Carlos Galán-Arriola1, Manuel Lobo2, Jean Paul Vílchez-Tschischke2, Gonzalo J López3, Antonio de Molina-Iracheta3, Claudia Pérez-Martínez4, Jaume Agüero5, Rodrigo Fernández-Jiménez6, Ana Martín-García7, Eduardo Oliver3, Rocío Villena-Gutierrez3, Gonzalo Pizarro8, Pedro L Sánchez7, Valentin Fuster9, Javier Sánchez-González10, Borja Ibanez11. 1. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain. 2. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; Complejo Hospitalario Ruber Juan Bravo, Madrid, Spain. 3. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain. 4. Facultad de Veterinaria de León, León, Spain. 5. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain; Cardiology Department, Hospital Universtitari i Politecnic La Fe, Valencia, Spain. 6. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain; Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York. 7. Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain; Cardiology Department, Hospital Universitario de Salamanca-IBSAL, Salamanca, Spain. 8. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain; Complejo Hospitalario Ruber Juan Bravo, Madrid, Spain. 9. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York. 10. Philips Healthcare, Madrid, Spain. Electronic address: Javier.Sanchez.Gonzalez@philips.com. 11. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain; Cardiology Department, IIS-Fundación Jiménez Díaz Hospital, Madrid, Spain. Electronic address: bibanez@cnic.es.
Abstract
BACKGROUND: Anthracycline-induced cardiotoxicity is a major clinical problem, and early cardiotoxicity markers are needed. OBJECTIVES: The purpose of this study was to identify early doxorubicin-induced cardiotoxicity by serial multiparametric cardiac magnetic resonance (CMR) and its pathological correlates in a large animal model. METHODS: Twenty pigs were included. Of these, 5 received 5 biweekly intracoronary doxorubicin doses (0.45 mg/kg/injection) and were followed until sacrifice at 16 weeks. Another 5 pigs received 3 biweekly doxorubicin doses and were followed to 16 weeks. A third group was sacrificed after the third dose. All groups underwent weekly CMR examinations including anatomical and T2 and T1 mapping (including extracellular volume [ECV] quantification). A control group was sacrificed after the initial CMR. RESULTS: The earliest doxorubicin-cardiotoxicity CMR parameter was T2 relaxation-time prolongation at week 6 (2 weeks after the third dose). T1 mapping, ECV, and left ventricular (LV) motion were unaffected. At this early time point, isolated T2 prolongation correlated with intracardiomyocyte edema secondary to vacuolization without extracellular space expansion. Subsequent development of T1 mapping and ECV abnormalities coincided with LV motion defects: LV ejection fraction declined from week 10 (2 weeks after the fifth and final doxorubicin dose). Stopping doxorubicin therapy upon detection of T2 prolongation halted progression to LV motion deterioration and resolved intracardiomyocyte vacuolization, demonstrating that early T2 prolongation occurs at a reversible disease stage. CONCLUSIONS: T2 mapping during treatment identifies intracardiomyocyte edema generation as the earliest marker of anthracycline-induced cardiotoxicity, in the absence of T1 mapping, ECV, or LV motion defects. The occurrence of these changes at a reversible disease stage shows the clinical potential of this CMR marker for tailored anthracycline therapy.
BACKGROUND:Anthracycline-induced cardiotoxicity is a major clinical problem, and early cardiotoxicity markers are needed. OBJECTIVES: The purpose of this study was to identify early doxorubicin-induced cardiotoxicity by serial multiparametric cardiac magnetic resonance (CMR) and its pathological correlates in a large animal model. METHODS: Twenty pigs were included. Of these, 5 received 5 biweekly intracoronary doxorubicin doses (0.45 mg/kg/injection) and were followed until sacrifice at 16 weeks. Another 5 pigs received 3 biweekly doxorubicin doses and were followed to 16 weeks. A third group was sacrificed after the third dose. All groups underwent weekly CMR examinations including anatomical and T2 and T1 mapping (including extracellular volume [ECV] quantification). A control group was sacrificed after the initial CMR. RESULTS: The earliest doxorubicin-cardiotoxicity CMR parameter was T2 relaxation-time prolongation at week 6 (2 weeks after the third dose). T1 mapping, ECV, and left ventricular (LV) motion were unaffected. At this early time point, isolated T2 prolongation correlated with intracardiomyocyte edema secondary to vacuolization without extracellular space expansion. Subsequent development of T1 mapping and ECV abnormalities coincided with LV motion defects: LV ejection fraction declined from week 10 (2 weeks after the fifth and final doxorubicin dose). Stopping doxorubicin therapy upon detection of T2 prolongation halted progression to LV motion deterioration and resolved intracardiomyocyte vacuolization, demonstrating that early T2 prolongation occurs at a reversible disease stage. CONCLUSIONS: T2 mapping during treatment identifies intracardiomyocyte edema generation as the earliest marker of anthracycline-induced cardiotoxicity, in the absence of T1 mapping, ECV, or LV motion defects. The occurrence of these changes at a reversible disease stage shows the clinical potential of this CMR marker for tailored anthracycline therapy.
Authors: Srilakshmi Vallabhaneni; Kathleen W Zhang; Jose A Alvarez-Cardona; Joshua D Mitchell; Henning Steen; Pamela K Woodard; Daniel J Lenihan Journal: Int J Cardiovasc Imaging Date: 2021-05-12 Impact factor: 2.357