Ayşegül DURAK, Erkan TUNCAY, Sinan DEĞİRMENCİ, Belma TURAN

Tip 1 Diyabetli Sıçan Kalbi Elektriksel ve Mekanik Aktivitelerine Antiagregan Ajan Tikagrelorun Etkisinin İncelenmesi

Amaç: Günümüze diabetes mellitus (DM) yaygın olarak görülmekte olup kardiyovasküler bozukluklar için önemli bir risk faktörüdür. DM’li hastalarda vasküler bozukluklardan bağımsız olarak gelişen diyabetik kardiyomiyopati yanında, yüksek trombosit-reaktivitesi gelişmektedir. Bu çalışmada, bir P2Y12 reseptör blokörü tikagrelorun (TİKA), DM’li sıçan kalp fonksiyonuna etkisinin incelenmesi hedeflenmiştir. Gereç ve Yöntem: Bu çalışmada ağırlıkları 250-300 gr arasında değişen Wistar türü erkek sıçanlar kullanılarak bir grup sıçana tek doz streptozotosin (STZ; 50 mg/kg) uygulanarak DM (48-saat sonra kan şekeri ölçülerek) oluşturulmuştur. DM olan sıçanların bir grubuna 8 hafta sonra gavaj yoluyla TİKA (150 mg/kg/gün) 4 hafta boyunca uygulanmıştır (DM+TİKA grubu). STZ enjekte edilen ikinci gruba bu süre içinde su uygulanmıştır (DM grubu). Üçüncü grup sıçana aynı süre su uygulanmıştır (Kon grubu). Uygulama sonrasında sıçanlarda hafif anestezi altında in situ elektrokardiyografi (EKG) kaydedilmiş ve kalpler izole edilerek Langendorff-perfüzyon sisteminde kalbin mekanik aktivitesi ölçülmüştür. Bulgular: Hem DM’li hem de DM+TİKA’lı grup sıçanların kilo kaybederek, vücut-ağırlıklarının Kon-grubuna göre önemli derecede azalmış olduğu (p0,05) gözlenmiştir. Ayrıca, DM’li grupta deprese olan sol ventrikül-içi basınç ile ve sol ventrikül-içi diyastol sonu basınç değişimlerinin DM+TİKA’lı grupta da benzer olduğu, buna karşın DM’li grupta uzamış olan gevşeme süresinin bu grupta daha fazla uzamış olduğu gözlenmiştir (p

Investigation of the Effect of the Antiaggregant Agent Ticagrelor on the Electrical and Mechanical Activities of Rat Heart With Type 1 Diabetes

Objectives: Diabetes mellitus (DM) is presently a worldwide health problem and leads to high risks for cardiovascular disfunction. Besides vascular disorders in dependent diabetic-cardiomyopathy, high thrombocyte reactivity is developed in DM. In this study, we aimed to examine the effect of P2Y12 receptor blocker ticagrelor (TICA) on heart function of DM rats. Materials and Methods: DM was induced by a single-dose of streptozotocin (STZ) injection in 3-month-old Wistar male rats (250-300g) and confirmed by blood glucose level, 48-hour following STZ-injection. After DM confirmation, those animals were kept for 8 weeks and then, they were divided into two groups. One half DM rats was treated with TICA (150 mg/kg/day, orally) for 4 weeks (DM+TICA group), while the second half group was treated with water (DM group). A third group of rats was treated with only water (Con-group). In situ electrocardiography (ECG)-recording was performed under mild anesthesia and mechanical activities of isolated hearts were examined by Langendorff-perfusion-system. Results: The body weight of the DM group was significantly reduced compared to the Con group (p0.05). Furthermore, TICA treatment did not affect reduced left ventricular pressure and increased left ventricular enddiastolic pressure of the DM group. However, TICA treatment was further prolonged half relaxation time of left ventricular pressure, which was also prolonged in the DM group (p

PDF

___

1. Andersson C, Lyngbæk S, Nguyen CD, et al. Association of clopidogrel treatment with risk of mortality and cardiovascular events following myocardial infarction in patients with and without diabetes. JAMA. 2012;308:882-889.
2. Hu L, Chang L, Zhang Y, et al. Platelets Express Activated P2Y12 Receptor in Patients With Diabetes Mellitus. Circulation. 2017;136:817-833.
3. Ferreiro JL, Angiolillo DJ. Diabetes and antiplatelet therapy in acute coronary syndrome. Circulation. 2011;123:798-813.
4. Ferreira IA, Mocking AI, Feijge MA, et al. Platelet inhibition by insulin is absent in type 2 diabetes mellitus. Arterioscler Thromb Vasc Biol. 2006;26:417-422.
5. Wisman PP, Roest M, Asselbergs FW, et al. Platelet-reactivity tests identify patients at risk of secondary cardiovascular events: a systematic review and meta-analysis. J Thromb Haemost. 2014;12:736-747.
6. Ozturk C, Unlu M, Yildirim AO, et al. The progressed atrioventricular block associated with ticagrelor therapy may not require permanent pacemaker after acute coronary syndrome; it may be reversible. Int J Cardiol. 2016;203:822-824.
7. He M, Li D, Zhang Y, et al. Effects of different doses of ticagrelor on platelet aggregation and endothelial function in diabetic patients with stable coronary artery disease. Platelets. 2019;30:752-761.
8. Yang XM, Gadde S, Audia JP, et al. Ticagrelor Does Not Protect Isolated Rat Hearts, Thus Clouding Its Proposed Cardioprotective Role Through ENT 1 in Heart Tissue. J Cardiovasc Pharmacol Ther. 2019;24:371-376.
9. Li DT, Li SB, Zheng JY, et al. Analysis of Ticagrelor’s Cardio-protective Effects on Patients with ST-segment Elevation Acute Coronary Syndrome Accompanied with Diabetes. Open Med (Wars). 2019;14:234-240.
10. Roffi M, Patrono C, Collet JP, et al. 2015 ESC Guidelines for the Management of Acute Coronary Syndromes in Patients Presenting Without Persistent STsegment Elevation. Rev Esp Cardiol (Engl Ed). 2015;68:1125.
11. Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines: An Update of the 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention, 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery, 2012 ACC/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease, 2013 ACCF/ AHA Guideline for the Management of ST-Elevation Myocardial Infarction, 2014 AHA/ACC Guideline for the Management of Patients With Non-STElevation Acute Coronary Syndromes, and 2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery. Circulation. 2016;134:123-155.
12. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045- 1057.
13. Bonaca MP, Bhatt DL, Cohen M, et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med. 2015;372:1791-1800.
14. Goldberg A, Rosenfeld I, Nordkin I, et al. Life-threatening complete atrioventricular block associated with ticagrelor therapy. Int J Cardiol. 2015;182:379-380.
15. Goldberg A, Rosenfeld I, Nordkin I, et al. Ticagrelor therapy in patients with advanced conduction disease: Is it really safe? Int J Cardiol. 2016;202:948- 949.
16. Nicol M, Deblaise J, Choussat R, et al. Side effects of ticagrelor: Sinus node dysfunction with ventricular pause. Int J Cardiol. 2015;191:56-57.
17. Scirica BM, Cannon CP, Emanuelsson H, et al. The incidence of bradyarrhythmias and clinical bradyarrhythmic events in patients with acute coronary syndromes treated with ticagrelor or clopidogrel in the PLATO (Platelet Inhibition and Patient Outcomes) trial: results of the continuous electrocardiographic assessment substudy. J Am Coll Cardiol. 2011;57:1908-1916.
18. Ünlü M, Demirkol S, Yildirim AO, et al. Atrioventricular block associated with ticagrelor therapy may require permanent pacemaker. Int J Cardiol. 2016;202:946-947.
19. Antman EM, Wiviott SD, Murphy SA, et al. Early and late benefits of prasugrel in patients with acute coronary syndromes undergoing percutaneous coronary intervention: a TRITON-TIMI 38 (TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel-Thrombolysis In Myocardial Infarction) analysis. J Am Coll Cardiol. 2008;51:2028-2033.
20. Becker RC, Bassand JP, Budaj A, et al. Bleeding complications with the P2Y12 receptor antagonists clopidogrel and ticagrelor in the PLATelet inhibition and patient Outcomes (PLATO) trial. Eur Heart J. 2011;32:2933-2944.
21. Lee JH, Ahn SG, Park B, et al. A pharmacodynamic study of the optimal P2Y12 inhibitor regimen for East Asian patients with acute coronary syndrome. Korean J Intern Med. 2015;30:620-628.
22. Sharma M, Mascarenhas DA. Ticagrelor Associated Heart Block: The Need for Close and Continued Monitoring. Case Rep Cardiol. 2017;2017:5074891.
23. Low A, Leong K, Sharma A, et al. Ticagrelor-associated ventricular pauses: a case report and literature review. Eur Heart J Case Rep. 2018;3:156.
24. Yaras N, Ugur M, Ozdemir S, et al. Effects of diabetes on ryanodine receptor Ca release channel (RyR2) and Ca2+ homeostasis in rat heart. Diabetes. 2005;54:3082-3088.
25. Preusch MR, Rusnak J, Staudacher K, et al. Ticagrelor promotes atherosclerotic plaque stability in a mouse model of advanced atherosclerosis. Drug Des Devel Ther. 2016;10:2691-2699.
26. Husted S, Emanuelsson H, Heptinstall S, et al. Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. Eur Heart J. 2006;27:1038-1047.
27. Teng R, Butler K. Pharmacokinetics, pharmacodynamics, and tolerability of single and multiple doses of ticagrelor in Japanese and Caucasian volunteers. Int J Clin Pharmacol Ther. 2014;52:478-491.
28. Ford ES, Ajani UA, Croft JB, et al. Explaining the decrease in U.S. deaths from coronary disease, 1980-2000. N Engl J Med. 2007;356:2388-2398.
29. Unal B, Critchley JA, Capewell S. Explaining the decline in coronary heart disease mortality in England and Wales between 1981 and 2000. Circulation. 2004;109:1101-1107.
30. Wild S, Roglic G, Green A, et al. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 2004;27:1047-1053.
31. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, et al. Platelet function profiles in patients with type 2 diabetes and coronary artery disease on combined aspirin and clopidogrel treatment. Diabetes. 2005;54:2430-2435.
32. Bonello L, Laine M, Kipson N, et al. Ticagrelor increases adenosine plasma concentration in patients with an acute coronary syndrome. J Am Coll Cardiol. 2014;63:872-877.
33. Kucuk M, Celen MC, Yamasan BE, et al. Effects of Ticagrelor on Ionic Currents and Contractility in Rat Ventricular Myocytes. Cardiovasc Drugs Ther. 2015;29:419-424.
34. Armstrong D, Summers C, Ewart L, et al. Characterization of the adenosine pharmacology of ticagrelor reveals therapeutically relevant inhibition of equilibrative nucleoside transporter 1. J Cardiovasc Pharmacol Ther. 2014;19:209-219.
35. Rose JB, Naydenova Z, Bang A, et al. Equilibrative nucleoside transporter 1 plays an essential role in cardioprotection. Am J Physiol Heart Circ Physiol. 2010;298:771-777.
36. Olgar Y, Tuncay E, Billur D, et al. Ticagrelor reverses the mitochondrial dysfunction through preventing accumulated autophagosomes-dependent apoptosis and ER stress in insulin-resistant H9c2 myocytes. Mol Cell Biochem. 2020;469:97-107.
37. Grzesk G, Kozinski M, Navarese EP, et al. Ticagrelor, but not clopidogrel and prasugrel, prevents ADP-induced vascular smooth muscle cell contraction: a placebo-controlled study in rats. Thromb Res. 2012;130:65-69.
38. Dobesh PP, Oestreich JH. Ticagrelor: pharmacokinetics, pharmacodynamics, clinical efficacy, and safety. Pharmacotherapy. 2014;34:1077-1090.
39. Zhou D, Andersson TB, Grimm SW. In vitro evaluation of potential drugdrug interactions with ticagrelor: cytochrome P450 reaction phenotyping, inhibition, induction, and differential kinetics. Drug Metab Dispos. 2011;39:703-710.