Characterization of the Changes in Cardiac Structure and Function in Mice Treated With Anthracyclines Using Serial Cardiac Magnetic Resonance Imaging

Farhad, Hoshang; Staziaki, Pedro V.; Addison, Daniel; Coelho‐Filho, Otávio R.; Shah, Ravi; Mitchell, Richard N.; Szilveszter, Bálint; Abbasi, S. A.; Kwong, Raymond Y.; Scherrer‐Crosbie, Marielle; Hoffmann, Udo; Jerosch‐Herold, Michael; Neilan, Tomas G.

doi:10.1161/circimaging.115.003584

Cited by 87 publications

(76 citation statements)

References 44 publications

(54 reference statements)

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“…Farhad et al . found increased myocardial T2 times in mice treated with anthracyclines at 5 weeks after beginning of anthracycline treatment, which resolves upon a 20 week follow‐up …”

Section: Discussionsupporting

confidence: 94%

“…Farhad et al found increased myocardial T2 times in mice treated with anthracyclines at 5 weeks after beginning of anthracycline treatment, which resolves upon a 20 week follow-up. 32 In our opinion, timing of imaging is crucial for interpretation of results. Cardiotoxicity of anthracyclines may not translate into a single long-term pathophysiolic mechanism but may rather consist of several phases.…”

Section: Discussionmentioning

confidence: 99%

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Native myocardial T1 time can predict development of subsequent anthracycline‐induced cardiomyopathy

et al. 2018

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AimsThis study aims to assess subclinical changes in functional and morphological myocardial magnetic resonance parameters very early into an anthracycline treatment, which may predict subsequent development of anthracycline‐induced cardiomyopathy (aCMP).Methods and resultsThirty sarcoma patients with planned anthracycline‐based chemotherapy (360–400 mg/m2 doxorubicin‐equivalent) were recruited. Median treatment time was 19.1 ± 2.1 weeks. Enrolled individuals received three cardiovascular magnetic resonance studies (before treatment, 48 h after first anthracycline treatment, and upon completion of treatment). Native T1 mapping (modified Look–Locker inversion recovery 5s(3s)3s), T2 mapping, and extracellular volume maps were acquired in addition to a conventional cardiovascular magnetic resonance with steady‐state free precession cine imaging at 1.5 T. Patients were given 0.2 mmol/kg gadoteridol for extracellular volume quantification and late gadolinium enhancement imaging. Development of relevant aCMP was defined as drop of left ventricular ejection fraction (LVEF) by >10%. For analysis, 23 complete data sets were available. Nine patients developed aCMP with LVEF reduction >10% until end of chemotherapy. Baseline LVEF was not different between patients with and without subsequent aCMP. When assessed 48 h after first dose of antracyclines, patients with subsequent aCMP had significantly lower native myocardial T1 times compared with before therapy (1002.0 ± 37.9 vs. 956.5 ± 29.2 ms, P < 0.01) than patients who did not develop aCMP (990.9 ± 56.4 vs. 978.4 ± 57.4 ms, P > 0.05). Patients with aCMP had decreased left ventricular mass upon completion of therapy (86.9 ± 24.5 vs. 81.1 ± 22.3 g; P = 0.02), while patients without aCMP did not show a change in left ventricular mass (81.8 ± 21.0 vs. 79.2 ± 18.1 g; P > 0.05). No patient developed new myocardial scars or compact myocardial fibrosis under chemotherapy.ConclusionsEarly decrease of T1 times 48 h after first treatment with anthracyclines can predict the development of subsequent aCMP after completion of chemotherapy.

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“…Farhad et al . found increased myocardial T2 times in mice treated with anthracyclines at 5 weeks after beginning of anthracycline treatment, which resolves upon a 20 week follow‐up …”

Section: Discussionsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Native myocardial T1 time can predict development of subsequent anthracycline‐induced cardiomyopathy

et al. 2018

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“…The finding that early mass increases may be a pathologic finding after anthracycline therapy is consistent with recent studies of adults exposed to anthracyclines,16 25 but differs from prior studies in long-term cancer survivors, which demonstrate reductions in LV mass 5. It is possible that myocardial oedema plays a role in these early changes,26 and it is notable that there was a subsequent decrease in mass by the later time point, which may reflect an evolving process.…”

Section: Discussionsupporting

confidence: 82%

Dexrazoxane preferentially mitigates doxorubicin cardiotoxicity in female children with sarcoma

et al. 2019

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ObjectiveWe sought to determine how sex and dexrazoxane therapy influence cardiac remodelling in children with sarcoma receiving high-dose doxorubicin.MethodsIn a retrospective cohort of 85 children with sarcoma receiving high-dose doxorubicin, echocardiography measures prior to, early after (within 6 months of doxorubicin completion) and 1 – 2 years after doxorubicin completion were quantified. At each follow-up visit, multivariable, propensity-adjusted linear regression models evaluated dexrazoxane’s effects on changes in left ventricular (LV) shortening fraction (SF), structure, strain and wall stress for subgroups divided by sex. Likelihood ratio tests assessed the interaction between sex and dexrazoxane in determining these changes.ResultsEarly after doxorubicin completion, males not treated with dexrazoxane (n = 15) developed increased cavity size and diminished circumferential strain; females (n = 8) developed diminished SF and strain indices, and increased cavity size and wall stress. With dexrazoxane, males (n = 33) demonstrated less deterioration in circumferential strain by 3.4% (95% CI 0.01 to 6.8), and females (n = 29) demonstrated less reduction in SF by 5.7% (95% CI 2.1 to 9.3), and had mitigation of increases in cavity size and wall stress. In interaction analyses, females had greater protection with dexrazoxane with regard to SF (p = 0.019) and cavity size in diastole (p = 0.002) and systole (p ≤ 0.001). These findings largely persisted 1 – 2 years after doxorubicin therapy.ConclusionsEarly, sustained alterations in LV structure and function occur in children with sarcoma after high-dose doxorubicin, with adverse changes and protective effects of dexrazoxane more pronounced in females as compared with males. Dexrazoxane may have sex-specific cardioprotective effects.

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“…To investigate the mechanism of protection, we therefore explored mitochondrial dynamics (fusion/fission) and authophagy 30 . Our TEM analysis revealed that mitochondria from doxorubicin-injected pigs not undergoing RIPC were abnormally small, had irregular and aberrant morphology, and contained a hyper-dense matrix, confirming previous reports 28,31 .…”

Section: Discussionsupporting

confidence: 90%

Remote Ischemic Preconditioning Ameliorates Anthracycline-induced Cardiotoxicity and Preserves Mitochondrial Integrity

Galán‐Arriola

Villena-Gutiérrez

Higuero-Verdejo

et al. 2020

Preprint

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AimsAnthracycline-induced cardiotoxicity (AIC) is a serious adverse effect in a significant proportion of cancer patients. A central mechanism of AIC is irreversible mitochondrial damage. Despite major efforts, there are currently no effective therapies able to prevent AIC. Methods and ResultsForty Large-White pigs were included. In Study 1, 20 pigs were randomized 1:1 to remote ischemic pre-conditioning (RIPC, 3 cycles of 5 min leg ischemia followed by 5 min reperfusion) or no pretreatment. RIPC was performed immediately before each of five intracoronary doxorubicin injections (0.45 mg/kg) given at weeks 0, 2, 4, 6, and 8. A group of 10 pigs with no exposure to doxorubicin served as healthy controls. Pigs underwent serial cardiac magnetic resonance (CMR) exams at baseline and at weeks 6, 8, 12, and 16. After 16week CMR, pigs were sacrificed and tissue samples collected. In study 2, 10 new pigs received 3 doxorubicin injections (with/out preceding RIPC) and were sacrificed 2 weeks after the third dose.In Study 1, LVEF remained unchanged in doxorubicin-treated pigs until week 6 (time of the fourth doxorubicin injection). From there on, LVEF progressively declined, but LVEF depression was blunted animals receiving RIPC before doxorubicin (RIPC-Doxo), which had a significantly higher LVEF at week 16 than doxorubicin treated pigs that received no pretreatment (Untreated-Doxo) (41.5±9.1% vs 32.5±8.7%, p=0.04). Preserved LVEF was mainly due to conserved contractile function, as evidenced by smaller LVESV, and better regional contractile function. In Study 2, transmission electron microscopy (TEM) after 3 doxorubicin doses showed fragmented mitochondria with severe morphological abnormalities in RIPC+Doxo pigs, together with upregulation of fission proteins and autophagy markers on western blot. At the end of the 16-week Study 1 protocol, TEM revealed overt mitochondrial Galan-Arriola et al. Remote ischemic conditioning and Cardiotoxicity 3 fragmentation with structural fragmentation in Untreated-Doxo pigs, whereas interstitial fibrosis was significantly less severe in the RIPC+Doxo pigs. ConclusionIn a translatable large animal model of AIC, RIPC applied immediately before each doxorubicin injection resulted in preserved cardiac contractility with significantly higher longterm LVEF and less cardiac fibrosis. RIPC prevented mitochondrial fragmentation and dysregulated autophagy from the early stages of AIC. RIPC is a promising intervention for testing in clinical trials in AIC.

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Characterization of the Changes in Cardiac Structure and Function in Mice Treated With Anthracyclines Using Serial Cardiac Magnetic Resonance Imaging

Cited by 87 publications

References 44 publications

Native myocardial T1 time can predict development of subsequent anthracycline‐induced cardiomyopathy

Native myocardial T1 time can predict development of subsequent anthracycline‐induced cardiomyopathy

Dexrazoxane preferentially mitigates doxorubicin cardiotoxicity in female children with sarcoma

Remote Ischemic Preconditioning Ameliorates Anthracycline-induced Cardiotoxicity and Preserves Mitochondrial Integrity

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