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Doxorubicin-associated Cardiac Remodeling Followed by CMR in Breast Cancer Patients
Doxorubicin-associated Cardiac Tissue Remodeling Followed by CMR of Myocardial Extracellular Volume and Myocyte Size in Breast Cancer Patients
Studie Overzicht
Toestand
Gedetailleerde beschrijving
This prospective cohort study was performed at the State University of Campinas, Brazil. The Institutional Review Board of the State University of Campinas approved the study and all participants provided informed consent. Female patients with breast cancer who received anthracycline (doxorubicin or daunorubicin or epirubicin) as part of their chemotherapy protocol were enrolled in the study.
Detailed medical history, standard anthropometric data, and measurement hemogram, troponin, CKMB, cholesterol, serum glucose, CRP and biomarkers were obtained.
As in adults, chronic anthracycline-related cardiotoxicity typically presents early, within one year after termination of chemotherapy and the peak time for the appearance of symptoms of heart failure is about three months after the last anthracycline dose, patients underwent CMR before and three times serially after DOX (two, five and twelve months).
Patients were imaged in supine position in a 3T magnet (Achieva, Philips Medical Systems, Best, The Netherlands). The CMR protocol consisted of electrocardiographically gated cine imaging with steady state free-precession to assess left ventricular (LV) function and LV mass. For imaging of late gadolinium enhancement (LGE) we used an inversion-recovery-prepared, gradient-echo sequence with segmented acquisition, which was triggered every other heartbeat. LGE images were acquired during end-expiratory breath-holding for slices matching the slice locations for cine imaging, starting within 10 min after bolus administration of a cumulative dose of 0.2 mmol/Kg of gadoterate meglumine (Dotarem, Guerbet, Aulnay-sous-Bois, France). T1 was performed with a Look-Locker sequence with a non-slice-selective adiabatic inversion pulse, followed by segmented gradient-echo acquisition for 17 times after inversion, covering approximately two cardiac cycles. The Look-Locker sequence was performed in a single short-axis slice at the level of the mid left ventricle. T1 imaging was repeated in the same LV short-axis slice, once before and five to seven times after the injection of gadolinium to cover an approximately 30-min period of slow contrast clearance.
All images were analyzed with MASS CMR software (Mass Research, Leiden University Medical Center, Leiden, the Netherlands). For LV mass and function quantification, the endocardial and epicardial borders of the LV myocardium were manually traced on short-axis cine images at end-diastole and systole. Papillary muscles were excluded from LV mass, and LV mass was indexed to body surface area.
For each Look-Locker image series, the endocardial and epicardial borders of the LV were traced and divided into six standard segments. Signal intensity versus time curves for each segment and the blood pool were used to determine segmental T1* by nonlinear, least-squares fitting to an analytic expression for the magnitude signal measured during the inversion recovery. T1 was calculated from the T1* and the amplitude parameters to correct for the effects of radiofrequency pulses applied during the inversion recovery.
Pairs of R1 values for myocardial tissue and blood data were fit with a two-space water-exchange model of equilibrium transcytolemmal water exchange. The myocardial extracellular volume fraction (ECV) and the intracellular lifetime of water (τic), a cell size-dependent parameter, were adjustable parameters of this model. The measured blood hematocrit was a fixed parameter of the model. All R1 measurements for each patient were used to fit the model to determine ECV and τic.
Studietype
Inschrijving (Werkelijk)
Fase
- Niet toepasbaar
Contacten en locaties
Studie Locaties
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São Paulo
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Campinas, São Paulo, Brazilië, 13083-887
- State University of Campinas
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Deelname Criteria
Geschiktheidscriteria
Leeftijden die in aanmerking komen voor studie
Accepteert gezonde vrijwilligers
Geslachten die in aanmerking komen voor studie
Beschrijving
Inclusion Criteria:
- Breast cancer and had prescribed an anthracycline agent as part of their chemotherapy regimen
Exclusion Criteria:
- Strict contraindications to MRI
- Acute or chronic kidney failure
- Previously diagnosed myocardial infarction, heart failure, valvular disease or cardiomyopathy.
Studie plan
Hoe is de studie opgezet?
Ontwerpdetails
- Primair doel: Diagnostisch
- Toewijzing: NVT
- Interventioneel model: Opdracht voor een enkele groep
- Masker: Geen (open label)
Wapens en interventies
Deelnemersgroep / Arm |
Interventie / Behandeling |
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Ander: Cardiovascular Magnetic Resonance
Twenty-seven female patients were imaged in a 3T magnet after consecutively enrolled in the study if they had received a breast cancer diagnosis at the Center for Integral Attention to Women's Health (University of Campinas) and had prescribed endovenous doxorubicin as part of their chemotherapy regimen.
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Patients had prescribed endovenous doxorubicin as part of their chemotherapy regimen (mean cumulative dose 102,66 mg/m2, administered in 4 doses with 21 days interval).
Andere namen:
Patients were imaged in supine position in a 3T magnet (Achieva, Philips Medical Systems, Best, The Netherlands).
The protocol consisted of electrocardiographically gated cine imaging with steady state free-precession to assess left ventricular (LV) ejection fraction and LV mass.
For imaging of late gadolinium-DTPA enhancement (LGE) we used an inversion-recovery-prepared, gradient-echo sequence with segmented acquisition, which was triggered every other heartbeat.
LGE images were acquired during end-expiratory breath-holding, after administration of Dotarem.
T1 was performed with a Look-Locker sequence with a non-slice-selective adiabatic inversion pulse, followed by segmented gradient-echo acquisition for 17 times after inversion, covering approximately two cardiac cycles.
T1 imaging was repeated in the same LV short-axis slice, once before and five to seven times after the injection of gadolinium to cover an approximately 30-min period of slow contrast clearance.
Andere namen:
LGE images were acquired starting within 10 min after bolus administration of a cumulative dose of 0.2 mmol/Kg of gadoterate meglumine (Dotarem, Guerbet, Aulnay-sous-Bois, France).
Andere namen:
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Wat meet het onderzoek?
Primaire uitkomstmaten
Uitkomstmaat |
Maatregel Beschrijving |
Tijdsspanne |
---|---|---|
Quantification of fibrosis index by Cardiac Magnetic Resonance
Tijdsspanne: two years
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Estimate the extracellular volume fraction derived from gadolinium-DTPA partition Coefficient of the myocardium
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two years
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Intracellular lifetime of water (τic) by Cardiac Magnetic Resonance
Tijdsspanne: two years
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This metric estimates the myocyte size using Cardiac Magnetic Resonance T1 mapping data
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two years
|
Secundaire uitkomstmaten
Uitkomstmaat |
Maatregel Beschrijving |
Tijdsspanne |
---|---|---|
Left ventricular mass by Cardiac Magnetic Resonance
Tijdsspanne: two years
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Electrocardiographically gated cine imaging with steady state free-precession to assess left ventricular mass.
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two years
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Left ventricular volumes by Cardiac Magnetic Resonance
Tijdsspanne: two years
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Electrocardiographically gated cine imaging with steady state free-precession to assess left ventricular volume.
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two years
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Left ventricular ejection fraction by Cardiac Magnetic Resonance
Tijdsspanne: two years
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Electrocardiographically gated cine imaging with steady state free-precession to assess left ventricular ejection fraction.
|
two years
|
Left ventricular myocardial edema fraction by Cardiac Magnetic Resonance
Tijdsspanne: two years
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Using T2-weighted sequences to visualize myocardial edema
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two years
|
Andere uitkomstmaten
Uitkomstmaat |
Maatregel Beschrijving |
Tijdsspanne |
---|---|---|
Ultra-sensitive troponin
Tijdsspanne: two years
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Cardiac troponin (ng/mL)
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two years
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Medewerkers en onderzoekers
Sponsor
Onderzoekers
- Hoofdonderzoeker: Otávio R. Coelho-Filho, MD, MPH, PhD, University of Campinas, Brazil
Publicaties en nuttige links
Algemene publicaties
- 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 Jul 13;122(2):138-44. doi: 10.1161/CIRCULATIONAHA.109.930636. Epub 2010 Jun 28.
- Cardinale D, Sandri MT, Colombo A, Colombo N, Boeri M, Lamantia G, Civelli M, Peccatori F, Martinelli G, Fiorentini C, Cipolla CM. Prognostic value of troponin I in cardiac risk stratification of cancer patients undergoing high-dose chemotherapy. Circulation. 2004 Jun 8;109(22):2749-54. doi: 10.1161/01.CIR.0000130926.51766.CC. Epub 2004 May 17.
- Tandri H, Saranathan M, Rodriguez ER, Martinez C, Bomma C, Nasir K, Rosen B, Lima JA, Calkins H, Bluemke DA. Noninvasive detection of myocardial fibrosis in arrhythmogenic right ventricular cardiomyopathy using delayed-enhancement magnetic resonance imaging. J Am Coll Cardiol. 2005 Jan 4;45(1):98-103. doi: 10.1016/j.jacc.2004.09.053.
- Von Hoff DD, Layard MW, Basa P, Davis HL Jr, Von Hoff AL, Rozencweig M, Muggia FM. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med. 1979 Nov;91(5):710-7. doi: 10.7326/0003-4819-91-5-710.
- Kim RJ, Fieno DS, Parrish TB, Harris K, Chen EL, Simonetti O, Bundy J, Finn JP, Klocke FJ, Judd RM. Relationship of MRI delayed contrast enhancement to irreversible injury, infarct age, and contractile function. Circulation. 1999 Nov 9;100(19):1992-2002. doi: 10.1161/01.cir.100.19.1992.
- Kim RJ, Wu E, Rafael A, Chen EL, Parker MA, Simonetti O, Klocke FJ, Bonow RO, Judd RM. The use of contrast-enhanced magnetic resonance imaging to identify reversible myocardial dysfunction. N Engl J Med. 2000 Nov 16;343(20):1445-53. doi: 10.1056/NEJM200011163432003.
- Hunold P, Wieneke H, Bruder O, Krueger U, Schlosser T, Erbel R, Barkhausen J. Late enhancement: a new feature in MRI of arrhythmogenic right ventricular cardiomyopathy? J Cardiovasc Magn Reson. 2005;7(4):649-55. doi: 10.1081/jcmr-65608.
- Harris PA, Lorenz CH, Holburn GE, Overholser KA. Regional measurement of the Gd-DTPA tissue partition coefficient in canine myocardium. Magn Reson Med. 1997 Oct;38(4):541-5. doi: 10.1002/mrm.1910380406.
- Flacke SJ, Fischer SE, Lorenz CH. Measurement of the gadopentetate dimeglumine partition coefficient in human myocardium in vivo: normal distribution and elevation in acute and chronic infarction. Radiology. 2001 Mar;218(3):703-10. doi: 10.1148/radiology.218.3.r01fe18703.
- Elliott P. Pathogenesis of cardiotoxicity induced by anthracyclines. Semin Oncol. 2006 Jun;33(3 Suppl 8):S2-7. doi: 10.1053/j.seminoncol.2006.04.020.
- Iles L, Pfluger H, Phrommintikul A, Cherayath J, Aksit P, Gupta SN, Kaye DM, Taylor AJ. Evaluation of diffuse myocardial fibrosis in heart failure with cardiac magnetic resonance contrast-enhanced T1 mapping. J Am Coll Cardiol. 2008 Nov 4;52(19):1574-80. doi: 10.1016/j.jacc.2008.06.049.
- Ellinor PT, Sasse-Klaassen S, Probst S, Gerull B, Shin JT, Toeppel A, Heuser A, Michely B, Yoerger DM, Song BS, Pilz B, Krings G, Coplin B, Lange PE, Dec GW, Hennies HC, Thierfelder L, MacRae CA. A novel locus for dilated cardiomyopathy, diffuse myocardial fibrosis, and sudden death on chromosome 10q25-26. J Am Coll Cardiol. 2006 Jul 4;48(1):106-11. doi: 10.1016/j.jacc.2006.01.079. Epub 2006 Jun 21.
- Ong DS, Scherrer-Crosbie M, Coelho-Filho O, Francis SA, Neilan TG. Imaging methods for detection of chemotherapy-associated cardiotoxicity and dysfunction. Expert Rev Cardiovasc Ther. 2014 Apr;12(4):487-97. doi: 10.1586/14779072.2014.893824.
- Kehr E, Sono M, Chugh SS, Jerosch-Herold M. Gadolinium-enhanced magnetic resonance imaging for detection and quantification of fibrosis in human myocardium in vitro. Int J Cardiovasc Imaging. 2008 Jan;24(1):61-8. doi: 10.1007/s10554-007-9223-y. Epub 2007 Apr 12.
- Swain SM. Doxorubicin-induced cardiomyopathy. N Engl J Med. 1999 Feb 25;340(8):654; author reply 655. No abstract available.
- Aiken MJ, Suhag V, Garcia CA, Acio E, Moreau S, Priebat DA, Chennupati SP, Van Nostrand D. Doxorubicin-induced cardiac toxicity and cardiac rest gated blood pool imaging. Clin Nucl Med. 2009 Nov;34(11):762-7. doi: 10.1097/RLU.0b013e3181b7d76f.
- Ewer MS, O'Shaughnessy JA. Cardiac toxicity of trastuzumab-related regimens in HER2-overexpressing breast cancer. Clin Breast Cancer. 2007 Jun;7(8):600-7.
- Perez EA. Cardiac toxicity of ErbB2-targeted therapies: what do we know? Clin Breast Cancer. 2008 Mar;8 Suppl 3:S114-20. doi: 10.3816/cbc.2008.s.007.
- Chien AJ, Rugo HS. The cardiac safety of trastuzumab in the treatment of breast cancer. Expert Opin Drug Saf. 2010 Mar;9(2):335-46. doi: 10.1517/14740331003627441.
- Ewer MS, Lenihan DJ. Left ventricular ejection fraction and cardiotoxicity: is our ear really to the ground? J Clin Oncol. 2008 Mar 10;26(8):1201-3. doi: 10.1200/JCO.2007.14.8742. Epub 2008 Jan 28. No abstract available.
- Von Hoff DD, Rozencweig M, Layard M, Slavik M, Muggia FM. Daunomycin-induced cardiotoxicity in children and adults. A review of 110 cases. Am J Med. 1977 Feb;62(2):200-8. doi: 10.1016/0002-9343(77)90315-1.
- Coelho-Filho OR, Mongeon FP, Mitchell R, Moreno H Jr, Nadruz W Jr, Kwong R, Jerosch-Herold M. Role of transcytolemmal water-exchange in magnetic resonance measurements of diffuse myocardial fibrosis in hypertensive heart disease. Circ Cardiovasc Imaging. 2013 Jan 1;6(1):134-41. doi: 10.1161/CIRCIMAGING.112.979815. Epub 2012 Nov 15.
- Rickers C, Wilke NM, Jerosch-Herold M, Casey SA, Panse P, Panse N, Weil J, Zenovich AG, Maron BJ. Utility of cardiac magnetic resonance imaging in the diagnosis of hypertrophic cardiomyopathy. Circulation. 2005 Aug 9;112(6):855-61. doi: 10.1161/CIRCULATIONAHA.104.507723.
- Landis CS, Li X, Telang FW, Molina PE, Palyka I, Vetek G, Springer CS Jr. Equilibrium transcytolemmal water-exchange kinetics in skeletal muscle in vivo. Magn Reson Med. 1999 Sep;42(3):467-78. doi: 10.1002/(sici)1522-2594(199909)42:33.0.co;2-0.
- Coelho-Filho OR, Shah RV, Mitchell R, Neilan TG, Moreno H Jr, Simonson B, Kwong R, Rosenzweig A, Das S, Jerosch-Herold M. Quantification of cardiomyocyte hypertrophy by cardiac magnetic resonance: implications for early cardiac remodeling. Circulation. 2013 Sep 10;128(11):1225-33. doi: 10.1161/CIRCULATIONAHA.112.000438. Epub 2013 Aug 2.
- Ferreira de Souza T, Quinaglia A C Silva T, Osorio Costa F, Shah R, Neilan TG, Velloso L, Nadruz W, Brenelli F, Sposito AC, Matos-Souza JR, Cendes F, Coelho OR, Jerosch-Herold M, Coelho-Filho OR. Anthracycline Therapy Is Associated With Cardiomyocyte Atrophy and Preclinical Manifestations of Heart Disease. JACC Cardiovasc Imaging. 2018 Aug;11(8):1045-1055. doi: 10.1016/j.jcmg.2018.05.012.
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Meer informatie
Termen gerelateerd aan deze studie
Aanvullende relevante MeSH-voorwaarden
- Hartziekten
- Hart-en vaatziekten
- Huidziektes
- Neoplasmata
- Neoplasmata per site
- Borst ziekten
- Borstneoplasmata
- Cardiomyopathieën
- Moleculaire mechanismen van farmacologische werking
- Enzymremmers
- Antineoplastische middelen
- Topoisomerase II-remmers
- Topoisomeraseremmers
- Antibiotica, antineoplastiek
- Chelaatvormers
- Sequestrerende agenten
- Doxorubicine
- Gadolinium 1,4,7,10-tetraazacyclododecaan-N,N',N'',N'''-tetraacetaat
Andere studie-ID-nummers
- DOX-0675014600011
Plan Individuele Deelnemersgegevens (IPD)
Bent u van plan om gegevens van individuele deelnemers (IPD) te delen?
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