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Reperfused Myocardial Infarction: The Road to CCS Classification of Acute MI and Beyond.

Authors: Rohan Dharmakumar|||Robert A Kloner|||Michael Fishbein|||Gerd Heusch|||Keyur P Vora|||Robert Gropler|||Timothy Henry|||Fai Shing-Chan|||Dhirendra Singh|||Nithya Jambunathan|||Ramesh Subramanian|||Rolf P Kreutz|||Grant W Reed|||Richard J Kovacs|||Edward Fry|||Ankur Kalra|||Andreas Kumar|||Subha V Raman

Journal: JACC. Advances

Publication Type: Journal Article

Date: 2025

DOI: PMC11905164

ID: 40021272

Affiliations:

Affiliations

    Krannert Cardiovascular Research Center, Indiana University School of Medicine, Indianapolis, Indiana, USA. Electronic address: rdkumar@iu.edu.|||Huntington Medical Research Institute, Pasadena, California, USA; Department of Medicine, Keck School of Medicine at University of Southern California, Los Angeles, California, USA.|||Department of Pathology, David Geffen School of Medicine, University of California, Los Angeles, California, USA.|||Department of Pathophysiology, University of Essen, Essen, Germany.|||Krannert Cardiovascular Research Center, Indiana University School of Medicine, Indianapolis, Indiana, USA.|||Department of Radiological Sciences, Washington University School of Medicine at St. Louis, St. Louis, Missouri, USA.|||Carl and Edyth Lindner Center for Research, The Christ Hospital, Cincinnati, Ohio, USA.|||Krannert Cardiovascular Research Center, Indiana University School of Medicine, Indianapolis, Indiana, USA.|||Krannert Cardiovascular Research Center, Indiana University School of Medicine, Indianapolis, Indiana, USA.|||Krannert Cardiovascular Research Center, Indiana University School of Medicine, Indianapolis, Indiana, USA.|||Krannert Cardiovascular Research Center, Indiana University School of Medicine, Indianapolis, Indiana, USA.|||Krannert Cardiovascular Research Center, Indiana University School of Medicine, Indianapolis, Indiana, USA.|||Division of Cardiovascular Medicine, Heart, Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, Ohio, USA.|||Krannert Cardiovascular Research Center, Indiana University School of Medicine, Indianapolis, Indiana, USA.|||Ascension St. Vincent Heart Center, Indianapolis, Indiana, USA.|||Krannert Cardiovascular Research Center, Indiana University School of Medicine, Indianapolis, Indiana, USA; Department of Cardiology, Franciscan Health, Lafayette, Indiana, USA.|||Clinical Sciences Division, Northern Ontario School of Medicine, University and Health Sciences, Sudbury, Ontario, Canada.|||Heart and Vascular Division, OhioHealth, Columbus, Ohio, USA.

Abstract

The Canadian Cardiovascular Society recently put forth a new classification of acute reperfused myocardial infarction (MI) based on stages of myocardial injury. Backed by more than 5 decades of intense investigation in the field, the key message of this new classification is that not all MIs are the same and that the type and extent of myocardial injury should be considered in diagnosing and treating MI. We review the literature with the goal of highlighting the progressive advances that enabled the synthesis of the Canadian Cardiovascular Society classification into 4 distinct stages of tissue injury. We emphasize the major breakthroughs from insights gained from experimental, translational, and clinical studies to date. We also identify current gaps in knowledge and critical research directions that need to be pursued to improve patient care and reduce post-MI complications such as chronic heart failure and malignant arrhythmias, whose risk is linked to stage and extent of myocardial injury.


Reference List

    Parikh N.I., Gona P., Larson M.G., et al. Long-term trends in myocardial infarction incidence and case fatality in the National Heart, Lung, and Blood Institute's Framingham Heart study. Circulation. 2009;119:1203–1210.|||Martin S.S., Aday A.W., Almarzooq Z.I., et al. 2024 heart disease and stroke statistics: a report of US and global data from the American heart association. Circulation. 2024;149:e347–e913.|||Salari N., Morddarvanjoghi F., Abdolmaleki A., et al. The global prevalence of myocardial infarction: a systematic review and meta-analysis. BMC Cardiovasc Disord. 2023;23:206.|||Kalra A., Jose A.P., Prabhakaran P., et al. The burgeoning cardiovascular disease epidemic in Indians - perspectives on contextual factors and potential solutions. Lancet Reg Health Southeast Asia. 2023;12|||Murugiah K., Wang Y., Nuti S.V., et al. Are non-ST-segment elevation myocardial infarctions missing in China? Eur Heart J Qual Care Clin Outcomes. 2017;3:319–327.|||Krumholz H.M., Normand S.T., Wang Y. Twenty-year trends in outcomes for older adults with acute myocardial infarction in the United States. JAMA Netw Open. 2019;2|||Kumar A., Connelly K., Vora K., et al. The Canadian cardiovascular society classification of acute atherothrombotic myocardial infarction based on stages of tissue injury severity: an expert consensus statement. Can J Cardiol. 2024;40:1–14.|||Heusch G. Myocardial ischemia: lack of coronary blood flow, myocardial oxygen supply-demand imbalance, or what? Am J Physiol Heart Circ Physiol. 2019;316:H1439–h1446.|||Jennings R.B., Ganote C.E., Reimer K.A. Ischemic tissue injury. Am J Pathol. 1975;81:179–198.|||Fishbein M.C., Maclean D., Maroko P.R. The histopathologic evolution of myocardial infarction. Chest. 1978;73:843–849.|||Bouchardy B., Majno G. Histopathology of early myocardial infarcts. A new approach. Am J Pathol. 1974;74:301–330.|||Roger V.L., Weston S.A., Redfield M.M., et al. Trends in heart failure incidence and survival in a community-based population. JAMA. 2004;292:344–350.|||Baroldi G. Different types of myocardial necrosis in coronary heart disease: a pathophysiologic review of their functional significance. Am Heart J. 1975;89:742–752.|||Reimer K.A., Lowe J.E., Rasmussen M.M., Jennings R.B. The wavefront phenomenon of ischemic cell death. 1. Myocardial infarct size vs duration of coronary occlusion in dogs. Circulation. 1977;56:786–794.|||Demirkiran A., Beijnink C.W.H., Kloner R.A., et al. Impact of symptom-to-reperfusion-time on transmural infarct extent and left ventricular strain in patients with ST-segment elevation myocardial infarction: a 3D view on the wavefront phenomenon. Eur Heart J Cardiovasc Imaging. 2024;25:347–355.|||Reimer K.A., Jennings R.B. The "wavefront phenomenon" of myocardial ischemic cell death. II. Transmural progression of necrosis within the framework of ischemic bed size (myocardium at risk) and collateral flow. Lab Invest. 1979;40:633–644.|||Heusch G. Myocardial ischemia/reperfusion: translational pathophysiology of ischemic heart disease. Med. 2024;5:10–31.|||Kloner R.A., Creech J.L., Stone G.W., O'Neill W.W., Burkhoff D., Spears J.R. Update on cardioprotective strategies for STEMI: focus on supersaturated oxygen delivery. JACC Basic Transl Sci. 2021;6:1021–1033.|||Pizarro G., Fernández-Friera L., Fuster V., et al. Long-term benefit of early pre-reperfusion metoprolol administration in patients with acute myocardial infarction: results from the METOCARD-CNIC trial (Effect of Metoprolol in Cardioprotection during an Acute Myocardial Infarction) J Am Coll Cardiol. 2014;63:2356–2362.|||Kloner R.A.H.S. Myocardial infarction. Elsevier; 2017. Reperfusion injury: prevention and management.|||Galli M., Niccoli G., De Maria G., et al. Coronary microvascular obstruction and dysfunction in patients with acute myocardial infarction. Nat Rev Cardiol. 2024;21:283–298.|||Heusch G. Myocardial stunning and hibernation revisited. Nat Rev Cardiol. 2021;18:522–536.|||Kloner R.A., Dow J.S., Bhandari A. First direct comparison of the late sodium current blocker ranolazine to established antiarrhythmic agents in an ischemia/reperfusion model. J Cardiovasc Pharmacol Ther. 2011;16:192–196.|||Heusch G. Coronary microvascular obstruction: the new frontier in cardioprotection. Basic Res Cardiol. 2019;114:45.|||Liu T., Howarth A.G., Chen Y., et al. Intramyocardial hemorrhage and the "wave front" of reperfusion injury compromising myocardial salvage. J Am Coll Cardiol. 2022;79:35–48.|||Berg R., Buhari C. Treating and preventing no reflow in the cardiac catheterization laboratory. Curr Cardiol Rev. 2012;8:209–214.|||Maria G.L.D., Alkhalil M., Wolfrum M., et al. Index of microcirculatory resistance as a tool to characterize microvascular obstruction and to predict infarct size regression in patients with STEMI undergoing primary PCI. JACC Cardiovasc Imaging. 2019;12:837–848.|||Ganz W., Watanabe I., Kanamasa K., Yano J., Han D.S., Fishbein M.C. Does reperfusion extend necrosis? A study in a single territory of myocardial ischemia--half reperfused and half not reperfused. Circulation. 1990;82:1020–1033.|||Zhao Z.Q., Corvera J.S., Halkos M.E., et al. Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol Heart Circ Physiol. 2003;285:H579–H588.|||Heusch G. Myocardial ischaemia-reperfusion injury and cardioprotection in perspective. Nat Rev Cardiol. 2020;17:773–789.|||Kloner R.A., Hale S.L., Dai W., Shi J. Cardioprotection: where to from here? Cardiovasc Drugs Ther. 2017;31:53–61.|||Rochitte C.E., Lima J.A., Bluemke D.A., et al. Magnitude and time course of microvascular obstruction and tissue injury after acute myocardial infarction. Circulation. 1998;98:1006–1014.|||Lother A., Kohl P. The heterocellular heart: identities, interactions, and implications for cardiology. Basic Res Cardiol. 2023;118:30.|||Davidson S.M., Adameová A., Barile L., et al. Mitochondrial and mitochondrial-independent pathways of myocardial cell death during ischaemia and reperfusion injury. J Cell Mol Med. 2020;24:3795–3806.|||Heusch G., Andreadou I., Bell R., et al. Health position paper and redox perspectives on reactive oxygen species as signals and targets of cardioprotection. Redox Biol. 2023;67|||Liu Y., Lian K., Zhang L., et al. TXNIP mediates NLRP3 inflammasome activation in cardiac microvascular endothelial cells as a novel mechanism in myocardial ischemia/reperfusion injury. Basic Res Cardiol. 2014;109:415.|||Sandanger O., Ranheim T., Vinge L.E., et al. The NLRP3 inflammasome is up-regulated in cardiac fibroblasts and mediates myocardial ischaemia-reperfusion injury. Cardiovasc Res. 2013;99:164–174.|||Gottlieb R.A., Burleson K.O., Kloner R.A., Babior B.M., Engler R.L. Reperfusion injury induces apoptosis in rabbit cardiomyocytes. J Clin Investig. 1994;94:1621–1628.|||Braunwald E. The path to myocardial salvage by thrombolytic therapy. Circulation. 1987;76:Ii2–Ii7.|||Vora K.P., Kumar A., Krishnam M.S., Prato F.S., Raman S.V., Dharmakumar R. Microvascular obstruction and intramyocardial hemorrhage in reperfused myocardial infarctions: pathophysiology and clinical insights from imaging. JACC Cardiovasc Imaging. 2024;17:795–810.|||Krug A., de Du Mesnil R., Korb G. Blood supply of the myocardium after temporary coronary occlusion. Circ Res. 1966;19:57–62.|||Kloner R.A., Ganote C.E., Jennings R.B. The "no-reflow" phenomenon after temporary coronary occlusion in the dog. J Clin Invest. 1974;54:1496–1508.|||Niccoli G., Montone R.A., Ibanez B., et al. Optimized treatment of ST-elevation myocardial infarction. Circ Res. 2019;125:245–258.|||Antman E.M., Cooper H.A., Gibson C.M., et al. Determinants of improvement in epicardial flow and myocardial perfusion for ST elevation myocardial infarction; insights from TIMI 14 and InTIME-II. Eur Heart J. 2002;23:928–933.|||Porter T.R., Li S., Oster R., Deligonul U. The clinical implications of no reflow demonstrated with intravenous perfluorocarbon containing microbubbles following restoration of Thrombolysis in Myocardial Infarction (TIMI) 3 flow in patients with acute myocardial infarction. Am J Cardiol. 1998;82:1173–1177.|||Wu K.C., Kim R.J., Bluemke D.A., et al. Quantification and time course of microvascular obstruction by contrast-enhanced echocardiography and magnetic resonance imaging following acute myocardial infarction and reperfusion. J Am Coll Cardiol. 1998;32:1756–1764.|||Bresnahan G.F., Roberts R., Shell W.E., Ross J., Jr., Sobel B.E. Deleterious effects due to hemorrhage after myocardial reperfusion. Am J Cardiol. 1974;33:82–86.|||Fishbein M.C., J Y.R., Lando U., Kanmatsuse K., Mercier J.C., Ganz W. The relationship of vascular injury and myocardial hemorrhage to necrosis after reperfusion. Circulation. 1980;62:1274–1279.|||Chen B., Frangogiannis N.G. Chemokines in myocardial infarction. J Cardiovasc Transl Res. 2021;14:35–52.|||Kumar A., Green J.D., Sykes J.M., et al. Detection and quantification of myocardial reperfusion hemorrhage using T2∗-weighted CMR. JACC Cardiovasc Imaging. 2011;4:1274–1283.|||Eitel I., Desch S., Fuernau G., et al. Prognostic significance and determinants of myocardial salvage assessed by cardiovascular magnetic resonance in acute reperfused myocardial infarction. J Am Coll Cardiol. 2010;55:2470–2479.|||van Kranenburg M., Magro M., Thiele H., et al. Prognostic value of microvascular obstruction and infarct size, as measured by CMR in STEMI patients. JACC Cardiovasc Imaging. 2014;7:930–939.|||Carrick D., Haig C., Ahmed N., et al. Myocardial hemorrhage after acute reperfused ST-segment-elevation myocardial infarction: relation to microvascular obstruction and prognostic significance. Circ Cardiovasc Imaging. 2016;9|||Niccoli G., Scalone G., Lerman A., Crea F. Coronary microvascular obstruction in acute myocardial infarction. Eur Heart J. 2016;37:1024–1033.|||Honda S., Asaumi Y., Yamane T., et al. Trends in the clinical and pathological characteristics of cardiac rupture in patients with acute myocardial infarction over 35 years. J Am Heart Assoc. 2014;3|||Lechner I., Reindl M., Stiermaier T., et al. Clinical outcomes associated with various microvascular injury patterns identified by CMR after STEMI. J Am Coll Cardiol. 2024;83:2052–2062.|||Westman P.C., Lipinski M.J., Luger D., et al. Inflammation as a driver of adverse left ventricular remodeling after acute myocardial infarction. J Am Coll Cardiol. 2016;67:2050–2060.|||van Hout G.P., Bosch L., Ellenbroek G.H., et al. The selective NLRP3-inflammasome inhibitor MCC950 reduces infarct size and preserves cardiac function in a pig model of myocardial infarction. Eur Heart J. 2017;38:828–836.|||Liao Y., Liu K., Zhu L. Emerging roles of inflammasomes in cardiovascular diseases. Front Immunol. 2022;13|||Frangogiannis N.G. The inflammatory response in myocardial injury, repair, and remodelling. Nat Rev Cardiol. 2014;11:255–265.|||Prabhu S.D., Frangogiannis N.G. The biological basis for cardiac repair after myocardial infarction: from inflammation to fibrosis. Circ Res. 2016;119:91–112.|||Ortega-Gómez A., Perretti M., Soehnlein O. Resolution of inflammation: an integrated view. EMBO Mol Med. 2013;5:661–674.|||Hilgendorf I., Gerhardt L.M., Tan T.C., et al. Ly-6Chigh monocytes depend on Nr4a1 to balance both inflammatory and reparative phases in the infarcted myocardium. Circ Res. 2014;114:1611–1622.|||Liu H., Gao W., Yuan J., et al. Exosomes derived from dendritic cells improve cardiac function via activation of CD4(+) T lymphocytes after myocardial infarction. J Mol Cell Cardiol. 2016;91:123–133.|||Palano M.T., Cucchiara M., Gallazzi M., et al. When a friend becomes your enemy: natural killer cells in atherosclerosis and atherosclerosis-associated risk factors. Front Immunol. 2021;12|||Weirather J., Hofmann U.D., Beyersdorf N., et al. Foxp3+ CD4+ T cells improve healing after myocardial infarction by modulating monocyte/macrophage differentiation. Circ Res. 2014;115:55–67.|||Thrane P.G., Olesen K.K.W., Thim T., et al. Mortality trends after primary percutaneous coronary intervention for ST-segment elevation myocardial infarction. J Am Coll Cardiol. 2023;82:999–1010.|||Jenča D., Melenovský V., Stehlik J., et al. Heart failure after myocardial infarction: incidence and predictors. ESC Heart Fail. 2021;8:222–237.|||Heusch G., Gersh B.J. The pathophysiology of acute myocardial infarction and strategies of protection beyond reperfusion: a continual challenge. Eur Heart J. 2017;38:774–784.|||Hausenloy D.J., Barrabes J.A., Bøtker H.E., et al. Ischaemic conditioning and targeting reperfusion injury: a 30 year voyage of discovery. Basic Res Cardiol. 2016;111:70.|||Murry C.E., Jennings R.B., Reimer K.A. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986;74:1124–1136.|||Przyklenk K., Bauer B., Ovize M., Kloner R.A., Whittaker P. Regional ischemic preconditioning protects remote virgin myocardium from subsequent sustained coronary occlusion. Circulation. 1993;87:893–899.|||Heusch G., Bøtker H.E., Przyklenk K., Redington A., Yellon D. Remote ischemic conditioning. J Am Coll Cardiol. 2015;65:177–195.|||Heusch G. Molecular basis of cardioprotection: signal transduction in ischemic pre-, post-, and remote conditioning. Circ Res. 2015;116:674–699.|||Lieder H.R., Kleinbongard P., Skyschally A., Hagelschuer H., Chilian W.M., Heusch G. Vago-splenic Axis in signal transduction of remote ischemic preconditioning in pigs and rats. Circ Res. 2018;123:1152–1163.|||Curran J., Burkhoff D., Kloner R.A. Beyond reperfusion: acute ventricular unloading and cardioprotection during myocardial infarction. J Cardiovasc Transl Res. 2019;12:95–106.|||Heusch G., Rassaf T. Time to give up on cardioprotection? A critical appraisal of clinical studies on ischemic pre-, post-, and remote conditioning. Circ Res. 2016;119:676–695.|||Heusch G. Critical issues for the translation of cardioprotection. Circ Res. 2017;120:1477–1486.|||Heusch G. Reduction of infarct size by ischaemic post-conditioning in humans: fact or fiction? Eur Heart J. 2012;33:13–15.|||Heusch G. Treatment of myocardial ischemia/reperfusion injury by ischemic and pharmacological postconditioning. Compr Physiol. 2015;5:1123–1145.|||Heusch G. 25 years of remote ischemic conditioning: from laboratory curiosity to clinical outcome. Basic Res Cardiol. 2018;113:15.|||Botker H.E., Kharbanda R., Schmidt M.R., et al. Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial. Lancet. 2010;375:727–734.|||Hausenloy D.J., Kharbanda R.K., Møller U.K., et al. Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial. Lancet. 2019;394:1415–1424.|||Gaspar A., Lourenço A.P., Pereira M., et al. Randomized controlled trial of remote ischaemic conditioning in ST-elevation myocardial infarction as adjuvant to primary angioplasty (RIC-STEMI) Basic Res Cardiol. 2018;113:14.|||Saku K., Kakino T., Arimura T., et al. Left ventricular mechanical unloading by total support of Impella in myocardial infarction reduces infarct size, preserves left ventricular function, and prevents subsequent heart failure in dogs. Circ Heart Fail. 2018;11|||Møller J.E., Engstrøm T., Jensen L.O., et al. Microaxial flow pump or standard care in infarct-related cardiogenic shock. N Engl J Med. 2024;390:1382–1393.|||Albus H., Groot J.A., Siegenbeek van Heukelom J. Effects of glucose and ouabain on transepithelial electrical resistance and cell volume in stripped and unstripped goldfish intestine. Pflugers Arch. 1979;383:55–66.|||Nidorf S.M., Fiolet A.T.L., Mosterd A., et al. Colchicine in patients with chronic coronary disease. N Engl J Med. 2020;383:1838–1847.|||Ferdinandy P., Andreadou I., Baxter G.F., et al. Interaction of cardiovascular nonmodifiable risk factors, comorbidities and comedications with ischemia/reperfusion injury and cardioprotection by pharmacological treatments and ischemic conditioning. Pharmacol Rev. 2023;75:159–216.|||Heusch G., Bøtker H.E., Ferdinandy P., Schulz R. Primordial non-responsiveness: a neglected obstacle to cardioprotection. Eur Heart J. 2023;44:1687–1689.|||Lukhna K., Hausenloy D.J., Ali A.S., et al. Remote ischaemic conditioning in STEMI patients in sub-saharan AFRICA: rationale and study design for the RIC-AFRICA trial. Cardiovasc Drugs Ther. 2023;37:299–305.|||Cokic I., Chan S.F., Guan X., et al. Intramyocardial hemorrhage drives fatty degeneration of infarcted myocardium. Nat Commun. 2022;13:6394.|||Kali A., Cokic I., Tang R., et al. Persistent microvascular obstruction after myocardial infarction culminates in the confluence of ferric iron oxide crystals, proinflammatory burden, and adverse remodeling. Circ Cardiovasc Imaging. 2016;9|||Fu Y., Goodman S., Chang W.C., Van De Werf F., Granger C.B., Armstrong P.W. Time to treatment influences the impact of ST-segment resolution on one-year prognosis: insights from the assessment of the safety and efficacy of a new thrombolytic (ASSENT-2) trial. Circulation. 2001;104:2653–2659.|||Vyas R., Changal K.H., Bhuta S., et al. Impact of intramyocardial hemorrhage on clinical outcomes in ST-elevation myocardial infarction: a systematic review and meta-analysis. J Soc Cardiovasc Angiogr Interv. 2022;1:100444.|||Gaba P., Bhatt D.L. Promise of a novel classification system for acute myocardial infarction. Can J Cardiol. 2024;40:15–17.|||Jennings R.B., Sommers H.M., Smyth G.A., Flack H.A., Linn H. Myocardial necrosis induced by temporary occlusion of a coronary artery in the dog. Arch Pathol. 1960;70:68–78.|||Fishbein M.C., Meerbaum S., Rit J., et al. Early phase acute myocardial infarct size quantification: validation of the triphenyl tetrazolium chloride tissue enzyme staining technique. Am Heart J. 1981;101:593–600.|||Ibanez B., Aletras A.H., Arai A.E., et al. Cardiac MRI endpoints in myocardial infarction experimental and clinical trials. JACC Scientific Expert Panel. J Am Coll Cardiol. 2019;74:238–256.|||Smith C.C., Davidson S.M., Lim S.Y., Simpkin J.C., Hothersall J.S., Yellon D.M. Necrostatin: a potentially novel cardioprotective agent? Cardiovasc Drugs Ther. 2007;21:227–233.|||Oerlemans M.I., Liu J., Arslan F., et al. Inhibition of RIP1-dependent necrosis prevents adverse cardiac remodeling after myocardial ischemia-reperfusion in vivo. Basic Res Cardiol. 2012;107:270.|||Shi H., Gao Y., Dong Z., et al. GSDMD-mediated cardiomyocyte pyroptosis promotes myocardial I/R injury. Circ Res. 2021;129:383–396.|||Toldo S., Abbate A. The role of the NLRP3 inflammasome and pyroptosis in cardiovascular diseases. Nat Rev Cardiol. 2023;21:219–237.|||Jiang X., Stockwell B.R., Conrad M. Ferroptosis: mechanisms, biology and role in disease. Nat Rev Mol Cell Biol. 2021;22:266–282.|||Fang X., Ardehali H., Min J., Wang F. The molecular and metabolic landscape of iron and ferroptosis in cardiovascular disease. Nat Rev Cardiol. 2023;20:7–23.|||Bravo-San Pedro J.M., Kroemer G., Galluzzi L. Autophagy and mitophagy in cardiovascular disease. Circ Res. 2017;120:1812–1824.|||Sciarretta S., Forte M., Frati G., Sadoshima J. New insights into the role of mTOR signaling in the cardiovascular system. Circ Res. 2018;122:489–505.|||Titus A.S., Sung E.A., Zablocki D., Sadoshima J. Mitophagy for cardioprotection. Basic Res Cardiol. 2023;118:42.