NT-Probnp as a Marker of Cardiopulmonary Compromise and Exercise Limitation In Adults with Sickle Cell Anemia In the Walk-PHaSST Study

The N-terminal (NT) pro-brain natriuretic peptide (proBNP) hormone mediates natriuresis and vasodilation and down-regulates the renin-angiotensin-aldosterone axis. Elevated NT-proBNP levels have been reported in left heart failure [1] and pulmonary hypertension, [2] and the degree of NT-proBNP elevation appears to reflect the clinical and hemodynamic status of these patients. [3] Levels ≥160 pg/ml have been associated with pulmonary hypertension in adults with sickle cell disease, with a positive predictive value of 78%. [4] Elevated levels are highly predictive of mortality in the Cooperative Study of Sickle Cell Disease cohort (Machado et al, unpublished observations, 2009). Based on these data, we investigated the relationship of serum NT-proBNP levels with Doppler-echocardiographic estimates of right ventricular systolic pressure and left ventricular diastolic dysfunction, and exercise capacity in a large, prospective, multi-center, international cohort of sickle cell anemia patients in a cross-sectional manner.

Walk-PHaSST (treatment of Pulmonary Hypertension and Sickle cell disease with Sildenafil Therapy) includes an on-going observational study of sickle cell disease patients at nine United States Centers and one United Kingdom Center. In the screening phase of the study, patients had clinical evaluation, echocardiography, six-minute walk (6MW) testing and serum NT-proBNP measured. Of 720 patients screened, 483 had hemoglobin SS phenotype. The study prospectively defined 3 TRV cohorts: < 2.7 m/sec, 2.7–2.9 m/sec and TRV as ≥3.0 m/sec.

Of 483 hemoglobin SS patients, the median age was 35 years (range of 12 to 69 years) and the gender split was 250 females to 233 males. The 6MW test was performed in 475 patients, TRV in 453, NT-proBNP concentration in 447, and lateral wall E/Ea in 436. TRV was 2.7–2.9 m/sec in 22% and ≥3.0 m/sec in 17%. The median NT-proBNP concentration was 79 pg/ml with an interquartile range of 35–180. 119 (27%) of participants had levels ≥160 pg/ml.

By multiple linear regression, NT-ProBNP (natural log) correlated with creatinine >1.4 mgdL (standardized beta = 0.31; P <0.0005), lower hemoglobin concentration (standardized beta = -0.29; P <0.0005), older age (standardized beta = 0.22; P <0.0005), higher TRV categories (standardized beta = 0.12; P = 0.005), and higher log LV lateral wall E/Ea ratios (standardized beta = 0.08; P = 0.066).

NT-proBNP ≥160 had a positive predictive value of 58% for TRV 2.7–2.9 m/sec, 37% for TRV ≥3.0 m/sec, 68% for LV lateral wall E/Ea above the median (>6.4), and 38% for an upper quartile value of LV lateral wall E/Ea (>8.0).

By multiple linear regression, higher 6MW distance (6MWD) correlated with lower NT-proBNP levels after adjustment for age and gender. An elevated NT-proBNP level was associated with an estimated 22 m lower 6MWD (P = 0.026).

In this prospective, multicenter, international study of patients with sickle cell anemia, elevated NT-proBNP levels appear to be an independent predictor of: 1) higher estimated right ventricular systolic pressure and left ventricular filling pressure as assessed by Doppler-echocardiography and 2) lower 6MWD. These data validate the use of NT-proBNP in screening patients with sickle cell anemia for cardiac dysfunction and exercise limitations, and as an exploratory endpoint in controlled studies.

1. Tsutamoto, T., et al., Attenuation of compensation of endogenous cardiac natriuretic peptide system in chronic heart failure: prognostic role of plasma brain natriuretic peptide concentration in patients with chronic symptomatic left ventricular dysfunction. Circulation, 1997. 96(2): p. 509-16.

2. Kragelund, C., et al., N-terminal pro-B-type natriuretic peptide and long-term mortality in stable coronary heart disease. N Engl J Med, 2005. 352(7): p. 666-75.

3. Leuchte, H.H., et al., Clinical significance of brain natriuretic peptide in primary pulmonary hypertension. J Am Coll Cardiol, 2004. 43(5): p. 764-70.

4. Machado, R.F., et al., N-terminal pro-brain natriuretic peptide levels and risk of death in sickle cell disease. JAMA, 2006. 296(3): p. 310-8.

Barst:Pfizer: Consultancy, Research Funding. Rosenzweig:Pfizer: Research Funding. Hassell:Novartis: Research Funding. Gibbs:Pfizer: Speakers Bureau. Badesch:Pfizer: Honoraria, Research Funding.