Impact of Acute Hyperglycemia on Myocardial Infarct Size, Area at Risk, and Salvage in Patients With STEMI and the Association With Exenatide Treatment: Results From a Randomized Study

In patients with ST-segment elevation myocardial infarction (STEMI), timely treatment with primary percutaneous coronary intervention (PCI) is recommended to restore coronary blood flow and increase myocardial salvage, and thereby to minimize infarct size (1). However, after the opening of an occluded vessel, reperfusion injury may paradoxically cause additional irreversible myocardial damage that may account for as much as 50% of the infarct size (2). The mechanisms behind reperfusion injury have not been fully elucidated, but hyperglycemia, which is observed in approximately half of patients with STEMI upon hospital admission (3), may be unfavorable during reperfusion and has been linked to the subsequent injury (4). Previous studies have demonstrated larger infarct size (5–8) and poorer prognosis in patients with hyperglycemia upon hospital admission compared with patients without hyperglycemia, both in patients with and without diabetes mellitus (3,5,8–20). Until now, the impact of hyperglycemia on myocardial salvage has been evaluated in only a limited number of patients (21), and no data exist regarding the relationship between hyperglycemia and area at risk. Thus, the causal role of hyperglycemia in STEMI remains unknown, and whether the association between hyperglycemia and myocardial damage may be attributed to a larger myocardium at risk or is the cause of reperfusion injury leading to decreased myocardial salvage needs to be elucidated. Cardiovascular magnetic resonance (CMR) provides an accurate method for in vivo assessment of infarct size (22,23), area at risk (24–27), and myocardial salvage index (28,29).

In a previously published proof-of-concept study (30,31) on patients with STEMI and thrombolysis in myocardial infarction (TIMI) grade 0 or 1 flow before primary PCI, we demonstrated a cardioprotective effect of exenatide. Exenatide is a glucagon-like peptide analog that is known to increase insulin secretion and cellular glucose uptake, and subsequently reduce the level of blood glucose (32). The cardioprotective effect of exenatide may be related to these glucose homeostatic effects (33), and it may be hypothesized that the effect of exenatide depends on the patient’s glucose level upon hospital admission and before undergoing PCI.

The aims of the current study were to evaluate (1) the association between hyperglycemia upon hospital admission and area at risk and myocardial salvage index in STEMI patients, and (2) the interaction between glycemic state upon hospital admission and the cardioprotective effect of exenatide.

The patients in this post hoc study participated in a randomized clinical trial comparing intravenous administration of exenatide with placebo in STEMI patients (30). Patients with STEMI were randomized to receive either exenatide or placebo saline solution intravenously 15 min prior to intervention and continued 6 h post-PCI. Exenatide treatment resulted in increased myocardial salvage index, and exenatide also reduced the final infarct size in patients with short system delays; for more details, see the existing publications (30,31). STEMI was defined as ST-segment elevation in two contiguous electrocardiogram (ECG) leads of >0.1 mV in V₄–V₆ or limb leads II, III, and aVF, or >0.2 mV in leads V₁–V₃. Patients were not considered for study enrollment if they presented with cardiogenic shock or were unconscious. Similarly, patients with STEMI caused by stent thrombosis, known renal insufficiency, or previous coronary artery bypass graft surgery were excluded from the study. Finally, patients with no subsequent rise in levels of cardiac biomarkers were excluded from the study. All patients eligible for primary PCI were pretreated with aspirin (300 mg orally or 500 mg i.v.), clopidogrel (600 mg orally), and heparin (10,000 units i.v.). On arrival at the catheterization laboratory, a coronary angiography was performed to identify the culprit lesion, and primary PCI was performed according to contemporary guidelines, as previously described (30). All patients were treated with clopidogrel, 75 mg daily for 12 months, and aspirin, 75 mg daily indefinitely. Cardiac biomarkers (troponin T) were measured before intervention and immediately after, 6 h after, 12–18 h after, and on the day after intervention. The proximal location of the culprit lesion was defined as the first segment of the right coronary artery, the left coronary descending artery, and the left circumflex artery. All patients were informed orally and in writing, and all gave their written consent before inclusion. The study was performed according to the Helsinki Declaration guidelines for good clinical practice, and The Danish National Committee on Biomedical Research Ethics approved the protocol. The study was registered at www.clinicaltrial.gov (NCT00835848).

Blood glucose level was measured upon hospital admission at the PCI center before the first angiogram was performed as part of a standard evaluation. For patients without known diabetes, a cutoff value of 8.3 mmol/L (149 mg/dL) was used for the definition of hyperglycemia, whereas for patients with known diabetes a cutoff value of 12.8 mmol/L (231 mg/dL) was used (17). These particular cutoff values were chosen, since they previously have been identified as the most optimal cutoff values for prediction of outcome in STEMI patients undergoing primary PCI for diabetic and nondiabetic patients, respectively (17). Moreover, different cutoff values were used for diabetic and nondiabetic patients, since previous studies (5,17) have demonstrated that the infarct size in nondiabetic patients increases with hyperglycemia, but only with server hyperglycemia among nondiabetic patients. However, a separate analysis was also performed using the same cutoff value independent of the diabetic state (8.3 mmol/L). Hypoglycemia was defined as a blood glucose level of <3.3 mmol/L (60 mg/dL) (11).

The angiograms were analyzed for collateral flow to the infarct-related artery according to the Rentrop classification grade (0–3), TIMI flow grade (0–3), and for area at risk according to the APPROACH (Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease) score (34).

The CMR protocol and image analyses has previously been described in detail (30). In brief, a CMR scan was performed from day 1 to day 7 after the primary PCI (25–28), and a second CMR was repeated 3 months ± 3 weeks after the primary PCI. Both scans were performed on a 1.5 Tesla scanner (Avanto; Siemens, Erlangen, Germany) using a 6-channel body array coil. The myocardial area at risk was assessed on the first CMR scan as myocardial edema using a T2-weighted short tau inversion recovery sequence (Fig. 1A). On the second CMR examination, delayed enhancement images were obtained to determine the final infarct size using an ECG triggered inversion-recovery sequence (Fig. 1B). These images were acquired 10 min after intravenous injection of 0.1 mg/kg body weight gadolinium-diethylenetriaminepentaacetic acid (Gadovist; Bayer Schering, Berlin, Germany). Left ventricular (LV) volumes and function were measured from both CMR examinations using an ECG-triggered, balanced steady-state, free precession cine sequence.

An observer blinded to all clinical data analyzed the images, and for all analyses the endocardial and epicardial borders were manually traced by the incorporation of papillary muscles as part of the LV cavity. The final infarct size was measured using the free software Segment, version 1.8 (http://segment.heiberg.se) (Fig. 1C) (35). The infarct size, defined as the hyperenhanced myocardium on the delayed enhancement images, was determined by an automatic approach, as previously described (35). The infarct size was expressed as a percentage of the total LV mass and as an absolute mass. Using a postprocessing tool (Argus; Siemens, Erlangen, Germany), the area at risk was defined as the hyperintense area on T2-weighted images. A myocardial area was regarded as hyperintense whenever the signal intensity was >2 SDs of the signal intensity in the normal myocardium (Fig. 1D). The salvage index was calculated as follows: (area at risk − infarct size)/area at risk (29). On cine short-axis CMR images, the LV volume was calculated in all 25 phases by manually tracing the endocardial borders using a postprocessing tool (Argus; Siemens). According to the blood pool area, the LV diastolic and systolic frames were then identified; and LV end-diastolic volume, LV end-systolic volume, and LV ejection fraction were calculated.

Patients with normoglycemia and hyperglycemia were compared using the two-tailed χ² or Fisher exact test for categorical variables and the Student t test or Mann-Whitney U test according to normality for continuous variables. Normality was evaluated by histograms of the standardized residuals. To compare the relationship between the area at risk and the infarct size, a regression analysis was performed, and an ANCOVA was used to test for equality of the regression lines for the patients with normoglycemia and hyperglycemia. Multivariable regression models were performed to adjust for potential confounders using any baseline variable with P < 0.10 for the difference between normoglycemia and hyperglycemia, and diabetes mellitus status was forced into the model owing to the possible interaction with hyperglycemia. Among the nondiabetic patients, the correlation between blood glucose levels upon hospital admission as a continuous variable with area at risk, final infarct size, and myocardial salvage index was also evaluated using linear regression analyses. Since reperfusion injury occurs in the first minutes after reperfusion and TIMI flow grade 0/1 seems pivotal for cardioprotection (4), the patients with pre-PCI TIMI 0/1 flow were also analyzed separately. Exenatide treatment may potentially be a confounder; thus, a separate analysis was performed for patients treated with placebo. To evaluate the association between exenatide treatment and glycemic state upon hospital admission, the patients with TIMI 0/1 flow were stratified according to normoglycemia and hyperglycemia, and the effect of exenatide treatment upon myocardial salvage index was evaluate for each of these groups. Interaction between glycemic state and exenatide treatment in terms of myocardial salvage index was evaluated by ANCOVA. The models were constructed as follows: glycemic state, exenatide/placebo, and glycemic state * exenatide/placebo. A two-sided P value <0.05 was considered statistically significant. All statistical analyses were performed with SPSS software, version 20 (SPSS, Chicago, IL).

The patient flowchart is shown in Fig. 2. Blood glucose level upon hospital admission was not available in 41 patients, and a further 44 patients were not considered for study inclusion owing to having aborted STEMI. A total of 92 patients (30%) considered for inclusion in this study were lost to CMR. The patients lost to CMR were older, had shorter system delays, and had better pre-PCI TIMI flow compared with the included patients (Table 1). We included 210 STEMI patients, of whom 25 patients were lost to the first CMR, leaving 185 patients with measurements of both the area at risk and final infarct size. The median blood glucose levels (interquartile range [IQR]) in patients without and with diabetes were 7.9 mmol/L (6.7–9.0 mmol/L) and 11.2 mmol/L (9.2–20.3 mmol/L), respectively. No patients had hypoglycemia upon hospital admission. One hundred twenty-five patients (60%) were in a normoglycemic state upon hospital admission, and 85 patients (40%) were in a hyperglycemic state. Baseline characteristics are presented in Table 2. Patients with hyperglycemia had a higher frequency of pre-PCI TIMI flow 0/1, higher levels of glucose, higher peak troponin T level, higher maximum ST-segment elevation before PCI, higher heart rate at hospital discharge, and shorter time from symptom onset until PCI; they were also more frequently treated with thrombectomy and less frequently randomized to receive exenatide (Table 2). Moreover, these patients tended to have a higher frequency of proximal occlusion (Table 2). Importantly, patients with known diabetes were equally distributed between the two groups (Table 2). The first and second CMRs were performed a median time of 2 days (IQR 1–2 days) and 90 days (IQR 83–95 days) after the STEMI, respectively, with no difference between the groups. A total of 78% of the population underwent the first CMR within 48 h after the STEMI.

STEMI patients with hyperglycemia had a larger area at risk measured by CMR than patients with normoglycemia, with medians of 32% LV (IQR 26–39% LV) and 29% LV (IQR 23–36% LV), respectively (Fig. 3A), as measured by the angiographic APPROACH score (Table 2). As expected, the final median infarct size measured by CMR was also larger in the hyperglycemic patients compared with the normoglycemic patients (11% LV [IQR 6–17% LV] vs. 8% LV [IQR 5–13% LV]) (Fig. 3B). However, the median myocardial salvage index determined by CMR did not differ between the groups (0.71 [IQR 0.64–0.82] and 0.73 [IQR 0.61–0.82], respectively) (Fig. 3C). Using the angiographic APPROACH score to calculate the median myocardial salvage index did not change the result (0.61 [IQR 0.47–0.74] vs. 0.62 [IQR 0.45–0.80], respectively; P = 0.58). The final infarct was not different adjusting for area at risk, since the regression lines for the hyperglycemic and normoglycemic patients were superimposed (Fig. 3D). In a multivariable analysis, hyperglycemia was not independently associated with final infarct size (Table 3).

Using a cutoff value of 8.3 mmol/L to define hyperglycemia, patients with hyperglycemia still had a larger median area at risk measured by CMR (29% LV [IQR 22–37% LV] vs. 32% LV [IQR 25–39% LV]; P = 0.049) and the angiographic APPROACH score (27% LV [IQR 19–29% LV] vs. 28% LV [IQR 21–33% LV]; P = 0.036). The association between hyperglycemia and final infarct size seems to be weaker (9% LV [5–13% LV] vs. 10% LV [IQR 6–16% LV]; P = 0.06). The myocardial salvage index did not differ between the groups (0.72 [IQR 0.61–0.82] vs. 0.72 [IQR 0.64–0.83]; P = 0.59). Accordingly, the infarct size was not different adjusting for area at risk (P = 0.57). Among the nondiabetic patients the level of blood glucose upon hospital admission as a continuous variable correlated with final infarct size (r = 0.17; P = 0.018), area at risk by CMR (r = 0.28; P < 0.001), and APPROACH score (r = 0.15; P = 0.042), but not myocardial salvage index (r = 0.07; P = 0.36).

A total of 141 patients had pre-PCI TIMI grade 0/1 flow, of whom 76 (54%) had normal glucose levels upon hospital admission and 65 (46%) had elevated levels. Evaluating only patients with TIMI 0/1 grade flow before undergoing PCI, hyperglycemia was associated with a larger area at risk compared with normoglycemia (33% LV [IQR 27–44% LV] vs. 30% LV [IQR 25–38]; P = 0.042), just as final infarct size tended to be larger (13% LV [IQR 8–18% LV] vs. 10% LV [IQR 7–14% LV]; P = 0.07). However, either the median myocardial salvage index determined by CMR (0.70 [IQR 0.62–0.77] vs. 0.68 [IQR 0.57–0.76]; P = 0.44) or the final infarct size adjusting for the area at risk (P = 0.98) were significantly different between the two groups.

When the patients randomized to receive placebo alone (n = 89) were analyzed, the overall results did not change. Patients with hyperglycemia had a larger myocardium area at risk than normoglycemic with median values of 32% LV (IQR 26–39% LV) and 27% LV (IQR 22–32% LV) (P = 0.008). The final infarct size was numerically larger with a median of 12% LV (IQR 6–17% LV) compared with 9% LV (IQR 5–13% LV) (P = 0.15). The median myocardial salvage index as determined by CMR was 0.70 (IQR 0.60–0.79) for patients with hyperglycemia and 0.69 (IQR 0.58–0.84) for patients with normoglycemia (P = 0.98).

Among patients with TIMI 0/1 grade flow before undergoing PCI, exenatide treatment was associated with a lower blood glucose level upon hospital admission, immediately after the PCI, and 6 h after the PCI (Fig. 4). In patients with normoglycemia, treatment with exenatide resulted in a mean myocardial salvage index determined by CMR of 0.68 ± 0.17 compared with 0.62 ± 0.12 for patients treated with placebo (P = 0.08). Among the patients with hyperglycemia, the myocardial salvage index determined by CMR was 0.73 ± 0.11 for patients treated with exenatide, and 0.64 ± 0.15 for patients treated with placebo (P = 0.017). However, there was no statistically significant interaction between the glycemic state upon hospital admission and treatment allocation (exenatide vs. placebo) with regard to myocardial salvage index (P = 0.71).

In the current study, we found that hyperglycemia upon hospital admission in STEMI patients treated with primary PCI is related to a larger myocardium area at risk and final infarct size, without affecting the potential for myocardial salvage. Also, despite the lower blood glucose level in patients treated with exenatide, there was no interaction between glycemic state and exenatide treatment, indicating that the cardioprotective effect of exenatide treatment is independent of glucose level upon hospital admission.

This is the first study to assess the association of glycemic state upon hospital admission with the myocardium area at risk and myocardial salvage in a large cohort of patients with STEMI. Our data suggest that the excessive myocardial damage (5–8) and adverse prognosis (3,5,8–19) reported in patients with hyperglycemia are the results of a larger myocardial area at risk, and not of a smaller myocardial salvage. Similarly, since there was no association between hyperglycemia and infarct size when adjusting for the area at risk, the current study demonstrates that the association between hyperglycemia and infarct size is dependent on the size of the area at risk, and hyperglycemic patients can therefore be considered to be at higher risk per se. The patients with hyperglycemia more frequently have anterior infarct location and pre-PCI TIMI flow grade 0/1 and a shorter time from symptom onset until balloon (5,8,17). However, it has previously been demonstrated that the blood glucose level upon hospital admission fails to predict prognosis when adjusted for other predictors including duration of symptoms, TIMI flow, and infarct location (8); likewise, hyperglycemia in the current study failed to predict infarct size in the multivariable analysis. The relationship between hyperglycemia and duration of symptoms might indicate that the early presenters with more pronounced symptoms and faster reaction are at higher risk (36). Importantly, there was no difference in system delay, which is a stronger predictor than time from the onset of symptoms to balloon angioplasty (37,38). Thus, it seems more plausible that hyperglycemia upon hospital admission in STEMI patients is an indicator of increased myocardium area at risk and a marker for the severity of the myocardial damage, rather than being a deteriorating factor in itself.

Cell death owing to lethal reperfusion injury cannot be distinguished from ischemia-induced cell death in vivo, but since it occurs during the reperfusion phase a decrease in myocardial salvage or a larger infarct size adjusted for area at risk would be expected. In this study, hyperglycemia was not related to either of these in the entire cohort of patients with STEMI or in patients with pre-PCI TIMI grade 0/1 flow, which indicates that hyperglycemia does not lead to further irreversible myocardial damage during and after reperfusion with PCI. Thus, our findings suggest that hyperglycemia upon hospital admission is not related to lethal reperfusion injury and does not reduce the potential of salvage. This suggests that hyperglycemia is not directly involved in the death of the myocytes, but is the consequence of metabolic derangements caused by an increased myocardium at risk leading to more extensive myocardial damage. Interestingly, after an acute myocardial infarction the level of serum insulin is not associated with biomarkers reflecting the infarct size and paradoxically is weakly positively correlated with glucose levels (39). Hyperglycemia upon hospital admission is therefore not explained by a decrease in serum insulin level, but may be the result of increased levels of stress hormones leading to greater glucose availability, which may in fact benefit the hibernating myocytes and prevent further apoptosis (40). This may also help to explain the overall disappointing results of previous studies of glucose-lowering therapy in patients with acute coronary syndrome (41). In randomized settings, de Mulder et al. (41) evaluates the effect of insulin treatment on infarct size in patients presenting with STEMI and hyperglycemia, and concluded that glucose-lowering therapy with insulin did not reduce infarct size, but paradoxically tended to increase the infarct size. In contradiction, in the POSTCON II study exenatide therapy resulted in lower glucose levels, an increase in myocardial salvage and decrease in the infarct size adjusted for the area at risk (30). But the cardioprotective effect of exenatide is still not determined and probably involves a direct cardiac action (see below), and the glucose-lowering effect of exenatide is not as dramatic and abrupt as the effect of insulin and does not result in hypoglycemia. Interestingly, Selker et al. (42) reported a reduction in infarct size in patients with suspected acute coronary syndrome and in STEMI patients after prehospital treatment with glucose-insulin-potassium. However, the protective effect of glucose-insulin-potassium treatment is considered to be the cause of increased glucose uptake and improved metabolic support to the ischemic myocardium and not a reduction in the blood glucose level (40,42).

The cardioprotective effects of glucagon-like peptide 1 (GLP-1) and its analogs may be mediated through both cardiac and noncardiac sites of action. GLP-1 receptors have been described in cardiomyocytes, endocardium, vascular endothelium, and smooth muscle cells of rodent hearts (43), and several survival signaling pathways have been proposed to be activated by these receptors (33). However, the expression of GLP-1 receptors in human hearts remains controversial (44). Cardiac as well as noncardiac insulinotropic and insulinomimetic effects, including an increased glucose uptake, might also contribute to the cardioprotective action of GLP-1 analogs. Indeed, we observed a reduced level of glucose before and after the PCI after treatment with intravenous exenatide. However, the cardioprotective effect of exenatide is independent of hyperglycemia upon hospital admission in STEMI patients, but whether the effect is dependent on increased glucose uptake remains unknown.

In contrast to findings in the current study, a previous study by Teraguchi et al. (21) reports a decreased myocardial salvage index in patients with hyperglycemia. The following important differences between that study and ours should be taken into account: 1) Teraguchi et al. (21) did not report data on the area at risk or infarct size, and information regarding pre-PCI TIMI flow is missing, which is an important predictor for myocardial salvage index (45); 2) the time from symptom onset until reperfusion is twice as long in the study by Teraguchi et al. (21) compared with the present study, with means of 375 and 180 min, respectively; and 3) Teraguchi et al. (21) used a cutoff value of 10 mmol/L (180 mg/dL) to identify the patients with hyperglycemia among both diabetic and nondiabetic patients, which does not seem to be optimal in terms of predicting outcome. Eitel et al. (5) demonstrated that a glucose level >7.8 mmol/L is related to larger infarct size in nondiabetic patients, whereas in patients with diabetes a glucose level exceeding 11.1 mmol/L was related to larger infarct size. Similar, Teraguchi et al. (21) found that a glucose level exceeding 10 mmol/L was related to infarct size in nondiabetic patients but not in patients with diabetes. Planer et al. (17) also report different cutoff values for diabetic and nondiabetic patients. In 3,405 STEMI patients, they identified 8.3 and 12.8 mmol/L as the most optimal cutoff values for predicting 30-day mortality in nondiabetic and diabetic patients, respectively (17). Thus, these particular cutoff values were used in the current study, and the findings confirm these values as related to outcome. However, it is still uncertain whether or not to use the same or different cutoff values according to patients with diabetes, but previous observations indicate that the importance of glucose levels in STEMI patients depends on the diabetic state. The current study includes an additional analysis with one definition of hyperglycemia (8.3 mmol/L) without changing the overall results, but the association between hyperglycemia and final infarct size may be weaker. Too few patients with diabetes were included in this study, and it lacks sufficient power to draw any firm conclusions regarding the use of the same or different cutoff values to define hyperglycemia. Using one cutoff value will place most patients with diabetes in the hyperglycemic group, resulting in an inherent bias. Interestingly, Eitel et al. (5) found that hyperglycemia was related to microvascular obstruction by CMR, but the patients were not stratified according to pre-PCI TIMI flow, a pivotal factor for the PCI-induced reperfusion injury (4). Also, there are no data on the area at risk or multivariate analysis; thus, whether hyperglycemia is a cause or a consequence of microvascular obstruction remains unknown. Unfortunately, no data regarding microvascular obstruction were available, since delayed enhancement images were not acquired during the initial scan, which is a limitation to this study.

Owing to the post hoc nature of our study findings, regarding the association between exenatide and blood glucose levels may only be considered hypothesis generating. Patients in this study were randomized to receive either placebo or exenatide, which could have affected the association between hyperglycemia and myocardial damage, especially since the blood samples were collected after randomization. It is therefore important to underscore that evaluating only the patients treated with placebo did not change the results. Thus, a possible confounding role of exenatide appears unlikely, but using all patients in this substudy increases the statistical power. Area at risk was evaluated by assessing myocardial edema after reperfusion; thus, hyperglycemia may potentially also change the level of myocardial edema. Using CMR has some obvious advantages, as mentioned in the 1Introduction, but also carries inherent limitations owing to contraindications. In the current study, a total of 30% of the patients intended for analysis were lost to CMR, which induces a certain risk of selection bias. Furthermore, the excluded patients and the patients lost to CMR may present some of the most critically ill patients (e.g., patients with renal failure, unconsciousness, or cardiogenic shock), which introduces a risk of selection bias. However, the patients lost to CMR were older, but in contrast had better pre-PCI TIMI flow and shorter system delay; thus, these patients were not sicker, which further limits the risk for selection bias. A relatively wide time window was allowed for the first CMR, but the same time window has been used in previous studies that have validated T2-weighted CMR to delineate area at risk (25–28). The majority of the patients underwent the first CMR scan within 48 h (78%), and there was no difference between the groups. Importantly, other estimates of the area at risk, such as by the angiography APPROACH score and ST-segment elevation prior to PCI, were also higher among patients with hyperglycemia, which supports the CMR findings. In the original study, patients were included when they had TIMI flow grade 0/1 before intervention and no other stenosis >70% than the culprit lesion (30). While preprocedural TIMI flow is well-established as a pivotal determinant of reperfusion injury, the role of multivessel disease is more controversial (4). Consequently, in order to increase the statistical power of the present analysis patients with multivessel disease were not excluded. Owing to many statistical comparisons, some significant differences may be observed by chance leading to a risk of type II errors, and the results must be interpreted cautiously and need to be confirmed.

The association between hyperglycemia upon hospital admission and larger infarct size in STEMI patients treated with PCI is explained by a larger myocardial area at risk but not by a reduction in myocardial salvage. Also, cardioprotection by exenatide treatment is independent of hospital admission glucose levels. Thus, we conclude that hyperglycemia does not influence the effect of the reperfusion treatment but rather serves as a marker for the severity of myocardium at risk and injury.

Funding. This research was supported by the Danish National Research Foundation for Heart Arrhythmia, the Novo Nordisk Foundation, Danielsen’s Foundation, Rigshospitale's Research Foundation, and the Danish Heart Foundation.

Duality of Interest. H.E.B. is a shareholder in CellAegis Inc. P.C. has received grants from Eli Lilly. T.E. has received grants from and is a member of the advisory board of Eli Lilly. No other potential conflicts of interest relevant to this article were reported.

Authors Contributions. J.L. contributed to the conceptual design, the follow-up of patients, and data quality control; performed the cardiovascular magnetic resonance scan and analysis and angiography; researched the data; performed the general data analysis; and wrote the manuscript, including statistics, tables, and figures. N.V. and W.Y.K. contributed to conceptual design and participated in the cardiovascular magnetic resonance scan protocol and analysis. H.K., E.J., S.H., L.H., K.S., H.E.B., P.C., and M.T. contributed to conceptual design and data analysis and recruitment and enrollment of patients. L.N.-C. contributed to conceptual design, data analysis, data research, and follow-up of patients. T.E. was principal investigator and contributed to conceptual design and data analysis, angiographic data analysis, data research, and recruitment and enrollment of patients. All authors have contributed significantly to the making of the manuscript, to trial design, and to the reviewing and editing of the manuscript. J.L. and T.E. are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Prior Presentation. Parts of this study were presented at the 25th Transcatheter Cardiovascular Therapeutics Annual Scientific Symposium, San Francisco, CA, 27 October–1 November 2013.