Biomarkers in the emergency workup of chest pain: Uses, limitations, and future
ABSTRACTWhen patients present with chest pain, their levels of cardiac biomarkers are only one piece of the clinical picture, albeit an important one. Together with the history, physical examination, and electrocardiography (ECG), these levels help estimate the probability that the patient is experiencing an acute coronary syndrome and will have an adverse clinical outcome.
KEY POINTS
- Biomarkers of cardiac necrosis, particularly troponins I and T, can aid in risk assessment, but one must pay close attention to the underlying clinical context.
- Stable patients at low risk with no evidence of ischemia on initial assessment can be admitted to a chest pain unit for observation with serial biomarker testing and ECG.
- Highly sensitive troponin assays can improve the early diagnosis of acute myocardial infarction, but how best to use them is not yet defined.
- Biomarkers, used alone or in combination, have the potential to complement or replace stress testing, permitting more timely, accurate, and cost-effective diagnosis and earlier discharge of patients at low risk.
- Newer markers such as brain-type natriuretic peptide, cystatin C, and ischemia-modified albumin have shown promise but need to be thoroughly evaluated.
BRAIN-TYPE NATRIURETIC PEPTIDE
BNP is a 32-amino-acid natriuretic peptide that is released from myocytes. The amount released depends on wall stress brought on by heart failure, ischemic heart disease, or other conditions.
In a study of the diagnostic utility of BNP in the workup of acute chest pain, Haaf et al40 found that BNP levels at presentation were significantly higher in patients with acute MI than in patients with other diagnoses. However, the diagnostic accuracy of BNP was lower than that of cardiac troponin T at presentation, though its independent predictive value for all-cause mortality was more accurate than that of troponin T.
Elevation of the BNP 41 or the N-terminal pro-BNP 42,43 level was shown to also provide unique prognostic information in patients with suspected and confirmed acute coronary syndrome and was associated with higher rates of short-term and long-term mortality. Therefore, BNP appears useful for the prognosis but not the diagnosis of acute coronary syndromes.
CYSTATIN C
The protein cystatin C, widely used as a biomarker for kidney disease, has more recently been touted as a prognostic marker in acute coronary syndromes.
Jernberg et al44 reported that, in patients with a suspected or confirmed acute coronary syndrome, a single measurement of cystatin C significantly improved the early stratification of risk.44 Specifically, the cystatin C level was independently associated with mortality risk but not with the risk of subsequent MI.
In another study,45 the cystatin C concentration independently predicted the risk of cardiovascular death or MI in non-ST-segment elevation acute coronary syndrome. However, the additive predictive value of cystatin C in these patients was found to be small when clinical risk factors and biomarkers of MI were used in the prediction model. Therefore, cystatin C may predict global risk but does not appear to be useful in diagnosing MI.
ISCHEMIA-MODIFIED ALBUMIN
A major limitation of troponin is that it cannot detect reversible myocardial ischemia in the absence of cardiac necrosis, making stress testing necessary to unmask potential reversible ischemia.
Ischemia-modified albumin has been proposed as a means of detecting cardiac ischemia even if necrosis is absent. It is a product of the N-terminus alteration of albumin caused by myocardial ischemia, which reduces the ability of cobalt to bind to albumin and can be detected with the albumin cobalt binding test. This marker might have a high negative predictive value, ruling out acute coronary syndromes in conditions of low pretest probability with negative necrosis markers and ECG.13,46
Although ischemia-modified albumin does show promise, doubt remains as to its validity as a biomarker, as its mechanism of generation is not known. Some have suggested that it is in fact a marker of oxidative stress.47
PANELS OF MARKERS
The individual biomarkers we have discussed here have advantages and limitations in the emergency workup of chest pain. The concept of using a multimarker panel has been raised as a way of amplifying the positive attributes of individual biomarkers and compensating for their shortcomings.
Sabatine et al48 tested this approach in patients with acute coronary syndromes who were at high risk of an adverse outcome. When patients were categorized at presentation on the basis of the number of elevated biomarkers such as cardiac troponin I, C-reactive protein, and BNP, the risk of death nearly doubled with each additional biomarker that was elevated.
The relationship was similar for the end points of MI, heart failure, and the composite at 30 days and 10 months. In a cohort of 1,635 patients, the number of elevated biomarkers remained a predictor of the composite end point after adjustment for known clinical predictors. The risk of death, MI, or heart failure by 6 months was 2.1 times higher in patients with one elevated biomarker, 3.1 times higher in those with two, and 3.7 times higher in those with three.
The authors concluded that a multimarker strategy that categorizes patients on the basis of the number of elevated biomarkers at presentation allows risk-stratification of short- and long-term cardiac events.
Tello-Montoliu et al49 tested this idea in patients with non-ST-segment elevation acute coronary syndromes using a panel consisting of cardiac troponin T, C-reactive protein, N-terminal pro-BNP, and fibrin D-dimer. The risk of a major event (death, new acute coronary syndrome, revascularization, or heart failure) at 6 months was associated with abnormal biomarker levels, especially with the presence of three positive biomarkers, even after adjustment for clinical characteristics and ECG findings.
van der Zee et al43 showed that a positive biomarker panel consisting of C-reactive protein and N-terminal pro-BNP identified patients with chest pain and a normal or nondiagnostic ECG who have a high long-term risk of cardiovascular death.
Glaser et al50 evaluated the combination of cardiac troponin I, BNP, homocysteine, C-reactive protein, placental growth factor, myeloperoxidase, choline, soluble CD40 ligand, ischemia-modified albumin, and lipoprotein-associated phospholipase A2 in patients with a suspected acute coronary syndrome. The combination of BNP, placental growth factor, and estimated glomerular filtration rate was the most accurate predictor of major adverse cardiovascular events compared with any other biomarker or clinical factor. With appropriate cutoff values, the negative predictive value for a major adverse cardiovascular event at 1 year was as high as 99.1%.
This study highlighted the importance of combining biomarkers, showing that with a negative predictive value of 97% for 30-day events, the combination of placental growth factor, BNP, and cardiac troponin I may help surmount the delay from symptom onset to cardiac troponin increase, thus permitting a more timely diagnosis and safe discharge within 12 hours.
Comment. These studies raise the promise that panels of biomarkers can be used in patients deemed to be at low risk after clinical assessment and troponin evaluation to enable them to be safely discharged early and to obviate the need for stress testing.
If we assume that unstable cardiac disease requiring hospitalization accounts for 35% of patients with chest pain, a hypothetical panel of biomarkers with a sensitivity and specificity of 95% for adverse cardiac outcomes would have a positive predictive value of 91% and a negative predictive value of 97%. The negative likelihood ratio of this hypothetical biomarker panel would be 0.05, while the positive likelihood ratio would be 19. This performance level means that in patients with a pretest probability less than 50%, the posttest probability can be reduced to below 10%, so that such patients can be safely discharged without further hospital evaluation.
Conversely, a positive test result in patients with pretest probability of 30% or greater raises the posttest probability to nearly 90%, meaning that such patients should be considered for aggressive intervention without the need for stress testing.
RETURN TO OUR SCENARIOS
Chest pain remains a nonspecific complaint, and the interpretation of biomarkers to find the cause presents clinicians with challenges, as illustrated by the cases introduced at the beginning of this article.
The cardiac troponin I elevation in scenario 1 led to an initial diagnosis of unstable angina. However, coronary angiography showed lesion-free coronary arteries, thus excluding ischemic heart disease. When other diseases that could cause elevated cardiac troponin I were considered and investigated with further diagnostic tests such as D-dimer, pulmonary embolism became the new working diagnosis, and this was confirmed by CT angiography.
Similarly, given the laboratory values for the patient in scenario 2, the condition could have been mistaken for an acute coronary syndrome. However, the absence of evidence on ECG to support this diagnosis would indicate an erroneously elevated biomarker secondary to his background of chronic renal insufficiency.
