Featured in this issue: Volume 20 Number 1 MORE CHOICE MORE SUSTAINED CONTROL1 UNIQUE SCORED 90 mgMR F O RMU L AT I O N A compelling choice in sulphonylurea treatment: Once daily formulation Improved compliance 2 DYNACAZ 30, 60, 90 mg MR. Each tablet contains 30, 60, 90 mg gliclazide respectively. S3 A42/21.2/0249, A48/21.2/1194, A53/21.2/0083. For full prescribing information, refer to the professional information approved by SAHPRA, 15 June 2021. 1) McGavin JK, et al. Gliclazide modified release. Drugs 2002;62(9):13571364. 2) Crepaldi G and Fioretto P. Gliclazide modified release: Its place in the therapeutic armamentarium. Metabolism 2000;49(10)supplement 2:21-25. DCZB933/05/2023. www.pharmadynamics.co.za CUSTOMER CARE LINE +27 21 707 7000 NEW INTRODUCING OUR GLICLAZIDE MR RANGE MR GLICLAZIDE 60 mg 90 mg Dynacaz 30 mg June 2023 SAJDVD The South African Journal of DIABETES & VASCULAR DISEASE The electronic version of the journal is available at www.diabetesjournal.co.za • Empagliflozin significantly prevents QTc prolongation due to amitriptyline intoxication • Effect of insulin resistance on left ventricular remodelling in essential hypertensives • Potential benefits of cinnamon for type 2 diabetes
MORE CHOICE MORE SUSTAINED CONTROL1 For further product information contact PHARMA DYNAMICS Email info@pharmadynamics.co.za CUSTOMER CARE LINE +27 21 707 7000 www.pharmadynamics.co.za DYNACAZ 30, 60, 90 mg MR. Each tablet contains 30, 60, 90 mg gliclazide respectively. S3 A42/21.2/0249 , A48/21.2/1194, A53/21.2/0083. For full prescribing information, refer to the professional information approved by SAHPRA, 15 June 2021. 1) McGavin JK, et al. Gliclazide modified release. Drugs 2002;62(9):1357-1364. 2) Crepaldi G and Fioretto P. Gliclazide modified release: Its place in the therapeutic armamentarium. Metabolism 2000;49(10)supplement 2:21-25. DCZB933/05/2023. A compelling choice in sulphonylurea treatment: 2 Once daily formulation Improved compliance UNIQUE SCORED 90 mgMR F O R M U L AT I O N NEW INTRODUCING OUR GLICLAZIDE MR RANGE MR GLICLAZIDE 60 mg 90 mg Dynacaz 30 mg
HYPERINSULINAEMIA ISSN 1811-6515 THE SOUTH AFRICAN JOURNAL OF Diabetes & Vascular Disease Corresponding Editor DR FA MAHOMED Head of Internal Medicine Madadeni Hospital Newcastle KwaZulu-Natal Consulting Editor PROF J-C MBANYA National Editorial Board DR A AMOD Centre for Diabetes, Endocrinology and Metabolic Diseases, Life Healthcare, Chatsmed Gardens Hospital, Durban SR K BECKERT Diabetes Nurse, Paarl PROF F BONNICI Emeritus Professor, Faculty of Health Sciences, University of Cape Town and President of Diabetes South Africa PROF R DELPORT Department of Family Medicine, University of Pretoria DR L DISTILLER Director of the Centre of Diabetes and Endocrinology, Houghton, Johannesburg PROF WF MOLLENTZE Head of Department of Internal Medicine, University of the Free State, Bloemfontein PROF CD POTGIETER Specialist Nephrologist, University of Pretoria and Jakaranda Hospital, Pretoria PROF K SLIWA Associate Professor of Medicine and Cardiology, Baragwanath Hospital, University of the Witwatersrand, Johannesburg PROF YK SEEDAT Emeritus Professor of Medicine and Honorary Research Associate, University of Natal, Durban International Editorial Board PROF IW CAMPBELL Physician, Victoria Hospital, Kircaldy, Scotland, UK PROF PJ GRANT Professor of Medicine and head of Academic Unit of Molecular Vascular Medicine, Faculty of Medicine and Health, University of Leeds; honorary consultant physician, United Leeds Teaching Hospitals NHS Trust, UK PROF J-C MBANYA Professor of Endocrinology, Faculty of Medicine and Biomedical Sciences, University of Yaounde I, Cameroon and President, International Diabetes Federation PROF N POULTER Professor of Preventive Cardiovascular Medicine, Imperial College, School of Medicine, London, UK DR H PURCELL Senior Research Fellow in Cardiology, Royal Brompton National Heart and Lung Hospital, London, UK VOLUME 20 NUMBER 1 • JUNE 2023 www.diabetesjournal.co.za CONTENTS 3 From the Editor’s Desk FA Mahomed Research Article 4 Empagliflozin significantly prevents QTc prolongation due to amitriptyline intoxication VO Barış, E Gedikli, AB Dinçsoy, A Erdem 9 Effect of insulin resistance on left ventricular remodelling in essential hypertensives: a cross- sectional study BK Phanzu, AN Natuhoyila, EK Vita, B Longo-Mbenza, J-R M’Buyamba Kabangu Review 17 Potential benefits of cinnamon for type 2 diabetes C Mohan
Production Editor SHAUNA GERMISHUIZEN TEL: 021 785 7178 FAX: 086 628 1197 e-mail: shauna@clinicscardive.com Financial & Production Co-ordinator ELSABÉ BURMEISTER TEL: 021 976 8129 CELL: 082 775 6808 FAX: 086 664 4202 e-mail: elsabe@clinicscardive.com Content Manager MICHAEL MEADON (Design Connection) TEL: 021 976 8129 FAX: 086 655 7149 e-mail: michael@clinicscardive.com The South African Journal of Diabetes and Vascular Disease is published twice a year for Clinics Cardive Publishing (Pty) Ltd and printed by Durbanville Commercial Printers/Tandym Print. Online Services: Design Connection. All correspondence to be directed to: THE EDITOR PO BOX 1013 DURBANVILLE 7551 or elsabe@clinicscardive.com TEL: 021 976 8129 FAX: 086 664 4202 INT: +27 (0)21 976-8129 To subscribe to the journal or change address, email elsabe@clinicscardive.com Full text articles available on: www.diabetesjournal.co.za via www.sabinet.co.za The opinions, data and statements that appear in any articles published in this journal are those of the contributors. The publisher, editors and members of the editorial board do not necessarily share the views expressed herein. Although every effort is made to ensure accuracy and avoid mistakes, no liability on the part of the publisher, editors, the editorial board or their agents or employees is accepted for the consequences of any inaccurate or misleading information. 2 VOLUME 20 NUMBER 1 • JUNE 2023
VOLUME 20 NUMBER 1 • JUNE 2023 3 SA JOURNAL OF DIABETES & VASCULAR DISEASE FROM THE EDITOR’S DESK From the Editor’s Desk Correspondence to: FA Mahomed Head of Internal Medicine, Madadeni Hospital Newcastle, KwaZulu-Natal This issue takes a look at the potential cardiac benefit of empagliflozin, the effect of insulin resistance on left ventricular modelling in hypertensives and the benefits of cinnamon in diabetes management. Baris et al., in Gaziantep, Turkey, (page 4) showed that in an animal model, empagliflozin, a selective sodium-glucose transporter-2 (SGLT2) inhibitor, attenuated the QT prolongation associated with amitriptyline use. QT prolongation is associated with negative cardiac outcomes, such as torsade de pointes and sudden cardiac death.1 The authors give a plausible physiological explanation in terms of effect on calcium channels. Many of the common antidepressants may also prolong the QT interval. These medications include selective serotonin reuptake inhibitors (SSRIs), such as citalopram, fluoxetine and venlafaxine. Other antidepressant options, namely bupropion or mirtazapine, may be considered since they carry minimal to no risk of QT prolongation.2 Further studies on empagliflozin in a clinical setting may be warranted. Phanzu et al., in Kinshasa, DRC, (page 9) determined at the effect of hyperinsulinaemia and insulin resistance on left ventricular remodelling. Left ventricular hypertrophy is associated with increased rates of morbidity and mortality. Various elements are important, such as posterior ventricular wall changes, interventricular septal changes and left ventricular mass. This can lead to diastolic and systolic dysfunction, arrythmias and increased ischaemic events.3 The authors tried to tease out whether there is a difference in effect of hyperinsulinaemia versus insulin resistance on cardiac function and what the implications might be. They highlight the early changes in cardiac function and elaborate on possible pathophysiology Cholesterol passport for adolescents to halt the world’s deadliest disease, atherosclerosis The United Nations Declaration of Human Rights that everyone has the right to life could as well be extended to include the right to an ‘elevated cholesterol-free life’, a viewpoint by Dr Andrew Agbaje of the University of Eastern Finland, published in Frontiers in Pediatrics, concludes. Globally, atherosclerotic cardiovascular disease has remained the leading cause of death in the past decades, despite huge advancements in medical treatment. The staggering cost of longterm treatment of atherosclerotic cardiovascular disease forms a significant proportion of annual health expenditure. Based on strong evidence from studies among adults, risk factor assessments for atherosclerotic cardiovascular disease have been established by middle age. However, emerging studies in the paediatric population describe two main problems. Firstly, the likelihood of genetic conditions, which result in extremely high levels of cholesterol from birth with the risk of heart attack and sudden death by age 20 years. Secondly, the prevalence of elevated cholesterol in 20% of adolescents without genetic alterations, which could rise to 25% of young adults within seven years. This second category constitutes the majority of people who progress to developing atherosclerotic cardiovascular disease in mid-adulthood. There is a call to shift to prevention as the gold standard for addressing this deadly disease through the initiation of a universal paediatric lipid screening in the latest European Atherosclerosis Continued on page 16 linking these two factors to their cardiac consequences. Mohan, from the University of KwaZulu-Natal, (page 17) reviewed the use of cinnamon in type 2 diabetes. She documents the history, types, physiological effects and evidence for benefit from cinnamon. Cinnamon can also have a beneficial effect on lipids,4 and therefore modify a cardiovascular risk factor in diabetes. Few comprehensive studies have been done and this deserves further study. Herbs and natural remedies have a fascinating history over thousands of years. References 1. Vandael E, Vandenberk B, Vandenberghe J, Willems R, Foulon V. Risk factors for QTc-prolongation: systematic review of the evidence. Int J Clin Pharm 2017; 39(1): 16–25. 2. https://www.acc.org/latest-in-cardiology/articles/2019/01/04/07/59/current-updatesregarding-antidepressant-prescribing-in-cv-dysfunction. Accessed 28/06/2023. 3. Sayin BY, Oto A. Left ventricular hypertrophy: etiology-based therapeutic options. Cardiol Ther 2022; 11(2): 203–230. 4. Allen RW, Schwartzman E, Baker WL, Coleman CI, Phung OJ. Cinnamon use in type 2 diabetes: an updated systematic review and meta-analysis. Ann Fam Med 2013; 11(5): 452–459. CARVETREND 6,25, 12,5, 25 mg. Each tablet contains 6,25, 12,5, 25 mg carvedilol respectively. S3 A37/7.1.3/0276, 0277, 0278. NAM NS2 08/7.1.3/0105, 0104, 0103. BOT S2 BOT1101790, 1791, 1792. For full prescribing information, refer to the professional information approved by SAHPRA, 13 December 2019. 1) Panagiotis C Stafylas, Pantelis A Sarafidis. Carvedilol in hypertension treatment. Vascular Health and Risk Management 2008;4(1):23-30. CDA891/09/2022. RESTORE cardiac function ß C A R V E D I L O L 6,25 mg 12,5 mg 25 mg CARVEDILOL: • is indicated twice daily for mild to moderate stable symptomatic congestive heart failure • is indicated once daily for essential mild to moderate hypertension • has no significant metabolic e ects1 CUSTOMER CARE LINE +27 21 707 7000 www.pharmadynamics.co.za
RESEARCH ARTICLE SA JOURNAL OF DIABETES & VASCULAR DISEASE 4 VOLUME 20 NUMBER 1 • JUNE 2023 Empagliflozin significantly prevents QTc prolongation due to amitriptyline intoxication VEYSEL ÖZGÜR BARIŞ, ESRA GEDIKLI, ADNAN BERK DINÇSOY, AYŞEN ERDEM Correspondence to: Özgür Barış Esra Gedikli, Adnan Berk Dinçsoy, Ayşen Erdem Physiology Department, Hacettepe University, Gaziantep, Turkey e-mail: veyselozgurbaris@gmail.com Published online in Cardiovasc J Afr, 7 June 2023 S Afr J Diabete Vasc Disc 2023; 20: 4–8 Abstract Aim: Empagliflozin (EMPA) is a sodium-glucose transporter-2 inhibitor used in the treatment of type 2 diabetes and has positive effects on cardiovascular outcomes. Amitriptyline (AMT) can be used in many clinical indications but leads to cardiotoxicity by causing QT prolongation. Our aim in this study was to determine how the effects of the concomitant use of empagliflozin and amitriptyline, which have been shown to have effects on sodium and calcium metabolism in cardiomyocytes, would cause an effect on QT and QTc intervals in clinical practice. Methods: Twenty-four male Wistar albino rats were randomised into four groups. The control group received only physiological serum (1 ml) via orogastric gavage (OG). The EMPA group received empagliflozin (10 mg/kg) via OG. The AMT group received amitriptyline (100 mg/kg) via OG. The AMT+EMPA group (n = 6) received amitriptyline (100 mg/kg) and empagliflozin (10 mg/kg). Under anaesthesia, QT and QTc intervals were measured at baseline, and in the first and second hours. Results: In the AMT group, QT intervals and QTc values were found to be statistically longer than in the control group (p ≤ 0.001). Empagliflozin significantly ameliorated amitriptyline-induced QT and QTc prolongation. In the AMT+EMPA group, QT and QTc intervals were significantly lower compared to that in the AMT group (p < 0.01) Conclusion: In this study, we determined that empagliflozin significantly ameliorated amitriptyline-induced QT and QTc prolongation. This effect was probably due to the opposite effects of these two agents in the intracellular calcium balance. With more clinical trials, the routine use of empagliflozin may be suggested to prevent QT and QTc prolongation in diabetic patients receiving amitriptyline. Keywords: empagliflozin, amitriptyline, QTc prolongation Empagliflozin (EMPA) is a selective sodium-glucose transporter-2 (SGLT-2) inhibitor used in patients with type 2 diabetes mellitus (DM).1 There are data showing that EMPA reduces cardiovascular mortality in patients with type 2 DM in addition to its antidiabetic effects.2 Although there is not yet a physiopathological explanation for these positive effects of EMPA, it has been shown that EMPA causes changes in the intracellular sodium (Na) and calcium (Ca) balance and in the duration of action potentials in cardiomyocytes, regardless of SGLT-2 inhibition.3,4 Tricyclic antidepressant (TCA) drugs can be used in many situations in clinical practice. However, TCA may cause cardiotoxicity that leads to high rates of mortality and morbidity, and AMT is the most common agent causing TCA toxicity.5,6 AMT may cause cardiotoxicity due to ventricular arrhythmias caused by its Na channel inhibition and changes in intracellular Ca metabolism.7,8 The toxicity caused by TCA is dose independent and this toxicity manifests itself with prolongation in PR, QT and QTc intervals, measured on the ECG.9 QT prolongation on ECG is a predictor for toxicity and indicates a poor prognosis.10 In this study, we aimed to determine how the effects of the concomitant use of EMPA and AMT, which are used in the treatment of type 2 DM and which have been shown to have effects on Na and Ca metabolism in cardiomyocytes, could cause an effect on QT and QTc intervals in clinical practice. Methods Twenty-four male Wistar albino rats (350–400 g) obtained from Kobay AŞ (local corporation) and housed in the Physiology Department of Hacateppe University was used for this study. All rats were kept under controlled conditions at 21 ± 2°C and 30–70% relative humidity with 12-h dark/12-h light illumination sequence (the lights were on between 07.00 and 19.00) with ad libitum access to tap water and standard rat chow. The study was approved by the Hacateppe University School of Medicine institutional ethics committee for animal experiments (dated 11/11/2019 and numbered 2019/12-02). All the study procedures were performed according to the Guiding Principles for the Care and Use of Laboratory Animals. The experimental animals were randomised into four groups. The first group was the control group (n = 6) and physiological serum (1 ml) was administered to the animals of this group via an orogastric tube. The second group was the EMPA group and EMPA (10 mg/kg, Jardiance, Boehringer Ingelheim) was administered to the animals of this group via an orogastric tube (based on a previous study11) (Fig. 1A). The third group was the AMT group and AMT (100 mg/kg; Laroxyl 25 mg, Roche) was administered to the animals of this group via an orogastric tube (based on a previous study12). The fourth group was the AMT+EMPA group and AMT (100 mg/kg) and EMPA (10 mg/kg) were administered to the animals of this group via an orogastric tube. All drugs were suspended in physiological serum. Tablets containing 10 mg active EMPA (Jardiance, Boehringer Ingelheim) and 25 mg AMT (100 mg/kg, Laroxyl 25 mg, Roche), which weighed nearly 257 mg and 194.6 mg with other supplemental products, respectively, were dissolved in physiological
SA JOURNAL OF DIABETES & VASCULAR DISEASE RESEARCH ARTICLE VOLUME 20 NUMBER 1 • JUNE 2023 5 serum to yield a concentration of 5 mg/ml and 50 mg/ml, respectively. According to the weight of each rat, the suspended drug solution was completed to 2 ml with physiological serum. All subjects were anaesthetised intraperitoneally with ketamine (40 mg/kg; Ketalar, Pfizer) and xylazine hydrochloride (4 mg/kg; Alfazyne 1, Ege Vet, Alfasan International BV). After the subjects were placed in a prone position, ECG recordings were taken from the D2 lead with needle electrodes (Fig. 1B). ECG recordings were evaluated with the Biopac MP36 system. RR and QT intervals and heart rates (HR) were measured by ECG recordings at baseline, and at the first and second hour, respectively. Heart rate was calculated as 1 500 per number of small squares between consecutive R waves. After the QT interval and HR measurements were performed, the corrected QT (QTc) was calculated with the Bazzet formula (QT/ RR1/2). QTc prolongation, measured by serial ECG, was the accepted main endpoint. In a similar previous experimental model researchers showed that the QTc difference of rats two hours after drug administration was 43 ms between the control and amitriptyline groups.12 It is generally accepted that a 20-ms change in QTc interval is significant.13 Therefore, in order to detect a difference of 20 ms in QTc interval between the groups, six rats per group would be required for a total of 24 rats to be able to reject the null hypothesis with a probability (power) of 0.8. The type I error probability associated with this test of the null hypothesis was 0.05. Statistical analysis Statistical analyses were performed with SPSS 22 (IBM Corp, Armonk, NY, USA). The mean and median QT, HR and QTc durations of all groups were calculated. The Shapiro–Wilk test was used to evaluate whether the data fitted a normal distribution. All ECG parameters at all available time points (baseline, first and second hours) were compared with repeated measurements of one-way analysis of variance (ANOVA), followed by Tukey’s or Tamhane post hoc tests. ECG parameters of all of the study groups at each time point (baseline, first and second hours) were also separately compared. Data without a normal distribution are expressed as median and interquartile range (IQR) and were compared by Kruskal–Wallis analysis (HR at first hour). Data with a normal distribution are expressed as mean ± standard deviation (SD) and were compared using ANOVA, followed by Tukey’s test for post hoc analysis (for other parameters). Differences of p < 0.05 were considered significant. Results After anaesthesia, ECG recordings of the four groups at baseline, and first and second hours were obtained and compared between Fig. 1. A. Drug administration to the animals via an oral tube. B. ECG recording of the rats from the D2 lead in a supine position with the Biopac MP36 system. A B Table 1. QT, QTc durations and heart rate for all groups at basal, first and second hour Variables Control Empagliflozin Amitriptilin Amitriptilin + empagliflozin p-value Baseline Qt (ms), mean ± SD 77.33 ± 9.02 78.33 ± 6.28 71.50 ± 5.68 73.33 ± 8.02 0.35 QTc (ms), mean ± SD 165.42 ±18.34 152.57± 11.07 163.11 ± 11.59 159.97 ±15.18 0.453 HR, mean ± SD 263.00 ± 39.38 230.00 ± 10.06 314.83 ± 42.48 287.50 ± 29.99 0.002 First hour Qt (ms), mean ± SD 73.50 ± 2.26 75.67 ± 4.27 108.67 ± 5.96A 90.33 ±5.39B < 0.001 QTc (ms), mean ± SD 166.63 ± 17.92 154.60 ± 20.43 227.45 ± 26.89A 179.40 ±17.63C < 0.001 HR, median (IQR) 335.50 (75.75) 245.00 (144.25) 248.50 (123.50) 232.50 (107.25) 0.279 Second hour Qt (ms), mean ± SD 78.17 ± 6.18 77.33 ± 7.31 106.00 ± 12.60A 87.83 ± 4.54C < 0.001 QTc (ms), mean ± SD 184.65 ± 12.86 171.63 ± 20.36 229.89 ± 19.83D 191.66 ± 10.93C < 0.001 HR, mean ± SD 335.83 ± 21.99 295.67 ± 30.54 288.67 ± 53.86 326.30 ± 36.97 0.118 Aamitiriptilin vs control < 0.001 Bamitriptilin + empagliflozin vs amitriptilin < 0.001 Camitriptilin + empagliflozin vs amitriptilin < 0.01 Dempagliflozin vs amitriptilin: 0.001.
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
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
RESEARCH ARTICLE SA JOURNAL OF DIABETES & VASCULAR DISEASE 8 VOLUME 20 NUMBER 1 • JUNE 2023 Conclusion The preventative effects of EMPA on the QT and QTc prolongation due to AMT, a tricyclic antidepressant, have been shown in our study. According to our research, this is the first study to show this benefit of EMPA, which can prevent AMT cardiotoxicity. We attribute these effects to the opposite effects of both molecules in the intracellular Ca balance. From the results of this study, it can be deduced that it is beneficial to use EMPA as an antidiabetic agent to prevent QT and QTc prolongation and concurrent arrhythmic events in diabetic patients with cardiovascular diseases when AMT is prescribed. In addition to these basic animal experiments, clinical research is needed to confirm this effect. Moreover, this study shows how EMPA could be beneficial in patients with heart failure with preserved ejection fraction. Acknowledgements We thank Meltem Tuncer for her constructive comments. References 1. Grempler R, Thomas L, Eckhardt M, Himmelsbach F, Sauer A, Sharp DE, et al. Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with other SGLT-2 inhibitors. Diabetes Obes Metab 2012; 14: 83–90. 2. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015; 373: 2117–2128. 3. Baartscheer A, Schumacher CA, Wust RC, Fiolet JW, Stienen GJ, Coronel R, et al. Empagliflozin decreases myocardial cytoplasmic Na(+) through inhibition of the cardiac Na(+)/H(+) exchanger in rats and rabbits. Diabetologia 2017; 60: 568–573. 4. Lee TI, Chen YC, Lin YK, Chung CC, Lu YY, Kao YH, et al. Empagliflozin attenuates myocardial sodium and calcium dysregulation and reverses cardiac remodeling in streptozotocin-induced diabetic rats. Int J Mol Sci 2019; 20. 5. Kerr GW, McGuffie AC, Wilkie S. Tricyclic antidepressant overdose: a review. Emerg Med J 2001; 18: 236–241. 6. Woolf AD, Erdman AR, Nelson LS, Caravati EM, Cobaugh DJ, Booze LL, et al. Tricyclic antidepressant poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila) 2007; 45: 203–233. 7. Barber MJ, Starmer CF, Grant AO. Blockade of cardiac sodium channels by amitriptyline and diphenylhydantoin. Evidence for two usedependent binding sites. Circ Res 1991; 69: 677–696. 8. Zima AV, Qin J, Fill M, Blatter LA. Tricyclic antidepressant amitriptyline alters sarcoplasmic reticulum calcium handling in ventricular myocytes. Am J Physiol Heart Circ Physiol 2008; 295: H2008–2016. 9. Blaber MS, Khan JN, Brebner JA, McColm R. ‘’Lipid rescue’’ for tricyclic antidepressant cardiotoxicity. J Emerg Med 2012; 43: 465–467. 10. Foianini A, Joseph Wiegand T, Benowitz N. What is the role of lidocaine or phenytoin in tricyclic antidepressant-induced cardiotoxicity? Clin Toxicol (Phila) 2010; 48: 325–330. 11. Mizuno M, Kuno A, Yano T, Miki T, Oshima H, Sato T, et al. Empagliflozin normalizes the size and number of mitochondria and prevents reduction in mitochondrial size after myocardial infarction in diabetic hearts. Physiol Rep 2018; 6: e13741. 12. Basol N, Erbas O. The effects of diltiazem and metoprolol in QTc prolongation due to amitriptyline intoxication. Hum Exp Toxicol 2016; 35: 29–34. 13. Kulmatycki KM, Abouchehade K, Sattari S, Jamali F. Drug-disease interactions: reduced beta-adrenergic and potassium channel antagonist activities of sotalol in the presence of acute and chronic inflammatory conditions in the rat. Br J Pharmacol 2001; 133: 286–294. 14. Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020; 383: 1413–1424. 15. Bakris GL, Molitch M. Microalbuminuria as a risk predictor in diabetes: the continuing saga. Diabetes Care 2014; 37: 867–875. 16. Bennett PB, Yazawa K, Makita N, George AL, Jr. Molecular mechanism for an inherited cardiac arrhythmia. Nature 1995; 376: 683–685. 17. Cardoso CR, Ferreira MT, Leite NC, Salles GF. Prognostic impact of aortic stiffness in high-risk type 2 diabetic patients: the Rio de Janeiro Type 2 Diabetes Cohort Study. Diabetes Care 2013; 36: 3772–3778. 18. Cherney DZ, Perkins BA, Soleymanlou N, Har R, Fagan N, Johansen OE, et al. The effect of empagliflozin on arterial stiffness and heart rate variability in subjects with uncomplicated type 1 diabetes mellitus. Cardiovasc Diabetol 2014; 13: 28. 19. Connelly KA, Zhang Y, Visram A, Advani A, Batchu SN, Desjardins JF, et al. Empagliflozin improves diastolic function in a nondiabetic rodent model of heart failure with preserved ejection fraction. J Am Coll Cardiol Basic Transl Sci 2019; 4: 27–37. 20. Lee HC, Shiou YL, Jhuo SJ, Chang CY, Liu PL, Jhuang WJ, et al. The sodiumglucose co-transporter 2 inhibitor empagliflozin attenuates cardiac fibrosis and improves ventricular hemodynamics in hypertensive heart failure rats. Cardiovasc Diabetol 2019; 18: 45. 21. Santos-Gallego CG, Requena-Ibanez JA, San Antonio R, Ishikawa K, Watanabe S, Picatoste B, et al. Empagliflozin ameliorates adverse left ventricular remodeling in nondiabetic heart failure by enhancing myocardial energetics. J Am Coll Cardiol 2019; 73: 1931–1944. 22. Yurista SR, Sillje HHW, Oberdorf-Maass SU, Schouten EM, Pavez Giani MG, Hillebrands JL, et al. Sodium-glucose co-transporter 2 inhibition with empagliflozin improves cardiac function in non-diabetic rats with left ventricular dysfunction after myocardial infarction. Eur J Heart Fail 2019; 21: 862–873. 23. Dinleyici EC, Kilic Z, Sahin S, Tutuncu-Toker R, Eren M, Yargic ZA, et al. Heart rate variability in children with tricyclic antidepressant intoxication. Cardiol Res Pract 2013; 2013: 196506. 24. Beach SR, Celano CM, Noseworthy PA, Januzzi JL, Huffman JC. QTc prolongation, torsades de pointes, and psychotropic medications. Psychosomatics 2013; 54: 1–13. 25. Thanacoody HK, Thomas SH. Tricyclic antidepressant poisoning: cardiovascular toxicity. Toxicol Rev 2005; 24: 205–214. 26. Schwartz PJ, Priori SG, Locati EH, Napolitano C, Cantu F, Towbin JA, et al. Long QT syndrome patients with mutations of the SCN5A and HERG genes have differential responses to Na+ channel blockade and to increases in heart rate. Implications for gene-specific therapy. Circulation 1995; 92: 3381–3386. 27. Moss AJ, Zareba W, Schwarz KQ, Rosero S, McNitt S, Robinson JL. Ranolazine shortens repolarization in patients with sustained inward sodium current due to type-3 long-QT syndrome. J Cardiovasc Electrophysiol 2008; 19: 1289–1293. 28. Priori SG, Blomstrom-Lundqvist C, Mazzanti A, Blom N, Borggrefe M, Camm J, et al. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Eur Heart J 2015; 36: 2793–2867. 29. Ozgur Baris V, Dincsoy B, Gedikli E, Erdemb A. Empagliflozin significantly attenuates sotalol-induced QTc prolongation in rats. Kardiol Pol 2021; 79: 53–57. 30. Kaplan YC, Hocaoglu N, Oransay K, Kalkan S, Tuncok Y. Effect of glucagon on amitriptyline-induced cardiovascular toxicity in rats. Hum Exp Toxicol 2008; 27: 321–325. 31. Akgun A, Kalkan S, Hocaoglu N, Gidener S, Tuncok Y. Effects of adenosine receptor antagonists on amitriptyline-induced QRS prolongation in isolated rat hearts. Clin Toxicol (Phila) 2008; 46: 677–685. 32. Oransay K, Kalkan S, Hocaoglu N, Arici A, Tuncok Y. An alternative antidote therapy in amitriptyline-induced rat toxicity model: theophylline. Drug Chem Toxicol 2011; 34: 53–60. 33. Basol N, Aygun H, Gul SS. Beneficial effects of edaravone in experimental model of amitriptyline-induced cardiotoxicity in rats. Naunyn Schmiedebergs Arch Pharmacol 2019; 392: 1447–1453. 34. Anker SD, Butler J, Filippatos G, Ferreira JP, Bocchi E, Bohm M, et al. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med 2021; 385: 1451– 1461.
SA JOURNAL OF DIABETES & VASCULAR DISEASE RESEARCH ARTICLE VOLUME 20 NUMBER 1 • JUNE 2023 9 Effect of insulin resistance on left ventricular remodelling in essential hypertensives: a cross-sectional study BERNARD KIANU PHANZU, ALIOCHA NKODILA NATUHOYILA, ELEUTHÈRE KINTOKI VITA, BENJAMIN LONGO-MBENZA, JEAN-RENÉ M’BUYAMBA KABANGU Correspondence to: Bernard Kianu Phanzu Department of Internal Medicine, Division of Cardiology, University of Kinshasa Hospital, and Centre Médical de Kinshasa, Kinshasa, Democratic Republic of the Congo e-mail: doctorkianu@gmail.com Eleuthère Kintoki Vita, Benjamin Longo-Mbenza, Jean-René M’Buyamba Kabangu Department of Internal Medicine, Division of Cardiology, University of Kinshasa Hospital, Kinshasa, Democratic Republic of the Congo Aliocha Nkodila Natuhoyila Department of Biostatistics, School of Public Health, Kinshasa, Democratic Republic of the Congo Published online in Cardiovasc J Afr; 21 June 2023 S Afr J Diabetes Vasc Dis 2023; 20: 9–16 Abstract Background: In clinical practice, left ventricular hypertrophy (LVH) is definedbyphysical findings andelectrocardiographic criteria, which are useful but imperfect tools, echocardiographic criteria and cardiac magnetic resonance imaging. In echocardiography, LVH is defined not by left ventricular wall thicknesses but by left ventricular mass. The latter is calculated according to Devereux’s formula, and is increased by insulin resistance/hyperinsulinaemia. It is however unclear whether insulin resistance, hyperinsulinaemia, or both, is actually causative and what their collective or individual influence is on the components of Devereux’s formula and parameters of left ventricular diastolic function. This study evaluated the associations of the homeostatic model assessment for insulin resistance (HOMAIR) and fasting plasma insulin levels with components of Devereux’s formula and parameters of left ventricular diastolic function. Methods: Relevant clinical data were collected from 220 hypertensive patients recruited between January and December 2019. The associations of components of Devereux’s formula and parameters of diastolic function with insulin resistance were tested using binary ordinal, conditional and classical logistic regression models. Results: Thirty-two (14.5%) patients (43.9 ± 9.1 years), 99 (45%) patients (52.4 ± 8.7 years) and 89 (40.5%) patients (53.1 ± 9.8 years) had normal left ventricular geometry, concentric left ventricular remodelling and concentric left ventricular hypertrophy, respectively. In multivariable adjusted analysis, 46.8% of variation in interventricular septum diameter (R² = 0.468; overall p = 0.001) and 30.9% of E-wave deceleration time (R² = 0.309; overall p = 0.003) were explained by insulin level and HOMAIR, 30.1% of variation in left ventricular end-diastolic diameter (R² = 0.301; p = 0.013) by HOMAIR alone, and 46.3% of posterior wall thickness (R² = 0.463; p = 0.002) and 29.4% of relative wall thickness (R² = 0.294; p = 0.007) by insulin level alone. Conclusions: Insulin resistance and hyperinsulinaemia did not have the same influence on the components of Devereux’s formula. Insulin resistance appeared to act on left ventricular end-diastolic diameter, while hyperinsulinaemia affected the posterior wall thickness. Both abnormalities acted on the interventricular septum and contributed to diastolic dysfunction via the E-wave deceleration time. Keywords: hyperinsulinaemia, insulin resistance, left ventricular remodelling, diastolic dysfunction, hypertension Hypertensive patients with insulin resistance (IR) are at increased cardiovascular risk compared to hypertensive patients without IR.1 Likewise, the presence of target-organ damage, including left ventricular hypertrophy (LVH), is associated with a poor prognosis in hypertensive patients.2 International guidelines therefore recommend considering hypertensive patients with target-organ damage, including LVH, as being at high cardiovascular risk.3-5 Hypertension-induced LVH is a known corollary not only of barometric overload secondary to high blood pressure, but also of various metabolic abnormalities induced by IR6,7 and hyperinsulinaemia.8,9 LVH represents a phenotype of the formidable capacity of the heart to adapt to various constraints in order to maintain a cardiac output sufficient to meet the metabolic needs of the whole organism. This left ventricular (LV) remodelling is defined as the set of changes in the size, shape and function of the left ventricle.10 LVH has a poor prognosis.2,10-12 It is defined not by the ventricular wall thickness, but by the left ventricular mass (LVM), calculated according to the formula of Devereux, also known as Penn’s formula,13 as: LVM (g) = 0.8 × 1.04 [(LVED + IVS + PWT)3 – LVED3] + 0.6 g, where LVED indicates left ventricular end-diastolic diameter, IVS indicates interventricular septal thickness and PWT indicates posterior wall thickness. Therefore, any factor that increases LVM might affect at least one of the following components: LVED and/or IVS and/or PWT. Because IR and hyperinsulinaemia increase LVM, the purpose of this study was to assess the collective and isolated influence of IR/ hyperinsulinaemia on each component of the Devereux formula and on diastolic functional parameters. Methods This was a cross-sectional study conducted in the Centre Médical de Kinshasa (CMK) between January and December 2019. The CMK is a reference clinic with a cardiology centre named Pôle de
RESEARCH ARTICLE SA JOURNAL OF DIABETES & VASCULAR DISEASE 10 VOLUME 20 NUMBER 1 • JUNE 2023 Cardiologie, where cardiovascular explorations such as Doppler echocardiography, coronary scanning and cardiopulmonary exercise testing are performed. It operates with highly qualified, regularly retrained personnel. This research was conducted in strict compliance with the recommendations of the Helsinki Declaration III. Approval to conduct the study was obtained from the ethics committee of the University of Kinshasa Public Health School prior to its commencement. Each participant provided written, informed consent to participate in the study. All respondents were debriefed on the results of the study. Two hundred and twenty asymptomatic hypertensive patients (133 men, 60.4%), aged 51.5 ± 9.7 years, were consecutively enrolled during out-patient consultations at the Pôle de Cardiologie of the CMK between January and December 2019. The inclusion criteria were age of 20 years and above and absence of clinical or laboratory evidence of secondary hypertension, renal or hepatic disease. Patients with heart disease unrelated to high blood pressure were excluded from participation. Demographic data (age, gender), lifestyle habits (heavy alcohol consumption, current smoking, sedentary behaviour), medical history including cardiovascular risk factors (age at diagnosis of high blood pressure, history of diabetes mellitus, dyslipidaemia, hyperuricaemia, menopause), previous cardiovascular events (stroke, ischaemic heart disease, heart failure, chronic kidney disease, cardiovascular surgery), and current medication use for chronic disease (antihypertensive treatment, antidiabetic treatment and other treatments including statins, antiplatelet agents, hypo-uricaemics, oral contraception and hormone replacement therapy) were collected during an in-person directed interview using an ad hoc questionnaire. Anthropometric parameters measured by a trained observer consisted of measurements of body weight, height, and waist and hip circumference according toWHO recommendations. Body weight was measured in kilograms using a validated electronic balance on a stable and flat surface, with participants in light clothing and shoes. The reading was taken to the nearest 100 g. Height was measured with a measuring rod, to the nearest centimetre, with participants standing barefoot and bareheaded. Body mass index (BMI) was obtained by dividing the weight (kg) by the height (m) squared. Waist circumference was measured to the nearest 0.1 cm, using a measuring tape applied directly to the skin along the horizontal line passing through the umbilicus. Body surface area (BSA) was calculated using the DuBois formula,14 as follows: BSA = height 0.725 × weight 0.425 × 0.007184. Blood pressure was measured non-invasively by 24-hour ambulatory blood pressure monitoring using a Tonoport V (GE Healthcare, Freiburg, Germany) type recorder. During this recording, the participant was asked to maintain his usual way of life. LV measurements were obtained according to the updated 2015 American Society of Echocardiography and European Association of Cardiovascular Imaging guidelines for cardiac chamber quantification,15 using a Vivid T8 (GE) type ultrasound system equipped with 3.5-MHz transducers. Two-dimensionally guided M-mode echocardiography was performed in the parasternal longaxis view. IVS, LVED and PWT were measured at end-diastole at a level just below the mitral valve leaflets. Simultaneous ECG was used to correlate measurements with the cardiac cycle. Diastolic wall thickness was measured at the onset of the QRS wave. LVMwas calculated according to the American Society of Echocardiography simplified cubed equation linear method using the equation of Devereux (see above).13 LVM was indexed by BSA and by height2.7. The relative wall thickness (RWT) of the left ventricle was calculated as (2 × PWT)/ LVED. In accordance with international recommendations,16 the parameters of LV diastolic function were measured by recording transmitral flow velocity using conventional Doppler echocardiography. With pulsed-wave (PW) Doppler, transmitral flow velocity was recorded from the apical transducer position with the sample volume situated between the mitral leaflet tips. E (peak E-wave velocity), A (peak A-wave velocity) and deceleration time of early filling (DT) were recorded in the apical four-chamber view with colour-flow imaging for optimal alignment of PW Doppler with blood flow. PW Doppler sample volume (1–3 mm axial size) was placed between the mitral leaflet tips using low wall filter setting (100–200 MHz) and low signal gain, so that the optimal spectral waveforms would not display spikes. E, A and DT were measured as the averages of five consecutive cardiac cycles. The E/A ratio was calculated. Tissue Doppler echocardiography, which measures the velocity of the regional cardiac wall, was performed by activating the tissue Doppler echocardiographic function as for two-dimensional and M-mode echocardiography. Mitral annular velocities were recorded from the apical window. Sample volumes were located at the lateral site of the mitral annulus. Peak early diastolic mitral annular velocity (E′, cm/s) was measured over five cardiac cycles and the mean was calculated. The ratio E/e′ was used as a parameter of left atrial pressure, which is elevated with progression of LV diastolic dysfunction. These parameters, obtained by tissue Doppler echocardiography, were also used as parameters of LV diastolic function. For all analyses, a blood sample was taken between 7:00 and 9:00 from the cubital vein of the patient who had been fasting since 22:00 the previous day. All analyses were carried out at the CMK laboratory. For the determination of serum uric acid, total cholesterol, low-density lipoprotein cholesterol (LDL-C), highdensity lipoprotein cholesterol (HDL-C) and triglycerides, blood was collected in a dry tube and the assay was performed by colorimetric spectrophotometer (Helios Epsilon, Milwaukee, USA). The blood glucose test was performed on plasma oxalate by colorimetric method using standard reagents (Biolabs) and was measured by the Helios Epsilon spectrophotometer. The dosage of insulin was performed on EDTA plasma by ELISA. Reading the optical density was done on a string read from the firm Humareader Human (Germany). Hyperinsulinaemia was defined as a fasting insulin level > 90 mmol/l and IR was defined by a HOMAIR ≥ 2.5.17 Normal LVM was defined as ≤ 115 g/m2 or ≤ 48 g/m2.7 in males and ≤ 95 g/m2 or ≤ 44 g/m2.7 in females, with LVH defined as LVM exceeding those values.18 Four LV geometric patterns were defined as follows:18,19 normal geometry (normal LVM and RWT ≤ 0.42); concentric remodelling (normal LVM and RWT > 0.42); concentric hypertrophy (LVH and RWT > 0.42); and eccentric hypertrophy (LVH and RWT ≤ 0.42). Three patterns of diastolic dysfunction were defined as follows:20,21 abnormal relaxation (grade I: E/A ratio < 1 and prolonged deceleration time); pseudo-normal relaxation (grade II: E/A ratio > 1 and intermediate values of deceleration time); and restrictive patterns (reversible and irreversible, grade III–IV, respectively; E/A ratio > 2 and shortened deceleration time). The dilation of the left atrium was defined by left atrial area > 20 cm2 of body surface area.15
RkJQdWJsaXNoZXIy NDIzNzc=