A 51-year-old woman with a history of mild hypertension and mild hyperlipidemia had presented with a 2-h episode of substernal chest discomfort for the first time. She was receiving a statin but refused treatment for hypertension. She was an avid runner and had never had chest discomfort previously. The discomfort occurred at rest and radiated to her arms and her neck. Her electrocardiogram (ECG)3 revealed minor ST-segment and T-wave changes in the inferior and lateral leads. Her initial cardiac troponin T (cTnT) concentration was 0.04 μg/L (99th-percentile upper reference limit, <0.01 μg/L) but increased to 0.32 μg/L and then to 0.76 μg/L. An emergent coronary angiogram was interpreted as normal with the exception of slow flow in the circumflex coronary artery. An echocardiogram was normal.
A 62-year-old woman was referred for evaluation of atypical chest pain and an equivocal stress test result. She had a history of hypertension and smoking for >25 years. Her chest discomfort was mild and radiated to the right shoulder. It occurred at rest and during exercise but had not changed in intensity or duration for >2 months. Her ECG was normal, and the cTnT concentration measured with the fourth-generation assay on the day of a computed tomography (CT) angiography evaluation was <0.01 μg/L (99th-percentile upper reference limit, <0.01 μg/L). A cTnT concentration measured with a high-sensitivity cTnT (hs-cTnT) assay of the same sample was mildly increased (15 ng/L; 99th-percentile value for women, 10 ng/L).
QUESTIONS TO CONSIDER
How should acute myocardial infarction (AMI) be diagnosed according to the “universal MI” definition?
Define the 2 subtypes of “spontaneous” MI.
What additional testing might be performed for each patient?
What change in cardiac troponin should be considered clinically important?
Cardiac troponin is the preferred biomarker for the diagnosis of myocardial necrosis because it is the most sensitive and specific biochemical marker. Consequently, practice guidelines and the Joint ESC/ACCF/AHA/WHF Task Force recommendations have mandated that cardiac troponins are the biochemical gold standard for the diagnosis of myocardial necrosis (1). According to the “universal MI” definition, AMI should be diagnosed in the presence of an increasing and/or decreasing pattern of cardiac troponin, with at least 1 value above the 99th percentile of a healthy reference population if there are symptoms suggestive of myocardial ischemia, or ECG changes indicative of ischemia, or imaging evidence of new loss of viable myocardium or new wall-motion abnormality.
Several AMI subtypes have been defined (1). Spontaneous AMI related to a primary coronary event such as plaque erosion or rupture, fissuring, or dissection is referred to as a type 1 AMI. An AMI secondary to ischemia owing to an imbalance between oxygen demand and supply (due, for example, to endothelial dysfunction, frank coronary spasm, anemia, hypertension, or hypotension) is a type 2 AMI.
Typically, coronary angiography reveals a substantial coronary stenosis in type 1 AMI, whereas a recognizable culprit lesion may be absent in type 2 AMI (1–4), as in our first case. As this case indicates, a normal or near-normal coronary angiography result cannot be used as a gold standard for AMI; clinical judgment and at times additional evaluations are necessary. In many patients with type 2 AMI, however, fixed and apparently stable coronary artery disease may be present (1). Discrimination between type 1 and type 2 disease is challenging. Frequently, the best that can be done is to adjudicate these types retrospectively by integrating the clinical presentation, laboratory findings, and imaging results.
The introduction of more-sensitive (high-sensitivity) cardiac troponin assays has the advantage of detecting MI earlier and identifying more cases of AMI, usually with decreasing diagnoses of unstable angina (5, 6). It is now clear that clinical specificity for AMI decreases as assay sensitivity increases (7). Type 2 AMIs are believed to be associated with lower cardiac troponin concentrations, on average. Thus, it is likely that the relative proportion of type 2 AMIs will increase as well. The clinical challenge is to discriminate patients with acute coronary syndrome in need of aggressive anticoagulation therapy, glycoprotein IIb/IIIa antiplatelet agents, and an early invasive strategy (including type 1 AMI patients) from patients with type 2 AMI, who may not need such intervention, and from the many other disease entities that can cause an increased cTnT value.
The patient in case 1 (who had a type 2 AMI) exemplifies this dilemma, which is likely to become important as assay sensitivity increases. Because the patient's clinical presentation was convincing, an MRI study was obtained. The results documented a small area, 3% of her left ventricle, of delayed hyperenhancement in the subendocardial inferolateral wall that suggested infarction (Fig. 1). That is one reasonable way to approach such a patient. Therefore, she was treated appropriately for a non–ST-segment elevation MI (non-STEMI) with statins, an angiotensin-converting enzyme inhibitor, and β-blockers. This woman's presentation is consistent with several series that have documented that patients presenting with a possible AMI but who have normal or near normal coronary arteries can have a pattern of delayed subendocardial hyperenhancement on MRI suggestive of AMI (2, 3). The vast majority of such patients are women, who are known to have less severe coronary artery disease and likely more endothelial dysfunction. Ong et al. have reported that up to 30% of patients who present with acute coronary syndrome do not have a recognizable culprit lesion but that many recapitulate their chest pain syndrome in response to acetylcholine (4), suggesting an endothelial abnormality. These individuals have a favorable prognosis compared with patients with type 1 AMI (4). The use of acetylcholine in this situation may increase in time, but this approach is not standard at present. The increasing frequency of type 2 AMI may be the reason why a recent study that used an hs-cTnT assay failed to show any prognostic significance for acute troponin increases at 30 days follow-up (6), whereas so many other studies that used less-sensitive assays have shown robust prognostic significance at that time point. This explanation may also provide a link to observations that when an insensitive cTnT assay was used, women with a clinical diagnosis of unstable angina were harmed by an invasive strategy. By definition, a diagnosis of unstable angina means that troponin was not increased. With the advent of high-sensitivity cardiac troponin assays, these patients may now be found to have increases, and it may be important to attempt to distinguish this group without severe coronary disease before intervention, because these patients may be the same group that seemed to experience adverse consequences in a clinical trial that used an invasive strategy.
The other disease entity that is a mimic in this area and can be readily unmasked with MRI is myocarditis. Myocarditis can present like STEMI. In one study, nearly 50% of patients with possible AMI and normal coronary arteries had the MRI signature of myocarditis (3). Fulminant myocarditis is the only entity other than type 1 AMI that can cause marked increases in cardiac troponin. Furthermore, this disease can present in a variety of ways, both acutely and chronically, and it can involve only part of the myocardium. Some etiologies can evoke coronary vasospasm.
Type 2 AMIs may also occur when there is fixed coronary artery disease and some alteration to the oxygen supply–demand balance, such as tachycardia, hypertension, or hypotension (1). Many acutely ill patients and postoperative patients experience this type of AMI; in general, their prognoses are adverse (1). It is not at all clear that such patients require aggressive intervention. That said, it might be difficult to distinguish this type of patient from one with a plaque-rupture event for which such therapy would be helpful.
NON-AMI RELEASE OF CARDIAC TROPONIN
Troponin can be released after irreversible myocardial damage via a variety of ischemic and nonischemic mechanisms. Thus, an increased cardiac troponin concentration is not synonymous with AMI. Some patients with stable coronary artery disease, chronic renal failure, chronic heart failure, or severe left ventricular hypertrophy can show chronic increases in cardiac troponin that may or may not exhibit short-term changes (8). Patients without a changing pattern should not be diagnosed as having experienced an AMI or another acute reason for the increase. That was the situation in case 2 after serial measurements with the hs-cTnT assay showed no change. CT angiographic imaging of the coronary arteries can be performed if the technology is available and has been validated for this use. If CT angiography is not an option, one could proceed directly to coronary angiography. In case 2, 256-row coronary CT angiography revealed 3-vessel coronary artery disease with noncalcified (soft) plaque in the middle portion of the left anterior descending coronary artery (Fig. 2) and several calcified, soft, and mixed lesions in other vessels. The patient was given a diagnosis of stable coronary artery disease. Because of the severity of the lesion, she underwent coronary angiography and successful percutaneous coronary intervention with stenting of the lesion in the left anterior descending coronary artery.
The ability of an increased cardiac troponin value to detect patients at risk with stable coronary artery disease has previously been shown. Such increases in this group are likely to be even more frequent with the novel high-sensitivity cardiac troponin assays, as in our case 2. Recent data suggest that perhaps these increases are not chronic but acute intermittent ones, because the plaques that occur in patients with such increases appear to be in an active state and thus perhaps vulnerable to rupture or thrombosis (9). The extent of disease can increasingly be probed with the use of CT angiography, thereby avoiding the need for invasive assessment (10).
Not only can stable coronary artery disease evoke increases in cardiac troponin, but any structural heart disease can also evoke such increases. Whether symptomatic or asymptomatic, these patients are at an accentuated long-term risk (1).
Of note is that some patients without features of myocardial ischemia (such as those with myocarditis, sepsis, pulmonary embolism, exposure to toxic agents, and/or mechanical trauma) can manifest an increasing and/or decreasing pattern of cardiac troponin concentrations. Unfortunately, the metrics for the magnitude of an increase and/or decrease from a normal baseline value have not been well defined and likely are assay dependent. It is clear that the changes are marked, as with most overt events, but the best metric to detect unstable disease may be to use the minimal δ to maximize the sensitivity for detecting acute events. A 20% relative change had been proposed to identify acute changes in patients with chronic small increases in cardiac troponin, such as in patients with end-stage renal failure. It is unlikely, however, that this change criterion will be applicable to patients with acute coronary syndrome, who may start from normal concentrations.
POINTS TO REMEMBER
Cardiac troponin is the preferred biochemical standard for diagnosis of MI because it is the most sensitive and cardiospecific marker.
According to the “universal MI” definition, AMI should be diagnosed in the presence of an increasing and/or decreasing pattern of cardiac troponin concentrations, with at least 1 value above the 99th percentile of a healthy reference population if there are symptoms suggestive of myocardial ischemia, or ECG changes indicative of ischemia, or imaging evidence of new loss of viable myocardium or new wall-motion abnormality.
More-sensitive cardiac troponin assays, including some contemporary and novel high-sensitivity cardiac troponin assays, now detect troponin in many healthy individuals.
Use of a recommended diagnostic cutoff at the 99th percentile of a healthy reference population provides earlier and more accurate diagnosis of MI, is associated with adverse short- and intermediate-term outcomes, and increases not only the prevalence of non-STEMI but also the prevalence of troponin increases not due to myocardial ischemia. Different cutoff values may be needed for men and women, and for diabetic and elderly individuals, who often manifest a different distribution of cardiac troponin concentrations.
An increased cardiac troponin value is not synonymous with MI but occurs in numerous acute and chronic conditions associated with myocardial damage. Cardiac troponin results should not be interpreted in isolation but within the extant clinical context and on the basis of changes observed in serial samples.
The proper metric to define an increase and/or decrease in troponin has not been fully determined—yet. At present, a serial change of at least 20% from presentation in cases with a baseline increase above the 99th percentile value should be applied (1). More data are needed to define how to best determine an increasing and/or decreasing pattern when baseline values are not increased.
↵3 Nonstandard abbreviations:
- cardiac troponin T;
- computer tomographic;
- high-sensitivity cTnT (assay);
- acute myocardial infarction;
- ST-segment elevation MI.
Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.
Authors' Disclosures or Potential Conflicts of Interest: Upon manuscript submission, all authors completed the Disclosures of Potential Conflict of Interest form. Potential conflicts of interest:
Employment or Leadership: None declared.
Consultant or Advisory Role: E. Giannitsis, Roche Diagnostics; A.S. Jaffe, Alere, Critical Diagnostics, Radiometer, Beckman Coulter, Pfizer, and Siemens. A.S. Jaffe is or has been a consultant for most of the major diagnostics companies.
Stock Ownership: None declared.
Honoraria: H.A. Katus, AstraZeneca, Bayer, Daiichi-Sankyo, Novartis, and Roche; E. Giannitsis, Roche Diagnostics, and AstraZeneca; A.S. Jaffe, Roche and Abbott Laboratories.
Research Funding: E. Giannitsis, Roche Diagnostics.
Expert Testimony: None declared.
Other Remuneration: H.A. Katus developed the cTnT assay and holds a patent jointly with Roche Diagnostics.
- Received for publication July 22, 2011.
- Accepted for publication October 7, 2011.
- © 2012 The American Association for Clinical Chemistry