Guidelines for Evaluating Myocardial Cell Death

Overview

Journal Am J Physiol Heart Circ Physiol

Publisher American Physiological Society

Specialties Cardiology & Vascular Diseases
Physiology

Date 2019 Aug 17

PMID 31418596

Citations 103

Authors

Paras K Mishra

Adriana Adameova

Joseph A Hill

Christopher P Baines

Peter M Kang

James M Downey

Jagat Narula

Masafumi Takahashi

Antonio Abbate

Hande C Piristine

Sumit Kar

Shi Su

Jason K Higa

Nicholas K Kawasaki

Takashi Matsui

Affiliations

Soon will be listed here.

Abstract

Cell death is a fundamental process in cardiac pathologies. Recent studies have revealed multiple forms of cell death, and several of them have been demonstrated to underlie adverse cardiac remodeling and heart failure. With the expansion in the area of myocardial cell death and increasing concerns over rigor and reproducibility, it is important and timely to set a guideline for the best practices of evaluating myocardial cell death. There are six major forms of regulated cell death observed in cardiac pathologies, namely apoptosis, necroptosis, mitochondrial-mediated necrosis, pyroptosis, ferroptosis, and autophagic cell death. In this article, we describe the best methods to identify, measure, and evaluate these modes of myocardial cell death. In addition, we discuss the limitations of currently practiced myocardial cell death mechanisms.

Citing Articles

Necrosis-like cell death modes in heart failure: the influence of aetiology and the effects of RIP3 inhibition.

Jarabicova I, Horvath C, Hrdlicka J, Boros A, Olejnickova V, Zabrodska E Basic Res Cardiol. 2025; .

PMID: 40088261 DOI: 10.1007/s00395-025-01101-4.

Mitochondrial Dysfunction in Congenital Heart Disease.

Pires Da Silva J, Casa de Vito M, Miyano C, Sucharov C J Cardiovasc Dev Dis. 2025; 12(2).

PMID: 39997476 PMC: 11856204. DOI: 10.3390/jcdd12020042.

Inhibition of mir-155-5p alleviates cardiomyocyte pyroptosis induced by hypoxia/reoxygenation via targeting SIRT1-mediated activation of the NLRP3 inflammasome.

Lu Q, Shen Q, Su J, Li X, Xia B, Tang A J Cardiothorac Surg. 2025; 20(1):135.

PMID: 39972472 PMC: 11837669. DOI: 10.1186/s13019-025-03366-1.

Taxifolin Protects Against 5-Fluorouracil-Induced Cardiotoxicity in Mice Through Mitigating Oxidative Stress, Inflammation, and Apoptosis: Possible Involvement of Sirt1/Nrf2/HO-1 Signaling.

Abukhalil M, Al-Alami Z, Alfwuaires M, Imran M, Aladaileh S, Althunibat O Cardiovasc Toxicol. 2025; 25(3):455-470.

PMID: 39827225 DOI: 10.1007/s12012-025-09962-w.

Recent advances associated with cardiometabolic remodeling in diabetes-induced heart failure.

Sharma G, Chaurasia S, Carlson M, Mishra P Am J Physiol Heart Circ Physiol. 2024; 327(6):H1327-H1342.

PMID: 39453429 PMC: 11684949. DOI: 10.1152/ajpheart.00539.2024.

References

Shao W, Yeretssian G, Doiron K, Hussain S, Saleh M . The caspase-1 digestome identifies the glycolysis pathway as a target during infection and septic shock. J Biol Chem. 2007; 282(50):36321-9. DOI: 10.1074/jbc.M708182200. View

Conos S, Chen K, De Nardo D, Hara H, Whitehead L, Nunez G . Active MLKL triggers the NLRP3 inflammasome in a cell-intrinsic manner. Proc Natl Acad Sci U S A. 2017; 114(6):E961-E969. PMC: 5307433. DOI: 10.1073/pnas.1613305114. View

Lomonosova E, Chinnadurai G . BH3-only proteins in apoptosis and beyond: an overview. Oncogene. 2009; 27 Suppl 1:S2-19. PMC: 2928556. DOI: 10.1038/onc.2009.39. View

Wang H, Sun L, Su L, Rizo J, Liu L, Wang L . Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3. Mol Cell. 2014; 54(1):133-146. DOI: 10.1016/j.molcel.2014.03.003. View

Hikoso S, Yamaguchi O, Nakano Y, Takeda T, Omiya S, Mizote I . The I{kappa}B kinase {beta}/nuclear factor {kappa}B signaling pathway protects the heart from hemodynamic stress mediated by the regulation of manganese superoxide dismutase expression. Circ Res. 2009; 105(1):70-9. DOI: 10.1161/CIRCRESAHA.108.193318. View

Pang X, Panee J, Liu X, Berry M, Chang S, Chang L . Regional variations of antioxidant capacity and oxidative stress responses in HIV-1 transgenic rats with and without methamphetamine administration. J Neuroimmune Pharmacol. 2013; 8(3):691-704. PMC: 3773562. DOI: 10.1007/s11481-013-9454-8. View

Miceli C, Santin Y, Manzella N, Coppini R, Berti A, Stefani M . Oleuropein Aglycone Protects against MAO-A-Induced Autophagy Impairment and Cardiomyocyte Death through Activation of TFEB. Oxid Med Cell Longev. 2018; 2018:8067592. PMC: 5892212. DOI: 10.1155/2018/8067592. View

Ma X, Liu H, Foyil S, Godar R, Weinheimer C, Hill J . Impaired autophagosome clearance contributes to cardiomyocyte death in ischemia/reperfusion injury. Circulation. 2012; 125(25):3170-81. PMC: 3397471. DOI: 10.1161/CIRCULATIONAHA.111.041814. View

Jing L, Song F, Liu Z, Li J, Wu B, Fu Z . MLKL-PITPα signaling-mediated necroptosis contributes to cisplatin-triggered cell death in lung cancer A549 cells. Cancer Lett. 2017; 414:136-146. DOI: 10.1016/j.canlet.2017.10.047. View

10.

Bai Y, Chang R, Wang H, Xiao F, Ge R, Wang L . ENPP2 protects cardiomyocytes from erastin-induced ferroptosis. Biochem Biophys Res Commun. 2018; 499(1):44-51. DOI: 10.1016/j.bbrc.2018.03.113. View

11.

Laker R, Taddeo E, Akhtar Y, Zhang M, Hoehn K, Yan Z . The Mitochondrial Permeability Transition Pore Regulator Cyclophilin D Exhibits Tissue-Specific Control of Metabolic Homeostasis. PLoS One. 2016; 11(12):e0167910. PMC: 5179060. DOI: 10.1371/journal.pone.0167910. View

12.

Tait S, Oberst A, Quarato G, Milasta S, Haller M, Wang R . Widespread mitochondrial depletion via mitophagy does not compromise necroptosis. Cell Rep. 2013; 5(4):878-85. PMC: 4005921. DOI: 10.1016/j.celrep.2013.10.034. View

13.

Linkermann A, Heller J, Prokai A, Weinberg J, De Zen F, Himmerkus N . The RIP1-kinase inhibitor necrostatin-1 prevents osmotic nephrosis and contrast-induced AKI in mice. J Am Soc Nephrol. 2013; 24(10):1545-57. PMC: 3785275. DOI: 10.1681/ASN.2012121169. View

14.

Nakai A, Yamaguchi O, Takeda T, Higuchi Y, Hikoso S, Taniike M . The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress. Nat Med. 2007; 13(5):619-24. DOI: 10.1038/nm1574. View

15.

Ytrehus K, Liu Y, Tsuchida A, Miura T, Liu G, Yang X . Rat and rabbit heart infarction: effects of anesthesia, perfusate, risk zone, and method of infarct sizing. Am J Physiol. 1994; 267(6 Pt 2):H2383-90. DOI: 10.1152/ajpheart.1994.267.6.H2383. View

16.

Nakagawa T, Shimizu S, Watanabe T, Yamaguchi O, Otsu K, Yamagata H . Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature. 2005; 434(7033):652-8. DOI: 10.1038/nature03317. View

17.

Luedde M, Lutz M, Carter N, Sosna J, Jacoby C, Vucur M . RIP3, a kinase promoting necroptotic cell death, mediates adverse remodelling after myocardial infarction. Cardiovasc Res. 2014; 103(2):206-16. DOI: 10.1093/cvr/cvu146. View

18.

Hou H, Wang Y, Li Q, Li Z, Teng Y, Li J . The role of RIP3 in cardiomyocyte necrosis induced by mitochondrial damage of myocardial ischemia-reperfusion. Acta Biochim Biophys Sin (Shanghai). 2018; 50(11):1131-1140. DOI: 10.1093/abbs/gmy108. View

19.

Oerlemans M, Liu J, Arslan F, den Ouden K, van Middelaar B, Doevendans P . Inhibition of RIP1-dependent necrosis prevents adverse cardiac remodeling after myocardial ischemia-reperfusion in vivo. Basic Res Cardiol. 2012; 107(4):270. DOI: 10.1007/s00395-012-0270-8. View

20.

Frank D, Vince J . Pyroptosis versus necroptosis: similarities, differences, and crosstalk. Cell Death Differ. 2018; 26(1):99-114. PMC: 6294779. DOI: 10.1038/s41418-018-0212-6. View