Acute coronary syndromes represent a significant health burden and convey a prognosis that is far from benign. Indeed, United Kingdom registry data reveal that 6 months following admission for a non-ST elevation myocardial infarction (NSTEMI), there is a 12.2% rate of death or non-fatal MI, and a 30% rate of death, MI, refractory angina or readmission for unstable angina.1 A number of trials have demonstrated that early revascularization has a significant beneficial impact on patients with NSTEMI,2,3,4 prompting international guidelines to recommend early angiography and revascularization for high-risk NSTEMI patients.5 A significant proportion of these patients, however, are found to have normal coronary arteries on angiography (10% in a series by Curzen et al,6 9% in one by Germing et al).7In this subgroup of patients, the finding of unobstructed coronary arteries raises a fundamental question as to whether they should be labeled with a diagnosis of NSTEMI. This diagnosis has significant implications for the patient in terms of prognosis, need for secondary prevention, psychological well-being and subsequent occupational and health insurance sequelae. Delayed enhancement cardiovascular magnetic resonance (DE-CMR) has been shown to provide an accurate, noninvasive quantification of even small areas of MI,8,9 and thereby could represent a useful tool to determine if such patients have any definitive evidence of MI. DE-CMR also allows the opportunity to assess the presence of myocarditis in this population.10 In this study we examined the incidence and extent of DE-CMR-defined myocardial necrosis in patients with clinical evidence of NSTEMI (including an abnormal electrocardiogram [ECG] and elevated biomarkers), but angiographically normal coronary arteries. Methods This is a clinical observational series that included 25 consecutive patients diagnosed using standard clinical criteria as having a NSTEMI and who underwent inpatient coronary angiography with a view to percutaneous intervention, and who were found to have normal coronary arteries. All patients went on to have DE-CMR. Inclusion criteria. NSTEMI was defined as a combination of: typical cardiac-sounding chest pain, a significant rise in troponin, with no clear alternative cause with ST-segment depression, nonspecific T-wave changes or an unremarkable ECG. CMR protocol. Patients were studied using a 1.5T clinical CMR scanner (Sonata, Siemens AGA, Medical Solutions, Erlangen, Germany), with steady-state free precession images acquired in two long- and a stack of short-axis images that encompassed the entire left ventricle, as previously described.11 A gadolinium contrast agent (Gadodiamide, Omniscan, Nycomed Amersham, United Kingdom) was then administered intravenously at a dose of 0.1 mmol per kilogram of body weight. Long- and short-axis DE-CMR images were acquired after a 10-minute delay using an inversion recovery segmented gradient echo sequence. Typical voxel size was 1.9 x 1.4 x 7 mm. All data images were reported by three operators experienced in DE-CMR (NB, CP, SH), and all were blinded to the troponin level or the appearance of the ECG. Results Baseline characteristics. Twenty-five patients with a mean age of 56 ± 11 years underwent DE-CMR. Risk factors were as follows: current smoker 27%, ex-smoker 32%, diabetes 50%, hypertension 45%, mean cholesterol 5.7 ± 1.6 mmol/L, and family history of premature cardiovascular disease 50%. All patients initially received treatment with aspirin and clopidogrel, 91% received a statin, 77% beta-blockers and 68% an angiotensin-converting enzyme inhibitor. No patients received glycoprotien IIb/IIIa antagonists prior to coronary angiography. All patients had typical cardiac-sounding chest pain, ST-segment depression or nonspecific T-wave changes on ECG. The mean troponin I level was 7 ± 11 mg/L (range: 0.18–28 mg/L). CMR findings. Four patients (16%) had hyperenhancement consistent with MI (Figure 1), with full thickness myocardial enhancement of one segment, and all were associated with a regional wall motion abnormality. The myocardial mass of each MI was 2.0, 4.8, 6.1 and 6.7 g/cm2. Eight patients (32%) had patchy areas of hyperenhancement consistent with myocarditis (Figure 2), 5 of which were associated with a wall motion abnormality. Thirteen patients (52%) had no areas of hyperenhancement. Discussion In this study, we have confirmed that the diagnostic conundrum provided by patients presenting with cardiac chest pain with troponin elevation but unobstructed coronary arteries is relatively common, and that DE-CMR has the potential to improve diagnostic accuracy in such patients. In only 16% of patients was there clear evidence of MI. We assume that such patients would continue to benefit prognostically from aggressive secondary preventive therapy and that they should declare the diagnosis of heart attack during future insurance and occupational inquiry. By contrast, 84% of these patients who would otherwise be clinically diagnosed as having NSTEMI had no evidence of myocardial necrosis. Given the published sensitivity of DE-CMR in detecting even small areas of myocardial damage,7 it may be reasonable to suggest that such patients can be told that they did not, after all, experience a heart attack on this presentation and that their secondary preventive therapy may be both inappropriate and potentially hazardous.13 In terms of insurance applications, this would clearly not be served well by the diagnostic label of NSTEMI. Interestingly, Table 1 illustrates how the current ACC, DVLA, DE-CMR and critical illness definition of acute coronary syndromes (ACS) would have classified the patients in this clinical series. The consensus critical illness definition of MI from representative insurance companies was “death of a portion of heart muscle due to inadequate blood supply that has resulted in all of the following evidence of MI: typical chest pain, new ECG changes, a rise in cardiac enzymes”.14,15 In recent years, there has been a significant expansion in the utilization of sensitive cardiac biomarkers of myocardial necrosis, to the extent that the definition, risk stratification and the management of patients are increasingly determined by them. In 2000, there was a consensus change in the definition of MI as a typical rise and fall of troponin (or CK-MB), with at least one of the following: (1) ischemic symptoms; (2) development of Q-waves; (3) ST-elevation or depression; (4) coronary intervention.16 Although it is clear that troponin was not 100% specific, a MI was nevertheless diagnosed if troponin was elevated, particularly in the presence of suggestive symptoms and ECG changes.17 The British Cardiac Society Working Group later suggested a nomenclature of ACS with clinical MI for those patients with a troponin-T > 1.0 ng/ml (reference value for troponin I depends upon the manufacturer, but is > 0.5 ng/ml for AccuTnI).18 All patients in this study satisfy all of these MI definitions. Several studies demonstrated that not only are patients with elevated cardiac markers at higher risk for adverse events, but early intervention resulted in improved outcome.4 Consequent international guidelines, therefore, advocate early angiography and intervention in patients with ACS. In clinical practice, however, many of these patients satisfying the definition of ACS and, in particular NSTEMI, are found to have angiographically normal coronary arteries.6,7 This raises the question of whether these patients have actually sustained a MI, particularly in light of the concern about possible over-reliance on the result of troponin tests in the assessment of this patient group.19 It is well recognized that the finding of angiographically “normal” coronary arteries does not exclude the presence of significant coronary artery disease being demonstrated by other more sensitive imaging modalities such as intravascular ultrasound.20 Furthermore, some patients may recanalize an acute thrombotic occlusion of a nonobstructive coronary artery plaque or suffer an acute event as a result of an embolism. In all of these scenarios, however, the diagnosis of NSTEMI would be based, correctly upon the history and biochemical evidence of myocardial damage. The latter should be detected by DE-CMR. Alternatively, some patients with chest pain and a rise in troponin may not have had an ischemic event at all, but may have an alternative explanation (Table 2). In these cases, such patients would not be expected to have DE-CMR findings consistent with myocardial necrosis. Although there is evidence to suggest that patients have a poorer outcome in the presence of elevated troponin, this has only thus far been demonstrated in patients with significant coronary heart disease or in the critically ill, but not in patients with a normal coronary angiogram.21 The implications of an inaccurate diagnosis of NSTEMI are profound for the patients and the healthcare system. Firstly, it condemns them to long-term secondary preventive therapy. Secondly, the diagnosis is likely to have a significant impact on the psychological well-being of the patient. Thirdly, it will almost certainly impact upon their future application for occupational, life or health insurance. DE-CMR has been validated in both animal and human studies in demonstrating the accurate quantification of even small areas of myocardial necrosis, with remarkably close agreement between histopathological and DE-CMR depiction of infarct.24,8,9 It has superior spatial resolution to single-photon emission computed tomography (SPECT),23 and in the setting of percutaneous intervention, for example, Ricciardi et al illustrated the presence of small areas of percutaneous coronary intervention (PCI)-induced myocardial necrosis (corresponding to a minimal HE mass of 0.66 g, median 2.0 g).12 Furthermore, Sevanayagam et al demonstrated that not only small rises in cardiac troponin represented myocardial necrosis on DE-CMR, but that the magnitude of troponin elevation post-PCI gives an accurate estimate of the size of the MI.24 DE-CMR is also well validated for the diagnosis of myocarditis, with contrast enhancement found in 88% of cases in a recent study of patients diagnosed on clinical grounds.25 Study limitations. This study has several limitations. The patient population is small, and there is no specific control group. It would have been interesting to document the frequency and patterns of DE-CMR enhancement in patients who presented in the same manner, but did have coronary artery disease, however, this was outside the scope of this study. For logistical reasons, the mean time between angiography and DE-CMR was 3 months. If the DE-CMR had been performed earlier, it may have led to an increase in the number of patients with patchy hyperenhancement, a pattern consistent with myocarditis. The time delay would not, however, have led to any significant change in the hyperenhancement pattern of MI, which remains subendocardial and undergoes only a mild degree of resorption with time.26 This paper illustrates the difficulty in defining a diagnosis of NSTEMI in some patients with troponin-positive chest pain. It suggests that DE-CMR may well be useful in determining which patients have indeed suffered myocardial necrosis, thereby directing their further management appropriately. The findings demand further investigation of this potentially management-altering tool in larger cohorts of patients. For example, the long-term follow up of a large cohort of patients with troponin-positive ACS, but normal coronary arteries and normal DE-CMR, may well reveal no greater risk of future cardiac events and strengthen the case for the routine use of CMR in the diagnosis of MI.
References 1. Collinson J, Flather MD, Fox KA, et al. Clinical outcomes, risk stratification and practice patterns of unstable angina and myocardial infarction without ST elevation: Prospective registry of Acute Ischaemic Syndromes in the UK (PRAIS-UK). Eur Heart J 2000;21:1450‚Äì1457. 2. Fragmin and Fast Revascularization during InStability in Coronary artery disease Investigators Invasive compared to non-invasive treatment in unstable coronary-artery disease: FRISC II prospective randomised multi-center study. Lancet 1999;354:708‚Äì715. 3. Cannon CP, Weintraub WS, Demopoulos LA, et al. TACTICS (Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy). Thrombolysis in Myocardial Infarction 18 Investigators. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with glycoprotein IIb/IIIa inhibitor tirofiban. N Engl J Med 2001;344:1879‚Äì1887. 4. Fox KA, Poole-Wilson PA, Henderson RA, et al. Randomized Intervention Trial of unstable Angina Investigators. Randomised Interventional trial of unstable Angina (RITA) Investigators. Interventional versus conservative treatment for patients with unstable angina or non-ST elevation MI: The British Heart Foundation RITA 3 randomised trial. Lancet 2002;360:743‚Äì751. 5. Barnwell E, Antman EM, Beasley JW, et al. American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina). ACC/AHA guideline update for the management of patients with unstable angina and nonST segment elevation myocardial infarction. Circulation 2002;106:1893‚Äì1900. 6. Curzen PN, Patel DJ, Kemp M, et al. Can C reactive protein or itroponins T and I predict outcome in patients with intractable unstable angina? Heart 1998;80:23‚Äì27. 7. Germing A, Lindstaedt M, Ulrich S, Grewe P, et al. Normal angiofram in acute coronary syndrome-preangiographic risk stratification, angiographic findings and follow-up. Int J Cardiol 2005;99:25‚Äì27. 8. Kim RJ, Fieno DS, Parrish TB, et al. Relationship of MRI delayed contrast enhancement to irreversible injury, infarct age, and contractile function. Circulation 1999;100:1992‚Äì2002. 9. Kim RJ, Wu E, Rafael A, et al. The use of contrast-enhanced magnetic resonance imaging to identify reversible myocardial dysfunction. N Engl J Med 2000;343:1488‚Äì1490. 10. Varghese A, Davies S, Pennell DJ. Diagnosis of myocarditis by cardiovascular magnetic resonance Heart 2005;91:567. 11. Bellenger NG, Davies LC, Francis JM, et al. Reduction in sample size for studies of remodelling in heart failure by the use of cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2000;2:271‚Äì278. 12. Ricciardi MJ, Wu E, Davidson CJ, et al. Visualization of discrete micro infarction after percutaneous coronary intervention associated with mild CK-MB elevation. Circulation 2001;103:2780‚Äì2783. 13. Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006;354. 14. www.directline.com/critical_illness/fixed_critical_key.pdf 15. www.norwichunion.com/library/pdfs/pt07001.pdf 16. The Joint European Society of Cardiology/American College of Cardiology Committee. Myocardial infarction redefined ‚Äî A consensus document of the Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. Eur Heart J 2000;21:1502‚Äì1513. 17. Luepker RV, Apple FS, Christenson RH, et al. AHA Council on Epidemiology and Prevention; AHA Statistics Committee; World Heart Federation Council on Epidemiology and Prevention; European Society of Cardiology Working Group on Epidemiology and Prevention; Centers for Disease Control and Prevention; National Heart, Lung, and Blood Institute. Case definitions for acute coronary heart disease in epidemiology and clinical research studies: A statement from the AHA Council on Epidemiology and Prevention; AHA Statistics Committee; World Heart Federation Council on Epidemiology and Prevention; The European Society of Cardiology Working Group on Epidemiology and Prevention; Centers for Disease Control and Prevention; and the National Heart, Lung, and Blood Institute. Circulation 2003;108:2543‚Äì2549. Epub 2003 Nov 10. 18. Fox KAA, Birkhead J, Wilcox R, et al. British Cardiac Society Working Group on the definition of myocardial infarction. Heart 2004;90:603‚Äì609. 19. Curzen N. Troponins in patients with chest pain: A mixed blessing? Br Med J 2004;329:1357‚Äì1358. 20. Nissen S. Coronary angiography and intravascular ultrasound. Am J Cardiol 2001;87:15A‚Äì20A. 21. Ammann P, Maggiorini M, Bertel O, et al. Troponin as a risk factor for mortality in critically ill patients without acute coronary syndromes. J Am Coll Cardiol 2003;41:2004‚Äì2009. 22. Dymarkowski S, Ni Y, Miao Y, et al. Value of T2 weighted MRI early after MI in dogs: Comparison with bis-gadolinium-mesoporphyrin enhanced T1-weighted MRI and functional data from cine MRI. Invest Radiol 2002;37:77‚Äì85. 23. Wagner A, Mahrholdt H, Holly TA, et al. Contrast-enhanced MRI detects subendocardial myocardial infarcts that are missed by routine SPECT perfusion imaging. Lancet 2003;361:374‚Äì379. 24. Selvanayagam JB, Porto I, Channon K, et al. Troponin elevation after percutaneous coronary intervention directly represents the extent of irreversible myocardial injury. Insights from CMRI. Circulation 2005;111:1027‚Äì1032. 25. Mahrholdt H, Goedecke C, Wagner A, et al. Cardiovascular magnetic resonance assessment of human myocarditis. A comparison to histology and molecular biology. Circulation 2004;109:1250‚Äì1258. 26. Fieno DS, Hillenbrand HB, Rehwald WG, et al. Infarct resorption, compensatory hypertrophy, and differing patterns of ventricular remodeling following myocardial infarctions of varying size. J Am Coll Cardiol 2004;43:2124‚Äì2131.