Metabolic and electrolyte abnormalities as risk factors in drug-induced long QT syndrome

TeBay, Clifford; Hill, Adam P.; Windley, Monique J.

doi:10.1007/s12551-022-00929-7

Cited by 17 publications

(9 citation statements)

References 107 publications

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“…The exact mechanism of QT prolongation from anti-VEGF TKIs is unclear, while it has been hypothesized that these TKIs might interact with the human ether-a-go-go-related gene (hERG) potassium channels, predisposing to QT prolongation (113). Of major significance, hypomagnesemia, possibly due to abnormal TRPM7 activity, is a major cause of long QT syndrome (114).…”

Section: Qt Prolongationmentioning

confidence: 99%

Cardiovascular toxicity of tyrosine kinase inhibitors during cancer treatment: Potential involvement of TRPM7

Liu

Qiu

et al. 2023

Front. Cardiovasc. Med.

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Receptor tyrosine kinases (RTKs) are a class of membrane spanning cell-surface receptors that transmit extracellular signals through the membrane to trigger diverse intracellular signaling through tyrosine kinases (TKs), and play important role in cancer development. Therapeutic approaches targeting RTKs such as vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR), and platelet-derived growth factor receptor (PDGFR), and TKs, such as c-Src, ABL, JAK, are widely used to treat human cancers. Despite favorable benefits in cancer treatment that prolong survival, these tyrosine kinase inhibitors (TKIs) and monoclonal antibodies targeting RTKs are also accompanied by adverse effects, including cardiovascular toxicity. Mechanisms underlying TKI-induced cardiovascular toxicity remain unclear. The transient receptor potential melastatin-subfamily member 7 (TRPM7) is a ubiquitously expressed chanzyme consisting of a membrane-based ion channel and intracellular α-kinase. TRPM7 is a cation channel that regulates transmembrane Mg2+ and Ca2+ and is involved in a variety of (patho)physiological processes in the cardiovascular system, contributing to hypertension, cardiac fibrosis, inflammation, and atrial arrhythmias. Of importance, we and others demonstrated significant cross-talk between TRPM7, RTKs, and TK signaling in different cell types including vascular smooth muscle cells (VSMCs), which might be a link between TKIs and their cardiovascular effects. In this review, we summarize the implications of RTK inhibitors (RTKIs) and TKIs in cardiovascular toxicities during anti-cancer treatment, with a focus on the potential role of TRPM7/Mg2+ as a mediator of RTKI/TKI-induced cardiovascular toxicity. We also describe the important role of TRPM7 in cancer development and cardiovascular diseases, and the interaction between TRPM7 and RTKs, providing insights for possible mechanisms underlying cardiovascular disease in cancer patients treated with RTKI/TKIs.

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Section: Qt Prolongationmentioning

confidence: 99%

Cardiovascular toxicity of tyrosine kinase inhibitors during cancer treatment: Potential involvement of TRPM7

Liu

Qiu

et al. 2023

Front. Cardiovasc. Med.

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“…Unfortunately, the available antiarrhythmic drugs show proarrhythmic potential that can manifest by the occurrence of torsades de pointes , an increased number of premature heartbeats, or reentry [ 33 , 34 , 35 ]. In particular, elderly patients with impaired heart muscle contractility and patients with electrolyte disturbances are susceptible to arrhythmogenic effects of antiarrhythmic drugs [ 36 , 37 ]. Therefore, next, we evaluated the influence of HBK-10 on normal ECG in rats.…”

Section: Discussionmentioning

confidence: 99%

HBK-10, A Compound with α1-Adrenolytic Properties, Showed Antiarrhythmic and Hypotensive Effects in Rats

et al. 2022

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Arrhythmia, an irregular heartbeat, might be a life-threatening condition but also a risk factor for stroke or worsen the prognosis after myocardial infarction. The limited efficacy and proarrhythmic potential of the available drugs require searching for new, more effective, and safer pharmacotherapies. Studies indicate that the blockade of α1-adrenoceptors could be effective in treating heart rhythm abnormalities. In this study, we aimed to assess the antiarrhythmic and hypotensive potential of HBK-10, a novel 2-methoxyphenylpiperazine derivative, as well as its binding to the selected adrenergic receptors. Radioligand binding studies demonstrated that HBK-10 showed a high affinity for α1 but not for α2 or β1 receptors. Next, we evaluated the ability of HBK-10 to protect against an adrenaline-induced arrhythmia in rats. The compound showed potent prophylactic antiarrhythmic properties in this arrhythmia model. Notably, the compound did not show proarrhythmic potential in normotensive rats since it did not influence the ECG parameters at antiarrhythmic doses. Finally, the compound showed hypotensive properties in rats, which were not observed after coadministration with adrenaline, noradrenaline, or methoxamine, which suggests α1-adrenolytic properties of HBK-10. Our results confirm that compounds with a 2-methoxyphenylpiperazine group show a high affinity for α1-adrenoceptors and a significant antiarrhythmic effect. Given the promising results of our study, further evaluation of HBK-10 is necessary to unravel the mechanisms behind its pharmacological effects and evaluate the safety profile.

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“…This circumstance explains why many of these drugs have contraindications or precautions in their prescribing information that include the consideration of carefully evaluating their association with other drugs that cause QT prolongation or any of the predisposing factors. We refer readers interested in reviewing this LQTS topic in greater detail to the more specific literature [28][29][30][31].…”

Section: Qt Interval Prolongationmentioning

confidence: 99%

Recommendations on the use of azole antifungals in hematology-oncology patients

Risco-Risco¹,

Martínez-Urbistondo²,

Villar³

et al. 2023

Rev Esp Quimioter

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The administration of antifungals for therapeutic and, especially, prophylactic purposes is virtually a constant in patients requiring hematology-oncology treatment. Any attempt to prevent or treat Aspergillus or Mucor infections requires the administration of some drugs in the azole group, which include voriconazole, posaconazole and isavuconazole, noted for their activity against these pathogens. One very relevant aspect is the potential risk of interaction when associated with one of the antineoplastic drugs used to treat hematologic tumors, with serious complications. In this regard, acalabrutinib, bortezomib, bosutinib, carfilzomib, cyclophosphamide, cyclosporine A, dasatinib, duvelisib, gilteritinib, glasdegib, ibrutinib, imatinib, nilotinib, ponatinib, prednisone, ruxolitinib, tacrolimus, all-transretinoic acid, arsenic trioxide, venetoclax, or any of the vinca alkaloids, are very clear examples of risk, in some cases because their clearance is reduced and in others because of increased risk of QTc prolongation, which is particularly evident when the drug of choice is voriconazole or posaconazole.

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Metabolic and electrolyte abnormalities as risk factors in drug-induced long QT syndrome

Cited by 17 publications

References 107 publications

Cardiovascular toxicity of tyrosine kinase inhibitors during cancer treatment: Potential involvement of TRPM7

Cardiovascular toxicity of tyrosine kinase inhibitors during cancer treatment: Potential involvement of TRPM7

HBK-10, A Compound with α1-Adrenolytic Properties, Showed Antiarrhythmic and Hypotensive Effects in Rats

Recommendations on the use of azole antifungals in hematology-oncology patients

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