Biomarkers in Acute Cardiovascular Disease
Jill Howie-Esquivel PhD, RN, NP Megan White RN, MS, ACNP
Journal of Cardiovascular NursingMarch/April 2008 Volume 23 Number 2Pages 124 - 131
Jill Howie-Esquivel, PhD, RN, NP Associate Clinical Professor and Nurse Practitioner, Department of Physiological Nursing, University of California, San Francisco.
Megan White, RN, MS, ACNP Nurse Practitioner Cardiology, Bluhm Cardiovascular Institute, Northwestern Memorial Hospital, Chicago, Illinois.
Corresponding author Jill Howie-Esquivel, PhD, RN, NP, School of Nursing, University of California, #2 Koret Way, Box 0610, San Francisco, CA 94143 (jill.howie-esquivel@nursing.ucsf.edu).
Keywords: biomarkers, BNP, troponin
Abstract
Cardiovascular disease today remains a formidable foe affecting 1 in 3 Americans. The emergence of cardiac biochemical markers has provided clinicians unique insight into the state of the myocardium. In fact, cardiac biomarkers now represent an essential criterion in the definition of acute myocardial infarction. There has been impressive development of efficient and reliable assays to detect biomarkers in the serum. Together with patient history and electrocardiographic analysis, the invaluable information gained from serum cardiac biomarkers supports diagnosis, therapy selection, and determination of prognosis. Biomarkers such as troponin and creatine kinase MB have received well-deserved attention for their ability to detect myocardial ischemia. Clinicians today use cardiac markers to identify ischemia as well as alternate clinical states. B-type natriuretic peptide, for instance, reflects myocardial stretch as seen in heart failure exacerbations and may well have promising prognostic significance. The purpose of this review is to discuss current and emerging cardiac biomarkers in acutely ill patients. The advantages and disadvantages of biomarkers will also be presented in the context of their clinical uses. Present markers are highly sensitive and specific to myocardial injury; however they do not specifically identify the method of injury. An exciting potential exists for future biomarkers to demonstrate enhanced specificity and earlier detection of compromised myocardium.
Cardiovascular disease occurs in an estimated 79.4 million or in 1 of 3 American adults.1 Data from the Framingham Heart Study indicate the lifetime risk for cardiovascular disease is 2 in 3 for men and greater than 1 in 2 for women at age 40. Nearly 2,400 Americans die of cardiovascular disease each day with more lives claimed than from cancer, chronic respiratory diseases, accidents, and diabetes mellitus combined.1 Although this is the age of technological revolution, cardiovascular disease continues to account for more deaths than any other cause of death since 1900 (except 1918).
Each day millions of patients with dyspnea and chest pain present to emergency departments (EDs) with a substantial portion of them suffering from noncardiac conditions. The consequences for missing an evolving myocardial infarction (AMI) or acute exacerbation of heart failure (HF) may have severe adverse outcomes. Accordingly, there are unnecessary admissions to the hospital when discharge might be just as appropriate. Diagnostic challenges are experienced for patients with these cardiac conditions, but the emergence of biomarkers has improved the clinician's arsenal for detection.
For a biomarker to be clinically useful, it needs to assist in diagnosis, define prognosis, or guide therapy.2 Ideally, a biomarker in the acute care setting defines risk so appropriate disposition decisions can be made and subsequent events minimized.3 Although new biomarkers bring hope, an understanding of their function and limitations is important. The purpose of this review is to discuss current and emerging cardiac biomarkers in acutely ill patients. A description of current biomarkers, their strengths and limitations, and a summary of their clinical use will be provided followed by a discussion of future biomarkers that may provide promise.
Investigations of biomarkers have uncovered greater understanding related to the process of vascular inflammation (see Figure 1 ). For example, proinflammatory cytokines, such as interleukin-6, are present upstream from markers of ischemia and necrosis, that is, they are present before the ischemic event occurs and are not implicated in unstable angina (UA) at this time.3 In contrast, B-type natriuretic peptide (BNP) is present with myocardial stretch suggesting myocardial dysfunction, an event that can occur as a result of ischemia. Although new biomarkers such as cardiac troponins have greatly enhanced diagnostic accuracy, issues remain (Table 1 ). When evaluating a new analyte, there is bias in favor of positive reports. A negative evaluation of a biomarker is unlikely to be the first published report on that biomarker, and therefore, once a positive report is published, negative reports are less likely to be published because of comparisons with the positive reports.2,3 FIGURE 1. Biomarkers in vascular inflammation (adapted with permission from Apple et al 3 ). IL-6 indicates interleukin 6; TNF-[alpha], tumor necrosis factor alpha; MMP-9, metalloproteinase-9; MPO, myeloperoxidase; sSSCD40L, soluble SSCD40 ligand; PAPP-A, pregnancy-associated plasma protein A; CRP, C-reactive protein; IMA, ischemia-modified albumin; cTnT, cardiac troponin T; cTnI, cardiac troponin I; BNP, brain natriuretic peptide; NT-proBNP, N-terminal proBNP. *Biomarkers covered in this review.
TABLE 1 New Biomarker Questions
The acute coronary syndromes (ACS) broadly encompass the clinical states UA, ST elevation myocardial infarction, and non-ST elevation myocardial infarction. Each diagnosis is united by common pathophysiologic characteristics that include atherosclerotic plaque formation, rupture, thrombus formation, and ultimately discontinuous blood flow and compromised myocardium.4 The differentiation among the 3 states is made based on the degree of blood flow limitation and thus the extent of myocardial damage. Determining the latter is not always easy and requires information gathered from patient history, electrocardiogram (ECG), the measurement of cardiac biomarkers, and cardiac imaging. Chest pain characterized by varying duration and severity is commonly found in a patient experiencing ACS. However, chest pain may also not be cardiac in nature, making the differential diagnosis vast and complicated. Although the ECG is an invaluable diagnostic tool, in isolation it is neither sensitive nor specific enough to make a definitive diagnosis. A normal ECG, although reassuring, does not rule out an acute AMI.
Biomarkers may have the ability to detect ischemia earlier and with greater sensitivity than ECG changes, which may not happen until irreversible damage has occurred. In fact, the ECG is diagnostic only 40% of the time.5 Biochemical markers for ischemia include myoglobin, lactate dehydrogenase, cardiac troponin, and creatinine kinase (CK), and its subform creatinine kinase MB (CKMB). Cardiac troponin and CKMB are current biomarkers discussed here and may well enhance the clinician's ability to detect ischemic episodes earlier. Determining the diagnosis of AMI using cardiac troponin or CKMB provides higher sensitivity and specificity, when compared with past biomarkers, to detect myocardial-related ischemia or necrosis. The sensitivity of a biomarker provides an understanding of the proportion of people who truly have a disease, whereas specificity refers to the proportion of people who aretruly free of a disease.6 A test that provides a sensitivity and specificity of 100% will ensure with certainty that a person who has a disease will test positively (sensitivity) and a person without the disease will test negatively (specificity). An example where cardiac biomarkers have provided a diagnostic edge over the standard ECG is in a patient who presents with a non-ST elevation myocardial infarction and a clinical history suggestive of coronary disease. Additional information as provided by serum biomarkers has proven helpful in elucidating a final diagnosis, as well as risk-stratifying patients with ACS for future events.
Cardiac Troponin
Troponin T or I is superior to other markers for the diagnosis of AMI due to its cardiac specificity.7 Sensitivity is also improved because this assay will detect even minimal myocardial damage. Initial investigations into troponin considered the role it played in regulating cardiac muscle contraction. It is recommended that an elevation of troponin significant to detect necrosis exceed the 99th percentile of troponin values in a reference control group within 24 hours of the clinical event (ie, chest pain).7 Troponin is prognostic in addition to diagnostic as the higher the troponin level, the greater the infarct and poorer predicted outcome. Also, the longer the troponin is elevated, the more severe the infarct. Several reports have demonstrated in both ST elevation myocardial infarction and non-ST elevation myocardial infarction patients that troponin elevations are indicative of more extensive disease and ultimately higher mortality rates.8 Troponin is released 4 to 12 hours after myocardial necrosis, peaking at approximately 12 to 48 hours from initial symptom onset. Troponin is particularly efficient in diagnosing an AMI up to 2 weeks after symptom onset and may remain elevated 10 to 14 days after ischemia onset.9 Troponin may be elevated in a number of conditions not associated with coronary disease and myocardial injury.
However, there are limitations with the troponin biomarker. It does a poor job of detecting reinfarction and is not detectable until myocardial necrosis occurs.9 Troponin elevations may be present when oxygen demand exceeds supply as with sepsis and atrial fibrillation or other tachycardias.8,10 Heart failure may also cause increases in troponin levels, as well as pericarditis, myocarditis, and acute pulmonary embolism due to myocardial strain. Finally, direct cardiac trauma may cause elevated troponins, such as with structural heart disease, contusion, and implantable defibrillator shocks.8,10
Creatinine Kinase/Creatinine Kinase MB
Biomarkers are not a completely novel concept, as they were first reported in 1954 when elevated aspartate transaminase levels were found in patients with AMI.9 However, what has changed is the sensitivity and specificity with which these biochemical markers can detect ischemia. Lactate dehydrogenase and, subsequently, CK were linked to cardiac injury. creatinine kinase is found in skeletal and cardiac muscle, as well as the gastrointestinal tract. Total CK cannot be used alone to diagnose AMI, rather it can be used in combination with a more sensitive marker such as troponin or CKMB.7 Creatinine kinase MB, although useful, is far less specific to cardiac muscle than troponin. Overall, the assay has been found to be less dependable than cardiac troponin. For example, a CKMB elevation may occur in a patient with renal disease, a muscular injury, or myopathy. However, when the troponin assay is not available, CKMB is an appropriate alternative.7 The benefit of CKMB is that it can detect subsequent infarction (after the initial event); however, the assay loses specificity in setting of skeletal muscle injury or cardiac surgery.9 Creatinine kinase MB may rise within 3 to 4 hours of injury and decline to normal levels 24 to 36 hours later. The requirements for CKMB to detect myocardial necrosis are that values from 2 successive blood samples exceed the 99th percentile in a control group.7 For both troponin and CKMB, the recommendation is to draw blood tests serially upon admission, at 6 hours, and at 12 hours.7
The drawback of biomarkers is that they do not reflect the mechanism of injury. For example, after cardiac surgery, a patient may exhibit elevated cardiac enzymes, but the etiology is obscure as the elevation may be from the surgery itself (ie, direct trauma or surgical manipulation) or from an occluded vessel and acute infarction. In addition, in the absence of cardiac ischemia, the clinician must seek alternative differentials, such as myocarditis, HF, or pulmonary embolism. However, one can evaluate the value of marker increase; as the higher the value, the more damage sustained by the myocardium. As is the case of cardiac troponin; the higher the value, the more unfavorable the outcome.
Emerging Biomarkers
BNP and Pro-BNP
B-type natriuretic peptide is a 32-amino-acid peptide released from the ventricles in response to ventricular volume expansion and pressure overload.2 B-type natriuretic peptide is cosecreted with the inactive amino-terminal pro-BNP (NT-proBNP). Cleavage of proBNP produces 2 molecules: BNP, the active molecule, and NT-proBNP, the inactive molecule.11 Left ventricular end-diastolic wall stress and wall stiffness are thought to be the triggers of BNP release, and therefore, BNP is elevated in both systolic and diastolic HF. The severity of ventricular dysfunction determines individual BNP levels.12 Mitral regurgitation also contributes to increases in BNP levels.
The BNP and NT-proBNP values are useful for the detection of HF. B-type natriuretic peptide values <100 class="li-txtcontent" href="http://www.nursingcenter.com/library/static.asp?pageid=798256#68">13 B-type natriuretic peptide levels greater than 500 ng/L HF are very likely, with an associated positive predictive value of 90%. The values between 100 and 500 ng/L, where many patient values lie, have lower predictive value, and accuracy of the biomarker declines. For NT-proBNP values >450 ng/L in patients younger than 50 years, the biomarker is both sensitive and specific for HF.14 For NT-proBNP values >900 ng/L in patients older than 50 years, the biomarker is again both sensitive and specific for HF. Several studies have now demonstrated that, when used in combination with clinical judgment, BNP and NT-proBNP enhance diagnostic accuracy for patients with symptoms of HF.15,16
The potential prognostic value of BNP and NT-proBNP is promising.14,17 Patients with higher values upon hospital admission and at discharge generally have worse outcomes. Those who have substantial reductions in BNP values during treatment have better outcomes. However, the biological variability with BNP suggests that the natriuretic peptide system may take time to up-regulate and down-regulate.2 In other words, the time needed for the system to autoregulate is longer than expected despite the short half-life of both molecules (20 minutes for BNP and 2 hours for NT-proBNP).
The robust associations between natriuretic peptides and outcomes in patients with ACS imply that potential early risk stratification may be possible for patients with myocardial ischemia.14,18 A prospective study of ED patients with chest pain demonstrated that the use of BNP, CKMB, and troponin I used in combination upon admission increased sensitivity and negative predictive value when compared with CK-MB or troponin I alone.19 In addition, when patients had normal troponin I levels, elevated BNP levels were associated with a significantly greater risk of AMI. B-type natriuretic peptide and pro-BNP elevations are prognostic for death in ACS, but data are conflicting for recurrent MI.2 Higher BNP values do identify higher risk patients with ACS, but how this influences treatment is unclear. Only 1 trial has evaluated treatment options. The trial involved BNP or C-reactive protein (CRP) values in women with ACS. Women with elevated BNP or CRP benefited from early percutaneous coronary intervention even when cardiac troponin levels were normal.20 This could be an important adjunct when evaluating patients with ACS.
When BNP and then pro-BNP assays were first introduced, there had never been a blood test for HF; enthusiasm was abundant. Limitations of the biomarker are now evident. Women and older individuals have higher values.21 Those with renal failure have often substantially higher values,22 and obese individuals have lower values.23 This is more pronounced in NT-proBNP levels. Because there is substantial biologic variability, some suggest that if formal values are relied on, values need to half or double to suggest a definite change.2 It is now appreciated that patients with sepsis, volume overload, stroke, cor pulmonale, pulmonary edema, and acute mitral regurgitation have higher BNP and pro-BNP values. Finally, few studies have involved nonwhite or nonwhite ethnicity. Thus, questions arise regarding what are appropriate cutoff values in varied patient populations, genders, and conditions.
B-type natriuretic peptide and pro-BNP provide useful diagnostic information for patients who present to the ED with dyspnea. Patients with acute dyspnea present a challenging and time-consuming workup because the etiology of dyspnea is wide ranging. The prognostic value of BNP and pro-BNP at hospital discharge may also be relied upon to identify patients who will have poorer outcomes, although when these outcomes occur and in which patient populations are not clear. Until the limitations are further defined, BNP and pro-BNP use will be limited.
C-reactive Protein
C-reactive protein (CRP) is an acute-phase reactant (or one that elevates by 25% or more during inflammatory disorders) protein made in the liver.2 In 1997, it was reported that high-sensitivity CRP (hs-CRP) is an independent predictor of AMI and stroke in healthy men.24,25 C-reactive protein provided a new appreciation that atherothrombosis was, in part, an inflammatory disorder.26 Further investigation has shown elevated hs-CRP to predict type 2 diabetes and hypertension.27 In 2002, levels were established based on data from almost 28,000 healthy women followed for10 years such that an hs-CRP of 1, 1 to 3, and >3 mg/L represented lower, average, or higher vascular risk, respectively, when added to traditional risk factors.28 One group of investigators added hs-CRP to traditional risk factors to predict cardiovascular risk and found that 30% of individuals originally classified as 'intermediate risk“ were further reclassified into higher or lower risk categories enabling more specific risk prediction.29 The recently reported Reynolds Risk Score added the 2 biomarkers, hs-CRP and family history, to traditional risk factors and found that the accuracy of risk prediction was, again, markedly improved.27 Based on this evidence, many healthcare providers have come to use CRP in addition to other biomarkers to provide additional cardiovascular risk prediction.
Several reports address CRP in relation to the acute care setting and use of CRP levels after AMI. Initially, data suggested that the titration of statin therapy based on CRP levels would result in fewer events and enhance regression of atherosclerosis.21,30 Patients were given statins, and CRP values were obtained 30 days after AMI (not sooner so as to avoid the influence of myocardial necrosis on CRP). In patients who had low-density lipoprotein cholesterol levels <70 id="37" name="37">
There is controversy regarding CRP levels. Some argue that the levels of CRP vary greatly and fluctuate within individuals; if the patient is acutely ill or has an AMI, the test should be repeated 2 weeks later.31 C-reactive protein levels vary by gender and ethnicity,32 and values >10 mg/L are likely due to illness.33 Those values between 1 and 3 mg/L reflect an intermediate risk.29 Recent guidelines suggest the use of CRP in patients who are at intermediate risk for coronary disease to assist in determining treatment goals.34 For those clinicians following patients after AMI, CRP levels may be a helpful adjunct in gauging statin therapy.
Developing Biomarkers
Myeloperoxidase
Myeloperoxidase is a degranulation product from white blood cells 3 released into the systemic circulation during inflammatory conditions. This enzyme is found in higher concentrations in the culprit lesions of patients with UA or AMI than in stable coronary artery disease.3 Because current biomarkers measure only the onset of necrosis, myeloperoxidase offers an exciting alternative as it reflects inflammation or activation of hemostasis after plaque rupture that may give early information before irreversible injury.35
A few clinical studies have examined the role of myeloperoxidase as a marker of risk for ACS. In patients undergoing angiography, patients with coronary artery disease had higher activity levels of myeloperoxidase than in a comparison normal group, but no information was provided on subsequent rate of adverse events.36 Two groups of investigators studied myeloperoxidase in relation to risk stratification.37,38 In the CAPTURE trial myeloperoxidase concentration was measured in 1,090 ACS patients, with death and AMI rates determined 6 months after hospital discharge.37 Those with a cutoff of >350 µg/L had a more than 2 times greater hazard of death or AMI. Interestingly, the effects of myeloperoxidase were also noted in patients with negative cardiac troponin T levels; however, only the admission cardiac troponin T level was used. Another group examining 604 chest pain patients in the ED demonstrated an increased odds ratio for major adverse effects at 30 days and 6 months corresponding with increasing quartile myeloperoxidase concentrations.38 The results were similar to the CAPTURE study, but differences in study designs make it impossible to directly compare the results. One group used a higher cardiac troponin T cutoff of.10 µg/L, and neither used the same assay. Standardization of assays and comparisons with accepted cutoffs are needed. In summary, myeloperoxidase is a marker of plaque instability but is not unique to ACS. It is associated with neutrophil activation and can be found in association with any infectious, inflammatory, or infiltrative disease process.
Although this biomarker seems to provide additional important data in the evaluation of chest pain patients, considerable limitations require further investigation. Comparisons of myeloperoxidase with troponin levels have used high troponin cutoff levels or only admission troponin levels.2 In addition, myeloperoxidase lacks specificity and can be increased in other conditions.2 Not all institutions may offer the test or have timely results to assist in clinical decision making.
Pregnancy-Associated Plasma Protein
Pregnancy-associated plasma protein A (PAPP-A) is an insulin-like growth factor thought to be released when neovascularization occurs and therefore may be a marker of plaque rupture.3 The presence of PAPP-A was found in unstable plaques from patients who died sudden cardiac causes39 In a series of 136 patients presenting to the ED with suspected ACS, an increase in PAPP-A was an independent predictor of future ischemic events as well as percutaneous coronary intervention or cardiac bypass surgery.40 The correlation between PAPP-A and CKMB was poor, indicating that increases in PAPP-A cannot be associated with necrosis; that is, PAPP-A increases were associated with events before necrosis occurred. Elevated PAPP-A levels were also found in patients without increased concentrations of cardiac troponin I, potentially identifying high-risk patients who might not otherwise be identified.
Pregnancy-associated plasma protein A is thought to be different from PAPP-A collected during pregnancy versus the serum of ACS patients. The immunoassays that are designed to detect PAPP-A in pregnancy serum have not been developed for the measurement of PAPP-A as a cardiac marker.3 In addition, the concentration of PAPP-A is affected by some laboratory tube additives, so correct collection and measuring systems are needed.3 In summary, acceptance of PAPP-A as independent biomarker for cardiovascular risk in ACS requires more investigation.
Ischemia-Modified Albumin
Ischemia-modified albumin (IMA) is a novel marker of cardiac ischemia. It is measured in the serum by the albumin cobalt binding test, which is based on the premise that albumin in the blood of patients with myocardial ischemia demonstrated less ability to bind with cobalt than the albumin in serum of normal subjects.41 Therefore, the albumin cobalt binding test measures reduced albumin binding to cobalt.8 A positive IMA may reflect cardiac ischemia reflected as a reduced metal binding capacity of albumin.
One group of investigators examined the usefulness of IMA in patients presenting to the ED with chest pain, normal or indeterminate ECG, and negative troponin.42 One hundred thirty-one patients with suspected ACS were chosen based on arrival to the ED within 3 hours of last episode of chest pain, a normal or indeterminate ECG, and negative cardiac troponin upon admission.42 The results revealed higher IMA levels in those patients with ACS when compared with those found to have nonischemic chest pain. In addition, the authors found that using both IMA and troponin increases the sensitivity and specificity of identifying patients with ACS. The results also seemed to favor the idea that IMA levels increase before any change in troponin level, suggesting that IMA represents an earlier marker of myocardial ischemia.
Ischemia-modified albumin is not without its problems. It should be noted that elevated IMA levels have been found in patients with injury to other organs besides the myocardium.8 Ischemia-modified albumin levels also seem to be influenced by serum albumin levels.
Soluble CD40 Ligand
Another biochemical marker receiving attention due to its relationship with the inflammation process leading to coronary thrombosis is CD40 ligand. It is a protein within the tumor necrosis factor family and is expressed on cells such as platelets, vascular endothelial cells, smooth muscle cells, and monocytes.43 In the process of thrombus formation, CD40 expressed on the surface of platelets is cleaved into soluble CD40 ligand, which can then be detected in the blood. One study assessed the ability of CD40 to predict risk in patients with ACS when compared with a control group.43 Results showed that CD40 levels above the median in patients with ACS were associated with risk for recurrent AMI. The specificity of CD40, however, must be questioned given the fact that levels can be detected in other inflammatory conditions aside from coronary atherosclerosis. For example, elevated concentrations of CD40 have been seen in inflammatory disorders, such as inflammatory bowel disease, as well as multiple sclerosis, stroke, and diabetes.3
Conclusion
The development and standardization of new markers of cardiac damage is a rigorous process that ideally brings sensitive and specific information assisting clinical decision making. Questions are posed regarding the utility, reliability, cost, measurement, and handling of the assay.44 Perhaps the most crucial and appropriate question considered is what will this new biomarker assay add to patient care? And what is the purpose of a new assay: early detection, diagnosis, risk stratification, monitoring of disease progression, or to help to select appropriate therapies?3,44 Cardiac imaging provides additional valuable information about heart function and has become increasingly sophisticated. However, it is expensive and may not be accessible. Cardiac markers represent efficient, cost-effective measures of myocardial viability. Future markers may provide clinicians a magnified view of the impaired myocardium.
Although new cardiac markers are highly scrutinized, there are several on the horizon that have promising potential (Table 2 ). Emerging markers may help to further identify patients who require hospitalization versus those who can be safely discharged, thus reducing the number of unnecessary hospital admissions. The novel aspect of many of these markers is their ability to detect states of inflammation, injury, and stretch, or processes that occur before actual myocardial necrosis. Therefore, these markers could potentially identify damage earlier and further risk stratify patients when compared with present markers (ie, cardiac troponin and CKMB). TABLE 2 Strengths and Limitations of Developing Biomarkers 3,34,40,41
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KEY WORDS: biomarkers; BNP; troponin
