H-FABP in Pre Capillary Pulmonary Hypertension: Comparison to Other Surrogate Parameters for Prediction of Severity and Outcome

Hagen Schroetter, Michael Halank, Dirk Stolte, Peggy Barthel, Gert Hoeffken, Ruediger C. Braun-Dulleaus, Ruth H. Strasser, Alexander Schmeisser

.

DOI: 10.4236/ojrd.2011.11001                

Abstract

Background: Heart-type fatty acid-binding protein (H-FABP) is a promising novel biomarker for risk stratification of patients with chronic thromboembolic pulmonary hypertension (CTEPH). Whether disease severity in a group of patients with pre capillary pulmonary hypertension (PH) can be predicted by determination of plasma H-FABP levels remains unknown. Methods: 41 consecutive patients with a mean (±SD) age of 60.6 ± 2.1 years and severe PH were studied with a mean follow up to 541 days (95% CI: 420; 661 days). H-FABP, but also the biomarkers NT-Pro-BNP and big-endothelin (Big-ET1), were correlated to parameters derived from right sided cardiac catheterization and cardio-pulmonary exercise test. Results: At baseline H-FABP levels ranged from 620 to 15200 pg/ml (3648 ± 502 pg/ml) and were weakly but significantly correlated to VO2AT (r = –0.37, p = 0.04) and VO2 peak (r =–0.38, p = 0.03). However, invasively measured hemodynamic parameters of PH and right ventricular dysfunction did not correlate with H-FABP levels. In- terestingly, moderate to high correlations between H-FABP and NT-Pro-BNP (r = 0.51, p = 0.01) and Big-ET1 (r = 0.65, p = 0.01) and between Big-ET1 and NT-Pro-BNP (r = 0.5, p = 0.01) could be observed. In contrast to H-FABP, NT-Pro-BNP, and even more Big-ET1, showed significant correlations to different invasively measured hemodynamic parameters of the disease indicating severity and consequently prognosis of severe pre-capillary pulmonary hypertension. However, in a multivariate Cox regression analysis, PVR, mixed venous oxygen saturation and the VE/VCO2 slope (>60) as well as the heart rate recovery within one minute (HRR) but none of the biomarkers were identified as independent factors of poor prognosis. In con- trast, peak workload and mixed venous saturation were identified as risk markers in the idiopathic pulmonary arterial hypertension subgroup. Conclusions: In contrast to the predictive value of H-FABP in CTEPH H-FABP fails to be a reliable marker in PH or to be a novel predictor of mid and long term outcome. The data suggest that an increased slope of VE/VCO2 and a decreased extent of HRR within one minute represent more promising diagnostic non invasive parameters.

Keywords

Human Fatty Acid Binding Protein, Biomarker, Pulmonary Hypertension, Prognosis

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	W. Klepetko, E. Mayer, J. Sandoval, E. P. Trulock, J. L. Vachiery, P. Dartevelle, J. Pepke-Zaba, S. W. Jamieson, I. Lang and P. Corris, “Interventional and Surgical Modalities of Treatment for Pulmonary Arterial Hypertension,” Journal of the American College of Cardiology, Vol. 43, No. 12, 2004, pp. 73S-80S. doi:10.1016/j.jacc.2004.02.039
[2]	R. J. Barst, M. McGoon, A. Torbicki, O. Sitbon, M. J. Krowka, H. Olschewski and S. Gaine, “Diagnosis and Differential Assessment of Pulmonary Arterial Hypertension,” Journal of the American College of Cardiology, Vol. 43, No. 12, 2004, pp. 40S-47S. doi:10.1016/j.jacc.2004.02.032
[3]	V. V. McLaughlin, K. W. Presberg, R. L. Doyle, S. H. Abman, D. C. McCrory, T. Fortin and G. Ahearn, “Prog-nosis of Pulmonary Arterial Hypertension: ACCP Evidence-Based Clinical Practice Guidelines,” Chest, Vol. 126, No. 1, 2004, pp. 78S-92S. doi:10.1378/chest.126.1_suppl.78S
[4]	A. Torbicki, M. Kurzyna, P. Kuca, A. Fijalkowska, J. Sikora, M. Florczyk, P. Pruszczyk, J. Burakowski and L. Wawrzynska, “Detectable Serum Cardiac Troponin T as a Marker of Poor Prognosis among Patients with Chronic Precapillary Pulmonary Hypertension,” Circulation, Vol. 108, No. 7, 2003, pp. 844-848. doi:10.1161/01.CIR.0000084544.54513.E2
[5]	S. B. Eysmann, H. I. Palevsky, N. Reichek, K. Hackney, P. S. Douglas, “Two-Dimensional and Doppler- Echocardiographic and Cardiac Catheterization Correlates of Survival in Primary Pulmonary Hypertension,” Circulation, Vol. 80, 1989, pp. 353-360. doi:10.1161/01.CIR.80.2.353
[6]	R. J. Raymond, A. L. Hinderliter, P. W. Willis, et al., “Echocardiographic Predictors of Adverse Outcomes in Primary Pulmonary Hypertension,” Journal of the American College of Cardiology, Vol. 39, No. 7, 2002, pp. 1214-1219. doi:10.1016/S0735-1097(02)01744-8
[7]	N. Galie, A. L. Hinderliter, A. Torbicki, et al., “Effects of the Oral Endothelin-Receptor Antagonist Bosentan on Echocardiographic and Doppler Measures in Patients with Pulmonary Arterial Hypertension,” Journal of the American College of Cardiology, Vol. 41, No. 8, 2003, pp. 1380-1386. doi:10.1016/S0735-1097(03)00121-9
[8]	S. M. Kawut, E. M. Horn, K. K. Berekashvili, et al., “New Predictors of Outcome in Idiopathic Pulmonary Arterial Hypertension,” The American Journal of Cardiology, Vol. 95, No. 2, 2005, pp. 199-203. doi:10.1016/j.amjcard.2004.09.006
[9]	N. Nagaya, T. Nishikimi, M. Uematsu, et al., “Plasma Brain Natriuretic Peptide as a Prognostic Indicator in Pa-tients with Primary Pulmonary Hypertension,” Circulation, Vol. 102, 2000, pp. 865-870.
[10]	H. H. Leuchte, N. M. El, J. C. Tuerpe, et al., “N-terminal Pro-brain Natriuretic Peptide and Renal Insufficiency as Predictors of Mortality in Pulmonary Hypertension,” Chest, Vol. 131, No. 2, 2007, pp. 402-409. doi:10.1378/chest.06-1758
[11]	H. H. Leuchte, M. Holzapfel, R. A. Baumgartner, et al., “Clinical Significance of Brain Natriuretic Peptide in Primary Pulmonary Hypertension,” Journal of the Amer-ican College of Cardiology, Vol. 43, No. 5, 2004, pp. 764-770. doi:10.1016/j.jacc.2003.09.051
[12]	N. Nagaya, T. Nishikimi, Y. Okano, et al., “Plasma Brain Natriuretic Peptide Levels Increase in Proportion to the Extent of Right Ventricular Dysfunction in Pulmonary Hypertension,” Journal of the American College of Cardiology, Vol. 31, No. 1, 1998, pp. 202-208. doi:10.1016/S0735-1097(97)00452-X
[13]	N. Nagaya, T. Nishikimi, M. Uematsu, et al., “Plasma Brain Natriuretic Peptide as a Prognostic Indicator in Pa-tients with Primary Pulmonary Hypertension,” Circulation, Vol. 102, 2000, pp. 865-870.
[14]	A. Fijalkowska, M. Kurzyna, A. Torbicki, et al., “N-terminal Brain Natriuretic Peptide as a Prognostic Parameter in Patients with Pulmonary Hypertension,” Chest, Vol. 129, No. 5, 2006, pp. 1313-1321. doi:10.1378/chest.129.5.1313
[15]	M. M. Pelsers, W. T. Hermens and J. F. Glatz, “Fatty Acid-Binding Proteins as Plasma Markers of Tissue In-jury,” Clinica Chimica Acta, Vol. 352, No. 1-2, 2005, pp. 15-35. doi:10.1016/j.cccn.2004.09.001
[16]	H. A. Alhadi and K. A. Fox, “Do We Need Additional Markers of Myocyte Necrosis: The Potential Value of Heart Fatty-acid-binding Protein,” QJM, Vol. 97, No. 4, 2004, pp. 187-198. doi:10.1093/qjmed/hch037
[17]	M. M. Pelsers, W. T. Hermens, J. F. Glatz, “Fatty Acid-Binding Proteins as Plasma Markers of Tissue Injury,” Clinica Chimica Acta, Vol. 352, No. 1-2, 2005, pp. 15-35. doi:10.1016/j.cccn.2004.09.001
[18]	M. Puls, C. Dellas, M. Lankeit, et al., “Heart-Type Fatty Acid-Binding Protein Permits Early Risk Stratification of Pulmonary Embolism,” European Heart Journal, Vol. 28, No. 2, 2007, pp. 224-229. doi:10.1093/eurheartj/ehl405
[19]	A. Kaczynska, M. M. Pelsers, A. Bochowicz, et al., “Plasma Heart-Type Fatty Acid Binding Protein is Superior to Troponin and Myoglobin for Rapid Risk Stratification in Acute Pulmonary Embolism,” Clinica Chimica Acta, Vol. 371, No. 1-2, 2006, pp. 117-123. doi:10.1016/j.cca.2006.02.032
[20]	M. Lankeit, C. Dellas, A. Panzenbock, et al., “Heart-Type Fatty Acid-Binding Protein for Risk Assessment of Chronic Thromboembolic Pulmonary Hypertension,” European Respiratory Journal, Vol. 31, No. 5, 2008, pp. 1024-1029. doi:10.1183/09031936.00100407
[21]	J. L. Snow and S. M. Kawut, “Surrogate End Points in Pulmonary Arterial Hypertension: Assessing the Response to Therapy,” Clinics in Chest Medicine, Vol. 28, No. 1, 2007, pp. 75-89. doi:10.1016/j.ccm.2006.11.005
[22]	ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories, “ATS statement: Guidelines for the Six-Minute Walk Test,” American Journal of Respiratory and Critical Care Medicine, Vol. 166, No. 1, 2002, pp. 111-117.
[23]	N. Nagaya, T. Nishikimi, M. Uematsu, et al., “Plasma Brain Natriuretic Peptide as a Prognostic Indicator in Pa-tients with Primary Pulmonary Hypertension,” Circulation, Vol. 102, 2000, pp. 865-870.
[24]	H. H. Leuchte, N. M. El, J. C. Tuerpe, et al., “N-terminal Pro-brain Natriuretic Peptide and Renal Insufficiency as Predictors of Mortality in Pulmonary Hypertension,” Chest, Vol. 131, No. 2, 2007, pp. 402-409. doi:10.1378/chest.06-1758
[25]	J. A. de Lemos, D. K. McGuire and M. H. Drazner, “B-type Natriuretic Peptide in Cardiovascular Disease,” Lancet, Vol. 362, No. 9380, 2003, pp. 316-322. doi:10.1016/S0140-6736(03)13976-1
[26]	S. Rosenkranz, “Pulmonary Hypertension: Current Diagnosis and Treatment,” Clinical Research in Cardiology, Vol. 96, No. 8, 2007, pp. 527-541. doi:10.1007/s00392-007-0526-8
[27]	Y. Arai, J. P. Saul, P. Albrecht, et al., “Modulation of Cardiac Autonomic Activity during and Immediately after Exercise,” American Journal of Physiology, Vol. 256, No. 1, 1989, pp. H132-H141.
[28]	K. Imai, H. Sato, M. Hori, et al., “Vagally Mediated Heart Rate Recovery after Exercise is Accelerated in Athletes but Blunted in Patients with Chronic Heart Failure,” Journal of the American College of Cardiology, Vol. 24, No. 6, 1994, pp. 1529-1535. doi:10.1016/0735-1097(94)90150-3
[29]	P. J. Schwartz, M. T. La Rovere and E. Vanoli, “Auto-nomic Nervous System and Sudden Cardiac Death. Ex-perimental Basis and Clinical Observations for Post-Myocardial Infarction Risk Stratification,” Circula-tion, Vol. 85, 1992, pp. I77-I91.
[30]	C. R. Cole, E. H. Blackstone, F. J. Pashkow, et al., “Heart-Rate Recovery Immediately after Exercise as a Predictor of Mortality,” The New England Journal of Medicine, Vol. 341, 1999, pp. 1351-1357. doi:10.1056/NEJM199910283411804
[31]	M. Guazzi, J. Myers, M. A. Peberdy, et al., “Heart Rate Recovery Predicts Sudden Cardiac Death in Heart Fail-ure,” International Journal of Cardiology, Vol. 144, No. 1, 2009, pp. 121-123. doi:10.1016/j.ijcard.2008.12.149
[32]	N. Seshadri, T. R. Gildea, K. McCarthy, et al., “Association of an Abnormal Exercise Heart Rate Recovery with Pulmonary Function Abnormalities,” Chest, Vol. 125, No. 4, 2004, pp. 1286-1291. doi:10.1378/chest.125.4.1286
[33]	S. Velez-Roa, A. Ciarka, B. Najem, et al., “Increased Sympathetic Nerve Activity in Pulmonary Artery Hyper-tension,” Circulation, Vol. 110, 2004, pp. 1308-1312. doi:10.1161/01.CIR.0000140724.90898.D3
[34]	A. Ciarka, J. L. Vachiery, A. Houssiere, et al., “Atrial Septostomy Decreases Sympathetic Overactivity in Pul-monary Arterial Hypertension,” Chest, Vol. 131, No. 6, 2007, pp. 1831-1837. doi:10.1378/chest.06-2903
[35]	J. J. Swigris, J. Swick, F. S. Wamboldt, et al., “Heart Rate Recovery after 6-Minute Walk Test Predicts Survival in Patients with Idiopathic Pulmonary Fibrosis,” Chest, Vol. 136, No. 3, 2009, pp. 841-848. doi:10.1378/chest.09-0211
[36]	S. Miyamoto, N. Nagaya, T. Satoh, et al., “Clinical Correlates and Prognostic Significance of Six-Minute Walk Test in Patients with Primary Pulmonary Hypertension: Comparison with Cardiopulmonary Exercise Testing,” American Journal of Respiratory and Critical Care Medicine, Vol. 161, No. 2, 2000, pp. 487-492.