Abstract
Background
Recent evidence underlined the importance of right (RV) involvement in suspected myocarditis. We aim to analyze the possible incremental prognostic value from RV global longitudinal strain (GLS) by CMR.
Methods
Patients referred for CMR, meeting clinical criteria for suspected myocarditis and no other cardiomyopathy were enrolled in a dual-center register cohort study. Ejection fraction (EF), GLS and tissue characteristics were assessed in both ventricles to assess their association to first major adverse cardiovascular events (MACE) including hospitalization for heart failure (HF), ventricular tachycardia (VT), recurrent myocarditis and death.
Results
Among 659 patients (62.8% male; 48.1 ± 16.1 years), RV GLS was impaired (> − 15.4%) in 144 (21.9%) individuals, of whom 76 (58%), 108 (77.1%), 27 (18.8%) and 40 (32.8%) had impaired right ventricular ejection fraction (RVEF), impaired left ventricular ejection fraction (LVEF), RV late gadolinium enhancement (LGE) or RV edema, respectively. After a median observation time of 3.7 years, 45 (6.8%) patients were hospitalized for HF, 42 (6.4%) patients died, 33 (5%) developed VT and 16 (2.4%) had recurrent myocarditis. Impaired RV GLS was associated with MACE (HR = 1.07, 95% CI 1.04–1.10; p < 0.001), HF hospitalization (HR = 1.17, 95% CI 1.12–1.23; p < 0.001), and death (HR = 1.07, 95% CI 1.02–1.12; p = 0.004), but not with VT and recurrent myocarditis in univariate analysis. RV GLS lost its association with outcomes, when adjusted for RVEF, LVEF, LV GLS and LV LGE extent.
Conclusion
RV strain is associated with MACE, HF hospitalization and death but has neither independent nor incremental prognostic value after adjustment for RV and LV function and tissue characteristics. Therefore, assessing RV GLS in the setting of myocarditis has only limited value.
Similar content being viewed by others
Explore related subjects
Find the latest articles, discoveries, and news in related topics.Background
Myocarditis is an important cause of heart failure (HF) that has recently gained attention due to the increasing number of patients undergoing high-sensitive noninvasive imaging modalities for myocardial tissue characterization such as cardiac magnetic resonance imaging (CMR). Both, clinical presentation and long-term outcomes of patients with myocarditis vary and can range from asymptomatic, mild and benign course to patients that suffer from a large spectrum of adverse cardiac events including HF with need for hospitalizations, ventricular tachycardia (VT), recurrent myocarditis, and death [1,2,3]. This underlines the unmet need for adequate risk-stratification tools that can support the physician in guiding patient management within this clinical setting. Based on right ventricular (RV) ejection fraction (EF), recent data underscore the important prognostic role of RV involvement in suspected myocarditis [4, 5]. However, RVEF does not fully characterize RV myocardial energetics as it is influenced by ventricular preload and afterload across the cardiac cycle and other factors [6, 7]. Feature tracking based assessment of global longitudinal strain (GLS) by CMR is a modern technique that has demonstrated high reproducibility [8], and incremental prognostic value by evaluating the left ventricle (LV) of patients with acute myocarditis [9], but has never been investigated in the RV in this setting and is not routinely performed in clinical practice. We tested the hypothesis that RV GLS might provide incremental prognostic value for clinical outcomes after suspected myocarditis over RVEF alone and other established predictors such as LVEF [10] and the presence of late gadolinium enhancement (LGE) [11,12,13].
Methods
Patients and design
The design of the ‘Inflammatory Cardiomyopathy Bern Registry’ (FlamBeR) (NCT04774549) and the ‘CMR Features in Patients With Suspected Myocarditis’ (CMRMyo) (NCT03470571) registry was previously described [5]. In brief, consecutive patients who were referred for CMR at Inselspital, University Hospital Bern, Switzerland and Brigham and Women’s Hospital, Harvard Medical School Boston, Massachusetts, USA due to clinically suspected myocarditis between 2002 and January 2019 were enrolled in this register cohort study. Clinically suspected myocarditis was defined according to the position statement of the European Society of Cardiology (ESC) Working Group on Myocardial and Pericardial Diseases including clinical (acute chest pain, dyspnea or fatigue, palpitation, arrhythmia, syncope or sudden cardiac death or unexplained cardiogenic shock) and diagnostic criteria (positive ECG, elevated troponin, functional or structural abnormalities on cardiac imaging such as the presence of edema or LGE of classical myocarditis pattern in CMR) [1]. Myocarditis is clinically suspected if the patient meets either (a) ≥ 1 clinical criteria and ≥ 1 diagnostic criteria or (b) ≥ 2 diagnostic criteria [1]. Patients with evidence of coronary artery disease (medical history, anatomical or functional imaging findings including suspected ischemia by any imaging modality or endocardial LGE by CMR consistent with infarction, or invasive coronary angiography), or evidence of pre-existing pulmonary artery hypertension, pulmonary embolism or severe pulmonary disease, hypertrophic cardiomyopathy, arrhythmogenic cardiomyopathy, cardiac amyloidosis, Takotsubo cardiomyopathy, ventricular non-compaction, persistent severe valve disease, prior heart transplantation or prior cardiovascular surgery were excluded (Fig. 1). The primary outcome of first major adverse cardiovascular events (MACE) included HF hospitalization, documented VT lasting more than 30 s, recurrent myocarditis according to above mentioned criteria [1], and death. HF hospitalization was defined according to the ESC guideline definition of HF events [14]. The individual components of MACE were considered as secondary endpoints. Outcome was assessed by the patient’s chart review, documentations from referring physicians, hospital discharge summaries and by telephone interviews if there was a lack of documentation. Censoring events were the last available follow-up or the patient’s death. Both registries were approved by the local ethics committees and the study was conducted in accordance with the Declaration of Helsinki. All participants provided written informed consent.
Study cohort. CMR: cardiac magnetic resonance. Criteria for clinically suspected myocarditis was defined according to Caforio et al. [1]
Image acquisitions and analysis
CMR was performed at 1.5- or a 3.0 Tesla scanner (Magnetom Trio and Aera, Siemens Healthineers, Erlangen, Germany) as previously described [8, 9]. Patients received bodyweight-adjusted gadolinium (cumulative dose 0.1–0.2 mmol/kg). Post processing was performed with the CVI42 application (Circle Cardiovascular Imaging, Calgary, Canada, version 5.13.8) following standardized protocols in the core laboratory at Inselspital Bern. Investigators were blinded to clinical patient characteristics and outcomes. Feature tracking based RV GLS was assessed in cine images of a 4-chamber view (CV) after automatic and manually corrected tracing of the endo- and epicardial borders of the RV free wall without the RV septal wall (Fig. 2). LV GLS was averaged from assessments in the apical 2-, 3-, and 4-CV by tracing endo- and epicardial borders. Papillary muscles were included in the blood pool. End-systole and end-diastole were volumetrically defined. LGE was evaluated visually in each American Heart Association (AHA) segment [15] and quantified using the full-width-half-max (FWHM) approach at a short-axis stack. Cut-off values for females and males for LVEF (< 51%), RVEF (< 46% and < 42%), and RV end diastolic volume index (EDVi) (> 104 ml/m2 and > 123 ml/m2) were defined according to Kawel-Boehm et al. as the lower limit of the mean in healthy volunteers [16] (see Fig. 3). Cut-off values for feature tracking strain were determined from studies that also used CVI42. Cut-off for impaired RV GLS was defined at > − 15.4% independent of gender [17]. LV GLS was considered impaired if ≥ − 13.4 in women and ≥ − 13.0 in men [18]. Cut-off values for LV global radial strain (GRS) and LV global circumferential strain (GCS) were ≤ 21.4% and ≥ − 14.8% in females and ≤ 18.7% and in ≥ − 13.5% in males [18]. The presence of edema was assessed in T2-weighted images (signal intensity ratio of the myocardium to skeletal muscle ≥ 2 [19]) in both ventricles and in the LV also in T2 maps if available.
Examples of 6 patients referred to CMR for suspected myocarditis. LGE is marked with red asterisks. LGE images and short-axis slices were acquired in end-diastole (red contours). Blue contours represent the position of end-systolic contours. Strain overlays represent end-systolic peak strain, blue color mirrors more negative strain, while red color represents neutral or positive strain. CAD: coronary artery disease; EF: ejection fraction; GLS: global longitudinal strain; LV: left ventricle, RV: right ventricle
Correlation of right ventricular global longitudinal strain to other parameters of right ventricular and left ventricular function. Cut-off values were chosen according to [16,17,18]. BSA: body surface area; EF: ejection fraction; GLS/GRS/GCS: global longitudinal/radial/circumferential strain; EDV: end diastolic volume; LV: left ventricle, RV: right ventricle
Statistical analysis
Statistical analysis was performed with IBM SPSS Statistics 25 (IBM Corp., Armonk, New York, USA) and R software version 4.1.3 (R Foundation for Statistical Computing, Vienna, Austria). Results are presented as absolute frequencies (percentages) or as mean ± standard deviation (SD) whenever appropriate. Non-normally distributed variables were provided as the median with the corresponding interquartile range (IQR). Bivariate Pearson correlation was used to describe a correlation between RV GLS and other parameters of LV and RV function. Uni- and multivariate Cox regression was used to investigate associations to primary and secondary endpoints. The prognostic capability of stepwise models with sequentially included variables was evaluated by the goodness of fit, indicated by χ2 and compared to the subsequent model by a likelihood ratio test. Variables with > 10% missing values (e.g. biomarkers, results for LV or RV edema) were excluded. Time to event curves were plotted according to the Kaplan–Meier method. Results were considered to be statistically significant if the two-sided p-value was < 0.05.
Results
1125 patients referred to CMR for suspected myocarditis were screened for eligibility. Of those, 75 patients were excluded due to known (medical records, invasive angiography) or suspected (according to CMR) coronary artery disease, 40 patients due to evidence of other structural cardiomyopathy and 4 patients due to known pulmonary artery hypertension. Among the remaining 941 patients, 162 did not meet ESC-criteria for clinically suspected myocarditis, in 114 RV strain analysis was not possible due to poor image quality, RV foreshortening, or breathing or arrhythmic artefacts and 6 (0.53%) were lost to follow-up. Finally, 659 patients (mean age 48.1 ± 16.1 years; 414 (62.8%) male) were included (Fig. 1) and underwent CMR imaging at median 10 (IQR 4–28) days after symptom onset. Clinical patient characteristics at baseline are presented in Table 1. LV function was impaired in 297 (45.6%) patients based on LVEF and in 302 (46.1%) based on LV GLS. Impaired LV function was more frequent in patients with impaired RV GLS (Table 2). RV function was impaired in 162 (25.9%) according to RVEF and in 144 (21.9%) patients according to RV GLS. Epicardial or transmural (originating from epicardial) LGE was present in 430 (65.3%) patients in the LV and 76 (11.5%) in the RV. Impaired RV GLS was significantly associated with the presence of RV LGE (p < 0.001) and RV edema (p = 0.042) but not LV LGE (p = 0.698) and LV edema (p = 0.125). Poor image quality or missing T2-weighted images or T2 maps did not allow the assessment of edema in 129 (19.6%) patients in the LV and in 159 patients (24.1%) in the RV. RV GLS was significantly correlated to LVEF, LV GLS, LV GCS and LV GRS in addition to moderate correlation to RVEF and weak correlation to the body-surfaced area (BSA)-indexed RV EDV (Fig. 3).
During the observation time of median 3.7 (IQR 2.1 to 6.3) years, first MACE occurred in 115 patients (17.6%), of whom 45 (6.8%) patients were hospitalized due to HF, 42 (6.4%) patients died, 33 (5%) developed VT and 16 (2.4%) suffered from recurrent myocarditis. A total of 21 patients experienced more than one event type. Univariate Cox regression analysis demonstrated the significant association of female gender, elevated N-terminal pro-hormone brain natriuretic peptide (NT-proBNP), LV LGE and LV LGE extent, reduced LVEF and RVEF, LV strains and RV GLS to the combined endpoint (Table 3). In multivariable Cox regression analysis, model 1a including the imaging variables LGE extent, LV GLS and impaired LVEF and RVEF predicted MACE with a χ2 of 41.97 (p < 0.001). Implementing RV GLS in addition (model 1b) or instead of LV GLS (model 1c) did not significantly improve prognostication (χ2 = 51.65; p = 0.932 for model 1b and χ2 = 47.6; p = 0.623 for model 1c).
Regarding the secondary endpoints, male sex, elevated NT-proBNP, LV LGE extent, impaired RV and LV ejection fraction and strain were associated to HF hospitalizations in univariate analysis (Table 4). Nested models with imaging parameters demonstrated the incremental prognostic value of LV GLS and RVEF (model 2a) as reported previously [5, 9]. The addition of RV GLS (model 2b) did not improve prognostication (χ2 = 85.2; p = 0.194 vs. model 2a). However, implementing RV GLS instead of LV GLS in the newly constructed model 2c achieved comparable prognostic capability, as reflected by a significant model χ2 of 80.8 (p = 0.048 vs. without RV GLS). RV GLS remained independently associated with the occurrence of HF hospitalizations, adjusted to the effects of the other variables in the model (HRadjusted = 1.07, 95% CI 1.01–1.15; p = 0.048). Regarding the other secondary endpoints, RV GLS was univariately associated with death (HR = 1.07; 95% CI 1.02–1.12; p = 0.004), but not after adjustment for LVEF and RVEF or LV GLS (Table 5). RV GLS was not associated to VT (HR = 1.02; 95% CI 0.96–1.08; p = 0.509) or recurrent myocarditis (HR = 0.95; 95% CI 0.86–1.04; p = 0.258) (Table 6).
The adjusted time to event curves for the combined endpoint of first MACE and for the secondary endpoint of HF hospitalizations are plotted in Fig. 4 after dichotomizing the cohort into patients with normal versus impaired RV GLS and adjustment for LGE extent, RVEF, LVEF (bottom row) and LV GLS (upper row). Baseline results stratified by the occurrence of first MACE are presented in Additional file 1: Table S1.
Discussion
The present study demonstrated that nearly one quarter of patients with suspected myocarditis suffers from RV injury and impaired RV GLS. Impaired RV GLS was associated with the presence of LGE and edema in the RV, but not in the LV and linked to reduced LVEF and RVEF. RV GLS was strongly associated in the univariate analysis to cardiovascular outcomes in the clinical setting of suspected myocarditis but did not provide incremental prognostic value in the prediction of MACE after adjustment for RVEF, LVEF, LV GLS and LGE extent. Nevertheless, the study demonstrated that RV GLS may provide additional predictive value beyond RVEF, LVEF and LGE extent for HF hospitalizations in suspected myocarditis. This effect was comparable to the prognostic power of LV GLS in this setting, but not superior and restricted to HF hospitalizations as an endpoint. Therefore, RV GLS has only limited value in the clinical setting of suspected myocarditis.
Feature tracking based LV GLS analysis has proven its capability to refine risk-stratification across a large spectrum of cardiac diseases [20]. Recently, RV GLS has demonstrated prognostic value in right heart diseases such as arrhythmogenic cardiomyopathy but also dilated cardiomyopathy [21,22,23]. Both CMR parameters RV GLS and RVEF are highly robust, and reproducibility does not seem to limit their predictive power. Intraclass correlation coefficient for inter- and intra-reader variability for RV GLS ranged from 0.67 to 0.96 in prior studies [21, 24,25,26], in line with previously published results from our cohort (0.83 to 0.91) [8], and are comparable to the reproducibility of RVEF, ranging from 0.61 to 0.95 [27,28,29]. RV and LV GLS mirror different patterns of myocardial contractility compared to LVEF and RVEF which can be altered following different kind of injuries [30]. The volumetric measurement of EF is not exclusively determined by myocardial contractility but can be influenced by systemic or pulmonary artery blood pressure, volume status, valve disease, or obstructive disorders like pulmonary embolism. Changes in the end diastolic volume can lead to variations in EF independent of myocardial function and stroke volume [7]. LV strain measurements have been proven to overcome some of these limitations and inherit higher prognostic value than LVEF [9, 31], attributable to the potential to detect even subtle myocardial injury when LVEF is often preserved [9]. However, in this study, as well as in other reports [24, 32], more or a comparable number of patients suffered from impaired strain and impaired EF. This ratio might be partly explained by the selection of cut-off values, characteristics of the study cohort, post-processing software, and methodology across studies, while the high prognostic value of LV GLS was consistent across studies.
RV GLS is derived from a single slice (4CV) which makes it acquisition less time-intensive, but on the other hand also prone to impaired image quality. In our study, a relevant number of patients had to be excluded from RV based image analysis due to arrhythmia, breathing artefact, or foreshortening in the RV which limited the interpretation of our findings.
Improvement of RV image acquisition with dedicated RV focused views (i.e. carefully avoiding RV foreshortening in the 4-CH, dedicated 2-CH RV view, transaxial or transversal stacks) and RV adapted inversion time, could minimize the exclusion of images and help to exploit the additional information from RV tissue characteristics and RV function, including biplane RV GLS and radial or circumferential RV strain in future studies.
As previously discussed [5], impaired RV function and its association with adverse events in suspected myocarditis can result from primary inflammation of the RV myocardium, as a consequence of left sided HF and pulmonary hypertension or from pre-existing RV injury. In our study, impaired RV GLS was associated with RV LGE and RV edema, but not with LV LGE or LV edema, which is in line with prior reports that frequently observed dominant RV involvement in myocarditis in endocardial biopsy [33, 34]. Additionally, Luetkens et al. observed impaired RV GLS in patients with acute myocarditis that improved after recovery at 3 months compared to the baseline CMR [32], also pointing out that RV injury may directly occur from acute myocarditis and may lead to impaired RV GLS. On the other hand, RV function is of high prognostic relevance also in primary LV systolic dysfunction without RV inflammation [35], and due to the large number of inconclusive findings from the analysis of RV LGE and RV edema, our results cannot fully confirm or exclude a relationship between impaired RV function and acute RV inflammation. Pre-existing RV injury that might explain impaired RV GLS and its prognostic implications independent from the presence of myocarditis might be negligible in our study population because patients with known right heart disease by CMR findings or prior history were excluded. At baseline, patients with impaired RV GLS were more likely to exhibit HF features such as dyspnea and left-bundle branch block. In contrast, they less commonly presented with chest pain syndrome, elevated troponin levels, and ST-segment elevations in the ECG. We hypothesize that patients with primary LV involvement and associated chest pain syndrome, mimicking myocardial infarction, may have presented earlier in the course of the disease when troponin peaks and ST-elevations were still present. In contrast, patients with impaired RV GLS and dyspnea may have presented at later stages of myocarditis, coinciding with the onset of HF and a higher risk of future HF hospitalizations. This is further supported by our observation that patients with impaired RV GLS had a longer time gap between symptom onset and the conduction of CMR compared to those with normal RV GLS.
Regarding other imaging parameters, this study confirmed the high prognostic power of LV LGE and LV GLS in suspected myocarditis, which were both independently associated with MACE. The sole presence of LV LGE was associated with the composite of MACE and VT, but not with death, which contrasts prior studies [13, 36]. Myocardial scarring, indicated by LGE, can create a substrate for ventricular arrhythmias [37], but seems to be less important in the prediction of HF associated events following suspected myocarditis. Large extents of scarring however also can alter cardiac function, and trigger HF hospitalizations and mortality, evidenced by the observed association of LGE extent to HF hospitalizations. Consistently, Greulich et al. [13] observed an association between LGE and mortality in a cohort where LGE extent was larger, with LGE affecting an average of 4 segments. In our cohort, LGE extended over a mean of 2.9 segments, which may explain divagating findings regarding its association to mortality.
Our findings underline the important role of CMR in suspected myocarditis. CMR does not only allow to accurately assess LV dimension/function and tissue characteristics, but also proved to inherit important information from RV function. Echocardiography represents a reproducible method to derive RV GLS and RVEF but may be challenging in patients with impaired echo window [38], and RV GLS values only moderately agree to those of CMR, underlining the need for separate cut-off values [24, 39]. CMR-based evaluation of the updated Lake-Louise Criteria [40] and endomyocardial biopsy are currently the cornerstones in the diagnosis of myocarditis, also incorporating powerful outcome prognosticators from LV function and tissue characteristics [9, 11,12,13, 19, 41]. In patients without confirmed—, but clinically suspected myocarditis according to standardized criteria [1], feature tracking based strain analysis in the LV [9] may be helpful in the management of these patients, while—as demonstrated by this study—it is of limited value in the RV.
Limitations
The retrospective design of this observational study inherits several limitations. The lack of standardized blood sampling protocols goes along with a relevant number of missing values for biomarkers such as NT-proBNP and troponin and their prognostic relevance could not be fully assessed. The prognostic implications of features that were incorporated in our inclusion criteria (e.g. sole presence of LGE or elevated biomarkers such as NT-proBNP) might be underestimated. Secondly, in order to cover the full spectrum of myocarditis, we included patients with clinically suspected myocarditis according to standardized criteria, which is one of the most common reasons for referral to CMR [42]. Nevertheless, we cannot fully exclude a selection bias since atypical right-sided myocarditis might not be fully reflected in the ESC-criteria and therefore less severe RV myocarditis might be underrepresented. Additionally, we did not conduct endomyocardial biopsy or genetic testing to exclude alternative diagnosis in all patients, which however represents current clinical practice among many centers [43]. The lack of systematic collection of endomyocardial biopsy samples and invasively assessed hemodynamic data precluded us from determining the etiology of RV dysfunction. Thirdly, we cannot exclude a bias resulting from the time gap of CMR imaging from symptom onset that did not follow predefined protocols and might have varied over time and across centers. The prevalence of features indicating acute inflammation such as edema or the amount of LGE might therefore be underestimated. The lack of follow-up imaging did not allow us to assess these changes over time. Fourthly, mortality was assessed by hospital reports, and telephone interviews with family member, and the causes of death cannot be provided. Fifthly, it is important to note that our study spanned a considerable period, from 2005 to 2019. Consequently, modern sequences like parametric mapping were not available for a significant number of scans and were not thoroughly explored in our study. Finally, our statistical analysis is partially based on dichotomization of the patient cohort into those with normal versus impaired RV GLS. The cutoff value was chosen according to the results of a relatively small sample of 100 patients at another center [17]. Site-specific reference values might go along with different findings.
Conclusions
Right ventricular global longitudinal strain determined by CMR feature tracking is associated with first MACE, heart failure hospitalizations and death in the univariate analysis, but has neither independent nor incremental prognostic value after adjustment for LV/RV-function and tissue characteristics. Although RV GLS may provide some prognostic value for heart failure hospitalizations, its overall utility as a predictor of adverse cardiovascular events in the clinical setting of myocarditis remains limited.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Abbreviations
- AHA:
-
American Heart Association
- BMI:
-
Body mass index
- BSA:
-
Body surface area
- CAD:
-
Coronary artery disease
- CI:
-
Confidence intervals
- CMR:
-
Cardiac magnetic resonance
- CV:
-
Chamber view
- Df:
-
Degrees of freedom
- ECG:
-
Electrocardiogram
- EDV:
-
End diastolic volume
- EF:
-
Ejection fraction
- EMB:
-
Endomyocardial biopsy
- ESC:
-
European Society of Cardiology
- FWHM:
-
Full width half max
- GCS:
-
Global circumferential strain
- GLS:
-
Global longitudinal strain
- GRS:
-
Global radial strain
- HF:
-
Heart failure
- IQR:
-
Interquartile range
- LGE:
-
Late gadolinium enhancement
- LV:
-
Left ventricle
- MACE:
-
Major adverse cardiovascular events
- NT-proBNP:
-
N-terminal pro-hormone brain natriuretic peptide
- NYHA:
-
New York Heart Association
- RV:
-
Right ventricle
- SD:
-
Standard deviation
- VT:
-
Ventricular tachycardia
References
Caforio AL, Pankuweit S, Arbustini E, Basso C, Gimeno-Blanes J, Felix SB, Fu M, Heliö T, Heymans S, Jahns R, Klingel K, Linhart A, Maisch B, McKenna W, Mogensen J, Pinto YM, Ristic A, Schultheiss HP, Seggewiss H, Tavazzi L, Thiene G, Yilmaz A, Charron P, Elliott PM. Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J. 2013;34(2636–48):2648a–2648d. https://doi.org/10.1093/eurheartj/eht210.
Cooper LT Jr. Myocarditis. N Engl J Med. 2009;360:1526–38. https://doi.org/10.1056/NEJMra0800028.
Eichhorn C, Bière L, Schnell F, Schmied C, Wilhelm M, Kwong RY, Gräni C. Myocarditis in athletes is a challenge: diagnosis, risk stratification, and uncertainties. JACC Cardiovasc Imaging. 2020;13:494–507. https://doi.org/10.1016/j.jcmg.2019.01.039.
Aquaro GD, Negri F, De Luca A, Todiere G, Bianco F, Barison A, Camastra G, Monti L, Dellegrottaglie S, Moro C, Lanzillo C, Scatteia A, Di Roma M, Pontone G, Perazzolo Marra M, Di Bella G, Donato R, Grigoratos C, Emdin M, Sinagra G. Role of right ventricular involvement in acute myocarditis, assessed by cardiac magnetic resonance. Int J Cardiol. 2018;271:359–65. https://doi.org/10.1016/j.ijcard.2018.04.087.
Bernhard B, Schnyder A, Garachemani D, Fischer K, Tanner G, Safarkhanlo Y, Stark AW, Schütze J, Pavlicek-Bahlo M, Greulich S, Johner C, Wahl A, Benz DC, Kwong RY, Gräni C. Prognostic value of right ventricular function in patients with suspected myocarditis undergoing cardiac magnetic resonance. JACC Cardiovasc Imaging. 2023;16:28–41. https://doi.org/10.1016/j.jcmg.2022.08.011.
Konstam MA, Abboud FM. Ejection fraction: misunderstood and overrated (changing the paradigm in categorizing heart failure). Circulation. 2017;135:717–9. https://doi.org/10.1161/circulationaha.116.025795.
Marwick TH. Ejection fraction pros and cons: JACC State-of-the-Art Review. J Am Coll Cardiol. 2018;72:2360–79. https://doi.org/10.1016/j.jacc.2018.08.2162.
Fischer K, Linder OL, Erne SA, Stark AW, Obrist SJ, Bernhard B, Guensch DP, Huber AT, Kwong RY, Gräni C. Reproducibility and its confounders of CMR feature tracking myocardial strain analysis in patients with suspected myocarditis. Eur Radiol. 2022;32:3436–46. https://doi.org/10.1007/s00330-021-08416-5.
Fischer K, Obrist SJ, Erne SA, Stark AW, Marggraf M, Kaneko K, Guensch DP, Huber AT, Greulich S, Aghayev A, Steigner M, Blankstein R, Kwong RY, Gräni C. Feature tracking myocardial strain incrementally improves prognostication in myocarditis beyond traditional CMR imaging features. JACC Cardiovasc Imaging. 2020;13:1891–901. https://doi.org/10.1016/j.jcmg.2020.04.025.
Eichhorn C, Greulich S, Bucciarelli-Ducci C, Sznitman R, Kwong RY, Gräni C. Multiparametric cardiovascular magnetic resonance approach in diagnosing, monitoring, and prognostication of myocarditis. JACC Cardiovasc Imaging. 2022;15:1325–38. https://doi.org/10.1016/j.jcmg.2021.11.017.
Gräni C, Bière L, Eichhorn C, Kaneko K, Agarwal V, Aghayev A, Steigner M, Blankstein R, Jerosch-Herold M, Kwong RY. Incremental value of extracellular volume assessment by cardiovascular magnetic resonance imaging in risk stratifying patients with suspected myocarditis. Int J Cardiovasc Imaging. 2019;35:1067–78. https://doi.org/10.1007/s10554-019-01552-6.
Gräni C, Eichhorn C, Bière L, Kaneko K, Murthy VL, Agarwal V, Aghayev A, Steigner M, Blankstein R, Jerosch-Herold M, Kwong RY. Comparison of myocardial fibrosis quantification methods by cardiovascular magnetic resonance imaging for risk stratification of patients with suspected myocarditis. J Cardiovasc Magn Reson. 2019;21:14. https://doi.org/10.1186/s12968-019-0520-0.
Greulich S, Seitz A, Müller KAL, Grün S, Ong P, Ebadi N, Kreisselmeier KP, Seizer P, Bekeredjian R, Zwadlo C, Gräni C, Klingel K, Gawaz M, Sechtem U, Mahrholdt H. Predictors of mortality in patients with biopsy-proven viral myocarditis: 10-year outcome data. J Am Heart Assoc. 2020;9:e015351. https://doi.org/10.1161/jaha.119.015351.
McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, Burri H, Butler J, Čelutkienė J, Chioncel O, Cleland JGF, Coats AJS, Crespo-Leiro MG, Farmakis D, Gilard M, Heymans S, Hoes AW, Jaarsma T, Jankowska EA, Lainscak M, Lam CSP, Lyon AR, McMurray JJV, Mebazaa A, Mindham R, Muneretto C, Francesco Piepoli M, Price S, Rosano GMC, Ruschitzka F, Kathrine SA. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42:3599–726. https://doi.org/10.1093/eurheartj/ehab368.
Cerqueira MD, Weissman NJ, Dilsizian V, Jacobs AK, Kaul S, Laskey WK, Pennell DJ, Rumberger JA, Ryan T, Verani MS. Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart. A statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association. Circulation. 2002;105:539–42. https://doi.org/10.1161/hc0402.102975.
Kawel-Boehm N, Hetzel SJ, Ambale-Venkatesh B, Captur G, Francois CJ, Jerosch-Herold M, Salerno M, Teague SD, Valsangiacomo-Buechel E, van der Geest RJ, Bluemke DA. Reference ranges (“normal values”) for cardiovascular magnetic resonance (CMR) in adults and children: 2020 update. J Cardiovasc Magn Reson. 2020;22:87. https://doi.org/10.1186/s12968-020-00683-3.
Liu B, Dardeer AM, Moody WE, Edwards NC, Hudsmith LE, Steeds RP. Normal values for myocardial deformation within the right heart measured by feature-tracking cardiovascular magnetic resonance imaging. Int J Cardiol. 2018;252:220–3. https://doi.org/10.1016/j.ijcard.2017.10.106.
Lim C, Blaszczyk E, Riazy L, Wiesemann S, Schüler J, von Knobelsdorff-Brenkenhoff F, Schulz-Menger J. Quantification of myocardial strain assessed by cardiovascular magnetic resonance feature tracking in healthy subjects-influence of segmentation and analysis software. Eur Radiol. 2021;31:3962–72. https://doi.org/10.1007/s00330-020-07539-5.
Gräni C, Eichhorn C, Bière L, Murthy VL, Agarwal V, Kaneko K, Cuddy S, Aghayev A, Steigner M, Blankstein R, Jerosch-Herold M, Kwong RY. Prognostic value of cardiac magnetic resonance tissue characterization in risk stratifying patients with suspected myocarditis. J Am Coll Cardiol. 2017;70:1964–76. https://doi.org/10.1016/j.jacc.2017.08.050.
Kalam K, Otahal P, Marwick TH. Prognostic implications of global LV dysfunction: a systematic review and meta-analysis of global longitudinal strain and ejection fraction. Heart. 2014;100:1673–80. https://doi.org/10.1136/heartjnl-2014-305538.
Bourfiss M, Vigneault DM, Aliyari Ghasebeh M, Murray B, James CA, Tichnell C, Mohamed Hoesein FA, Zimmerman SL, Kamel IR, Calkins H, Tandri H, Velthuis BK, Bluemke DA, Te Riele A. Feature tracking CMR reveals abnormal strain in preclinical arrhythmogenic right ventricular dysplasia/ cardiomyopathy: a multisoftware feasibility and clinical implementation study. J Cardiovasc Magn Reson. 2017;19:66. https://doi.org/10.1186/s12968-017-0380-4.
Cittar M, Cipriani A, Merlo M, Vitrella G, Masè M, Carrer A, Barbati G, Belgrano M, Pagnan L, De Lazzari M, Giorgi B, Cova MA, Iliceto S, Basso C, Stolfo D, Sinagra G, Perazzolo MM. Prognostic significance of feature-tracking right ventricular global longitudinal strain in non-ischemic dilated cardiomyopathy. Front Cardiovasc Med. 2021;8:765274. https://doi.org/10.3389/fcvm.2021.765274.
Liu T, Gao Y, Wang H, Zhou Z, Wang R, Chang SS, Liu Y, Sun Y, Rui H, Yang G, Firmin D, Dong J, Xu L. Association between right ventricular strain and outcomes in patients with dilated cardiomyopathy. Heart. 2020;107:1233–9. https://doi.org/10.1136/heartjnl-2020-317949.
Erley J, Tanacli R, Genovese D, Tapaskar N, Rashedi N, Bucius P, Kawaji K, Karagodin I, Lang RM, Kelle S, Mor-Avi V, Patel AR. Myocardial strain analysis of the right ventricle: comparison of different cardiovascular magnetic resonance and echocardiographic techniques. J Cardiovasc Magn Reson. 2020;22:51. https://doi.org/10.1186/s12968-020-00647-7.
Liu B, Dardeer AM, Moody WE, Edwards NC, Hudsmith LE, Steeds RP. Reference ranges and reproducibility studies for right heart myocardial deformation by feature tracking cardiovascular magnetic resonance imaging. Data Brief. 2018;16:244–9. https://doi.org/10.1016/j.dib.2017.11.037.
Schmidt B, Dick A, Treutlein M, Schiller P, Bunck AC, Maintz D, Baeßler B. Intra- and inter-observer reproducibility of global and regional magnetic resonance feature tracking derived strain parameters of the left and right ventricle. Eur J Radiol. 2017;89:97–105. https://doi.org/10.1016/j.ejrad.2017.01.025.
Catalano O, Antonaci S, Opasich C, Moro G, Mussida M, Perotti M, Calsamiglia G, Frascaroli M, Baldi M, Cobelli F. Intra-observer and interobserver reproducibility of right ventricle volumes, function and mass by cardiac magnetic resonance. J Cardiovasc Med (Hagerstown). 2007;8:807–14. https://doi.org/10.2459/JCM.0b013e32801105ef.
Caudron J, Fares J, Vivier PH, Lefebvre V, Petitjean C, Dacher JN. Diagnostic accuracy and variability of three semi-quantitative methods for assessing right ventricular systolic function from cardiac MRI in patients with acquired heart disease. Eur Radiol. 2011;21:2111–20. https://doi.org/10.1007/s00330-011-2152-0.
Luijnenburg SE, Robbers-Visser D, Moelker A, Vliegen HW, Mulder BJ, Helbing WA. Intra-observer and interobserver variability of biventricular function, volumes and mass in patients with congenital heart disease measured by CMR imaging. Int J Cardiovasc Imaging. 2010;26:57–64. https://doi.org/10.1007/s10554-009-9501-y.
Fischer K, Neuenschwander MD, Jung C, Hurni S, Winkler BM, Huettenmoser SP, Jung B, Vogt AP, Eberle B, Guensch DP. Assessment of myocardial function during blood pressure manipulations using feature tracking cardiovascular magnetic resonance. Front Cardiovasc Med. 2021;8:743849. https://doi.org/10.3389/fcvm.2021.743849.
Romano S, Judd RM, Kim RJ, Kim HW, Klem I, Heitner JF, Shah DJ, Jue J, White BE, Indorkar R, Shenoy C, Farzaneh-Far A. Feature-tracking global longitudinal strain predicts death in a multicenter population of patients with ischemic and nonischemic dilated cardiomyopathy incremental to ejection fraction and late gadolinium enhancement. JACC Cardiovasc Imaging. 2018;11:1419–29. https://doi.org/10.1016/j.jcmg.2017.10.024.
Luetkens JA, Petry P, Kuetting D, Dabir D, Schmeel FC, Homsi R, Schild HH, Thomas D. Left and right ventricular strain in the course of acute myocarditis: a cardiovascular magnetic resonance study. Rofo. 2018;190:722–32. https://doi.org/10.1055/a-0585-0271.
Yilmaz A, Kindermann I, Kindermann M, Mahfoud F, Ukena C, Athanasiadis A, Hill S, Mahrholdt H, Voehringer M, Schieber M, Klingel K, Kandolf R, Böhm M, Sechtem U. Comparative evaluation of left and right ventricular endomyocardial biopsy: differences in complication rate and diagnostic performance. Circulation. 2010;122:900–9. https://doi.org/10.1161/circulationaha.109.924167.
Stiermaier T, Föhrenbach F, Klingel K, Kandolf R, Boudriot E, Sandri M, Linke A, Rommel KP, Desch S, Schuler G, Thiele H, Lurz P. Biventricular endomyocardial biopsy in patients with suspected myocarditis: feasibility, complication rate and additional diagnostic value. Int J Cardiol. 2017;230:364–70. https://doi.org/10.1016/j.ijcard.2016.12.103.
Mikami Y, Jolly U, Heydari B, Peng M, Almehmadi F, Zahrani M, Bokhari M, Stirrat J, Lydell CP, Howarth AG, Yee R, White JA. Right ventricular ejection fraction is incremental to left ventricular ejection fraction for the prediction of future arrhythmic events in patients with systolic dysfunction. Circ Arrhythm Electrophysiol. 2017. https://doi.org/10.1161/circep.116.004067.
Grün S, Schumm J, Greulich S, Wagner A, Schneider S, Bruder O, Kispert EM, Hill S, Ong P, Klingel K, Kandolf R, Sechtem U, Mahrholdt H. Long-term follow-up of biopsy-proven viral myocarditis: predictors of mortality and incomplete recovery. J Am Coll Cardiol. 2012;59:1604–15. https://doi.org/10.1016/j.jacc.2012.01.007.
Gulati A, Jabbour A, Ismail TF, Guha K, Khwaja J, Raza S, Morarji K, Brown TD, Ismail NA, Dweck MR, Di Pietro E, Roughton M, Wage R, Daryani Y, O’Hanlon R, Sheppard MN, Alpendurada F, Lyon AR, Cook SA, Cowie MR, Assomull RG, Pennell DJ, Prasad SK. Association of fibrosis with mortality and sudden cardiac death in patients with nonischemic dilated cardiomyopathy. JAMA. 2013;309:896–908. https://doi.org/10.1001/jama.2013.1363.
Bernhard B, Grogg H, Zurkirchen J, Demirel C, Hagemeyer D, Okuno T, Brugger N, De Marchi S, Huber AT, Berto MB, Spano G, Stortecky S, Windecker S, Pilgrim T, Gräni C. Reproducibility of 4D cardiac computed tomography feature tracking myocardial strain and comparison against speckle-tracking echocardiography in patients with severe aortic stenosis. J Cardiovasc Comput Tomogr. 2022;16:309–18. https://doi.org/10.1016/j.jcct.2022.01.003.
Freed BH, Tsang W, Bhave NM, Patel AR, Weinert L, Yamat M, Vicedo BM, Dill K, Mor-Avi V, Gomberg-Maitland M, Lang RM. Right ventricular strain in pulmonary arterial hypertension: a 2D echocardiography and cardiac magnetic resonance study. Echocardiography. 2015;32:257–63. https://doi.org/10.1111/echo.12662.
Ferreira VM, Schulz-Menger J, Holmvang G, Kramer CM, Carbone I, Sechtem U, Kindermann I, Gutberlet M, Cooper LT, Liu P, Friedrich MG. Cardiovascular magnetic resonance in nonischemic myocardial inflammation: expert recommendations. J Am Coll Cardiol. 2018;72:3158–76. https://doi.org/10.1016/j.jacc.2018.09.072.
Kindermann I, Kindermann M, Kandolf R, Klingel K, Bültmann B, Müller T, Lindinger A, Böhm M. Predictors of outcome in patients with suspected myocarditis. Circulation. 2008;118:639–48. https://doi.org/10.1161/circulationaha.108.769489.
Uhlig J, Lücke C, Vliegenthart R, Loewe C, Grothoff M, Schuster A, Lurz P, Jacquier A, Francone M, Zapf A, Schülke C, May MS, Bremerich J, Lotz J, Gutberlet M. Acute adverse events in cardiac MR imaging with gadolinium-based contrast agents: results from the European Society of Cardiovascular Radiology (ESCR) MRCT Registry in 72,839 patients. Eur Radiol. 2019;29:3686–95. https://doi.org/10.1007/s00330-019-06171-2.
Georgiopoulos G, Figliozzi S, Sanguineti F, Aquaro GD, di Bella G, Stamatelopoulos K, Chiribiri A, Garot J, Masci PG, Ismail TF. Prognostic impact of late gadolinium enhancement by cardiovascular magnetic resonance in myocarditis: a systematic review and meta-analysis. Circ Cardiovasc Imaging. 2021;14:e011492. https://doi.org/10.1161/circimaging.120.011492.
Acknowledgements
We thank Lukas Lüthi, Sakthivel Subramaniam and Laura Morf from the research study team for their excellent support.
Funding
None.
Author information
Authors and Affiliations
Contributions
All authors significantly contributed to this work, read and approved the final manuscript.
Corresponding author
Ethics declarations
Ethics approval and consent to participate
The ‘Inflammatory Cardiomyopathy Bern Registry’ (FlamBeR) (NCT04774549) and the ‘CMR Features in Patients With Suspected Myocarditis’ (CMRMyo) (NCT03470571) registry were approved by the local ethics committees and all participants provided written informed consent.
Consent for publication
Not applicable.
Competing interests
Dr. Gräni received research funding from the Swiss National Science Foundation, Innosuisse, GAMBIT foundation and from the Center for Artificial Intelligence in Medicine Research Project Fund University Bern, outside of the submitted work. Dr. Bernhard and Dr. Benz report a career development grant from the Swiss National Science Foundation. Ms. Safarkhanlo received research funding from the Center for Artificial Intelligence in Medicine Research Project Fund University Bern, outside of the submitted work. Dr. Huber has received research grants from the Swiss National Science Foundation, the Swiss Academy of Medical Sciences, the Helmut-Hartweg Foundation and the Foundation to Fight against Cancer, all for work outside the submitted study. He has received speaker/consulting honoraria or travel support from Bayer, Bracco and Siemens, all for work outside the submitted study. All other authors report no conflicts.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Additional file 1: Table S1.
Baseline characteristics in patients with and without major adverse cardiovascular events (MACE).
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
About this article
Cite this article
Bernhard, B., Tanner, G., Garachemani, D. et al. Predictive value of cardiac magnetic resonance right ventricular longitudinal strain in patients with suspected myocarditis. J Cardiovasc Magn Reson 25, 49 (2023). https://doi.org/10.1186/s12968-023-00957-6
Received:
Accepted:
Published:
DOI: https://doi.org/10.1186/s12968-023-00957-6