Zooming in on the Enigmas of Type 2 Myocardial Infarction

HomeCirculationVol. 145, No. 16Zooming in on the Enigmas of Type 2 Myocardial Infarction Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBZooming in on the Enigmas of Type 2 Myocardial Infarction Harvey D. White, DSc Harvey D. WhiteHarvey D. White Correspondence to: Harvey D. White, DSc, Green Lane Cardiovascular Service, Auckland City Hospital, Private Bag 92024, Victoria St West, Auckland 1142, New Zealand. Email E-mail Address: [email protected] https://orcid.org/0000-0001-7712-6750 Green Lane Cardiovascular Department, Auckland City Hospital and Auckland University, New Zealand. Search for more papers by this author Originally published18 Apr 2022https://doi.org/10.1161/CIRCULATIONAHA.122.059454Circulation. 2022;145:1201–1204This article is a commentary on the followingCoronary Artery and Cardiac Disease in Patients With Type 2 Myocardial Infarction: A Prospective Cohort StudyThere are myriad enigmas related to type 2 myocardial infarction (MI), including the definition, the diagnostic criteria, whether subjective or objective criteria for ischemia should be used, role of imaging, and management.1–4 Bularga et al5 in this issue of Circulation report the prevalence of coronary artery disease (CAD) in a prospective cohort study of 100 patients with type 2 MI.Article, see p 1188On an historical note, as cochair (along with Dr Kristian Thygesen and Dr Joseph Alpert) at a 2007 Universal Definition of Myocardial Infarction (UDMI) meeting, I proposed a new typing system for MI with 5 types of MI. My thoughts were that defining different types of MI would enable clinicians and researchers to focus on the different pathophysiology, the different prognostic implications of each type of MI, and the different possible management approaches that would in turn enable research to improve outcomes for patients with MI. Type 1 would be the wild-type or spontaneous type attributable to plaque rupture or fissuring and associated with thrombus. The management approaches were to increase myocardial blood supply by decreasing the clot with primary percutaneous coronary intervention or fibrinolysis that was well established. I had spent my training working with Dr Robin Norris at Green Lane Hospital in Auckland, New Zealand, attempting to decrease infarct size by decreasing myocardial oxygen demands by decreasing heart rate, blood pressure, and contractility with β-blockers. It therefore seemed intuitive that type 2 MI should involve an imbalance of oxygen supply/demand. Type 3 would embrace sudden death, and types 4 and 5 would include MIs associated with percutaneous coronary intervention and coronary artery bypass graft, respectively.6,7 The introduction of cardiac troponins played no role in the development of this concept.My suggestion met with minimal enthusiasm at first but after further discussion it was decided that it was a good idea and that led to the current 5 types of MI. The fourth UDMI requires the following for the diagnosis of a type 2 MI: a rise and/or fall of troponin values with at least 1 value >99th percentile upper reference limit, evidence of an imbalance between myocardial oxygen supply/demand unrelated to acute coronary atherothrombosis, and at least 1 of the following: symptoms of myocardial ischemia, new ischemic ECG changes, development of pathological Q waves, or imaging evidence of a new loss of viable myocardium or new regional wall motion abnormality in a pattern consistent with an ischemic pathogenesis.7,8In the study by Bularga et al,5 patients were defined as having type 2 MI if they fulfilled the UDMI (except for development of new Q waves and the requirement for new regional wall motion abnormalities; see Limitations and Effects on Interpretation) and there was evidence of supply/demand imbalance. Strict cutoffs for supply/demand clinical variables, such as blood pressure, oxygen saturations, or hemoglobin concentrations were not used. Patients were excluded if the responsible clinician suspected type 1 MI, severe renal or hepatic impairment, and advanced frailty. Men made up 57% of the cohort, and the median age was 71 years.The findings are very interesting. Regarding subjective ischemic symptoms, 77% had chest pain with others having shortness of breath, palpitations, or syncope, indicating that, in patients presenting with type 2 MI, atypical symptoms occur typically. Objective evidence of ischemia included ECGs and echocardiograms. ST-segment elevation occurred in 17%, ST depression in 41%, and T-wave inversion in 41%. The primary causes of supply/demand imbalance were coronary in 19% (dissection, embolism, vasospasm), systemic in 32% (anemia 9%, hypotension 5%, hypoxemia 11%, hypertension 8%), and arrhythmia in 48% (bradyarrhythmia 1%, tachyarrhythmia 47%). Echocardiography was performed in 77% and MRI in 23%. Ejection fractions were <55% in 30% of patients and <35% in 7% of patients. MRI showed late gadolinium enhancement consistent with MI in 50% of patients, with one-third being transmural and two-thirds being subendocardial.Coronary angiography was performed in 93 patients with invasive coronary angiography performed in 61% and computerized tomographic coronary angiography performed in 39%. Angiography showed significant CAD (>70% stenosis) in 33% with left main stenosis (>50% stenosis) in 3%. Four percent of patients underwent percutaneous coronary intervention and 1% underwent coronary artery bypass grafting. Thirty-eight percent had no obstructive lesions and 29% had obstructive lesions <70% stenosis. Coronary artery dissection was found in 8%, coronary embolism in 8%, and epicardial vasospasm in 5%.Changes in Diagnosis and Management After ImagingThe diagnosis of type 2 MI was changed to type 1 MI in 7 patients on the basis of finding thrombus at angiography or optical coherence tomography in 1 patient; this diagnosis was changed to type 4b (stent thrombosis) in 4 patients and to myocardial injury in 2 patients: 1 with Takotsubo syndrome and 1 with myocarditis. The results of imaging changed management in 40% of patients with CAD with the initiation of new preventative treatment and new left ventricle (LV) dysfunction therapy in 34% of patients.Limitations and Effects on InterpretationThere was no requirement for regional wall motion abnormalities on echocardiography to be new and in a pattern consistent with an ischemic pathogenesis as in the UDMI.8 This may have led to overestimating the diagnosis of MI. More than one-third of patients had normal coronary arteries. There are limited reports of MI with nonobstructive coronary arteries (defined as stenosis <50%) with type 2 MI. The management should be the same, in general, as for patients with type 2 MI, in first determining the cause of the supply/demand imbalance and then treating the cause. Although treatable causes need to be clinically considered (eg, vasospastic angina for which calcium channel blockers could be prescribed), indications for routine testing for coronary artery spasm and microvascular disease need to be further defined.9The diagnosis of type 2 MI should not be changed on the basis of whether there is a scar or LV systolic dysfunction. The presence of a scar depends on the size and confluence of the myocyte necrosis. Of note in the UDMI, MRI is not considered the gold standard for the diagnosis of MI. The presence of LV systolic dysfunction depends on the size of MI. Nor should the diagnosis depend on whether invasive coronary angiography, computerized tomographic coronary angiography, or position emission tomography/myocardial perfusion imaging are performed. It is possible, but rare, for a type 2 MI to be changed to a type 1 MI if thrombus and a ruptured plaque are seen on a coronary angiogram or optical coherence tomography. It must be noted that thrombus itself is almost invariably found at postmortem in patients who have had an MI regardless of type.10Ischemic Threshold, Subjective and Objective Evidence of IschemiaSymptoms of myocardial ischemia depend on the ischemic threshold in an individual patient and likely on the type of MI. Patients with type 2 MI and more extensive CAD will have a lower ischemic threshold than patients without CAD. Patients with more extensive CAD may also be expected to have greater myocardial damage and higher troponin levels. Clinical experience shows that a substantial portion of patients with type 1 MIs also have atypical symptoms occurring typically. Moreover, patients with type 1 MI may have on-and-off symptoms because of the infarct-related artery opening and closing11 related to changes in coronary artery tone and as the thrombus disintegrates with endogenous lysis and embolization downstream. Patients with both type 1 and type 2 MIs may be less symptomatic if they are elderly or have diabetes.In a prospective, observational cohort study involving 1640 consecutive emergency department patients, 74 (4.5%) patients had type 1 MI, 103 (6.3%) had type 2 MI, and 245 (15%) had myocardial injury.3 Patients with type 1 MI compared with patients who had type 2 MI were more likely to have ischemic symptoms (97% versus 83%), new ST-T wave changes (74% versus 51%), and new regional wall motion abnormality (64% versus 11%). Type 2 MIs were more likely to be diagnosed using subjective criteria (symptoms alone) than type 1 MIs (42% versus 12%, P<0.0001). Patients with objective type 2 MI, but not subjective type 2 MI, had a 2-fold increase in 30-day mortality compared with myocardial injury, hazard ratio 2.3 (0.9–6.2).Therefore, the presence of objective evidence of myocardial ischemia may identify a higher-risk group of patients with type 2 MI in whom early outcomes are worse than myocardial injury. Emphasis on using objective evidence of myocardial ischemia to diagnose type 2 MI may result in a more precise and specific definition.Why would imaging and coronary angiography not be performed in patients with a type 2 MI?Only between 10% and 20% of patients with a type 2 MI undergo coronary angiography.3,12 This is explained in part by less than one-third of patients with type 2 MI being looked after by cardiologists.13,14 Many of these patients should be referred for coronary angiography.Bularga et al5 state that their “novel observations provide useful insights that will encourage clinicians to consider imaging in these patients.” I agree. However, they also state “If cardiac imaging does not identify coronary artery disease or infarction, then it is unlikely the patient will benefit from therapies targeting coronary atherosclerosis. In this setting, the value of a diagnosis of type 2 myocardial infarction isquestionable.”5 I disagree with this statement for the following reasons. I believe that all patients with an MI should have assessment of LV function unless there is lack of availability or there are cost issues. Until LV function is measured, it is unknown what the ejection fraction is; patients could have undetected previous MIs, underlying cardiomyopathy attributable to other causes such as hypertrophic cardiomyopathy, ischemic or nonischemic cardiomyopathy, or important valve disease. Finding an impaired ejection fraction dramatically changes the prognosis and the management with the requirement for beginning LV impairment therapy.After considering risks and contraindications, such as bleeding, the possibility of acute kidney injury following contrast, cost, and patient preferences, most patients who have had a type 2 MI should have an assessment of their coronary arteries either invasively or noninvasively. This should be performed acutely if ST elevation is present so that primary percutaneous coronary intervention can be performed in a timely manner.The US cholesterol guidelines do not mention type 2 MIs nor do they mention whether findings on a coronary angiogram should influence the decision to commence lipid-lowering treatment. The guidelines recommend reducing low-density lipoprotein cholesterol (to <70 mg/dL after an MI of atherosclerotic origin.15 However, it would seem reasonable that patients with a type 2 MI and coronary artery stenosis ≥50% should begin statins to reduce future atherosclerotic risk. In addition, all patients with type 2 MI should have 10-year risk assessment and, if it is high (≥20%) they should also begin statins to lower low-density lipoprotein cholesterol to <70 mg/dL. Other diagnoses, such as found in this study after invasive coronary angiography, of coronary artery dissection, embolism, epicardial spasm, or MI with nonobstructive coronary arteries would also be expected to change management.The Bularga study was small, and only 1.2% of the population was included. This raises the issue of generalizability to a more general population. However, the study was prospective, well designed, and well executed, and there are several interesting and novel findings. The study found a high prevalence of unrecognized and untreated CAD. It is surprising that only 5% of patients underwent revascularization. These findings strongly support performing coronary angiography in most patients with type 2 MI. The results also support the concept of subdividing type 2 MIs into 2 groups, those with and those without CAD to begin preventative treatments. By zooming in on the prevalence of CAD, Bularga et al have helped clarify 1 enigma of type 2 MI.Article InformationSources of FundingNone.Disclosures Dr White has received grant support paid to the institution and fees for serving on Steering Committees of the ODYSSEY trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) from Sanofi and Regeneron Pharmaceuticals, the ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) and the MINT (Myocardial Ischemia and Transfusion) studies from the National Institutes of Health, the STRENGTH trial (Outcomes Study to Assess Statin Residual Risk Reduction With EpaNova in High CV Risk Patients With Hypertriglyeridemia) from Omthera Pharmaceuticals, the HEART-FID study (Randomized Placebo Controlled Trial of FCM as Treatment for Heart Failure With Iron Deficiency) from American Regent, the DAL-GENE study (Effect of Dalcetrapib vs Placebo on CV Risk in a Genetically Defined Population With a Recent ACS) from DalCor Pharma UK Inc., the AEGIS-II study (Study to Investigate CSL112 in Subjects With Acute Coronary Syndrome) from CSL Behring, the SCORED trial (Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients With Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk) and the SOLOIST-WHF trial (Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post Worsening Heart Failure) from SanofiAventis Australia Pty Ltd, and the CLEAR OUTCOMES study (Evaluation of Major Cardiovascular Events in Patients With, or at High Risk for, Cardiovascular Disease Who Are Statin Intolerant Treated With Bempedoic Acid (ETC-1002) or Placebo) from Esperion Therapeutics.FootnotesCirculation is available at www.ahajournals.org/journal/circThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Sources of Funding and Disclosures, see page 1203.Correspondence to: Harvey D. White, DSc, Green Lane Cardiovascular Service, Auckland City Hospital, Private Bag 92024, Victoria St West, Auckland 1142, New Zealand. Email [email protected]govt.nzReferences1. Alpert JS, Thygesen KA, White HD, Jaffe AS. Diagnostic and therapeutic implications of type 2 myocardial infarction: review and commentary.Am J Med. 2014; 127:105–108. doi: 10.1016/j.amjmed.2013.09.031CrossrefMedlineGoogle Scholar2. Rafiudeen R, Barlis P, White HD, van Gaal W. Type 2 MI and myocardial injury in the era of high-sensitivity troponin.Eur Cardiol. 2022; 17:e03. doi: 10.15420/ecr.2021.42CrossrefMedlineGoogle Scholar3. Sandoval Y, Smith SW, Sexter A, Schulz K, Apple FS. Use of objective evidence of myocardial ischemia to facilitate the diagnostic and prognostic distinction between type 2 myocardial infarction and myocardial injury.Eur Heart J Acute Cardiovasc Care. 2020; 9:62–69. doi: 10.1177/2048872618787796CrossrefMedlineGoogle Scholar4. White HD. Adding insult to injury: are there treatments for myocardial injury and type 2 myocardial infarction?J Am Heart Assoc. 2021; 10:e019796. doi: 10.1161/JAHA.120.019796LinkGoogle Scholar5. Bularga A, Hung J, Daghem M, Stewart S, Taggart C, Wereski R, Singh T, Meah MN, Fujisawa T, Ferry AV, et al.. Coronary artery and cardiac disease in patients with type 2 myocardial infarction: a prospective cohort study.Circulation. 2022; 145:1188–1200. doi: 10.1161/CIRCULATIONAHA.122.059454LinkGoogle Scholar6. White HD, Thygesen K, Alpert JS, Jaffe AS. Clinical implications of the Third Universal Definition of Myocardial Infarction.Heart. 2014; 100:424–432. doi: 10.1136/heartjnl-2012-302976CrossrefMedlineGoogle Scholar7. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD, Katus HA, Lindahl B, Morrow DA, Clemmensen PMet al.; Joint ESC/ACCF/AHA/WHF Task Force for the Universal Definition of Myocardial Infarction. Third universal definition of myocardial infarction.Circulation. 2012; 126:2020–2035. doi: 10.1161/CIR.0b013e31826e1058LinkGoogle Scholar8. Thygesen K, Alpert JS, Jaffe AS, Chaitman BR, Bax JJ, Morrow DA, White HDfor the Executive Group on behalf of the Joint ESC/ACCF/AHA/WHF Task Force for the Universal Definition of Myocardial Infarction. Fourth universal definition of myocardial infarction (2018).Circulation. 2018; 138:e618–e651. Published correction appears in Circulation. 2018; 138:e652.LinkGoogle Scholar9. Tamis-Holland JE, Jneid H, Reynolds HR, Agewall S, Brilakis ES, Brown TM, Lerman A, Cushman M, Kumbhani DJ, Arslanian-Engoren C, et al.; American Heart Association Interventional Cardiovascular Care Committee of the Council on Clinical Cardiology; Council on Cardiovascular and Stroke Nursing; Council on Epidemiology and Prevention; and Council on Quality of Care and Outcomes Research. Contemporary diagnosis and management of patients with myocardial infarction in the absence of obstructive coronary artery disease: a scientific statement from the American Heart Association.Circulation. 2019; 139:e891–e908. doi: 10.1161/CIR.0000000000000670LinkGoogle Scholar10. Schwartz RS, Burke A, Farb A, Kaye D, Lesser JR, Henry TD, Virmani R. Microemboli and microvascular obstruction in acute coronary thrombosis and sudden coronary death: relation to epicardial plaque histopathology.J Am Coll Cardiol. 2009; 54:2167–2173. doi: 10.1016/j.jacc.2009.07.042CrossrefMedlineGoogle Scholar11. Hackett D, Davies G, Chierchia S, Maseri A. Intermittent coronary occlusion in acute myocardial infarction. Value of combined thrombolytic and vasodilator therapy.N Engl J Med. 1987; 317:1055–1059. doi: 10.1056/NEJM198710223171704CrossrefMedlineGoogle Scholar12. McCarthy CP, Olshan DS, Rehman S, Jones-O’Connor M, Murphy S, Cohen JA, Singh A, Vaduganathan M, Januzzi JL, Wasfy JH. Cardiologist evaluation of patients with type 2 myocardial infarction.Circ Cardiovasc Qual Outcomes. 2021; 14:e007440. doi: 10.1161/CIRCOUTCOMES.120.007440LinkGoogle Scholar13. DeFilippis AP, Chapman AR, Mills NL, de Lemos JA, Arbab-Zadeh A, Newby LK, Morrow DA. Assessment and treatment of patients with type 2 myocardial infarction and acute nonischemic myocardial injury.Circulation. 2019; 140:1661–1678. doi: 10.1161/CIRCULATIONAHA.119.040631LinkGoogle Scholar14. Furie N, Israel A, Gilad L, Neuman G, Assad F, Ben-Zvi I, Grossman C. Type 2 myocardial infarction in general medical wards: clinical features, treatment, and prognosis in comparison with type 1 myocardial infarction.Medicine (Baltimore). 2019; 98:e17404. doi: 10.1097/MD.0000000000017404CrossrefMedlineGoogle Scholar15. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun LT, de Ferranti S, Faiella-Tommasino J, Forman DE, et al.. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.Circulation. 2019; 139:e1082–e1143. doi: 10.1161/CIR.0000000000000625LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesCoronary Artery and Cardiac Disease in Patients With Type 2 Myocardial Infarction: A Prospective Cohort StudyAnda Bularga, et al. Circulation. 2022;145:1188-1200 April 19, 2022Vol 145, Issue 16 Advertisement Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.122.059454PMID: 35436133 Originally publishedApril 18, 2022 Keywordscoronary artery diseaseEditorialsleft ventricular dysfunctionpercutaneous coronary interventionmyocardial infarctionPDF download Advertisement SubjectsCardiovascular DiseaseMyocardial Infarction