The main finding of this study is that myocardial scarring detected by DE-CMR strongly predicts death or appropriate ICD discharge for sustained ventricular arrhythmia in patients undergoing evaluation for possible ICD placement. On multivariable analysis, which included LVEF and electrophysiological study results, scar size was an independent predictor of adverse outcome when considered as a continuous variable or dichotomized at 5% of LV mass. For the latter, the hazard ratio was 4.6 [1.8-11.8] in all patients and 4.4 [1.7-11.6] in patients undergoing EPS (n=105). Furthermore, scar size >5% was an independent predictor of both secondary endpoints, SCD or ICD discharge and all-cause mortality alone.
Scar tissue is believed to be a fundamental component of the anatomical substrate for lethal ventricular arrhythmias.(10
) In the setting of coronary disease, electrical mapping studies have revealed that reentrant VT usually originates from the subendocardial surface of infarcted myocardium, adjacent to dense scar.(11
) In the setting of nonischemic cardiomyopathy, scar is less common and some characteristics are different (less confluence, less endocardial involvement)(17
) but again VT appears primarily the result of myocardial reentry associated with scar.(13
) In both settings, histological analysis of myocardial specimens have shown that regions that are crucially involved in the reentry circuit consist of isolated bundles of surviving myocytes interwoven with strands of fibrous scar tissue—the consequence of which is nonuniform anisotropic conduction and other electrophysiological abnormalities that can result in VT.(11
The potential relevance of scar as detected by DE-CMR was initially investigated by comparisons with electrophysiological testing. Bello et al.(34
) observed that infarct scar size (or surface area) was a better predictor of inducible monomorphic VT on EPS than LVEF in patients with coronary disease. Similarly, Nazarian et al.(48
) demonstrated that DE-CMR assessment of scar distribution was the strongest predictor of inducible VT in patients with nonischemic cardiomyopathy. More recently, in patients referred for radiofrequency ablation of VT or symptomatic premature ventricular complexes, Bogun et al.(46
) reported that DE-CMR diagnosed scar in all patients with history of sustained VT; and when a critical site of VT was identified, it occurred within areas of scar in all cases. Moreover, the location of scar was a reliable guide to catheter ablation—for predominantly endocardial scar, an endocardial approach was necessary, for epicardial scar, an epicardial approach was needed, and for mid-wall intramural scar, ablation was uniformly ineffective. Thus, these data present compelling evidence that DE-CMR identified scar is associated with ventricular arrhythmias, and offer mechanistic insight into why scar assessment may be better at predicting prognosis than LVEF or indices of LV morphology.
The results of the present study corroborate and extend those of earlier reports investigating the prognostic significance of scarring identified by DE-CMR.(19
) These studies have consistently demonstrated the additive value of scar (or infarct) assessment for predicting adverse outcome. However, most studies had few hard endpoints(19
) and/or were retrospective evaluations of patients who had undergone clinically ordered CMR in which scan results were used to determine patient management.(21
) In the current study, all patients were prospectively enrolled prior to CMR and in most (80%) CMR was performed only for research purposes and scan results were not used to guide clinical decision-making. The overall crude mortality rate of 6.8%/year was similar to that in comparable populations at risk for arrhythmia,(3
) and 39 patients reached the prespecified primary endpoint of death or appropriate ICD discharge. Although still relatively small, the number of events compares favorably with recently published prospective CMR studies by Wu,(23
) and Wu et al.(24
) that involved 18, 23, and 15 events, respectively overall, and 2, 10, and 7 events after excluding hospitalization events.
The present study is the first to directly compare CMR scar assessment with invasive EPS for predicting prognosis. EPS has distinct advantages over LVEF in that the actual induction of VT directly establishes the presence of an arrhythmic substrate, is more specific for predicting an arrhythmic death,(51
) and a risk stratification strategy involving EPS has higher efficiency (fewer ICDs needed /life saved) than one focused primarily on LVEF.(52
) Nonetheless, a negative EP study is not reassuring and does not indicate low likelihood for arrhythmic death especially in patients with low LVEF or with nonischemic cardiomyopathy.(37
) In our relatively broad patient population we observed that inducibilty of VT on EPS was a significant univariable predictor of adverse events, but on multivariable analysis DE-CMR scar assessment was superior to EPS in predicting both primary and secondary endpoints.
Although significant left ventricular dysfunction identifies a cohort at particularly high risk for SCD, it is a well-recognized paradox that most patients that die suddenly have less severe dysfunction. For instance, the Maastricht prospective registry found that 81% of patients experiencing SCD had an LVEF >30% before the event.(54
) Likewise, the Oregon sudden death study reported that 70% of patients suffering SCD had an LVEF >35% before the event. The present investigation was not a community-wide population study, but it is notable that of the 72 patients that would have been considered low-risk solely from an LVEF perspective (LVEF >30%), 14 died or had an appropriate ICD discharge during followup. Importantly, scar >5% on DE-CMR classified 12 of these 14 as high- rather than low-risk individuals. DE-CMR images of two of these patients are shown in (Patient C
On the other hand, it is also recognized that among patients that meet the current definition of high-risk LVEF (≤30%-35%), the majority will not derive any benefit from ICD implantation, since 14-18 patients with high-risk LVEF need to have an ICD implanted to prevent one death.(3
) In the present study 65 patients had LVEF ≤30%, among whom 25 died or had an appropriate ICD discharge during followup. However, those with scar ≤5% had a 3-year event rate that was below or similar to that of the entire group with low-risk LVEF ().
Eligibility for ICD implantation is based primarily on the presence of LV dysfunction, since LVEF is considered the strongest independent predictor of SCD among traditional clinical markers.(55
) However, our data corroborate prior investigations reporting LVEF lacks both sensitivity and specificity in predicting clinical events.(55
) Although preliminary, our findings highlight the potential of scar assessment by DE-CMR to improve the sensitivity of risk stratification by identifying patients with relatively preserved LVEF who nevertheless are at considerable risk for poor outcome. Because most SCD occurs in patients with preserved LVEF substantial effort is justified in evaluating new noninvasive risk stratification strategies in this group.(55
) Our results also suggest that DE-CMR scar assessment may be useful in identifying patients with low LVEF who may not benefit from ICD therapy. This hypothesis requires extensive further testing but seems warranted given the substantial cost of ICD therapy and the potential for harm, from unnecessary shocks, procedural complications, manufacturer recalls, and possible proarrhythmia.(56
There are limitations in using ICD discharges—even after classification as appropriate or not based on stored electrograms—as a surrogate for SCD.(57
) However, our findings were similar when using all-cause mortality as the endpoint () and we believe the main associations between scar and adverse outcome in the study are unlikely to be spurious.
We compared scar with LVEF, EPS, QRS duration, and many other clinical indices, but several others with high potential for improving risk stratification, such as T-wave alternans and heart rate variability, were not tested. A systematic comparison between scar and these other risk metrics was beyond the scope of the present study but would be an important area of future research.
An exploratory analysis of scar morphology () suggests other characteristics besides size may be important for risk stratification, such as the number of separate scars, but this will require prospective testing to fully explore their significance. There are several ways to quantitatively assess the grey zone, and it is possible that a different analysis method than the one used in the present study may have provided different results. Likewise, there may be different thresholds in scar size to optimally stratify risk when considering CAD and non-CAD patients separately. Interestingly, similar to the results of the present study, we note that Assomull et al.(19
) found that scar >4.8% was the optimal threshold to predict outcome in patients with nonischemic cardiomyopathy, and Kwong et al.(21
) observed a sharp step-up in risk with even a small amount of scarring in patients with coronary disease. It is speculative, but these results are consistent with experimental investigations that have suggested that a “critical mass” of scar is necessary for reentrant VT to occur.(58
Finally, an important limitation is that the conclusions are based on a limited number of events (the primary endpoint occurred in 39 patients), and this raises the possibility of overfitted multivariable models; larger studies are vital to confirm these findings.
In patients undergoing evaluation for possible ICD implantation, myocardial scarring detected by DE-CMR predicts worse outcome. Even in patients with LVEF >30% considered low-risk from an LVEF perspective, significant scarring (>5%) identifies a cohort with a high rate of adverse events and one similar in risk to those with LVEF ≤30%. Additionally, in patients with LVEF ≤30%, minimal-or-no scarring identifies a cohort with lower risk similar those with LVEF >30%. The findings suggest that DE-CMR scar assessment is superior to LVEF for risk stratification, and justify future studies prospectively testing whether patient management guided by CMR findings can improve patient outcome.