The cardioprotective mechanism of phenylaminoethyl selenides (PAESe) against doxorubicin-Induced cardiotoxicity involves frataxin

Doxorubicin (DOX) is an anthracycline cancer chemotherapeutic that exhibits cumulative dose-limiting cardiotoxicity and limits its clinical utility. DOX treatment results in the development of morbid cardiac hypertrophy that progresses to congestive heart failure and death. Recent evidence suggests that during the development of DOX mediated cardiac hypertrophy, mitochondrial energetics are severely compromised, thus priming the cardiomyocyte for failure. To mitigate cumulative dose (5 mg/kg, QIW x 4 weeks with 2 weeks recovery) dependent DOX, mediated cardiac hypertrophy, we applied an orally active selenium based compound termed phenylaminoethyl selenides (PAESe) (QIW 10 mg/kg x 5) to our animal model and observed that PAESe attenuates DOX-mediated cardiac hypertrophy in athymic mice, as observed by MRI analysis. Mechanistically, we demonstrated that DOX impedes the stability of the iron-sulfur cluster biogenesis protein Frataxin (FXN) (0.5 fold), resulting in enhanced mitochondrial free iron accumulation (2.5 fold) and reduced aconitase activity (0.4 fold). Our findings further indicate that PAESe prevented the reduction of FXN levels and the ensuing elevation of mitochondrial free iron levels. PAESe has been shown to have anti-oxidative properties in part, by regeneration of glutathione levels. Therefore, we observed that PAESe can mitigate DOX mediated cardiac hypertrophy by enhancing glutathione activity (0.4 fold) and inhibiting ROS formation (1.8 fold). Lastly, we observed that DOX significantly reduced cellular respiration (basal (5%) and uncoupled (10%)) in H9C2 cardiomyoblasts and that PAESe protects against the DOX-mediated attenuation of cellular respiration. In conclusion, the current study determined the protective mechanism of PAESe against DOX mediated myocardial damage and that FXN is implicitly involved in DOX-mediated cardiotoxicity

Distribution of Coronary Artery Anomalies and Their Evaluation with Different Imaging Modalities

Introduction: Coronary artery anomalies (CAA) are diverse abnormalities. Methods: A retrospective review of coronary imaging of 17,245 patients over 2 years was performed. Patients with CAA detected on echocardiography, invasive coronary angiography (CAG) and multidetector computed tomographic angiography (MDCTA) were compared. Results: CAAs were detected in 257 patients (1.49%). Prevalence were: absent left main trunk- 0.319%, anomalous coronary artery from opposite sinus (ACAOS)- 0.516%, coronary fistulae- 0.203%, myocardial bridge- 0.093%, malignant anomalies- 0.3%. The commonest CAA was absent left main trunk. The yield of echocardiography negatively correlated with age (r=-0.6). CAG and MDCTA were equal (p=1) for detection of absent left main trunk. CAG had low sensitivity (58.3%) and MDCTA was better than it (p<0.01) for detection of abnormal high origin. For ACAOS, detection by both were not different (p=0.5) but the course was delineated better with MDCTA than with CAG (p=0.05). Both were equal for detection of intramyocardial course (p=0.5). However, MDCTA delineated its course better than CAG (p<0.01). Echocardiography had 93% sensitivity for fistula in those <12 years in age. Radiation exposure with CAG, 7.3 ± 2mSv, was lower than that with MDCTA, 14.5 ± 3mSv (p<0.01). It correlated with CAA score (r=0.3), with CAG but not with MDCTA. Contrast exposure correlated with CAA score (r=0.4) for adults with CAG but not with MDCTA. Conclusion: Echocardiography reliably detects CAAs in children. CAG and MDCTA are comparable for detection of most CAA. MDCTA delineates the course better than CAG. For MDCTA, radiation exposure is not correlated with complexity of CAA in contrast to that with CAG