Natriuretic Peptides
The natriuretic peptides are cardiac neurohormones that are released in response to myocardial wall stress.11 B-type natriuretic peptide (BNP; previously known as brain natriuretic peptide) is synthesized and released from the ventricular myocardium in times of volume expansion and increased pressure burden. Initially, the prohormone proBNP is released and is enzymatically cleaved to N-terminal proBNP (NT-proBNP) and then to “mature” BNP.11
Today, BNP is used widely as a biomarker for congestive heart failure.22 In the Breathing Not Properly (BNP) study,23 BNP was able to accurately distinguish dyspnea caused by heart failure from that with a pulmonary etiology; it was found to be the strongest predictor for the diagnosis of heart failure. In the evaluation of serum BNP, a level below 100 ng/L makes heart failure unlikely (negative predictive value, 90%). If the value rises above 500 ng/L, heart failure is highly likely (positive predictive value, 90%).23
As for NT-proBNP, levels exceeding 450 ng/L in patients younger than 50 and exceeding 900 ng/L in patients 50 or older have been found highly sensitive and specific for heart failure–related dyspnea.24 Current studies suggest that NT-proBNP may have greater sensitivity and specificity than standard BNP when these age-related cut-off limits are applied.25
Researchers for the International Collaborative of NT-proBNP Study reported that when NT-proBNP was measured in the emergency department (ED) in patients with dyspnea, patients were less likely to require hospitalization for heart failure.26 Instead, patients were presenting with exacerbations of chronic obstructive pulmonary disease, which would best be managed on an outpatient basis. Those who were admitted experienced shorter lengths of stay with subsequent reductions in health care costs, and had no significant difference in readmission or mortality rates.
Use of BNP as a cardiac biomarker does not come without its limitations. In addition to right-sided heart failure, ACS, and MI, elevations in BNP have been associated with septic shock, sepsis, renal dysfunction, and acute pulmonary embolus.27 Correlations have been made between the degree of BNP elevation and the extent of myocardial ischemia; increased levels of both BNP and cTnI were associated with higher mortality rates.28
C-Reactive Protein
Inflammation is known to play a key role in the development of atherosclerotic plaques. Measuring byproducts of the atherosclerotic process, from the initial development of fatty streaks to plaque rupture, can help determine whether a patient is at an increased risk for a cardiovascular event.29 Primary proinflammatory markers from the local site of intravascular inflammation signal messenger cytokines that are altered in the liver via an acute-phase reaction.
One of the major acute-phase reactants, C-reactive protein (CRP) is simply a byproduct of inflammation—yet it has become a major indicator of atherosclerotic plaque stability.30 A high-sensitivity CRP assay (hsCRP) can be a significantly effective predictor for MI, stroke, and peripheral vascular disease, even in patients who appear to be healthy.31 Studies have suggested that hsCRP is a better indicator of unstable plaque, and a better predictor of adverse cardiovascular events, than is low-density lipoprotein cholesterol (LDL-C), when these markers are used independently.32 When detected together, however, hsCRP and LDL-C elevations have been shown to be an even better predictor of adverse events in patients with no overt cardiovascular risk factors.31
As a risk factor, elevated hsCRP has been called as important as smoking or hypertension—highlighting the role of inflammation in formation of atherosclerosis at every level.33
In the evaluation of serum hsCRP, it is important to know that levels tend to be stable over long periods of time, have no circadian rhythms, and are not affected by various prandial states. Levels can be measured conveniently during the standard annual cholesterol screening. Relative cardiovascular risk is deemed low, medium, and high, in patients with an hsCRP measurement of less than 1 mg/L, 1 to 3 mg/L, and greater than 3 mg/L, respectively.2 Values exceeding 8.0 mg/L may be consistent with an acute infectious or inflammatory process, thus exposing the nonspecific nature of this popular biomarker.34 However, when used in conjunction with cTn, BNP, and patient history, hsCRP still proves to be an important clinical tool, offering prognostic information to facilitate clinical decision making.
Chronically elevated hsCRP signifies a very high risk for future cardiovascular events and should prompt the clinician to target the patient’s modifiable risk factors, including consideration of statin therapy as a part of the treatment regimen.35 According to results from the PROVE IT–TIMI 22 trial,35 statin use appears particularly cardioprotective in patients whose hsCRP levels are lower than 2 mg/L and who maintain LDL-C below 70 mg/dL. Researchers for this study group recommend monitoring hsCRP along with serum lipids for a more comprehensive cardiovascular risk profile.