SA JOURNAL OF DIABETES & VASCULAR DISEASE RESEARCH ARTICLE VOLUME 20 NUMBER 1 • JULY 2023 7 mechanisms of this improvement in QT prolongation were not included, it was shown that edaravone leads to a decrease in the retention of technetium pyrophosphate and an increase in cardiac troponin levels, as a result of myocardial damage caused by AMT. Also in this study, it was concluded that AMT caused cardiotoxicity by increasing ROS activity, and edaravone ameliorated this situation.33 In another study by Basol et al., the effects of diltiazem and metoprolol in QT prolongation due to AMT was investigated. In this study, it was shown that both molecules (diltiazem and metoprolol) had beneficial effects against QT prolongation due to AMT. It was interpreted that this effect may be due to both molecules reducing the amount of cytosolic Ca in phase 2 of the cardiac action potential.12 In addition, in the EMPERORPreserved trial, the beneficial effect of EMPA in patients with heart failure with preserved ejection fraction may also be due to its preventative effects on intracellular Ca accumulation, which was also shown in our study.34 Limitations In this study, the positive effects of EMPA on AMT-induced QT prolongation were basically attributed to intracellular Ca balance. However, since this study did not include cellular biophysics research, this opinion remains a hypothesis. In addition, the study was only an ECG study, other markers such as troponin and scintigraphy, which may show AMT-induced cardiotoxicity, were not used in this study. cardiotoxicity caused by AMT is not dose dependent, it is important to monitor the ECG findings.23 In our study, we found that EMPA significantly prevented AMT-induced QTc prolongation. This protective effect can be explained by reviewing the effects of these two drugs on cellular Na and Ca balances. In the established medical literature, it has been reported that AMT and other TCAs cause cardiotoxicity, mainly by Na channel blockage.24 In the toxicity of AMT, QRS prolongation, right bundle branch block mimicking Brugada pattern or PR segment prolongation can be observed on ECG due to Na channel inhibition.25 However, Na channel inhibition cannot explain QTc prolongation in the toxicity of AMT. Actually, it is known that Na channel activation, in contrast to its inhibition, may lead to long QT. The SCN5a gene encodes the fast Na channels activated in phase 0 of the cardiac action potential, and congenital long QT syndrome is observed in SCN5a gene mutants, increasing the activity of this channel.16 In the treatment of this condition, quinidine26 and ranolazine,27 which indicate their activities with Na channel inhibition, are effective and are recommended in the guidelines.28 Therefore, it is insufficient to explain this situation only with QTc prolongation caused by Na channel inhibition. In fact, in a study by Baartscheer et al., it has been shown that EMPA reduces the amount of cytosolic Na during systole by inhibiting the NHE activity in myocytes.3 If this effect of EMPA is considered together with the Na channel blockade caused by AMT, it would be expected that EMPA extends QT prolongation further, instead of its effect on preventing QT prolongation in AMT toxicity. In a study by Aleksey et al., it has been shown that there are crucial cellular mechanisms in which AMT cardiotoxicity can occur with intracellular Ca metabolism.8 In this study, it was shown that the toxic dose of AMT increased the amount of sarcoplasmic Ca and the Ca permeability of ryanodine channels, and decreased SERCA-mediated Ca re-uptake by decreasing the Ca binding capacity of calsequestrin. The toxic dose of AMT may lead to cardiotoxicity by increasing Ca release during systole via the sarcoplasmic reticulum as a result of this.8 In a study by Lee et al., it was shown that EMPA increased Ca re-uptake by causing a significant increase in SERCA activity, and decreased Ca sparks by causing inhibition of ryanodine activity.4 Also, in this study, it was found on ECG that EMPA had antiarrhythmic effects against QT prolongation by both reducing reactive oxygen species (ROS) activity and shortening action potential duration.4 Our previous findings have also shown that EMPA can prevent QTc prolongation, induced by sotalol, in an in vivo animal study.29 In our study, we believe that the beneficial effects of EMPA on AMT-induced QT prolongation originates from these pathways affecting intracellular Ca homeostasis. In the literature, there are many studies on the cardiotoxicity of AMT. In a study by Akgun et al., it was shown that glucagon had beneficial effects on hypotension and QRS prolongation caused by AMT.30 It was observed that theophylline and adenosine receptor antagonists ameliorated the AMT-induced QRS prolongation.31,32 However, there are very few studies on QT prolongation, which is the most important indicator of AMT toxicity seen on ECG. In a study by Basol et al., it was stated that edaravone, a potent antioxidant, ameliorated the AMT-induced QT prolongation.33 In this study, while the possible physiopathological and cellular NEW IMPROVE QUALITY OF LIFE minutes 16 An onset of action as early as TADALAFIL HAS 1: Up to HRS duration of action 36 TRAVEL L IGHT TADALAFIL 5, 20 mg DYNA. Each film coated tablet contains 5, 20 mg respectively. S4 A49/7.1.5/0285, 0286. For full prescribing information, refer to the professional information approved by SAHPRA, August 2022. 1) Professional information. TDLA901/04/2023. CUSTOMER CARE LINE +27 21 707 7000 www.pharmadynamics.co.za 5 mgSTRENGTH PACKED IN 30’s
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