Long-term QT prolongation in monkeys after doxorubicin administration at doses similar to breast cancer therapy
BackgroundStudies in small animals and human patients have suggested that anthracyclines may prolong cardiac repolarization, or at least inhibit repolarization reserve, predisposing to QT prolongation and dangerous arrhythmias such as Torsades de pointes. This association in humans is difficult to c...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-12-01
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| Series: | Frontiers in Cardiovascular Medicine |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcvm.2023.1247273/full |
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| author | George M. Bodziock Giselle C. Meléndez Giselle C. Meléndez |
| author_facet | George M. Bodziock Giselle C. Meléndez Giselle C. Meléndez |
| author_sort | George M. Bodziock |
| collection | DOAJ |
| description | BackgroundStudies in small animals and human patients have suggested that anthracyclines may prolong cardiac repolarization, or at least inhibit repolarization reserve, predisposing to QT prolongation and dangerous arrhythmias such as Torsades de pointes. This association in humans is difficult to confirm due to multiple confounding variables such as the presence of other medications and concurrent illness.ObjectivesIdentify a long-term association between anthracycline administration and repolarization prolongation in nonhuman primates, which can be measured as prolonged QT/QTc intervals on surface electrocardiogram.MethodsFive female African Green monkeys (AGMs) aged 13 ± 1 years received Doxorubicin (Dox) at doses similar to women treated for breast cancer (30–60 mg/m2/biweekly IV, total cumulative dose: 240 mg/m2) and underwent 12-lead electrocardiogram (ECG) before and 15 weeks after the final dose of Dox treatment. A blinded paired analysis was performed on ECG derived heart rate (HR), QRS, QT and QT corrected for HR (QTc) interval durations.ResultsAfter Dox, all monkeys exhibited increased QT (BL: 323.2 ± 27.4 ms vs. Post-Dox: 366.4 ± 18.7 ms, p = 0.002) and QTc (BL: 440.2 ± 22.8 ms vs. Post-Dox: 500.8 ± 22.0 ms, p = 0.009) intervals, without any significant changes in HR or QRS duration (p = 0.92 and p = 0.47 respectively).ConclusionsAGMs treated with Dox exhibited long-term QT and QTc prolongation, along with the expected cardiotoxicity (LVEF decrease). While similar findings were shown in small animal studies, confounders make human association difficult to prove. Our finding provides a valuable intermediary step, showing direct effect of Dox on repolarization in nonhuman primates. |
| first_indexed | 2024-03-09T00:02:10Z |
| format | Article |
| id | doaj.art-8f1a1cd00a184d7bb83a9083f4a37695 |
| institution | Directory Open Access Journal |
| issn | 2297-055X |
| language | English |
| last_indexed | 2024-03-09T00:02:10Z |
| publishDate | 2023-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cardiovascular Medicine |
| spelling | doaj.art-8f1a1cd00a184d7bb83a9083f4a376952023-12-12T16:39:22ZengFrontiers Media S.A.Frontiers in Cardiovascular Medicine2297-055X2023-12-011010.3389/fcvm.2023.12472731247273Long-term QT prolongation in monkeys after doxorubicin administration at doses similar to breast cancer therapyGeorge M. Bodziock0Giselle C. Meléndez1Giselle C. Meléndez2Department of Internal Medicine, Section of Cardiovascular Medicine, Cardiac Electrophysiology, Wake Forest University School of Medicine, Winston-Salem, NC, United StatesDepartment of Internal Medicine, Section of Cardiovascular Medicine, Cardiac Electrophysiology, Wake Forest University School of Medicine, Winston-Salem, NC, United StatesDepartment of Pathology, Section on Comparative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, United StatesBackgroundStudies in small animals and human patients have suggested that anthracyclines may prolong cardiac repolarization, or at least inhibit repolarization reserve, predisposing to QT prolongation and dangerous arrhythmias such as Torsades de pointes. This association in humans is difficult to confirm due to multiple confounding variables such as the presence of other medications and concurrent illness.ObjectivesIdentify a long-term association between anthracycline administration and repolarization prolongation in nonhuman primates, which can be measured as prolonged QT/QTc intervals on surface electrocardiogram.MethodsFive female African Green monkeys (AGMs) aged 13 ± 1 years received Doxorubicin (Dox) at doses similar to women treated for breast cancer (30–60 mg/m2/biweekly IV, total cumulative dose: 240 mg/m2) and underwent 12-lead electrocardiogram (ECG) before and 15 weeks after the final dose of Dox treatment. A blinded paired analysis was performed on ECG derived heart rate (HR), QRS, QT and QT corrected for HR (QTc) interval durations.ResultsAfter Dox, all monkeys exhibited increased QT (BL: 323.2 ± 27.4 ms vs. Post-Dox: 366.4 ± 18.7 ms, p = 0.002) and QTc (BL: 440.2 ± 22.8 ms vs. Post-Dox: 500.8 ± 22.0 ms, p = 0.009) intervals, without any significant changes in HR or QRS duration (p = 0.92 and p = 0.47 respectively).ConclusionsAGMs treated with Dox exhibited long-term QT and QTc prolongation, along with the expected cardiotoxicity (LVEF decrease). While similar findings were shown in small animal studies, confounders make human association difficult to prove. Our finding provides a valuable intermediary step, showing direct effect of Dox on repolarization in nonhuman primates.https://www.frontiersin.org/articles/10.3389/fcvm.2023.1247273/fullantracyclinesQT prolongationmonkeysrepolarization reservecardiomyopathyTorsade de point |
| spellingShingle | George M. Bodziock Giselle C. Meléndez Giselle C. Meléndez Long-term QT prolongation in monkeys after doxorubicin administration at doses similar to breast cancer therapy Frontiers in Cardiovascular Medicine antracyclines QT prolongation monkeys repolarization reserve cardiomyopathy Torsade de point |
| title | Long-term QT prolongation in monkeys after doxorubicin administration at doses similar to breast cancer therapy |
| title_full | Long-term QT prolongation in monkeys after doxorubicin administration at doses similar to breast cancer therapy |
| title_fullStr | Long-term QT prolongation in monkeys after doxorubicin administration at doses similar to breast cancer therapy |
| title_full_unstemmed | Long-term QT prolongation in monkeys after doxorubicin administration at doses similar to breast cancer therapy |
| title_short | Long-term QT prolongation in monkeys after doxorubicin administration at doses similar to breast cancer therapy |
| title_sort | long term qt prolongation in monkeys after doxorubicin administration at doses similar to breast cancer therapy |
| topic | antracyclines QT prolongation monkeys repolarization reserve cardiomyopathy Torsade de point |
| url | https://www.frontiersin.org/articles/10.3389/fcvm.2023.1247273/full |
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