A 67-year-old man with a history of type 2 diabetes mellitus (DM) and hypertension presents with chest pain that began the night before while watching television. The pain is midsternal, nonradiating, sharp, nonpleuritic, nonpositional, and 6 out of 10 in intensity. It has waxed and waned since onset. Physical activity has been minimal. Aside from mild shortness of breath, his review of systems is negative.

The patient has no history of chest pain or coronary artery disease (CAD). He takes aspirin 81 mg daily, metformin 500 mg twice daily, lisinopril 10 mg daily, and simvastatin 40 mg daily. His initial vital signs are as follows: temperature 37.6°F, blood pressure 153/94 mm Hg, heart rate 96 bpm, respiratory rate 17 breaths/min, and oxygen saturation 98% on room air. An electrocardiogram (ECG) shows sinus rhythm with a normal axis, right bundle branch block, normal ST segments, and flattened T waves in V₄-V₆, with no prior available ECG for comparison. A point-of-care troponin assay is negative.

What additional workup, if any, is required to establish a diagnosis, and what are the next best steps in management?

An acute coronary syndrome (ACS) occurs when a patient experiences the acute onset of myocardial ischemia. The ACS spectrum (Figure 8-1) is divided into the following:

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  ST-segment elevation myocardial infarction (STEMI), in which patients have a clinical picture consistent with myocardial ischemia and ST-segment elevations in 2 or more contiguous leads on the surface ECG. Biomarkers of myocardial necrosis, such as serum troponin, may not yet be detectable.

  
  
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  Non–ST-segment elevation myocardial infarction (NSTEMI), in which patients have elevated biomarkers consistent with myocardial infarction (MI) but do not meet STEMI criteria.

  
  
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  Unstable angina (UA), in which patients have chest pain characteristic of myocardial ischemia but negative biomarkers. Unlike chronic stable angina, the pain is either new or has become more severe, longer lasting, or provokable with minimal or no exertion.

Patients with chest pain can be rapidly assessed for STEMI; however, biomarkers of myocardial necrosis may not become positive until several hours after initial presentation. Thus, NSTEMI and UA are often indistinguishable early in the clinical course and are therefore grouped together as non–ST-segment elevation ACS (NSTEACS).

Each year in the United States, 635,000 patients have a first-time coronary event causing hospitalization or death, 155,000 patients have a clinically silent event, and 300,000 patients have a recurrent event.¹ The average age at presentation is 65 years for men and 72 years for women.

Data from the National Registry of Myocardial Infarction (NRMI) revealed important epidemiologic differences between STEMI and NSTEMI²:

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  From 1990 to 2006, the proportion of MIs classified as NSTEMI increased from 14.2% to 59.1% (Figure 8-2).

  
  
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  From 1998 to 2006, the proportion of ACS patients with measured troponin levels increased from 67.1% to 95.5%.

  
  
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  Patients with NSTEMI are, on average, 2 to 3 years older than patients with STEMI.

  
  
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  The proportion of female NSTEMI patients has been increasing (~40% in 2006), while the proportion of female STEMI patients has been stable (~33%-35%).

A separate analysis of more than 46,000 patients hospitalized for acute MI in a large hospital system from 1999 to 2008 found similar trends, with the proportion of STEMIs decreasing from 47.0% to 22.9%.³ The increase in the relative incidence of NSTEMI likely reflects the following:

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  Aging of the population and greater prevalence of CAD risk factors, such as DM, chronic kidney disease, and obesity

  
  
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  Wider use of therapies, such as aspirin and statins, that prevent progression of ACS to STEMI

  
  
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  Wider use of more sensitive troponin assays, which has shifted prevalence from UA to NSTEMI

Surprisingly, in the analysis of hospitalizations from 1999 to 2008, the 30-day mortality associated with NSTEMI decreased from 10.0% to 7.6%, whereas the mortality associated with STEMI did not change. This difference may reflect an increasing proportion of milder NSTEMIs detected using highly sensitive troponin assays. It may also reflect milder cases of ACS being shifted from STEMI to NSTEMI by the use of medications for primary and secondary prevention.

Finally, a single-center review of more than 4000 patients who underwent angiography for MI⁴ found that mortality is initially higher for STEMI but is higher for NSTEMI after 2 months (Figure 8-3). This review also noted that patients with NSTEMI are more likely than those with STEMI to have left main or triple-vessel disease.

In ambulatory patients, nearly all ACS events result from degeneration of atherosclerotic coronary plaque. The PROSPECT study⁵ used intravascular ultrasound to identify plaques most likely to cause ACS. Such plaques have:

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  Thin (<65 μm) fibrous caps overlying large necrotic cores (Figure 8-4)

  
  
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  A plaque burden (lumen size divided by vessel size) ≥70%

  
  
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  A minimal luminal area of ≤4.0 mm²

In most cases, the thin fibrous cap ruptures or erodes, initiating a sequence of events that culminates in vessel thrombosis.⁶ The cap is chronically weakened by local release of cytokines, which disrupt collagen synthesis, and metalloproteinases, which cause interstitial matrix breakdown. Rupture may be accelerated by episodes of high adrenergic tone, as increased heart rate and contractile force mechanically strain the plaque at its lateral attachments (“shoulders”).

Acute plaque disruption exposes blood to subendothelial von Willebrand factor (vWF) and collagen, which stimulate platelet binding via the glycoprotein (GP) Ib/Ix and GP Ia/IIa receptors (Figure 8-5), as well as to tissue factor, which activates the extrinsic coagulation cascade.

Bound platelets release thromboxane A₂ and adenosine diphosphate (ADP), which attach to platelet receptors in an autocrine and paracrine manner. Several ADP receptors are involved in this process, the most essential being P2Y₁₂. Platelet activation ensues, causing:

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  A flattened configuration, with the platelet lying more parallel to the vessel well

  
  
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  Expression of surface phosphatidylserine, which facilitates assembly of clotting complexes

  
  
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  Release of granules containing clotting factors, vWF, ADP, serotonin, and many other signaling molecules, which further promote coagulation and platelet activation

  
  
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  Conformational change of GP IIb/IIIa receptors to bind fibrinogen, which cross-links platelets (see Figure 8-5)

Meanwhile, progression of the coagulation cascade generates thrombin, which further activates platelets and cleaves fibrinogen to fibrin. Thromboxane promotes vasoconstriction, slowing blood flow and facilitating thrombosis. The final result is a fibrin- and platelet-rich plug lying within a constricted vessel that is partially or totally occluded (Figure 8-6).

The degree of occlusion generally determines the clinical presentation:

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  UA occurs when there is intermittent or partial occlusion.

  
  
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  NSTEMI occurs when there is subtotal occlusion or when there is total occlusion but the downstream myocardium has collateral perfusion.

  
  
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  STEMI occurs when there is total occlusion and the downstream myocardium has no collateral perfusion.

Less often, acute MI results from other causes, as reflected in the Universal Definition of Myocardial Infarction⁷ categories (Figure 8-7):

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  Type 1: An atherosclerotic plaque in a coronary artery acutely ruptures or erodes, as described above.

  
  
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  Type 2:

  
  
  
  
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    Coronary blood flow is acutely decreased through a mechanism other than plaque degeneration (eg, coronary vasospasm, embolus from intracardiac infection, or prosthetic valve thrombus); or

    
    
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    Myocardial oxygen demand is acutely increased (eg, tachyarrhythmia, anemia, sepsis, thyroid storm) but coronary blood flow cannot adequately increase, usually because of atherosclerosis that was clinically silent at baseline. This phenomenon is also termed “demand ischemia.”

  
  
  
  
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  Type 3: Death likely from MI, but there is no proof of myocardial necrosis (eg, biomarkers were not yet elevated or serum was not collected).

  
  
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  Type 4a: MI related to percutaneous coronary intervention (PCI).

  
  
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  Type 4b: MI related to stent thrombosis.

  
  
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  Type 5: MI related to coronary artery bypass grafting (CABG).

The predominant symptom of ACS is chest pain (Figure 8-8). The pain typically originates in the mid or left chest and can radiate to the jaw, neck, shoulder, proximal arm, and/or epigastrium. Typical pain is pressure-like, nonpleuritic, nonpositional, not reproducible with palpation, and worse with exertion; however, anginal pain often presents atypically, and a lack of classic symptoms does not exclude ACS.

Other symptoms may accompany or even occur in lieu of chest pain.

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  Nausea reflects afferent vagal tone, generally arising from the inferior cardiac wall.

  
  
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  Palpitations and diaphoresis reflect high adrenergic tone.

  
  
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  Dyspnea may reflect elevated filling pressures secondary to ventricular or valvular dysfunction.

In the NRMI dataset,⁸ patients with NSTEMI were less likely to report chest pain than patients with STEMI. Women, diabetics, and elderly patients are also less likely to report typical chest pain.

Physical examination findings are variable.

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  Tachycardia may occur secondary to increased adrenergic tone, or bradycardia may occur if there is ischemic disruption of the conduction system or high vagal tone (ie, from an inferior wall MI).

  
  
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  Hypertension may occur secondary to high adrenergic tone, whereas hypotension may occur if cardiac output is reduced by ventricular dysfunction or severe bradycardia.

  
  
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  Fever may occur from physiologic stress, even in the absence of infection.

  
  
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  Respiratory failure may occur from pulmonary edema. Acute heart failure may also cause an S₃ gallop and/or jugular venous distension.

Of note, patients with type II NSTEMI, or “demand ischemia,” may have a wide variety of signs and symptoms related to their underlying state (eg, sepsis, acute bleeding).

An ECG should be assessed within 10 minutes of presentation. In NSTEACS, the ECG lacks ST-segment elevations by definition and can even appear normal, but changes may include ST-segment depressions and T-wave inversions or flattening. Note that ST-segment depressions in the anterior leads may represent reciprocal changes from a posterior STEMI, which should be assessed using leads V₇-V₉. Likewise, deep, symmetric anterior T-wave inversions may represent significant proximal left anterior descending artery disease. Finally, patients with ongoing angina and a normal-appearing ECG should have serial ECGs (as ST changes can be transient), as well as V₇-V₉ leads, to assess for posterior MI, which can otherwise be electrically silent.

Once STEMI has been ruled out, serum troponin levels distinguish NSTEMI from UA. Troponin is present in skeletal and cardiac muscle.⁹ In the baseline state, troponin is bound to actin and tropomyosin in a configuration that prevents actin-myosin cross-linking. When calcium enters the cytosol, it binds to troponin and thereby induces a conformational change in tropomyosin that allows cross-linking. Troponin has 3 subunits: troponin I (TnI; binds myosin), troponin T (TnT; binds tropomyosin), and troponin C (TnC; binds calcium).

When myocyte cell death occurs, troponin enters the serum. Myocardial TnI and TnT can be distinguished from skeletal isoforms, and either can be used to diagnose MI when:

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  Levels exceed the 99th percentile of normal, and

  
  
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  Serial levels rise and fall, consistent with an acute injury

Levels should become elevated within 3 hours of myocardial ischemia (Figure 8-9). Therefore, if the patient’s symptoms began immediately prior to presentation and troponin levels are initially negative, repeat the levels after 3 to 6 hours.

Conditions other than myocardial ischemia (eg, myocarditis, transplant rejection, cardiac injury) can cause myocardial cell death and elevated troponin levels in the absence of an ACS. Likewise, troponins are renally cleared and may be chronically mildly elevated in patients with chronic kidney disease.

The first step in the management of NSTEACS is to determine the likely underlying pathophysiology. A patient with a type 2 MI secondary to demand ischemia should receive treatment for the underlying condition. A patient with type 1 MI, in contrast, should receive medications to arrest the thrombotic process and undergo invasive revascularization if appropriate.

The medications administered in NSTEACS address several domains (Figure 8-10): platelet activation and aggregation (aspirin, P2Y₁₂ inhibitors, GP IIb/IIIa inhibitors), coagulation (unfractionated heparin, low-molecular-weight heparins, bivalirudin), myocardial work and ischemia (β-blockers, nitrates), and lipid metabolism (statins).

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