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Authors: Almeida AG, Almeida A, Melo T, Guerra L, Lopes L, Ribeiro P, Duarte M, Mota A, Fontes-Carvalho R

Abstract

The use of tyrosine kinase inhibitors (TKIs) for the treatment of chronic myeloid leukemia has significantly altered the prognosis of this disease, enabling close to normal life expectancy. Despite their undeniable benefits, the use of TKIs is associated with an increased risk of side effects on the cardiovascular system, particularly of atherothrombotic events. It is therefore necessary to understand and prevent the adverse effects of these drugs, in order to enable antileukemic therapy to continue and to minimize patients' toxic exposure. This multidisciplinary consensus document, developed through a collaboration between hematologists and cardiologists, aims to review the cardiovascular toxicity associated with various TKIs and to establish recommendations for the follow-up of these patients. Measures are also proposed for the assessment and reduction of cardiovascular risk in these patients and referral criteria, and relevant drug interactions are discussed.

PMID: 30686651 [PubMed - indexed for MEDLINE]

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International Multisite Study of Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes for Drug Proarrhythmic Potential Assessment.

//www.ncbi.nlm.nih.gov/corehtml/query/egifs/https:--linkinghub.elsevier.com-ihub-images-celloa.png //www.ncbi.nlm.nih.gov/corehtml/query/egifs/https:--www.ncbi.nlm.nih.gov-corehtml-pmc-pmcgifs-pubmed-pmc-MS.gif Related Articles

International Multisite Study of Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes for Drug Proarrhythmic Potential Assessment.

Cell Rep. 2018 09 25;24(13):3582-3592

Authors: Blinova K, Dang Q, Millard D, Smith G, Pierson J, Guo L, Brock M, Lu HR, Kraushaar U, Zeng H, Shi H, Zhang X, Sawada K, Osada T, Kanda Y, Sekino Y, Pang L, Feaster TK, Kettenhofen R, Stockbridge N, Strauss DG, Gintant G

Abstract

To assess the utility of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) as an in vitro proarrhythmia model, we evaluated the concentration dependence and sources of variability of electrophysiologic responses to 28 drugs linked to low, intermediate, and high torsades de pointes (TdP) risk categories using two commercial cell lines and standardized protocols in a blinded multisite study using multielectrode array or voltage-sensing optical approaches. Logistical and ordinal linear regression models were constructed using drug responses as predictors and TdP risk categories as outcomes. Three of seven predictors (drug-induced arrhythmia-like events and prolongation of repolarization at either maximum tested or maximal clinical exposures) categorized drugs with reasonable accuracy (area under the curve values of receiver operator curves ∼0.8). hiPSC-CM line, test site, and platform had minimal influence on drug categorization. These results demonstrate the utility of hiPSC-CMs to detect drug-induced proarrhythmic effects as part of the evolving Comprehensive In Vitro Proarrhythmia Assay paradigm.

PMID: 30257217 [PubMed - indexed for MEDLINE]

19 December 2019

12:37

Cardiotoxicity News

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Efficacy and Safety of Tailored and Dose-Dense Adjuvant Chemotherapy and Trastuzumab for Resected HER2-Positive Breast Cancer: Results From the Phase 3 PANTHER Trial.

Cancer. 2019 Dec 18;:

Authors: Papakonstantinou A, Matikas A, Bengtsson NO, Malmström P, Hedayati E, Steger G, Untch M, Hübbert L, Johansson H, Hellström M, Gnant M, Loibl S, Greil R, Moebus V, Foukakis T, Bergh J

Abstract

BACKGROUND: Dose-dense (DD) adjuvant chemotherapy improves outcomes in early breast cancer (BC). However, there are no phase 3 randomized data to inform on its combination with trastuzumab for patients with human epidermal growth factor receptor 2 (HER2)-positive disease.

METHODS: This was a protocol-predefined secondary analysis of the randomized phase 3 Pan-European Tailored Chemotherapy (PANTHER) trial. Women 65 years old or younger with node-positive or high-risk, node-negative BC were randomized 1:1 to either tailored (according to hematologic nadirs) and DD epirubicin and cyclophosphamide followed by docetaxel or standard 5-fluorouracil, epirubicin, and cyclophosphamide plus docetaxel every 3 weeks. Patients with HER2-positive disease received 1 year of adjuvant trastuzumab. The primary endpoint was BC relapse-free survival. In addition, HER2-positive patients and an equal number of HER2-negative patients matched for age, treatment group, and institution who were enrolled at Swedish sites were asked to participate in a predefined study of cardiac safety and underwent echocardiography or multigated acquisition scanning and electrocardiography at the baseline and at 4 and 6 years of follow-up.

RESULTS: There were 342 HER2-positive patients; 335 received at least 1 dose of trastuzumab, and 29 patients discontinued trastuzumab prematurely. Relapse-free survival was not statistically significantly in favor of the tailored and DD group (hazard ratio, 0.68; 95% confidence interval, 0.37-1.27; P = .231). Cardiac outcomes after 4 and 6 years of follow-up did not differ significantly between HER2-positive and HER2-negative patients or between the 2 treatment groups.

CONCLUSIONS: The combination of DD chemotherapy and trastuzumab decreased the relative risk for relapse by 32% in comparison with standard treatment, a statistically nonsignificant difference. Its efficacy and safety merit further evaluation as part of both escalation and de-escalation strategies.

PMID: 31851385 [PubMed - as supplied by publisher]

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Immune Checkpoint Inhibitor-Associated Cardiotoxicity: Current Understanding on Its Mechanism, Diagnosis and Management.

Front Pharmacol. 2019;10:1350

Authors: Zhou YW, Zhu YJ, Wang MN, Xie Y, Chen CY, Zhang T, Xia F, Ding ZY, Liu JY

Abstract

Immune checkpoint inhibitors (ICIs) that target cytotoxic T lymphocyte antigen 4, programmed cell death-1, and PD-ligand 1 have revolutionized cancer treatment, achieving unprecedented efficacy in multiple malignancies. ICIs are increasingly being used in early cancer settings and in combination with various other types of therapies, including targeted therapy, radiotherapy, and chemotherapy. However, despite the excellent therapeutic effect of ICIs, these medications typically result in a broad spectrum of toxicity reactions, termed immune-related adverse events (irAEs). Of all irAEs, cardiotoxicity, uncommon but with high mortality, has not been well recognized. Herein, based on previous published reports and current evidence, we summarize the incidence, diagnosis, clinical manifestations, underlying mechanisms, treatments, and outcomes of ICI-associated cardiotoxicity and discuss possible management strategies. A better understanding of these characteristics is critical to managing patients with ICI-associated cardiotoxicity.

PMID: 31849640 [PubMed]

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Clinical manifestation and management of immune checkpoint inhibitor-associated cardiotoxicity.

Thorac Cancer. 2019 Dec 17;:

Authors: Guo X, Wang H, Zhou J, Li Y, Duan L, Si X, Zhang L, Fang L, Zhang L

Abstract

Immune checkpoint inhibitors (ICIs) targeting programmed death-1 (PD-1), its ligand (PD-L1), and cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) have revolutionized cancer treatment by recovering the attack of T lymphocytes on the malignant cells. They have improved clinical outcomes dramatically in multiple types of advanced-stage malignancies. Even though the tolerance and safety profiles are generally good, it has been widely reported that ICIs can cause severe or fatal immune-related adverse events (irAEs), since the activated T lymphocytes are not specific for tumor cells. Cardiac irAEs appear to occur less frequently than irAEs in other organ systems but are notorious for high mortality. Here, we aim to identify and characterize the ICI-associated cardiotoxicity and summarize the optional diagnosis and treatment strategies.

PMID: 31849171 [PubMed - as supplied by publisher]

20 December 2019

13:44

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Pulmonary exposure to silver nanoparticles impairs cardiovascular homeostasis: Effects of coating, dose and time.

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Pulmonary exposure to silver nanoparticles impairs cardiovascular homeostasis: Effects of coating, dose and time.

Toxicol Appl Pharmacol. 2019 03 15;367:36-50

Authors: Ferdous Z, Al-Salam S, Greish YE, Ali BH, Nemmar A

Abstract

Pulmonary exposure to silver nanoparticles (AgNPs) revealed the potential of nanoparticles to cause pulmonary toxicity, cross the alveolar-capillary barrier, and distribute to remote organs. However, the mechanism underlying the effects of AgNPs on the cardiovascular system remains unclear. Hence, we investigated the cardiovascular mechanisms of pulmonary exposure to AgNPs (10 nm) with varying coatings [polyvinylpyrrolidone (PVP) and citrate (CT)], concentrations (0.05, 0.5 and 5 mg/kg body weight), and time points (1 and 7 days) in BALB/C mice. Silver ions (Ag+) were used as ionic control. Exposure to AgNPs induced lung inflammation. In heart, tumor necrosis factor α, interleukin 6, total antioxidants, reduced glutathione and 8-isoprostane significantly increased for both AgNPs. Moreover, AgNPs caused oxidative DNA damage and apoptosis in the heart. The plasma concentration of fibrinogen, plasminogen activation inhibitor-1 and brain natriuretic peptide were significantly increased for both coating AgNPs. Likewise, the prothrombin time and activated partial thromboplastin time were significantly decreased. Additionally, the PVP- and CT- AgNPs induced a significant dose-dependent increase in thrombotic occlusion time in cerebral microvessels at both time points. In vitro study on mice whole blood exhibited significant platelet aggregation for both particle types. Compared with AgNPs, Ag+ increased thrombogenicity and markers of oxidative stress, but did not induce either DNA damage or apoptosis in the heart. In conclusion, pulmonary exposure to AgNPs caused cardiac oxidative stress, DNA damage and apoptosis, alteration of coagulation markers and thrombosis. Our findings provide a novel mechanistic insight into the cardiovascular pathophysiological effects of lung exposure to AgNPs.

PMID: 30639276 [PubMed - indexed for MEDLINE]

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Pediatric Anthracycline-Induced Cardiotoxicity: Mechanisms, Pharmacogenomics, and Pluripotent Stem-Cell Modeling.

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Pediatric Anthracycline-Induced Cardiotoxicity: Mechanisms, Pharmacogenomics, and Pluripotent Stem-Cell Modeling.

Clin Pharmacol Ther. 2019 03;105(3):614-624

Authors: Tripaydonis A, Conyers R, Elliott DA

Abstract

Anthracycline-induced cardiotoxicity (ACT) is a severe adverse drug reaction for a subset of children treated with anthracyclines as part of chemotherapy protocols. The identification of genetic markers associated with increased ACT susceptibility has clinical significance toward improving patient care and our understanding of the molecular mechanisms involved in ACT. Human-induced pluripotent stem cell-derived cardiomyocytes represent a novel approach to determine the pharmacogenomics of ACT and guide the development of genetic screening tests.

PMID: 30460992 [PubMed - indexed for MEDLINE]

21 December 2019

14:25

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Chimeric Antigen Receptor T-Cell Therapy for Cancer and Heart: JACC Council Perspectives.

J Am Coll Cardiol. 2019 Dec 24;74(25):3153-3163

Authors: Ganatra S, Carver JR, Hayek SS, Ky B, Leja MJ, Lenihan DJ, Lenneman C, Mousavi N, Park JH, Perales MA, Ryan TD, Scherrer-Crosbie M, Steingart RM, Yang EH, Zaha V, Barac A, Liu JE