THE EFFECT OF TARGETED TEMPERATURE MANAGEMENT THERAPY ON PYROPTOSIS IN PATIENTS WITH RETURN OF SPONTANEOUS CIRCULATION POST CARDIAC ARREST: A PROSPECTIVE STUDY WITH HEALTHY CONTROL GROUP

Öz

Objective: To investigate the effect of targeted temperature management (TTM) on pyroptosis in patients who achieved return of spontaneous circulation (ROSC) following cardiopulmonary resuscitation (CPR) after cardiac arrest (CA). Methods: This study included 30 patients with CA in whom CPR was initiated within the first 15 minutes after arrest and lasted no longer than 60 minutes, as well as 30 age- and sex-matched healthy volunteers. The study was conducted at Harran University Medical Faculty Hospital between 2021 and 2022. The patient group received TTM therapy for 48 hours. Exclusion criteria were age <18 years, pregnancy, coagulopathy, thrombocytopenia, uncontrolled arrhythmia, end-stage disease, pre-existing neurological disease with cognitive impairment, persistent cardiogenic shock, suspected or confirmed acute intracerebral hemorrhage/acute stroke, and malignancy. Blood samples were collected from patients at three time points: at initiation of TTM (baseline), at 24 hours, and at 48 hours. Serum levels of NLRP3, caspase-1, gasdermin-D, and IL-1β were measured. Results: Serum NLRP3, caspase-1, gasdermin-D, and IL-1β levels were significantly higher in the patient group compared with the control group at all time points. Although not reaching statistical significance, NLRP3, caspase-1, and gasdermin-D levels showed a decreasing trend during the 48-hour follow-up after TTM compared with baseline values. Conclusion: Pyroptosis markers were significantly elevated following cardiac arrest compared with healthy controls. Although the reductions observed after TTM did not reach statistical significance, a downward trend in pyroptosis markers was noted during treatment.

Anahtar Kelimeler

• Cardiac arrest
• Targeted temperature management
• Pyroptosis
• Acute myocardial infarction

Destekleyen Kurum

Harran university scientific research projects coordination unit

Proje Numarası

20140

Etik Beyan

Harran University Faculty of Medicine Clinical Research Ethics Committe (no:08/25)

KARDİYAK ARREST SONRASI SPONTAN DOLAŞIMIN GERİ DÖNDÜĞÜ HASTALARDA HEDEFE YÖNELİK SICAKLIK TEDAVİSİNİN PİROPTOZİS ÜZERİNE ETKİSİ: SAĞLIKLI KONTROL GRUBU İLE PROSPEKTİF BİR ÇALIŞMA

Öz

Amaç: Kardiyopulmoner resüsitasyon (KPR) sonrası spontan dolaşımı geri dönen hastalarda hedefe yönelik sıcaklık yönetiminin (TTM) Piroptoz üzerindeki etkisini araştırmak. Yöntem: 2021 ve 2022 yılları arasında Harran Üniversitesi Tıp Fakültesi Hastanesi’nde, Kardiyak arrest (KA) sonrası ilk 15 dakika içinde başlatılan ve toplamda 60 dakikadan fazla sürmeyen KPR uygulanan 30 KA hastası ile yaş ve cinsiyet açısından eşleştirilmiş 30 sağlıklı gönüllü çalışmaya dahil edildi. Çalışma grubu 48 saat boyunca TTM tedavisi aldı. 18 yaşından küçük hastalar, gebelik, koagülopati, trombositopeni, kontrolsüz aritmi, son dönem hastalıklar, bilişsel bozukluk öyküsü olan önceki nörolojik hastalık, persistan kardiyojenik şok, şüpheli veya doğrulanmış akut intraserebral kanama/akut inme ve malignite olan hastalar çalışmadan hariç tutuldu. Çalışma grubundan üç kez kan örneği alındı: TTM’nin başlangıcında, TTM’nin 24. saatinde ve TTM’nin 48. saatinde. NLRP3, kaspaz-1, gasdermin-D ve IL-1B proteinleri ölçüldü. Bulgular: NLRP3, kaspaz-1, gasdermin D ve IL-1B düzeylerinin tüm zaman noktalarında kontrol grubuna göre denek grubunda anlamlı olarak daha yüksek olduğu saptandı. Öte yandan, istatistiksel olarak anlamlı olmasa da, NLRP3, kaspaz-1 ve gasdermin-D düzeyleri, 48 saatlik takip süresi boyunca TTM tedavisi sonrası test grubunda başlangıç değerlerine kıyasla azaldı. Sonuç: Kalp durması sonrasında piroptozis belirteçleri, sağlıklı kontrollere kıyasla anlamlı derecede artmıştır. TTM sonrasında gözlemlenen azalmalar istatistiksel olarak anlamlı olmasa da, tedavi sırasında piroptozis belirteçlerinde aşağı yönlü bir eğilim kaydedilmiştir

Anahtar Kelimeler

• Kardiyak Arrest
• Hedefe yönelik sıcaklık yönetimi
• Piroptoz
• Akut miyokard enfarktüsü

Destekleyen Kurum

Harran Üniversitesi Bilimsel Araştırma Projeleri Birimi

Proje Numarası

20140

Etik Beyan

Harran Üniversitesi Tıp Fakültesi Klinik Araştırmalar Etik Kurulu (no:08/25)

Kaynakça

1. D’Arcy MS. Cell death: a review of the major forms of apoptosis,necrosis and autophagy. Cell Biol Int. 2019;43(6):582-92.
2. Ji N, Qi Z, Wang Y, Yang X, Yan Z, Li M, Ge Q, Zhang J.Pyroptosis: A New Regulating Mechanism in CardiovascularDisease. J Inflamm Res. 2021; 14:2647-66.
3. Man SM, Karki R, Kanneganti TD. Molecular mechanisms andfunctions of pyroptosis, inflammatory caspases, and inflammasomesin infectious diseases. Immunol Rev. 2017;277(1):61-75.
4. Zheng Z, Li G. Mechanisms and Therapeutic Regulation ofPyroptosis in Inflammatory Diseases and Cancer. Int J Mol Sci.2020;21(4):1456.
5. Zeng C, Wang R, Tan H. Role of Pyroptosis in CardiovascularDiseases and its Therapeutic Implications. Int J Biol Sci.2019;15(7):1345-57.
6. Kawaguchi M, Takahashi M, Hata T, Kashima Y, Usui F,Morimoto H, et al. Inflammasome activation of cardiac fibroblastsis essential for myocardial ischemia/reperfusion injury.Circulation. 2011;123(6):594-604.
7. Lalaoui N, Lindqvist LM, Sandow JJ, Ekert PG. The molecularrelationships between apoptosis, autophagy, and necroptosis.Semin Cell Dev Biol. 2015; 39:63-9.
8. Cunningham LM, Mattu A, O’Connor RE, Brady WJ.Cardiopulmonary resuscitation for cardiac arrest: the importanceof uninterrupted chest compressions in cardiac arrestresuscitation. Am J Emerg Med. 2012;30(8):1630-8.

9. Panchal AR, Bartos JA, Cabañas JG, Donnino MW, DrennanIR, Hirsch KG, et al; Adult Basic and Advanced Life SupportWriting Group. Part 3: Adult Basic and Advanced LifeSupport: 2020 American Heart Association Guidelines forCardiopulmonary Resuscitation and Emergency CardiovascularCare. Circulation. 2020;142(16_suppl_2): S366-S468.
10. Fink SL, Cookson BT. Apoptosis, pyroptosis, and necrosis:mechanistic description of dead and dying eukaryotic cells.Infect Immun. 2005;73(4):1907-16.
11. Long H, Xu B, Luo Y, Luo K. Artemisinin protects miceagainst burn sepsis through inhibiting NLRP3 inflammasomeactivation. Am J Emerg Med. 2016;34(5):772-7.
12. Song D, Li M, Yu X, Wang Y, Fan J, Yang W, et al. TheMolecular Pathways of Pyroptosis in Atherosclerosis. FrontCell Dev Biol. 2022; 10:824165.
13. Chen X, Tian PC, Wang K, Wang M, Wang K. Pyroptosis:Role and Mechanisms in Cardiovascular Disease. FrontCardiovasc Med. 2022; 9:897815.
14. Erecinska M, Thoresen M, Silver IA. Effects of hypothermiaon energy metabolism in the mammalian central nervoussystem. J Cereb Blood Flow Metab. 2003;23(5):513-30.
15. Perkins GD, Graesner JT, Semeraro F, Olasveengen T,Soar J, Lott C, et al; European Resuscitation Council GuidelineCollaborators. European Resuscitation Council Guidelines 2021:Executive summary. Resuscitation. 2021; 161:1-60.
16. Chiu PY, Chung CC, Tu YK, Tseng CH, Kuan YC.Therapeutic hypothermia in patients after cardiac arrest: Asystematic review and meta-analysis of randomized controlledtrials. Am J Emerg Med. 2023; 71:182-189.
17. Shao ZH, Sharp WW, Wojcik KR, Li CQ, Han M, ChangWT, et al. Therapeutic hypothermia cardioprotection via Akt- andnitric oxide-mediated attenuation of mitochondrial oxidants. AmJ Physiol Heart Circ Physiol. 2010;298(6):H2164-73.
18. Diao MY, Zhu Y, Yang J, Xi SS, Wen X, Gu Q, et al.Hypothermia protects neurons against ischemia/reperfusion-inducedpyroptosis via m6A-mediated activation of PTEN andthe PI3K/Akt/GSK-3β signaling pathway. Brain Res Bull. 2020;159:25-31.
19. Gao R, Zhao H, Wang X, Tang B, Cai Y, Zhang X, et al.Mild Hypothermia Therapy Lowers the Inflammatory Level andApoptosis Rate of Myocardial Cells of Rats with MyocardialIschemia-Reperfusion Injury via the NLRP3 InflammasomePathway. Comput Math Methods Med. 2021; 2021:6415275.
20. Jiang L, Li X, Hu J, Tang Z. Mild Hypothermia AlleviatesCLP-induced Multiple Organ Dysfunction by MitigatingPyroptosis Through the TLR4/NF-κB/NLRP3 Signaling Pathway.Arch Med Res. 2023;54(1):7-16.
21. Tomura S, de Rivero Vaccari JP, Keane RW, Bramlett HM,Dietrich WD. Effects of therapeutic hypothermia on inflammasomesignaling after traumatic brain injury. J Cereb Blood FlowMetab. 2012;32(10):1939-47.