Acute cardiac syndromes, investigations and interventions

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Chapter 16 Acute cardiac syndromes, investigations and interventions

Cardiovascular disease (CVD) accounts for 35–40%¹ of deaths in western industrialised society, with coronary artery disease (CAD) being responsible for about half of these. In patients over age 40, acute myocardial infarction (MI) is the cause of approximately 20% of all deaths. Up to 80–90% of these deaths occur outside hospital. Of patients admitted to hospital, mortality is 8–9%,¹ much higher in at-risk groups. Lowering in-hospital mortality from CAD requires us to identify rapidly patients who are at risk and to implement evidence-based treatment regimens.

MYOCARDIAL INFARCTION

MI is necrosis of myocardial cells due to ischaemic injury. Diagnosis is usually made on the basis of clinical suspicion, although tests such as electrocardiography (ECG) and biomarkers, echocardiography or autopsy findings are required to confirm the diagnosis.

Acute MI can occur in association with or result from a number of different pathological and epidemiological mechanisms:²

• a primary coronary artery event such as plaque erosion and/or rupture, fissuring or dissection

• a problem of oxygen supply demand such as coronary spasm, coronary embolism, vasculitis, drug abuse, arrhythmia, anaemia or hypotension

• sudden cardiac death where death precludes determination of causation

• percutaneous coronary intervention (PCI)

• coronary artery bypass grafting (CABG)

Each mechanism may have a different long-term prognosis despite similar biomarker and ECG changes. Such classifications may be clinically important when interpreting the results of clinical trials.²

ACUTE CORONARY SYNDROMES (ACS)

ACS represent the largest group of patients developing MI. They describe the spectrum of patients who present with chest discomfort or other symptoms caused by acute myocardial ischaemia (Figure 16.1). ACS can be further divided into acute MI and unstable angina (USA). Both are invariably caused by recent thrombus formation on pre-existing coronary artery plaque leading to impaired myocardial oxygen supply. In this sense they differ from stable angina, which is usually precipitated by increased myocardial oxygen demand with severe background coronary artery narrowing. Both represent medical emergencies and are one of the most frequent causes of hospital and coronary care unit (CCU) admission.

Figure 16.1 Classification of acute coronary syndromes.

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:

• Antiplatelet agents prevent platelet adherence and heaping, which limits and even reverses the development of ‘white thrombus’. These agents may target the adenosine diphosphate receptor (e.g. ticlopidine and clopidogrel) or may inhibit cyclooxygenase (e.g. aspirin). Although aspirin has been the major antiplatelet agent and blocks synthesis of thromboxane A₂, it fails to block platelet activation by thrombin, adenosine diphosphate and collagen.

• Fibrinolytic agents lyse ‘red thrombus’ but are not active against ‘white thrombus’.

• Antithrombin agents (e.g. heparins) may limit thrombin activation. Current thrombolytic agents lyse fibrin and red cell thrombus, but paradoxically may increase surface thrombin activation.

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:

• left ventricular (LV) systolic function impairment

• stroke volume decrease

• ventricular filling pressure rise (leads to pulmonary congestion and hypotension that may impair coronary perfusion pressures and exacerbate the myocardial ischaemia)

• LV diastolic dysfunction

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

HISTORY

Patients with myocardial ischaemia can present with chest pain or pressure, syncope, palpitations, dyspnoea or sudden death. Prodromal symptoms of USA occur in the days preceding infarction in 20–60% of patients.

Typically, the pain of acute MI:

• is severe, constant and restrosternal, spreading across the chest

• lasts for more than 20 min and is without a clear precipitant

• may radiate to the throat and jaw, down the ulnar aspect of both arms and to the interscapular area

Sweating, nausea, pallor, dyspnoea and anxiety are common.

The pain of USA may be similar but milder in nature. Features that may suggest it to be ischaemic are:

• waxing and waning characteristics

• reproducibility upon minimal exertion or with emotion

• association with autonomic symptoms

The pain may sometimes be atypical:

• epigastric (leading to possible misdiagnosis)

• confined to the jaw, arms, wrists or interscapular region

• burning or a ‘pressure-like’ sensation

• sharp or stabbing in nature

• reproduced by chest pressure

These features do not necessarily exclude infarction.⁵ Differential diagnosis includes:

• aortic dissection

• pericarditis

Atypical or silent presentations are common: 20–60% of non-fatal infarctions are unrecognised at onset.⁴ This presentation is more common in patients who are elderly, diabetic, have hypertension, who smoke or take non-steroidal anti-inflammatory agents.

The assessment of clinical symptoms alone is insufficient for risk stratification and severity of pain does not usually correlate with the extent of infarction.

PHYSICAL EXAMINATION

Examination of patients with USA is often unremarkable. With more severe infarction and extensive myocardial injury, signs of autonomic activation (pallor, sweating, agitation, clamminess) as well as heart failure and even shock may be apparent. Pericardial friction rubs occur frequently after MI but are usually transient.

LV failure is associated with a higher mortality. Signs include gallop rhythm, tachycardia, tachypnoea and basal crackles. A fourth heart sound is often heard, but a third heart sound usually indicates a large infarction with extensive muscle damage. A systolic murmur may be present and may be transient or persistent. These murmurs can have prognostic significance and usually result from mitral regurgitation, due to either papillary muscle dysfunction or LV dilatation.

Cardiogenic shock, hypotension, oliguria and other features of low cardiac output are associated with particularly poor outcome. Shock may be present without hypotension ⁶ and may develop many hours after onset of symptoms. Right ventricle (RV) infarction results in hypotension and marked elevation of the jugular venous pressure (also seen with major LV dysfunction, usually in association with marked pulmonary venous congestion).

Conditions with similar presentations that do not benefit from thrombolysis are:

• pericarditis (auscultate for pericardial rub)

• aortic dissection (arterial pulses are compared; review chest X-ray if concerned)

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

• These are more sensitive indicators than CK and its CK-MB isomer. Up to 20–40% of patients with ACS but normal CK-MB may have elevated cTn levels.

• There is a strong correlation between troponin level, intracoronary thrombus and amount of threatened or ischaemic myocardium.

• Identify patients who will derive benefit from therapies such as low-molecular-weight heparins (LMWHs), glycoprotein inhibitors (GPIs) and early PCI.

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

TROPONINS IN CRITICAL ILLNESS

Cardiac-specific troponins are frequently elevated in critical illness, including but not confined to sepsis, pulmonary embolus and renal insufficiency.¹³ It is likely that they are of cardiac origin and are indicative of myocardial injury. Their elevation does correspond with adverse outcomes. Most will not be due to ‘unstable plaque’, however, and the role of standard NSTEMI therapies is uncertain. Clinical context is necessary to decide those likely to have significant underlying CAD that may require acute or subsequent investigation.²

Please also see the latest information at the end of the chapter.

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:

• assess infarct size, especially if thrombolysis has interfered with biomarker measurement

• diagnose RV infarction and infarct extension

• assist management by bedside assessment of LV function

• diagnose specific complications, for example, mitral regurgitation, pericardial effusion, mural thrombus and myocardial rupture, including ventricular septal defect

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:

• submaximal stress testing (to a heart rate of 120 beats/min), predischarge, upon patients with an uncomplicated course

• maximal symptom-limited stress test 3–6 weeks postinfarction

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:

• refractory angina with ischaemic ECG changes

• ischaemia associated with haemodynamic instability or arrhythmia

• recurrent ST-segment change with elevated cTn levels

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