Atherosclerosis

Question 1

What is Atherosclerosis?

Answer 1

• chronic disease of the arterial system characterised by abnormal hardening, thickening of vessel walls and loss of elasticity associated with ageing and uncontrolled hypertension
• Inflammatory cellular response = formation of fibro-fatty lesions (plaques) in the intimal layer of the large and medium-sized arteries (aorta, its branches, coronary arteries and vessels supplying the brain)
• The continued growth of lesions can involve other layers of the arterial wall which narrows the lumen of the vessel
Signs and symptoms do not become evident for years and major complications include ischemic heart disease (IHD), acute myocardial infarction (AMI) and stroke

Question 2

What are the modifiable risk factors to atherosclerosis?

Answer 2

• Obesity and increased abdominal adiposity (waist-to-hip ratio >1)
• High-calorie/salt diet
• Hyperlipidaemia
○ Elevated total cholesterol (TC) >5.5 mmol/L (Ideal: TC <4.0 mmol/L)
○ Low HDL – cholesterol (C) levels <1 mmol/L (Ideal: HDL-C >1.0 mmol/L)
○ Elevated low-density lipoproteins (LDL) – cholesterol levels >4 mmol/L (Ideal: LDL-C <2.0 mmol/L)
○ Elevated triglyceride (TG) levels >2 mmol/L – (Ideal: TG <1.5 mmol/L)
• Insufficient physical activity
• Smoking – active/passive
• Diabetes (lifestyle related)

Question 3

What are the non-modifiable risk factors to atherosclerosis?

Answer 3

age, gender (premature menopause in females), family history of premature coronary heart disease of a close relative aged ≤60 years, ethnicity (Indigenous Australians and Torres Strait Islanders) and low socioeconomic groups

Question 4

What are the mechanisms of plaque development (aetiology)

Answer 4

• Insudation hypothesis: proposal that elevated plasma lipoprotein = focal accumulation of lipids in the vessel wall (consistent with elevated blood lipids as a risk factor)
  
  • Reaction to injury Hypothesis or Inflammatory hypothesis or Atherothrombosis: endothelial injury = inflammatory response = stimulated release of growth factors (platelet-derived growth factor, PDGF) = stimulate the proliferation of smooth muscle cells

Question 5

What is the pathophysiology/ stages of atherosclerosis?

Answer 5

Lesions develop in the tunica intima (often at branch points) There are three distinct types of lesions:

1. Fatty streaks
2. Fibrous plaque
3. Complicated plaques

Question 6

What are fatty streaks?

Answer 6

• Development occurs in childhood and thought to be a precursor to later plaque development. Children in high risk groups should be assessed for dyslipidaemia to prevent formation.
  
  • Macrophages and smooth muscle cells that have become distended with lipid
  • Foam cells (macrophages filled with LDL) accumulate in significant amounts = leads to formations of fatty streaks
  • Thin, flat and yellow intimal discolorations
  • Produce toxic oxygen radicals = inflammatory changes = progressive damage to the vessel wall

Question 7

What are fibrous plaques?

Answer 7

• Accumulation of lipids, proliferation of vascular smooth muscle cells, scar tissue forms and results in calcification
  
  • Elevated thickening of the intimal layer covered by a fibrous cap containing smooth muscle cells, monocytes, lymphocytes, foam cells and connective tissue
  • Grey to pearly white
  • As the lesion progresses, endothelial injury impairs normal anticoagulant properties of the endothelium = thrombus = thrombus becomes incorporated into the plaque = reduce blood flow. Clinical symptoms occur when ≥50% of lumen is occluded

Question 8

What are complicated plaques?

Answer 8

• Unstable form which damages the vessel to a degree that it can rupture. It can occur in ≥50% of plaque cases with potentially catastrophic effects
  
  • May cause occlusion of vessels in the heart and brain (angina, ischemia, stroke, infarction, tissue death)
  • Ruptured plaque = underlying tissue exposed = activates platelets = clotting cascade = new thrombus to form

Question 9

What are the clinical manifestations of atherosclerosis and what does it depend on ?

Answer 9

Clinical Manifestations: depends on the vessels involved and the extent of vessel obstruction
• Partial obstruction may only mean transient ischemic effects
• Complicated plaques which rupture can cause MI or with diffuse lesions may increase total resistance causing hypertension

Question 10

Diagnosis of Atherosclerosis

Answer 10

• Detailed patient history is required to identify the presence of risk factors and CVD
  
  • Laboratory tests: serum for lipid profile, C-reactive protein and erythrocyte sedimentation rate
  • If CAD is suspected after these examinations, diagnostic imaging (e.g. angiography)

Question 11

What are the 2 aims of pharmacological management?

Answer 11

(1) preventative; and (2) restorative
• Following the detection of plaques, consideration should be given for pharmacology to stabilise plaques or restore adequate blood flow (if blood flow is obstructed)

Question 12

If an immediate intervention is not needed, to prevent endothelial injury and plaque formation, risk factors can be reduced:

Answer 12

• smoking cessation
• lowering LDL levels
• nutrition
• lower alcohol consumption
• physical activity to control weight (abdominal
circumference ≤90 cm males, ≤80 cm females)

Question 13

What are preventative pharmacological managements of atherosclerosis ?

Answer 13

1. Anti-Platelet Drugs (Aspirin)
2. Lipid lowering drugs (statin)
3. Un-fractioned (standard) Heparin: Short-term treatment low molecular weight heparins (LMWHs) and Warfarin

Question 14

What are restorative pharmacological managements of atherosclerosis ?

Answer 14

Thrombolytic (Fibrinolytic) Agents

Question 15

Aspirin

Answer 15

(in CAD): preventative measure against stroke and AMI in patients with high risk factors
○ Dose: typically 75-150 mg/day
○ Inhibit cyclo-oxygenase (COX) enzyme = reduce synthesis of thromboxane A2 (platelet stickiness and vasoconstriction) = inhibit platelet aggregation
Common adverse effects: bleeding, GI irritation (at higher doses) and allergy response (asthma, rhinitis)

Question 16

Statins

Answer 16

(in hypercholesterolaemia (dyslipidaemia)): im to prevent AMI and stroke
○ Inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, an enzyme responsible for total cholesterol syntheses = reduces total cholesterol
○ Common adverse effects: GI irritation, headaches, increased BGL, liver function abnormalities, rhabdomyolysis (0.1% affected), increased skeletal muscle destruction, altered cognition, and risk of MS
○ Clinically increasing statin levels in the blood can cause myopathy and antibiotics (erythromycin) can increase the risk of rhabdomyolysis
E.g. Atorvastatin, Fluvastatin, Simvastatin, Pravastatin

Question 17

Short-term treatment low molecular weight heparins (LMWHs)

Answer 17

Enoxaparin (subcutaneous) - low dose for prevention, high dose for treatment

Question 18

Warfarin (oral)

Answer 18

Long-term anti-thrombotic that inhibits synthesis of clotting factors which reduces the chance of further clots

Question 19

Thrombolytic (Fibrinolytic) Agents

Answer 19

• Used to treat acute vascular occlusions: DVT, PE, ischemic stroke and MI
• Convert plasminogen to plasmin - proteolytic enzyme that breaks the cross-links (structural integrity) between fibrin molecules which dissolves the thrombus/embolus (‘clot busting’)
• Adverse effects: haemorrhage (due to degradation of clotting factors) and allergic reactions
• Clinical considerations: avoiding IM injections and other invasive procedures (insertion of NG tube, intubation) during IV therapy. If severe bleeding occurs, stop infusion
• Contraindications: active internal bleeding, neurosurgery within past 6 months, recent (<1 month) major surgery or trauma, intracranial neoplasm, and intracranial aneurysm
E.g. (end in -ase): Alteplase, Streptokinase, Urokinase