Search

Introduction:Although doxorubicin (DOX) is an efficient anthracycline agent used to treat cancer, it induces cardiotoxicity and mortality in cancer survivors. Cardioprotection is inadequate. The vitamin B6-derivative pyridoxamine (PM) has shown to be cardioprotective in diverse cardiac diseases. Whether PM offers cardioprotection after DOX treatment is unknown. We hypothesized that PM limits cardiac impairment after DOX treatment by reducing cardiac fibrosis and inflammation.Methods:Female Sprague Dawley rats were weekly treated with 2 mg/kg DOX or saline IV for 8 weeks. At DOX treatment onset, 2 extra groups received PM (1 g/L) via the drinking water. Echocardiographic (4D) and hemodynamic parameters were assessed at week 8, together with plasma BNP. PCR analysis was performed on left ventricular tissue to evaluate fibrosis and inflammation. Data were compared using 1-way ANOVA, Kruskal-Wallis test or 2-way ANOVA with post-hoc tests as appropriate.Results:As shown in Table 1, cardiac impairment by DOX was prevented by PM. In addition, DOX significantly increased the expression of fibrosis markers, such as TGFβ (0.29 ± 0.02 vs. 0.69 ± 0.09 a.u., p<0.0001), LOX (0.055 ± 0.002 vs. 0.590 ± 0.174 a.u., p<0.01), collagen type 1 (0.21 ± 0.02 vs. 0.62 ± 0.11 a.u., p<0.001) and interstitial collagen (4.6 ± 0.3 vs. 7.7 ± 0.6%, p<0.001). DOX also increased the inflammation marker IL-6 (0.13 ± 0.03 vs. 0.73 ± 0.13 a.u., p<0.01). PM treatment significantly lowered all these parameters (p<0001, p<0.001, p<0.01, p<0.01 and p<0.01 respectively).Conclusions:In conclusion, our data show that DOX causes dilated cardiomyopathy with reduced ejection fraction, accompanied by cardiac fibrosis and myocarditis. As PM limits this adverse phenotype, it could be a novel cardioprotective strategy for DOX-treated cancer patients.

Introduction:Myocardial infarction (MI) is the leading cause of heart failure (HF) worldwide. Current therapies are unable to replace lost cardiac tissue after MI and fail to prevent progression towards HF. Our research group identified a new cardiac stem cell type, the cardiac atrial appendage stem cells (CASCs), with superior cardiomyogenic differentiation potential. Whether CASCs transplantation can prevent loss of cardiac function and adverse cellular remodeling following MI, remains unknown.Methods:Permanent LAD ligation was performed in female Sprague Dawley rats. MI animals were randomly assigned to either CASCs injection (2.5x106? 1x106cells) in the MI border zone (MI+CASCs, n=12) or no injection (MI, n=12) at surgery. SHAM-operated animals served as control (n=10). Four weeks post-surgery, global cardiac function was assessed by conventional echocardiography and hemodynamic measurements. LV single cardiomyocytes were enzymatically isolated from the border zone. Contractile properties of single cardiomyocytes were assessed by unloaded cell shortening at 4Hz. Interstitial collagen deposition was evaluated from cryosections.Results:CASCs transplantation improved LV ejection fraction (86%?3 MI+CASCs vs 58%?5 MI) and reduced the increased end-systolic volume seen in MI (26?l?7 MI+CASCs vs 101?l?20 MI). Anterior wall thickness was normalized in the MI+CASCs group (1.47?0.06 cm vs 1.06?0.08 cm in MI group). Mean LV systolic pressure significantly decreased (32mmHg?2 MI+CASCs vs 45mmHg?2 MI) and dP/dtmaxsignificantly increased after CASCs transplantation (9001 mmHg/s?704 vs 6224 mmHg/s?234 in MI). There was no difference in dP/dtmin. Unloaded cell shortening of single cardiomyocytes from the transplanted group (7.1%?0.5) was improved compared to MI cardiomyocytes (5.4%?0.3). Finally, global cardiac fibrosis tended to be smaller in the MI+CASCs group.Conclusions:CASCs transplantation improves global cardiac function in vivoand prevents adverse cardiomyocyte remodeling after MI. Altogether, this study suggests that CASCs therapy is a promising cellular tool to restore cardiac function after ischemic injury.