/year_5/Sci_Prac_Med_500/Tutorial_17/    

Keywords Acute coronary syndrome Pathophysiology Diagnosis Therapy Prognosis Secondary prevention

Acute coronary syndrome Associate Professor Joseph Hung, Associate Professor Jennet HarveyAt 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 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 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 diagnosisThis man’s clinical presentation and ECG pattern is consistent with an acute anterolateral ST-elevation infarctionHowever, a differential has to be considered particularly where there are no diagnostic ECG changes (NB. 40-50% 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

ATHEROSCLEROSISAtherosclerotic plaque rupture and resulting intracoronary thrombosis are thought to account for most acute coronary syndromes. athere - gruel sclerosis- hardening

MORPHOLOGY OF ATHEROMABasic lesion: atheromatous plaque

3 components; cells connective tissue, ECM lipids

Atheroma:Early lesion

Atheroma:Atherosclerotic plaque

Atheroma:LM - early lesionNote accumulationof lipid (red)

Atheroma:LM - Atheromatous plaque

Atheroma: LM-(trichrome stain)advanced lesion(atheromatous plaque)Note "cholesterol clefts"

SEMmonocytes adhering to endothelium over atheromatous plaque

TEMLipid 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-1TNF-aFGF

TGF-aTGF-b

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MACROPHAGE INGESTION OF LIPID

(FOAM CELLS)

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SMOOTH MUSCLE PROLIFERATION,

SYNTHESIS, SECRETIONClick here for

more information

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PLAQUE RUPTURE

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THROMBOSIS AND OTHER COMPLICATIONS

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Intimal lipid accumulationThe 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 MacrophagesMonocytes 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 ProliferationThe 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)

Fibrous (eccentric)

Lipid rich (concentric)

Lipid rich (eccentric)Lipid rich expandingperipherally with littlestenosis

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 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

Assessment 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 approachIncrease MVO2 supply Reduce MVO2 demand

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 agentsAntiplatelet Antithrombin Fibrinolytic

Aspirin Unfractionated Heparin Non-fibrin Specific Streptokinase Urokinase

ClopidogrelTiclopodineDipyridamole

LMWHs Fibrin Specific Alteplase(tPA) Reteplase TNK-tPA

GPIIb/IIa antagonists Direct thrombin inhibitors(hirudin, hirulog)

 

ECG presentation and effect of fibrinobolytic therapyPresentation 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 therapyRisk 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 CardiologyIf 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 contra-indications to thrombolytic Rx

o Lower risk of intracranial haemorrhage

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 ofUF 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-thrombolysisPatient 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?

PATHOLOGYAssociate Professor Jennet Harvey

Vascular Changes in Myocardial Infarction 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 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

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Ischaemic damage to cardiac myocytes reversible injury 'stunned' myocardium irreversible injury (necrosis)

Myocardial Infarct(7 days post occlusion).Note area of pale ischaemic necrosiswith haemorrhage border

Myocardial Infarction:extensive subendocardial infarcts (pale areas)

Myocardial infarction:LM- heavy neutrophilic infiltrationbetween myocytes showing coagulative necrosis(3 days post-occlusion)

Myocardial Infarct (healed)(Note fibrous scarring)

Healed Myocardial infarction

Effects of Reperfusion 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 transmural (plaque rupture ± complete obstructive thrombosis) subendocardial (complete or incomplete diffuse stenosis involving >1 vessel)

Consequences and Complications of Myocardial Infarction 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 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 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)

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?

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