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Cardiac MRI left ventricular global function index and quantitative late gadolinium enhancement in unrecognized myocardial infarction
European Journal of Radiology 92 (2017) 11–16
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Research papers
Cardiac MRI left ventricular global function index and quantitative late gadolinium enhancement in unrecognized myocardial infarction
MARK
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Patrick Krumma, Tanja Zitzelsbergera, , Melanie Weinmanna, Stefanie Mangolda, Dominik Rathb, Konstantin Nikolaoua, Meinrad Gawazb, Ulrich Kramera, Bernhard Daniel Klumppa a b
Department of Diagnostic and Interventional Radiology, University of Tübingen, Germany Department of Internal Medicine III, Cardiology and Cardiovascular Medicine, University of Tübingen, Germany
A R T I C L E I N F O
A B S T R A C T
Keywords: Infarction Magnetic resonance imaging Myocardial infarction Myocardium Ventricular function Left
Purpose: To compare left ventricular global function index (LVGFI) and quantitative late gadolinium enhancement (LGE) in patients with unrecognized myocardial infarction (UMI), recognized myocardial infarction (RMI) and without myocardial infarction (MI). Material and methods: Under waiver of the Institutional Review Board 235 patients (age 63.5 ± 10.5 years, 57 female) were retrospectively evaluated. All patients had undergone cardiac MRI at 1.5T for symptoms of CAD. 67 patients (29%) had suffered a known RMI before. Functional imaging and full-intensity late gadolinium enhancement (LGE) imaging were evaluated for LVGFI and quantitative LGE mass. Results: Of 168 patients without history of RMI, 48 patients (29%) had UMI, 120 patients had no MI. LVGFI was lower in RMI patients (34 ± 8% [range 16;52]), and UMI patients (35 ± 8% [range 10;51]), compared to patients with no MI (38 ± 7% [range 16;55]) respectively and similar between RMI and UMI patients. RMI patients had full-intensity LGE in 11 ± 6% of left ventricular myocardial mass (LVMM). UMI patients had LGE in 9 ± 5% of LVMM. RMI patients had significantly more LGE than UMI patients (p = 0.0096). Conclusion: LGE quantification is effective to assess infarction scar size in RMI and UMI patients. LVGFI provides information on cardiac function and morphology but does not allow for a reliable differentiation between patients with and without history of MI, due small differences and wide overlap of LVGFI values for all three patient groups. This may be a reason why LVGFI is not applied in clinical routine.
1. Introduction Coronary artery disease (CAD) is a common morbidity among the aging population in the industrialized world, with a significant mortality [1]. In a significant number of patients with CAD, the presence of chronic myocardial infarction (MI) can be expected, even without a clinical history of acute MI, either due to clinical silent MI, or negligence of possibly atypical symptoms [2]. However, clinically unrecognized myocardial infarction (UMI) is associated with an increased risk of cardiac adverse events, demanding appropriate therapy [3]. UMI is a common finding in late gadolinium enhancement (LGE) cardiac magnetic resonance imaging (MRI) in patients with age-related prevalence of cardiovascular disease [3–5]. Risk stratification for major adverse cardiac events (MACE) includes several independent parameters evaluable with cardiac MRI: LGE MRI is commonly regarded as the method of choice to determine myocardial viability [6,7]. Myocardial stress perfusion is suitable to independently predict long-term
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outcome in patients with suspected ischemia as well as after myocardial revascularization [8–10]. Moreover, high risk patients can be identified by assessment of left ventricular (LV) function [1,11]. Recently, a novel MR imaging biomarker for cardiac functional performance emerged: the left ventricular global function index (LVGFI). LVGFI is a percentage quotient of LV stroke volume, LV end-diastolic volume and myocardial volume. It integrates left ventricular myocardial mass (LVMM) as a structural index to functional assessment and is supposed to show pathologic values in LV concentric hypertrophy or eccentric hypertrophy due to dilation earlier than established functional parameters in cardiac imaging, i.e., left ventricular ejection fraction (LVEF) [12]. LVGFI is also regarded to be of prognostic value in patients after STsegment elevation myocardial infarction (STEMI) [13,14]. To date, only initial clinical studies have been published concerning the clinical application of LVGFI in the evaluation of cardiac morphology and function. The aim of this retrospective study was to evaluate LVGFI in patients with UMI compared to patients with recognized MI and
Corresponding author at: University of Tübingen, Department of Diagnostic and Interventional Radiology, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany. E-mail address: [email protected] (T. Zitzelsberger).
http://dx.doi.org/10.1016/j.ejrad.2017.04.012 Received 14 August 2016; Received in revised form 8 April 2017; Accepted 14 April 2017 0720-048X/ © 2017 Elsevier B.V. All rights reserved.
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were drawn manually to evaluate functional parameters: Left ventricular end-diastolic volume (LVEDV), end-systolic volume (LVESV), stroke volume (LVSV), ejection fraction (LVEF) and myocardial mass (LVMM). LVGFI in % was calculated according to the equation introduced by Mewton et al., and myocardial density defined as 1.05 g/ml [12]:
patients without myocardial infarction to further assess this novel marker in clinical context. 2. Material and methods 2.1. Patient population
LVGFI =
Two hundred thirty-five patients (age 63.5 ± 10.5 years, 57 female) were retrospectively evaluated. All patients had symptoms of CAD and were referred to MRI stress perfusion to assess myocardial perfusion and viability, to decide on further therapy. 67 patients (29%) had recognized MI in their clinical history. The institutional review board of the Medical Faculty of the University of Tübingen approved this retrospective study and waived informed consent.
LVSV (LVEDV + LVESV ) 2
+
LVMM Myocardial density
*100
2.2.3. Statistical analysis Statistical analysis was performed with JMP (Version 12.2, SAS Institute Inc., Cary NC, USA). Continuous variables are indicated as mean value ± standard deviation (SD). Range is given in closed brackets. A group analysis was performed: Patients with recognized MI and positive LGE were assigned to group 1. Patients with no clinical history of MI were divided into group 2 (unrecognized myocardial infarction in LGE imaging) and group 3 (no infarction in LGE imaging). The interobserver-variability for continuous variables as rated by two observers in quantitative analysis was evaluated with Bland-Altman difference plots: Mean difference and the limits of agreement defined as ± 1.96 SD were calculated for LVEDV, LVESV, LVMM and quantitative LGE mass. Normal distribution of parameters was assessed visually in curves. Paired two-sided t-tests were applied to test for difference of LVGFI between groups 1 and 3, groups 2 and 3, as well as for groups 1 and 2. The same test was applied for difference of LGE mass in group 1 and 2. Level of significance was corrected with a Bonferroni correction [17] for four tests (k = 4): Global level of significance α glob = 0.05 was chosen. Local level of significance (α loc) for each test with dependent variables was corrected according to the Bonferroni equation α loc = α glob/k = 0.0125. Each test was considered significant if p ≤ α loc. For other data without p-values, descriptive statistic was applied.
2.2. Methods 2.2.1. Image acquisition Cardiac MRI examinations were performed on a 1.5T scanner (MAGNETOM Avanto, SIEMENS Healthcare, Erlangen, Germany), using a body array coil and spine coil for reception of MR-signals. Sequences were ECG-triggered and performed in breath hold technique. The examination protocol included perfusion, functional and viability imaging. For assessment of myocardial perfusion, saturation recovery gradient echo (SR GRE) sequences were acquired at rest and at stress induced by adenosine infusion (140 μg/kg body weight per minute for four minutes), applying i.v. Gadobutrol contrast agent (Gadovist, Bayer Healthcare, Leverkusen, Germany) with a dosage of 0.1 mmol/kg body weight for each stress and rest perfusion imaging. To evaluate myocardial viability, 2D inversion recovery gradient echo sequences were acquired in four-chamber view, two-chamber view and a stack of short-axis views, 10 min after last administration of contrast agent. To suppress signal from viable myocardium, an inversion time localizer was used, to determine the optimal inversion time (TI scout). Sequence parameters for LGE imaging were as follows: 2D inversion recovery (IR) gradient recovery echo (GRE) sequence, TR 11 ms, TE 4.4 ms, flip angle 30°, slice thickness 6 mm, baseline matrix 256. The inversion time was adjusted individually to 260–340 ms, to minimize signal from normal myocardium. To assess myocardial function, cine steady state free precession (SSFP) loops were acquired in four chamber view, two chamber view and a stack of short axis views in the time interval between resting perfusion and viability imaging. The slice position was chosen with the identical centre of the acquisition slab for viability and functional imaging.
3. Results 3.1. Viability imaging All 67 patients assigned to group 1 with recognized MI in clinical history had positive full-intensity LGE affecting 10.62 ± 6% of myocardial mass. Of all 168 patients without any recognized MI in clinical history, 48 patients (29%) had UMI (group 2) with full-intensity LGE in 8.81 ± 5% of myocardial mass (Fig. 1). Patients with recognized MI (group 1) had significantly larger volumes of full-intensity LGE than UMI patients (group 2): p = 0.0096. 120 patients had no MI (group 3) and full-intensity LGE in 0.47 ± 1.81% of myocardial mass (Table 1). 92 (77%) of the patients without MI (group 3) had ischemia provokable in stress perfusion. The location of MI depicted by full-intensity LGE differed between group 1 and group 2 (Table 2): In patients with recognized MI (group 1), 44% of all segments with myocardial infarction were considered to be supplied by the LAD, 25% by the LCX, and 31% by the RCA. In patients with UMI (group 2) 30% of infarcted segments were supplied by the LAD, 41% by the LCX, and 29% by the RCA. The segmental analysis revealed 42% of infarcted segments in UMI were located in four infero-lateral segments (segments 4, 5, 10 and 11; Fig. 2).
2.2.2. Image analysis Image analysis was performed by two independent and blinded readers (1 and 6 years of experience) at an offline workstation CVI42 (Circle Cardiovascular Imaging, Calgary AB, Canada). Myocardial viability in LGE imaging was analysed in accordance with the recommendations of the Society for Cardiovascular Magnetic Resonance task force [15]: For quantification of full-intensity LGE extent in per cent of the myocardial mass, a semi-automated threshold with normal remote myocardium +5 standard deviations (SD) was chosen. Assessment of LGE localization was based on the AHA 17segment model introduced by Cerqueira et al. [16]. Accordingly, segments 1, 2, 7, 8, 13, 14 and 17 were assigned to the left anterior descending coronary artery (LAD) vascular supply territory, segments 3, 4, 9, 10 and 15 to the right coronary artery (RCA) and segments 5, 6, 11, 12 and 16 to the left circumflex coronary artery (LCX), assuming a normal coronary anatomy with balanced blood supply. Myocardial stress perfusion was evaluated visually as dichotomous trait (ischemia yes or no). In functional analysis, end-diastole and end-systole were determined visually. In short-axis views, endocardial and epicardial contours
3.2. Functional imaging One dataset in group 3 (without MI) was not evaluable for functional assessment. Patients with MI had higher LVEDV than patients without MI: In group 1 with recognized MI LVEDV was 168 ± 50 ml; in group 2 with UMI LVEDV was 164 ± 49 ml, and in group 3 without MI 131 ± 43 ml, respectively. LVMM was higher in MI patients (LVMM group 1: 123 ± 27 g; group 2: 129 ± 36 g) than 12
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Table 2 Distribution of myocardial infarction. Vessel
LAD LCX RCA
Group1 recognized MI (RMI) n = 67
Group 2 unrecognized MI (UMI) n = 48
Number of LGE segments
Percentage within group
Number of LGE segments
Percentage within group
148 84 106
44% 25% 31%
46 64 44
30% 41% 29%
Table 2 indicates number of segments per vessel territory involved by full-intensity LGE in group 1 and 2. In patients with recognized MI (group 1) most MI were localized in LAD territory, whereas UMI were predominantly localized in vessel territory of LCX. MI: myocardial infarction, RMI: recognized MI, UMI: unrecognized MI, LGE: late gadolinium enhancement, LAD: left anterior descending artery, LCX: left circumflex coronary artery, RCA: right coronary artery.
in patients with no MI (LVMM group 3: 114 ± 32 g). LVEF was lower in patients with recognized MI (LVEF group 1: 49 ± 10%) and UMI (LVEF group 2: 52 ± 10%) compared to group 3 (LVEF: 58 ± 10%). LVGFI was significantly lower in group 1 with recognized MI (34 ± 8% [range 16; 52], p < 0.0001), and group 2 with UMI (35 ± 8% [range 10; 51], p = 0.0079), compared to group 3 with no MI (38 ± 7% [range 16; 55]) respectively. LVGFI was not significantly different between group 1 and 2 (p = 0.2). Detailed volumetric results including range of all values are tabulated in Table 1. LVGFI and LGE mass were normally distributed. The evaluation of interobserver-variability indicated a mean difference between readers for LVEDV of 1.6 ± 8 ml, with limits of agreement from −13.6 ml to 16.8 ml. For LVESV, the mean difference between readers was −3.4 ± 6 ml, with limits of agreement from −14.8 ml to 7.9 ml. For LVMM, the mean difference between readers was −4.3 ± 6 g, with limits of agreement from −16 g to 7.6 g. For LGE, mass the mean difference between readers was 0.1 ± 1.8%, with limits of agreement from −3.5% to 1.6%. 4. Discussion In this study we present the evaluation of the left ventricular global functional index and quantitative LGE in patients with unrecognized myocardial infarction, comparing these values to patients with recognized MI and patients with suspected CAD.
Fig. 1. LGE imaging in four-chamber (a) and short-axis (b) view of a 69-year old male patient with clinical history of CAD and UMI discovered in cardiac MRI. Arrows depict a partially transmural MI affecting the lateral wall.LGE: late gadolinium enhancement, CAD: coronary artery disease, UMI: unrecognized MI, MI: myocardial infarction
4.1. Viability imaging As could be expected, recognized MI came along with the largest extent in quantitative evaluation of the LGE mass, followed by a significantly but not relevantly smaller extent of LGE mass in UMI
Table 1 Volumetric analysis of patient Groups. Parameter
Group1 recognized MI (RMI) n = 67
Group 2 unrecognized MI (UMI) n = 48
Group 3 no MI n = 120
LVEDV (ml) LVESV (ml) LVSV (ml) LVMM (g) LVEF (%) LVGFI (%) Full-intensity LGE (%)
168 ± 50 [93; 333] 89 ± 42 [38; 250] 80 ± 19 [38; 125] 123 ± 27 [69; 223] 49 ± 10 [25; 66] 34 ± 8 [16; 52] 11 ± 6 [2; 30]
164 ± 49 [95; 333] 82 ± 43 [36; 283] 80 ± 22 [38; 145] 129 ± 36 [75; 215] 52 ± 10 [19; 76] 35 ± 8 [10; 51] 9 ± 5 [2; 36]
131 ± 43 [65; 290] 57 ± 31 [31; 201] 76 ± 22 [42; 150] 114 ± 32 [62; 232] 58 ± 10 [27; 77] 38 ± 7 [16; 55] 0.5 ± 1.8 [0; 10]
Table 1 indicates mean value ± standard deviation and range in closed brackets. MI: myocardial infarction, RMI: recognized MI, UMI: unrecognized MI, LVEDV: Left ventricular enddiastolic volume, LVESV: end-systolic volume, LVSV: stroke volume, LV-MM: left ventricular myocardial mass, LVEF: ejection fraction, LVGFI: left ventricular global function index; LGE: late gadolinium enhancement.
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a less extended myocardial ischemia and less characteristic symptoms. UMI has a higher prevalence in patients with a predisposition to atypical symptoms such as diabetic patients, elderly patients, and women [2,22]. These symptoms typically include epigastric pain, neck and back pain, nausea, vomiting, palpitations and sweating [23]. The distribution of UMI has predominantly been described in basal inferolateral segments, which is reproduced in our study [24]. Interestingly, UMI predominantly affects an area of overlapping or at least adjacent vascular supply by the RCA and LCX, but not confined to a certain vessel territory supplied by one single coronary artery in the most frequent normal variants of coronary artery anatomy [16]. Increased occurrence of UMI in infero-lateral segments may also arise from atypical symptoms associated with MI of the infero-lateral wall [25]. 4.2. Functional imaging As could be expected, patients without MI featured the highest LVGFI and LVEF values. Both LVGFI as well as LVEF were reduced in patients with recognized MI compared to patients with UMI. The cut-off value for LVGFI in healthy controls was predetermined at 37% [12]. A major limitation of the clinical use of LVGFI as a relevant imaging biomarker lies in the fact, that already relatively small changes on the percent scale may indicate highly pathologic values, other than we are used to from LVEF. This is reflected in our study by only small absolute LVGFI mean value differences between patients with and without history of MI, ranging around the threshold of 37%. In spite of significant differences between groups with and without history of infarction, a pathologic LVGFI cut-off value could not be identified or established in our study: the standard deviation and range of LVGFI values do not enable a reliable differentiation due to wide overlap. Another shortcoming of LVGFI is the integration of myocardial mass and volumes, making it hard to differentiate the etiology of cardiomyopathy. Primary volumetric data of myocardial volumes, ejection fraction and mass is still needed to understand the type of pathology. This may be a reason why LVGFI has not yet been commonly applied in clinical routine. LVGFI values could not be used to differentiate between patients with recognized MI and UMI in our study, which correlates with similar LGE masses found in our study for both groups. Recognized MI and UMI found in cardiac MRI were also reported to be associated with similar mortality, so that significant differences between both groups regarding functional parameters are not expected [26,27]. LVEF can be determined using different methods with similar bias: cardiac CT, ventriculography, echocardiography and singlephoton emission CT (SPECT) [28], but LVGFI is a MRI specific biomarker. For the comparison between previously published studies and methods in Table 3 this study provided values for LVEF. The studies do not meet the criteria for a meta-analysis, for different methods were applied and different selection of cohorts may have had an influence on different functional parameters. As the only study compared, Nordenskjöld et al. reported higher LVEF (67%) in their UMI cohort compared to LVEF of 66% in patients with no MI [3]. Pooled echocardiography data since 1979 have recently shown a higher risk for morbidity and mortality in borderline reduced LVEF of 50% to > 55% [29]. In our study, LVMM was higher in patients with MI compared to patients with no MI. This may also be a secondary effect due to postischemic LV dilation. Kim et al. found that LGE due to UMI undetectable by Q-waves in electrocardiogram was 3-fold higher than UMI revealed with Q-waves [30], underlining the role of MRI in the diagnosis of UMI. Whereas the pathogenesis of UMI has been reported not concordant with atherosclerosis [24,31], a recent prospective trial found UMI associated with age and extent of CAD [3]. To date, there is no general recommendation to routinely examine all patients with suspected CAD to rule out UMI. To evaluate prognostic value of LGE MRI in UMI, large scale controlled studies are needed to examine the difference in prognosis of a UMI in
Fig 2. (a) Indicates percentage of segments infarcted in recognized MI: Infarcted segments were predominantly (44%) located in the vessel territory of the LAD which supplies more segments than other vessels (shaded). (b) indicates percentage of segments infarcted in UMI. 42% of infarcted segments occurred in four inferolateral segments (shaded).MI: myocardial infarction, LAD: left anterior descending coronary artery, UMI: unrecognized MI. Segment number is given in corner of segments. Apical segment 17 is located in the centre.
patients. A small LGE mass (below 1%) in patients with no MI (group 3, suspected CAD) can be explained by image noise or suboptimal inversion time for LGE imaging and should therefore be regarded as false positive due to imaging artefacts and suboptimal image quality, respectively. Nuclear cardiologic alternative imaging methods for detection of post-ischemic myocardial scar are SPECT and PET [18,19]. LGE MRI provides higher sensitivity for detection of smaller and non-transmural UMI [20,21]. One possible reason why MI had not been recognized in UMI patients may be the smaller extent of the scar, presumably preceded by 14
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Table 3 Comparison of the results with previously published data. Study/Value Modality
Current study MRI
Ammar et al. [32] Echo
Kwong et al. [33] MRI
Kwong et al. [34] MRI
Kim et al. [30] MRI
Yoon et al. [35] MRI
Nordenskjöld et al. [3] MRI
LVEF no MI LVEF UMI LVEF RMI
58% 52% 49%
66% 61% 55%
60% 41%
60% 47%
63% 48/52%
63/62%b 54/56%b
63% 61%
a
Table 3 compares the LVEF results of our study with previously published data in UMI in the literature. In some previous studies, different methods were applied and different selection of cohorts may have had an influence on functional parameters. MI: myocardial infarction, UMI: unrecognized MI, LVEF: ejection fraction, MRI: Magnetic Resonance Imaging, Echo: Transthoracal Echocardiography. a Kim et al. differentiated between Q-wave and Non-Q-wave UMI b Yoon et al. differentiated between impaired fasting glucose and diabetes mellitus patients.
contrast to extended CAD alone. In this study, no follow-up examinations have been performed to provide the prognostic value of the data collected. To date, available data for LVGFI is limited: only introductory and initial clinical studies have been published. Not all studies have reported superiority of LVGFI over LVEF [14]. LVGFI cannot be used to identify UMI and remains an unspecific marker to evaluate changes in LV morphology and function.
[5]
[6]
[7]
5. Conclusion In conclusion, this study confirms that MRI-based LGE quantification is an effective tool to assess infarction scar size in patients with recognized and unrecognized myocardial infarction. Left ventricular global function index (LVGFI) provides additional information on cardiac function and morphology, but does not enable to reliably differentiate between patients with and without history of MI, due to a wide overlap. This may be a reason why LVGFI is not commonly applied in clinical routine.
[8]
[9]
Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Statement on behalf of all authors:
[10]
Conflicts of interest [11]
None. Appendix A. Supplementary data
[12]
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.ejrad.2017.04.012. References
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Contents lists available at ScienceDirect
European Journal of Radiology journal homepage: www.elsevier.com/locate/ejrad
Research papers
Cardiac MRI left ventricular global function index and quantitative late gadolinium enhancement in unrecognized myocardial infarction
MARK
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Patrick Krumma, Tanja Zitzelsbergera, , Melanie Weinmanna, Stefanie Mangolda, Dominik Rathb, Konstantin Nikolaoua, Meinrad Gawazb, Ulrich Kramera, Bernhard Daniel Klumppa a b
Department of Diagnostic and Interventional Radiology, University of Tübingen, Germany Department of Internal Medicine III, Cardiology and Cardiovascular Medicine, University of Tübingen, Germany
A R T I C L E I N F O
A B S T R A C T
Keywords: Infarction Magnetic resonance imaging Myocardial infarction Myocardium Ventricular function Left
Purpose: To compare left ventricular global function index (LVGFI) and quantitative late gadolinium enhancement (LGE) in patients with unrecognized myocardial infarction (UMI), recognized myocardial infarction (RMI) and without myocardial infarction (MI). Material and methods: Under waiver of the Institutional Review Board 235 patients (age 63.5 ± 10.5 years, 57 female) were retrospectively evaluated. All patients had undergone cardiac MRI at 1.5T for symptoms of CAD. 67 patients (29%) had suffered a known RMI before. Functional imaging and full-intensity late gadolinium enhancement (LGE) imaging were evaluated for LVGFI and quantitative LGE mass. Results: Of 168 patients without history of RMI, 48 patients (29%) had UMI, 120 patients had no MI. LVGFI was lower in RMI patients (34 ± 8% [range 16;52]), and UMI patients (35 ± 8% [range 10;51]), compared to patients with no MI (38 ± 7% [range 16;55]) respectively and similar between RMI and UMI patients. RMI patients had full-intensity LGE in 11 ± 6% of left ventricular myocardial mass (LVMM). UMI patients had LGE in 9 ± 5% of LVMM. RMI patients had significantly more LGE than UMI patients (p = 0.0096). Conclusion: LGE quantification is effective to assess infarction scar size in RMI and UMI patients. LVGFI provides information on cardiac function and morphology but does not allow for a reliable differentiation between patients with and without history of MI, due small differences and wide overlap of LVGFI values for all three patient groups. This may be a reason why LVGFI is not applied in clinical routine.
1. Introduction Coronary artery disease (CAD) is a common morbidity among the aging population in the industrialized world, with a significant mortality [1]. In a significant number of patients with CAD, the presence of chronic myocardial infarction (MI) can be expected, even without a clinical history of acute MI, either due to clinical silent MI, or negligence of possibly atypical symptoms [2]. However, clinically unrecognized myocardial infarction (UMI) is associated with an increased risk of cardiac adverse events, demanding appropriate therapy [3]. UMI is a common finding in late gadolinium enhancement (LGE) cardiac magnetic resonance imaging (MRI) in patients with age-related prevalence of cardiovascular disease [3–5]. Risk stratification for major adverse cardiac events (MACE) includes several independent parameters evaluable with cardiac MRI: LGE MRI is commonly regarded as the method of choice to determine myocardial viability [6,7]. Myocardial stress perfusion is suitable to independently predict long-term
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outcome in patients with suspected ischemia as well as after myocardial revascularization [8–10]. Moreover, high risk patients can be identified by assessment of left ventricular (LV) function [1,11]. Recently, a novel MR imaging biomarker for cardiac functional performance emerged: the left ventricular global function index (LVGFI). LVGFI is a percentage quotient of LV stroke volume, LV end-diastolic volume and myocardial volume. It integrates left ventricular myocardial mass (LVMM) as a structural index to functional assessment and is supposed to show pathologic values in LV concentric hypertrophy or eccentric hypertrophy due to dilation earlier than established functional parameters in cardiac imaging, i.e., left ventricular ejection fraction (LVEF) [12]. LVGFI is also regarded to be of prognostic value in patients after STsegment elevation myocardial infarction (STEMI) [13,14]. To date, only initial clinical studies have been published concerning the clinical application of LVGFI in the evaluation of cardiac morphology and function. The aim of this retrospective study was to evaluate LVGFI in patients with UMI compared to patients with recognized MI and
Corresponding author at: University of Tübingen, Department of Diagnostic and Interventional Radiology, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany. E-mail address: [email protected] (T. Zitzelsberger).
http://dx.doi.org/10.1016/j.ejrad.2017.04.012 Received 14 August 2016; Received in revised form 8 April 2017; Accepted 14 April 2017 0720-048X/ © 2017 Elsevier B.V. All rights reserved.
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were drawn manually to evaluate functional parameters: Left ventricular end-diastolic volume (LVEDV), end-systolic volume (LVESV), stroke volume (LVSV), ejection fraction (LVEF) and myocardial mass (LVMM). LVGFI in % was calculated according to the equation introduced by Mewton et al., and myocardial density defined as 1.05 g/ml [12]:
patients without myocardial infarction to further assess this novel marker in clinical context. 2. Material and methods 2.1. Patient population
LVGFI =
Two hundred thirty-five patients (age 63.5 ± 10.5 years, 57 female) were retrospectively evaluated. All patients had symptoms of CAD and were referred to MRI stress perfusion to assess myocardial perfusion and viability, to decide on further therapy. 67 patients (29%) had recognized MI in their clinical history. The institutional review board of the Medical Faculty of the University of Tübingen approved this retrospective study and waived informed consent.
LVSV (LVEDV + LVESV ) 2
+
LVMM Myocardial density
*100
2.2.3. Statistical analysis Statistical analysis was performed with JMP (Version 12.2, SAS Institute Inc., Cary NC, USA). Continuous variables are indicated as mean value ± standard deviation (SD). Range is given in closed brackets. A group analysis was performed: Patients with recognized MI and positive LGE were assigned to group 1. Patients with no clinical history of MI were divided into group 2 (unrecognized myocardial infarction in LGE imaging) and group 3 (no infarction in LGE imaging). The interobserver-variability for continuous variables as rated by two observers in quantitative analysis was evaluated with Bland-Altman difference plots: Mean difference and the limits of agreement defined as ± 1.96 SD were calculated for LVEDV, LVESV, LVMM and quantitative LGE mass. Normal distribution of parameters was assessed visually in curves. Paired two-sided t-tests were applied to test for difference of LVGFI between groups 1 and 3, groups 2 and 3, as well as for groups 1 and 2. The same test was applied for difference of LGE mass in group 1 and 2. Level of significance was corrected with a Bonferroni correction [17] for four tests (k = 4): Global level of significance α glob = 0.05 was chosen. Local level of significance (α loc) for each test with dependent variables was corrected according to the Bonferroni equation α loc = α glob/k = 0.0125. Each test was considered significant if p ≤ α loc. For other data without p-values, descriptive statistic was applied.
2.2. Methods 2.2.1. Image acquisition Cardiac MRI examinations were performed on a 1.5T scanner (MAGNETOM Avanto, SIEMENS Healthcare, Erlangen, Germany), using a body array coil and spine coil for reception of MR-signals. Sequences were ECG-triggered and performed in breath hold technique. The examination protocol included perfusion, functional and viability imaging. For assessment of myocardial perfusion, saturation recovery gradient echo (SR GRE) sequences were acquired at rest and at stress induced by adenosine infusion (140 μg/kg body weight per minute for four minutes), applying i.v. Gadobutrol contrast agent (Gadovist, Bayer Healthcare, Leverkusen, Germany) with a dosage of 0.1 mmol/kg body weight for each stress and rest perfusion imaging. To evaluate myocardial viability, 2D inversion recovery gradient echo sequences were acquired in four-chamber view, two-chamber view and a stack of short-axis views, 10 min after last administration of contrast agent. To suppress signal from viable myocardium, an inversion time localizer was used, to determine the optimal inversion time (TI scout). Sequence parameters for LGE imaging were as follows: 2D inversion recovery (IR) gradient recovery echo (GRE) sequence, TR 11 ms, TE 4.4 ms, flip angle 30°, slice thickness 6 mm, baseline matrix 256. The inversion time was adjusted individually to 260–340 ms, to minimize signal from normal myocardium. To assess myocardial function, cine steady state free precession (SSFP) loops were acquired in four chamber view, two chamber view and a stack of short axis views in the time interval between resting perfusion and viability imaging. The slice position was chosen with the identical centre of the acquisition slab for viability and functional imaging.
3. Results 3.1. Viability imaging All 67 patients assigned to group 1 with recognized MI in clinical history had positive full-intensity LGE affecting 10.62 ± 6% of myocardial mass. Of all 168 patients without any recognized MI in clinical history, 48 patients (29%) had UMI (group 2) with full-intensity LGE in 8.81 ± 5% of myocardial mass (Fig. 1). Patients with recognized MI (group 1) had significantly larger volumes of full-intensity LGE than UMI patients (group 2): p = 0.0096. 120 patients had no MI (group 3) and full-intensity LGE in 0.47 ± 1.81% of myocardial mass (Table 1). 92 (77%) of the patients without MI (group 3) had ischemia provokable in stress perfusion. The location of MI depicted by full-intensity LGE differed between group 1 and group 2 (Table 2): In patients with recognized MI (group 1), 44% of all segments with myocardial infarction were considered to be supplied by the LAD, 25% by the LCX, and 31% by the RCA. In patients with UMI (group 2) 30% of infarcted segments were supplied by the LAD, 41% by the LCX, and 29% by the RCA. The segmental analysis revealed 42% of infarcted segments in UMI were located in four infero-lateral segments (segments 4, 5, 10 and 11; Fig. 2).
2.2.2. Image analysis Image analysis was performed by two independent and blinded readers (1 and 6 years of experience) at an offline workstation CVI42 (Circle Cardiovascular Imaging, Calgary AB, Canada). Myocardial viability in LGE imaging was analysed in accordance with the recommendations of the Society for Cardiovascular Magnetic Resonance task force [15]: For quantification of full-intensity LGE extent in per cent of the myocardial mass, a semi-automated threshold with normal remote myocardium +5 standard deviations (SD) was chosen. Assessment of LGE localization was based on the AHA 17segment model introduced by Cerqueira et al. [16]. Accordingly, segments 1, 2, 7, 8, 13, 14 and 17 were assigned to the left anterior descending coronary artery (LAD) vascular supply territory, segments 3, 4, 9, 10 and 15 to the right coronary artery (RCA) and segments 5, 6, 11, 12 and 16 to the left circumflex coronary artery (LCX), assuming a normal coronary anatomy with balanced blood supply. Myocardial stress perfusion was evaluated visually as dichotomous trait (ischemia yes or no). In functional analysis, end-diastole and end-systole were determined visually. In short-axis views, endocardial and epicardial contours
3.2. Functional imaging One dataset in group 3 (without MI) was not evaluable for functional assessment. Patients with MI had higher LVEDV than patients without MI: In group 1 with recognized MI LVEDV was 168 ± 50 ml; in group 2 with UMI LVEDV was 164 ± 49 ml, and in group 3 without MI 131 ± 43 ml, respectively. LVMM was higher in MI patients (LVMM group 1: 123 ± 27 g; group 2: 129 ± 36 g) than 12
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Table 2 Distribution of myocardial infarction. Vessel
LAD LCX RCA
Group1 recognized MI (RMI) n = 67
Group 2 unrecognized MI (UMI) n = 48
Number of LGE segments
Percentage within group
Number of LGE segments
Percentage within group
148 84 106
44% 25% 31%
46 64 44
30% 41% 29%
Table 2 indicates number of segments per vessel territory involved by full-intensity LGE in group 1 and 2. In patients with recognized MI (group 1) most MI were localized in LAD territory, whereas UMI were predominantly localized in vessel territory of LCX. MI: myocardial infarction, RMI: recognized MI, UMI: unrecognized MI, LGE: late gadolinium enhancement, LAD: left anterior descending artery, LCX: left circumflex coronary artery, RCA: right coronary artery.
in patients with no MI (LVMM group 3: 114 ± 32 g). LVEF was lower in patients with recognized MI (LVEF group 1: 49 ± 10%) and UMI (LVEF group 2: 52 ± 10%) compared to group 3 (LVEF: 58 ± 10%). LVGFI was significantly lower in group 1 with recognized MI (34 ± 8% [range 16; 52], p < 0.0001), and group 2 with UMI (35 ± 8% [range 10; 51], p = 0.0079), compared to group 3 with no MI (38 ± 7% [range 16; 55]) respectively. LVGFI was not significantly different between group 1 and 2 (p = 0.2). Detailed volumetric results including range of all values are tabulated in Table 1. LVGFI and LGE mass were normally distributed. The evaluation of interobserver-variability indicated a mean difference between readers for LVEDV of 1.6 ± 8 ml, with limits of agreement from −13.6 ml to 16.8 ml. For LVESV, the mean difference between readers was −3.4 ± 6 ml, with limits of agreement from −14.8 ml to 7.9 ml. For LVMM, the mean difference between readers was −4.3 ± 6 g, with limits of agreement from −16 g to 7.6 g. For LGE, mass the mean difference between readers was 0.1 ± 1.8%, with limits of agreement from −3.5% to 1.6%. 4. Discussion In this study we present the evaluation of the left ventricular global functional index and quantitative LGE in patients with unrecognized myocardial infarction, comparing these values to patients with recognized MI and patients with suspected CAD.
Fig. 1. LGE imaging in four-chamber (a) and short-axis (b) view of a 69-year old male patient with clinical history of CAD and UMI discovered in cardiac MRI. Arrows depict a partially transmural MI affecting the lateral wall.LGE: late gadolinium enhancement, CAD: coronary artery disease, UMI: unrecognized MI, MI: myocardial infarction
4.1. Viability imaging As could be expected, recognized MI came along with the largest extent in quantitative evaluation of the LGE mass, followed by a significantly but not relevantly smaller extent of LGE mass in UMI
Table 1 Volumetric analysis of patient Groups. Parameter
Group1 recognized MI (RMI) n = 67
Group 2 unrecognized MI (UMI) n = 48
Group 3 no MI n = 120
LVEDV (ml) LVESV (ml) LVSV (ml) LVMM (g) LVEF (%) LVGFI (%) Full-intensity LGE (%)
168 ± 50 [93; 333] 89 ± 42 [38; 250] 80 ± 19 [38; 125] 123 ± 27 [69; 223] 49 ± 10 [25; 66] 34 ± 8 [16; 52] 11 ± 6 [2; 30]
164 ± 49 [95; 333] 82 ± 43 [36; 283] 80 ± 22 [38; 145] 129 ± 36 [75; 215] 52 ± 10 [19; 76] 35 ± 8 [10; 51] 9 ± 5 [2; 36]
131 ± 43 [65; 290] 57 ± 31 [31; 201] 76 ± 22 [42; 150] 114 ± 32 [62; 232] 58 ± 10 [27; 77] 38 ± 7 [16; 55] 0.5 ± 1.8 [0; 10]
Table 1 indicates mean value ± standard deviation and range in closed brackets. MI: myocardial infarction, RMI: recognized MI, UMI: unrecognized MI, LVEDV: Left ventricular enddiastolic volume, LVESV: end-systolic volume, LVSV: stroke volume, LV-MM: left ventricular myocardial mass, LVEF: ejection fraction, LVGFI: left ventricular global function index; LGE: late gadolinium enhancement.
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a less extended myocardial ischemia and less characteristic symptoms. UMI has a higher prevalence in patients with a predisposition to atypical symptoms such as diabetic patients, elderly patients, and women [2,22]. These symptoms typically include epigastric pain, neck and back pain, nausea, vomiting, palpitations and sweating [23]. The distribution of UMI has predominantly been described in basal inferolateral segments, which is reproduced in our study [24]. Interestingly, UMI predominantly affects an area of overlapping or at least adjacent vascular supply by the RCA and LCX, but not confined to a certain vessel territory supplied by one single coronary artery in the most frequent normal variants of coronary artery anatomy [16]. Increased occurrence of UMI in infero-lateral segments may also arise from atypical symptoms associated with MI of the infero-lateral wall [25]. 4.2. Functional imaging As could be expected, patients without MI featured the highest LVGFI and LVEF values. Both LVGFI as well as LVEF were reduced in patients with recognized MI compared to patients with UMI. The cut-off value for LVGFI in healthy controls was predetermined at 37% [12]. A major limitation of the clinical use of LVGFI as a relevant imaging biomarker lies in the fact, that already relatively small changes on the percent scale may indicate highly pathologic values, other than we are used to from LVEF. This is reflected in our study by only small absolute LVGFI mean value differences between patients with and without history of MI, ranging around the threshold of 37%. In spite of significant differences between groups with and without history of infarction, a pathologic LVGFI cut-off value could not be identified or established in our study: the standard deviation and range of LVGFI values do not enable a reliable differentiation due to wide overlap. Another shortcoming of LVGFI is the integration of myocardial mass and volumes, making it hard to differentiate the etiology of cardiomyopathy. Primary volumetric data of myocardial volumes, ejection fraction and mass is still needed to understand the type of pathology. This may be a reason why LVGFI has not yet been commonly applied in clinical routine. LVGFI values could not be used to differentiate between patients with recognized MI and UMI in our study, which correlates with similar LGE masses found in our study for both groups. Recognized MI and UMI found in cardiac MRI were also reported to be associated with similar mortality, so that significant differences between both groups regarding functional parameters are not expected [26,27]. LVEF can be determined using different methods with similar bias: cardiac CT, ventriculography, echocardiography and singlephoton emission CT (SPECT) [28], but LVGFI is a MRI specific biomarker. For the comparison between previously published studies and methods in Table 3 this study provided values for LVEF. The studies do not meet the criteria for a meta-analysis, for different methods were applied and different selection of cohorts may have had an influence on different functional parameters. As the only study compared, Nordenskjöld et al. reported higher LVEF (67%) in their UMI cohort compared to LVEF of 66% in patients with no MI [3]. Pooled echocardiography data since 1979 have recently shown a higher risk for morbidity and mortality in borderline reduced LVEF of 50% to > 55% [29]. In our study, LVMM was higher in patients with MI compared to patients with no MI. This may also be a secondary effect due to postischemic LV dilation. Kim et al. found that LGE due to UMI undetectable by Q-waves in electrocardiogram was 3-fold higher than UMI revealed with Q-waves [30], underlining the role of MRI in the diagnosis of UMI. Whereas the pathogenesis of UMI has been reported not concordant with atherosclerosis [24,31], a recent prospective trial found UMI associated with age and extent of CAD [3]. To date, there is no general recommendation to routinely examine all patients with suspected CAD to rule out UMI. To evaluate prognostic value of LGE MRI in UMI, large scale controlled studies are needed to examine the difference in prognosis of a UMI in
Fig 2. (a) Indicates percentage of segments infarcted in recognized MI: Infarcted segments were predominantly (44%) located in the vessel territory of the LAD which supplies more segments than other vessels (shaded). (b) indicates percentage of segments infarcted in UMI. 42% of infarcted segments occurred in four inferolateral segments (shaded).MI: myocardial infarction, LAD: left anterior descending coronary artery, UMI: unrecognized MI. Segment number is given in corner of segments. Apical segment 17 is located in the centre.
patients. A small LGE mass (below 1%) in patients with no MI (group 3, suspected CAD) can be explained by image noise or suboptimal inversion time for LGE imaging and should therefore be regarded as false positive due to imaging artefacts and suboptimal image quality, respectively. Nuclear cardiologic alternative imaging methods for detection of post-ischemic myocardial scar are SPECT and PET [18,19]. LGE MRI provides higher sensitivity for detection of smaller and non-transmural UMI [20,21]. One possible reason why MI had not been recognized in UMI patients may be the smaller extent of the scar, presumably preceded by 14
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Table 3 Comparison of the results with previously published data. Study/Value Modality
Current study MRI
Ammar et al. [32] Echo
Kwong et al. [33] MRI
Kwong et al. [34] MRI
Kim et al. [30] MRI
Yoon et al. [35] MRI
Nordenskjöld et al. [3] MRI
LVEF no MI LVEF UMI LVEF RMI
58% 52% 49%
66% 61% 55%
60% 41%
60% 47%
63% 48/52%
63/62%b 54/56%b
63% 61%
a
Table 3 compares the LVEF results of our study with previously published data in UMI in the literature. In some previous studies, different methods were applied and different selection of cohorts may have had an influence on functional parameters. MI: myocardial infarction, UMI: unrecognized MI, LVEF: ejection fraction, MRI: Magnetic Resonance Imaging, Echo: Transthoracal Echocardiography. a Kim et al. differentiated between Q-wave and Non-Q-wave UMI b Yoon et al. differentiated between impaired fasting glucose and diabetes mellitus patients.
contrast to extended CAD alone. In this study, no follow-up examinations have been performed to provide the prognostic value of the data collected. To date, available data for LVGFI is limited: only introductory and initial clinical studies have been published. Not all studies have reported superiority of LVGFI over LVEF [14]. LVGFI cannot be used to identify UMI and remains an unspecific marker to evaluate changes in LV morphology and function.
[5]
[6]
[7]
5. Conclusion In conclusion, this study confirms that MRI-based LGE quantification is an effective tool to assess infarction scar size in patients with recognized and unrecognized myocardial infarction. Left ventricular global function index (LVGFI) provides additional information on cardiac function and morphology, but does not enable to reliably differentiate between patients with and without history of MI, due to a wide overlap. This may be a reason why LVGFI is not commonly applied in clinical routine.
[8]
[9]
Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Statement on behalf of all authors:
[10]
Conflicts of interest [11]
None. Appendix A. Supplementary data
[12]
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.ejrad.2017.04.012. References
[13]
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