Cardiovascular Pathology

Blood Vessels

• Basic constituents include endothelial cells, smooth muscle + ECM (elastin, collagen, glycosaminoglycans)
• 3 layers:
  • Intima = single layer endothelial cells on BM, underlaid by thin ECM. Separated from media by internal elastic lamina.
  • Media = smooth muscle, varies according to functional demands
  • Adventitia = loose connective tissue with nerve fibres and vasa vasorum
• 3 types:
  • Large (elastic) such as aorta
  • Medium (muscular) smaller aortic branches
  • Small (<2mm diameter) arteries and arterioles
• Veins = less rigid walls so can dilate and compress, reverse flow prevented by valves

Atherosclerosis

• Risk factors include:
  • Modifiable = cholesterol, smoking, hypertension, diabetes
  • Non modifiable = LDL receptor gene mutations, age 40-60 years, gender
  • Other = inflammation, hyperhomocysteinaemia, metabolic syndrome, lipoprotein A or factors affected haemostasis
• Atheromas = intimal lesions consist of soft, yellow lipid core with white fibrous cap -> protrude into vessel lumen
• Grow slowly over decades, plaques can be stable (dense fibrous cap, minimal lipid accumulation = chronic ischaemia sx by narrowing lumens) or unstable (thin caps, large lipid cores and dense inflammatory infiltrates = fatal ischaemic complications)
• Three principal components:
  • Smooth muscle cells, macrophages and T cells
  • ECM
  • Intra/extracellular fluid
• Pathologic changes:
  • Mechanically obstruct blood flow
  • Haemorrhage into plaque may expand it or induce rupture
  • Atheroembolism -> microemboli
  • Rupture to exposed tissue factor and lead to thrombosis
  • Weaken underlying media -> aneurysm formation
  • Healing of subclinical plaques + resorption of overlying thrombi 
• Pathogenesis: “Response to injury” hypothesis = chronic inflammatory and healing process of arterial wall to endothelial injury
  • Endothelial injury and dysfunction
    • Causes: haemodynamic disturbance, hypercholesterolaemia (increased LDL/ decreased HDL/increased lipoprotein A)
    • Inflammation is triggered by accumulation of cholesterol cystals + FFA in macrophages
  • Accumulation of lipoproteins
  • Monocyte adhesion to endothelium
  • Platelet adhesion
  • Factor release
  • Smooth muscle proliferation, ECM production and recruitment of T cells
    • Convert fatty streak (lipid filled macrophage) -> mature atheroma
  • Lipid accumulation
• Vessels involved = lower abdominal aorta, coronaries, popliteal arteries, ICA and circle of willis
• Consequences = MI, CVA, AAA, PVD, mesenteric ischaemia
  • Plaques responsible for MI/ ACS are often asymptomatic prior to acute change, such as
    • Adrenergic stimulation associated with wakening can cause BP spikes + heightened PLT reactivity -> circadian periodicity for AMI (0600-1200)
    • Acute emotional stress
  • Vasoconstriction can potentiate plaque disruption by increasing local mechanical forces
    • Stimulated by adrenergic activity, locally released PLT contents, endothelial cell dysfunction, mediators from perivascular inflammatory cells

Aneurysms and Dissections

Aneurysm = localised abnormal dilatation in blood vessel/ heart that may acquired or congenital

Occur when structure/ function of connective tissue is compromised.

• Inherited defects:
  • Marfans (defective synthesis of scaffolding protein fibrillin)
  • Ioeys- Dietz (defective elastin/ collagen I and III synthesis)
  • Ehlers-Danlos (defective collagen III synthesis)
  • Vitamin D deficiency (altered collagen cross linking)
• Acquired:
  • Atherosclerosis
  • Hypertension
  • Other = trauma, vasculitis, infection (mycotic aneurysm = embolization of septic embolus eg. Complication of IE OR extension of adjacent suppurative process OR circulating organisms directly infiltrating vascular wall)
• Vascular wall weakened through loss of smooth muscle cells or synthesis of non- collagenous/ elastic ECM:
  • Ischaemia of inner media when atherosclerotic thickening occurs of intima
  • Systemic hypertension narrows vasa vasorum
• Types:
  • True = attenuated but intact artery wall or thinned heart ventricle
    • Saccular (spherical outpouchings involving only portion of vessel wall, often contain thrombus)
    • Fusiform (diffuse circumferential dilations of long vascular segment)
      • Atherosclerotic/ syphilitic/ congenital vascular aneurysms
      • LV aneurysm post MI
  • False (pseudo) aneurysm = defect in vascular wall -> extravascular haematoma that freely communicates with intravascular space (pulsating haematoma)
    • Leak at sutured junction of vascular graft with natural artery
    • Ventricular rupture contained by pericardial adhesion
• Abdominal aortic aneurysm
  • Occur more frequently in men, smokers post age 50
  • Positioned below renal arteries and above bifurcation of aorta
  • Saccular or fusiform
  • Frequently contains bland, poorly laminated mural thrombus -> can affect renal/ superior or inferior mesenteric arteries by direct extension or mural thrombi
  • Sx: asymptomatic/ incidental, rupture with massive haemorrhage, obstruction of branching vessel causing mesenteric/ renal/ iliac ischaemia
  • Risk of rupture related to size:
    • <4cm = nil risk
    • 4-5cm = 1% per year
    • 5-6cm = 11% per year
    • >6cm = 25% per year
  • Most expand 0.2-0.3cm per year, ~20% more aggressive
  • Aneurysms >5cm managed surgically
• Thoracic aortic aneurysm
  • Associated with hypertension
  • Sx: respiratory difficulties (encroachment on lungs/airways), dysphagia (compression of oesophagus), persistent cough (compression recurrent laryngeal nerves), pain (erosion of bone), cardiac disease (AV valve dilatation with insufficiency or narrowing coronary ostia), rupture

Dissection = blood separates laminar planes of media to form blood filled channel within aortic wall

• Hypertension main risk factor -> hypertrophy of vasa vasorum + degenerative change in ECM (cystic medial degeneration)
• If ruptures through adventitia, haemorrhage can be catastrophic
• Affects:
  • Men aged 40-60 years with antecedent hypertension (>90% cases)
  • Younger adults with connective tissue diseases affecting aorta
  • Iatrogenic following CABG
  • Pregnancy related in third trimester (rare)
• Morbidity and mortality depend on part of aorta involved: more serious if dissection between aortic valve and distal arch
• Types:
  • Ascending (DeBakey II) +/- descending aorta (DeBakey I)
    • More common and dangerous
    • Require rapid diagnosis and surgical rx
  • Type B = distal to subclavian artery (DeBakey III)
    • Conservative rx
• Sx: Excruciating chest pain radiating to the back -> rupture into pericardial/ pleural or peritoneal spaces = tamponade or aortic insufficiency

Hypertensive vascular disease

• Hypertension:
  • 5% secondary due to underlying renal or adrenal disease
  • 95% idiopathic “essential” hypertension
• Major risk factor for atherosclerosis, CCF, renal failure
• Physiology:
  • BP = CO x TPR
    • TPR regulated at level of arterioles influenced by neural and hormonal inputs. Vascular tone = balance between vasoconstrictors (angiotensin II, catecholamines, inflammatory chemicals) and vasodilators (kinins, PGs and NO)
    • Resistance vessels also exhibit autoregulation = blood flow induced vasoconstriction to protect tissues against hypoxia
    • Fine-tuned by tissue pH, hypoxia, a and b adrenergic systems to accommodate local metabolic demands
    • CO determined by HR/ SV ß blood volume ß renal sodium excretion or resorption
• Normal regulation:
  • Reduced blood volume -> decreased glomerular blood flow and pressure in afferent arteriole -> increased reabsorption of sodium by PCT -> renin secretion -> RAAS pathway
  • Natriuretic factors (ANP/ BNP) respond to volume expansion to inhibit sodium reabsorption in DCT -> sodium and water excretion + vasodilation
• Essential HTN: Complex and multifactorial
  • Genetic factors influence BP regulation
  • Reduced renal sodium excretion in presence of normal arterial pressure may be key initiating event
  • Vasoconstrictive influences -> increased TPR
  • Environmental = stress, obesity, smoking, physical inactivity and heavy salt consumption
• Secondary HTN:
  • Renovascular – renal artery stenosis/ acute glomerulonephritis/chronic renal failure/polycystic kidney disease/vasculitis/renin-secreting tumors
    • liquorice ingestion
    • Exogenous = glucocorticoids, oestrogen, sympathomimetics, MAO-I
    • Phaeochromocytoma
    • Acromegaly
    • Hypo/ hyperthyroidism
    • Pregnancy induced
  • CVS – coarctation of aorta, polyarteritis nodosa, increased intravascular volume, increased CO, rigidity of aorta
  • Neurologic – psychogenic, increased ICP, sleep apnoea, acute stress (surgery)
• Genetic disorders:
  • Gene defects in aldosterone metabolism
  • Mutations affecting proteins in change of sodium reabsorption (Liddle syndrome)
• Histologically:
  • Hyaline arteriosclerosis = thickening of arterial walls caused by hyaline deposits + proliferation of smooth muscle cells and reduplication of basement membranes
  • Hyperplastic arteriosclerosis = malignant HTN, “onion skin lesions” concentric laminated thickening of walls + luminal narrowing

The Heart

Cardiomyopathy

• Intrinsic cardiac muscle disease
• 3 categories:
  • Dilated (90%) = systolic dysfunction (contractile)
    • Caused by myocarditis, ETOH, pregnancy or genetic cytoskeletal protein defects (tintin mutation)
    • Myocarditis due to inflammatory infiltrates (coxsackie A/B viruses) -> acute heart failure -> dilated CMP
  • Hypertrophic = diastolic dysfunction
    • Autosomal dominant mutations in contractile proteins
  • Restrictive = stiff, non compliant myocardium
    1. Amyloid, radiation or endomyocardial scarring

Pericardial disease

• Cause fluid accumulation, inflammation, fibrous constriction in association with cardiac or systemic disease:
  • Infective = viral, pyogenic bacteria, TB, fungi
  • Immunological = rheumatic fever, SLE, scleroderma, drug hypersensitivity reaction
  • Miscellaneous = MI (Dressler), uraemia, post cardiac surgery, neoplasia, trauma or radiation

Congestive heart disease

= Heart unable to pump blood to meet metabolic demands of body

Adaptive mechanisms

• Frank-Starling mechanism = increased filling volumes dilate heart -> increase functional cross bridge formation within sarcomeres -> enhance contractility
• Ventricular remodelling = hypertrophy or chamber dilation
• Neurohumoral
  • NE -> b R -> increases HR and contractility
  • RAAS and ANP -> adjust filling volumes/ pressures

Pathophysiology:

• Pressure/ volume overload + regional dysfunction
  • Hypertension
  • Valvular disease
  • MI
• Causes increased cardiac work -> wall stress -> cell stretch -> hypertrophy/ dilation
• Pressure- overload hypertrophy = sarcomeres positioned in parallel -> concentric hypertrophy -> increased ventricular wall thickness
• Volume-overload hypertrophy = sarcomeres positioned in series -> eccentric hypertrophy -> ventricular dilation
  • Increased heart size and mass
  • Increased protein synthesis and abnormal proteins
  • Induction of immediate- early genes and foetal genes
  • Fibrosis
  • Inadequate vasculature
• Cardiac dysfunction = heart failure, arrythmias, neurohumoral stimulation

Left HF

• Causes = IHD, HTN, aortic and mitral valve disease, myocardial infiltrative disorders 
• Congestion of pulmonary circulation + stasis of blood in left chambers + hypoperfusion of tissues and organ dysfunction
• Morphology
  • Heart = cardiac myocyte hypertrophy + dilation in ventricle and atria (leading to AF/ LA thrombus) + stenotic, deformed valves
  • Lungs = perivascular and interstitial oedema (interlobular septa = Kerley B lines on CXR) -> oedematous widening of alveolar septa -> fluid in alveoli -> extravasation of RBC and phagocytosis by macrophages forming hemosiderin laden macrophage/ “heart failure cells”
• Sx
  • Cough, dyspnoea, orthopnoea, PND
  • Atrial fibrillation
  • Pulmonary oedema (Decreased CO -> decreased renal perfusion -> activation RAAS -> retention of Na/ water -> expansion of volumes)
• Classification
  • Systolic = insufficient CO (pump failure)
  • Diastolic = CO preserved, however LV abnormally stiff and unable to relax during diastole, impaired filling. Unable to increase CO in response to increased metabolic demands. Can lead to flash APO.

Right HF

• Mostly caused by left HF
• Pure right HF is infrequent, called Cor Pulmonale
• Causes = pulmonary hypertension, PE, OSA, altitude sickness
• Systemic venous congestion
• Morphology
  • Heart = right sided hypertrophy/ dilation + valvular abnormalities, endocardial fibrosis (carcinoid heart disease)
  • Liver = congestive hepatomegaly (congestion around central veins within hepatic lobules = nutmeg liver) + centrilobular necrosis ->  cirrhosis
  • Pleural/ pericardial/ peritoneal space = fluid accumulation
  • Subcutaneous tissue = oedema, anasarca
• Sx
  • Hepatosplenomegaly
  • Peripheral oedema
  • Pleural effusion, ascites

Often biventricular failure is present.

Standard therapy

• Relieve fluid overload (diuretics)
• Block RAAS (ACE I/ ARB)
• Lower adrenergic tone (BB)

Ischaemic Heart Disease

Clinical syndromes = MI, angina pectoris, chronic IHD with heart failure, sudden cardiac death

Contributing factors = coronary atherosclerosis, coronary emboli, blockage of myocardial blood vessels

Aggravating factors = increased cardiac energy demand (tachycardia) or diminished blood/ oxygen (shock, hypoxia)

Pathogenesis = insufficient coronary perfusion relative to myocardial demand due to atherosclerotic narrowing of coronary arteries + plaque rupture + vasospasm

• Chronic atherosclerosis
  • Fixed obstruction leading to stenosis
  • >75% lumen -> ischaemia with exercise, 90% lumen -> ischaemia at rest
  • LAD/ LCx/ RCA +/- epicardial branches
• Acute plaque change
  • Rupture – superficial erosion – ulceration – fissuring or deep haemorrhage
  • Superimposed thrombus partially or completely occludes affected artery

• Consequences:
  • Stable angina = nil plaque disruption, fixed coronary artery obstruction
  • Unstable angina = plaque rupture + partially occlusive thrombus -> severe transient reductions in flow
  • MI = plaque rupture + totally occlusive thrombus -> myocardial death
  • Sudden death = myocardial ischaemia which leads to fatal ventricular arrhythmia

Angina Pectoris

= Caused by transient myocardial ischaemia without myocyte necrosis

Four patterns:

1. Stable (typical) = imbalance coronary perfusion due to chronic atherosclerosis) relative to myocardial demand -> produced by exercise/emotional excitement. Relieved by rest or GTN.
2. Prinzmetal variant = coronary artery vasospasm, unrelated to exercise/ HR/ BP. Responds to vasodilators.
3. Unstable (crescendo) = pattern of increasingly frequent pain, often prolonged, precipitated by lower levels of physical activity or at rest. Mostly caused by plaque disruption = warning that acute MI may be imminent.
4. Silent ischaemia

Myocardial infarction

= Caused by death of cardiac muscle in setting of prolonged ischaemia

Pathogenesis:

• Coronary arterial occlusion
  • Acute plaque change -> platelet adherence/ activation forming microthrombi + vasospasm -> TF activates coagulation cascade forming bulk of thrombus -> occlusion of vessel
  • Transmural MI (10% cases) due to vasospasm (cocaine use), emboli (LA thrombus, IE vegetations, paradoxical through patent FO), vasculitis
• Myocardial response:
  • Reversible changes:
    • Cessation of aerobic metabolism – lack of ATP within seconds
    • Myofibrillar relaxation + glycogen depletion + cell swelling
    • Loss of contractility ~2 mins 
  • Irreversible changes (20-40 min)
    • Necrosis of myocytes
    • Disruption of sarcolemmal membrane -> intracellular macromolecules leak out (troponin)
  • Zone of necrosis = subendocardium which then extends to myocardium
• Zones of perfusion: “Area at risk”
  • LAD – apex, anterior LV and anterior 2/3 ventricular septum
  • Dominant RCA vs LCx:
    • R dominant (majority) = RCA supplies RV free wall + posterobasal LV wall + posterior 1/3 septum and LCx supplies lateral LV wall
• Transmural = full thickness (STEMI) vs Subendocardial = limited to inner 1/3-1/2 wall (NSTEMI)
  • RCA obstruction usually involve posterior free wall LV and RV wall

Morphology

Interventions to limit infarct size

= Reperfusion to salvage ischaemic myocardium

• Coronary interventions include PCA, thrombolysis, angioplasty or CABG
• Effectiveness depends on timing and degree of reperfusion restored
• Complications associated such as arrhythmia, reperfusion injury, myocardial stunning (state of reversible heart failure) or haemorrhage
• Morphology of re-perfused infarct = haemorrhagic (injured vasculature leaks when flow restored)
  • Irreversibly injured myocytes contain “contraction bands” = closely packed sarcomeres with eosinophilic infiltrate -> due to exaggerated contraction post reperfusion
• Other therapy:
  • Aspirin, heparin = prevent further thrombosis
  • Oxygen = minimize ischaemia
  • Nitrates = systemic vasodilation, reduced cardiac workload, prevent vasospasm
  • Beta blockers = reduce cardiac oxygen demand, decrease arrhythmia risk
  • ACE I = limit ventricular dilation

Clinical features and laboratory testing

• Cardiac specific proteins troponin I and T
  • Rise at 2-4 hours and peak at 48 hours
  • Persist for 7-10 days post MI
• CK-MB (MB isoform in cardiac muscle) is sensitive not specific
  • Rise at 2-4 hours and peak at 24 hours
  • Normalises 72 hours
• Both troponin and CK peak earlier in patients who are successfully re-perfused because they are washed out of cells more rapidly
• Unchanged levels of troponin and CK over 2 days, excludes MI as diagnosis

Complications

• LV dysfunction, cardiogenic shock
• Arrhythmias – myocardial irritability
• Myocardial rupture – rupture of LV free wall with haemopericardium and tamponade, rupture of septum or papillary muscle. Occurs 3-7 days post MI.
• Pericarditis – Dressler’s Syndrome, 2-3 days post MI.
• RV infarction or infarct extension/ expansion
• Mural thrombus
• Ventricular aneurysm

Chronic IHD

= Appears post infarction due to functional decompensation of hypertrophied non infarcted myocardium

• Leads to CCF

Sudden Cardiac Death

= Unexpected death from cardiac causes in individuals without symptomatic heart disease or early after symptom onset (within 1 hour usually)

• Consequence of fatal arrhythmia in setting of AMI
• Other causes:
  • Congenital coronary abnormalities, AV stenosis, MVP, myocarditis, CMP, pulmonary HTN, cardiac hypertrophy, miscellaneous (drugs)
  • Hereditary or acquired cardiac arrythmias  = Long QT, Brugada, short QT, catecholaminergic polymorphic VT, WPW and sick sinus
    • Channelopathies = mostly autosomal dominant inheritance, involve Na/K/Ca channels -> Long QT

Valvular Heart Disease

= Stenosis (failure of valve opening) or regurgitation (failure of valve closing)

• Functional regurgitation = secondary to weak support structure
  • MVR due to dilated LV
• Clinical consequences depend on valve involved, degree of impairment, tempo of disease onset and quality of compensation mechanisms

Rheumatic Heart Disease

• Acute immunologically mediated inflammatory disease occurring few weeks after Group A Streptococcal Pharyngitis -> valvular disease
• Virtually the only cause of MS
• Antibodies directed against streptococcal M proteins recognise cardiac self antigens
• Morphology =
  • Acute RF
    • Aschoff bodies = foci T cells + activated macrophages (Anitschkow cells) + diffuse inflammation ~ pancarditis
    • Necrotic focal vegetations (verrucae)
    • Subendocardial thickenings (MacCallum plaques) in LA
  • Chronic RHD
    • Leaflet thickening
    • Commissural fusion
    • Thickening and fusion of tendinous cords
  • Can be mitral valve (2/3 cases) + AV (1/4 cases) + tricuspid (infrequent) + pulmonary (rare)
• Clinical features:
• Acute RF: occur 10 days to 6 weeks post initial infection
  • Migratory polyarthritis
  • Pancarditis = pericardial friction rub, arrhythmia, tachycardia
  • Subcutaneous nodules
  • Erythema marginatum
  • Sydenham chorea
• Chronic RHD: years- decades
  • Cardiac murmurs, hypertrophy + dilatation, CCF
  • Atrial fibrillation, mural thrombus

Infective Endocarditis

• Microbial infection of valves or mural endocardium -> vegetations composed of thrombotic debris + organisms + destruction of cardiac tissues
• Classified:
  • Acute = infection of previously normal heart with highly virulent organism (staph aureus) which rapidly produces necrotic tissues. Can lead to death, requires urgent IV/ surgery.
  • Subacute = organisms with lower virulence (strep viridans) that cause insidious infections of deformed valves with less destruction. Protracted course weeks to months, cure with Abx.
• Organisms:
  • Strep viridans = commensal in oral cavity
  • Staph aureus = IVDU
  • Staph epidermidis = prosthetic valves
• Clinical features: Fever, chills, weakness + new murmur + microthromboemboli (if longstanding) with splinter haemorrhages/ Janeway lesions (non-tender in palms or soles)/ Oslers nodes (subcutaneous nodules in pulp of digits)/ Roth spots (retinal eye haemorrhages)

Non infected vegetations

1. Non-bacterial thrombotic endocarditis
2. Small sterile thrombi on cardiac leaflets ~1-5mm
3. Found in debilitated patients with cancer or sepsis
4. SLE “Libman- Sacks endocarditis”
5. Mitral and tricuspid valvulitis
6. Lesions 1-4mm located on undersurfaces of valves, endocardium/ chords

Carcinoid Heart Disease

• Carcinoid syndrome = flushing, diarrhoea, dermatitis, bronchoconstriction caused by biochemical compounds (serotonin) released by carcinoid tumour
• Cardiac lesions do not occur until there is large hepatic metastatic burden, as liver usually catabolizes circulating mediators before they reach the heart
• Endocardium and valves R) heart plaques develop 

Complications of prosthetic valves (mechanical and tissue)

• Thromboembolism
• Structural deterioration
• IE
• Inadequate healing causing paravalvular leak
• Exuberant healing causing obstruction

Last Updated on August 20, 2021 by Andrew Crofton