Doxorubicin Cardiotoxicity and Cardiac Function Improvement After Stem Cell Therapy Diagnosed by Strain Echocardiography

Abstract

Doxorubicin (Dox) is one of the most effective chemotherapeutic agents; however, it causes dose-dependent cardiotoxicity. Evaluation of left ventricular function relies on measurements based on M-mode echocardiography. A new technique based on quantification of myocardial motion and deformation, strain echocardiography, has been showed promising profile for early detection of cardiac dysfunction. Different therapy strategies, such as flavonoid plant extracts and stem cells, have been investigated to improve heart function in toxic cardiomyopathy. This work aimed to assess early cardiac function improvement after treatments with either flavonoid extract from Camellia sinensis or mesenchymal stem cells in Dox cardiotoxicity using strain echocardiography. Twenty Wistar rats were randomly assigned to four groups. They received water (control, Dox, Dox + stem cells) or 100 mg/kg C. sinensis extract (Dox + C. sinensis) via gavage, daily, for four weeks. Animals also received saline (control) or 5 mg/kg doxorubicin (Dox, Dox + C. sinensis, Dox + stem cells) via intraperitoneal injection, weekly, for four weeks. Stem cells were injected (3 × 106 cells) through tail vein prior the beginning of the experiment (Dox + stem cells). Animals were evaluated by hematological, electrocardiography, echocardiography, and histopathological examinations. Dox cardiotoxicity was only diagnosed with strain echocardiography, detecting a decrease in ventricular function. C. sinensis extract did not prevent ventricular dysfunction induced by Dox. However, strain echocardiography examination revealed that Dox cardiotoxicity was significantly suppressed in rats treated with stem cells. In conclusion, strain echocardiography was able to detect precocity signs of heart failure and stem cell therapy showed cardioprotection effect against Dox cardiotoxicity.

Functional and Structural Assessment of the Effect of Human Umbilical Cord Blood Mesenchymal Stem Cells in Doxorubicin‐Induced Cardiotoxicity

“…At the end of the 6th week, MSCs-treated group (III), showed improved physical condition with better activity, significantly increased body weight, and moderate ascites compared to DOX group (II). These findings are consistent with previous studies [Di et al, 2012;Mohammadi Gorji et al, 2012;Oliveira et al, 2013;Ammar et al, 2015], reflecting the beneficial effects of MSCs on DOX-induced cardiotoxicity and heart failure. Moreover, MSCstreated group, showed improved survival as reported by Di et al [2012] and Pinarli et al [2013].…”

“…The MSCs-treated group showed a significant increase of MVP, EDP, dP/dt max, and dP/dt min at the end of the 6th week; consistent with previous studies [Rota et al, 2007;Ammar et al, 2015]. General improvement of the left ventricular function after systemic administration of MSCs was also shown by Oliveira et al [2013] and Pinarli et al [2013]. MSCs-mediated cardiac repair and function saving effects include modulation of inflammation, promotion of angiogenesis and reducing cardiac fibrosis that is critical in improving the performance and the function of the affected heart [Loffredo et al, 2011].…”

“…However, it causes cardiotoxicity that may lead to heart failure [Gianni et al, 2008]. The mechanism of DOX cardiotoxicity is still incompletely understood, but can be grouped into three theories: generation of reactive oxygen species (ROS), mitochondrial dysregulation; and apoptosis [Oliveira et al, 2013;Bernstein and Burridge, 2014].…”

The current understanding of mesenchymal stem cells as potential attenuators of chemotherapy‐induced toxicity

“…Anthracycline‐induced cardiotoxicity is attributed mainly to free radical formation in the mitochondria resulting in apoptosis of cardiac cells; MSCs were able to improve histopathologic and functional features and result in improved cardiac function after doxorubicin treatment in animal models . Additionally, bmMSCs were shown to regenerate doxorubicin‐induced nephropathy by reducing glomerular inflammation and preserving podocyte viability .…”

Improving the preclinical models for the study of chemotherapy-induced cardiotoxicity: a Position Paper of the Italian Working Group on Drug Cardiotoxicity and Cardioprotection

“…CSCs and CPCs offer novel and promising cardioprotective strategy for cancer therapy-induced cardiotoxicity, mainly through paracrine effects [56, [89][90][91][92][93][94]. Several signaling pathways including Akt [92] and Notch [91] are advocated to mediate the cardioprotective effects of CSCs and CPCs.…”