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Javid Moslehi - One of the best experts on this subject based on the ideXlab platform.

  • immune checkpoint inhibitors and Cardiovascular Toxicity
    Lancet Oncology, 2018
    Co-Authors: Alexander R Lyon, Nadia Yousaf, Nicolo Matteo Luca Battisti, Javid Moslehi, James Larkin
    Abstract:

    Summary Immune checkpoint inhibitors are a new class of anticancer therapies that amplify T-cell-mediated immune responses against cancer cells. Immune checkpoint inhibitors have shown important benefits in phase 3 trials, and several agents have been approved for specific malignancies. Although adverse events from immune checkpoint inhibitors are a common occurrence, cardiotoxic effects are uncommon, but are often serious complications with a relatively high mortality. Most cardiotoxic effects appear to be inflammatory in nature. Clinical assessment of a combination of biomarkers, electrocardiography, cardiac imaging, and endomyocardial biopsy can be used to confirm a possible diagnosis. In this Review, we discuss the epidemiology of immune checkpoint inhibitor-mediated cardiotoxic effects, as well as their clinical presentation, subtypes, risk factors, pathophysiology, and clinical management, including the introduction of a new surveillance strategy.

  • radiation induced Cardiovascular Toxicity mechanisms prevention and treatment
    Current Treatment Options in Cardiovascular Medicine, 2018
    Co-Authors: Johan Spetz, Javid Moslehi, Kristopher A Sarosiek
    Abstract:

    Ionizing radiation is a highly effective treatment for a wide range of malignancies, yet the Cardiovascular (CV) Toxicity that can result from chest radiotherapy impairs the long-term health of cancer survivors and can be a limiting factor for its use. Despite over 100 years of successful clinical use, the mechanisms by which high-energy photons damage critical components within cells of the heart’s myocardium, pericardium, vasculature, and valves remain unclear. Recent studies exploring the acute and chronic effects of radiation therapy on cardiac and vascular tissue have provided new insights into the development and progression of heart disease, including the identification and understanding of age- and complication-associated risk factors. However, key questions relating to the connection from upstream signaling to fibrotic changes remain. In addition, advances in the delivery of chest radiotherapy have helped to limit heart exposure and damage, but additional refinements to delivery techniques and cardioprotective therapeutics are absolutely necessary to reduce patient mortality and morbidity. Radiation therapy (RT)-driven CV Toxicity remains a major issue for cancer survivors and more research is needed to define the precise mechanisms of Toxicity. However, recent findings provide meaningful insights that may help improve patient outcomes.

  • tyrosine kinase inhibitor associated Cardiovascular Toxicity in chronic myeloid leukemia
    Journal of Clinical Oncology, 2015
    Co-Authors: Javid Moslehi, Michael W Deininger
    Abstract:

    For most patients with chronic myeloid leukemia, tyrosine kinase inhibitors (TKIs) have turned a fatal disease into a manageable chronic condition. Imatinib, the first BCR-ABL1 TKI granted regulatory approval, has been surpassed in terms of molecular responses by the second-generation TKIs nilotinib, dasatinib, and bosutinib. Recently, ponatinib was approved as the only TKI with activity against the T315I mutation. Although all TKIs are associated with nonhematologic adverse events (AEs), experience with imatinib suggested that toxicities are typically manageable and apparent early during drug development. Recent reports of Cardiovascular AEs with nilotinib and particularly ponatinib and of pulmonary arterial hypertension with dasatinib have raised concerns about long-term sequelae of drugs that may be administered for decades. Here, we review what is currently known about the Cardiovascular toxicities of BCR-ABL1 TKIs, discuss potential mechanisms underlying Cardiovascular AEs, and elucidate discrepancies between the reporting of such AEs between oncology and Cardiovascular trials. Whenever possible, we provide practical recommendations, but we concede that cause-directed interventions will require better mechanistic understanding. We suggest that chronic myeloid leukemia heralds a fundamental shift in oncology toward effective but mostly noncurative long-term therapies. Realizing the full potential of these treatments will require a proactive rational approach to minimize long-term Cardiovascular and cardiometabolic toxicities.

  • tyrosine kinase inhibitor associated Cardiovascular Toxicity in chronic myeloid leukemia
    Journal of Clinical Oncology, 2015
    Co-Authors: Javid Moslehi, Michael W Deininger
    Abstract:

    For most patients with chronic myeloid leukemia, tyrosine kinase inhibitors (TKIs) have turned a fatal disease into a manageable chronic condition. Imatinib, the first BCR-ABL1 TKI granted regulatory approval, has been surpassed in terms of molecular responses by the second-generation TKIs nilotinib, dasatinib, and bosutinib. Recently, ponatinib was approved as the only TKI with activity against the T315I mutation. Although all TKIs are associated with nonhematologic adverse events (AEs), experience with imatinib suggested that toxicities are typically manageable and apparent early during drug development. Recent reports of Cardiovascular AEs with nilotinib and particularly ponatinib and of pulmonary arterial hypertension with dasatinib have raised concerns about long-term sequelae of drugs that may be administered for decades. Here, we review what is currently known about the Cardiovascular toxicities of BCR-ABL1 TKIs, discuss potential mechanisms underlying Cardiovascular AEs, and elucidate discrepancie...

Michael W Deininger - One of the best experts on this subject based on the ideXlab platform.

  • tyrosine kinase inhibitor associated Cardiovascular Toxicity in chronic myeloid leukemia
    Journal of Clinical Oncology, 2015
    Co-Authors: Javid Moslehi, Michael W Deininger
    Abstract:

    For most patients with chronic myeloid leukemia, tyrosine kinase inhibitors (TKIs) have turned a fatal disease into a manageable chronic condition. Imatinib, the first BCR-ABL1 TKI granted regulatory approval, has been surpassed in terms of molecular responses by the second-generation TKIs nilotinib, dasatinib, and bosutinib. Recently, ponatinib was approved as the only TKI with activity against the T315I mutation. Although all TKIs are associated with nonhematologic adverse events (AEs), experience with imatinib suggested that toxicities are typically manageable and apparent early during drug development. Recent reports of Cardiovascular AEs with nilotinib and particularly ponatinib and of pulmonary arterial hypertension with dasatinib have raised concerns about long-term sequelae of drugs that may be administered for decades. Here, we review what is currently known about the Cardiovascular toxicities of BCR-ABL1 TKIs, discuss potential mechanisms underlying Cardiovascular AEs, and elucidate discrepancies between the reporting of such AEs between oncology and Cardiovascular trials. Whenever possible, we provide practical recommendations, but we concede that cause-directed interventions will require better mechanistic understanding. We suggest that chronic myeloid leukemia heralds a fundamental shift in oncology toward effective but mostly noncurative long-term therapies. Realizing the full potential of these treatments will require a proactive rational approach to minimize long-term Cardiovascular and cardiometabolic toxicities.

  • tyrosine kinase inhibitor associated Cardiovascular Toxicity in chronic myeloid leukemia
    Journal of Clinical Oncology, 2015
    Co-Authors: Javid Moslehi, Michael W Deininger
    Abstract:

    For most patients with chronic myeloid leukemia, tyrosine kinase inhibitors (TKIs) have turned a fatal disease into a manageable chronic condition. Imatinib, the first BCR-ABL1 TKI granted regulatory approval, has been surpassed in terms of molecular responses by the second-generation TKIs nilotinib, dasatinib, and bosutinib. Recently, ponatinib was approved as the only TKI with activity against the T315I mutation. Although all TKIs are associated with nonhematologic adverse events (AEs), experience with imatinib suggested that toxicities are typically manageable and apparent early during drug development. Recent reports of Cardiovascular AEs with nilotinib and particularly ponatinib and of pulmonary arterial hypertension with dasatinib have raised concerns about long-term sequelae of drugs that may be administered for decades. Here, we review what is currently known about the Cardiovascular toxicities of BCR-ABL1 TKIs, discuss potential mechanisms underlying Cardiovascular AEs, and elucidate discrepancie...

Alice E Zemljicharpf - One of the best experts on this subject based on the ideXlab platform.

  • molecular mechanisms of anthracycline Cardiovascular Toxicity
    Clinical Science, 2021
    Co-Authors: Anna Narezkina, Hari K Narayan, Alice E Zemljicharpf
    Abstract:

    Anthracyclines are effective chemotherapeutic agents, commonly used in the treatment of a variety of hematologic malignancies and solid tumors. However, their use is associated with a significant risk of Cardiovascular toxicities and may result in cardiomyopathy and heart failure. Cardiomyocyte Toxicity occurs via multiple molecular mechanisms, including topoisomerase II-mediated DNA double-strand breaks and reactive oxygen species (ROS) formation via effects on the mitochondrial electron transport chain, NADPH oxidases (NOXs), and nitric oxide synthases (NOSs). Excess ROS may cause mitochondrial dysfunction, endoplasmic reticulum stress, calcium release, and DNA damage, which may result in cardiomyocyte dysfunction or cell death. These pathophysiologic mechanisms cause tissue-level manifestations, including characteristic histopathologic changes (myocyte vacuolization, myofibrillar loss, and cell death), atrophy and fibrosis, and organ-level manifestations including cardiac contractile dysfunction and vascular dysfunction. In addition, these mechanisms are relevant to current and emerging strategies to diagnose, prevent, and treat anthracycline-induced cardiomyopathy. This review details the established and emerging data regarding the molecular mechanisms of anthracycline-induced Cardiovascular Toxicity.

Zhiwei Sun - One of the best experts on this subject based on the ideXlab platform.

  • Cardiovascular Toxicity evaluation of silica nanoparticles in endothelial cells and zebrafish model
    Biomaterials, 2013
    Co-Authors: Junchao Duan, Zhiwei Sun
    Abstract:

    Environmental exposure to nanomaterials is inevitable as nanomaterials become part of our daily life, and as a result, nanoToxicity research is gaining attention. However, most investigators focus on the evaluation of overall Toxicity instead of a certain organism system. In this regard, the evaluation of Cardiovascular effects of silica nanoparticles was preformed in vitro and in vivo. It's worth noting that silica nanoparticles induced cytoToxicity as well as oxidative stress and apoptosis. ROS and apoptosis were considered as major factor to endothelial cells dysfunction, involved in several molecular mechanisms of Cardiovascular diseases. In vivo study, mortality, malformation, heart rate and whole-embryo cellular death were measured in zebrafish embryos. Results showed that silica nanoparticles induced pericardia Toxicity and caused bradycardia. We also examined the expression of Cardiovascular-related proteins in embryos by western blot analysis. Silica nanoparticles inhibited the expression of p-VEGFR2 and p-ERK1/2 as well as the downregulation of MEF2C and NKX2.5, revealed that silica nanoparticles could inhibit the angiogenesis and disturb the heart formation and development. In summary, our results suggest that exposure to silica nanoparticles is a possible risk factor to Cardiovascular system.

  • Cardiovascular Toxicity of different sizes amorphous silica nanoparticles in rats after intratracheal instillation
    Cardiovascular Toxicology, 2013
    Co-Authors: Dali Zhao, Li Jing, Guanqun Cui, Minghua Jin, Xiaomei Liu, Ying Liu, Caixia Guo, Xianqing Zhou, Zhiwei Sun
    Abstract:

    The purpose of this work was to investigate the Cardiovascular Toxicity of different sizes and different dosages of silica nanoparticles in Wistar rats. The three silica nanoparticles (30, 60, and 90 nm) and one fine silica particles (600 nm) at three doses of 2, 5, and 10 (mg/Kg bw) were used in the present experiment. After intratracheal instillation for a total of 16 times, concentration of Si in hearts and serum was measured by inductively coupled plasma optical emission spectrometer. The hematology parameters were analyzed by an automated hematology analyzer, and the inflammatory reaction, oxidative stress, endothelial dysfunction, and the myocardial enzymes in serum were measured by kits. Our results showed intratracheal-instilled silica nanoparticles could pass through the alveolar-capillary barrier into systemic circulation. Concentration of Si in the heart and serum depended on the particles size and dosage. The levels of reactive oxygen species (ROS) at 5, 10 mg/Kg bw of the three silica nanoparticles were higher than the fine silica particles. Blood levels of inflammation-related high-sensitivity C-reactive protein and cytokines such as interleukin-1beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha were increased after exposure to three silica nanoparticles at 10 mg/Kg bw. Moreover, the levels of IL-1β and IL-6 at 10 mg/Kg bw of silica nanoparticles (30 nm) were higher than the fine silica particles. Significant decrease in superoxide dismutase, glutathione peroxidase and significant increase in malondialdehyde were observed at 10 mg/Kg bw of the three silica nanoparticles. A significant decrease in nitric oxide (NO) production was induced which coincided with the reduction of nitric oxide synthase (NOS) activity and the excessive generation of ROS in rats. The levels of intercellular adhesion molecule-l and vascular cell adhesion molecule-l elevated significantly after exposure to three silica nanoparticles at 10 mg/Kg bw, which are considered as early steps of endothelial dysfunction. We conclude that Cardiovascular Toxicity of silica nanoparticles could be related to the particles size and dosage. Oxidative stress could be involved in inflammatory reaction and endothelial dysfunction, all of which could aggravate Cardiovascular toxicology. In addition, endothelial NO/NOS system disorder caused by nanoparticles could be one of the mechanisms for endothelial dysfunction.

Yaoxian Xuan - One of the best experts on this subject based on the ideXlab platform.

  • human cardiotoxic drugs delivered by soaking and microinjection induce Cardiovascular Toxicity in zebrafish
    Journal of Applied Toxicology, 2014
    Co-Authors: Yiqiao Xu, Hangping Yu, Yaoxian Xuan, Changjiang Huang, Jianhui He, Qiaoxiang Dong, Chunqi Li
    Abstract:

    Cardiovascular Toxicity is a major challenge for the pharmaceutical industry and predictive screening models to identify and eliminate pharmaceuticals with the potential to cause Cardiovascular Toxicity in humans are urgently needed. In this study, taking advantage of the transparency of larval zebrafish, Danio rerio, we assessed Cardiovascular Toxicity of seven known human cardiotoxic drugs (aspirin, clomipramine hydrochloride, cyclophosphamide, nimodipine, quinidine, terfenadine and verapamil hydrochloride) and two non-Cardiovascular Toxicity drugs (gentamicin sulphate and tetracycline hydrochloride) in zebrafish using six specific phenotypic endpoints: heart rate, heart rhythm, pericardial edema, circulation, hemorrhage and thrombosis. All the tested drugs were delivered into zebrafish by direct soaking and yolk sac microinjection, respectively, and Cardiovascular Toxicity was quantitatively or qualitatively assessed at 4 and 24 h post drug treatment. The results showed that aspirin accelerated the zebrafish heart rate (tachycardia), whereas clomipramine hydrochloride, cyclophosphamide, nimodipine, quinidine, terfenadine and verapamil hydrochloride induced bradycardia. Quinidine and terfenadine also caused atrioventricular (AV) block. Nimodipine treatment resulted in atrial arrest with much slower but regular ventricular heart beating. All the tested human cardiotoxic drugs also induced pericardial edema and circulatory disturbance in zebrafish. There was no sign of Cardiovascular Toxicity in zebrafish treated with non-cardiotoxic drugs gentamicin sulphate and tetracycline hydrochloride. The overall prediction success rate for cardiotoxic drugs and non-cardiotoxic drugs in zebrafish were 100% (9/9) as compared with human results, suggesting that zebrafish is an excellent animal model for rapid in vivo Cardiovascular Toxicity screening. The procedures we developed in this report for assessing Cardiovascular Toxicity in zebrafish were suitable for drugs delivered by either soaking or microinjection. Copyright © 2013 John Wiley & Sons, Ltd.

  • human cardiotoxic drugs delivered by soaking and microinjection induce Cardiovascular Toxicity in zebrafish
    Journal of Applied Toxicology, 2014
    Co-Authors: Junjing Zhu, Qiaoxiang Dong, Changjiang Huang, Jimin Gao, Yaoxian Xuan
    Abstract:

    Cardiovascular Toxicity is a major challenge for the pharmaceutical industry and predictive screening models to identify and eliminate pharmaceuticals with the potential to cause Cardiovascular Toxicity in humans are urgently needed. In this study, taking advantage of the transparency of larval zebrafish, Danio rerio, we assessed Cardiovascular Toxicity of seven known human cardiotoxic drugs (aspirin, clomipramine hydrochloride, cyclophosphamide, nimodipine, quinidine, terfenadine and verapamil hydrochloride) and two non-Cardiovascular Toxicity drugs (gentamicin sulphate and tetracycline hydrochloride) in zebrafish using six specific phenotypic endpoints: heart rate, heart rhythm, pericardial edema, circulation, hemorrhage and thrombosis. All the tested drugs were delivered into zebrafish by direct soaking and yolk sac microinjection, respectively, and Cardiovascular Toxicity was quantitatively or qualitatively assessed at 4 and 24 h post drug treatment. The results showed that aspirin accelerated the zebrafish heart rate (tachycardia), whereas clomipramine hydrochloride, cyclophosphamide, nimodipine, quinidine, terfenadine and verapamil hydrochloride induced bradycardia. Quinidine and terfenadine also caused atrioventricular (AV) block. Nimodipine treatment resulted in atrial arrest with much slower but regular ventricular heart beating. All the tested human cardiotoxic drugs also induced pericardial edema and circulatory disturbance in zebrafish. There was no sign of Cardiovascular Toxicity in zebrafish treated with non-cardiotoxic drugs gentamicin sulphate and tetracycline hydrochloride. The overall prediction success rate for cardiotoxic drugs and non-cardiotoxic drugs in zebrafish were 100% (9/9) as compared with human results, suggesting that zebrafish is an excellent animal model for rapid in vivo Cardiovascular Toxicity screening. The procedures we developed in this report for assessing Cardiovascular Toxicity in zebrafish were suitable for drugs delivered by either soaking or microinjection.