Top

Journal of Cardiovascular Magnetic Resonance

Published in:

Open Access 01-12-2013 | Research

Diffuse myocardial fibrosis by T₁-mapping in children with subclinical anthracycline cardiotoxicity: relationship to exercise capacity, cumulative dose and remodeling

Authors: Edythe B Tham, Mark J Haykowsky, Kelvin Chow, Maria Spavor, Sachie Kaneko, Nee S Khoo, Joseph J Pagano, Andrew S Mackie, Richard B Thompson

Published in: Journal of Cardiovascular Magnetic Resonance | Issue 1/2013

Abstract

Background

The late cardiotoxic effects of anthracycline chemotherapy influence morbidity and mortality in the growing population of childhood cancer survivors. Even with lower anthracycline doses, evidence of adverse cardiac remodeling and reduced exercise capacity exist. We aim to examine the relationship between cardiac structure, function and cardiovascular magnetic resonance (CMR) tissue characteristics with chemotherapy dose and exercise capacity in childhood cancer survivors.

Methods

Thirty patients (15 ± 3 years), at least 2 years following anthracycline treatment, underwent CMR, echocardiography, and cardiopulmonary exercise testing (peak VO₂). CMR measured ventricular function, mass, T₁ and T₂ values, and myocardial extracellular volume fraction, ECV, a measure of diffuse fibrosis based on changes in myocardial T₁ values pre- and post-gadolinium. Cardiac function was also assessed with conventional and speckle tracking echocardiography.

Results

Patients had normal LVEF (59 ± 7%) but peak VO₂ was 17% lower than age-predicted normal values and were correlated with anthracycline dose (r = −0.49). Increased ECV correlated with decreased mass/volume ratio (r = −0.64), decreased LV wall thickness/height ratio (r = −0.72), lower peak VO₂(r = −0.52), and higher cumulative dose (r = 0.40). Echocardiographic measures of systolic and diastolic function were reduced compared to normal values (p < 0.01), but had no relation to ECV, peak VO₂ or cumulative dose.

Conclusions

Myocardial T₁ and ECV were found to be early tissue markers of ventricular remodeling that may represent diffuse fibrosis in children with normal ejection fraction post anthracycline therapy, and are related to cumulative dose, exercise capacity and myocardial wall thinning.

Available only for authorised users

Elbl L, Hrstkova H, Chaloupka V: The late consequences of anthracycline treatment on left ventricular function after treatment for childhood cancer. Eur J Pediatr. 2003, 162 (10): 690-696. 10.1007/s00431-003-1275-y.CrossRefPubMed

Marchandise B, Schroeder E, Bosly A, Doyen C, Weynants P, Kremer R, Pouleur H: Early detection of doxorubicin cardiotoxicity: interest of Doppler echocardiographic analysis of left ventricular filling dynamics. Am Heart J. 1989, 118 (1): 92-98. 10.1016/0002-8703(89)90077-X.CrossRefPubMed

Ewer MS, Ali MK, Mackay B, Wallace S, Valdivieso M, Legha SS, Benjamin RS, Haynie TP: A comparison of cardiac biopsy grades and ejection fraction estimations in patients receiving Adriamycin. J Clin Oncol. 1984, 2: 112-117.PubMed

Steinherz LJ, Steinherz PG, Tan CT, Heller G, Murphy ML: Cardiac toxicity 4 to 20 years after completing anthracycline therapy. JAMA. 1991, 266 (12): 1672-1677. 10.1001/jama.1991.03470120074036.CrossRefPubMed

Shankar SM, Marina N, Hudson MM, Hodgson DC, Adams MJ, Landier W, Bhatia S, Meeske K, Chen MH, Kinahan KE, Steinberger J, Rosenthal D, 2: Monitoring for cardiovascular disease in survivors of childhood cancer: report from the cardiovascular disease task force of the Children’s oncology group. Pediatrics. 2008, 121: e387-e396. 10.1542/peds.2007-0575. Epub 2008 Jan 10CrossRefPubMed

Takenaka K, Kuwada Y, Sonoda M, Uno K, Asakawa M, Sakurai S, Takahashi T, Sasaki K, Matsuzaki M, Kikuchi A, Amagai R, Furudate N, Nagai R: Anthracycline-induced cardiomyopathies evaluated by tissue Doppler tracking system and strain rate imaging. J Cardiol. 2001, 37 (Suppl 1): 129-132.PubMed

Cheung YF, Hong WJ, Chan GC, Wong SJ, Ha SY: Left ventricular myocardial deformation and mechanical dyssynchrony in children with normal ventricular shortening fraction after anthracycline therapy. Heart. 2010, 96 (14): 1137-1141. 10.1136/hrt.2010.194118.CrossRefPubMed

Sawaya H, Sebag IA, Plana JC, Januzzi JL, Ky B, Cohen V, Gosavi S, Carver JR, Wiegers SE, Martin RP, Picard MH, Gerszten RE, Halpern EF, Passeri J, Kuter I, Scherrer-Crosbie M: Early detection and prediction of cardiotoxicity in chemotherapy-treated patients. Am J Cardiol. 2011, 107: 1375-1380. 10.1016/j.amjcard.2011.01.006.PubMedCentralCrossRefPubMed

Jurcut R, Wildiers H, Ganame J, D’hooge J, De Backer J, Denys H, Paridaens R, Rademakers F, Voigt JU: Strain rate imaging detects early cardiac effects of pegylated liposomal Doxorubicin as adjuvant therapy in elderly patients with breast cancer. J Am Soc Echocardiogr. 2008, 21 (12): 1283-1289. 10.1016/j.echo.2008.10.005.CrossRefPubMed

10.

Flett AS, Hayward MP, Ashworth MT, Hansen MS, Taylor AM, Elliott PM, McGregor C, Moon JC: Equilibrium contrast cardiovascular magnetic resonance for the measurement of diffuse myocardial fibrosis: preliminary validation in humans. Circulation. 2010, 122 (2): 138-144. 10.1161/CIRCULATIONAHA.109.930636.CrossRefPubMed

11.

Gouya H, Vignaux O, Le Roux P, Chanson P, Bertherat J, Bertagna X, Legmann P: Rapidly reversible myocardial edema in patients with acromegaly: assessment with ultrafast T2 mapping in a single-breath-hold MRI sequence. Am J Roentgenol. 2008, 190: 1576-1582. 10.2214/AJR.07.2031.CrossRef

12.

Chow K, Flewitt J, Pagano JJ, Green JD, Friedrich M, Thompson RB: T₂-dependent errors in MOLLI T₁ values: simulations, phantoms, and in-vivo studies [abstract]. J Cardiovasc Magn Reson. 2012, 14 (Suppl 1): P281-10.1186/1532-429X-14-S1-P281.PubMedCentralCrossRef

13.

Chow K, Flewitt JA, Green JD, Friedrich MG, Thompson RB: Characterization of myocardial T₁ and partition coefficient as a function of time after gadolinium delivery in healthy subjects [abstract]. J Cardiovasc Magn Reson. 2011, 13 (Suppl 1): P31-10.1186/1532-429X-13-S1-P31.PubMedCentralCrossRef

14.

Schelbert EB, Testa SM, Meier CG, Ceyrolles WJ, Levenson JE, Blair AJ, Kellman P, Jones BL, Ludwig DR, Schwartzman D, Shroff SG, Wong TC: Myocardial extravascular extracellular volume fraction measurement by gadolinium cardiovascular magnetic resonance in humans: slow infusion versus bolus. J CardiovascMagnReson. 2011, 13: 16-

15.

Jones NL, Makrides L, Hitchcock C, Chypchar T, McCartney N: Normal standards for an incremental progressive cycle ergometer test. Am Rev Respir Dis. 1985, 131 (5): 700-708.PubMed

16.

Marcus KA, Mavinkurve-Groothuis AM, Barends M, van Dijk A, Feuth T, de Korte C, Kapusta L: Reference values for myocardial two-dimensional strain echocardiography in a healthy pediatric and young adult cohort. J Am Soc Echocardiogr. 2011, 24 (6): 625-636. 10.1016/j.echo.2011.01.021.CrossRefPubMed

17.

Buechel EV, Kaiser T, Jackson C, Schmitz A, Kellenberger CJ: Normal right- and left ventricular volumes and myocardial mass in children measured by steady state free precession cardiovascular magnetic resonance. J Cardiovasc Magn Reson. 2009, 11: 19-10.1186/1532-429X-11-19.PubMedCentralCrossRefPubMed

18.

Robbers-Visser D, Boersma E, Helbing WA: Normal biventricular function, volumes, and mass in children aged 8 to 17 years. J Magn Reson Imaging. 2009, 29: 552-559. 10.1002/jmri.21662.CrossRefPubMed

19.

Puntmann VO, Voigt T, Chen Z, Mayr M, Karim R, Rhode K, Pastor A, Carr-White G, Razavi R, Schaeffter T, Nagel E: Native T1 mapping in differentiation of normal myocardium from diffuse disease in hypertrophic and dilated cardiomyopathy. JACC Cardiovasc Imaging. 2013, 6 (4): 475-484. 10.1016/j.jcmg.2012.08.019.CrossRefPubMed

20.

Sibley CT, Noureldin RA, Gai N, Nacif MS, Liu S, Turkbey EB, Mudd JO, van der Geest RJ, Lima JA, Halushka MK, Bluemke DA: T1 Mapping in cardiomyopathy at cardiac MR: comparison with endomyocardial biopsy. Radiology. 2012, 265 (3): 724-732. 10.1148/radiol.12112721.PubMedCentralCrossRefPubMed

21.

Kellman P, Wilson JR, Xue H, Bandettini WP, Shanbhag SM, Druey KM, Ugander M, Arai AE: Extracellular volume fraction mapping in the myocardium, part 2: initial clinical experience. J Cardiovasc Magn Reson. 2012, 14: 64-10.1186/1532-429X-14-64.PubMedCentralCrossRefPubMed

22.

Ugander M, Oki AJ, Hsu LY, Kellman P, Greiser A, Aletras AH, Sibley CT, Chen MY, Bandettini WP, Arai AE: Extracellular volume imaging by magnetic resonance imaging provides insights into overt and sub-clinical myocardial pathology. Eur Heart J. 2012, 33 (10): 1268-1278. 10.1093/eurheartj/ehr481.PubMedCentralCrossRefPubMed

23.

Messroghli DR, Walters K, Plein S, Sparrow P, Friedrich MG, Ridgway JP, Sivananthan MU: MyocardialT1mapping: application to patients with acute and chronic myocardial infarction. MagnReson Med. 2007, 58 (1): 34-40. 10.1002/mrm.21272.CrossRef

24.

Sado DM, Flett AS, Banypersad SM, White SK, Maestrini V, Quarta G, Lachmann RH, Murphy E, Mehta A, Hughes DA, McKenna WJ, Taylor AM, Hausenloy DJ, Hawkins PN, Elliott PM, Moon JC: Cardiovascular magnetic resonance measurement of myocardial extracellular volume in health and disease. Heart. 2012, 98 (19): 1436-1441. 10.1136/heartjnl-2012-302346.CrossRefPubMed

25.

Piechnik SK, Ferreira VM, Lewandowski AJ, Ntusi NA, Banerjee R, Holloway C, Hofman MB, Sado DM, Maestrini V, White S, Lazdam M, Karamitso T, Moon JC, Neubauer S, Leeson P, Robson MD: Normal variation of magnetic resonance t1 relaxation times in the human population at 1.5t using shMOLLI. J Cardiovasc Magn Reson. 2013, 15: 13-10.1186/1532-429X-15-13.PubMedCentralCrossRefPubMed

26.

Messroghli DR, Plein S, Higgins DM, Walters K, Jones TR, Ridgway JP, Sivananthan MU: Human myocardium: single-breath-hold MR T1 mapping with high spatial resolution–reproducibility study. Radiology. 2006, 238 (3): 1004-1012. 10.1148/radiol.2382041903.CrossRefPubMed

27.

Ferreira VM, Piechnik SK, Dall’armellina E, Karamitsos TD, Francis JM, Choudhury RP, Friedrich MG, Robson MD, Neubauer SM: Non-contrast T1-mapping detects acute myocardial edema with high diagnostic accuracy: a comparison to T2-weighted cardiovascular magnetic resonance. J Cardiovasc Magn Reson. 2012, 14 (1): 42-10.1186/1532-429X-14-42.PubMedCentralCrossRefPubMed

28.

Messroghli DR, Greiser A, Frohlich M, Dietz R, Schulz-Menger J: Optimization and validation of a fully-integrated pulse sequence for modified look-locker inversion-recovery (MOLLI) T1 mapping of the heart. J Magn Reson Imaging. 2007, 26 (4): 1081-1086. 10.1002/jmri.21119.CrossRefPubMed

29.

Nacif MS, Turkbey EB, Gai N, Nazarian S, van der Geest RJ, Noureldin RA, Sibley CT, Ugander M, Liu S, Arai AE, Lima JA, Bluemke DA: Myocardial T1 mapping with MRI: comparison of look-locker and MOLLI sequences. J Magn Reson Imaging. 2011, 34 (6): 1367-73. 10.1002/jmri.22753.PubMedCentralCrossRefPubMed

30.

Gai ND, Stehning C, Nacif M, Bluemke DA: Modified Look-Locker T1 evaluation using Bloch simulations: human and phantom validation. Magn Reson Med. 2013, 69 (2): 329-36. 10.1002/mrm.24251.CrossRefPubMed

31.

Rodgers CT, Piechnik SK, Delabarre LJ, Van de Moortele PF, Snyder CJ, Neubauer S, Robson MD, Vaughan JT: Inversion recovery at 7 T in the human myocardium: Measurement of T(1) , inversion efficiency and B(1) (+). Magn Reson Med. 2012, 29: [Epub ahead of print]

32.

Neilan TG, Coelho-Filho OR, Shah RV, Feng JH, Pena-Herrera D, Mandry D, Pierre-Mongeon F, Heydari B, Francis SA, Moslehi J, Kwong RY, Jerosch-Herold M: Myocardial extracellular volume by cardiac magnetic resonance imaging in patients treated with anthracycline-based chemotherapy. Am J Cardiol. 2013, 111 (5): 717-722. 10.1016/j.amjcard.2012.11.022.PubMedCentralCrossRefPubMed

33.

Perel RD, Slaughter RE, Strugnell WE: Subendocardial late gadolinium enhancement in two patients with anthracycline cardiotoxicity following treatment for Ewing’s sarcoma. J CardiovascMagnReson. 2006, 8 (6): 789-791.

34.

Lipshultz SE, Colan SD, Gelber RD, Perez-Atayde AR, Sallan SE, Sanders SP: Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood. N Engl J Med. 1991, 324 (12): 808-815. 10.1056/NEJM199103213241205.CrossRefPubMed

35.

Goorin AM, Chauvenet AR, Perez-Atayde AR, Cruz J, McKone R, Lipshultz SE: Initial congestive heart failure, six to ten years after doxorubicin chemotherapy for childhood cancer. J Pediatr. 1990, 116: 144-147. 10.1016/S0022-3476(05)81668-3.CrossRefPubMed

36.

Bernaba BN, Chan JB, Lai CK, Fishbein MC: Pathology of late-onset anthracycline cardiomyopathy. Cardiovasc Pathol. 2010, 19 (5): 308-311. 10.1016/j.carpath.2009.07.004.CrossRefPubMed

37.

Thavendiranathan P, Walls M, Giri S, Verhaert D, Rajagopalan S, Moore S, Simonetti OP, Raman SV: Improved detection of myocardial involvement in acute inflammatory cardiomyopathies using t2 mapping. CircCardiovasc Imaging. 2012, 5 (1): 102-110. 10.1161/CIRCIMAGING.111.967836.CrossRef

38.

Giri S, Chung YC, Merchant A, Mihai G, Rajagopalan S, Raman SV, Simonetti OP: T2 quantification for improved detection of myocardial edema. J CardiovascMagnReson. 2009, 11: 56-

39.

Motoki H, Koyama J, Nakazawa H, Aizawa K, Kasai H, Izawa A, Tomita T, Miyashita Y, Kumazaki S, Takahashi M, Ikeda U: Torsion analysis in the early detection of anthracycline-mediated cardiomyopathy. European heart journal cardiovascular Imaging. 2012, 13 (1): 95-103. 10.1093/ejechocard/jer172.CrossRefPubMed

40.

Karila C, de Blic J, Waernessyckle S, Benoist MR, Scheinmann P: Cardiopulmonary exercise testing in children: an individualized protocol for workload increase. Chest. 2001, 120 (1): 81-87. 10.1378/chest.120.1.81.CrossRefPubMed

41.

De Caro E, Smeraldi A, Trocchio G, Calevo M, Hanau G, Pongiglione G: Subclinical cardiac dysfunction and exercise performance in childhood cancer survivors. Pediatr Blood Cancer. 2011, 56 (1): 122-126. 10.1002/pbc.22606.CrossRefPubMed

42.

Perhonen MA, Franco F, Lane LD, Buckey JC, Blomqvist CG, Zerwekh JE, Peshock RM, Weatherall PT, Levine BD: Cardiac atrophy after bed rest and spaceflight. J ApplPhysiol. 2001, 91 (2): 645-653.

Title: Diffuse myocardial fibrosis by T1-mapping in children with subclinical anthracycline cardiotoxicity: relationship to exercise capacity, cumulative dose and remodeling
Authors: Edythe B Tham
Mark J Haykowsky
Kelvin Chow
Maria Spavor
Sachie Kaneko
Nee S Khoo
Joseph J Pagano
Andrew S Mackie
Richard B Thompson
Publication date: 01-12-2013
Publisher: BioMed Central
Published in: Journal of Cardiovascular Magnetic Resonance / Issue 1/2013
Electronic ISSN: 1532-429X
DOI: https://doi.org/10.1186/1532-429X-15-48

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Diffuse myocardial fibrosis by T₁-mapping in children with subclinical anthracycline cardiotoxicity: relationship to exercise capacity, cumulative dose and remodeling

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2013

Myocardial T1 mapping and extracellular volume quantification: a Society for Cardiovascular Magnetic Resonance (SCMR) and CMR Working Group of the European Society of Cardiology consensus statement

SHILO, a novel dual imaging approach for simultaneous HI-/LOw temporal (Low-/Hi-spatial) resolution imaging for vascular dynamic contrast enhanced cardiovascular magnetic resonance: numerical simulations and feasibility in the carotid arteries

Atlas-based analysis of cardiac shape and function: correction of regional shape bias due to imaging protocol for population studies

Comparison of diffusion-weighted with T2-weighted imaging for detection of edema in acute myocardial infarction

Early detection of subclinical ventricular deterioration in aortic stenosis with cardiovascular magnetic resonance and echocardiography

Right and left ventricular function and myocardial scarring in adult patients with sickle cell disease: a comprehensive magnetic resonance assessment of hepatic and myocardial iron overload