The Canadian Cardiovascular Society Classification of acute atherothrombotic myocardial infarction provides a novel staging scheme based on tissue injury severity

Early reperfusion for acute myocardial infarction (AMI) is lifesaving: it preserves salvageable myocardium, thereby reducing the risk of heart failure, arrhythmias, and death. Despite advances in diagnosis and management, AMI remains the leading cause of death in the world.1 Importantly, post-infarction heart failure has been skyrocketing, and curbing it from the current epidemic levels will require paradigm-shifting advances. Cardiomyocyte necrosis evolves as a wavefront2 within an area-at-risk, myocardial oedema precedes cardiomyocyte necrosis.3 Microvascular injury can occur, comprising of microvascular obstruction manifesting as ‘no reflow,’ and myocardial haemorrhage.4 Early landmark studies relied mostly on ex vivo standards. Today’s modern non-invasive imaging technologies allow for tissue changes in AMI to be assessed in vivo, which permits serial follow-up in the same patients over extended periods of time. This has allowed for the garnering of a wealth of knowledge and shed light on the pathophysiology of AMI. Based on the cumulative evidence, the Canadian Cardiovascular Society (CCS) recently proposed that tissue changes in reperfused AMI do not simply represent independent components, but rather a sequence of four progressively severe stages of myocardial ischaemia and reperfusion injury5–7 (Figure 1): CCS Stage 1: aborted myocardial infarction, primarily reversible injury, characterized by myocardial oedema; CCS Stage 2: irreversible injury: cardiomyocyte necrosis; CCS Stage 3: occurrence of microvascular dysfunction (microvascular obstruction); and CCS Stage 4: microvascular destruction (haemorrhage). The Canadian Cardiovascular Society Classification of acute atherothrombotic myocardial infarction. Overview of the Canadian Cardiovascular Society Classification of acute atherothrombotic myocardial infarction. Tissue changes and clinical characteristics are displayed for each stage In detail, the stages are as follows: CCS Stage 1: aborted myocardial infarction: myocardial oedema with absence or minimal cardiomyocyte necrosis If ischaemia is short, myocardial injury is almost entirely reversible. Here, cardiomyocytes become dysfunctional without loss of structural integrity, with hallmark evidence of oedema. Troponin levels remain negative or at most minimally elevated. Temporary loss of contractility (ischaemic stunning) may lead to detectable wall motion abnormalities on echocardiography. Ischaemic ST-segment changes resolve without development of Q-waves after reperfusion. Tissue oedema can be visualized on cardiac magnetic resonance imaging (CMR) in the absence of gross late enhancement (no significant cardiomyocyte necrosis). Many non-ST-segment elevation myocardial infarctions (NSTEMIs), early aborted ST-segment elevation myocardial infarctions (STEMIs), and promptly reperfused STEMIs (<60 min) fall into this category. If ischaemia is not reversed at this stage, then MI will progress to Stage 2, and the rate of major adverse events increases 2- to 10-fold. CCS Stage 2: cardiomyocyte necrosis without microvascular involvement Here, the threshold for reversible cardiomyocyte injury is surpassed, but the threshold for microvascular injury is not yet reached. The hallmark of Stage 2 injury is cardiomyocyte necrosis. Cardiac troponin is significantly elevated. Following reperfusion therapy, normal coronary flow is usually restored, and ST-segment elevation resolves. Q-waves may ensue if the MI is large. Echocardiography typically shows a regional wall motion abnormality which may, depending on the extent of irreversible injury, become permanent; and CMR shows both myocardial oedema (present from Stage 1 onwards) and late gadolinium enhancement (reflecting necrosis), which will resolve into chronic scar. There is no detectable microvascular injury. CCS Stage 3: cardiomyocyte necrosis with microvascular obstruction The hallmark of Stage 3 myocardial infarction is microvascular obstruction. Here, in addition to oedema and cardiomyocyte necrosis, the ischaemic threshold of the microvasculature is surpassed. This leads to microvascular dysfunction while microvascular anatomy is preserved. Despite epicardial coronary artery reperfusion, microvascular flow is now reduced. Clinically, Thrombolysis in Myocardial Infarction flow may be reduced on fluoroscopic coronary angiography, and tissue perfusion is reduced on contrast echocardiography and CMR. ST-elevation may persist after reperfusion. Patients with Stage 3 AMI experience an increase in adverse event rates around two- to four-fold higher than in patients without microvascular involvement (CCS Stages 1, 2). CCS Stage 4: haemorrhagic myocardial infarction The hallmark of Stage 4 MI is reperfusion haemorrhage. In addition to oedema and cardiomyocyte necrosis, severe ischaemic injury now affects the microvasculature to an extent where its structural integrity is compromised. Here, microvascular injury leads to microvascular destruction. Reperfusion into a necrotic microvascular bed drives extravasation of blood, defining haemorrhagic myocardial infarction. Post reperfusion cardiac troponin peaks early and higher than in non-haemorrhagic MI. Haemorrhage occurs early after reperfusion and leads to infarct expansion, an increase in infarct size after reperfusion.4 This results in large infarctions compared with CCS Stage 3, reduced left ventricular function, and marked loss of salvageable myocardium. ST-elevation may persist. Mechanical complications such as myocardial rupture have been associated with haemorrhagic MI. Haemorrhage is detectable on CMR. Haemorrhage resolves into crystalized iron deposits, triggers a long-lasting chronic pro-inflammatory process, and drives a unique pathway to heart failure.8,9 Adverse event rates associated with CCS Stage 4 MI are two- to six-fold higher than those experiencing non-haemorrhagic MI (Stage 1, 2, or 3).10 The CCS Classification of AMI captures the natural history of tissue damage from myocardial ischaemia-reperfusion injury in an easily usable four-stage schematic. This can help to qualitatively determine the type and severity of myocardial injury. This classification is vastly different from the current electrocardiogram-based dichotomization of STEMI vs. NSTEMI, or the aetiology-based ‘Universal Definition of Myocardial Infarction’.11 A key advantage of this new staging scheme is that it permits clinical grading of severity of cardiac injury beyond commonly used markers (e.g. troponin level, infarct size, or left ventricular function), and could therefore be used as an advanced clinical risk stratification tool. The classification is a tool, which provides refined tissue injury-based endpoints and outcome measures for research as novel treatments (devices, drugs, algorithms, and etc.) may be deemed effective, if they can be cardioprotective, halting injury at an earlier stage and preventing injury progression to an advanced stage.6 Lastly, the stages themselves could serve as therapeutic targets. With each stage, a new characteristic type of injury adds to the injury of the previous stage, leading to increased event rates. Targeting the stage-specific injury may thus evolve as key to the discovery of novel, injury-stage-directed treatments to improve patient outcomes. The new CCS Classification of acute atherothrombotic myocardial infarction provides a tool for a differentiated, personalized approach to AMI risk assessment and care. Not all AMIs are the same, and future research in AMI may benefit from taking the CCS stages of tissue injury in AMI into account. A.K. is in part supported by a research grant from the Northern Ontario Academic Medicine Association, grant C-22-8. He is the President of the Canadian Society of Cardiovascular Magnetic Resonance Imaging. D.L.B. discloses the following relationships—Advisory Board: Angiowave, Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Stasys; Board of Directors: American Heart Association New York City, Angiowave (stock options), Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock); Consultant: Broadview Ventures, Hims, SFJ, Youngene; Data Monitoring Committees: Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic, Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical; for ALLAY-HF, funded by Alleviant Medical), Novartis, Population Health Research Institute; Rutgers University (for the NIH-funded MINT Trial); Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol-Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (AHA lecture), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), WebMD (CME steering committees), Wiley (steering committee); Other: Clinical Cardiology (Deputy Editor); Patent: Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women’s Hospital who assigned to Lexicon; neither I nor Brigham and Women’s Hospital receive any income from this patent); Research Funding: Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, 89Bio; Royalties: Elsevier (Editor, Braunwald’s Heart Disease); Site Co-Investigator: Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, Vascular Solutions; Trustee: American College of Cardiology; Unfunded Research: FlowCo. None of the other authors report any relevant disclosures. R.D. was funded in part by grants from the United States National Institutes of Health, NIH (HL133407, HL136578, and HL147133). R.D. has ownership interest in Cardio-Theranostics, LLC.

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