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      Doxorubicin induced heart failure: Phenotype and molecular mechanisms

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          Abstract

          Long term survival of childhood cancers is now more than 70%. Anthracyclines, including doxorubicin, are some of the most efficacious anticancer drugs available. However, its use as a chemotherapeutic agent is severely hindered by its dose-limiting toxicities. Most notably observed is cardiotoxicity, but other organ systems are also degraded by doxorubicin use. Despite the years of its use and the amount of information written about this drug, an understanding of its cellular mechanisms is not fully appreciated. The mechanisms by which doxorubicin induces cytotoxicity in target cancer cells have given insight about how the drug damages cardiomyocytes. The major mechanisms of doxorubicin actions are thought to be as an oxidant generator and as an inhibitor of topoisomerase 2. However, other signaling pathways are also invoked with significant consequences for the cardiomyocyte. Further the interaction between oxidant generation and topoisomerase function has only recently been appreciated and the consequences of this interaction are still not fully understood. The unfortunate consequences of doxorubicin within cardiomyocytes have promoted the search for new drugs and methods that can prevent or reverse the damage caused to the heart after treatment in cancer patients. Alternative protocols have lessened the impact on newly diagnosed cancer patients. However the years of doxorubicin use have generated a need for monitoring the onset of cardiotoxicity as well as understanding its potential long-term consequences. Although a fairly clear understanding of the short-term pathologic mechanisms of doxorubicin actions has been achieved, the long-term mechanisms of doxorubicin induced heart failure remain to be carefully delineated.

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          Most cited references87

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          Doxorubicin Cardiomyopathy

          Established doxorubicin cardiomyopathy is a lethal disease. When congestive heart failure develops, mortality is approximately 50%. Extensive research has been done to understand the mechanism and pathophysiology of doxorubicin cardiomyopathy, and considerable knowledge and experience has been gained. Unfortunately, no effective treatment for established doxorubicin cardiomyopathy is presently available. Extensive research has been done and is being done to discover preventive treatments. However an effective and clinically applicable preventive treatment is yet to be discovered.
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            Medical assessment of adverse health outcomes in long-term survivors of childhood cancer.

            Improved survival of children with cancer has been accompanied by multiple treatment-related complications. However, most studies in survivors of childhood cancer focused on only 1 late effect. To assess the total burden of adverse health outcomes (clinical or subclinical disorders ["adverse events"]) following childhood cancer in a large cohort of childhood cancer survivors with long-term and complete medical follow-up. Retrospective cohort study of 1362 five-year survivors of childhood cancer treated in a single institution in the Netherlands between 1966 and 1996. All survivors were invited to a late-effects clinic for medical assessment of adverse events. Adverse events occurring before January 2004 were graded for severity in a standardized manner. Treatment-specific prevalence of adverse events (according to severity) at end of follow-up and relative risk of high or severe burden of disease (> or =2 severe or > or =1 life-threatening or disabling adverse events) associated with various treatments. Medical follow-up was complete for 94.3% of survivors (median follow-up, 17.0 years). The median attained age at end of follow-up was 24.4 years. Almost 75% of survivors had 1 or more adverse events, and 24.6% had 5 or more adverse events. Furthermore, 40% of survivors had at least 1 severe or life-threatening or disabling adverse event. A high or severe burden of adverse events was observed in 55% of survivors who received radiotherapy only and 15% of survivors treated with chemotherapy only, compared with 25% of survivors who had surgery only (adjusted relative risks, 2.18 [95% confidence interval, 1.62-2.95] and 0.65 [95% confidence interval, 0.46-0.90], respectively). A high or severe burden of adverse events was most often observed in survivors of bone tumors (64%) and least often in survivors of leukemia or Wilms tumor (12% each). In young adulthood, a substantial proportion of childhood cancer survivors already has a high or severe burden of disease, particularly after radiotherapy. This underscores the need for lifelong risk-stratified medical surveillance of childhood cancer survivors.
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              Two-dimensional strain-a novel software for real-time quantitative echocardiographic assessment of myocardial function.

              We sought to assess the feasibility of 2-dimensional strain, a novel software for real-time quantitative echocardiographic assessment of myocardial function. Conventional and a novel non-Doppler-based echocardiography technique for advanced wall-motion analysis were performed in 20 patients with myocardial infarction and 10 healthy volunteers from the apical views. Two-dimensional strain is on the basis of the estimation that a discrete set of tissue velocities are present per each of many small elements on the ultrasound image. This software permits real-time assessment of myocardial velocities, strain, and strain rate. These parameters were also compared with Doppler tissue imaging measurements in 10 additional patients. In all, 80.3% of infarct and 97.8% of normal segments could be adequately tracked by the software. Peak systolic strain, strain rate, and peak systolic myocardial velocities, calculated from the software, were significantly higher in the normal than in the infarct segments. In the 10 additional patients, velocities, strain, and strain rate obtained with the novel software were not significantly different from those obtained with Doppler tissue imaging. Two-dimensional strain can accomplish real-time wall-motion analysis, and has the potential to become a standard for real-time automatic echocardiographic assessment of cardiac function.
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                Author and article information

                Contributors
                Journal
                Int J Cardiol Heart Vasc
                Int J Cardiol Heart Vasc
                International Journal of Cardiology. Heart & Vasculature
                Elsevier
                2352-9067
                24 November 2015
                March 2016
                24 November 2015
                : 10
                : 17-24
                Affiliations
                Department of Physiology, New York Medical College, Valhalla, NY, United States
                Author notes
                [* ]Corresponding author at: Department of Physiology, New York Medical College, 15 Dana Road, Valhalla, NY, United States.Department of PhysiologyNew York Medical College15 Dana RoadValhallaNYUnited States j_edwards@ 123456nymc.edu
                Article
                S2352-9067(15)30044-0
                10.1016/j.ijcha.2015.11.004
                4871279
                27213178
                3a9c1545-3245-4eb4-90db-d5c38c0b23e5
                © 2015 Published by Elsevier Ireland Ltd.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 11 June 2015
                : 23 October 2015
                : 22 November 2015
                Categories
                Article

                doxorubicin,cardiomyopathy,topoisomerase,heart failure,cancer,mitochondria,oxidant stress,dna damage

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