Atherosclerosis pathogenesis (Lionel)


Risk factors:

1. Age

a. Atherosclerosis is typically a progressive process
b. Precipitation only in middle age or later, becoming clinically manifest

2.Gender

a. ?oestrogen protective
b. Premenopausal women relatively protected
c. Post-menopause, protection lost

3. Genetics

a. Possible clustering of risk factors eg. hypertension, diabetes
b. Well-defined genetic derangements eg. familial hypercholesterolaemia

4. Hyperlipidaemia

a. LDL cholesterol is of major interest – delivers cholesterol to peripheral tissues
b. HDL mobilises cholesterol from developing and existing atheromas and transports it to the liver for bile excretion

5. Hypertension

6. Cigarette smoking

7. Diabetes mellitus

a. Induces hypercholesterolaemia

8. Inflammation (as marked by CRP)

a. Inflammation plays a significant causal role

9. Hyperhomocystinaemia

10. Lipoprotein a

11. Factors affecting haemostasis

a. Prothrombotic states eg. suppression of endothelium-derived prostacyclin without inhibition of platelet-derived thromboxane A2 with use of selective COX-2 inhibitors

12. Other factors

a. Lack of exercise
b. Competitive, stressful lifestyle
c. Obesity

Pathogenesis:


Atherosclerosis.JPG

1. Contemporary hypothesis: atherosclerosis as a chronic inflammatory response of arterial wall to endothelial injury

2. Endothelial injury: increased endothelial permeability, enhanced leukocyte adhesion, altered gene expression

a. Early endothelial dysfunction

i. Toxins from cigarette smoke
ii. Homocysteine
iii. Infectious agents
iv. Inflammatory cytokines
v. Haemodynamic disturbance
vi. Hypercholesterolaemia

b. Haemodynamic disturbance

i. Non-laminar, turbulent flow

c. Lipids

i. Increases local production of reactive oxygen species which accelerate nitric oxide decay, damping its vasodilator activity and increasing local shear stress
ii. Chronic: lipoprotein accumulation within intima – oxidised through action of oxygen free radicals locally generated by macrophages or endothelial cells
  • Oxidised LDL ingested by macrophages, forming foam-cells
  • Oxidised LDL stimulates release of growth factors, cytokines, chemokines by endothelial cells and macrophages, increasing monocyte recruitment
  • Oxidised LDL is cytotoxic to endothelial cells and smooth muscle cells induces further endothelial dysfunction

d. Inflammation

i. Dysfunctional endothelial cells express adhesion molecules that encourage leukocyte adhesion
ii. T lymphocytes elaborate inflammatory cytokines, stimulating macrophages, endothelial cells and smooth muscle cells – smooth muscle cell proliferation and extra-cellular matrix synthesis

e. Infection

3. Smooth muscle proliferation

a. Several growth factors implicated in proliferation and extra-cellular matrix synthesis eg. fibroblast growth factor, transforming growth factor α, platelet-derived growth factor released by locally adherent platelets, macrophages, endothelial cells, smooth muscle cells

b. Synthesised extra-cellular matrix (notably collagen) stabilises plaque

c. Activated inflammatory cells cause intimal smooth muscle cell apoptosis, increasing extra-cellular matrix catabolism: unstable plaques


Evolution to clinical syndromes:


Stable_angina_pectoris.JPG

1. Stable angina pectoris

a. 50% reduction in luminal diameter causes haemodynamically significant stenosis
b. Increase in myocardial oxygen demand provokes ischaemia

Unstable_angina_pectoris.JPG

2. Unstable angina pectoris

a. Rupture/erosion of fibrous cap of plaque: platelet aggregation and adhesion, localised thrombosis, vasoconstriction, distal thrombus embolisation
b. Sub-total occlusive thrombus

Myocardial_infarction.JPG

3. Myocardial infarction

a. Thrombus totally occludes lumen

Sources: Kumar & Clark Clinical medicine 6th ed., Robbin's Basic Pathology 8th ed.

Heart Sounds
Normal heart sounds
S1:
- Due to mitral and tricuspid valve closures
- Indicates the start of ventricular systole

S2
- Softer and shorter than S1
- Marks the end of systole
- Arises from aortic and pulmonary valve closures

Additional heart sounds
S3 (due to volume-overload)
- Occurs just after S2
- S3 is pathological over the age of 30
- A loud S3 occurs in a dilated left ventricle with rapid ventricular filling (mitral regurgitation, VSD) or poor left ventricular function (post MI, dilated cardiomyopathy)

S4 (due to pressure overload)
- Occurs just before S1
- Always abnormal
- Represent atrial contraction against a ventricle made stiff by any cause, eg aortic stenosis

Common important murmurs
Ejection systolic murmurs (aka ejection midsystolic murmur)
- Does not begin right at the start of the first heart sound
- Intensity is greatest in midsystole or later, and wanes again late in systole (crescendo-decrescendo murmur)
- Usually caused by turbulent flow through the aortic or pulmonary valve orifices or by greatly increased flow through a normal-sized orifice or outflow tract
- Causes include
o Aortic stenosis (radiates to the carotids)
o Pulmonary stenosis
o HOCM

Pan systolic murmurs
- Extends throughout systole, beginning with the first heart sound, then going right up to the second heart sound
- Occurs when a ventricle leaks to a lower chamber pressure of vessel
- Causes include
o Mitral regurgitation (radiates to the axilla)
o Tricuspid regurgitation
o VSD

Dynamic manoeuvres
Deep expiration (murmurs are accentuated)
The Valsalva manoevre
- To differentiate HOCM from AS or MR


Sources:
Heart sounds à http://www.med.ucla.edu/wilkes/inex.htm
Talley and O’Connor
OCHM 7th edition

ECG Evidence for AMI and Artery Occlusion

It's been emailed to you.
The pictures are really helpful and I can't seem to load them so please print it off separately, I assure you it's worth the extra effort.
Sorry for the technological incompetence guys
Gaya

CABG

Aims: Reperfusion of heart muscle due to occluded coronary artery (CAD, ruptured plaque, AMI)
Sources of Grafts: Great Saphenous vein, internal thoracic arteries, radial arteries.
How to connect the grafts: Saphenous vein (aorta + distal to occlusion on coronary artery, remember to reverse graft!) Internal thoracic arteries, (leave proximal end attached to subclavian artery, graft distal end of artery distal to occlusion)
Procedure: Midline incision anterior chest wall, median sternotomy. Connect circulatory system to cardio pulmonary bypass pump (heart lung machine). Heart is stopped to allow grafts to be sewn in place. Restore heart function (defibrillator), attach temporary pacemaker. Disconnect heart lung machine, wire sternum together, suture skin close. Temporary drainage tube is inserted into pericardial sac to drain fluid collections.



Stenting
Aims: Reperfusion, prop open coronary arteries.
How: During angioplasty. Stent is collapsed to a small diameter and put over a balloon catheter. It's then moved into the area of the blockage. When the balloon is inflated, the stent expands, locks in place and forms a scaffold. This holds the artery open. The stent stays in the artery permanently, holds it open, improves blood flow to the heart muscle and relieves symptoms (usually chest pain). Within a few weeks of the time the stent was placed, the inside lining of the artery (the endothelium) grows over the metal surface of the stent.
Complications: Re-narrowing (common!) especially with techniques just using a balloon catheter to crush the plaque into the vessel walls. Torn arteries, thromboembolism, scrapping plaque off the vessel walls à AMI
Precautions: Anti-coagulants! + Anti-platelet meds!
New stuff: Drug eluting stents (DES) – coated with drugs, slow release into bloodstream. Drug blocks cell proliferation à fibrosis of arterial wall, plaque recollection and restenosis.

MARC

Cholesterol and its Management (Sarah)

Lipoproteins transport lipids/cholesterol in the blood (contains a hydrophobic centre and has hydrophilic coat).

3 types of lipoproteins:
VLDL: Very Low-Density Lipoproteins
Transported as triglycerides, unable to penetrate vessel wall
LDL: Low-Densitiy Lipoproteins
HDL: High-Densitiy Lipoproteins

Transport of lipids
Endogeneous pathway
Cholesterol synthesized in the liver, transported out as VLDL and hydrolysed by muscle to form LDLs.
Hyperlipidemia involves both hypertriglyceridemia, and hypercholesterolemia.

Medical Management:
1. Statins
2. Fibrates
3. Bile-acid binding resin

1. Statin
e.g. simvastatin, atorvastatin, pravastatin

Mechanism:
Competitive enz that inhibits cholesterol synthesis
Reduces cholesterol in hepatocytes so that more LDL receptors can be synthesized.

Outcome: increases HDL, and decreases LDL and TG

Uses:

· Primary prevention arterial disease (high risk with elevated cholesterol)
· High risk CHD (with/without elevated chol)
· Secondary prevention of myocardial infarction & stroke (symptomatic)

2. Fibrates
e.g. Gemfibrozil

Mechanism:

· Stimulate lipoprotein lipase in muscle/adipose tissue
· Decrease liver production of VLDL
· Decrease liver uptake of LDL

Outcome
Increases HDL, maintains/decreases LDL and decrease TG


3. Bile-acid Binding Resin
e.g. Colestipol, Cholestyamin

Mechanism:

· Bind with bile acids
· Decreases absorption of exogenous cholesterol
· Increases metabolism of endogenous cholesterol to bile salt
· Decreases intracellular cholesterol in hepatocytes
· Compensatory increase in LDL receptors

Indications:
Hypercholesterolaemia, mixed hyperlipidaemia


Other Drugs:

1. Ezetimibe
• inhibits cholesterol reabsorption across intestinal wall. Usually added on to statins
2. Nicotinic acid

· Inhibit fatty acid release from adipose tissue
· ↓LDL, ↓TG, ↑HDL
3. Fish oils

· omega-3 fatty acids
· ↓TG in gram ++ quantities (variable FA content) •


Secondary prevention and heart disease – drugs (Jess)

Areas of interest…
  • Blood pressure
  • Lipids
  • Blood sugars /HbA1c
  • Coagulative state
  • Arrhythmias

Blood pressure

  • BP should generally be below 140/90, or 130/80 in patients with renal disease or diabetes
  • First line treatment is often ACE inhibitor (e.g. captopril) or B blocker
  • Captopril inhibits the action of ACE, thus decreasing the amount of Ang II à more excretion of Na and water à decreased BP (watch out for hyperkalemia – do not use with K-sparing diuretics!)
  • B blockers may be selective e.g. atenolol (B1) or non-selective e.g. propanolol. They block the actions of NA/A à reduce the excitability of the heart à decreasing HR and CO
  • Thiazides e.g. chlorothiazide may also be used, which work by inhibiting the Na/Cl transporter in the kidney, thus increasing the excretion of Na, Cl, K

Lipids

  • Hyperlipidemia is a major risk factor for IHD
  • If no other risk factors, it is recommended that LDL levels are no higher than 5.5mmols/L; if there are other cardiovascular risk factors or pre-existing CVD, then the aim for the LDL levels would be less than 2.5 mmol/L
  • Statins such as atarvastatin inhibit HMG-CoA reductase (rate limiting enzyme in cholesterol synthesis) à decreased cholesterol synthesis and increased synthesis of LDL receptors à increased clearance of LDL from the bloodstream
  • Fibrates e.g. Gemfibrozil are used to treat hypertriglyceridemia, or as a second line therapy for high cholesterol – they stimulate lipoprotein lipase, hydrolyzing TG; decrease VLDL production and increase LDL uptake

Blood sugars

  • Diabetes predisposes to macrovascular and microvascular disease
  • Normal blood sugar levels are below 6 (fasting); target HBA1c in diabetics is 7%
  • Range of anti-diabetic medications are available: metformin is often a first line treatment, especially in overweight patients (works by decreasing hepatic gluconeogenesis and increasing insulin sensitivity), as are the sulphonylureas (work by stimulating insulin release)

Coagulative state

  • Many patients with artherosclerosis are prescribed aspirin, in order to minimise the risk of a CVA if part of a plaque breaks off

Secondary Prevention - Lifestyle

Patients should be advised to

  • Take regular physical activity

o to increase exercise capacity
o building up physical activity to 20–30 min/day to the point of slight breathlessness.
  • Stop smoking. Offer support and advice, and pharmacotherapy to those who have expressed a desire to quit.
  • Eat a Mediterranean-style diet
o more bread, fruit, vegetables and fish; less meat; and replace butter and cheese with products based on vegetable and plant oils
  • Consume at least 7 g of omega-3 fatty acids per week from 2–4 portions of oily fish per week. If within 3 months of a myocardial infarction and they are not achieving this, consider providing at least 1 g daily of omega-3-acid ethyl esters treatment licensed for secondary prevention after myocardial infarction for up to 4 years.
  • Achieve and maintain a healthy weight.
  • Restrict alcohol intake to
o 14 units per week for women and 21 units per week for men, and avoid binge drinking
Patients should be advised against taking:

  • Supplements containing beta-carotene (may increase risk of cardiovascular death).
  • Antioxidant supplements and Folic acid supplements (no evidence of benefit).

Cardiac rehabilitation

  • Should include the following components: exercise (reduces mortality), health education, and stress management (reduces anxiety, depression and the risk of non-fatal myocardial infarction)
  • Should involve partners or carers, if the patient wishes
http://heart.bmj.com.ezproxy.lib.monash.edu.au/content/93/7/862.full


MANAGEMENT OF ACUTE CHEST PAIN

1. Give O2

2. Determine whether chest pain is of cardiac origin
- ECG
- Sublingual nitroglycerin (eg. Anginine) should improve chest pain
- Lab tests (FBE, U/E, CK-MB, Trop T/I, Myoglobin, Ca and Mg)

3. Analgesia
- Morphine (with antiemetic metoclopramide)

4. Antiplatelet
- Aspirin
- Clopidogrel (avoid if CABG is planned)

5. Reduce Myocardial energy consumption
- Beta blockers (beware of C/I)

6. Coronary vasodilatation
- Glyceryl trinitrate (monitor BP)

7. Plaque stabilisation/ventricular remodelling
- Statins
- ACE inhibitors (-pril, monitor renal function)
Plus for NSTEMI:
8. Antithrombin
- Clexane
9. Glycoprotein IIB/IIA inhibitors
- Abciximab
- Eptifibatide
- Tirofiban
Plus for STEMI:
8. Thrombolysis
- Streptokinase, Alteplase
Early medical management
Rapid triage for chest pain (Time is muscle)
· Aspirin 150-300mg chewed
· Sublingual glyceryl trinitrate 0.3-1mg. Repeat.
· Oxygen - nasal cannula 2-4L/min
· ECG
· Brief history/risk factors. Examination
· IV access plus lab test
· IV opiate eg. Diamorphine 2.5-5mg, metoclopramide 10 mg
· Beta blocker (if no c/I) for ongoing chest pain, hypertension, tachycardia
· If primary PCI available, give GP IIb/IIIa inhibitor. Alternatively, give thrombolysis.