Prognostic value of the myocardial salvage index measured by T2-weighted and T1-weighted late gadolinium enhancement magnetic resonance imaging after ST-segment elevation myocardial infarction: A systematic review and meta-regression analysis.

In all patients with ST-segment elevation myocardial infarction, risk stratification should be performed before discharge. The measurement of therapy efficiency with magnetic resonance imaging has been proposed as part of the risk assessment, but it has not been adopted widely. This meta-analysis was conducted to summarize published data on the prognostic value of the proportion of salvaged myocardium inside previously ischemic myocardium (myocardial salvage index) measured by T2-weighted and T1-weighted late gadolinium enhancement magnetic resonance imaging after ST-segment elevation myocardial infarction. Random and mixed effects models were used for analyzing the data of 10 studies with 2,697 patients. The pooled myocardial salvage index, calculated as the proportion of non-necrotic myocardium inside edematous myocardium measured by T2-weighted and T1-weighted late gadolinium enhancement MRI, was 43.0% (95% confidence interval: 37.4, 48.6). The pooled length of follow-up was 12.3 months (95% confidence interval: 7.0, 17.6). The pooled incidence of major cardiac events during follow-up, defined as cardiac death, nonfatal myocardial infarction, or admission for heart failure, was 10.6% (95% confidence interval: 5.7, 15.5). The applied mixed effects model showed an absolute decrease of 1.7% in the incidence of major cardiac events during follow-up (95% confidence interval: 1.6, 1.9) with every 1% of increase in the myocardial salvage index. The heterogeneity between studies was considerable (τ = 21.3). Analysis of aggregated follow-up data after ST-segment elevation myocardial infarction suggests that the myocardial salvage index measured by T2-weighted and T1-weighted late gadolinium enhancement magnetic resonance imaging provides prognostic information on the risk of major cardiac events, but considerable heterogeneity exists between studies.

Introduction

In patients with ST-segment elevation myocardial infarction (STEMI), risk assessment should be performed early using information available at the time of presentation [1, 2]. The risk stratification should be recalibrated based on information obtained during hospitalization. Patients having a low risk of complications may be candidates for early discharge. Interventions reducing the risk of major cardiac events (MACE) should be considered in high-risk patients. The left ventricular ejection fraction is one of the strongest predictors of survival and should therefore be measured in all patients in addition to the assessment of clinical markers of high risk, including older age, fast heart rate, hypotension, Kilip class > 1, anterior myocardial infarction, previous myocardial infarction, elevated initial serum creatinine, and history of heart failure or peripheral arterial disease. Moreover, noninvasive testing for ischemia, such as exercise testing or pharmacological stress myocardial perfusion, should be performed before discharge in patients who did not undergo primary percutaneous intervention and may be performed in patients with non-infarct artery disease who have undergone successful primary percutaneous intervention of the infarct artery. Several other strategies, including the measurement of therapy efficiency with magnetic resonance imaging (MRI), have been proposed for risk assessment after STEMI; however, these strategies have not been adopted widely, mainly because of unclear performance characteristics [1, 2].

Therapy efficiency is assessed by MRI through quantification of the salvaged myocardium. Salvage of ischemic myocardium is the main objective of emergency therapy in STEMI, so the amount of salvaged myocardium is a valid marker for therapy efficiency [3]. Myocardial salvage is defined as the difference between the previously ischemic myocardium distal to the infarct artery, the so-called area at risk, and the final necrotic myocardium. To compare the therapy efficiency among infarcts of different sizes, the myocardial salvage index can be calculated as the proportion of non-necrotic myocardium inside the area at risk. For assessing the myocardial salvage index with MRI, T2-weighted MRI and T1-weighted late gadolinium enhancement MRI have most commonly been combined and used based on the assumptions that myocardial edema on T2-weighted MRI allows delineating the ischemic area at risk, and that myocardial necrosis on T1-weighted late gadolinium enhancement MRI can be used to delineate the final necrotic infarct size [4].

This meta-analysis was performed to summarize published data on the prognostic value of the myocardial salvage index measured by T2-weighted and T1-weighted late gadolinium enhancement MRI after STEMI.

Materials and methods

We reported this meta-analysis according to the PRISMA guidelines [5].

Eligibility criteria

The following inclusion criteria were applied: a) diagnosis of STEMI in the study patients; b) primary percutaneous intervention as emergency therapy; c) MRI in week 1 after STEMI with reporting of the myocardial salvage index measured by T2-weighted and T1-weighted late gadolinium enhancement MRI or, alternatively, the spatial extent of edematous left ventricular myocardium measured by T2-weighted MRI along with the spatial extent of left ventricular necrotic myocardium measured by T1-weighted late gadolinium enhancement MRI, so that it was possible to calculate the myocardial salvage index; d) usage of a volumetric unit compatible to the percentage of left ventricular myocardium for the measurement of edema and necrosis with MRI; e) reporting of the standard deviation, interquartile range, or confidence interval (CI) for the myocardial salvage index or the spatial extents of edema and necrosis measured by T2-weighted and T1-weighted late gadolinium enhancement MRI; f) follow-up assessment of MACE defined as cardiac death, nonfatal myocardial infarction, or admission for heart failure; and g) English, French, or German as publication language. We excluded animal studies.

The eligibility criteria were determined by the two reviewers and discussed in the research group on noninvasive cardiovascular imaging at Charité–Universitätsmedizin Berlin.

Search strategy

We searched in the electronic databases MEDLINE (via PubMed), EMBASE (via Ovid), and ISI Web of Science for references published between the inception of the databases and May 15, 2019. We used a search term that was adjusted according to the standards of the respective databases. The full adjusted search terms can be found in S1 Appendix A. The titles and abstracts of references revealed by the database search were screened, and a full-text review of remaining articles was performed. Additionally, we searched in the bibliographies of finally included studies and reviews revealed by the database search for studies that were missed by the database search.

The search term was determined by the two reviewers and discussed in the research group on noninvasive cardiovascular imaging at Charité–Universitätsmedizin Berlin. The search in the databases, the title and abstract review, and the full-text review were performed by one reviewer (BK); ambiguities were resolved by discussion with the second reviewer (MD).

Data extraction

A datasheet was predefined, and the following information was extracted from every included study: a) title, first author, publishing journal, and year of publication; b) purpose of the study as mentioned by the study authors; c) study design; d) number of included patients in every patient group; e) myocardial salvage index measured by T2-weighted and T1-weighted late gadolinium enhancement MRI or both the spatial extent of edematous left ventricular myocardium measured by T2-weighted MRI and the spatial extent of left ventricular necrotic myocardium measured by T1-weighted late gadolinium enhancement MRI so that the myocardial salvage index could be calculated; f) incidence of MACE during follow-up; and g) length of follow-up.

The datasheet was created by the two reviewers and discussed in the working group on noninvasive cardiovascular imaging at Charité–Universitätsmedizin Berlin. Data extraction was performed by one reviewer (BK); ambiguities were resolved by discussion with the second reviewer (MD).

Statistical analysis

The myocardial salvage index was calculated as the proportion of non-necrotic myocardium inside edematous myocardium if the studies did not state the myocardial salvage index measured by T2-weighted and T1-weighted late gadolinium enhancement MRI but provided the spatial extent of edematous left ventricular myocardium measured by T2-weighed MRI and the spatial extent of necrotic left ventricular myocardium measured by T1-weighted late gadolinium enhancement MRI.

Random effects models were used to calculate pooled values for the extracted clinical characteristics of the included study populations (age, gender, prevalence of diabetes, prevalence of hypertension, current smoking, and left ventricular ejection fraction), the time period between STEMI and MRI, the myocardial salvage index measured by T2-weighted and T1-weighted late gadolinium enhancement MRI, the length of follow-up, and the incidence of MACE during follow-up. Study was included as random effect in all random effects models to account for multiple observations per study. To evaluate the difference in the incidence of MACE between studies with a follow-up length of less than 12 months and studies with a follow-up length equal to or more than 12 months, we added the follow-up length as a categorical variable to the random effects model on the incidence of MACE during follow-up.

Afterwards, we evaluated whether a patient group’s mean myocardial salvage index measured by T2-weighted and T1-weighted late gadolinium enhancement MRI correlated with the incidence of MACE in this patient group during follow-up using a mixed effects model. The incidence of MACE during follow-up was used as the dependent variable. The myocardial salvage index was included as fixed effect. To correct for differences in the follow-up period, we included the centered length of follow-up as another fixed effect. Study was included as random effect, again to account for multiple observations per study, which was evaluated by applying Cochran’s Q test. On request of the reviewers, we performed a heterogeneity analysis. We suspected that a part of the between-study-heterogeneity could be explained by differences in the average cardiovascular risk of the study populations and the used MRI technique. We therefore included two main cardiovascular risk factors (mean age and prevalence of diabetes) and two main MRI technique parameters (timing of MRI and MRI interpretation) in the mixed effects model and compared the heterogeneity with that of the previous mixed effects model without the inclusion of these factors.

Each patient group’s result was weighted by the inverse of the squared estimated standard error of the mean of the myocardial salvage index. Statistical significance was assumed for p-values of 0.05 or smaller. We used R (version 3.6.0, 2019, R Foundation of Statistical Computing) for all calculations. Random and mixed effects models were generated using the metafor R package [6].

Statistics were planned in the research group on noninvasive cardiovascular imaging at Charité–Universitätsmedizin Berlin. Statistical analysis was performed by one reviewer (BK), and the results were discussed in the research group.

Risk of bias assessment

As we included studies with different study designs, we applied different quality assessment tools. According to a systematic review by Zeng et al. [7], the Cochrane Risk of Bias Tool [8] was used for randomized controlled trials, the Newcastle Ottawa Quality Assessment Scale [9] was used for nonrandomized cohort studies and case control studies, and an 18-item tool by Moga et al. [10] was used for case series studies. To test for the risk of publication bias across studies, Begg and Mazumdar’s rank correlation test with continuity correction and Egger’s regression test were used in the data on the myocardial salvage index in addition to visually inspecting a funnel plot for obvious asymmetry.

The risk of bias assessment was planned by the two reviewers. Application of the tools was done by one reviewer (BK); ambiguities were resolved by discussion with the second reviewer (MD).

Results

The search in the electronic databases revealed 1625 references. After removal of duplicates, we screened 1191 references for eligible studies. We excluded 1,019 records at the level of title and abstract. Another 163 references were excluded after the full-text review: 22 because the study patients did not have a STEMI diagnosis, 102 because T2-weighted and late gadolinium enhancement MRI was not done or not sufficiently reported to extract the myocardial salvage index, 38 because follow-up assessment of the incidence of MACE, defined as cardiac death, nonfatal myocardial infarction, or admission for heart failure, was not performed, and one study because of the language of publication. One eligibly study was found by searching the bibliographies of the included studies and reviews revealed by the database search. Thus, we finally included 10 studies [11-20] with a total of 2,697 patients: two randomized controlled trials [14, 15], six nonrandomized cohort studies [11, 13, 16–19], one case control study [12], and one case series study [20]. Fig 1 shows the PRISMA flow chart [5] summarizing the selection process. The extracted clinical characteristics of the study populations and the used MRI technique is summarized in Table 1.

Fig 1

PRISMA flow chart.

The search in the electronic databases revealed 1,625 references. A full-text review of 173 studies was performed. Ten studies were found to be eligible and were included in this meta-analysis. STEMI: ST-segment elevation myocardial infarction. MRI: magnetic resonance imaging, SD: standard deviation, IQR: interquartile range, CI: confidence interval, MACE: major cardiac events.

Table 1

Clinical characteristics of the study populations and the used MRI technique.

Clinical characteristics of the study populations	Pooled mean (95% CI)
Age, years	60.5 (95% CI: 58.4, 62.5)
Male, % of patients	80.3 (95% CI: 76.7, 84.0)
Diabetes, % of patients	22.7 (95% CI: 20.9, 24.7)
Hypertension, % of patients	51.7 (95% CI: 42.3, 61.2)
Dyslipidemia, % of patients	32.0 (95% CI: 24.8, 39.3)
Current smoking, % of patients	50.5 (95% CI: 43.5, 57.5)
Left ventricular ejection fraction, %	51.4 (95% CI: 49.3, 53.5)
MRI technique used in the studies	Pooled mean (95% CI)
Timing of MRI, days after STEMI	4.6 (95% CI: 3.2, 6.0)
T2-weighted MRI sequencea
T2-weighted dark-blood TSE/FSE with IR (STIR)	10 studies (2,697 patients)
T1-weighted late gadolinium enhancement MRI sequenceb
IR or PSIR using segmented FLASH readout (SPGR)	9 studies (2,393 patients)
IR with single-shot SSFP	1 study (304 patients)
MRI interpretationc
Signal intensity > 2 SD above remote myocardium for delineating myocardial edema on T2-weighted MRI and > 5 SD above remote myocardium for quantifying myocardial necrosis on T1-weighted late gadolinium enhancement MRI	6 studies (1,970 patients)
Manual contouring for both delineating myocardial edema on T2-weighted MRI and quantifying myocardial necrosis on T1-weighted late gadolinium enhancement MRI	4 studies (727 patients)
Type of gadolinium contrast agent
Gadobutrol	4 studies (1,404 patients)
Gadopentetate	3 studies (700 patients)
Gadoterate	2 studies (247 patients)
Gadobutrol or gadopentetate	1 study (346 patients)
Dose of gadolinium contrast agent
0.15 mmol/kg	5 studies (1,522 patients)
0.2 mmol/kg	4 studies (871 patients)
0.1 mmol/kg	1 study (304 patients)

MRI: magnetic resonance imaging, STEMI: ST-segment elevation myocardial infarction, MACE: major cardiac events, SD: standard deviation, TSE: turbo spin echo, FSE: fast spin echo, IR: inversion recovery, STIR: short tau inversion recovery, SSFP: steady state free precession, ACUTE: Acquisition for Cardiac Unified T2 Edema, PSIR: phase sensitive inversion recovery, FLASH: fast low angle shot, SPGR: spoiled gradient echo, MD: magnetization driven, FWHM: full width at half maximum, OAT: Otsu’s Automated Technique, FACT: automated feature analysis and combined thresholding infarct sizing.

aCategories: T2-weighted dark-blood TSE/FSE with IR (STIR), T2-prepared bright-blood single-shot balanced SSFP, hybrid TSE-SSFP (ACUTE), BLADE k-space coverage for dark-blood TSE.

bCategories: IR or PSIR using segmented FLASH readout (also referred to as SPGR), IR or PSIR with single-shot SSFP, MD steady state FLASH.

CCategories: signal intensity > 2 SD above remote myocardium, signal intensity > 3 SD above remote myocardium, signal intensity > 5 SD above remote myocardium, manual threshold, FWHM algorithm, manual contouring, OAT, FACT algorithm, Heiberg’s method.

The random effects models revealed a pooled myocardial salvage index measured by T2-weighted and T1-weighted late gadolinium enhancement MRI of 43.0% (95% confidence interval: 37.4, 48.6), a pooled length of follow-up of 12.3 months (95% CI: 7.0, 17.6), and a pooled incidence of MACE during follow-up of 10.6% (95% CI: 5.7, 15.5). Fig 2 shows the mean myocardial salvage index for all patient groups sorted by the incidence of MACE during follow-up in a forest plot.

Fig 2

Forest plot.

Mean myocardial salvage index, length of follow-up, and the incidence of MACE during follow-up for all patient groups. MACE: major cardiac events.

The mixed effects model showed a negative correlation between a patient group’s mean myocardial salvage index measured by T2-weighted and T1-weighted late gadolinium enhancement MRI and the incidence of MACE in this patient group during follow-up. There was an absolute decrease of 1.7% in the incidence of MACE during follow-up (95% CI: 1.6, 1.9) with every 1% of increase in the myocardial salvage index measured by T2-weighted and T1-weighted late gadolinium enhancement MRI. The heterogeneity between studies was considerable (τ = 21.3). Model details can be found in Table 2.

Table 2

Model parameters of the mixed effects model.

Dependent variable
Incidence of MACE during follow up, % of patients
Random effects
Factor	τ2	τ	Cochran’s Q test for heterogeneity
			p
study	452.32	21.27	< 0.001
Fixed effects
Factor	Estimate	p	Lower 95% CI	Upper 95%CI
(Intercept)	84.56	< 0.001	70.24	98.88
Myocardial salvage index, %	-1.73	< 0.001	-1.85	-1.60
Centered length of follow-up, monthsa	0.42	0.593	-1.13	1.98

MACE: major cardiac events, CI: confidence interval.

aThe centered length of follow-up was included into the model to correct for differences in the follow-up length among studies. There was a 9.5% difference in the incidence of MACE during follow-up (95% CI: 1.2, 17.8; P = 0.024) between studies with a follow-up length of less than 12 months and studies with a follow-up length equal to or more than 12 months.

The inclusion of two main cardiovascular risk factors (mean age and prevalence of diabetes) and two main MRI technique parameters (timing of MRI and MRI interpretation) in the model for the exploration of heterogeneity reduced the unexplained standard deviation between studies by 65.3% to τ = 7.4. The details of this adjusted model can be found in S4 Table.

The results of the risk of bias assessment in individual studies are summarized in S2 Table. In one study [12], the quality is reduced by the retrospective design and the uncertainty whether the dropouts were similarly distributed in the within-study groups. In four other studies [11, 15, 16, 19], the quality is reduced by a short follow-up length of 6 months. We did not find evidence of publication bias across studies in the data on the myocardial salvage index measured by T2-weighted and T1-weighted late gadolinium enhancement MRI after STEMI by applying Begg and Mazumdar’s rank correlation test (z = -1.67, P = 0.097) and Egger’s regression test (t = -1.17, P = 0.255) as well as by visually inspecting the created funnel plot for obvious asymmetry (S1 Fig).

Discussion

This study was conducted to summarize published data on the prognostic value of the myocardial salvage index measured by T2-weighted and T1-weighted late gadolinium enhancement MRI after STEMI. Meta-regression analysis of aggregated published data shows that a high myocardial salvage index measured by T2-weighted and T1-weighted late gadolinium enhancement MRI in week 1 after STEMI is associated with a low incidence of MACE during follow-up and vice versa with considerable heterogeneity between studies.

To the best of our knowledge, no previous meta-analysis has summarized published data on the prognostic value of the myocardial salvage index measured by T2-weighted and T1-weighted late gadolinium enhancement MRI after STEMI. Two clinical studies, which are included in this meta-analysis, compared the myocardial salvage index measured by T2-weighted and T1-weighted late gadolinium enhancement MRI between patients with and without occurrence of MACE during follow-up. Eitel et al. and de Waha et al. found a significant difference in the myocardial salvage index between patients with and without MACE during follow-up [12, 14]. De Waha et al. additionally identified the myocardial salvage index as an independent predictor for the incidence of MACE after adjusting for all traditional outcome parameters [12].

As stated in the introduction, the current American College of Cardiology/American Heart Association guideline for STEMI and the current European Society of Cardiology guideline for STEMI recommend risk stratification in all patients hospitalized for STEMI. As a part of the risk assessment, the resting left ventricular ejection fraction should always be measured before discharge, as it is one of the strongest prognostic predictors [1, 2]. Measurement of the resting left ventricular ejection fraction and valve function along with left ventricular thrombus assessment is most commonly performed by echocardiography [21]; however, cardiac cine MRI sequences can also be applied for this purpose [22]. The combination of cine sequences with T2-weighted and T1-weighted late gadolinium enhancement MRI may be used to assess the left ventricular ejection fraction, valve function, existence of a left ventricular thrombus, and the myocardial salvage index as additional prognostic parameter in one examination. Whether additional routine assessment of the myocardial salvage index using cardiac MRI improves the long-term outcome in STEMI patients by more effectively identifying patients who need intensified support or interventions could be studied in a randomized controlled trial.

This meta-analysis has limitations. First, a review protocol was not registered a priori, and so the likelihood that our post hoc decisions are biased is increased [5]. Second, one reviewer conducted the systematic search in the electronic databases, the data extraction, statistical analysis, and risk of bias assessment. This resulted in a higher likelihood of errors in these processes [5, 23]. Third, whether myocardial edema measured by T2-weighted MRI accurately delineates the previously ischemic area at risk is a controversial discussion; thus, whether the myocardial salvage index measured by T2-weighted and T1-weighted late gadolinium enhancement MRI provides an exact measure of the proportion of salvaged myocardium inside the previously ischemic area at risk is unclear [24]. Fourth, we decided against excluding study designs from our analysis, which increases the risk of bias in the analysis; however, we did not find publication bias in the data. Last, the statistical analysis revealed considerable heterogeneity between the included studies. Therefore, exact thresholds of the myocardial salvage index for a low or high risk of MACE cannot be provided.

As a large part of the between-study heterogeneity could be reduced by including cardiovascular risk factors and MRI technique parameters in the meta-regression model, the myocardial salvage index should be interpreted in conjunction with cardiovascular risk factors and the used MRI technique when applied for prognostic purposes. T2- and T1-weighted mapping MRI, as a relatively new and increasingly used alternative to conventional T2-weighted and T1-weighted late gadolinium enhancement MRI, allows a more consistent and less subjective delineation of edematous and fibrotic myocardium and may therefore reduce heterogeneity induced by differences in the used MRI technique between study sites in the future [25]. We decided to search for studies that measured myocardial oedema and necrosis with conventional T2-weighted and T1-weighted late gadolinium enhancement MRI, as only a few studies have applied mapping MRI for measuring the myocardial salvage index so far, and we were aiming to include enough data for a valid meta-regression analysis.

In conclusion, analysis of aggregated follow-up data after STEMI suggests that the myocardial salvage index measured by T2-weighted and T1-weighted late gadolinium enhancement MRI provides prognostic information on the risk of MACE, but considerable heterogeneity exists between studies.

Search terms.

(DOCX)

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Raw data.

(DOCX)

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Risk of bias in individual studies.

(DOCX)

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PRISMA checklist.

(DOCX)

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Exploration of heterogeneity.

(DOCX)

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Funnel plot.

(DOCX)

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30 Oct 2019

PONE-D-19-26741

Prognostic value of the myocardial salvage index measured by T2-weighted and T1-weighted late gadolinium enhancement magnetic resonance imaging after ST-segment elevation myocardial infarction: A systematic review and meta-regression analysis

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Reviewer #1: est map should be provided. As an important element in meta-analysis, the forest map describes the combined effect size and confidence interval for multiple studies.

2. You have mentioned that there was considerable heterogeneity between studies (The last line, page2). Therefore, regress analysis should be used to figure out the reason for heterogeneity.

3. There are a significant number of studies about prognosis after ST-elevation myocardial infarction after 2014, what is the reason that none of these is included in the current study?

Minor weaknesses:

1、 In Page4 line24, you said that your search deadline wass May 15, 2019. What is the search starting date?

2、 In the article you have used different effect models for different parameters. How do you determine when to use a random model or a fixed model？

3、 In order to prove that there is no publication bias in the included article, a funnel chart or other chart proof should be provided.

4、 Limitations should be grouped into a single paragraph.

5、 There are minor linguistic issues which warrant a linguistic revision by a native speaker.

Reviewer #2: The authors analyzed the published data on the prognostic value of the myocardial salvage index measured by T2-weighted and T1-weighted late gadolinium enhancement MRI after STEMI. The main results are clearly presented. However, I have some concerns in this paper listed below.

1) These are studies for examining the prognostic value of the myocardial salvage index, but the patients are highly selected from nonrandomized cohort studies and case control studies. I would urge the authors to present the more detailed information on diagnoses.

2) As the authors indicated, the heterogeneity may partly be explained by differences in MRI sequences. The authors should consider that the studies chosen rely on several different settings for MRI, which all have their own contrast-agent type and dose. Furthermore, the authors are unable to choose with age- and sex-matched studies.

3) The pooled length of follow-up was 12.3 months. The authors need also subgroup analyses between early period and late period (e.g. more than 12 months and less than 12 months).

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Reviewer #1: No

Reviewer #2: No

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17 Dec 2019

Academic Editor

Comment #1: In particular, I agree with reviewer 1 that the manuscript would be enhanced by a forest plot summarising the results of the analysis, as is provided in most meta-analyses.

We agree with you and have added a forest plot in the manuscript, which shows the mean myocardial salvage index measured by T2-weighted and T1-weighted late gadolinium enhancement magnetic resonance imaging (MRI) with confidence interval for every included patient group and the pooled value with confidence interval across all patient groups. To visualize the main result of our meta-regression analysis (negative correlation between a patient group’s mean myocardial salvage index and the incidence of major cardiac events [MACE] in this patient group during follow-up), we added the incidence of MACE during follow-up to the forest plot and sorted the patient groups by the incidence of MACE. Readers can now visually perceive the increasing incidence of MACE during follow-up with decreasing myocardial salvage index, as well as the considerable heterogeneity between studies. We are very thankful for this valuable comment.

Formatting and requirements of the journal.

For the sake of conciseness, we do not repeat here your advice on formatting and how to meet the journal’s requirements, but we have strictly followed your instructions. In particular, we have reformatted the manuscript according to the PLOS ONE style template, detailed the reasons for excluding articles, discussed the quality assessment of individual studies in the main text, added a sentence to the statement on competing interests, removed the funding-related text from the main text, and uploaded our figures to the Preflight Analysis and Conversion Engine. Thank you for the advice on how to meet the criteria for publication.

Reviewer #1

Comment #1: Forest map should be provided. As an important element in meta-analysis, the forest map describes the combined effect size and confidence interval for multiple studies.

Thank you for your suggestion. We have added a forest plot. Please refer to our answer to comment #1 of the Academic Editor for further details.

Comment #2: You have mentioned that there was considerable heterogeneity between studies (The last line, page2). Therefore, regress analysis should be used to figure out the reason for heterogeneity.

We agree with you and have added a heterogeneity analysis. We have included two main cardiovascular risk factors (mean age and prevalence of diabetes) and two main MRI technique parameters (timing of MRI and MRI interpretation) in the meta-regression model, which reduced the unexplained standard deviation between studies τ by 65 %.

Comment #3. There are a significant number of studies about prognosis after ST-elevation myocardial infarction after 2014, what is the reason that none of these is included in the current study?

We were also surprised that we did not find an eligible study published between 2015 and May 15, 2019. We found studies published during this period that performed MRI in week 1 after ST-segment elevation myocardial infarction (STEMI) with reporting of the myocardial salvage index measured by T2-weighted and T1-weighted late gadolinium enhancement MRI or sufficient data to calculate the myocardial salvage index; however, none of these studies assessed and stated the incidence of MACE during follow-up defined as cardiac death, nonfatal myocardial infarction, or admission for heart failure. On the other hand, there are prognostic studies published during this period that did not perform and report the results of T2-weighted and T1-weighted late gadolinium enhancement MRI after STEMI.

Minor weakness #1: In Page4 line24, you said that your search deadline was May 15, 2019. What is the search starting date?

We searched the databases from their date of inception until May 15, 2019. The start of the search is now specified in the text.

Minor weakness #2: In the article you have used different effect models for different parameters. How do you determine when to use a random model or a fixed model?

If a study provided results for sub-groups, we included these results separately in our analysis. We did not assume these observations to be independent from each other because of similar study methods and therefore included study as random effect into all models. Consequently, we used random effects models instead of fixed effects models to calculate pooled values and a mixed effects model instead of a fixed effects model for the meta-regression analysis. In the manuscript, we did not mention how we chose the models, but we have now added it as a result of this helpful comment.

Minor weakness #3: In order to prove that there is no publication bias in the included article, a funnel chart or other chart proof should be provided.

We agree with you and have added a funnel plot, which we inspected for apparent asymmetry.

Minor weakness #4: Limitations should be grouped into a single paragraph.

Thank you. We have done so accordingly.

Minor weakness #5: There are minor linguistic issues which warrant a linguistic revision by a native speaker.

Thank you for the advice. We have availed of professional proofreading services by an editing company, which helped to improve our paper considerably.

Reviewer #2

Comment #1: These are studies for examining the prognostic value of the myocardial salvage index, but the patients are highly selected from nonrandomized cohort studies and case control studies. I would urge the authors to present the more detailed information on diagnoses.

Thank you for the advice. We extracted details on included patients (age, gender, prevalence of diabetes, hypertension, dyslipidemia, current smoking, and left ventricular ejection fraction) and the used MRI technique (timing of MRI, applied MRI sequences, MRI interpretation, type of contrast agent, and dose of contrast agent) from every included study and summarized these information in a newly created table.

Comment #2: As the authors indicated, the heterogeneity may partly be explained by differences in MRI sequences. The authors should consider that the studies chosen rely on several different settings for MRI, which all have their own contrast-agent type and dose. Furthermore, the authors are unable to choose with age- and sex-matched studies.

We agree that differences in the MRI settings and study populations among the included studies should be considered. The revised manuscript thus includes a heterogeneity analysis. We evaluated whether the inclusion of two main cardiovascular risk factors (age and diabetes) and two main MRI technique parameters (timing of imaging and MRI interpretation) in the meta-regression model reduced the between-study heterogeneity, which it did by 65%. We agree that differences in sex distribution, contrast type, and contrast dose may also explain a part of the heterogeneity. However, we focused on the mentioned parameters and did not include all available parameters in the heterogeneity analysis to avoid overfitting of the meta-regression model.

Comment #3: The pooled length of follow-up was 12.3 months. The authors need also subgroup analyses between early period and late period (e.g. more than 12 months and less than 12 months).

We share your view that the effect of the length of follow-up on the incidence of MACE during follow-up should be taken into account. Therefore, we have included the centered length of follow-up as a fixed effect into the meta-regression analysis to correct for differences in the follow-up length among studies. We have added a subgroup analysis to compare the incidence of MACE in studies with a follow-up length of less than 12 months with the incidence of MACE in studies with a follow-up length of 12 months or longer.

23 Jan 2020

Prognostic value of the myocardial salvage index measured by T2-weighted and T1-weighted late gadolinium enhancement magnetic resonance imaging after ST-segment elevation myocardial infarction: A systematic review and meta-regression analysis

PONE-D-19-26741R1

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Reviewer #1: Yes: Minjie Lu

Reviewer #2: No

28 Jan 2020

PONE-D-19-26741R1

Prognostic value of the myocardial salvage index measured by T2-weighted and T1-weighted late gadolinium enhancement magnetic resonance imaging after ST-segment elevation myocardial infarction: A systematic review and meta-regression analysis

Dear Dr. Dewey:

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