Prognostic implications of unrecognized myocardial infarction and periprocedural myocardial injury on cardiac magnetic resonance imaging in patients with chronic coronary syndrome

This study sought to evaluate the prognostic implications of the presence of preprocedural unrecognized myocardial infarction (UMI) and periprocedural myocardial injury (PMI) evaluated by delayed gadolinium enhancement cardiac magnetic resonance (DE-CMR) in patients with chronic coronary syndrome (CCS) undergoing elective percutaneous coronary intervention (PCI). We enrolled 250 CCS patients scheduled for elective PCI. UMI was defined as the presence of late gadolinium enhancement (LGE) detected by pre-PCI CMR in the region without medical history of revascularization and/or MI. Periprocedural new occurrence or increased volume of LGE in the target territory detected by post-PCI CMR (PPL) were used to assess PMI. In the final analysis of 235 patients, UMI and PPL were detected in 43 patients (18.3%) and 45 patients (19.1%), respectively. During follow-up for a median of 2.2 years, major adverse cardiac events (MACE) occurred in 31 (13.2%) patients. On multivariable analysis, UMI and PPL remained as significant predictors of MACE after adjusting confounding factors (HR 4.62, 95% CI 2.24–9.54, P < 0.001, HR 2.33, 95% CI 1.11–4.91, P = 0.026). In patients with CCS who underwent elective PCI, UMI and PPL were independent predictors of worse outcomes. UMI and PPL on DE-CMR might provide additional potential insight for the risk stratification of patients undergoing elective PCI.

Ventricular volumes, ejection fraction, and LV mass were derived by contouring endo-and epicardial borders on the short-axis cine images.LV mass and volumes were calculated from Simpson's rule using CMR data 11 .The presence of MI was assessed on DE-CMR images by identifying regions of contrast enhancement with an ischemic distribution pattern as subendocardial or transmural hyperenhancement.The amount of LGE was assessed using a threshold of 5 standard deviations above the signal intensity of normal myocardium as proposed by current recommendations 12 .UMI was defined as the presence of LGE detected by pre-PCI CMR in the lesion without a medical history of revascularization and/or MI, and PMI was assessed by a new occurrence or increased volume of LGE in the target territory after revascularization (PPL) in this study.To assess the occurrence of periprocedural new or additional LGE adjacent to or overlapping with UMI of target territory infarct after revascularization, pre-PCI and post-PCI scans were read side by side in all cases to assess the difference between UMI and PPL.
Cardiac biomarker elevation after PCI.Blood samples for serial measurements of high-sensitivity cardiac troponin I level (hs-cTnI) and creatine kinase-MB (CK-MB) were collected before and 6, 12, 24, 48 h after PCI completion.Hs-cTnI was measured using the ARCHITECT i2000SR STAT hs-cTnI assay (Abbott Laboratories, North Chicago, IL, USA); the lower limit of detection was 1.5 ng L −1 and the 99th percentile upper reference limit (URL) is 26 ng L −1 according to the test obtained in healthy population with cardiovascular risk < 10%.
Assessment of outcomes.Patients were followed up for the occurrence of MACE, defined as cardiac death, nonfatal MI, hospitalization for congestive heart failure, stroke, and unplanned late revascularization requiring hospitalization after the index PCI.Cardiac death was defined as any death preceded by acute valvular regurgitation, decompensated heart failure, ventricular arrhythmia, or new acute MI or death preceded by mechanical complications of MI.Clinical endpoints were determined by the blinded assessment of hospital records or via telephone interviews.Time to event was calculated as the period between pre-PCI CMR study and the first occurrence of MACE.Patients without MACE were censored at the time of the last follow-up.

Statistical analysis.
Statistical analysis was performed using SPSS version 25.0 (SPSS, Inc., Chicago, IL, USA) and R version 4.1.2(The R Foundation for Statistical Computing, Vienna, Austria) software.Categorical data are expressed as absolute frequencies and percentages and were compared by the χ 2 or Fisher's exact tests.Continuous variables are expressed as mean ± standard deviation for normally distributed variables or as median (25th-75th percentile) for non-normally distributed variables and were compared using Student's t-tests and the Mann-Whitney U-test, respectively.Qualitative variables were compared using Cohen's kappa (κ) to quantify the level of agreement between infarct size assessment by cardiac biomarkers and DE-CMR.Survival curves were estimated using Kaplan-Meier estimates and were compared using log-rank tests.A Cox proportional hazards regression model was used to identify independent predictors of MACE.In the multivariate analysis, model 1 was adjusted for age and sex, and model 2 was adjusted for the covariates with P < 0.05.A collinearity index was used for checking linear combinations among covariates, and Akaike information criterion for avoiding overfitting.A two-sided P < 0.05 was considered statistically significant.

Results
Baseline patient characteristics, angiographical and CMR findings.Of 250 initially enrolled patients, the final analysis was conducted on 235 patients (Fig. 1).Patients underwent pre-PCI CMR within a median of 4 (2-7) days before PCI and post-PCI CMR within a median of 12 (7-18) days after PCI completion.www.nature.com/scientificreports/MI (P = 0.017, respectively), whereas there was no significant difference in the prevalence of prior history of MI between the patients with and without PPL (P = 0.14, respectively).

Discussion
The current study evaluated the prevalence or occurrence of UMI and PPL simultaneously using serial DE-CMR examinations and demonstrated the prognostic significance of these entities in CCS patients undergoing elective PCI in the same cohort for the first time.
The major findings of our studies are as follows: (1) the prevalence of UMI was 18.3%, and the occurrence of PPL was 19.1%; (2) UMI was significantly associated with atherosclerotic risk factors, including higher BSA, the prevalence of DM, SYNTAX Score, LVMI, and lesion stenosis; (3) the presence of UMI in the lesion downstream the target vessel was a significant factor to predict PPL; (4) the presence of UMI and the occurrence of PPL were www.nature.com/scientificreports/independently associated with worse outcomes after elective PCI, whereas cardiac marker elevation following PCI was not a significant predictor of MACE.
Considering the prognostic impact of UMI and PPL shown in the present study, these two factors might be relevant to outcomes after elective PCI and could play important roles as non-negligible confounding factors of adverse events because these factors are not routinely worked up in the clinical practice.

Association between UMI and PPL.
We present that UMI was significantly associated with atherosclerotic risk factors and that PCI performed for the lesion related to previous UMI was a significant factor in the occurrence of PPL, whereas PCI for lesions related to previously recognized MI was not.The exact mechanism of this finding remains to be determined, since the mechanism of UMI itself has not been fully established.We assume that target lesion plaque instability, stenosis severity, or microvascular dysfunction associated with UMI might at least partly explain the link between UMI and subsequent PPL.Increased atherosclerotic burden is another possible associated factor, as the distal coronary embolization of intracoronary thrombus and/or lipid-core plaque contents contribute to no-reflow phenomenon 13 .Undertreated atherosclerotic factors in the patients with UMI might also contribute to periprocedural myocardial injury presented by PPL.Previous studies reported that modifiable cardiovascular risk factors are strongly associated with the presence of UMI, whereas suspected CAD patients with UMI had a lower rate of optimal or guideline directed medical therapy compared to the patients with clinically recognized MI 1 .Since all the patients enrolled in this study were scheduled for elective PCI, they received guideline-directed medical therapy at the time of the enrollment.However, no secondary preventive therapy was initiated before the study enrollment in patients with UMI, as these patients are clinically unrecognized.Further large prospective studies are needed to test these hypotheses.
Relationship between UMI/PPL and prognosis after PCI.Importantly, UMI and PPL were independently associated with MACE, suggesting that even a small unrecognized and periprocedural infarction could be associated with MACE when detected as an infarct scar by DE-CMR.When the analysis is exploratorily limited for the MACE subgroup by excluding unplanned late revascularization, UMI and PPL were still found to be independently and significantly associated with worse outcomes (UMI: HR 4.89, 95% CI 1.58-15.2,P = 0.006; PPL: HR 9.83, 95% CI 2.95-32.8,P < 0.001, respectively), although the number of were small.In accordance with a previous study 9 , we report that PPL might provide better prognostic efficacy than cardiac biomarker elevation.We further show a moderate correlates with post-PCI cardiac biomarker elevations in the present study.Although cardiac biomarkers are easily accessible and available for detecting myocardium damage, it has been reported that post-PCI cardiac biomarker elevation may not reflect the loss of viable myocardium accurately, since post-PCI cardiac biomarker elevation is very sensitive but not specific, particularly for high-sensitivity cardiac troponin 14,15 .In this context, DE-CMR is the gold-standard imaging technique for the detection and quantification of irreversible myocardial injury.Further large prospective studies are required to  test our hypothesis for elucidating the mechanisms of the prognostic impact and association of UMI and PPL with worse outcomes.

Potential clinical implications.
It was recently reported that an initial invasive strategy failed to reduce ischemic events and improve survival in patients with CCS compared with an initial conservative strategy 16 , raising the debate on coronary revascularization in CCS.While such studies might favor conservative strategies in CCS, the possible reasons behind these findings should be elucidated before the strict preference of a conservative approach.A variety of patient and lesion characteristics and periprocedural factors have been demonstrated to be associated with worse outcomes in CCS patients undergoing PCI and might confound the results against invasive strategies 17,18 .The result of current study adds to these factors, suggesting that UMI and PPL detected by DE-CMR in patients who underwent elective PCI might provide significant prognostic information over conventional risk stratification.The current guidelines for secondary prevention after MI have focused on nonfatal MI, death, and heart failure hospitalization as key events to initiate the recommended treatment.Patients with UMI are precluded from the recommended aggressive preventive management strategy, leaving them undertreated.Although serial DE-CMR tests are not routinely worked up in clinical practice, and it remains elusive whether any specific intervention or aggressive treatment for patients with UMI and/or PPL improves prognosis after PCI, this substudy suggests UMI and PPL can be used as a risk stratification tool for patients undergoing revascularization since even a minute unrecognized and/or periprocedural infarction were associated with MACE.Further prospective studies are needed to test the hypothesis suggested by this study and identify patients in whom serial CMR examinations provide benefit in routine clinical practice since this hypothesis, based on our study, is merely speculative.It is also warranted to test if the primary intense intervention of conventional risk factors associated with the presence of UMI shown in this study could reduce the development of UMI, since undetected silent ischemia has been prevailingly considered to be the vital risk for adverse events in CCS patients 1,19 .

Study limitations.
The results of the present study should be interpreted with consideration for several significant limitations.This study included a relatively small number of patients from a single center which precluded extensive subgroup or powered multivariable analyses.Due to the small number of events and unadjusted confounders, our results that UMI and PPL were significant prognostic factors independent of conventional risk factors should not be taken as a decisive finding and should be tested in the future studies.Second, rigorous exclusion criteria and the CMR protocol limited the number of study patients and may have resulted in a certain level of selection bias, which may limit the generalizability of the present study.Most of the patients were male and patients with impaired EF were excluded.It should also be noted that, unlike previous studies, this study did not exclude patients with a history of MI to investigate the effects of recognized and unrecognized MI on the occurrence of PPL and subsequent events.Therefore, the possibility of underestimating the presence of UMI cannot be ruled out.Third, partial volume effects and cardiac motion might have affected the results, although the measurement reliability was acceptable for assessing LGE with the current spatial resolution of CMR.Furthermore, although CMR imaging was performed after a median of 12 (7-18) days of PCI, different time windows of CMR should be evaluated in future studies since changes in LGE volume over time might affect the diagnostic accuracy in detecting small periprocedural infarcts.Fourth, the assessment of involved myocardial segments by a coronary stenosis was determined by the coronary anatomy, and no objective method was applied, although there are no universally accepted criteria for this purpose.Fifth, T2 STIR was not performed in the present study, which may be useful to differentiate periprocedural infarcts after PCI.Finally, it must be taken into consideration that the potentially poor symptom recognition by patients with UMI may also contribute to lower events rates during the follow-up period, although this hypothetical possibility is more likely to result in an increase in the MACE risk of patients with UMI.

Conclusions
UMI and PPL evaluated by serial DE-CMR examinations before and after elective PCI were significantly associated with worse outcomes independent of conventional risk factors in patients with CCS.UMI and PPL detected by DE-CMR might provide additional potential insight for the risk stratification of patients undergoing elective PCI in this population.

Figure 1 .
Figure 1.Study flow chart.Figure shows the enrollment process with a total of 235 patients in the final analysis.

Figure 2 .
Figure 2. Representative cardiac magnetic resonance images and angiographies (a) of a patient with unrecognized myocardial infarction; (b) of a patient with periprocedural new occurrence of LGE after PCI.

Figure 3 .
Figure 3. Kaplan-Meier analysis for the incidence of MACE stratified by (a) the presence of UMI; (b) the occurrence of PPL.Event-free survival was significantly worse in patients with UMI and PPL.

Table 1 .
No significant CMR-related complications were observed and stent implantation was performed successfully in all patients for the final analysis.Baseline patient characteristics, angiographic and CMR findings of 235 patients are summarized in Table1, and the detailed data set according to the presence or absence of UMI and PPL are shown in Supplemental Table1.The mean age of the study population was 67 years, 15.3% were women, and the median left ventricular ejection fraction (LVEF) was 62 (54-68) %.A total of 40 (17.0%)patients had a prior history of MI.Compared to patients without UMI, those with UMI were less likely to have a history of The baseline clinical characteristics.EDV end diastolic volume, EF ejection fraction, ESV end systolic volume, FFR fractional flow reserve, HbA1c glycated hemoglobin, Hs-cTnI high-sensitivity troponin I, LAD left anterior descending coronary artery, LCx left circumflex coronary artery, LDL-chol low density lipoprotein cholesterol, LGE late gadolinium enhancement, LVMI left ventricular mass index, NT-proBNP N-terminal pro-B-type natriuretic peptide, OMI old myocardial infarction, PCI percutaneous coronary intervention, RCA right coronary artery. Vol:.(1234567890) During the follow-up period of 2.2 (1.4-3.0)years, 31 of 235 patients (13.2%) reached the composite endpoint, including 1 cardiovascular death (0.4%), 6 nonfatal MI (2.6%), 3 hospitalization for congestive heart failure (1.3%), 2 stroke (0.9%), and 19 (8.1%) unplanned late revascularization.Cox proportional hazard analysis revealed that the presence of UMI and the occurrence of PPL were independent predictors of MACE (Model 1 (adjusted by age and male sex): HR 4.62, 95% CI 2.24-9.54,P < 0.001; HR 2.33, 95% CI 1.11-4.91,P = 0.026; Model 2 (adjusted by EF and Syntax score): HR 4.62, 95% CI 2.23-9.57,P < 0.001; HR 2.33, 95% CI 1.11-4.93,P = 0.026) (Table

Table 2 .
Univariate and multivariate logistic regression analysis for parameters that correlated with UMI.DM diabetes mellitus, DS diameter stenosis, EF ejection fraction, FFR fractional flow reserve, Hs-cTnI highsensitivity troponin I, LVMI left ventricular mass index, PCI percutaneous coronary intervention.† Categorical variables.

Table 3 .
Univariate and multivariate logistic regression analysis for parameters that correlated with PPL.DM diabetes mellitus, FFR fractional flow reserve, HL hyperlipidemia, HT hypertension, NT proBNP N-terminal pro-B-type natriuretic peptide, OMI old myocardial infarction, PCI percutaneous coronary intervention, UMI unrecognized MI. † Categorical variables.

Table 4 .
Cox proportional-hazard regression analysis of MACE.DM diabetes mellitus, EF ejection fraction, HL hyperlipidemia, Hs-cTnI high-sensitivity troponin I, HT hypertension, LGE late gadolinium enhancement, PCI percutaneous coronary intervention, PPL periprocedural new occurrence or increased volume of LGE in the target territory after revascularization, UMI unrecognized myocardial infarction.