Prognostic value of visual and quantitative CMR regional myocardial function in patients with suspected myocarditis

Diagnosing myocarditis remains a challenge, due to its heterogeneous clinical presentation with a wide range of symptoms from asymptomatic cases to heart failure and sudden cardiac death [1, 2]. In the clinical setting of suspected myocarditis, cardiac magnetic resonance imaging (CMR) provides the ability to evaluate various functional and tissue characterization parameters in one comprehensive exam. The pivotal role of CMR to non-invasively diagnose myocarditis is underscored in the Lake Louise Criteria (LLC) [3]. In 2018 updated LLC encompass major criteria including non-ischemic myocardial injury evaluated by diffuse fibrosis and late gadolinium enhancement (LGE), and myocardial edema, while signs of pericarditis and global- as well as regional left ventricular (LV) dysfunction serve as supportive criteria [3]. For global LV function, the assessment of quantitative global longitudinal strain (GLS) by CMR feature tracking has proven to be of higher prognostic value over traditional functional assessments such as LV ejection fraction (EF) [4]. Currently, regional left ventricular (LV) dysfunction is mostly evaluated by qualitative visual assessment (i.e. visual regional wall motion abnormalities, RWMA). It is unclear whether RWMA or novel quantitative regional longitudinal peak strain (RLS) can help to risk stratify patients with suspected myocarditis. In this retrospective observational study, we sought to investigate the respective prognostic values of measurements of regional myocardial dysfunction from CMR (RWMA and RLS) for major adverse cardiovascular events (MACE) in suspected myocarditis. As myocarditis frequently affects localized regions, and patients present initially with normal global LV function, we also seek to determine if localized myocardial injury reflected by either RWMA or RLS is associated with adverse cardiac outcomes in patients with preserved global LV function.

Out of the 1,125 consecutive patients initially referred to CMR for suspected myocarditis, 75 (6.7%) were excluded due to evidence of coronary artery disease, 50 (4.4%) refused study participation, 44 (3.9%) suffered from other cardiomyopathies (e.g. cardiac amyloidosis, stress cardiomyopathy, hypertrophic cardiomyopathy, severe valvular heart disease, LV non-compaction) and 15 (1.3%) did not complete the CMR exam. Among the remaining 941 patients, in 82 (8.7%) cases regional strain analysis was not possible due to arrhythmia, missing or foreshortened 2-, 3-, or 4-chamber view or artefact. Another 161 (16.0%) patients did not meet ESC criteria for clinically suspected myocarditis (1) and 8 (1.1%) patients were lost to follow-up, leaving 690 patients for the current analysis (Fig. 1). Mean age was 48.0 ± 16.0 years and 260 (37.7%) were women (Table 1). Most common symptoms at admission were chest pain and dyspnea which were present in 259 (37.5%) and 300 (44.7%) patients, respectively. Common ECG alterations comprised T-wave inversions in 193 patients (30.4%), left bundle branch block in 55 (8.6%) and ST-segment elevation in 37 (5.4%) patients. Mean LVEF was 49.1 ± 15.0% and mean LV-GLS was -13.1 ± 4.4%. Global LV function, as defined by sex-specific cutoffs for LV-GLS mentioned above, was impaired in 303 (43.9%) patients (Table 2). LGE was present in 442 (64.1%) patients and edema in T2 weighted imaging or T2 mapping was observed in 211 (37.9%) of 557 patients without missing T2 based image sequences (Fig. 2). Regional analysis demonstrated high prevalence of LGE in the inferior and lateral region (i.e., AHA-segments 4, 5, 10 and 11) (Fig. 3). RWMA by visual assessment was most common (25%) in inferior and lateral regions and less common in the anterior segments. RLS across regions was associated with the presence of RWMA (p < 0.001) but not with the presence of LGE (p = 0.456) within that same region (Fig. 4). Mean RLS for each region with and without LGE or RWMA is displayed in Supplemental Fig. 1. RLS of all regions was correlated to LV-GLS with correlation coefficients ranging from 0.758 to 0.836 (Supplemental Fig. 2). Reproducibility of RLS was good to moderate and ICC for intra-reader reliability was between 0.84 and 0.93 and ranged from 0.70 to 0.89 for inter-reader reliability (Supplemental Table 1). Intra- and inter-reader agreement for assessment of RWMA was good and good to moderate, respectively (Supplemental Table 2).

At median follow up of 3.8 years, MACE occurred in 116 (16.8%) patients, including heart failure hospitalization (40; 5.8%), sustained ventricular tachycardia (29; 4.2%), recurrent myocarditis (18; 2.6%), and all-cause death (29; 4.2%). MACE stratified by LVEF is presented in Supplemental Table 3. In addition to parameters of global LV function such as LVEF, LV-GLS and the presence of visually assessed RWMA, LGE and clinical characteristics including body-mass index (BMI), smoking, and a history of diabetes were associated with MACE in the univariate analysis. Anterior, septal, inferior, and lateral RLS and RWMA were also univariately associated with outcomes, while septal LGE was the only regional LGE pattern associated with MACE (Table 3). A basic multivariable predictive model was defined based on the results of univariate cox-regression and included BMI, smoking, history of diabetes mellitus, LVEF, LV-GLS, and LGE extent (Model χ2 = 65.86). None of the regional findings (RLS, RWMA and LGE) sequentially added to this model improved prognostication (Table 4) for the overall cohort. Separate results after removing LV GLS and LVEF from the multivariable models are provided in Supplemental Table 4.

For sub analyses, patients were stratified by LV-GLS into those with normal and impaired global LV function. Those with normal LV function were younger (p = 0.001), more often male (p < 0.001), less commonly suffered from diabetes mellitus (p = 0.006) and had more often chest pain symptoms (p < 0.001) but less dyspnea (p < 0.001) at admission (Table 1). LV function by LVEF, RLS and presence of RWMA correlated strongly to LV-GLS (Table 2). In patients with impaired LV function, several imaging parameters, including LVEF, RLS and RWMA of all regions, and LGE extent were associated with MACE, while in patients with normal LV function only clinical characteristics (BMI and smoking) and septal RLS were associated with outcomes (Table 3). Basic models incorporated LVEF and LGE extent in patients with impaired LV function, while BMI and smoking were included in the basic model for patients with normal LV function. The addition of regional findings demonstrated incremental and independent prognostic value of septal RLS over clinical characteristics in patients with normal LV function (HR_adjusted = 1.132, 95% CI 1.020–1.256; p = 0.002), while no independent effect was observed in those with impaired LV function (Fig. 5). Visually assessed RWMA were not associated with outcomes in this subgroup of patients (Graphical Abstract).

This study for the first time investigated the prognostic value of visual and quantitative regional myocardial dysfunction in suspected myocarditis. Both the presence of RWMA and RLS had moderate to high measurement reproducibility and were associated with clinical outcomes. However, in the model adjusted to key clinical risk markers, regional LV dysfunction, indicated by either RLS or RWMA, did not independently predict clinical outcomes, thus is of limited predictive value in the overall cohort of patients with suspected myocarditis. In the subgroup of patients with preserved LV function septal RLS demonstrated incremental and independent association with MACE. Impaired septal RLS might represent a high-risk pattern and incorporation into risk stratification may refine the prediction of MACE in this subgroup.

RLS has been demonstrated to be useful in the detection of RWMA in patients with ischemic heart disease [13‐15], to be correlated with LGE [14‐16], and inherits predictive value in patients following myocardial infarction and chronic total occlusion [17, 18]. Our hypothesis was that also in suspected myocarditis impaired RLS and RWMA might indicate areas of regional inflammation or scarring. However, contrasting the findings made in ischemic heart disease, RLS and RWMA were neither associated with regional LGE nor had independent prognostic value over global LV function. Following myocardial infarction, myocardial scarring is more often transmural and limited to a specific area of coronary supply, while in myocarditis less dense subendocardial or patchy LGE pattern are common [7, 19], that are notably less strong associated to impaired regional function. Consequently, RLS and RWMA were strongly associated to LV-GLS in our study, which might explain the lack of incremental value over LV-GLS. Even if of limited prognostic value, RLS is a reproducible tool and correlated well to visually assessed RWMA, suggesting a diagnostic role as supportive criterion outlined in the updated LLC in patients with suspected myocarditis [3].

Consistent with our results, recent studies have shown the prognostic potential of several CMR parameters including LGE, LVEF and GLS in suspected myocarditis [4‐7, 20‐23]. However, in patients with normal global LV function, these parameters are of limited value and do not incrementally and independently predict outcomes. Although patients with normal LV function are at significantly lower risk for adverse events, a certain proportion of these patients still develops heart failure, ventricular tachycardia, or recurrent myocarditis at follow-up, underlying the need for better risk stratification in this subgroup. Impairment of septal RLS was associated with outcomes in this patient population, which is in line with previous studies, that identified septal involvement by LGE as a high-risk feature in myocarditis [7, 19] or ischemic heart disease [24]. Septal involvement might indicate extending of inflammation to the right ventricle or can go along with involvement of the conduction system, both of which are associated with poor outcomes [8, 25‐27]. In fact, whereas septal LGE was a strong outcome predictor in our sub-cohort with impaired LV function, septal LGE was not associated with outcomes in the subcohort with preserved LV function. Therefore, and in addition to widely established tissue characterization by LGE, septal RLS might represent a marker for septal involvement and may help to refine risk stratification especially in patients with preserved global LV function.

So far, RLS has not yet been implemented in clinical practice and is rather seen as a research tool. The application and interpretation of RLS is challenging and several limitations of the technique should be considered. First, RLS shows limited inter-reader reproducibility when assessed on basis of AHA-segmentation [28, 29], emphasizing the need to cluster segments to regions, as done by this study and to standardize the post-processing. However, a definition of which AHA-segments should be included to a region is rather arbitrary, especially in diseases like myocarditis without a coronary-anatomy-based distribution of lesions. Additionally, through a tethering of strain, regions with normal myocardium neighboring impaired segments can also exhibit low RLS [14, 30, 31]. Finally, no reference values exist for different RLS pattern, which is further complicated by inter-vendor variabilities and limited comparability to echocardiography. Addressing these aspects would allow for a more widespread use of RLS not only in suspected myocarditis, but also in other cardiac disease where regional differences in myocardial function are expected.

Several limitations require attention. First, this was a retrospective study, and the heterogeneous nature of myocarditis presentations makes the patient selection prone to selection bias. We tried to mitigate this concern by using standardized inclusion criteria for clinically suspected myocarditis according to the published ESC recommendations and by excluding all other cardiomyopathies and ischemic heart disease. Second, parametric mapping sequences (T1, T2 and extracellular volume fraction) were only available in more recently scanned patients and were therefore not included to outcome analysis or correlated to RLS. Third, since no reference values are available for regional peak strain assessed by CMR, cut-offs for Kaplan Meier curves were selected based on median values in our cohort. Fifths, follow-up imaging, such as repeat CMR to detect dilative cardiomyopathy as a consequence of acute myocarditis was not available for the majority of study participants. Sixths, although based on our experience we believe that the learning curve for the assessment of regional strain peaks early if a standardized protocol is followed, we did not analyze reproducibility over time. Finally, we did not confirm the diagnosis of myocarditis by a diagnostic gold-standard such as endomyocardial biopsy, which reflect current practice. Further, endomyocardial biopsy is prone to sampling error, associated with a non-negligible risk, and is currently reserved for more severe cases.

RLS is a feasible tool to assess regional impairment of myocardial function and correlates to visually assessed RWMA. Both are associated with outcomes but are of lower prognostic value when compared to LV GLS. Nevertheless, in the subgroup of patients with normal LV function, septal RLS represents a marker of regional LV dysfunction with higher prognostic value than RWMA and can be used to refine risk-stratification in suspected myocarditis.