• The development of lesions in vessel intimal wall
• Known as atherosclerotic plaques or atheromas
• Within intima of large and medium-sized vessels
  
  
• Grows over decades to physically obstruct vessels
• Prone to thrombogenic rupture
• Weakens vessel wall, leads to aneurysm
  
  
• Composition:
• inflammatory and immune cells
• smooth muscle cells, connective tissue
• lipid, cholesterol

• Extremely common in the Western world
• Leading cause of morbidity and mortality

• Incidence increasing for past 50 years
• Now peaked and declining in some areas (e.g. US)
• Still rising elsewhere (e.g. Japan)

• Responsible for 18% of all DALYs lost in the West
  
  
  
• Ischaemic heart disease
  
• angina
• myocardial infarction
  
• Stroke
  
• severe, long-term disability
  
• Peripheral arterial disease
  
• pain, cyanosis
  
• ulceration, gangrene
  

• Most common cause of Western death
• Implicated in 50% of all deaths

• A lesion slowly developing over 20-30 years
• May see initial stages (fatty streaks) in childhood
  
  
• Risk factors accelerate progression
• Chronic pathogenesis with acute complications

• Endothelial injury
• Endothelial dysfunction
• monocyte and platelet adhesion
• LDL permeability and uptake
• Engulfment
• of lipids by monocytes and smooth muscle
• foam cell formation
• Proliferation  of smooth muscle cells
• fibrous cap generation
• increasing size, vessel stenosis
• Neovascularisation
• potential for haemorrhage

• Endothelium becomes 'sticky' with adhesion molecules
• Platelet adhesion → thrombogenicity
• Monocyte infiltration
• Increased LDL permeability and uptake

• Smooth muscle cells proliferate
• in response to growth factors
• from platelets and macrophages
• Accumulated LDL is oxidised
• by free radicals released from macrophages and stressed endothelial cells
• oxLDL stimulates release of growth factors, cytokines, chemokines and recruits monocytes
• oxLDL is cytotoxic to endothelial and smooth muscle cells
• Macrophages and smooth muscle cells engulf oxLDL
• become foam cells

• Continued smooth muscle proliferation:
• extracellular matrix generation
• collagen secretion
• fibrous cap formation
• Increasing size:
• necrosis of thickening intima → necrotic core
• stimulation of neovascularisation

• Age: presentations in middle age and beyond
• Male gender: pre-menopausal women protected, risk equalises after menopause

• some Mendelial disorders
  
• (e.g. familial hypercholesterolaemia)
  
• mostly polygenic traits and polymorphisms
  

Family History

• especially 1st degree heart disease <50 y/o
  

• Systolic >140 mmHg
• Diastolic >90 mmHg
  
• Includes 25% of population 
  

• Risk: LDL
  
• distributes lipids to tissues
• Protective: HDL
• extracts lipids from atheromas
• transports to liver for excretion

• Smoking
  
• Obesity
• Little exercise
  

• Main effect: lipid profile alteration
• Bad:  cholesterol, saturated fats
• Good: omega-3 fatty acids, polyunsaturated fats

• Raised cholesterol levels
• Increased risk of stroke and MI
• Particularly increased risk of
  atherosclerosis-associated gangrene

• Fatty streaks form almost universally as young as childhood
• Especially at branch points and turbulent zones
• No clinical significance, don't necessarily progress
  
  

Atheroma

• Surface ulceration, fissuring
• Haemorrhage
• Aneurysm
• Rupture
• thomobosis and occulusion
• thomboembolism

• Main treatment is to modify risk factors for progression
• Lifestyle: diet, exercise, weight loss, smoking
• Hypertension: anti-hypertensives
• Hypercholesterolaemia: statins, fibrates
• Diabetes control
  
  
• Reduce risk of thrombosis: aspirin
  
  
• Surgical: stents, bypasses