Screening for in-vivo regional contractile defaults to predict the delayed Doxorubicin Cardiotoxicity in Juvenile Rat

Abstract

Anthracyclines are key chemotherapeutic agents used in various adult and pediatric cancers, however, their clinical use is limited due to possible congestive heart failure (HF) caused by acute and irreversible cardiotoxicity. Currently, there is no method to predict the future development of the HF in these patients. In order to identify early biomarkers to predict anthracycline cardiotoxicity in long-term survivors of childhood cancer, this longitudinal study aimed to analyze early and late in-vivo regional myocardial anthracycline-induced cardiotoxicity, related to in-vitro cardiac myocytes dysfunction, in a juvenile rat model. Methods: Young male Wistar rats (4 weeks-old) were treated with different cumulative doses of doxorubicin (7.5, 10 or 12.5 mg/kg) or NaCl (0.9%) once a week for 6 weeks by intravenous injection. Cardiac function was evaluated in-vivo by conventional (left ventricular ejection fraction, LVEF) and regional two-dimensional (2D) speckle tracking echocardiography over the 4 months after the last injection. The animals were assigned to preserved (pEF) or reduced EF (rEF) groups at the end of the protocol and were compared to controls. Results: We observed a preferential contractile dysfunction of the base of the heart, further altered in the posterior segment, even in pEF group. The first regional alterations appeared 1 month after chemotherapy. Functional investigation of cardiomyocytes isolated from the LV base 1 month after doxorubicin treatment showed that early in-vivo contractile alterations were associated with both decreased myofilament Ca 2+ sensitivity and length-dependent activation. Changes in post-translational modifications (phosphorylation; S-glutathionylation) and protein degradation of the cardiac myosin binding protein-C may contribute to these alterations. Conclusion: Our data suggest that screening of the contractile defaults of the base of the heart by regional 2D strain echocardiography is useful to detect subclinical myocardial dysfunction prior to the development of delayed anthracycline-induced cardiomyopathy in pediatric onco-cardiology.

Novel insights into sarcomere regulatory systems control of cardiac thin filament activation

“…Although the suppression of phosphorylation of cMyBP-C by this oxidation also requires more thorough investigation in cardiac disorders, there is evidence that the cross talk between cMyBP-C S-glutathionylation and PKA-dependent phosphorylation is an important determinant of altered cardiac function in stressful exercise in which the oxidation is increased and the phosphorylation is decreased ( Chakouri et al, 2018 ). A similar effect has been reported in doxorubicin-induced cardiac toxicity ( Chakouri et al, 2020 ).…”

Analysis of Models of Doxorubicin-Induced Cardiomyopathy in Rats and Mice. A Modern View From the Perspective of the Pathophysiologist and the Clinician

“…Other short-term models use 2–3.4 mg/kg of DOX every other day, six times intraperitoneally (the total dose is 12–20 mg/kg) ( Zbinden et al, 1978 ; Lanza et al, 1989 ; Carvalho et al, 2010 ; Razmaraii et al, 2016 ; Cappetta et al, 2018 ; Aygun and Gul, 2019 ; Barış et al, 2019 ). Long-term rat models typically use 1–5 mg/kg every week for 2–12 weeks with a cumulative dose of 3–25 mg/kg ( Villani et al, 1991 ; Sacco et al, 2001 ; Sayed-Ahmed et al, 2001 ; Rahimi Balaei et al, 2010 ; Hydock et al, 2012 ; Hole et al, 2013 ; Toblli et al, 2014 ; Kang et al, 2017 ; Medeiros-Lima et al, 2019 ; Wang et al, 2019 ; Chakouri et al, 2020 ; Sharma et al, 2020 ). Thus, a short-term high-dose injection model would be suitable for assessing acute cardiotoxicity, while a long-term low-dose model would be suitable for assessing chronic cardiotoxicity.…”

Doxorubicin Paradoxically Ameliorates Tumor-Induced Inflammation in Young Mice

“…Consequently, the rates of severe cardiovascular complications have decreased recently [35]. However, juvenile DOX-induced cardiotoxicity is often characterized in preclinical models using high cumulative doses of DOX that are enough to cause immediate or delayed cardiac dysfunction [36][37][38][39]. We have previously shown that low doses of DOX administered to young mice did not cause immediate cardiac dysfunction but rather a latent (subclinical) cardiotoxicity which can be unmasked by exposure to adult-onset cardiovascular stressors such as high blood pressure [25] or psychosocial stress [40].…”