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Keywords
Acute coronary syndrome
Pathophysiology
Diagnosis
Therapy
Prognosis
Secondary prevention
Acute coronary syndrome
Associate Professor Joseph Hung, Associate Professor Jennet Harvey
At the completion of CPC, students should be able to describe:
 the diagnosis and differential of acute myocardial infarction & unstable angina
 the pathophysiology of acute coronary syndromes (ACS)
 the pathophysiology of major cardiac complications after myocardial infarction
 therapy in ACS that has been shown by randomised clinical trials (RCTs) to improve clinical outcome
and survival
 natural history of ACS and major determinants of prognosis
 indications for coronary artery revascularisation (CABG or PCI)
 secondary prevention of MI and cardiac death
A case is presented of a 59 year old male with acute chest pain and diaphoresis and ECG showing ST
segment elevation. The diagnosis and management is discussed in the light of the mechanisms underlying
acute coronary syndromes and associated complications and the clinical trial evidence.
Harrison’s Principles of Internal Medicine
Robbin’s Pathologic basis of disease
Thompson PL, Stobie P. The acute coronary syndromes. MJA Practice Essentials. 1999; 171:154-59.
Hung J. Management of stable angina. Current Therapeutics Dec1998/Jan 1999 p55-62
Management of unstable angina guidelines - 2000. MJA 16 October 2000; Volume 173:Supplement. Pages S65-S88
http://www.acc.org/clinical/statements.htm ACC/AHA Practice Guidelines on Management of Acute
Myocardial Infarction
Acute coronary syndrome
Case
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59 year old male
Experiences a "vice-like" central chest pain radiating to neck and left arm which
occurred at rest
Pain progressively worsens over 30 min; he feels sweaty, nauseous and has difficulty breathing
Wife calls GP who arranges ambulance; he is taken to emergency department
Previous history - occasional episodes of "heartburn"
30 pack-years smoker
No PH of hypertension or diabetes
He is not aware of his cholesterol level
Father and uncle had suffered a heart attack in their mid-60’s yr age
Examination in emergency room (1 hr after chest pain onset)
 Anxious & diaphoretic
 Pale & cool peripheries
 Respiratory rate 20 per min
 HR 86/min, BP 170/90
 Jugular vein not distended
 4th HS, no cardiac bruit
 chest - bibasilar inspiratory crackles
Male 59 yr age. 12-lead ECG on presentation to ED
Specific Questions - 1
 What is the likely initial diagnosis in this man?
 What is the differential diagnosis?
Differential diagnosis
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Acute pericarditis
Aortic dissection
Pneumothorax
Pulmonary embolus
Acute upper GIT pathology (oesophageal, gastroduodenal, gallbladder)
An acute MI is presumed if a patient presents with ischaemic chest pain and ST elevation. Fibrinolytic
treatment, unless contraindicated, must be administered without delay in order to maximize benefit (see later
information regarding primary percutanious coronary intervention PCI)
Duration of Elevation Cardiac-Specific Affected by Renal Clearance
Myoglobin
1-12 hours
No
Yes
CK-MB (mass) 4-36 hours
Yes
Yes
Troponin I
4 hours - 7 days
Yes
Yes
Troponin T
4 hours - 14 days
Yes
Yes
Sensitivity of CK and Troponin T/I for diagnosis of acute MI is low at 3 hours and maximal at 8-12 hours after
chest pain onset. Therefore cardiac enzymes are not used for early diagnosis or management decisions in
ACS. They are useful for subsequent conformation (or exclusion) of MI and prognostic assessment.
Initial diagnosis
This man’s clinical presentation and ECG pattern is consistent with an acute anterolateral ST-elevation
infarction
However, a differential has to be considered particularly where there are no diagnostic ECG changes (NB. 4050% of patients subsequently found to have MI do not show ST-elevation on initial ECG)
Specific Questions - 2
 What causes coronary artery disease?
 What is the pathophysiology of acute coronary syndrome (unstable angina and acute myocardial
infarction)?
PATHOLOGY Associate Professor Jennet Harvey
ATHEROSCLEROSIS
Atherosclerotic plaque rupture and resulting intracoronary thrombosis are thought to account for most acute
coronary syndromes. athere - gruel sclerosis- hardening
MORPHOLOGY OF ATHEROMA
Basic lesion: atheromatous plaque
3 components;
 cells
 connective tissue, ECM
 lipids
Atheroma:
Early lesion
Atheroma:
Atherosclerotic
plaque
Atheroma:
LM - early lesion
Note accumulation
of lipid (red)
Atheroma:
LM - Atheromatous
plaque
Atheroma: LM(trichrome stain)
advanced lesion
(atheromatous
plaque)
Note "cholesterol
clefts"
SEM
monocytes adhering
to endothelium over
atheromatous
plaque
TEM
Lipid deposits in
intima
Atheroma:early
atheroma in aorta
(macroscopic
appearance)
Atheroma:Advanced
complicated lesion,
abdominal aorta
ATHEROGENESIS
There have been numerous theories put forward to explain what initiates the above chain of events.
Historically two main hypotheses have been considered ("lipid imbibition" theory, and "thrombogenic" theory).
The current view considers atherosclerosis to be a chronic inflammatory response of the arterial wall initiated
by injury to the endothelium. ("response to injury" hypothesis). Other theories include monoclonal hypothesis,
infective theory, haemorrhagic theory.
Atherogenesis consists of 3 related and overlapping processes;
 lipid accumulatiom
 smooth muscle proliferation and secretion
 necrosis and degenerative changes (cytokine mediated) resulting in a lipid-rich basal pool
CHRONIC
ENDOTHELIAL INJURY
Hyperlipidaemia
Hypertension Smoking
Haemodynamic factors
Toxins Viruses Immune
reactions Homocysteine
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ENDOTHELIAL
DYSFUNCTION
(increased permeability
monocyte emigration)
(ICAM-I)
(VCAM-I)
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LIPID ACCUMULATION
Click here for
more information
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SMOOTH MUSCLE
EMIGRATION
MACROPHAGE
ACTIVATION
IL-1
TNF-a
FGF
TGF-a
TGF-b
Click here for
more information
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MACROPHAGE
INGESTION OF LIPID
(FOAM CELLS)
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SMOOTH MUSCLE
PROLIFERATION,
SYNTHESIS,
SECRETION
Click here for
more information
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PLAQUE RUPTURE
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THROMBOSIS AND
OTHER
COMPLICATIONS
Click here for
more information
Intimal lipid accumulation
The lipid content of an atherosclerotic intima is increased many fold compared to normal intima. This lipid is
mainly present as cholesterol, and it enters the intima from the blood in the form of intact LDL. (The amount of
intralesional LDL correlates with plasma cholesterol and LDL levels). Hyperlipidaemia may itself impair
endothelial function. In the intimal wall both the lipid and protein portions of the lipoprotein molecule undergo
modification:
 Lecithin converted to lysolecithin (chemo attractant and cytotoxic)
 Peroxidation of polyunsaturated fatty acids (brought about by free radicles generated by endothelial
cells and macrophages) results in generation of alkenals, which interact with apoprotein B100, the main
carrier of LDL, so as to render the whole molecule recognizable by the 'scavenger receptor' of
macrophages and the host's immune system. The altered LDL molecule is a chemo attractant for blood
monocytes which migrate into the subendothelial space and become macrophages. The binding of
scavenger receptors on macrophages to LDL, facilitates endocytosis and the resultant lipid filled
macrophages become 'foam cells'. Altered LDL molecule inactivates macrophages so they persist in
the area, and is also toxic for endothelial cells and smooth muscle cells.
Role of Macrophages
Monocytes in blood adhere to endothelium (adhesion molecules on surface) migrate between endothelial cells
to intima. They are transformed into macrophages, engulf lipids to become foam cells. Macrophages are
attracted and immobilized by oxidised LDL. Activated macrophages synthesize growth factors including FGF,
TGFa, TGFß (the latter a stimulus for production of collagen which also inhibits cell proliferation). They also
secrete IL-I and TNF as well as MCD-I to recruit more inflammatory cells. Many other cytokines may also be
implicated in atherogenesis. (EGF, heparin-binding EGF-like growth factor, IGF-I, interferon g, interleukin 6
etc).
Connective Tissue Proliferation
The cell responsible for the overgrowth of connective tissue associated with atheroma is the arterial smooth
muscle cell which normally resides in the media. These cells exist in one of two phenotypes, dependent on the
local chemical environment (cytokine mediated). These are referred to as 'contractile ' and 'synthetic'
respectively and the latter phenotype is associated with the synthesis and secretion of extra cellular
components including collagen, elastin, proteoglycans. Important mitogens for arterial smooth muscle cells are
PDGF from endothelium (in response to thrombin, Factor Xa, and increased endothelial cell turnover), and
cytokines interleukin 1 and TNFa from activated macrophages, and from arterial smooth muscle cells (possibly
in response to exposure to native and oxidised LDL). PDGF probably also acts as a chemo attractant causing
muscles cells to migrate from media to intima.
Thus thrombogenesis is regarded as a late development in the atherogenic pathway rather than an initiating
event. Other theories of atherogenesis not discussed here:
 monoclonal hypothesis of atherogenesis
 haemorrhagic theory of atherogenesis
 'infective' theory of atherogenesis.
 Types of Atheromatous Plaques
Fibrous
(concentric)
Lipid rich (eccentric)
Fibrous
(eccentric)
Lipid rich
(concentric)
Lipid rich expanding
peripherally with little
stenosis
Clinical implications of plaque morphology
 Fibrous lesions generally produce progressive restriction of blood flow but are less likely to rupture,
particularly if fibrous bands extend across the lipid pool.
 Eccentric lesions generally result in abnormal mechanical stress on the contractile arterial wall and are
more likely to rupture.
 Lesions with a large lipid pool are easily deformed my haemodynamic stresses and more likely to
rupture.
 Atherosclerotic plaques which expand centrifugally may be difficult to detect angiographically and
clinically.
 Lesions with a high proportion of macrophages and a small population of smooth muscle cells in the
cap are also associated with an increased tendency to plaque rupture.
Specific Questions - 3
 What should be the initial therapy in this man?
 Are there any differences in the treatment of ACS with ST-elevation vs non-ST-elevation?
Initial Treatment
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ASA 300 mg - given by ambulance officer
Category 2 in ED; clinically assessed, placed on ECG monitor & IV line inserted within 10 min of
arrival
Given intranasal oxygen & morphine IV 2mg
GTN 400 µg by puffer - repeat ECG shows persistent ST V1-5 and new RBBB pattern
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Assessment
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The ECG still shows hyperacute anterolateral ST-elevation with new RBBB (?mechanism of RBBB).
Lack of response to GTN excludes vasospastic angina.
His abrupt onset of symptoms at rest suggests to you that this man has had a rupture of a "vulnerable"
coronary plaque which was not previously flow-limiting (no prior exertional angina).
The ST elevation likely indicates that the plaque rupture has led to complete thrombotic occlusion (?in
which coronary artery).
Acute coronary syndrome: Initial therapeutic approach
Increase MVO2 supply
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Reduce MVO2 demand
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Open an occluded coronary artery by
fibrinolytic agent or angioplasty (PCI)
Antiplatelet & antithrombin therapy
Nitrates
O2 therapy
Bed rest & pain relief
BP control
-blockade
Nitrates*
ACE inhibitor*
* especially if heart failure present
Further emergency therapy
 He is given tPA bolus/infusion
 Heparin bolus/infusion to aPTT 70-80 sec
 GTN infusion for pulmonary congestion
 Frusemide IV 20mg because of pulmonary congestion and SaO2
 -blocker IV for persistent sinus tachycardia and BP (after heart failure controlled)
Coronary thrombosis: therapeutic agents
Antiplatelet
Antithrombin
Fibrinolytic
Aspirin
Unfractionated Heparin
Non-fibrin Specific
 Streptokinase
 Urokinase
Clopidogrel
Ticlopodine
Dipyridamole
LMWHs
Fibrin Specific
 Alteplase(tPA)
 Reteplase
 TNK-tPA
GPIIb/IIa antagonists Direct thrombin inhibitors
(hirudin, hirulog)
ECG presentation and effect of fibrinobolytic therapy
Presentation ECG
Mortality Benefit
New BBB
Yes
ST elevation, anterior Yes
ST elevation, inferior Yes
ST elevation, other
Yes
ST Depression
No (? increased risk)
Other abnormality
No
Proportional effect of fibrinolytic therapy on 35-day mortality according to treatment delay
Lancet 1996
Contraindications to thrombolytic therapy
Risk of intracranial bleeding
o Poorly controlled hypertension (BP>180/110mmHg)
o Previous intracranial haemorrhage
o Recent stroke (<1 yr)
 Risk of systemic bleeding
o Major surgery or trauma within previous 14 days or recent arterial puncture
o Active peptic ulceration or history of significant upper GIT bleed
o Prolonged (<20 min) or traumatic CPR
o Known bleeding diathesis
o Pregnancy or postpartum
o Severe hepatic or renal disease
Intervention Cardiology
If brute force isn’t working, you’re not using enough of it ...
Primary PCI vs Thrombolytic Rx
 Advantages
o Achieves reperfusion rates with TIMI-3
flow in < 90% ( 50% with thrombolytic
Rx)
o Treats underlying stenosis as well as
thrombotic occlusion
o Effective for patients with
haemodynamic instability or contraindications to thrombolytic Rx
o Lower risk of intracranial haemorrhage
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Disadvantges
o Requires prompt access to cath lab and
trained personnel
o Costs
o Specific operator dependence
o Limited controlled trial evidence
Aspirin, Clopidrogrel, & GPIIb/IIIa antagonists
Mechanism of action of
UF Heparin &
LMW Heparin
Patients without ST elevation usually have subtotal coronary occlusion and are treated with antiplatelet and
antithrombotic therapy to prevent thrombus progression. They do not benefit from fibtinolytic therapy, unlike
patients presenting with ST elevation.
24 hours post-thrombolysis
Patient is pain free & clinically stable, HR 70 bpm, BP 130/80 SaO2 > 90% but persistent 4th HS & bibasilar
crackles Monitor shows sinus rhythm with 30 PVCs/hr CK peak at 2800 IU/L 15 hrs post-thrombolysis ACE
inhibitor started; ASA & -blocker continued GTN and heparin infusion titrated down, cease by 48 hrs Repeat
ECG
Specific Questions - 4
 What are the early and late pathological/functional consequences of acute myocardial infarction
 How is it modified by coronary reperfusion?
PATHOLOGY
Associate Professor Jennet Harvey
Vascular Changes in Myocardial Infarction
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often only moderate stenosis (50% - 70% reduction in area)
angiography performed within 4 hours shows thrombosis in 90%
angiography after 12-24 hours shows thrombosis in 60%
Myocardial Blood Flow and Ischaemia
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normally 80% coronary arterial oxygen used by resting heart
coronary arteries functional 'end arteries'
perfusion relatively less in inner third of myocardium
severe ischaemia causes functional, metabolic and ultrastructural abnormalities within seconds
irreversible cell injury occurs after 20-40 minutes proceeding to coagulative necrosis
healing commences after approximately 7 days
Click here for more information
Ischaemic damage to cardiac myocytes
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reversible injury
'stunned' myocardium
irreversible injury (necrosis)
Myocardial
Infarct
(7 days post
occlusion).
Note area of
pale ischaemic
necrosis
with
haemorrhage
border
Myocardial
Infarction:
extensive
subendocardial
infarcts (pale
areas)
Myocardial
infarction:
LM- heavy
neutrophilic
infiltration
between
myocytes
showing
coagulative
necrosis
(3 days postocclusion)
Myocardial
Infarct (healed)
(Note fibrous
scarring)
Healed
Myocardial
infarction
Effects of Reperfusion
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salvage of irreversible injury (±microvasculature salvage)
infarct appears haemorrhagic
contraction bands in necrotic fibres (Ca ions)
potential for new cellular damage (oxygen free radicals)
Myocardial Infarction
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transmural (plaque rupture ± complete obstructive thrombosis)
subendocardial (complete or incomplete diffuse stenosis involving >1 vessel)
Consequences and Complications of Myocardial Infarction
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contractile dysfunction (± cardiogenic shock)
arrhythmias (conduction disturbances/myocardial irritability)
myocardial rupture (ventricular, septal, papillary muscle)
papillary muscle dysfunction
pericarditis
infarct extension (may extend to RV)
infarct expansion
mural thrombosis
ventricular aneurysm
progressive late heart failure
Rupture of Papillary
Muscle
Post MI Ventricular
aneurysm
Ventricular Remodeling after acute MI
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Characterised by alterations in LV size, shape and wall thickness
Leads eventually to LV dilatation and impaired function
Involves both infarcted and non-infarcted areas
Both humoral and mechanical factors important in causation
Pathogenesis multifactorial
o rearrangement of wall structure(slippage)
o myocyte hyprtrophy
o increased muscle mass without increased wall thickness (eccenctric hypertrophy)
Related to
o site of infarct
o size of infarct
o patency of infarct related artery (reperfusion promotes healing)
o haemodynamic overload (restrictive filling pattern)
o myocardial viability (transmural versus subendocardal) microvascular integrity
Specific Questions - 5
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What post-MI complications might be anticipated in this man?
What is his expected mortality and the determinants of prognosis after AMI?
How can clinical complications and prognosis be assessed in this man?
Patient Risks
 Potential risks in this man include:
o Residual ischaemia & re-infarction
o LV remodelling  progressive heart failure
o Ventricular arrhythmias including VT/VF
o LV thrombus  thromboembolism
o Risk factors for CAD progression/plaque rupture
Assessment of Prognosis
 Echo shows mild LV dilatation, anteroapical akinesis, LVEF = 45% (normal >55%), no LV
 thrombus
 Pre-discharge (day 5) exercise myocardial perfusion study. The EST is positive at 6 mets with
 chest pain and 0.2mV ST segment depression V2 -V6.
 Scan shows moderately large area of reversible perfusion defect in anterior and septal LV wall (see
following)
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Investigations indicate a large area of residual ischaemia (jeopardized myocardium)
associated with persistent LV dysfunction (?myocardial stunning or hibernating myocardium).
The results suggest that he may be at increased risk of subsequent reinfarction, heart failure
and sudden cardiac death.
Subsequent coronary angiogram shows a severe LAD stenosis and LV dysfunction (see following).
59 yo man. Angiogram shows 95% LAD stenosis
Specific Questions - 6
 Would this patient benefit (either by improved symptoms or prognosis) from revascularisation vs
continued medical therapy?
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Choice of revascularisation procedure - coronary artery bypass grafting or PCI?
Indications for Revascularisation
 Symptoms (?silent ischaemia) not controlled by medical therapy
 In high-risk patients, CABG may improve survival vs medical therapy (particularly if left main or
multivessel disease &LV impaired)
 PCI superior in symptom relief but not proven to reduce risk of MI/death vs medical therapy (whereas
aspirin, -blocker, statins & ACE inhibitors are proven in secondary prevention)
He undergoes LAD angioplasty/stenting
Cardiac rehabilitation & secondary prevention
 His cardiac risk factors:
o Current smoker, sedentary lifestyle, central obesity.
o Fasting cholesterol 5.6, TG 2.5, HDL 0.90, LDL 3.9 mmol/L; fasting BSL 6.7 mmol/L.
o Effect strategies for cease smoking, low saturated fat diet, exercise program, and weight loss.
o He is started on statin therapy.
o Plan repeat fasting BSL (?GTT) after hospital discharge
o Discuss reasons for long-term Rx with aspirin, -blocker, ACE inhibitor, and statin.
Pooled results of randomised controlled trials (RCTs) of secondary prevention in acute MI
Patient followup
 You review this man after hospital discharge
 He remains asymptomatic and returns to work 3 weeks after his heart attack.
 He has stopped smoking, changed to a Mediterranean type diet, is exercising regularly, has lost
 5 kg weight and says that he feels "much better" than before.
 Repeat fasting BSL 5.5 mmol/L. Continue dietary management.
 Continue aspirin, -blocker, statin, & ACE inhibitor long-term. Review Rx targets
Key messages - acute coronary syndrome
 Underlying pathophysiology is plaque erosion or rupture with superimposed platelet-fibrin thrombus.
 Rupture prone plaques are often not flow limiting but have large lipid pool, thin cap, and increased
inflammation.
 Therapy such as cholesterol-lowering (lipid pool and inflammation), -blockers (shear stress) or ACE
inhibitors (endothelial function) may reduce the risk of plaque rupture.
 Initial diagnosis of ACS is based on the presenting clinical history and ECG and Rx must be
commenced without delay in order to derive the most benefit.
 Initial Rx consists of fibrinolytic, antiplatelet and antithrombotic therapy along with those treatments that
can reduce infarct injury (eg., -blockers).
 Management of ACS patients is similar except that fibrinolytic therapy is not indicated in non-ST
elevation MI.
 Post-MI risk assessment includes looking for residual ischaemia, LV dysfunction, risk of ventricular
tachyarrhythmias, and chronic vascular risk factors.
 Coronary artery revascularisation is effective for symptom relief and may improve prognosis in high-risk
patients.
 Secondary prevention in most patients should include aspirin, -blockers, statins, ACE inhibitors, as
well as multifactorial risk factor modification and cardiac rehabilitation
Treatment algorithms in acute coronary syndromes