AETIOLOGY AND RISK FACTORS

Atheroma deposits in the walls of coronary arteries provide the substrate for the development of ACS. Major risk factors for the development of coronary artery atheroma are seen in Figure 16.2. Up to 90% of the adult population possess at least one risk factor for the development of atheroma and CAD.

Figure 16.2 Risk factors for the development of atherosclerosis and coronary artery disease (CAD).

Cessation of smoking, lowering plasma cholesterol (diet and medications) and adoption of a more active lifestyle can all help prevent the development of CAD. Treatment of hypertensive patients produces a large and early reduction in stroke incidence (35–40%) and mortality, and a significant fall in MI (20–25%).³ Modification of risk factors is one of the most important means of decreasing the prevalence and mortality from CVD.

PATHOPHYSIOLOGY

Formation of thrombus upon disrupted, fissured or eroded atheromatous plaque is the usual precipitant of an ACS.⁴ Atherosclerotic plaque formation is probably initiated by injury to the vessel wall that may commence even as early as childhood. Highly activated macrophages are attracted to the site of injury and differentiate into tissue macrophages. Macrophages incorporate blood stream lipids into the connective tissue fibres of the plaque, forming a thrombogenic soft lipid core. Plaque development is slow, but is rapidly accelerated in people with risk factors.

‘Vulnerable plaque’ is often rich in lipid and covered by a thin fibrin cap. The cause of plaque rupture or fissuring is unknown but exposes thrombogenic lipid and collagen, which are potent activators of platelets. Development of thrombus upon this eroded plaque results from: (1) platelet adherence and activation; and (2) coagulation pathway activation.

Although many pathways initiate platelet activation, the final common pathway of thrombus formation is via activation of the glycoprotein (GP) IIb/IIIa receptor, the platelet surface membrane receptor for fibrinogen. Activated GP IIb/IIIa receptors cross-link fibrinogen between activated platelets, promoting the formation of platelet thrombi. Platelets aggregate to form ‘white thrombus’; however this thrombus is seldom totally occluding. Activation of coagulation pathways by exposed lipid and fibrin, as well as by the now activated platelets, leads ultimately to thrombin activation and the laying-down of fibrin clot. Red cells are enmeshed in this so-called ‘red thrombus’ complex, which surrounds the ‘white thrombus’. Sudden artery occlusion by thrombus may thus complicate even only moderate-sized plaque; 70% of ACS patients may have a < 50% stenotic lesion and in only 14% is the underlying stenosis > 70% of the lumen diameter (Figure 16.3).

Figure 16.3 (a) Plaque rupture exposes thrombogenic lipid. ‘White thrombus’ is formed by adherent activated platelets. Coronary artery narrowing, distal platelet embolisation or arterial spasm can cause ischaemic myocardial pain and possible myocardial necrosis. This lesion is unstable and may lead to thrombin activation. ‘White thrombus’ is not removed by thrombolytic therapy. (b) Thrombin activation leads to a mesh of fibrin and red blood cells (RBCs) or ‘red thrombus’. Arterial occlusion may result and, in arteries without adequate collateral circulation, myocardial necrosis follows. Complete arterial occlusion is suggested by ST-segment elevation on the electrocardiogram. Prompt reperfusion with thrombolytic therapy or with invasive coronary procedures may prevent extensive myocardial necrosis.

These processes have immediate relevance to treatment:

Totally occluding thrombus causes myocardial necrosis unless there is good collateral flow or the thrombus is rapidly cleared. Occlusion is often accompanied by ST-segment elevation on the ECG. If thrombus is largely ‘white thrombus’, with minimal or non-occlusive red thrombus, ST-segment elevation is far less likely. Non-occlusive thrombus may be asymptomatic, may cause USA or may cause MI, especially if spasm or distal embolisation of thrombus occurs. Although non-occlusive thrombus is less likely to be associated with early or sudden death, it is indicative of unstable plaque and is strongly associated with reinfarction and death in following months.

Ischaemia results in cellular disruption, loss of function, thinning and softening of the affected myocardium, and subsequently fibrosis and ventricular remodelling.

Infarct size determines:

Initially, infarcted muscle is softened, leading to an increase in ventricular compliance, but as fibrosis takes place compliance is decreased. With time, there is often expansion of the infarcted segment and compensatory hypertrophy of unaffected myocardial cells (i.e. ventricular remodelling). This can commence early after infarction, affecting overall ventricular function and prognosis.

CLINICAL PRESENTATION

The diagnosis of myocardial ischaemia is usually made (suspected) on the basis of clinical history and ECG.²

ELECTROCARDIOGRAPHY

Acute and complete occlusion of a coronary artery usually leads to serial ECG changes in leads subtending the area of ischaemia, where the:

• number of leads involved broadly reflects the extent of myocardium involved

• height of initial ST-segment elevation is modestly correlated with the degree of ischaemia

• acute resolution of ST-segment elevation correlates well with reperfusion⁸

Identification of classical acute and early changes where ST-segment elevation MI (STEMI) is present identifies patients in whom reperfusion therapy may interrupt, prevent or minimise myocardial necrosis (Figure 16.4). These are:

• hyperacute (0–20 min): tall, peaking T-waves and progressive upward coving and elevation of ST-segments

• acute (minutes to hours): persisting ST-segment elevation, gradual loss of R-wave in the infarcted area. ST-segments begin to fall and there is progressive inversion of T-waves

• early (hours to days): loss of R-wave and development of pathological Q-waves in area of ischaemia. Return of ST-segments to baseline. Persistence of T-wave inversion

• indeterminate (days to weeks): pathological Q-waves with persisting T-wave inversion. ST-segments normalise (unless there is aneurysm)

• old (weeks to months): persisting deep Q-waves with normalised ST-segments and T-waves

Figure 16.4 Total acute coronary occlusion leads to serial electrocardiogram changes. The evolution is variable and may be interrupted or altered by successful reperfusion. ST-segment elevation is an early and relatively specific indicator of the need for thrombolysis in patients with acute coronary syndrome.

Other causes of acute ST-segment elevation and T-wave changes that should not receive thrombolytic therapy are:

• normal variant

• metabolic disturbance, particularly hyperkalaemia

• drug toxicity, pericarditis

• LV hypertrophy

• LV aneurysm

• Wolff–Parkinson–White syndrome and Brugada syndrome

• apical ballooning syndrome (Takotsubo syndrome or ‘broken-heart’ syndrome)

The Takotsubo syndrome is characterised by precordial ST-segment elevation, apical ballooning on echocardiography but normal vessels on angiography. It may follow the onset of recent severe stress and may cause up to 1–2% of STEMI.⁹ It has been recognised in critical illness.¹⁰

Patients with ACS but without significant ST-segment elevation (generically, non-ST-segment elevation ACS (NSTEACS), until further subdivided by biomarker studies) may still be at high risk of infarction and death. They likely have active, non-occluding thrombus or, if it is occluding, then some collateral flow is present. ECGs in these patients may be normal or display:

• ST-segment depression

• ST-segment elevation (insufficient to meet thrombolysis criteria)

• T-wave inversion or ‘normalisation’ of previous inverted T-waves

A normal ECG does not exclude MI. Despite the absence of ST-segment elevation, a small percentage of patients progressively lose R-wave height and develop evidence of Q-waves and a small number progress to cardiogenic shock.

LOCALISATION OF INFARCTION

The left anterior descending (LAD) coronary artery supplies the anterior two-thirds of the interventricular septum (septal perforators), the anterior and lateral wall of the LV (diagonal branches) and sometimes part of the RV. The left circumflex artery supplies the LV lateral (anterolateral marginal branches) and posterior walls, and occasionally its inferior aspect (posterior LV arteries: 15% of patients) and the posterior septum. The right coronary artery (RCA) supplies the RV wall, and usually the posterior septum and inferior (diaphragmatic) wall of the left ventricle (posterior LV arteries; 85% of people). The RCA is ‘dominant’ (as opposed to the circumflex) if it gives rise to the posterior descending coronary artery (PDA) (Figure 16.5).

Figure 16.5 Coronary artery anatomy. Left anterior descending artery (LAD) supplies anterior two-thirds of the interventricular septum (septal perforators), anterior and lateral wall of the left ventricular (LV: diagonal branches) and sometimes part of the right ventricle (RV). Circumflex (Cx) supplies the LV lateral (anterolateral marginal branches) and posterior walls, and occasionally its inferior aspect (posterior LV arteries: 15% of patients) and the posterior septum. The right coronary artery (RCA) supplies the RV wall, and usually the posterior septum and inferior (diaphragmatic) wall of the LV (posterior LV arteries; 85% of people). The RCA is ‘dominant’ (as opposed to the circumflex) if it gives rise to the posterior descending coronary artery (PDA) and the posterior left ventricular arteries.

It is usual to use the ECG in initial clinical assessments to localise the area of myocardial ischaemia. The pattern of lead involvement may thus assist with localisation of the MI (Figure 16.6).^8,11,12 There is a reasonable correlation between the site of infarction as defined by the ECG and the occluded coronary artery and the infarcted region of myocardium (Figure 16.7). However, ECG localisation may differ from angiographic, echocardiographic and autopsy findings, especially where there is collateral circulation or previous CABG. Anterior wall infarctions usually result from occlusion of the LAD; inferior, true posterior and RV infarctions result from occlusion of the RCA or circumflex arteries.

Figure 16.6 Electrocardiogram patterns of myocardial injury. RCA, right coronary artery; LAD, left anterior descending coronary artery; Cx, circumflex coronary artery. *Initial ST-segment depression and T-wave inversion in V₁–V₂, subsequent evolution to tall R-waves in V₁–V₂ and loss of R-wave in V₆. The correlation of electrocardiogram localisation with culprit artery (determined at angiography) and echocardiographic or autopsy localisation is variable.

Figure 16.7 Acute Inferior myocardial infarction (ST-segment elevation in the inferior leads II, III and aVF) with reciprocal ST depression in leads I, aVL, V1 and V2. The addition of right sided (V4R) and posterior leads would help identify the presence of RV and posterior infarction. Reciprocal ST segment depression in leads remote from the site of infarction is a highly sensitive indicator of myocardial infarction. It may be seen in 70% of inferior and 30% of anterior infarctions.

Common ECG patterns of infarction are shown in Figure 16.6. Approximately 40–50% of patients present with anterior infarction and 50% with inferior infarction. Anterior wall infarctions may be extensive or localised (septal, anterior, lateral) whereas inferior infarctions may similarly involve extension to the lateral, posterior or RV myocardium. Of clinical importance:

• 8% of patients with MI will only display ST-elevation in posterior leads V₇–V₈ (true posterior) or in right precordial leads V₃R–V₆R (RV).^4,11

• True posterior infarction involves ‘mirror’ changes in leads V₁ and V₂ and is important to diagnose because the amount of threatened myocardium is similar to that of inferior infarction.

• RV infarction is usually concurrent with inferior wall infarction and very rare in isolation. A V₄R lead (V₄ lead in an equivalent position on the right anterior chest wall) is sensitive and specific for RV infarction.^11,12

The resting ECG does not have sufficient predictive value to stratify patients with NSTEACS reliably into those with infarction (NSTEMI) and those without (USA). Up to 18% of patients with MI show no changes on the initial ECG and up to 20% of patients with NSTEACS have normal or minimal CAD.^11,12 Cardiac biomarkers are necessary to confirm myocardial cellular injury and meet diagnostic criteria for MI.

CARDIAC BIOCHEMICAL MARKERS

• The increasing sensitivity and specificity of cardiac troponins (cTN) has made them the gold standard for the confirmation of myocardial necrosis. Elevated levels should be taken as evidence of myocardial injury and, in the correct setting, as confirmation of MI.^2,7

• Troponin measurements have generally replaced creatinine kinase (CK) as the biomarker used to identify the presence of myocardial necrosis.

The typical rise and fall of cardiac markers after infarction are shown in Figure 16.8.

Figure 16.8 Serum biochemical marker changes after acute myocardial infarction. The sensitivity and specificity of cardiac troponins makes them useful for the early diagnosis of MI. Their delayed fall may allow diagnosis where presentation is late. CK or CK-MB are useful if re-infarction with secondary biomarker rise is queried.

Two (cTnT, cTnI) of the three isoforms of the cTn complex are exclusively expressed in cardiac myocytes (specific). Troponin levels allow early and sensitive detection of myocardial necrosis.

TROPONINS

The increased sensitivity of troponins compared to CK means that a third of patients previously considered to have USA are now recognised or redefined as having evidence of myocardial necrosis. Troponins also have better specificity than CK, similar to that of its isomer CK-MB. They do not differentiate the cause of the myocardial injury (e.g. ischaemia, myocarditis, trauma), however, and thus clinical context must always be considered.² Troponins are more persistent in the serum (up to 7–10 days) and thus may be useful in diagnosis when presentation is delayed. Whilst CK-MB has traditionally been thought to be a better predictor of reinfarction, a rise in troponin of > 20% some 3–6 hours after onset of suspected reinfarction is also significant.²

Troponins should be checked in all patients with ACS and aggressive therapies should be targeted at patients with elevated levels.⁵

ECHOCARDIOGRAPHY

Two-dimensional transthoracic echocardiography with colour Doppler has good clinical utility as a non-invasive investigation during admission for an ACS. Its primary role is in assessing the degree of regional and global LV dysfunction.

Echocardiography detects regional wall motion abnormalities, which can help confirm or exclude the diagnosis of MI in the small percentage of cases where diagnosis is uncertain (e.g. left bundle branch block (LBBB) or old infarction with atypical presentations). Regional wall motion abnormality and loss of wall thickening with contraction are often present in these cases if due to ischaemia, while their absence suggests that ischaemia is not acute. It is useful for excluding differential diagnoses (e.g. aortic dissection or pericardial effusions), again in a small percentage of patients.²

Echocardiography is subsequently useful to:

Transoesophageal echocardiography may have an increasing role in the therapy of cardiogenic shock, giving some guide to volume therapy.

Dynamic or graded intravenous (IV) dobutamine stress echocardiography (2–10 days after MI) can assess myocardial viability and distinguish non-viable myocardium from stunned myocardium. Superiority to standard exercise testing has not been proven.

RADIONUCLIDE STUDIES

Radionuclide angiography has little practical role in the emergency-room diagnosis of ACS. Dynamic or functional radionuclide studies (thallium-201 or technetium-99m-sestamibi myocardial perfusion imaging studies) are useful in postinfarction risk stratification and are able to detect ‘threatened myocardium’. They are useful in the later risk assessment of patients who have presented with USA or NSTEMI and where the clinical significance of lesions noted on angiography is uncertain.

STRESS TESTING

Stress testing may be useful in risk stratification and diagnosis of stable angina. Following infarction, the following may be of use:

CORONARY ANGIOGRAPHY AND LEFT VENTRICULOGRAPHY

Coronary angiography is the gold standard for the diagnosis (and often treatment) of CAD; however the timing and need for this are determined by clinical risk. In the appropriate clinical setting, coronary angiography will usually identify a ‘culprit artery’ subtending an area of regional wall motion abnormality and additionally may allow definitive treatment of this abnormality. These indications are discussed later.

RISK STRATIFICATION OF ACUTE CORONARY SYNDROME (Figure 16.9)

An immediate goal is to identify patients with STEMI, who will then benefit from reperfusion therapy. This is almost always done on the basis of the presenting ECG.

Figure 16.9 Immediate stratification of acute coronary syndrome (ACS) into those with and without ST-segment elevation identifies patients requiring reperfusion therapy. Early and serial biomarker results in non-ST-segment elevation acute coronary syndrome (NSTEACS) identify patients with unstable angina (normal levels) and those with NSTEMI (elevated levels). Discharge electrocardiogram identifies patients who have sustained Q-wave myocardial infarction (QwMI) and non-Q-wave myocardial infarction (NQwMI). Successful reperfusion therapy may avert or limit the extent of Q-wave development. USA, unstable angina; PCI, percutaneous coronary intervention.

STEMI

STEMI (including new, presumed new LBBB) with persistent pain is the most lethal form of ACS and is usually due to complete occlusion of a coronary artery (> 90% of patients).⁵ It is an indication for reperfusion therapy. Such therapy may be successful and significantly reduce the size of the potential infarction, although some rise in troponin is usually inevitable. Patients who develop ST-segment elevation after admission should also then be stratified to this group.

NSTEACS

Patients have ischaemic chest pain but have ‘non-specific’ ECG changes (normal, ST-segment depression or minimal elevation, T-wave inversion). After serial biomarker testing, these patients will later prove to have either USA pectoris if troponins remain normal or NSTEMI (elevated troponin).

The therapy of NSTEMI aligns more clinically with that of USA than with that of STEMI. These two conditions, both forms of NSTEACS, represent a spectrum of disease and require common treatments directed at platelet inactivation and ‘plaque stabilisation’. The term ‘NSTEACS’ recognises that they are clinically indistinguishable at presentation. The more severe the ischaemia, the higher the need for more aggressive anticoagulation and invasive procedures. Early diagnostic classification using both ECG and troponins allows early risk stratification and evidence-based therapy. Only 35–75% of patients have evidence of coronary thrombus formation and thrombolytic therapy is not beneficial in this group. Indeed, it is associated with worse outcomes.^5,14

Figure 16.10 displays the incidence of major coronary events over the following 12 months in patients presenting with and without ST-segment elevation. ST-segment depression has lesser early mortality but a similar or higher mortality at 6 months and at 10 years than those presenting with ST-segment elevation.^15,16 Features that correlate with risk are:

Figure 16.10 (a) Thirty-day mortality according to British Cardiac Society category. (b) Kaplan–Meier survival area curves for events from admission to 6 months. ACS, acute coronary syndrome.

(Reproduced from Das R, Kilcullen N, Morrell C et al. The British Cardiac Society Working Group definition of myocardial infarction: implications for practice. Heart 2006; 92: 21–6 with permission.)

Q-wave MI (QwMI) or non-Q-wave MI (NqwMI) are older terms used to describe MI. The 10-year mortality of NqwMI (70%) is 10% higher than that of QwMI.¹⁶

IMMEDIATE MANAGEMENT OF ACUTE CORONARY SYNDROMES