Brain Hormone Predicts High Risk of Death in Sickle Cell Patients

BETHESDA, Md., July 19 -- A simple blood test for brain natriuretic peptide (BNP) has identified sickle cell patients with pulmonary hypertension, researchers here reported.

BNP is a hormone released in response to cardiomyocyte stretch, and high levels reflect cardiac chamber volume and pressure overload. The prognostic importance of BNP has been demonstrated in several cardiovascular disorders.

Adult patients with blood levels of BNP of 160 pg/mL or higher had a 78% chance of having pulmonary hypertension with a fivefold increased risk of death, according to a report in the July 19 issue of the Journal of the American Medical Association.

NT-proBNP levels were measured in 230 patients in the NIH Sickle Cell Disease-Pulmonary Hypertension Screening Study (2001-2005) and in 121 samples from patients enrolled (starting in 1996) in the Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH) Patients' Follow-up Study.

To confirm a diagnosis of pulmonary hypertension, the patients were given echocardiograms and other measurements of heart function, said Roberto Machado, M.D., of the National Heart, Lung, and Blood Institute here, and colleagues.

NT-proBNP levels were higher in patients with sickle cell pulmonary hypertension and correlated directly with tricuspid regurgitant jet velocity in the NIH cohort (R=0.50, P <.001), the researchers reported.

An NT-proBNP level of 160 pg/mL or greater had a 78% positive predictive value for the diagnosis of pulmonary hypertension and was an independent predictor of mortality (21 deaths at 31 months' median follow-up; risk ratio, 5.1; 95% confidence interval, 2.1-12.5; P <.001; 19.5% absolute increase in risk of death).

The level of 160 pg/mL or greater, representing the 75^th percentile for the population, provided a specificity of 91%, a likelihood ratio of 6.33, and a positive predictive value of 78%, according to the study authors.

To explore the prevalence and associated risk of pulmonary hypertension in the well-characterized 1996 MSH cohort, the researchers measured stored blood samples from 121 participants and found that 30% of the patients had an NT-proBNP level of 160 pg/mL or greater. Using the biomarker as a surrogate for pulmonary hypertension, the findings suggested a prevalence of pulmonary hypertension that is comparable to that in recent reports, the researchers said.

Pulmonary hypertension was remarkably common over the last decade in sickle cell patients, the investigators said, noting that the MSH patients came from major U.S. sickle cell centers, and at the time it was not known that pulmonary hypertension was a common complication of sickle cell disease.

The NT-proBNP level of 160 pg/mL or greater in the MSH cohort was also independently associated with mortality by Cox proportional hazards regression analysis (24 deaths at 47 months' median follow-up; risk ratio, 2.87; CI, 1.2-6.6; P=.02). The absolute increase in death was 11.9%.

These results and those from catheterized patients in the study suggest that an elevated NT-proBNP level largely reflects the severity of right ventricular dysfunction associated with pulmonary arterial hypertension rather than left ventricular filling abnormalities, and is strongly associated with advanced age, renal insufficiency, iron overload, and hemolytic anemia.

These data suggest that although the etiology of pulmonary hypertension is likely to be multifactorial, pulmonary vascular disease is the dominant pathophysiological process responsible for the pulmonary hypertension and that left ventricular diastolic dysfunction is a significant but less important contributor, Dr. Machado said.

Contrary to results from the Cooperative Study of Sickle Cell Disease, which found that clinical events such as frequent vaso-occlusive crisis and acute chest syndrome predicted early mortality, the data from this study suggest otherwise, the researchers said.

"The number of episodes of vaso-occlusive crisis and the acute chest syndrome do not appear to be associated with pulmonary hypertension, and pulmonary hypertension represents the single largest determinant of prospective risk of death in this population," they said.

"Our findings also provide further support for a mechanistic link between hemolytic anemia and pulmonary hypertension. The MSH analysis suggests that rates of pain episodes in this small sample of seriously ill patients were unrelated to risk of death; we speculate that the risk was largely determined by hemolytic anemia-associated occult pulmonary hypertension," Dr. Machado said.

The analysis of these two different groups of patients, he added, shows that this readily available biomarker provides diagnostic and mechanistic information about the development of pulmonary hypertension and identifies patients at the highest risk of death.

By combining blood BNP and echocardiography, which provides additional clinical information-- valve function, for example--"we hope to identify patients who can be treated more intensely to improve the management of the disease and hopefully their survival," Dr. Machado said. Studies testing drugs for pulmonary hypertension are currently under way, he added.