Cardiovascular magnetic resonance accurately detects obstructive coronary artery disease in suspected non-ST elevation myocardial infarction: a sub-analysis of the CARMENTA Trial

Background Invasive coronary angiography (ICA) is still the reference test in suspected non-ST elevation myocardial infarction (NSTEMI), although a substantial number of patients do not have obstructive coronary artery disease (CAD). Early cardiovascular magnetic resonance (CMR) may be a useful gatekeeper for ICA in this setting. The main objective was to investigate the accuracy of CMR to detect obstructive CAD in NSTEMI. Methods This study is a sub-analysis of a randomized controlled trial investigating whether a non-invasive imaging-first strategy safely reduced the number of ICA compared to routine clinical care in suspected NSTEMI (acute chest pain, non-diagnostic electrocardiogram, high sensitivity troponin T > 14 ng/L), and included 51 patients who underwent CMR prior to ICA. A stepwise approach was used to assess the diagnostic accuracy of CMR to detect (1) obstructive CAD (diameter stenosis ≥ 70% by ICA) and (2) an adjudicated final diagnosis of acute coronary syndrome (ACS). First, in all patients the combination of cine, T2-weighted and late gadolinium enhancement (LGE) imaging was evaluated for the presence of abnormalities consistent with a coronary etiology in any sequence. Hereafter and only when the scan was normal or equivocal, adenosine stress-perfusion CMR was added. Results Of 51 patients included (63 ± 10 years, 51% male), 34 (67%) had obstructive CAD by ICA. The sensitivity, specificity and overall accuracy of the first step to diagnose obstructive CAD were 79%, 71% and 77%, respectively. Additional vasodilator stress-perfusion CMR was performed in 19 patients and combined with step one resulted in an overall sensitivity of 97%, specificity of 65% and accuracy of 86%. Of the remaining 17 patients with non-obstructive CAD, 4 (24%) had evidence for a myocardial infarction on LGE, explaining the modest specificity. The sensitivity, specificity and overall accuracy to diagnose ACS (n = 43) were 88%, 88% and 88%, respectively. Conclusion CMR accurately detects obstructive CAD and ACS in suspected NSTEMI. Non-obstructive CAD is common with CMR still identifying an infarction in almost one-quarter of patients. CMR should be considered as an early diagnostic approach in suspected NSTEMI. Trial registration. The CARMENTA trial has been registered at ClinicalTrials.gov with identifier NCT01559467.


Background
Non-ST elevation myocardial infarction (NSTEMI) is an important acute manifestation of coronary artery disease (CAD) and a leading cause of death [1]. Early invasive coronary angiography (ICA) to assess the presence and severity of CAD is recommended in patients at high risk of adverse events. However, visual assessment is prone to under-or overestimate stenosis severity [2] and it is difficult to angiographically identify the culprit or ischemia-causing lesion [3].
High-sensitivity cardiac troponin (hs-cTn) assays have very high sensitivity for myocardial injury, but their specificity to detect myocardial infarction (MI) is limited [1]. This may partly explain why up to 30% of patients with suspected NSTEMI and elevated hs-cTn levels do not have obstructive CAD [4]. Nonetheless, MI with non-obstructive coronary arteries (MINOCA) is not uncommon. Potential etiologies include plaque rupture with distal embolization and/or temporary coronary artery occlusion with spontaneous reperfusion, as well as non-coronary etiologies including myocarditis, (stress) cardiomyopathy, structural and hypertensive heart disease, and pulmonary embolism. Altogether, these data raise the question whether ICA is still appropriate as an initial diagnostic test in patients with low-to-intermediate risk suspected NSTEMI.
The strength of cardiovascular magnetic resonance (CMR) is its ability to assess regional and global myocardial function, presence and pattern of scar, myocardial ischemia and to differentiate between coronary and noncoronary etiologies in a single investigation [5]. Vasodilator stress-perfusion CMR accurately detects obstructive CAD in a stable chest-pain population [6], and a CMRguided strategy lowers the probability of inappropriate ICA [7,8]. However, so far, no study has evaluated the diagnostic value of CMR in patients with suspected NSTEMI in the current hs-cTn era. The purpose of this study was to investigate the diagnostic value of CMR prior to ICA in this patient population. We evaluated both the accuracy of CMR in detecting obstructive CAD on ICA, as well as for detecting a final adjudicated diagnosis of acute coronary syndrome (ACS), given the prevalence of MINOCA.

Study population
This is a sub-analysis of the CARMENTA trial, a singlecenter randomized controlled trial [9]. In brief, CAR-MENTA included 207 consecutive patients without a known history of CAD or cardiomyopathy who were admitted because of acute chest pain, normal or nondiagnostic electrocardiogram and high sensitivity cardiac troponin T (hs-cTnT) values > 14 ng/L, at baseline or 3 h after presentation (i.e., suspected NSTEMI). Patients were randomized to routine clinical care, a computed tomography angiography (CTA)-first strategy or a CMRfirst strategy. A recommendation based on the CTA or CMR results was given to the treating cardiologist. However, follow-up diagnostic testing, medical therapy, and discharge were left at the discretion of the treating cardiologist. For the present sub-analysis, only patients from the CMR-first strategy who underwent CMR and subsequent ICA were included.

CMR scan protocol
The protocol included scout, anatomical, cine and T2-weighted images, rest-and adenosine stress-perfusion, and late gadolinium enhancement (LGE)-CMR. Because stress testing has historically been considered inappropriate for NSTEMI patients, a stepwise approach was used in CARMENTA to minimize scan duration and potential hazard for patients. First, anatomical, cine, T2-weighted, rest-perfusion and LGE-CMR imaging were performed and assessed during the scan. If a CMR diagnosis was clear, scanning was stopped. When findings were normal or equivocal, adenosine stress-perfusion imaging was subsequently performed.
short axis fully covering the LV using a balanced steadystate free precession sequence for functional analysis, (2) multi-slice black blood T2-weighted imaging in short axis fully covering the LV using a double inversion recovery, turbo spin echo sequence for edema imaging, (3) first-pass perfusion imaging at basal, midventricular and apical level using a T1-weighted turbo gradient echo sequence during an intravenous bolus of 0.05 mmol/kg gadolinium (Gadovist ® , Gadobutrol, Bayer Healthcare, Berlin, Germany) followed by a saline bolus flush (4 ml/ sec), (4) LGE in the same imaging plane as was used for cine imaging, 10-20 min after an additional intravenous bolus of 0.1 mmol/kg gadolinium using a 2D T1-weighted gradient echo inversion recovery sequence to image scar, and (5) first-pass, adenosine vasodilator stress-perfusion imaging (after 140 µg/kg/min adenosine for 3 min) using the identical protocol as the rest-perfusion, ~ 30 min after rest-perfusion imaging.

CMR analysis
CMR data were analyzed independently from the original assessment, blinded from the ICA and clinical data by two experienced observers and read in consensus (YvC and SB). Cine images were assessed for regional wallmotion abnormalities, T2-weighted and LGE images for the visual presence of edema and scar, respectively and rest-and stress-perfusion images for the presence of ischemia. Rest-perfusion imaging was only used to ascertain the stress perfusion defect. Each sequence was scored according to the American Heart Association 17-segment model [11], the true apex was excluded for the perfusion images.
The analysis comprised two steps. In step 1, cine, T2-weighted and LGE images were analyzed together. Underlying obstructive CAD (i.e. coronary etiology) was diagnosed in case of (1) regional wall-motion abnormalities and/or subendocardial/transmural hyperintensity on T2-weighted and/or LGE images in ≥ 2 segments or (2) at least 2 of the 3 sequences abnormal (i.e., regional wall-motion abnormalities, subendocardial/transmural hyperintensity on T2-weighted or LGE images) in a single segment (see Table 2). In case step 1 did not reveal a diagnosis, patients underwent stress-perfusion imaging in step 2. Underlying obstructive CAD was diagnosed when a regional, persistent perfusion defect was present in ≥ 2 adjacent segments, which was not considered an artifact [11]. The final analysis included the results of step 1 and 2 and was positive when either the combination of cine, T2-weighted imaging or LGE (step 1) or stress-perfusion imaging (step 2) suggested underlying obstructive CAD.

Adjudicated diagnosis committee
An independent committee (consisting of one interventional, one clinical and one imaging cardiologist) reviewed all available clinical data, including the CMR and ICA results. The following adjudicated diagnoses were made: ACS (either MI or unstable angina pectoris (UAP)), non-coronary but cardiac etiology (e.g., myocarditis, cardiomyopathy), or unknown etiology. The diagnosis of MI was based on the third universal definition [12].

Statistical analysis
Continuous variables are presented as mean ± standard deviation when normally distributed (based on Shapiro-Wilk test and visual assessment of histograms) or as median and interquartile ranges for skewed data. Categorical variables are given as frequencies and percentages. To compare the groups with and without obstructive CAD the independent-samples t-test or Mann-Whitney U-test was used for normal and skewed continuous data, respectively. The Pearson's chi-squared test (or Fisher's exact test in case of small numbers) was used for categorical variables. To assess the diagnostic accuracy of CMR, sensitivity, specificity and overall accuracy were calculated to detect obstructive CAD (≥ 70% stenosis by ICA) and ACS. Analyses were performed on a per-patient level. All statistical analyses were carried out using SPSS (version 25.0, Statistical Package for the Social Sciences, International Business Machines, Inc., Armonk, New York, USA). A p-value < 0.05 was considered statistically significant.

Study population
The CMR-first arm of the CARMENTA trial comprised 68 patients. For this sub-analysis, 17 patients were excluded because either CMR (n = 8) or ICA were not performed (n = 9). Therefore, this sub-analysis is based on 51 patients (Fig. 1, Table 1).
Two-thirds of patients (n = 34) had obstructive CAD, the majority (71%) having single-vessel disease. The average age was 63 ± 10 years. There were significantly fewer men in the non-obstructive CAD group compared to the obstructive CAD group (29% vs. 62%, P = 0.029). All remaining baseline characteristics were comparable between both subgroups (Tables 1 and 2). Most patients (90%) were at low-to-intermediate risk for 6-month death or MI with a GRACE risk-score of 114 ± 22 and were representative for the total CARMENTA population [9]. The median time between CMR and ICA was 1 day [1-3 days].

Safety
In general, CMR scanning was well tolerated and no serious adverse events or complications occurred. Mild side effects included dyspnea (n = 1), nausea (n = 2) and recognizable chest pain (n = 2), that disappeared after discontinuation of adenosine. No scan had to be terminated prematurely.
In those with non-obstructive CAD (n = 17), 9 patients (53%) were finally diagnosed with ACS (MI, n = 7; UAP, n = 2). Of these 9 ACS patients, 4 patients (44%) showed an LGE pattern consistent with MI and 1 had a stress-induced perfusion defect in the absence of LGE. An atypical LGE pattern (atypical focal hyperenhancement in one segment) was observed in 2 patients  Obstructive CAD = coronary artery disease (defined as ≥ 70% stenosis in any epicardial coronary artery); LGE = late gadolinium enhancement.
Step 3 abnormal: abnormal results step 1 or 2 CMR sequence Sensitivity (%) Specificity (%) Overall accuracy (%) Step and CMR was normal in 2 patients. Of the remaining 8 patients, 1 was diagnosed with a stress cardiomyopathy based on early CMR findings and follow-up imaging, while CMR was normal in 7 in whom the final diagnosis remained 'unknown' . In total, LGE showed an infarctpattern in 4 (24%), an atypical pattern in 2 (12%) and was absent in 11 (64%) patients (Table 2).

Discussion
The present study shows that a comprehensive multicomponent CMR analysis integrating a stepwise combination of cine, T2-weighted and LGE with adenosine vasodilator stress-perfusion imaging has excellent sensitivity, reasonable specificity and overall good accuracy to detect obstructive CAD in patients with hs-cTnT positive suspected NSTEMI (Fig. 5a, b). Although one-third of patients had non-obstructive CAD, 24% nonetheless had an MI based on CMR (Fig. 5c). When using the full diagnostic potential of CMR and testing its accuracy to detect ACS rather than obstructive CAD, specificity increased from 65 to 88% while sensitivity remained high at 88% (Fig. 5b).
Early and accurate detection of acute MI is critical to initiate appropriate management and improve prognosis. This can be challenging, especially when high sensitivity troponins are (mildly) elevated and symptoms and/ or the electrocardiogram less specific. In the appropriate clinical context and according to the fourth universal definition of MI, demonstrating either (regional) myocardial dysfunction or obstructive CAD can be diagnostic of acute MI [13]. In accordance with current guidelines, patients are often referred for ICA as initial diagnostic step to either demonstrate or exclude obstructive CAD [1]. However, 9-29% of patients with elevated troponin levels do not have obstructive CAD and are designated as having MINOCA [14,15]. Our results and those of a ROMICAT-2 sub-study show that non-obstructive CAD is even more prevalent (33%) in the current hs-cTn era, increasingly posing clinicians for a diagnostic dilemma [16]. Because higher initial hs-cTn levels and/or larger delta values increase the likelihood of a coronary etiology (acute MI), this diagnostic uncertainty mainly arises in patients in whom hs-cTn values are only mildly elevated (so-called observe zone) [4]. Moreover, the introduction of hs-cTn assays into clinical practice has increased the referral of patients to ICA and associated revascularization procedures without improving outcome [17]. Altogether, this raises the question whether ICA is still the preferable initial diagnostic step for patients with acute chest pain, especially when hs-cTn levels are mildly elevated [1]. Non-invasive imaging techniques with similarly high sensitivity to detect obstructive CAD could be realistic alternatives to improve patient selection for follow-up invasive management.
Thus far, several non-invasive diagnostic strategies to evaluate acute chest pain and improve patient management in the emergency department and selection for ICA have been investigated. CTA allows accurate exclusion of CAD as well as identification of high-risk coronary plaque features that increase the likelihood of acute MI. Implementing CTA early in the diagnostic work-up of NSTEMI patients safely reduced the number of ICA compared to standard of care in one trial [9] but not in another [18]. Nonetheless, only ~ 40% of unselected patients in the emergency department are eligible for this approach because of contraindications for CTA or pre-existing CAD that may complicate interpretation of CTA findings during the index visit [4]. Furthermore, additional non-invasive testing is often needed to find a diagnosis when CAD has been excluded by CTA. CMR may be useful in this setting as it can accurately detect myocardial ischemia [19] and differentiate acute from chronic myocardial injury [20]. CMR also allows differentiating ischemic from other patterns of myocardial injury and is a key diagnostic tool in MINOCA, revealing a new diagnosis in 65-77% [5,21].
Few studies have investigated the usefulness of comprehensive CMR imaging in patients with acute chest pain and suspected NSTEMI [22][23][24][25][26][27][28]. Although these studies cannot be compared directly because of differences in study population, design, prevalence of NSTEMI, CMR protocol and outcome measures, they all share a high sensitivity (up to 92%) and specificity (up to 96%). Our results corroborate that performing adenosine stress-perfusion CMR early (prior to ICA) is feasible and safe, because adenosine was well tolerated and no adverse events occurred [23,24,26,28]. Our study is the first to investigate the diagnostic accuracy of early vasodilator stress-perfusion CMR in patients with NSTEMI with elevated hs-cTn levels. By itself, stress-perfusion CMR had good sensitivity and specificity (86% and 92%, respectively) to detect obstructive CAD when the combination of cine, T2-weighted and LGE-CMR was normal or equivocal. Adding stress-perfusion CMR to the model further increased the sensitivity from 79 to 97%, while minimally affecting specificity, which remained modest at 65%. This modest specificity is largely explained by the detection of MI by CMR in the absence of obstructive CAD. In agreement, the specificity of CMR to detect ACS was very high at 88%, suggesting that the use of ICA as reference standard should be reconsidered.
Indeed, one-third of patients (n = 17) did not have obstructive CAD. CMR led to a diagnosis in 6 (35%), of whom 4 (24%) still had an MI by CMR. Potential mechanisms may include coronary artery spasm or transitory thrombotic occlusion with self-lysis. Without CMR, these MI probably would have been missed and appropriate medical therapy withheld.
One patient was diagnosed with a stress cardiomyopathy, because of regional wall-motion abnormalities that normalized during follow-up and one patient with microvascular disease (regional hypoperfusion), who was finally diagnosed with unstable angina. The diagnostic yield of CMR in our study is lower than in previous reports, in which CMR led to a diagnosis in approximately two-thirds of patients with chest pain, elevated troponins and non-obstructive CAD. The prevalence of MI in our study was similar to these previous studies, but myocarditis was not observed at all in our study [5,21]. The lower diagnostic yield in our study in comparison to previous studies, might be because patients had lower troponin levels and therefor too little necrosis to be detected by CMR. In addition, the requirement that both CMR and ICA had to be performed may have biased the results away from finding alternative diagnoses by CMR.

Future perspectives
Our results strongly support the gatekeeping potential of early CMR in patients with suspected NSTEMI and select those who benefit most from additional ICA. When shown cost-effective, early CMR may become routine clinical practice in the future. The present work Step 3 Combination of step 1 and 2 (n=51) Step 2 For example, our data already suggest that T2-weighted imaging may be omitted. A major advantage of early CMR is its overall diagnostic potential in a single investigation, leading to a diagnosis in a substantial number of patients, especially when obstructive CAD is excluded [21]. The diagnostic potential of CMR may be further increased when using myocardial blood flow quantification to improve the detection of microvascular disease and/or mapping techniques to improve the detection of myocarditis, iron overload, amyloid, Anderson-Fabry's disease or other cardiomyopathies [29].

Study limitations
This study is a sub-analysis of a larger randomized trial and included a relatively small number of patients. Nevertheless, this sample was representative of the original study population. While promising, prudence needs to be displayed to widely implement early CMR in all NSTEMI patients because our results may not apply to all patients and additional validation in multi-center studies is needed. In particular, patients with previously known CAD, known cardiomyopathy, evident type-2 MI and high-risk NSTEMI patients were excluded in the initial trial. For safety reasons, rest-perfusion imaging was performed prior to adenosine stress-perfusion imaging and this may have affected diagnostic accuracy. Although the sensitivity was still high at 86%, changing the order of performing stress prior to rest may have identified the only missed patient with obstructive CAD. Finally, we used an anatomical rather than a functional endpoint. Although functional assessment of CAD using fractional flow reserve (FFR) may overcome the limitations of luminography, usual care in NSTEMI is still based on visual interpretation of CAD severity. When we would have used FFR, this might have been to the advantage or disadvantage for CMR, since a visually obstructive lesion can be re-classified as non-significant or a non-obstructive lesion can be reclassified as significant by FFR. In the end, CMR has been shown to favorably compare with FFR [30].

Conclusions
Non-obstructive CAD is prevalent in suspected NSTEMI and a comprehensive multicomponent CMR analysis including adenosine stress-perfusion is feasible, safe and a potentially useful gatekeeper for ICA. Incorporating CMR early in the diagnostic strategy can safely avoid ICA in a substantial number of NSTEMI patients.