According to the American Heart Association, approximately five million Americans are diagnosed each year with congestive heart failure (CHF), a chronic and progressive condition resulting from the heart’s inability to pump blood fast enough to adequately supply the organs.

The symptoms of CHF—shortness of breath, edema, and fatigue—are seen in conditions other than heart failure, challenging physicians to differentiate between a severe heart problem and less-life-threatening conditions completely unrelated to the heart.

In recent years, cardiac markers have assumed a prominent role in helping clinicians accurately identify patients’ conditions. These cardiac-specific proteins have not only proven to be adept identifiers of CHF and myocardial infarction or heart attack, but they also possess prognostic properties for risk-stratification of patients with acute coronary syndromes (ACS), a term that covers a range of conditions that limit the flow of blood and oxygen to the heart.

Routinely used markers include creatine kinase-MB (CK-MB) and cardiac troponins I (cTnI) and T (cTnT); a study published last November indicates that NT-proBNP should be added to that list.

ICON
Led from Massachusetts General Hospital, the “International Collaborative of NT-proBNP” (ICON) Study pooled researchers from the United States, the Netherlands, Spain, and New Zealand. The group employed an NT-proBNP assay produced by Roche Diagnostics, which also funded the study.

The researchers examined data from 1,256 patients—720 of whom had acute CHF—to determine the usefulness of the amino-terminal pro-brain natriuretic peptide (NT-proBNP) assay in evaluating patients who presented with shortness of breath, clinically referred to as “dyspnea.”

What ICON found was that in patients having difficulty breathing, elevated levels of NT-proBNP were highly accurate for correctly identifying heart failure as the cause. Equally important, results indicated that NT-proBNP is just as accurate in excluding CHF as the source of the dyspnea.

 James Januzzi, Jr, MD

“It’s an important point because until the natriuretic peptide test, we had no impartial way of evaluating patients, from a laboratory perspective, for the presence of heart failure,” says James Januzzi, Jr, MD, FACC, assistant professor of medicine, Harvard Medical School, and associate medical director of the Coronary Care Unit at Massachusetts General Hospital (Boston). “What we have found is that these objective laboratory tests are as good—if not better—than the standard clinical judgment of clinicians evaluating patients with shortness of breath.”

Januzzi’s team concluded that the best possible patient care is achieved by using the blood test in conjunction with the evaluation made through the physician’s exam.

“That balance of clinical judgment, plus blood testing for NT-proBNP, seems to be the pairing that is most likely to provide the correct diagnosis or exclusion of heart failure,” says Januzzi, a co-lead author of the ICON study.

The ABCs of BNPs
In the United States, measuring a patient’s level of NT-proBNP or the related brain natriuretic peptide (BNP) has become routine in assessing how well the heart is doing its job. When disease damages the heart, the muscle struggles with every beat, causing the left ventricle to create proBNP, which then separates, releasing both an active (BNP) and an inactive (NT-proBNP) hormone—all of which is done in an effort to decrease its workload and reduce stress on the organ.

 Michael Samoszuk, MD

“ProBNP is a hormone produced by the heart to try to regulate the cardiovascular system by causing the blood vessels to relax so the blood pressure can go down,” explains Michael Samoszuk, MD, chief medical officer, Roche Diagnostics. Among other things, BNP works at ridding the body of sodium and also reduces the fluid retention accompanying CHF. “There is some evidence to suggest that these levels of NT-proBNP become elevated very early in the process, as soon as the heart has undergone the earliest changes associated with CHF—it’s kind of a call for help, if you will.”

Looking Into the Future
Much of the work with NT-proBNP followed another Massachusetts General Hospital study published in the April issue of the American Journal of Cardiology.1

Titled the “Pro-BNP Investigation of Dyspnea in the Emergency Department” (PRIDE) study, it was the first large-scale prospective analysis of NT-proBNP in the emergency-department setting.

“One very important, seminal observation from this study is that NT-proBNP values were the single strongest predicator of death in patients with shortness of breath after 1 year,” Januzzi says. He adds that an NT-proBNP result higher than 986 pg/mL was the strongest predictor of death in patients, both with and without heart failure. “It doesn’t really matter why it was high, but if it was, the patient’s risk was considerably elevated relative to someone below that threshold.”

Januzzi believes this broadens the prognostic value of NT-proBNP to predict death in a wide variety of clinical states, including ACS and pulmonary embolism (a circumstance when a clot travels to the lungs, which may also lead to acute right-sided heart failure), as well as critical illnesses, like gram-negative sepsis. The recommendation included in the study findings—published in February’s Archives of Internal Medicine—is that an NT-proBNP should be measured in every patient presenting with dyspnea.2

“If someone is sick enough to lead to heart dysfunction, the level of natriuretic peptide is going to be reflected in their risk for mortality,” Januzzi adds. “It tells physicians not only where the patient is right now, with respect to the presence or absence of heart failure, but it also gives clinicians a window into the future likelihood of death as well, even in those without acute CHF.”

Another Clinical Tool
NT-proBNP is not intended to replace existing cardiac markers, but rather will work in concert with them.

 Martin H. Kroll, MD, FASCP

“BNP and NT-proBNP will become part of the necessary information required for establishing the diagnosis of heart failure and for following those patients—it’s not going to replace any of the current markers we have for infarction,” says Martin H. Kroll, MD, FASCP, Dallas Veterans Affairs Medical Center and professor of pathology at the University of Texas, Southwestern School of Medicine at Dallas. “It also has a lot of possibility for use in identifying those patients who have some type of cardiac injury.”

Samoszuk agrees that the different markers provide complementary information. “The troponinT assay gives an index of how many heart cells have died, and the NT-proBNP assay gives an index of how the remaining heart cells are responding to the increased workload brought on by the event,” he explains. “You need to know both so you can get an idea of how much heart muscle has died and how much stress the remaining heart muscle is under.”

Garnering this additional information can only bode well for clinicians and patients alike. “NT-proBNP adds incremental prognostic information for patients with ACS, as well as patients with heart failure, particularly when used in conjunction with troponin,” Januzzi says. “This multimarker approach is going to be the way we evaluate our patients more thoroughly in the future.”

Improved evaluations will inevitably lead to superior patient care. The 2006 edition of Harrison’s Principles of Internal Medicine explicitly states that NT-proBNP and BNP levels are extremely valuable in therapy monitoring in patients with heart failure, according to Samoszuk.

“It is not an approved application at this time, but many doctors do use it for disease monitoring, as an off-label use of these tests,” he says. “The test helps them determine if the disease is getting better or worse in response to treatment, so they’re using it to monitor the stage or severity of the disease.”

Untapped Potential
Though it is currently used for its diagnostic and prognostic abilities, the potential exists for NT-proBNP to be included as a component in screening select populations.

“There is absolutely no doubt in my mind that these blood tests will eventually be used for screening patients in the physician’s office,” Januzzi says. He stresses that the screening test would only be as good as the patients to whom it is being applied. “If you’re adding an NT-terminal proBNP onto the usual blood tests for asymptomatic healthy 20-year-olds, that’s not necessarily where there’s going to be value. This is why prior studies of natriuretic peptide-based screening of populations were not as clearly positive as we would have liked.”

The test’s usefulness will be realized by homing in on patients most at risk for the development of heart failure, specifically patients who have concomitant diseases such as diabetes, hypertension, or high cholesterol; or those with suspected coronary artery disease or a family history of heart disease.

“It’s possible it will become a very good marker for heart damage, particularly in patients with coronary artery disease who have significant fibrosis occurring in their heart but don’t have evidence of a major infarct,” Kroll says. “It’s not always clear what’s going on with these patients, so it may be that BNP and NT-proBNP will turn out to be useful tools in assessing them.”

Looking Beyond the Heart
The presence of an elevated NT-proBNP or BNP level is a clear indicator to physicians that something is amiss with their patients.

“When it comes down to it, given the sensitivity of the tests, we really should accept the fact that when applied to patients in a logical fashion, there is probably no such thing as a false-positive natriuretic peptide value—if they’re elevated, they’re most often elevated for a reason,” Januzzi says. He cautions against jumping to the conclusion that heart failure is the only possible cause of high levels of NT-proBNP or BNP.

In the absence of a clinical diagnosis of heart failure, a myriad of maladies could be to blame. In such circumstances, the physician will be required to rely less on test results and more on the patient’s physical exam and history.

“The factors that elevate natriuretic peptide concentrations include atrial fibrillation; significant, yet asymptomatic structural heart disease such as valvular heart disease; coronary artery disease; and renal failure,” he says.

Notably, in the case of renal failure, it is known that renal clearance is an important egress from the body for both NT-proBNP and BNP, “so elevations of these markers in patients with chronic kidney disease could simply reflect reductions in their clearance, with passive accumulation,” Januzzi says. “However, keep in mind that these markers should not be there in the first place, so any accumulation is already a marker of risk, a marker of a disease state resulting in their release.” Januzzi noted that a majority of patients with significant kidney-function impairment also carry risk factors for structural heart disease. Hypertension and diabetes are just two examples. According to Januzzi, it follows that a highly sensitive measure for detecting structural heart disease—such as NT-proBNP or BNP—would thus be significantly affected by those with renal failure.

“If a doctor has a dyspneic patient with chronic kidney disease, and it is unclear whether that patient has destabilized heart failure, it’s important to consider that the NT-proBNP value will be elevated,” Januzzi says. “The relevant challenge is trying to figure out if that’s the blood test just doing what it’s supposed to do—telling you that this person with kidney disease has heart disease—or whether that elevation of natriuretic peptide is actually reflective of a destabilized heart-failure episode the person is having.”

Setting the Standard
One approach to solving such a dilemma is identifying typical levels of NT-proBNP in patients with chronic kidney disease when they’re stable. Even though such individuals are likely to have a higher “normal,” it would be apparent when substantial elevations occur when the patient becomes ill.

Having these baseline standards could also be helpful when treating patients with unclear medical conditions. “If someone comes in with a massive myocardial infarction, of course the test will be positive, but that’s not the type of patient you’re interested in—you’re looking at patients in which the results are equivocal,” Kroll says. He notes that traditionally, the challenge for many researchers has been following up on participants and finding out the precise results. “I believe we’ll see the same thing that happened with other cardiac markers happen with these studies: that is, we continually improve how each study is designed and show additional improvement in terms of identifying patients.”

Looking Forward
Beyond the current approved use—the diagnosis of congestive heart failure—the opportunities for broader application of these NT-proBNP assays seems certain.

“NT-proBNP is actually a remarkably versatile marker, and I think as we go into the future we’re going to find it has many more, very interesting applications than we originally envisioned,” Samoszuk says. He doesn’t advocate uses outside of established purviews, but is encouraged by literature being published suggesting that elevated NT-proBNP levels can identify patients rejecting a heart transplant, for example, or those with hearts damaged after chemotherapy. “It looks like NT-proBNP may be a final common pathway for many different diseases in terms of the effect on the heart.”

References
1. Januzzi JL, Camargo CA, Anwaruddin S, et al. N-terminal ProBNP for emergency evaluation of shortness of breath: The ProBNP investigation of dyspnea in the emergency department (PRIDE) study. Am J Cardiol. 2005;95(8):948–954.
2. Januzzi, JL, Sakhuja R, O’Donoghue M, et al. Utility of amino-terminal pro-brain natriuretic peptide testing for prediction of one-year mortality in emergency department patients with dyspnea. Arch Intl Med. 2006;166:315–320.