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Abstract

Anthracyclines is an effective chemotherapeutic treatment used for many types of cancer. However, high cumulative dosage of anthracyclines leads to cardiac toxicity and heart failure. Dysregulation of mitochondrial dynamics and function are major pathways driving this toxicity. Several pharmacological and non-pharmacological interventions aiming to attenuate cardiac toxicity by targeting mitochondrial dynamics and function have shown beneficial effects in cell and animal models. However, in clinical practice, there is currently no standard therapy for the prevention of anthracycline-induced cardiotoxicity. This review summarizes current reports on the impact of anthracyclines on cardiac mitochondrial dynamics and mitochondrial function and potential interventions targeting these pathways. The roles of mitochondrial dynamics and mitochondrial function in the development of anthracycline-induced cardiotoxicity should provide insights in devising novel strategies to attenuate the cardiac toxicity induced by anthracyclines.

PMID: 32336039 [PubMed - as supplied by publisher]

28 April 2020

11:52

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pubmed: tutte cardiotoxicity...

Mitophagy Inhibitor Liensinine Suppresses Doxorubicin-Induced Cardiotoxicity through Inhibition of Drp1-Mediated Maladaptive Mitochondrial Fission.

Pharmacol Res. 2020 Apr 24;:104846

Authors: Liang X, Wang S, Wang L, Ceylan AF, Ren J, Zhang Y

Abstract

Doxorubicin (DOX) is one of the most effective antineoplastic drugs. However, its clinical application has been greatly limited due to the development of cardiotoxicity with DOX utilization. A number of theories have been postulated for DOX-induced cardiotoxicity with a pivotal contribution from unchecked (excess) mitophagy and mitochondrial fission. Liensinine (LIEN), a newly identified mitophagy inhibitor, strengthens the antineoplastic efficacy of DOX although its action on hearts remains elusive. This study was designed to examine the effect of LIEN on DOX-induced cardiotoxicity and the underlying mechanisms involved with a focus on mitochondrial dynamics. Our data revealed that LIEN alleviated DOX-induced cardiac dysfunction and apoptosis through inhibition of dynamin-related protein 1 (Drp1)-mediated excess (unchecked) mitochondrial fission. LIEN treatment decreased Drp1 phosphorylation at Ser616 site, inhibited mitochondrial fragmentation, mitophagy (assessed by TOM20 and TIM23), oxidative stress, cytochrome C leakage, cardiomyocyte apoptosis, as well as improved mitochondrial function and cardiomyocyte contractile function in DOX-induced cardiac injury. In DOX-challenged neonatal mouse ventricular myocytes (NMVMs), LIEN-suppressed Drp1 phosphorylation, mitochondrial fragmentation, and apoptosis were blunted by Rab7 overexpression, the effect of which was reversed by the ERK inhibitor U0126. Moreover, activation of ERK or Drp1 abolished the protective effects of LIEN on cardiomyocyte mechanical anomalies. These data shed some lights towards understanding the role of LIEN as a new protective agent against DOX-associated cardiotoxicity without compromising its anti-tumor effects.

PMID: 32339784 [PubMed - as supplied by publisher]

11:52

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Cardiotoxicity of Sequential Aromatase Inhibitors Use in Women with Breast Cancer.

Am J Epidemiol. 2020 Apr 27;:

Authors: Khosrow-Khavar F, Bouganim N, Filion KB, Suissa S, Azoulay L

Abstract

The association between aromatase inhibitors and cardiovascular outcomes is controversial. While some observational studies have assessed their cardiovascular safety as up-front treatments, their cardiotoxic effects as sequential treatments with tamoxifen remains unknown. Thus, we conducted a population-based cohort study using the United Kingdom Clinical Practice Research Datalink linked to the Hospital Episode Statistics and Office for National Statistics databases. A prevalent new-user design was used to propensity score match, in a 1:2 ratio, patients switching from tamoxifen to aromatase inhibitors to patients continuing tamoxifen between 1998 and 2016. Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for the study outcomes (myocardial infarction, ischemic stroke, heart failure, and cardiovascular mortality). Overall, 1,962 patients switching to aromatase inhibitors were matched to 3,874 patients continuing tamoxifen. Compared with tamoxifen, aromatase inhibitors were associated with an increased risk of myocardial infarction (HR=2.08; 95% CI: 1.02, 4.27). The hazard ratio was elevated with ischemic stroke (HR=1.58; 95% CI: 0.85, 2.93), heart failure (HR=1.69; 95% CI: 0.79, 3.62), but not cardiovascular mortality (HR=0.87; 95% CI: 0.49, 1.54), with CIs including the null. The elevated HRs observed for the cardiovascular outcomes should be corroborated in future large observational studies.

PMID: 32338279 [PubMed - as supplied by publisher]

29 April 2020

10:28

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Impact of stopping trastuzumab in early breast cancer: a population-based study in Ontario, Canada.

J Natl Cancer Inst. 2020 Apr 28;:

Authors: Rushton M, Lima I, Tuna M, Johnson C, Ivars J, Pritchard K, Hawken S, Dent S

Abstract

BACKGROUND: Adjuvant trastuzumab for early stage (I-III) HER2 positive breast cancer (BC) has led to statistically significant improvement in cancer outcomes but carries a risk of cardiotoxicity. Trastuzumab is discontinued early in many patients for asymptomatic changes in left ventricular ejection fraction. We evaluated the impact of early discontinuation of trastuzumab on cancer outcomes.

METHODS: Retrospective population-based cohort study of early BC patients treated with adjuvant trastuzumab in Ontario, Canada, 2007-2016. Four groups were analyzed: A-full treatment, 17-18 cycles trastuzumab; B-Cardiac event within treatment period; C - ≤16 cycles, no cardiac events, stopped ≤30 days from last cardiac imaging (CI); D - ≤16 cycles, no cardiac events, stopped >30 days from CI. Primary outcome: disease-free survival; secondary outcomes: overall survival, cancer-specific, and cardiovascular mortality. Sensitivity analyses were performed 14 months after cycle 1 trastuzumab to control for early relapse.

RESULTS: 5547 patients met inclusion criteria; A: 3921, B: 309, C: 362 and D: 955. 5-year DFS was 94.1% in group A, 80.1% group B, 81.4% group C and 82.4% group D. Using a Cox model, HR (95% CI) for 5-year DFS was 3.15 (2.13-4.65) for group B, 1.94 (1.30 - 2.89) group C and 1.92 (1.46-2.53) group D. Overall, 26 patients (0.5%) died of cardiac causes.

CONCLUSIONS: BC patients in Ontario who did not complete adjuvant trastuzumab had a statistically significantly higher risk of BC relapse and death and low incidence of cardiac death. These findings support one year of adjuvant trastuzumab in early stage BC.

PMID: 32343801 [PubMed - as supplied by publisher]

10:28

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Evaluating biomarkers as predictors of cancer therapy cardiotoxicity: all you need is a meta-analysis? Reply.

Eur J Heart Fail. 2020 Apr 28;:

Authors: Michel L, Rassaf T, Totzeck M

PMID: 32343475 [PubMed - as supplied by publisher]

10:28

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Trastuzumab cardiotoxicity in HER2-positive breast cancer patients in tertiary health care center, sultanate of Oman.

J Oncol Pharm Pract. 2020 Apr 27;:1078155220919888

Authors: Alghafar DA, Younos I, Baimani KA, Al-Salhi D, Al-Riyami A, Rizvi S, Buckley NE

PMID: 32340535 [PubMed - as supplied by publisher]

30 April 2020

11:58

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Cardiovascular Toxicity in Cancer Patients Treated with Tyrosine Kinase Inhibitors: A Real-World Single-Center Experience.

Oncology. 2020 Apr 29;:1-7

Authors: Novo G, Di Lisi D, Bronte E, Macaione F, Accurso V, Badalamenti G, Rinaldi G, Siragusa S, Novo S, Russo A

Abstract

BACKGROUND: Target therapy can cause various cardiovascular complications. The aim of this study was to evaluate the burden of cardiovascular complications related to treatment with anti-BCR-ABL tyrosine kinase inhibitors (TKIs) and to determine if there are differences between the latest- and first-generation TKIs.

METHODS: A retrospective observational study was carried out on 55 patients (39 men, 16 women; mean age ± SD: 58 ± 11 years) treated with TKIs targeting Bcr-Abl for a median period of 3.5 years. Patients were divided in two groups according to the type of treatment. Group A included patients treated with latest-generation TKI (nilotinib, dasatinib, and ponatinib), while group B included patients treated with first-generation TKI (imatinib). Cardiological evaluation included electrocardiogram, echocardiogram with global longitudinal strain of left ventricle (GLS), and carotid ultrasound scan with arterial stiffness measurement (pulse wave velocity, PWV). Adverse cardiovascular events were recorded in both groups.

RESULTS: Statistical analysis showed that cardiovascular adverse events (myocardial ischemia, peripheral artery disease, deep vein thrombosis, and pleural effusion) were significantly more frequent in group A than group B (p value = 0.044). Moreover, there was a significant reduction in GLS and PWV in group A when compared to group B (respectively, p = 0.03 and p = 0.004).

CONCLUSIONS: Our study confirms that imatinib is a relatively safe drug, while it reveals that the latest-generation TKIs may cause a burden of cardiovascular complications. GLS and PWV allow detection of early signs of cardiac and vascular toxicity in oncohematologic patients treated with TKI, and their use is advisable.

PMID: 32348984 [PubMed - as supplied by publisher]

11:58

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Brazilian cardio-oncology: the 10-year experience of the Instituto do Cancer do Estado de Sao Paulo.

BMC Cardiovasc Disord. 2020 Apr 28;20(1):206

Authors: Costa IBSDS, Bittar CS, Fonseca SMR, E Silva CMPD, Dos Santos Rehder MHH, Rizk SI, Cruz CBBV, Figueiredo CS, de A Andrade FT, Barberino LA, de S Costa FA, Machado LP, González TB, Almeida MPC, Fukushima JT, Kalil Filho R, Hajjar LA