RESEARCH ARTICLE SA JOURNAL OF DIABETES & VASCULAR DISEASE 6 VOLUME 20 NUMBER 1 • JUNE 2023 Fig. 2. QTc comparisons for all groups at the basal, first and second hours. Fig. 3. ECG comparisons of all groups at basal, first and second hour. A. control, B. EMPA group, C. AMT group, D. AMT+EMPA group. A B C D all groups (Table 1). The measurements of the control group were within normal limits and consistent with the literature.13 In the control group, QT was 77.33 ± 9.02 ms at baseline, 73.50 ± 2.26 ms at the first hour, and 78.17 ± 6.18 ms at the second hour. The QTc calculation was 165.42 ± 18.34 ms at baseline, 166.63 ± 17.92 ms at the first hour, 184.65 ± 12.86 ms at the second hour (Table 1). ECG findings of the EMPA group were within normal limits and similar to the control group (Table 1). Although baseline HR were different between the groups, after anaesthesia all HR became similar and consistent with the literature (Table 1). The durations of QT interval and QTc were found to be statistically longer in the AMT group than in the control group at the first and second hours (p ≤ 0.001) (Table 1, Fig. 2). EMPA significantly ameliorated AMT-induced QT and QTc prolongation. The durations of the QT interval were significantly lower at the first (p < 0.001) and second hours (p < 0.01) in the AMT+EMPA group compared to the AMT group. Moreover, the QTc calculation was significantly lower in the AMT+EMP group than in the AMT group at the first and second hours (p < 0.01) (Table 1). ECG comparisons of all groups for one second within the second hour can be seen in Fig. 3. When the changes in baseline, and first and second hours of the QT intervals of the groups were compared with repeated measurements ANOVA, there was a significant difference between time points (p < 0.001). Moreover, there was a significant difference between the AMT group and all the other groups (p < 0.01). In addition, when the changes in baseline, and first and second hours of the QTc intervals of the groups were compared with repeated measurements ANOVA, there was a significant difference between time points (p < 0.001). There was also a significant difference between the AMT group and all the other groups (p < 0.001 for AMT vs control and EMPA groups, p < 0.01 for AMT vs AMT+EMPA). Discussion In this study, we investigated the effects on QT interval of the concomitant use of EMPA and AMT, which have different effects on Na and Ca metabolism in cardiomyocytes, and it was found that EMPA significantly inhibited AMT-induced QT prolongation. AMTinduced QT and QTc interval prolongations were measured in the first and second hours by ECG recording, and it was determined that EMPA significantly ameliorated these prolongations. EMPA exerts its antidiabetic effect by decreasing glucose absorption in the kidney proximal tubule as a result of its inhibitory activity in SGLT-2 channel.1 In the EMPA-REG OUTCOME clinical study, in addition to the antidiabetic effect of EMPA, it was shown that EMPA reduced all-cause mortality (including cardiovascular death) and hospitalisations caused by heart failure.2 Moreover, it was shown that EMPA reduced cardiovascular death and hospitalisation for heart failure in heart failure patients with or without diabetes mellitus. EMPA did not cause hypoglycaemia in patients without diabetes in the EMPEROR-Reduced trial.14 However, physiopathological explanation of this beneficial effect of EMPA on reducing cardiovascular mortality has not been fully achieved. In the literature, clinical studies revealed that EMPA reduced arterial stiffness, cardiac oxygen demand and albuminuria. Animal studies have shown that EMPA regressed left ventricular fibrosis/ remodelling and it had positive effects on left ventricular systolic and diastolic function.15-22 Also, in cellular studies conducted with diabetes models, it has been shown that EMPA reduced the amount of cytosolic Na in myocytes by inhibiting the sodium hydrogen exchanger (NHE).3 EMPA was also effective in intracellular Ca balance by increasing the L-type Ca channel activity, the amount of sarcoplasmic reticulum ATPase (SERCA2a) protein and the levels of ryanodine receptor-2,4 regardless of its SGLT-2 inhibition. AMT is a TCA drug that can be used in many indications, such as anxiety, depression and diabetic neuropathy. In addition to the wide clinical uses of TCA, the cardiotoxicity caused by the use of these drugs limits the use of all TCAs, primarily AMT.6 AMT may cause cardiotoxicity due to ventricular arrhythmias caused by the prolongation of the QRS, QTc and PR segments, as seen on ECG, as a result of Na channel inhibition caused by AMT.7 Since the
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