Scar border zone mass and presence of border zone channels assessed with cardiac magnetic resonance imaging are associated with ventricular arrhythmia in patients with ST-segment elevation myocardial infarction

Abstract

Aims

Late gadolinium enhancement cardiac magnetic resonance (CMR) permits characterization of left ventricular ischaemic scars. We aimed to evaluate if scar core mass, border zone (BZ) mass, and BZ channels are risk markers for subsequent ventricular arrhythmia (VA) in ST-segment elevation myocardial infarction (STEMI).

Methods and results

A sub-study of the DANish Acute Myocardial Infarction-3 multi-centre trial and Danegaptide phase II proof-of-concept clinical trial in which a total of 843 STEMI patients had a 3-month follow-up CMR. Of these, 21 patients subsequently experienced VA during 100 months of follow-up and were randomly matched 1:5 with 105 controls. A VA event was defined as: ventricular tachycardia, ventricular fibrillation, or sudden cardiac death. Ischaemic scar characteristics were automatically detected by specialized software. We included 126 patients with a median left ventricular ejection fraction of 51.0 ± 11.6% in cases with VA vs. 55.5 ± 8.5% in controls (P = 0.10). Cases had a larger mean BZ mass and more often BZ channels compared to controls [BZ mass: 17.2 ± 10.3 g vs. 10.3 ± 6.0 g; P = 0.0002; BZ channels: 17 (80%) vs. 44 (42%); P = 0.001]. A combination of ≥17.2 g BZ mass and the presence of BZ channels was five times more prevalent in cases vs. controls (P ≤ 0.00001) with an odds ratio of 9.40 (95% confidence interval 3.26–27.13; P ≤ 0.0001) for VA. This identified cases with 52% sensitivity and 90% specificity.

Conclusion(s)

Scar characterization with CMR indicates that a combination of ≥17.2 g BZ mass and the presence of BZ channels had the strongest association with subsequent VA in STEMI patients.

ClinicalTrials.gov

Unique identifier: NCT01435408 (DANAMI 3-iPOST and DANAMI 3-DEFER), NCT01960933 (DANAMI 3-PRIMULTI), and NCT01977755 (Danegaptide).

Graphical Abstract

Flowchart in the study population from ST-segment myocardial infarction to arrhythmic endpoint.

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Introduction

Advances in both medical and interventional strategies have improved outcomes in patients presenting with ST-segment elevation myocardial infarction (STEMI). However, morbidity and mortality remain substantial.¹ Risk stratification of scar-related ventricular arrhythmia (VA) after MI is critical, but currently difficult. Reduced left ventricular ejection fraction (LVEF) is considered the gold standard marker for identifying patients at arrhythmogenic risk post-STEMI.² It is the main indication for prophylactic implantable cardioverter defibrillator (ICD).² However, a universal measure of cardiac function does not give direct information about the underlying arrhythmic substrate, and the accuracy in predicting VA in STEMI remains suboptimal.³ Consequently, a substantial number of patients with significant VA post-STEMI, including sudden cardiac death (SCD), do not receive an ICD, and a significant proportion of patients with a prophylactic ICD may never experience VA or relevant ICD therapy.

A detailed characterization of the ischaemic scar and its components, core mass, border zone (BZ) mass, and BZ channels (corridors of BZ that cross core scar and connect two areas of healthy tissue), can be assessed after STEMI using a novel late gadolinium enhancement cardiac magnetic resonance (LGE-CMR) technique, and individual components have been shown to be potential risk markers of future arrhythmic events.⁴ BZ channels may correlate well with the electrical substrate of slow conductivity or VA isthmuses identified with voltage mapping during scar-related VA ablation procedures and consequently correspond with the arrhythmogenic substrate of the scar.⁵ However, definite BZ characteristics and their association with VA are currently unclear.

In this retrospective LGE-CMR sub-study of two STEMI populations, we hypothesized that detailed arrhythmogenic BZ substrate characterization 3 months after STEMI could identify risk markers for subsequent VA and may therefore contribute to risk stratification in patients surviving a STEMI.

Methods

Study design

This study is a retrospective, nested, case-control sub-study of the DANish Study of Optimal Acute Treatment of Patients with ST-segment Elevation Myocardial Infarction (DANAMI-3) multicentre trial⁶ and Danegaptide phase II proof-of-concept clinical trial.⁷

The DANAMI-3 trial investigated the effect of three treatment modalities namely deferred stenting (DANAMI 3-Deferred Stenting vs. Conventional Primary Percutaneous Coronary Intervention), ischaemic post-conditioning (DANAMI 3-Ischaemic Post-Conditioning vs. Conventional Primary Percutaneous Intervention), and complete revascularization of multi vessel disease in patients with STEMI (DANAMI 3-Complete vs. Culprit-Only Revascularization to Treat Multivessel Disease After Early PCI for STEMI). A total of 1.620 patients were admitted for primary percutaneous coronary intervention (PCI) treatment at Rigshospitalet, Copenhagen University Hospital, from 2011 to 2014, and randomized in the trial. A subset had CMR performed acutely and after 3 months.

The Danegaptide trial evaluated the effect of a suggested cardio protective compound, Danegaptide, on myocardial salvage in patients with STEMI. From 2013 to 2015, a total of 585 patients were admitted for primary PCI and randomly enrolled in the study at Rigshospitalet, Copenhagen University Hospital.

The trials were approved by the Central Danish Ethics Committee and were performed in accordance with the Declaration of Helsinki.

Thus, a total of 2.205 patients were randomized (DANAMI n = 1.620, Danegaptide n = 585), of which 17 patients were excluded due to unsuccessful PCI (Figure 1). Of 843 patients with a 3-month follow-up CMR, a total of 22 patients subsequently experienced VA. One patient was excluded due to poor image quality. Thus, 21 patients were randomly matched 1:5 with 105 controls without subsequent VA, who constituted the study population. Matching was performed using following variables: LVEF, infarct location, and revascularization status in patients with multi-vessel disease. We did matching to reduce the risk of confounding and based matching variables on their pre-established prognostic value in terms of hard end points.^8,9 The revascularization status was defined at the time of STEMI. Non-revascularized lesions were considered angiographically significant if at least 70% of the vessel diameter on visual estimation was stenotic or showed 50–69% stenosis together with a fractional flow reserve (FFR) measurement of 0.80 or less.

Study population

Patients presented with chest pain lasting ≤12 h, acute electrocardiographic ST elevation, and were treated guided by contemporary international guidelines,¹ in addition to the experimental treatment.

Detailed description of the DANAMI-3 studies has been previously published.^6,7,10–12 Briefly, three different treatment strategies in STEMI were tested [(i) immediate stenting vs. deferred strategy of stent implantation, (ii) mechanical post-conditioning vs. conventional primary PCI, and (iii) FFR-guided complete revascularization or culprit only revascularization]. Patients included in Danegaptide had thrombolysis in myocardial infarction (TIMI) flow 0–1, had single vessel disease, and were tested in a clinical proof-of-concept study with the therapeutic potential of Danegaptide at two-dose levels administered at the time of primary PCI.

Cardiovascular magnetic resonance

The CMR protocols for DANAMI-3 and Danegaptide have previously been described.¹³ In brief, a 1.5 T scanner was used (Avanto or Espree scanner; Siemens, Erlangen, Germany), and infarcted myocardium was directly quantified via LGE. As earlier studies have shown that the infarction reaches its final size after approximately 30 days, this sub-study only includes patients with a 3-month follow-up CMR scan.

Detection of arrhythmic substrate

All image data analysis was performed at the Cardiac MRI Research Unit, Rigshospitalet, using the ADAS 3D investigational software tool (ADAS 3D, Galgo Medical SL, Barcelona, Spain), as previously described.¹⁴ The LGE-CMR imaging post-processing is illustrated in Figure 2. In brief, myocardial-fibrotic tissue, identified by gadolinium enhancement, was divided into core and BZ using an algorithm based on maximum pixel signal intensity (MPSI). The term BZ was used since only grey zone scar around the core scar was quantified. The core was defined as a region with signal intensity >60% of MPSI in the scar area, whereas BZ was defined as the region with signal intensity <60% and >40% of MPSI. A BZ channel was automatically defined as a corridor of BZ connecting two areas of normal myocardium flowing between two core areas or between a core area and a valve annulus.¹⁵

The mean time of one image analysis (including image import and segmentation) was 20 min (range 15–40 min).

Study end points

The primary endpoint was the presence of BZ tissue and BZ channels and the association with subsequent VA 3 month after STEMI. A VA event was defined as composite arrhythmic event endpoint that included: sustained ventricular tachycardia (VT) lasting more than 30 s, ventricular fibrillation (VF), or SCD defined as death occurring unexpectedly in an otherwise stable subject last seen alive ≤24 h previously, with circumstances suggestive of sudden death.¹⁶ The secondary endpoints were cardiovascular and all-cause mortality. All events were validated through medical record review, and the exact clinical presentation of each event is specified in the results section. All patients in the control group went through medical record review to make sure none of them had a VA event and to verify the type of death. Patients were followed from the time of the 3-month follow-up CMR scan until the end point of interest, death, or end of the study, whichever came first.

Statistics

Demographic, procedural, and end point characteristics are presented as mean ± standard deviation for continuous variables and frequencies and percentages for categorical variables. The Wilcoxon rank-sum test was used to evaluate continuous variables and the χ² test or Fisher’s exact test (when appropriate) for categorical values. Missing values are reported. The odds ratios (ORs) of VA were analysed in five separate uni- and multivariable logistic regression models for scar (model 1), core (model 2), and BZ mass (model 3), the presence of BZ channels (model 4), and the combination of a cutpoint of ≥17.2 g BZ mass [evaluated with receiver operating curves (ROCs)] and the presence of BZ channels (model 5). Only scar characteristics were significant in the univariate analyses (P-value ≤ 0.05); thus, we adjusted each of the five models for LVEF ≤ 35% and left ventricular (LV) mass because of their established prognostic value. In order to analyse the effect of scar mass and the presence of BZ channels on VA, we did a two-way analysis of variance (ANOVA) and three multivariable logistic regression models for the presence of BZ channels adjusted for scar mass, LVEF ≤ 35%, and LV mass (model 1); core mass, LVEF ≤ 35%, and LV mass (model 2); and BZ mass, LVEF ≤ 35%, and LV mass (model 3). We did separate models since core and BZ mass depend on scar mass. ROCs were performed to estimate the predictive value of scar variables and to identify cutpoints of interest. There was no identifiable optimal cutpoint for LVEF. A sensitivity analysis on VA and all-cause mortality was performed in a randomly selected subset of excluded patients without a 3-month follow-up CMR (n = 345).

All analyses were performed with R Core Team (2022) (R: A language and environment for statistical computing; R Foundation for Statistical Computing, Vienna, Austria; URL https://www.R-project.org/). A two-sided P-value ≤0.05 was considered statistically significant.

Results

Patient sample

A total of 21 STEMI patients underwent a 3-month LGE-CMR and subsequently experienced VA during 100.3 months follow-up. After randomly matching 1:5 with 105 STEMI patients also undergoing a 3-month LGE-CMR, but without known VA, a total of 126 patients were enrolled in this sub-study. The time of inclusion was balanced in the two groups with year 2013 as median inclusion time (P = 0.5). Baseline clinical characteristics, angiographic, and procedural parameters are summarized in Table 1, without statistically significant differences between the two groups. The medications at discharge, including beta-blocker and angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, were balanced between cases and controls, and we found no associations between the medications at discharge and VA during follow-up (see Supplementary material online, Table S1).

Ventricular arrhythmic events

A total of 21 patients experienced a VA event with a median follow-up of 30.6 months after STEMI. The clinical characteristics of the arrhythmic events are listed in Supplementary material online, Table S2. The VA events were distributed as follows: 10 of 21 had a VF or VT out-/in-hospital cardiac arrest; 7/21 patients had VT, of which 4 of 7 had hospital episodes terminated by antiarrhythmics or cardioversion, and 3 of 7 had episodes terminated by ICD shocks; and the last 4 of 21 patients had SCD. A total of 3 of 21 had a primary prevention ICD implanted before their VA event, and 8 of 21 of the patients with a subsequent VA received a secondary prevention ICD. The remaining 10 of 21 patients did not receive an ICD due to reversible causes (5/10) or death (5/10). A total of 4 of 21 patients were admitted with acute MI in relation to the VA event.

Delayed enhanced cardiac magnetic resonance results

The LGE-CMR substrate derived parameters are shown in Table 2. The LV function was preserved; however, a trend towards a lower LVEF and number of patients with LVEF ≤35% were seen in cases with vs. controls. Cases presented significantly larger median total scar mass (consisting of core- and BZ mass), core mass, and BZ mass compared with controls. In total, 134 BZ channels were identified in 61 (48%) patients, with a median of 2 BZ channels per patient in both cases and controls. A significantly higher proportion of cases had BZ channels compared to controls. The distribution of scar mass plotted against BZ mass, core mass, the presence of BZ channels, and number of BZ channels in the study population are shown in Supplementary material online, Figure S1A–D. Two-way ANOVA revealed no statistically significant interaction between the effects of scar mass and the presence of BZ channels (P = 0.08).

We found a trend towards a larger LV mass, end-diastolic volume, and LV end-systolic volume in cases vs. controls.

The univariate ORs for VA revealed that none of the clinical baseline characteristics were associated with recurrent VA follow-up (see Supplementary material online, Table S1), whereas all scar parameters were significantly associated with the primary endpoint (Table 3). Four multivariable logistic regression models were created for scar, core, and BZ mass and the presence of BZ channels, adjusted by LVEF and LV mass (Table 3). We found scar mass, BZ mass, and the presence of BZ channels to be independent predictors of VA, whereas core mass, LVEF, and LV mass did not predict VA in any of the models. Likewise, we did three multivariable logistic regression models for BZ channels, adjusted by: scar mass, LVEF, and LV mass (model 1); core mass, LVEF, and LV mass (model 2); and BZ mass, LVEF, and LV mass (model 3) and found the presence of BZ channels to be an independent predictor of VA in model 1 + 2 (Table 4). In model 3, the presence of BZ channels and BZ mass were both predictors of VA.

The overall diagnostic performance of the different scar characteristics to differentiate cases and controls is shown in Table 5. The AUC for BZ mass was of 0.67 [95% confidence interval (CI) 0.51–0.81; P = 0.04] and for the presence of BZ channels of 0.70 (95% CI 0.60–0.79; P = 0.0001). The ROC curves for all the scar parameters analysed are shown in Figure 3. The cutpoints for the identification of patients with documented VA are listed in Table 5. The cutpoint for BZ mass was of ≥17.2 g (52% sensitivity, 86% specificity).

In Table 5 and Figure 4, the distribution of the optimal cutpoints for each scar parameter in cases vs. controls is shown. We found that a BZ mass ≥17.2 g was 4.3 times more prevalent in cases vs. controls. To identify the best model to predict VA events, we performed a sub-analysis on patients with a combination of a cutpoint of BZ mass ≥17.2 g and the presence of BZ channels. This combination proved five times more prevalent in cases vs. controls (Table 5 and Figure 4) and was an independent predictor of subsequent VA (Table 3). The AUC for this combination was 0.71 (95% CI 0.60–0.82; P =0.0003) and showed a 52% sensitivity and 90% specificity for the identification of patients with documented VA (Table 5 and Figure 3). Finally, we found a high negative predictive value for: scar mass <22.9 g, BZ mass <17.2 g, non-presence of BZ channels and a combined endpoint of BZ mass <17.2 g and non-presence of BZ channels. Whereas core mass ≥11.5 g and LVEF ≤35% had a high positive predictive value. However, the number of patients with LVEF ≤35% was low (cases, n = 2; controls, n = 2).

Cardiovascular death

The clinical characteristics of cardiovascular vs. all-cause mortality in the study population are shown in Supplementary material online, Table S3. Among patients in this cohort, 13 patients died; of which 6 of 13 died of cardiovascular causes with a median time from STEMI to death of 68.0 months. All patients with cardiovascular death had a previous or immediate VA event compared to one patient in the group of all-cause mortality (6/6 vs. 1/7; P = 0.004). The scar determinants were larger in patients with vs. without cardiovascular death.

Sensitivity analysis

Due to the low frequency of VA and mortality, we performed a sensitivity analysis on the frequency of VA events and all-cause mortality in a randomly selected subset of excluded patients without a 3-month follow-up CMR (n = 345). In this subset, we found a total of 26 (8%) VA events and 47 (14%) events of all-cause mortality. Compared with our study, a total of 22 of 843 (3%) of the patients with a 3-month CMR had subsequent VA and 13 of 126 (10%) of the study population died during follow-up.

Discussion

This nested case-control study describes myocardial scar characteristics visualized by LGE-CMR in a post-STEMI population and the association with subsequent VA at a long-term follow-up.

Our sub-study contributed with two novel findings. Firstly, it revealed that the combination of ≥17.2 g BZ mass and the presence of BZ channels was strongly associated with subsequent VA with a five-time higher prevalence in cases vs. controls. Secondly, individual scar characteristics, including total scar mass, BZ mass, and the presence of BZ channels themselves, were associated with subsequent VA. However, the sample size was small why conclusions must be taken with caution.

Although LVEF is the current key clinical parameter in post-STEMI arrhythmic risk stratification and ICD indication, the need for better predictors of VA is evident. The value of prophylactic ICDs has primarily been established in patients with severely reduced LVEF, though it has been suggested that these patients may represent a minority of the total SCD and only 25–30% of patients with an ICD for primary prevention will get appropriate therapy.¹⁷ Two recent studies by Zegard et al.^18,19 have demonstrated that greyzone myocardial fibrosis is strongly associated with VA and SCD, also in patients with LVEF >35%. This confirmed in other studies in which scar size and its heterogeneity, assessed with cardiac LGE-CMR, have been proved to be independent predictors of arrhythmic events and cardiovascular death in patients with a healed MI.^4,20 However, the combination of a specific cutpoint of BZ mass and the presence of BZ channels has not been investigated elsewhere in a post-STEMI population with mostly preserved LVEF using this unique LGE-CMR post-processing imaging technique.

Recent studies have demonstrated that both the BZ channels detection technique and the presence of BZ channels are feasible and predictive factors for subsequent VT recurrence after VT ablation^21,22 and correlate well with voltage channels identified under endocardial voltage mapping during scar-related VA ablation procedures.^15,23 Few studies have also investigated the BZ channel characterization as risk stratification for VA and SCD using the same imaging method as ours. Acosta et al.²⁴ found the presence, extension, heterogeneity, and qualitative distribution of BZ tissue of myocardial scar to independently predict appropriate ICD therapies and SCD. Similarly, Jáuregui et al.²⁵ demonstrated that the BZ channels mass was the strongest independent variable associated with the occurrence of VT in post-MI patients. Results are comparable to the current. Sánchez-Somonte et al.²⁶ showed that the absence of BZ channels and a scar mass <10 g identified patients with a low risk of VA in patients with ICD in primary prevention. Correspondingly, we found high negative predictive values for scar mass, BZ mass, the non-presence of BZ channels, and a combined endpoint of <17.2 g BZ mass and the non-presence of BZ channels, stressing the potential usefulness of scar characteristics to rule out patients at risk of VA. However, in contrast to our study, the studies addressed above exclusively included patients with impaired LV function, and the impact of an optimal cutpoint of BZ mass in combination with the presence of BZ channels has not been explored elsewhere. We show that not only were scar characteristics independently associated with VA events in post-STEMI patients, even with mostly preserved LVEF, but also that a combination of a specific cutpoint of BZ mass and the presence of BZ channels had a strong association with future VA events and highly separated cases from controls. We did not find any significant difference in the number of BZ channels between cases and controls. One could speculate that an increased number of BZ channels may be related to an increased risk of VA. However, to our knowledge, this has not been demonstrated in earlier studies using the same method as ours.^{5,14,15,21,24,25} Also, our study population was small and might not reach statistical significance due to lack of power.

The baseline demographics including medications at discharge were balanced between the two groups. The relevance of primary prevention ICD in patients with medical optimization is debated. Beta-blocker and angiotensin-converting enzyme inhibitor or angiotensin receptor blocker treatment have been suggested to prevent of VA.²⁷ However, we found no associations between the medications at discharge and VA during follow-up. Larger clinical trials are required to confirm this.

An accurate risk stratification tool is crucial for effective treatment strategy to avoid SCD after STEMI. This sub-study allows a better understanding of the arrhythmogenic BZ substrate among the ischaemic population with mostly preserved LVEF, though the sample size and the number of events were small. Based on the current evidence and our results, LGE-CMR post-processing imaging of LV scar in post-STEMI patients, including a well-defined cutpoint of BZ mass and BZ channels determination, may be considered as part of a multi-parametric approach to arrhythmic risk stratification and guide the need for ICD implantation, also in patients with preserved LV function. Randomized, controlled trials investigating this strategy are warranted.

Conclusion(s)

Scar characterization with CMR indicated that a combination of ≥17.2 g BZ mass and the presence of BZ channels had the strongest association with subsequent VA in STEMI patients. Additional studies to confirm the present findings are needed to explore this potential new risk factor.

Limitations

The primary limitation of this subs-study is the low rate of arrhythmic events, though the incidence is similar to larger studies previously published.^9,15 Correspondingly, mortality was low. Furthermore, a relatively large number of patients did not undergo CMR, introducing the risk of selection bias. We performed a sensitivity analysis in a subset of patients not undergoing a 3-month follow-up CMR. In this, the mortality rate was comparable; however, the incidence of VA events was higher. Excluded patients and patients lost to CMR likely represent some of the most critically ill patients whose clinical condition likely correlate with the size of LV fibrosis, low LVEF, and subsequent VA. Additionally, it is well described that the risk of arrhythmia is highest the first months post-STEMI,²⁸ and the limited number of patients included in this sub-study with only 21 clinical VA events indicates that the results should be interpreted with caution due to the risk of overfitting the analyses. Finally, data could be biased due to over-time events for example heart failure or new MI that may be associated with the risk of a VA event. Still, our results show a strong association between scar characteristics and subsequent VA in a randomly matched 1:5 nested case-control in a consecutive population of STEMI and supporting earlier studies. Further studies with larger sample sizes are needed to confirm the current findings.

Supplementary material

Supplementary material is available at Europace online.

Funding

The DANAMI-3 trial was funded by the Research Council of Rigshospitalet, the Danish Agency for Science, Technology and Innovation, and the Danish Council for Strategic Research (grant 09-066994). The Danegaptide phase II proof-of-concept clinical trial was funded by Zealand Pharma A/S, Denmark.

Data availability

Data are not available due to privacy/ethical restrictions.

References

Author notes