Anticancer drugs-related QTc prolongation, torsade de pointes and sudden death: current evidence and future research perspectives

Duan, Jialin; Tao, Jingwen; Zhai, Maocai; Li, Chengpeng; Zhou, Ning; Lv, Jiagao; Wang, Lin; Lin, Li; Bai, Rong

doi:10.18632/oncotarget.25008

Cited by 50 publications

(35 citation statements)

References 97 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…6G). This may reflect the acute arrhythmic phase of anticancer therapy [39]. However, in our in vivo ECG telemetry analyses, we only found one Dox treated mice with ventricular extrasystole at 2 weeks after the last injection and none on saline treated mice.…”

Section: Discussionmentioning

confidence: 68%

Progression of excitation-contraction coupling defects in doxorubicin cardiotoxicity

Llach

Mazevet

Matéo

et al. 2019

Journal of Molecular and Cellular Cardiology

View full text Add to dashboard Cite

Cardiac failure is a common complication in cancer survivors treated with anthracyclines. Here we followed up cardiac function and excitation-contraction (EC) coupling in an in vivo doxorubicin (Dox) treated mice model (iv, total dose of 10 mg/Kg divided once every three days). Cardiac function was evaluated by echocardiography at 2, 6 and 15 weeks after the last injection. While normal at 2 and 6 weeks, ejection fraction was significantly reduced at 15 weeks. In order to evaluate the underlying mechanisms, we measured [Ca 2+ ] i transients by confocal microscopy and action potentials (AP) by patch-clamp technique in cardiomyocytes isolated at these times. Three phases were observed: 1/ depression and slowing of the [Ca 2+ ] i transients at 2 weeks after treatment, with occurrence of proarrhythmogenic Ca 2+ waves, 2/ compensatory state at 6 weeks, and 3/ depression on [Ca 2+ ] i transients and cell contraction at 15 weeks, concomitant with invivo defects. These [Ca 2+ ] i transient alterations were observed without cellular hypertrophy or AP prolongation and mirrored the sarcoplasmic reticulum (SR) Ca 2+ load variations. At the molecular level, this was associated with a decrease in the sarcoplasmic reticulum Ca 2+ ATPase (SERCA2a) expression and enhanced RyR2 phosphorylation at the protein kinase A (PKA, pS2808) site (2 and 15 weeks). RyR2 phosphorylation at the Ca 2+ /calmodulin dependent protein kinase II (CaMKII, pS2814) site was enhanced only at 2 weeks, coinciding with the higher incidence of proarrhythmogenic Ca 2+ waves. Our study highlighted, for the first time, the progression of Dox treatment-induced alterations in Ca 2+ handling and identified key components of the underlying Dox cardiotoxicity. These findings should be helpful to understand the early-, intermediate-, and late-cardiotoxicity already recorded in clinic in order to prevent or treat at the subclinical level.

show abstract

Section: Discussionmentioning

confidence: 68%

Progression of excitation-contraction coupling defects in doxorubicin cardiotoxicity

Llach

Mazevet

Matéo

et al. 2019

Journal of Molecular and Cellular Cardiology

View full text Add to dashboard Cite

show abstract

“…Drug-induced QT prolongation has been associated with inhibition of the potassium ion channel encoded by the hERG gene; the proposed mechanisms for this inhibition include disruption of hERG plasma membrane protein trafficking or blockage of the ion-channel cavity [12, 13]. Monoclonal antibodies, such as avelumab, are considered unlikely to cause QT prolongation because they are too large to cross plasma membranes and, as such, are unable to block the inner cavity of the hERG channel [14]; however, some monoclonal antibodies have been found to prolong the QT interval, the mechanism of which is still unknown [15]. Furthermore, cases of immune checkpoint inhibitor-related cardiotoxicity have been reported, which may have been associated with QT prolongation [16], and animal studies have shown that deficiency of CTLA-4 and PD-1 can cause autoimmune myocarditis [17].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the potential for QTc prolongation with avelumab

Vugmeyster

Güzel

Hennessy

et al. 2019

Cancer Chemother Pharmacol

View full text Add to dashboard Cite

PurposeTo report integrated electrocardiogram (ECG) summary and exposure–QTc analyses for avelumab, a human immunoglobulin G1 monoclonal antibody that binds programmed cell death 1 ligand 1, to assess potential effects on cardiac repolarization.MethodsData were pooled from three-phase 1/2 studies of patients with advanced solid tumors who received avelumab monotherapy (22,000 ECGs from 1818 patients). All analyses used 12-lead singlet ECGs taken using local ECG machines before and approximately 2 h after avelumab infusion on prespecified days. The exposure–QTc and outlier analyses used locally read ECGs; since larger variability is known to be associated with local reading, outlier ECGs were subsequently reevaluated by central read. QTc derived from Fridericia’s formula (QTcF) and a project-specific formula (QTcP) were analyzed. Multivariable linear mixed-effects models were used to describe the relationship between serum concentration of avelumab and QTc absolute value or change from baseline (ΔQTc).ResultsExposure–QTc models showed that the effect of avelumab on QTc or ΔQTc was minimal and not statistically significant for both QTcP and QTcF. In addition, models including avelumab concentration and diphenhydramine premedication use did not show a clinically meaningful effect on the QT interval. The frequency of QTc outliers in both short and long ranges was overestimated by local reads. Six patients (0.3%) were QTc outliers; all had either received concomitant medication known to cause QT prolongation or had a preexisting cardiac condition.ConclusionAvelumab does not have any clinically relevant effect on cardiac repolarization.

show abstract

“…Cancer patients are treated with numerous medications and many of them cause QT prolongation such as tyrosine kinase inhibitors, histone deacetylase inhibitors, arsenic trioxide, antiemetics, antidepressants, and anxiolytics [65]. Furthermore, the medications that received emergency use approval by the United States Food and Drug Administration (FDA) for treatment of COVID-19, including hydroxychloroquine, chloroquine, and azithromycin as well as the antivirals such as lopinavir/ritonavir are all known to cause QT prolongation [66•].…”

Section: Qt Prolongation and Ventricular Arrhythmias In Patients Withmentioning

confidence: 99%

COVID-19 and Cardiovascular Health Among Patients with Cancer

2020

View full text Add to dashboard Cite

Purpose of review The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to spread with rising new cases and deaths. Patients with cancer represent a uniquely vulnerable population not only with higher susceptibility to COVID-19 but also at increased risk for its complications. This review focuses on the implications of COVID-19 in the cardiovascular health of patients with cancer. Recent findings Patients more susceptible to COVID-19 with increased severity of disease include those with cancer and cardiovascular comorbidities. In addition, the cardiovascular complications of COVID-19 including acute myocardial injury, thromboembolism, cardiomyopathy, myocarditis, and pericardial disease overlap with many of those encountered during cancer treatment. Summary Despite the absence of large studies of patients with both cancer and cardiovascular disease, the incidence of cardiovascular complications in cancer patients with COVID-19 is expected to be high. This has implications for cardiac monitoring, chemotherapy administration, and the diagnosis and treatment of cardiovascular disease during COVID-19.

show abstract

Anticancer drugs-related QTc prolongation, torsade de pointes and sudden death: current evidence and future research perspectives

Cited by 50 publications

References 97 publications

Progression of excitation-contraction coupling defects in doxorubicin cardiotoxicity

Progression of excitation-contraction coupling defects in doxorubicin cardiotoxicity

Evaluation of the potential for QTc prolongation with avelumab

COVID-19 and Cardiovascular Health Among Patients with Cancer

Contact Info

Product

Resources

About