ORLANDO—Evidence continues to accrue on the utility of brain natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) in cardiovascular disease. Now, two studies presented at the American College of Cardiology’s 54th Annual Scientific Session have shown that testing for both the hormone BNP and its inactive prohormone NT-proBNP appears to predict the presence of noncardiac vascular disease and stroke events in patients with known disease and in the general population.

One study showed that NT-proBNP is a powerful independent predictor of stroke in patients from the general population who have hypertension. A second paper suggested that BNP is significantly elevated in patients with noncardiac vascular disease compared with controls.

STROKE MARKER

BNP is secreted as an inactive prohormone that undergoes enzymatic cleavage to produce the active hormone BNP and the inactive NT-proBNP, said Ilan E. Raymond, MD, PhD, of the Department of Cardiology and Endocrinology at Frederiksberg University Hospital, Copenhagen, in an interview with Neurology Reviews. Assays for both BNP and NT-proBNP are used to help diagnose chronic and acute heart failure and have been shown to be useful for risk assessment in other cardiac settings.

While their prior work had examined this marker in heart failure and in the general population, in their current study, Dr. Raymond and colleagues evaluated the utility of NT-proBNP as a marker of stroke risk in patients with hypertension and preserved left ventricular systolic function (LVSF). Participants in the trial were taken from randomly selected general practices in Copenhagen. “In Denmark, everyone is signed up to a general practitioner, so it is the general population,” Dr. Raymond explained.

In this study, 658 participants with a median age of 68 (range 50 to 90) completed a heart failure questionnaire, which included a history of cardiovascular diseases and current medications; underwent ECG and echocardiography; and had measurements taken of NT-proBNP. Hypertension was defined as a history of hypertension or blood pressure above 150/90 mm Hg, and preserved LVSF was defined as a left ventricular ejection fraction of greater than 50%.

Of the overall group, 309 participants fulfilled criteria for both hypertension and preserved LVSF. Over a median follow-up of 3.5 years, there were 15 stroke events, Dr. Raymond reported.

Potential prognostic factors for stroke, including age, gender, systolic and diastolic blood pressure, atrial fibrillation, and NT-proBNP, were evaluated using Cox proportional hazards analysis. The investigators reported that NT-proBNP was a strong independent predictor of stroke risk in this population (hazard ratio, 4.1).

In a separate analysis discriminating patients with NT-proBNP above and below the median value of 35.6 pmol/L, and including the same variables, NT-proBNP remained an independent marker of stroke risk, while other traditional risk factors were found not to be independent predictors. “We found that NT-proBNP is much better to point out which of these patients have a high risk of these cardiovascular diseases compared to, for instance, the blood pressure,” Dr. Raymond noted.

Published findings from this same cohort showed that NT-proBNP was a strong independent predictor of mortality and cardiovascular risk in this population and was a better indicator of risk than were other markers such as high-sensitivity C-reactive protein or urinary albumin excretion. In another analysis, Dr. Raymond and his colleagues showed that the marker is also a stronger predictor of risk than are other traditional risk factors, including cholesterol, diabetes, or a history of cardiovascular disease. “So it may be a very valuable marker for general practitioners or cardiologists or neurologists in the future to see which of their patients with hypertension are at risk,” Dr. Raymond said.

PREDICTING NONCARDIAC RISK

In a separate report, Robert V. Kelly, MD, of the Division of Cardiology at the University of North Carolina, Chapel Hill, presented data evaluating levels of BNP among patients with noncardiac vascular disease. BNP has been shown to be elevated in patients with heart failure, acute coronary syndromes, and in those with left ventricular hypertrophy, the investigators said. It is a valuable marker for diagnosis, treatment, and risk stratification of patients with nonvascular heart failure and left ventricular systolic dysfunction (LVSD), they noted.

Dr. Kelly and colleagues have previously shown that congestive heart failure occurs five times more often in patients with stroke, transient ischemic attack (TIA), and peripheral arterial disease than in age- and sex-matched controls. In this study, they looked at BNP levels in 216 consecutive patients presenting for the first time with stroke, TIA, or a new onset of claudication and compared them with BNP levels in 161 age- and sex-matched controls.

In this analysis, all patients had undergone two-dimensional transthoracic echocardiography, a physical examination, and BNP measurement. “What is particularly interesting is that the BNPs are more elevated in the vascular patients compared with controls,” Dr. Kelly said.

The researchers reported that BNP was significantly elevated in all patients with noncardiac vascular disease compared with controls. The median BNP level was 46.5 pmol/L, compared with 33 pmol/L in controls. However, Dr. Kelly pointed out, BNP was more elevated in patients with cerebrovascular disease than in patients with peripheral arterial disease, despite a similar prevalence of LVSD and of diastolic heart failure.

Median BNP in the stroke patients was 53.4 pmol/L, 36.7 pmol/L in the patients with peripheral arterial disease, and 32.9 pmol/L among controls. LVSD was present in 28% of stroke patients, 31% of patients with peripheral arterial disease, and only 6% of controls. The rate of diastolic heart failure, however, was similar across groups, at 11% of both the stroke/TIA and control populations and at 15% of patients with peripheral arterial disease.

Dr. Kelly pointed out that there are some limitations to the analysis, because the data did not exclude patients who might have had a history of ischemic heart disease or other illnesses that are known to elevate BNP. “What we gathered from our results is that the BNP levels were increased a little bit more in the stroke population of patients than in the other groups,” he said.

The hypothesis that the BNP test is identifying those patients with the left ventricular dysfunction and heart failure, though, seems not to be borne out; LVSD was more common in those with high BNP levels, he said. “But when we actually do the analysis, it’s not the left ventricular dysfunction that the BNP appears to be picking up.”

Using various BNP cutoff levels, the investigators found that BNP was useful in identifying left ventricular dysfunction in control patients but not in those with stroke or TIA, he noted.

DISTINGUISHING FEATURE?

Previous studies in the literature suggest that acute ischemia can cause elevations of BNP, Dr. Kelly said. In addition, intracranial bleeding may have an indirect effect on BNP, possibly mediated through autonomic dysfunction.

Dr. Kelly said that he has been asked whether he thought BNP levels might be used to distinguish ischemic from hemorrhagic strokes. “I don’t think [they] can at the moment,” Dr. Kelly said. “I think it may reflect ischemia, whether it’s ischemia in the heart or in the brain, but I think it requires further evaluation.”

NR

—Anne Howe

Suggested Reading
Kistorp C, Raymond I, Pedersen F, et al. N-terminal pro-brain natriuretic peptide, C-reactive protein, and urinary albumin levels as predictors of mortality and cardiovascular events in older adults. JAMA. 2005;293:1609-1616.
Pedersen F, Raymond I, Kistorp C, et al. N-terminal pro-brain natriuretic peptide in arterial hypertension: a valuable prognostic marker of cardiovascular events. J Card Fail. 2005;11(5 suppl):70-75.

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