre hypertrophy, focal fibrosis, endocardial thickening, foci of inflammatory cells, (normal in 1/4).

Clinical: Relentless congestive failure, 25% five year survival.

Associations:• Alcohol: Direct effect, thiamine deficiency, cobalt.• Peripartum: Nutritional, hypertensive, metabolic effects, • occurs in poor multiparous women, regresses in 50%.• Genetic: dystrophin gene defect in 30%• Post Viral: Evidence of remote myocarditis.• Iron• Arrhythmogenic RV dysplasia, familial (ch 14 defect)

Hypertrophic Cardiomyopathy

Also termed: Asymmetric septal hypertrophy (ASH), Ideopathic hypertrophic subaortic stenosis (IHSS), Hypertrophic obstructive cardiomyopathy (HOCM)

• Heart enlarged, predominantly left ventricle, basal part (occasionally

other chambers predominate), Asymmetric or symmetric, banana-shaped cavity, outflow obstructed by muscle (a disorder of diastole).

• Endocardial thickening, mural plaques, mitral valve thickening,• Intramural coronary arteries.• Microscopy: Myocyte hypertrophy, disarray of cells and

myofilaments in 50% of septum, interstitial fibrosis

Hypertrophic Cardiomyopathy

Clinical:

• Young adult

• Asymptomatic,

• Sudden death (with exercise)

• Dyspnoea, angina, dizzyness, congestive failure, atrial fibrillation, auricular thrombus, emboli, infected endocarditis (mitral valve).

Pathogenesis: Autosomal dominant (50%)—abnormal sarcomeric genes: beta myosin heavy chain (in one third), cardiac troponin T, tropomyosin, myosin binding protein C

Increased left ventricle wall thickness and decreased compliance decreases volume of ventricle (decreased stroke volume), obstructs mitral valve, and obstructs outflow, (dilation of congestive failure may improve function).

Restrictive Cardimyopathy

• Amyloid.• Sarcoid.• Radiation• Endomyocardial fibrosis: Children, young adults,

Africa.

Heart transplantation

• 2500 transplants yearly, most for IHD and DCM, 5 year survival 60-85%

• Immediate failure (d 1-10): surgical factors, Hyperacute rejection

• Acute rejection, d 1-100 • Graft atherosclerosis

• Kidney: cyclosporine toxicity • Infections: 60% of deaths in first year (CMV, toxoplasmosis,)

• Malignancy: – A) Skin basal and squamous carcinomas, other carcinomas

– B) Lymphoproliferative disorder: EBV related, B-cell, high grade

Pericardial fluid

Effusion: Non-inflammatory, low protein, few cells.• Serous (congestive failure, hypoproteinaemia)• Serosanguinous (trauma, resuscitation)• Chylous (lymphatic rupture)• CholesterolExudate: Inflammatory, High protein, cells.• Acute: Serous, serofibrinous, fibrinous, purulent,

suppurative, haemorrhagic, caseous. • Chronic: Obliterative, adhesive, constrictive.

Acute PericarditisSerous: usually non-bacterial (collagen diseases, uremia, tumour).

Serofibrinous/fibrinous: (eg: myocardial infarct, collagen disease)

Fibrin resolves or organises (adhesive pericarditis). Clinically: Friction rub, pain, systemic febrile reaction, signs of congestive failure.

Purulent/suppurative: usually bacterial, direct spread from empyema, pneumonia, endocarditis

Haemorrhagic: Tuberculosis, malignancy

Chronic Pericarditis

• Obliterative pericarditis (incidental post-mortem finding).

• Adhesive mediastinopericarditis: previous suppuration, caseation, cardiac surgery, radiation. Heart is bound to surrounding structures. Develops marked hypertrophy.

• Constrictive pericarditis: Ideopathic or following suppuration or caseation. Small quiet heart, reduced output, congested veins, pulsus paradoxus.

Cardiac TumoursSecondary (in 5% of tumour autopsies). • Primary site: Lung, breast, melanoma, lymphoma, leukaemia. • Usually asymptomatic• in pericardium (pericarditis, effusion) • in myocardium (arrhythymias, obstruction, congestive failure)

Primary (rare)Myxoma: Most in atria, especially left

Effects: systemic reaction, syncope, sudden death, embolism. LipomaPapillary elastofibroma: Organised thrombus with papillary projections on valve leafletsRhabdomyoma: muscle hamartoma, children, tuberous sclerosis, may obstruct.