**3. Diagnostic approach**

#### **3.1. Clinical presentation**

Patients presenting with chest pain or discomfort with suspected ACS require urgent evaluation. The clinical spectrum of NSTEMI may range from patients free of symptoms at presentation to individuals with ongoing ischemia, electrical or hemodynamic instability due to large myocardium in jeopardy or cardiac arrest secondary to malignant ventricular ischemia. Therefore, it is essential to establish if the patient has ACS and if so, what is the likelihood the patient will have adverse clinical event [1]. Physicians will need to stratify the patients according to their risk status and according to the initial risk assessment to choose an appropriate management strategy. The initial risk assessment includes the history, examination, ECG, and cardiac biomarkers [1, 23].

#### **3.2. History and examination**

to the advent of more sensitive assays for myocardial injury, earlier pharmacotherapy, and

NSTEMI is a result of an acute imbalance between myocardial oxygen demand and supply, most commonly due to a reduction in myocardial perfusion. Type 1 MI is most commonly caused by a non-occlusive thrombus that develops in a disrupted atherosclerotic plaque, and leads to non-occlusive or near-complete thrombosis of a vessel supplying the myocardium. Plaque rupture usually occurs at the weakest and thinnest part of the atherosclerotic cap (often at the shoulder region). Ruptured plaques contain large numbers of inflammatory cells including monocytes, macrophages, and T lymphocytes [19, 20]. Although one third of occlusions occur at a site with the greatest stenosis, most (66–78%) arise from lesions with <50% stenosis, and <5% arise from lesions exhibiting >70% stenosis [19]. It is thought that the lack of ST elevation is because the infarct does not involve the full thickness of the myocardium (not

a transmural infarction). The severity of myocardial damage in NSTEMI depends on:

Classically it is thought that NSTEMI patients ultimately have a diagnosis of a non-Q-wave MI; however, 25% of patients with NSTEMI and elevated biomarkers go on to develop Q-wave MI in the weeks to follow [21]. In addition, approximately 25% of patients with a diagnosis of

NSTEMI may also be caused by other mechanisms, such as dynamic obstruction (i.e., focal coronary artery spasm or Prinzmetal angina), severe progressive atherosclerosis, restenosis following percutaneous coronary intervention, recreational drug use (e.g., cocaine or other stimulants), arterial inflammation (i.e., vasculitis), or extrinsic causes leading to myocardial

Patients presenting with chest pain or discomfort with suspected ACS require urgent evaluation. The clinical spectrum of NSTEMI may range from patients free of symptoms at presentation to individuals with ongoing ischemia, electrical or hemodynamic instability due to large myocardium

NSTEMI have a 100% occlusion of the affected artery on coronary angiography [22].

supply–demand mismatch (such as hypotension, hypovolemia, or hypoxia) [1].

reperfusion (and prevention) of STEMI [13, 18].

• Duration of ischemia and time to reperfusion

• Presence of collateral blood flow to the affected region

• Presence of other comorbidities (i.e., diabetes, renal failure, or HTN).

• Extent of underlying atherosclerosis

• Diameter of affected coronary vessel

• Degree of occlusion

**3. Diagnostic approach**

**3.1. Clinical presentation**

**2.2. Pathophysiology**

64 Myocardial Infarction

Angina pectoris is a kind of pain described as a sensation of tightness, heaviness, aching, burning, pressure, or squeezing typically localized at the retrosternal region. The pain can often radiate to the left arm but may also radiate to the lower jaw, neck, both arms, back, and epigastrium. It is associated with exertion or emotional stress and relieved by rest or administration of sublingual nitroglycerin [1].

In ACS patients other symptoms including sweating, nausea, abdominal pain, dyspnea and syncope may be present. Atypical presentations are also possible and characterized by epigastric pain, indigestion-like symptoms and isolated dyspnea. Atypical complaints are more often observed in the elderly, in women and in patients with diabetes mellitus, chronic renal disease or dementia [24, 25]. The relief of pain at rest increase the probability of myocardial ischemia while the relief of symptoms after nitrates administration is not specific for angina pectoris [25]. In patients presenting with suspected MI to the emergency department, overall, the diagnostic performance of chest pain characteristics for MI is limited [25].

Risk factors increase the likelihood of NSTEMI include: Older age, male gender, family history of CAD, diabetes, hyperlipidemia, hypertension, renal insufficiency, previous manifestation of CAD as well as peripheral or carotid artery disease.

Physical examination is frequently unremarkable in patients with suspected NSTEMI but may reveal HTN or hypotension, the presence of third and fourth heart sounds, and paradoxical splitting of the second heart sound. Cardiac auscultation may reveal a systolic murmur due to ischemic mitral regurgitation, which is associated with poor prognosis [26] or a mechanical complication (i.e. papillary muscle rupture or ventricular septal defect) of a subacute and possibly undetected MI. Signs of heart failure (raised jugular venous pressure, bilateral crepitation on auscultation of the lungs) or cardiogenic shock may also be present, and these signify a worse prognosis.

#### **3.3. Initial tests**

#### *3.3.1. Electrocardiogram*

Resting 12-lead ECG is the first diagnostic test for patients with chest pain and should be performed and interpreted within the first 10 min of the initial admission to the hospital [27]. ECG is critical for the diagnosis of STEMI as the cause for the chest pain, this has a tremendous therapeutic implication for the patient.

While the ECG in the setting of NSTEMI may be normal in more than one-third of patients, a serial ECG at 15- to 30-min intervals should be performed to detect the developing abnormalities.

• Brain natriuretic peptide (BNP) and N-terminal pro-BNP (NT-pro-BNP): measurement of BNP or NT-pro-BNP may be considered to supplement assessment of global risk in patients with suspected ACS, particularly cardiogenic shock associated with MI type 1 [1]. • Lipid profile: this test is indicated in the first 24 h of admission to the hospital to assess for

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Clinical assessment,12-lead ECG and biomarkers are crucial for the diagnosis, risk stratification and treatment of patients with suspected NSTEMI. Measurement, preferably, high-sensitivity cardiac troponin, is mandatory in all patients with suspected NSTEMI [7–9]. Cardiac troponins are more sensitive and specific markers of cardiomyocyte injury than creatine kinase (CK), its MB isoenzyme (CK-MB) and myoglobin. In patients with suspected myocardial ischemia, a dynamic elevation of cardiac troponin above the 99th percentile of healthy individuals indicates MI. Cardiac troponin levels rise rapidly (i.e. usually within 1 h if using high-sensitivity assays) after symptom onset and remain elevated for several days [8, 9].

The use of high-sensitivity assays, has shortened the time interval to the second cardiac troponin, reduced substantially the delay to diagnosis, translating into shorter stays in the emergency department and lower costs [6–9, 32–35]. In patients presenting very early, the second cardiac troponin level should be obtained at 3 h, due to the time dependency of troponin release; serial cardiac troponin testing should be pursued if the clinical suspicion remains high or whenever the patient develops recurrent chest pain [36, 37]. The negative predictive value for MI in patients assigned 'rule-out 'exceeded 98% [35–41] used in conjunction with clinical and ECG findings. The positive predictive value for MI in those patients meeting the 'rule-in' criteria was 75–80%.

Transthoracic echocardiography is useful to identify abnormalities suggestive of myocardial ischemia or necrosis (i.e. segmental hypokinesia or akinesia). Strain and strain rate imaging can detect subtle reduced regional function in the absence of overt wall motion abnormalities, which improve the diagnostic and prognostic value of conventional echocardiography [42, 43]. Evaluation of left ventricular systolic function by echocardiography, at the indexed hospital admission, is important to estimate prognosis. Echocardiography can help in discrimination of other pathologies including acute aortic dissection, pericardial effusion, aortic valve stenosis, hypertrophic cardiomyopathy or right ventricular dilatation associated with acute pulmonary embolism. Echocardiography is the diagnostic tool of choice for patients

In patients without ischemic changes on 12-lead ECGs and negative cardiac troponins (preferably high-sensitivity) who are free of chest pain for several hours, stress imaging can be performed during admission or shortly after discharge [1, 45, 46]. The sensitivity and specificity of these tests increase when combined with either nuclear imaging to look for myocardial

with hemodynamic instability of suspected cardiac origin [44].

lipid abnormalities and therefore the need for any lipid-lowering therapy.

*3.3.3. Biomarkers*

*3.3.4. Noninvasive imaging*

*3.3.5. Functional stress testing*

**Figure 1.** ECG showing ST depression in the inferolateral leads suggestive of inferior-lateral ischemia.

Classic ECG findings of ischemia in NSTEMI include horizontal or down sloping ST depression >0.5 mm and/or symmetrically inverted T waves >2.0 mm (**Figure 1**) [2, 28]. Standard leads may be inconclusive in some patients and additional leads may be necessary (e.g. in case of left circumflex artery occlusion or right ventricular MI may be detected only in V7–V9 and V3R and V4R, respectively) [8]. If it is possible a comparison with previous ECG's may be valuable. Diffuse precordial ST depression more pronounced in leads V4–V6 may indicate a culprit lesion located in the mid left anterior descending coronary artery, while changes more evident in leads V2–V3 may be more suggestive of a culprit lesion located in the left circumflex artery [29]. Diffuse ST depression including both precordial and extremity leads associated with ST-elevation ≥1 mm in lead aVR may indicate either left main coronary artery as the culprit lesion or proximal occlusion of the left anterior descending coronary artery in the presence of severe three-vessel CAD [30, 31].

#### *3.3.2. Blood tests*


#### *3.3.3. Biomarkers*

Classic ECG findings of ischemia in NSTEMI include horizontal or down sloping ST depression >0.5 mm and/or symmetrically inverted T waves >2.0 mm (**Figure 1**) [2, 28]. Standard leads may be inconclusive in some patients and additional leads may be necessary (e.g. in case of left circumflex artery occlusion or right ventricular MI may be detected only in V7–V9 and V3R and V4R, respectively) [8]. If it is possible a comparison with previous ECG's may be valuable. Diffuse precordial ST depression more pronounced in leads V4–V6 may indicate a culprit lesion located in the mid left anterior descending coronary artery, while changes more evident in leads V2–V3 may be more suggestive of a culprit lesion located in the left circumflex artery [29]. Diffuse ST depression including both precordial and extremity leads associated with ST-elevation ≥1 mm in lead aVR may indicate either left main coronary artery as the culprit lesion or proximal occlusion of the left anterior descending coronary artery in

**Figure 1.** ECG showing ST depression in the inferolateral leads suggestive of inferior-lateral ischemia.

• CBC: hemoglobin and hematocrit measurements may help to evaluate a secondary cause of NSTEMI (e.g., acute blood loss, anemia) and to evaluate thrombocytopenia to estimate

• BUN and serum creatinine: creatinine clearance should be estimated in NSTEMI patients and the doses of renally cleared drugs should be adjusted appropriately. In chronic kidney disease patients undergoing angiography, iso-osmolar contrast agents may be preferred

• Serum electrolytes: electrolyte derangements may predispose to cardiac arrhythmias.

• Liver function tests: useful if treatment with drugs that undergo hepatic metabolism is

the presence of severe three-vessel CAD [30, 31].

*3.3.2. Blood tests*

66 Myocardial Infarction

[1, 15].

considered.

risk of bleeding.

Clinical assessment,12-lead ECG and biomarkers are crucial for the diagnosis, risk stratification and treatment of patients with suspected NSTEMI. Measurement, preferably, high-sensitivity cardiac troponin, is mandatory in all patients with suspected NSTEMI [7–9]. Cardiac troponins are more sensitive and specific markers of cardiomyocyte injury than creatine kinase (CK), its MB isoenzyme (CK-MB) and myoglobin. In patients with suspected myocardial ischemia, a dynamic elevation of cardiac troponin above the 99th percentile of healthy individuals indicates MI. Cardiac troponin levels rise rapidly (i.e. usually within 1 h if using high-sensitivity assays) after symptom onset and remain elevated for several days [8, 9].

The use of high-sensitivity assays, has shortened the time interval to the second cardiac troponin, reduced substantially the delay to diagnosis, translating into shorter stays in the emergency department and lower costs [6–9, 32–35]. In patients presenting very early, the second cardiac troponin level should be obtained at 3 h, due to the time dependency of troponin release; serial cardiac troponin testing should be pursued if the clinical suspicion remains high or whenever the patient develops recurrent chest pain [36, 37]. The negative predictive value for MI in patients assigned 'rule-out 'exceeded 98% [35–41] used in conjunction with clinical and ECG findings. The positive predictive value for MI in those patients meeting the 'rule-in' criteria was 75–80%.

#### *3.3.4. Noninvasive imaging*

Transthoracic echocardiography is useful to identify abnormalities suggestive of myocardial ischemia or necrosis (i.e. segmental hypokinesia or akinesia). Strain and strain rate imaging can detect subtle reduced regional function in the absence of overt wall motion abnormalities, which improve the diagnostic and prognostic value of conventional echocardiography [42, 43]. Evaluation of left ventricular systolic function by echocardiography, at the indexed hospital admission, is important to estimate prognosis. Echocardiography can help in discrimination of other pathologies including acute aortic dissection, pericardial effusion, aortic valve stenosis, hypertrophic cardiomyopathy or right ventricular dilatation associated with acute pulmonary embolism. Echocardiography is the diagnostic tool of choice for patients with hemodynamic instability of suspected cardiac origin [44].

#### *3.3.5. Functional stress testing*

In patients without ischemic changes on 12-lead ECGs and negative cardiac troponins (preferably high-sensitivity) who are free of chest pain for several hours, stress imaging can be performed during admission or shortly after discharge [1, 45, 46]. The sensitivity and specificity of these tests increase when combined with either nuclear imaging to look for myocardial perfusion defects or echocardiography to assess wall motion abnormalities. Stress imaging is preferred over exercise ECG due to its greater diagnostic accuracy and superior prognostic value [47]. While studies have shown that normal exercise or pharmacological stress echocardiograms have high negative predictive value for ischemia and are associated with excellent patient outcomes ECG [48–50]. The addition of contrast to improve endocardial border detection and facilitate detection of ischemia [51].

To evaluate the extent of the CAD, a functional assessment using a submaximal exercise testing can be performed at 4 to 7 days after myocardial infarction, while symptom limited testing can be performed at 14 to 21 days post-myocardial infarction, when the patient has been free of active ischemic or heart failure symptoms [52].

#### *3.3.6. Cardiac magnetic resonance*

Cardiac magnetic resonance (CMR) can be used in the assessment of myocardial perfusion and wall motion abnormalities. Patients presenting with acute chest pain with a normal stress CMR have an excellent short and midterm prognosis [53]. CMR also permits detection of scar tissue (using late gadolinium enhancement) and can differentiate this from recent infarction (using T2-weighted imaging to delineate myocardial edema) [54, 55]. Moreover, CMR can facilitate the differential diagnosis between infarction and myocarditis or Takotsubo cardiomyopathy [56].

#### *3.3.7. Nuclear myocardial perfusion imaging*

Nuclear myocardial perfusion imaging has been shown to be useful for risk stratification in patients with acute chest pain suggestive for ACS. The presence of an area of myocardium that becomes deprived of perfusion during increased myocardial demand and reperfuses on stopping the activity on nuclear imaging stress tests is a reversible defect (**Figure 2**).

beneficial in the triage of low- to intermediate-risk patients presenting with acute chest pain to emergency departments without signs of ischemia on ECG and/or inconclusive cardiac troponins. At 6 months follow-up, there were no difference in the incidence of MI, post discharge emergency department visits or rehospitalizations, and no deaths in comparison to traditional management. Also, there were reduction in the cost and length of stay associated with MDCT [60, 62–65]. But there was an increase in the use of invasive angiography [65]. CCTA is not indicated for patients with high-risk features and it is not useful in patients with known CAD [66]. Other factors limiting CCTA include severe calcifications and tachycardia. CT imaging can effectively exclude other causes of acute chest pain that, if untreated, are associated with high mortality, namely pulmonary embolism, aortic dissection and tension pneumothorax [67].

**Figure 2.** Myocardial nuclear perfusion scan showing anterior, lateral and inferior reversible scan. Coronary angiogram

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ACS management requires continuous risk stratification for death or recurrent MI. Quantitative assessment of ischemic risk by means of scores is superior to the clinical assessment alone to further triage and assist in the selection of treatment options [1]. A number of risk scores exist which incorporate a number of variables, the GRACE risk score and the TIMI risk score are examples. The GRACE risk score provides the most accurate stratification of risk both on admission and at discharge [68, 69]. The GRACE 2.0 risk calculator provides a direct estimation, of mortality

**5. Risk assessment and outcomes**

confirmed three vessel disease.

Resting myocardial scintigraphy, can be helpful for the diagnosis of patients presenting with chest pain without ECG changes or elevated cardiac troponins [57]. Combined stress–rest imaging may further enhance assessment of ischemia, while a normal study is associated with excellent outcome [58, 59].
