Serial measurements of cardiac biomarkers in patients after allogeneic hematopoietic stem cell transplantation
© Roziakova et al; licensee BioMed Central Ltd. 2012
Received: 9 December 2011
Accepted: 9 February 2012
Published: 9 February 2012
Previous therapy with anthracyclines (ANT) and conditioning regimen followed by hematopoietic stem cell transplantation (HSCT) represents a high risk for development of cardiotoxicity. The aim of this study was to assess subclinical myocardial damage after HSCT using echocardiography and cardiac biomarkers - high sensitive cardiac troponin T (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) and to identify patients at risk of developing clinical cardiotoxicity.
Patients and methods
Thirty-seven patients who were treated with allogeneic HSCT for hematologic diseases at median age of 28 years at time of HSCT were studied. Conditioning regimen included either chemotherapy without total body irradiation (TBI) or combination of chemotherapy with TBI. Twenty-nine (78,3%) patients were pretreated with ANT therapy. Cardiac biomarkers were serially measured before conditioning regimen and at days 1, 14 and 30 after HSCT. Cardiac systolic and diastolic functions were assessed before conditioning regimen and 1 month after HSCT by echocardiography.
The changes in plasma NT-proBNP and hs-cTnT levels during the 30 days following the HSCT were statistically significant (P < 0,01 v.s. P < 0,01). Persistent elevations of NT-proBNP and hs-cTnT simultaneously for a period exceeding 14 days after HSCT were found in 29,7% patients. Serum concentrations of cardiomarkers were significantly elevated in ANT group compared to non-ANT group. These observations were underscored by the echocardiographic studies which did reveal significant changes in systolic and diastolic parameters. Five of 37 (13,5%) patients developed clinical manifestation of cardiotoxicity.
Elevations in both cardiac biomarkers were found before clinical signs of cardiotoxicity developed. Persistent elevations in NT-pro-BNP and hs-cTnT concentrations simultaneously for a period exceeding 14 days might be used for identification of patients at risk of developing cardiotoxicity and requiring further cardiological follow up.
KeywordsHematopoietic stem cell transplantation Cardiotoxicity Natriuretic peptides Cardiac troponins
Stem cells are widely used in the treatment of malignant and nonmalignant diseases . Advances in allogeneic hematopoietic stem cell transplantation (HSCT) have increased survival in hematologic diseases. Among those who survive the first 2 years, nearly 80% of allogeneic HSCT recipients are expected to become long-term survivors and by 2020 there may be up to half a million of these survivors worldwide [2, 3].
However, HSCT survivors are at risk of developing long-term complications. A fifth of HSCT survivors develop severe or life-threatening conditions . Cardiac complications are frequently found life-threatening conditions. When cardiac dysfunction develops, complete recovery of cardiac function occurs in only 42% of patients, despite pharmacological therapy . Hence, new approaches for early cardiotoxicity detection need to be validated widely. Measurement of cardiospecific biomarkers can be a valid diagnostic tool for early identification, assessment and monitoring of cardiotoxicity. This approach is minimally invasive, less expensive than echocardiography and easily repeated.
Cardiac biomarkers are routinely evaluated only in patients before HSCT with increased cardiac risk [6, 7]. Future research should focus on the best timing for sampling, well-standardized methods for biomarkers determination and cut-off concentration that gives the best diagnostic accuracy in terms of sensitivity, specificity and predictive values. We therefore evaluated cardiotoxicity using cardiac biomarkers - high sensitive cardiac troponin T (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) during HSCT in 37 patients in whom echocardiography was performed before and one month after HSCT.
Patients and methods
This prospective study involved 37 consecutive patients with a median age of 28 years (range: 19-58 years) who underwent an allogeneic hematopoietic stem cell transplantation (HSCT) from June 2009 to February 2011 at the Transplantation Centre of Hematology Department at University Hospital Bratislava. There were 24 males and 13 females. Their diagnosis included acute myeloid leukemia (AML) in 13 patients, acute lymphoblastic leukemia (ALL) in 14 patients, chronic myeloid leukemia (CML) in 2 patients, Hodgkin's lymhoma in one patient, myelodysplastic syndrome (MDS) in 3 patients, osteomyelofibrosis in one patient and severe aplastic anemia in 3 patients.
Twenty-seven patients were conditioned with myeloablative regimens including cyclophosphamide (CY) 60 mg/kg body weight intravenously on 2 consecutive days in combination with fractionated total body irradiation (TBI) 12 Gy in six fractions of 2 Gy over 3 days in 12 patiens or in combination with peroral busulphan 4 mg/kg body weight daily for 4 days in 15 patients. The remaining 10 patients were conditioned with nonmyeloablative regimens (cyclophosphamide, busulphan, fludarabine, etoposide, cytosine arabinoside, melphalan, idarubicin, carmustine or with combination of antithymocyte globulin). Fifteen patients received hematopoietic stem cells from an HLA-matched related donor and 22 patients from an HLA-matched unrelated donor.
Characteristics of patients
Age at HSCT (median)
19-58 (28 years)
Treatment before HSCT
cranial RT (24 Gy)
mediastinal RT (24 Gy)
The study was approved by the local ethics committee of University Hospital Bratislava. Written informed consent was obtained from all patients.
Evaluation of cardiac function
Together 148 blood samples were evaluated in 37 patients. Serial measurements of plasma NT-proBNP and hs-cTnT concentrations were performed the day before conditioning regimen (baseline), the day after HSCT (D + 1), 14 days after HSCT (D + 14) and 30 days after HSCT (D + 30) in all patients. Venous blood samples were obtained from an indwelling catheter in the morning and serum concentrations of biomarkers were measured immediately by electrochemiluminescence immunoassay on Elecsys 2010 analyzer (Roche Diagnostics). The upper reference limit (99th percentil) for hs-cTnT was 0.014 μg/L and cut-off values for NT-proBNP excluding acute heart failure were 450 and 900 pg/mL for ages < 50 and 50-75 years [8, 9].
Echocardiography was performed before the conditioning regimen and 1 month after HSCT. Parameters of systolic and diastolic left ventricular (LV) function were evaluated. Systolic LV dysfunction was defined as ejection fraction (EF) less than or equal to 50%. To evaluate LV diastolic function, the following parameters were recorded: peak flow velocity of early filling (E), peak flow velocity of late filling (A), ratio of peak early to peak late flow velocities (E/A), E-wave deceleration time (DT) and isovolumetric relaxation time (IVRT). Diastolic LV dysfunction was defined as E/A inversion and DT above 220 ms on the transmitral Doppler curve (impaired relaxation).
Continuous variables (echocardiographic parameters) are presented as mean ± SD (standard deviation) and cardiac biomarkers (NT-proBNP, hs-cTnT) as median and interquartile range. Comparisons between continuous or categorical variables were performed using the Student's t-test, Mann-Whitney and Wilcoxon test. Friedman test was used to test the difference between variables. Correlations were evaluated with Spearman correlation coefficient. A P-value less than 0,05 was considered statistically significant.
Echocardiographic parameters before and after HSCT
65 ± 5,7
61 ± 4,8
1,37 ± 0,22
1,07 ± 0,3
174 ± 20,9
182 ± 24,5
75,06 ± 7,5
79,11 ± 6,8
Characteristics of patients with clinical cardiotoxicity
Clinical manifestation of cardiotoxicity
Day after HSCT
CD ANT (mg/m2)
Chest pain, dyspnea
TBI + CY
Chest pain, dyspnea
Fluid retention, pericarditis
TBI + CY
TBI + CY
The results of this prospective and single-center study revealed, that persistently elevated cardiac biomarkers have important implications for identifying high-risk patients, particularly if levels of cardiac troponins and natriuretic peptides are simultaneously elevated for a period exceeding 14 days. We found that NT-proBNP and hs-cTnT might be a useful diagnostic tool for early detection of cardiotoxicity before its clinical manifestation. All patients with clinical cardiotoxicity had contemporary elevations in both cardiac biomarkers before clinical signs developed.
Natriuretic peptides elevations have been shown to reflect wall stress, and thus provide functional information. Although the usefulness of NT-proBNP is well known in detection of chemotherapy-induced cardiotoxicity, only a few reports have assessed the detection of cardiotoxicity using BNP/NT-proBNP after allogeneic HSCT [10–13] or after high dose cyclophosphamide . We found a significant rise in the plasma NT-proBNP level one day after HSCT. This initial elevation in NT-proBNP levels might be a consequence of myocardial dysfunction caused by the conditioning regimen (TBI and/or chemotherapy), or previous ANT. It has been reported that a conditioning regimen causes an activation of endothelial cells and macrophages releasing inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) or interleukins (IL) 1 and 6. There is increasing evidence that inflammatory cytokines may also play an important role in the pathogenesis of heart failure by inhibiting cardiac contractility, promoting myocardial hypertrophy and inducing cardiomyocyte apoptosis [15, 16]. Elevated levels of NT-proBNP were found in 62,2% of patients even 14 days after HSCT. The same abnormalities were also found by Niwa et al (2002). Persistent elevations of NT-proBNP concentrations 30 days after HSCT were observed in 29,7% of patients, which might reflect subclinical cardiotoxicity.
Cardiac troponins have been defined as the biomarkers potentially useful for assessing minimal myocyte damage or loss of cell membrane integrity, and thus give structural information. The recently introduced highly sensitive troponin tests will expand the diagnostic potential to the detection of minor injuries of the heart and also higher cTnT levels, below the detection range of currently available assays may be considered as a marker of "end organ" cardiovascular damage [17, 18]. For cardiotoxicity of anticancer drugs are typical low levels of cTnT. The majorities of these troponins are bound to actin and are released slowly. This characteristic, along with the slow clearance of troponins from the body permits the detection of not only acute damage but also of ongoing injury . Baseline plasma hs-cTnT levels were elevated in 5 (13,5%) patients which might be associated with previous anthracycline exposure. Persistent low-level elevations at least 30 days after HSCT have been observed in our study in almost one third of patients, suggesting prolonged effects of chemotherapy or radiotherapy on the myofibrillar system of cardiomyocytes. Only some authors have demonstrated the role of cardiac troponins in detection of cardiotoxicity after allogeneic HSCT [13, 20–22]. In fact, several studies have already shown continuous damage of chemotherapy or radiotherapy to the cardiac myofibrillar system [23–25]. In our study, levels of NT-proBNP showed positive correlation with hs-cTnT, which might indicate a relationship between the degree of structural myocyte damage and functional myocardial impairment. These observations were underscored by the echocardiographic studies which did reveal significant changes in systolic and diastolic parameters.
Persistent elevations in cardiac biomarkers may reflect the presence of an underlying reduced functional myocardial reserve or reduced cardiac tolerance to cardiac stressors. Serial measurements of plasma NT-proBNP and hs-cTnT concentrations might be a useful tool for identification of patients at risk of developing cardiotoxicity after allogeneic HSCT and requiring cardiological follow up. Further studies are needed to clarify whether combination of both biomarkers improve detection of cardiotoxicity. Continued follow up is required to bring more insight into the predictive value of these biomarkers.
Peak flow velocity of late filling
Acute lymphoblastic leukemia
Acute myeloid leukemia
E-wave deceleration time
Peak flow velocity of early filling
Hematopoietic stem cell transplantation
High sensitive cardiac troponin T
Isovolumetric relaxation time
N-terminal pro-B-type natriuretic peptide
Total body irradiation.
The authors thank Marek Polomsky, M.D. from the University of Rochester, New York, USA for revision of the manuscript. This work was supported by a grant from the Scientific Grant Agency of the Ministry of Health, Slovak Republic 2007/42-UK-18.
- Lodi D, Iannitti T, Palmieri B: Stem cells in clinical practice: applications and warnings. J Exp Clin Cancer Res. 2011, 30: 9-10.1186/1756-9966-30-9.PubMed CentralView ArticlePubMedGoogle Scholar
- Bhatia S, Francisco L, Carter A, Sun CL, Baker KS, Gurney JG, McGlave PB, Nademanee A, O'Donnell M, Ramsay NK, Robison LL, Snyder D, Stein A, Forman SJ, Weisdorf DJ: Late mortality after hematopietic stem cell transplantation and functional status of long-term survivors: report from the Bone Marrow Transplant Survivor Study. Blood. 2007, 110: 3784-3791. 10.1182/blood-2007-03-082933.PubMed CentralView ArticlePubMedGoogle Scholar
- Savani BN, Griffith ML, Jagasia S, Lee SJ: How I treat late effects in adults after allogeneic stem cell transplantation. Blood. 2011, 117 (11): 3002-3009. 10.1182/blood-2010-10-263095.PubMed CentralView ArticlePubMedGoogle Scholar
- Sun CL, Francisco L, Kawashima T, Leisenring W, Robison LL, Baker KS, Weisdorf DJ, Forman SJ, Bhatia S: Prevalence and predictors of chronic health conditions after hematopoietic cell transplantation: a report from the Bone Marrow Transplant Survivor Study. Blood. 2010, 116 (17): 3129-3139. 10.1182/blood-2009-06-229369.PubMed CentralView ArticlePubMedGoogle Scholar
- Cardinale D, Sandri MM: Role of biomarkers in chemotherapy-induced cardiotoxicity. Prog Cardiovasc Dis. 2010, 53 (2): 121-129. 10.1016/j.pcad.2010.04.002.View ArticlePubMedGoogle Scholar
- Palladini G, Merlini G: Transplantation vs conventional-dose therapy for amyloidosis. Curr Opin Oncol. 2011, 23 (2): 214-220. 10.1097/CCO.0b013e328342b840.View ArticlePubMedGoogle Scholar
- Coghlan JG, Handler CE, Kottaridis PD: Cardiac assessment of patients for haematopoietic stem cell transplantation. Best Pract Res Clin Haematol. 2007, 20: 247-263. 10.1016/j.beha.2006.09.005.View ArticlePubMedGoogle Scholar
- Herman EH, Zhang J, Lipshultz SE, Rifai N, Chadwick D, Takeda K, Yu ZX, Ferrans VJ: Correlation between serum levels of cardiac troponin-T and the severity of the chronic cardiomyopathy induced by doxorubicin. J Clin Oncol. 1999, 17 (7): 2237-2243.PubMedGoogle Scholar
- Januzzi JL, Van Kimmenade R, Lainchbury J, Bayes-Genis A, Ordonez-Llanos J, Santalo-Bel M, Pinto YM, Richards M: NT-proBNP testing for diagnosis and short-term prognosis in acute destabilized heart failure: an international pooled analysis of 1256 patients: the International Collaborative of NT-proBNP Study. Eur Heart J. 2006, 27: 330-337.View ArticlePubMedGoogle Scholar
- Snowden JA, Hill GR, Hunt P, Carnoutsos S, Spearing RL, Espiner E, Hart DN: Assessment of cardiotoxicity during haemopoietic stem cell transplantation with plasma brain natriuretic peptide. Bone Marrow Transplant. 2000, 26: 309-313. 10.1038/sj.bmt.1702507.View ArticlePubMedGoogle Scholar
- Niwa N, Watanabe E, Hamaguchi M, Kodera Y, Miyazaki H, Kodama I, Ohono M: Early and late elevation of plasma atrial and brain natriuretic peptides in patients after bone marrow transplantation. Ann Hematol. 2001, 80: 460-465. 10.1007/s002770100331.View ArticlePubMedGoogle Scholar
- Masuko M, Ito M, Kurasaki T, Yano T, Takizawa J, Toba K, Aoki S, Fuse I, Kodama M, Furukawa T, Aizawa Y: Plasma brain natriuretic peptide during myeloablative stem cell transplantation. Intern Med. 2007, 46: 551-555. 10.2169/internalmedicine.46.6188.View ArticlePubMedGoogle Scholar
- Horacek JM, Pudil R, Tichy M, Jebavy L, Zak P, Slovacek L, Maly J: Biochemical markers and assessment of cardiotoxicity during preparative regimen and hematopoietic cell transplantation in acute leukemia. Exp Oncol. 2007, 29: 343-347.Google Scholar
- Sandri MT, Salvatici M, Cardinale D, Zorzino L, Passerini R, Lentati P, Leon M, Civelli M, Martinelli G, Cipolla CM: N-terminal pro-B-type natriuretic peptide after high-dose chemotherapy: a marker predictive of cardiac dysfunction?. Clin Chem. 2005, 51: 1405-1410. 10.1373/clinchem.2005.050153.View ArticlePubMedGoogle Scholar
- Rr P, Libby P: Inflammation in atherosclerosis: from vascular biology to biomarker discovery and risk prediction. Clin Chem. 2008, 54: 24-38.Google Scholar
- Bujak M, Frangogiannis NG: The role of IL-1 in the pathogenesis of heart disease. Arch Immunol Ther Exp (Warsz). 2009, 57: 165-176. 10.1007/s00005-009-0024-y.View ArticleGoogle Scholar
- Mearns BM: Biomarkers: even low cTnT levels are indicative of structural heart disease and might be useful in screening. Nat Rev Cardiol. 2011, 8 (2): 61-10.1038/nrcardio.2010.211.View ArticlePubMedGoogle Scholar
- de Lemos JA, Drazner MH, Omland T, Ayers CR, Khera A, Rohatgi A, Hashim I, Berry JD, Das SR, Morrow DA, McGuire DK: Association of troponin T detected with a highly sensitive assay and cardiac structure and mortality risk in the general population. JAMA. 2010, 304 (22): 2503-2512. 10.1001/jama.2010.1768.View ArticlePubMedGoogle Scholar
- Schully R, Lipschultz SE: Cardiovascular toxicity of antitumor drugs: dimensions of the problem in children. Cardiotoxicity of non-cardiovascular drugs. Edited by: Minotti G, Wiley. 2010, 97-126.View ArticleGoogle Scholar
- Auner HW, Tinchon C, Brezinschek RI, Eibl M, Sormann S, Maizen C, Linkesch W, Schmon-Kampel R, Quehenberger F, Tiran A, Sill H: Monitoring of cardiac function by serum cardiac troponin T levels, ventricular repolarisation indices, and echocardiography after conditioning with fractionated total body irradiation and high-dose cyclophosphamide. Eur J Haematol. 2002, 69: 1-6. 10.1034/j.1600-0609.2002.01661.x.View ArticlePubMedGoogle Scholar
- Horacek JM, Tichy M, Pudil R, Jebavy L, Zak P, Ulrychova M, Slovacek L, Maly J: Multimarker approach to evaluation of cardiac toxicity during preparative regimen and hematopoietic cell transplantation. Neoplasma. 2008, 55: 532-537.PubMedGoogle Scholar
- Peres E, Levine JE, Khaled YA, Ibrahim RB, Braun TM, Krijanovski OI, Mineishi S, Abidi MH: Cardiac complications in patients undergoing a reduced-intensity conditioning hematopoietic stem cell transplantation. Bone Marrow Transplant. 2010, 45: 149-151. 10.1038/bmt.2009.97.PubMed CentralView ArticlePubMedGoogle Scholar
- Kremer L, Van Der Pal HJ, Offringa M, Van Dalen EC, Voûte PA: Frequency and risk factors of subclinical cardiotoxicity after anthracycline therapy in children: a systematic review. Ann Oncol. 2002, 13: 819-829. 10.1093/annonc/mdf167.View ArticlePubMedGoogle Scholar
- Auner HW, Tinchon C, Linkesch W, Tiran A, Quehenberger F, Link H, Sill H: Prolonged monitoring of troponin T for the detection of anthracycline cardiotoxicity in adults with hematological malignancies. Ann Hematol. 2003, 82: 218-221.PubMedGoogle Scholar
- Kilickap S, Barista I, Akgul E, Aytemir K, Aksoyek S, Aksoy S, Celik I, Kes S, Tekuzman G: CTnT can be a useful marker for early detection of anthracycline cardiotoxicity. Ann Oncol. 2005, 16: 798-804. 10.1093/annonc/mdi152.View ArticlePubMedGoogle Scholar
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