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Biventricular dyssynchrony on cardiac magnetic resonance imaging and its correlation with myocardial deformation, ventricular function and objective exercise capacity in patients with repaired tetralogy of Fallot
IJCA-26278; No of Pages 5 International Journal of Cardiology xxx (2018) xxx–xxx
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Biventricular dyssynchrony on cardiac magnetic resonance imaging and its correlation with myocardial deformation, ventricular function and objective exercise capacity in patients with repaired tetralogy of Fallot☆ Pantelis Kalaitzidis a, Stefan Orwat a, Aleksander Kempny e, Radke Robert a, Brigitte Peters d, Samir Sarikouch b, Philipp Beerbaum c, Helmut Baumgartner a, Gerhard-Paul Diller a,⁎, for the Competence Network for Congenital Heart Defects, DZHK (German Center for Cardiovascular Research) a
Division of Adult Congenital and Valvular Heart Disease, Department of Cardiovascular Medicine, University Hospital Muenster, Muenster, Germany Department of Heart-, Thoracic-, Transplantation- and Vascular Surgery, Hannover Medical School, Germany c Department of Pediatric Cardiology and Pediatric Intensive Care, Hannover Medical School, Germany d Institute for Biometry and Medical Informatics, University of Magdeburg, Germany e Adult Congenital Heart Centre and Centre for Pulmonary Hypertension, Royal Brompton Hospital, London, UK b
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Article history: Received 9 October 2017 Received in revised form 9 March 2018 Accepted 2 April 2018 Available online xxxx Keywords: Tetralogy of Fallot Magnetic resonance imaging Dyssynchrony
a b s t r a c t Background: Electrical dyssynchrony and prolonged QRS duration are common in patients with repaired tetralogy of Fallot (ToF). It has been linked to increased risk of sudden cardiac death and right ventricular (RV) dysfunction. We investigated myocardial dyssynchrony using cardiac magnetic resonance imaging (CMR) and feature tracking analysis (FT) in this setting and compared it to myocardial deformation, conventional parameters of ventricular dysfunction and clinical parameters. Methods and results: Patients underwent standardized CMR investigations as part of a nationwide study. We prospectively assessed myocardial deformation and analysed regional wall motion abnormalities of the RV and the left ventricle (LV) using CMR-FT. The main measure of dyssynchrony was the maximal time difference (wall motion delay) of the regional strain as a parameter of mechanical biventricular dyssynchrony. In addition, clinical parameters and measures of cardiopulmonary exercise capacity were available. Overall 345 patients were included. Parameters of biventricular wall motion delay correlated significantly with global FT-strain parameters (p b 0.0001 for all imaging planes assessed). Furthermore, we found a significant correlation between circumferential RV motion delay and QRS duration (p = 0.006). Higher LV and RV wall motion delay parameters were also associated with lower peak oxygen consumption (p b 0.05) and a worse LV and RV ejection fraction (p b 0.02). Conclusions: Assessment of mechanical dyssynchrony is feasible using CMR-FT in ToF patients. Parameters of mechanical dyssynchrony correlate with electrical dyssynchrony, biventricular function and objective exercise capacity in this setting. Due to the weak degree of correlation, however, the clinical significance of these findings remains to be clarified by further studies. © 2018 Published by Elsevier B.V.
1. Introduction
Abbreviations: Circ, circumferential; CMR, cardiac magnetic resonance imaging; CS, circumferential strain; EF, ejection fraction; FT, feature tracking; LAX, long axis; Long, longitudinal; LS, longitudinal strain; LV, left ventricle; rad, radial; RS, radial strain; RV, right ventricle; SAX, short axis; SCD, sudden cardiac death; VO2, oxygen uptake. ☆ This study was supported by a research grant from the EMAH Stiftung Karla Voellm, Krefeld, Germany and by the German Competence Network for Congenital Heart Defects (funded by the German Federal Ministry of Education and Research, BMBF - FKZ 01G10210, 01GI0601). ⁎ Corresponding author at: Division of Adult Congenital and Valvular Heart Disease, Department of Cardiovascular Medicine, University Hospital of Münster, AlbertSchweitzer-Campus 1, 48149 Münster, Germany. E-mail address: [email protected] (G.-P. Diller).
Contemporary patients with tetralogy of Fallot (ToF) are commonly affected by pulmonary valve regurgitation, right ventricular (RV) enlargement, biventricular dysfunction and an increased risk for malignant arrhythmias and sudden cardiac death [1–4]. Identification of ToF patients at particularly high risk of malignant arrhythmias and sudden cardiac death remains a major focus of research and novel parameters correlating with risk of adverse events are required. So far, parameters such as prolonged QRS duration ≥180 ms, pulmonary regurgitation, reduced right and especially left ventricular function, the presence of inducible ventricular tachycardia, impaired exercise capacity and potentially extensive RV scarring on late gadolinium cardiac magnetic
https://doi.org/10.1016/j.ijcard.2018.04.005 0167-5273/© 2018 Published by Elsevier B.V.
Please cite this article as: P. Kalaitzidis, et al., Biventricular dyssynchrony on cardiac magnetic resonance imaging and its correlation with myocardial deformation, ventricular func..., Int J Cardiol (2018), https://doi.org/10.1016/j.ijcard.2018.04.005
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P. Kalaitzidis et al. / International Journal of Cardiology xxx (2018) xxx–xxx
Maximum wall delay 222 ms
Fig. 1. Illustration of the measurement of maximum wall motion delay on feature tracking cardiac magnetic resonance imaging.
resonance imaging (CMR) have been related to outcome in this cohort [5–8]. Beyond non-invasive imaging, elevated left ventricular enddiastolic pressures on cardiac catheterization have also been identified as a major prognostic marker in this setting [8]. While the utility of regular transthoracic echocardiography in predicting outcome has been established [9], CMR has emerged as the gold standard imaging modality for assessing ventricular volumes in ToF patients. It has only recently, however, become possible to quantify mechanical dyssynchrony on CMR using standard CMR cine images. This is due to the introduction of CMR feature tracking (FT) analysis - a technique for the quantification of myocardial strain using standard steady-state-free precession (SSFP) images [10]. We have reported on the feasibility of using FT analysis for measuring myocardial deformation and its potential prognostic value [11,12]. However, information on the potential clinical utility of FT derived parameters of mechanical dyssynchrony are limited in contemporary ToF patients [13,14]. The pathophysiologic rationale for the evaluation of measures of mechanical dyssynchrony is provided by the observation that electrical dyssynchrony is a prognostic marker in ToF patients and by previous studies suggesting an association between mechanical asynchrony and outcome [6,14,21,30]. The current study was designed to evaluate the potential association between biventricular mechanical dyssynchrony on FT-CMR with parameters of biventricular mechanics, exercise capacity, clinical data and outcome in a large multicenter cohort of ToF patients. 2. Materials and methods The current study included patients enrolled in a nationwide, prospective study of ToF patients run by the German Competence Network for Congenital Heart Defects as described before [15]. In essence, patients with repaired ToF older than 8 years were recruited at various German centers (24 centers overall) between 2005 and 2008. All patients without contraindications for CMR (such as implanted pacemakers or ICD devices) were invited to participate. All enrolled ToF-patients underwent CMR investigations (avoiding sedation) using a standardized CMR protocol. Acquired datasets were stored on a central archiving database in a pseudonymized format. Further details on the CMR protocol, quality assurance measures and conventional (volumetric) analysis have been reported [15–17]. Feature tracking analysis was performed prospectively on all digitally archived datasets by using the TomTec 2D CPA MR software (TomTec, Unterschleissheim, Germany, Version 1.1.2.36-B) by GD and SO. There was no difference image quality between the right and left ventricle. Analysis was performed separately for both ventricles by delineating the endocardial border followed by automatic FT computation. For all analysis the quality and adequacy of myocardial displacement and the tracking contour was
controlled visually and the analysis repeated if required. Longitudinal and radial deformation parameters of the LV and RV were assessed in a four chamber view. Circumferential parameters of both LV and RV were assessed in the short axis view at the level of the papillary muscles. Additional details of the FT algorithm have been published by us and others [18–21]. Data on reproducibility of the FT-method in the setting of ToF has also been provided by our group [22]. As described previously [12], available clinical characteristics included the NYHA (New York Heart Association) functional class, the QRS duration on standard 12-lead ECG, as well as details of previous interventional and surgical procedures. Patients also were subjected to symptom-limited cardiopulmonary exercise testing on a treadmill or bicycle ergometer at the time of CMR [23]. Mechanical dyssynchrony was assessed by quantifying the maximum wall delay of the longitudinal, radial (both in a long axis and short axis view) as well as circular contraction of the right and left ventricle. The method of assessment of maximum wall delay is illustrated in Fig. 1. Follow-up was secured by using competence network infrastructure and/or by contacting local institutions or residents' registration office if required. As an endpoint of the study we chose a composite of documented ventricular tachycardia (sustained or non-sustained) or cardiac death, which included aborted cardiac death. The study protocol has been approved by the relevant ethics committee and all patients/guardians gave informed consent before recruitment/inclusion in the study.
2.1. Statistics Depending on data distribution parameter values are given as mean and standard deviation or median and interquartile range (25th and 75th percentile). Categorical variables are shown as frequencies and percentages. The association between parameters of mechanical dyssynchrony, myocardial deformation parameters, conventional volumetric markers of ventricular function and clinical status was assessed by Spearman's rank regression analysis. In addition, the potential association with outcome was studied by Cox proportional-hazard analysis. Due to the limited number of events no multivariate analyses were performed. For all analyses, a 2-tailed p-value b0.05 was used as the criterion for statistical significance. Statistical analyses were performed using MedCalc 17.6 (MedCalc Software, Mariakerke, Belgium) and R version 3.3.0 (The R Foundation for Statistical Computing).
3. Results Overall, adequate CMR images for FT assessment of mechanical dyssynchrony were available in 345 patients (56% male, mean age 17.5 ± 8.3 years, RV end-diastolic volume index 121 ± 33 ml/m2, RV ejection fraction 50 ± 9%; LV ejection fraction 57 ± 9%). Values of the measures of mechanical dyssynchrony are provided in Table A (Online Appendix). The majority of patients were asymptomatic and the objective exercise capacity as assessed by cardiopulmonary exercise testing
Please cite this article as: P. Kalaitzidis, et al., Biventricular dyssynchrony on cardiac magnetic resonance imaging and its correlation with myocardial deformation, ventricular func..., Int J Cardiol (2018), https://doi.org/10.1016/j.ijcard.2018.04.005
P. Kalaitzidis et al. / International Journal of Cardiology xxx (2018) xxx–xxx
same anatomical position and strain orientation (longitudinal, radial or circumferential). This is shown by the significant values (shaded areas in grey) on the diagonal of the correlation matrix provided in Fig. 2.
Table 1 Demographic and baseline characteristics. Parameter Demographic parameters Number of patients Gender Age at CMR Age at correction Previous palliation Transannular patch Previous pulmonary valve replacement Functional class NYHA class (I/II/III) Arrhythmia and ECG parameters Sinus rhythm at CMR Antiarrhythmic medication at CMR QRS duration Objective exercise capacity Peak VO2 Peak VO2 at anaerobic threshold % pred. peak VO2 Peak heart rate Selected conventional CMR measurements LVEDVi LVESVi LV EF LV mass RVEDVi RVESVi RV EF RV mass Pulmonary regurgitation fraction
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345 193 male 17.5 ± 8.3 years 2.4 ± 3.6 years 71 69 52 66/32/2% 99.70% 2% 146 ± 24 ms 31.9 ± 9.2 ml/kg/min 25.1 ± 10.3 ml/kg/min 80 ± 22% 168 ± 21 beats per minute 81 ± 17 mL/m2 35 ± 13 mL/m2 57 ± 9% 64.6 ± 14.0 g/m2 121 ± 33 mL/m2 62 ± 24 mL/m2 50 ± 9% 36.5 ± 14.1 g/m2 27 ± 19%
CMR = cardiac magnetic resonance imaging, LV = left ventricle, RV = right ventricle. EDVi = end diastolic volume index, ESVi = end systolic volume index, EF = ejection fraction.
was – on average – only mildly reduced. Further details on demographic and clinical information at presentation are given in Table 1. 3.1. Correlation between parameters of mechanical dyssynchrony and CMR strain Wall motion delay correlated significantly with myocardial displacement assessed by myocardial strain as illustrated in Fig. 2. As expected wall motion delay was negatively correlated to strain measures in the
3.2. Relationship between parameters of mechanical dyssynchrony, biventricular function and exercise capacity Wall motion delay parameters correlated significantly with left and right ventricular ejection fraction as shown in Fig. 3. In addition, circumferential LV and RV dyssynchrony was negatively correlated with objective exercise capacity (Fig. 3). In addition, RV short axis circumferential strain was found to correlate with symptoms (i.e. NYHA class N1) on logistic regression analysis (odds ratio 6.21 [95% CI 1.34–28.91]/%, p = 0.02). 3.3. Relationship between parameters of mechanical dyssynchrony and outcome During a median follow up time of 4.7 years (interquartile range 2.1–5.4 years), 10 patients experienced an event. This included 3 cardiac deaths, 2 aborted cardiac deaths with successful resuscitation and 5 documented non-sustained ventricular tachycardias. Table B (Online supplement) presents the results of the (univariate) Cox-proportional hazards analysis for conventional volumetric CMR parameters, myocardial deformation (strain measured by FT CMR), QRS duration and exercise parameters. None of the studied CMR-FT mechanical dyssynchrony markers correlated significantly with the risk of the pre-specified composite endpoint (p N 0.05 for all). 4. Discussion The current study illustrates the feasibility of assessing intraventricular mechanical dyssynchrony in patients with repaired tetralogy Fallot. Parameters of mechanical dyssynchrony were found to correlate with symptoms, exercise capacity and conventional parameters of biventricular function as well as with myocardial displacement. Despite the fact that the degree of correlation with clinical markers was not very pronounced, these novel physiologic parameters that can be derived from conventional CMR cine images might point to a potential value
Fig. 2. Correlation matrix illustrating the association between parameters of mechanical dyssynchrony and myocardial function (measured by myocardial strain). As expected the significant associations are mainly located on the diagonal of the matrix corresponding to similar anatomical position and geometric orientation of contraction. Circ. = circular, CS = circumferential strain, LAX = long axis, long. = longitudinal, LS = longitudinal strain, LV = left ventricle, rad. = radial, RV = right ventricle, RS = radial strain, SAX = short axis. Significant correlations are presented in grey.
Please cite this article as: P. Kalaitzidis, et al., Biventricular dyssynchrony on cardiac magnetic resonance imaging and its correlation with myocardial deformation, ventricular func..., Int J Cardiol (2018), https://doi.org/10.1016/j.ijcard.2018.04.005
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Fig. 3. Correlation matrix illustrating the association between parameters of mechanical dyssynchrony and biventricular ejection fraction as well as peak oxygen consumption (% of predicted) based on the results of Spearman's rank correlation analysis. Circ. = circumferential, EF = ejection fraction, Long = longitudinal, LV = left ventricle, RV = right ventricle, VO2 = oxygen uptake. Significant correlations are presented in grey.
of assessing CMR based mechanical myocardial dyssynchrony in ToF patients in future. Tetralogy of Fallot has been one of the prime focus areas of research in congenital heart disease in the last decades for various reasons. Firstly, ToF represents the most common form of cyanotic heart disease at birth. Secondly, despite initially successful surgical repair ToF patients are far from being cured [24]. Late complications include pulmonary regurgitation, heart failure symptoms and especially malignant arrhythmias associated with sudden cardiac death (SCD). Risk stratification algorithms have been developed but predicting individual risk of sudden cardiac death in ToF patients remains an unsolved problem. While survived SCD is a clear indication for secondary prevention implantation of an implantable cardioverter/defibrillator (ICD), identifying patients likely to benefit from such a device for primary prevention remains challenging. This is, in part, mediated by the low annual incidence rate of SCD. In addition, it has become obvious that multimodal assessment, integrating different clinical, electrical, invasive and imaging parameters into risk scores is required to identify patients at risk. Gatzoulis et al. have established a prolonged QRS-duration, exceeding 180 ms as a risk factor in this setting [6]. In isolation, however, this parameter is insufficiently discriminative to guide primary prevention ICD implantation. Interestingly, due to earlier repair and improved surgical expertise it now appears from more recent studies that prolongation of QRS duration is lower in more contemporary ToF patients. Although in part speculative, it seems that lower cut-off value for QRS duration, therefore, should be employed when assessing the risk of sudden cardiac death. Consistent with these data is the observation that only 9 patients (2.6%) included in the current study had a QRS duration above 180 ms. Khairy and colleagues have proposed a risk score based on medical history, QRS duration, the results of electrophysiological assessment (ventricular stimulation) and invasive measurements of LV enddiastolic pressures [8,25]. The need for invasive assessment remains one of the major drawbacks of this published risk score and limits its clinical uptake in routine practice. Left ventricular systolic dysfunction has been suggested as a surrogate for LV end-diastolic pressures in this setting but its clinical utility remains to be established [9,26,27]. The exact etiology of LV dysfunction in the setting of ToF, however, remains unclear and is likely related to the adverse impact of RV dilation/dysfunction on LV function (ventriculo–ventricular interaction) [28]. Ultimately, therefore, RV dysfunction and dyssynchrony remain central to the onset of malignant arrhythmia in ToF patients. We hypothesized that CMR based quantification of dyssynchrony could add to echocardiographic assessment by providing a wider field of view and allowing for free choice of imaging plane. In fact, CMR based parameters of dyssynchrony were found to be correlated with exercise capacity, electrical dyssynchrony as well as biventricular function in the current study. We could not establish a direct relationship between
CMR markers of mechanical dyssynchrony and outcome in a young cohort of largely asymptomatic ToF patients, however. The lack of an association is not entirely explained by the young population and the low event rate, as various other parameters were found to be significantly related to the combined end-point in our study (see Table B). Potentially, the inability of this novel CMR based technique to quantify RV outflow tract dyssynchrony limits its predictive value. Therefore, further efforts are required to implement software algorithms for the quantification of RV outflow tract disease in the commercially available FT software packages. This should be technically possible and could further supplement conventional CMR imaging describing functional impairment, wall motion abnormalities, aneurysms and myocardial fibrosis. As available data suggests that arrhythmias originate mainly in the RV outflow tract correlating outflow tract dyssynchrony with electrophysiological and outcome data appears promising and further research along this line is recommended [29]. Available data on the prognostic value of mechanical dyssynchrony in ToF is conflicting so far. While Ortega et al. have reported an association between LV dyssynchrony and outcome in 39 ToF patients, two later reports by Moon and Jing failed to confirm a significant relationship between CMR derived mechanical dyssynchrony and adverse outcome or clinical deterioration in 48 and 153 ToF patients, respectively [14,21,30]. The major strength of our dataset compared to the available literature is the large number of patients included. Given the results of over 300 patients investigated here, it appears that – using available technology – assessing mechanical dyssynchrony on CMR is unlikely to add significantly to established risk markers in contemporary ToF patients. Nonetheless, recording wall motion delay on CMR might in future add to clinical decision as part of the multimodal patient assessment and potentially highlighting the need for electrophysiological consultation in selected patients. 4.1. Limitations of the study The current study – despite its sizable patient population included – was not specifically (and a priori) powered to assess the prognostic value of novel FT parameters in ToF patients. The results of this study should, therefore, be regarded as hypothesis generating and be considered primarily as proof of feasibility and physiological relevance of the assessed FT parameters. Interventricular dyssynchrony was not assessed as part of the current study but could yield additional physiologic and prognostic value. As patients with implantable cardioverter defibrillators - the subset of patients deemed at particularly high risk of sudden cardiac death - had to be excluded from the study cohort, the studied population includes a selection bias, presumably favoring lower risk ToF patients.
Please cite this article as: P. Kalaitzidis, et al., Biventricular dyssynchrony on cardiac magnetic resonance imaging and its correlation with myocardial deformation, ventricular func..., Int J Cardiol (2018), https://doi.org/10.1016/j.ijcard.2018.04.005
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5. Conclusions Biventricular mechanical dyssynchrony can be quantified based on conventional cine CMR imaging using feature tracking techniques. Ventricular wall motion delay is associated with biventricular dysfunction, electrical dyssynchrony and exercise intolerance in contemporary ToF patients. Our data underscore the pathological importance of assessing the degree of dyssynchrony in ToF patients but questions its prognostic value at present. Due to the weak degree of correlation the clinical significance of these findings remains to be clarified by further studies before the inclusion of parameters of mechanical dyssynchrony in routine CMR assessment can be recommended.
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Conflicts of interest The authors report no relationships that could be construed as a conflict of interest. Acknowledgements This study was supported by a research grant from the EMAH Stiftung Karla Voellm, Krefeld, Germany. This study conducted by the Competence Network for Congenital Heart Defects was funded by the German Federal Ministry of Education and Research (BMBF), FKZ 01G10210 and 01GI0601.
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Appendix A. Supplementary data
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Supplementary data to this article can be found online at https://doi. org/10.1016/j.ijcard.2018.04.005.
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Please cite this article as: P. Kalaitzidis, et al., Biventricular dyssynchrony on cardiac magnetic resonance imaging and its correlation with myocardial deformation, ventricular func..., Int J Cardiol (2018), https://doi.org/10.1016/j.ijcard.2018.04.005
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Biventricular dyssynchrony on cardiac magnetic resonance imaging and its correlation with myocardial deformation, ventricular function and objective exercise capacity in patients with repaired tetralogy of Fallot☆ Pantelis Kalaitzidis a, Stefan Orwat a, Aleksander Kempny e, Radke Robert a, Brigitte Peters d, Samir Sarikouch b, Philipp Beerbaum c, Helmut Baumgartner a, Gerhard-Paul Diller a,⁎, for the Competence Network for Congenital Heart Defects, DZHK (German Center for Cardiovascular Research) a
Division of Adult Congenital and Valvular Heart Disease, Department of Cardiovascular Medicine, University Hospital Muenster, Muenster, Germany Department of Heart-, Thoracic-, Transplantation- and Vascular Surgery, Hannover Medical School, Germany c Department of Pediatric Cardiology and Pediatric Intensive Care, Hannover Medical School, Germany d Institute for Biometry and Medical Informatics, University of Magdeburg, Germany e Adult Congenital Heart Centre and Centre for Pulmonary Hypertension, Royal Brompton Hospital, London, UK b
a r t i c l e
i n f o
Article history: Received 9 October 2017 Received in revised form 9 March 2018 Accepted 2 April 2018 Available online xxxx Keywords: Tetralogy of Fallot Magnetic resonance imaging Dyssynchrony
a b s t r a c t Background: Electrical dyssynchrony and prolonged QRS duration are common in patients with repaired tetralogy of Fallot (ToF). It has been linked to increased risk of sudden cardiac death and right ventricular (RV) dysfunction. We investigated myocardial dyssynchrony using cardiac magnetic resonance imaging (CMR) and feature tracking analysis (FT) in this setting and compared it to myocardial deformation, conventional parameters of ventricular dysfunction and clinical parameters. Methods and results: Patients underwent standardized CMR investigations as part of a nationwide study. We prospectively assessed myocardial deformation and analysed regional wall motion abnormalities of the RV and the left ventricle (LV) using CMR-FT. The main measure of dyssynchrony was the maximal time difference (wall motion delay) of the regional strain as a parameter of mechanical biventricular dyssynchrony. In addition, clinical parameters and measures of cardiopulmonary exercise capacity were available. Overall 345 patients were included. Parameters of biventricular wall motion delay correlated significantly with global FT-strain parameters (p b 0.0001 for all imaging planes assessed). Furthermore, we found a significant correlation between circumferential RV motion delay and QRS duration (p = 0.006). Higher LV and RV wall motion delay parameters were also associated with lower peak oxygen consumption (p b 0.05) and a worse LV and RV ejection fraction (p b 0.02). Conclusions: Assessment of mechanical dyssynchrony is feasible using CMR-FT in ToF patients. Parameters of mechanical dyssynchrony correlate with electrical dyssynchrony, biventricular function and objective exercise capacity in this setting. Due to the weak degree of correlation, however, the clinical significance of these findings remains to be clarified by further studies. © 2018 Published by Elsevier B.V.
1. Introduction
Abbreviations: Circ, circumferential; CMR, cardiac magnetic resonance imaging; CS, circumferential strain; EF, ejection fraction; FT, feature tracking; LAX, long axis; Long, longitudinal; LS, longitudinal strain; LV, left ventricle; rad, radial; RS, radial strain; RV, right ventricle; SAX, short axis; SCD, sudden cardiac death; VO2, oxygen uptake. ☆ This study was supported by a research grant from the EMAH Stiftung Karla Voellm, Krefeld, Germany and by the German Competence Network for Congenital Heart Defects (funded by the German Federal Ministry of Education and Research, BMBF - FKZ 01G10210, 01GI0601). ⁎ Corresponding author at: Division of Adult Congenital and Valvular Heart Disease, Department of Cardiovascular Medicine, University Hospital of Münster, AlbertSchweitzer-Campus 1, 48149 Münster, Germany. E-mail address: [email protected] (G.-P. Diller).
Contemporary patients with tetralogy of Fallot (ToF) are commonly affected by pulmonary valve regurgitation, right ventricular (RV) enlargement, biventricular dysfunction and an increased risk for malignant arrhythmias and sudden cardiac death [1–4]. Identification of ToF patients at particularly high risk of malignant arrhythmias and sudden cardiac death remains a major focus of research and novel parameters correlating with risk of adverse events are required. So far, parameters such as prolonged QRS duration ≥180 ms, pulmonary regurgitation, reduced right and especially left ventricular function, the presence of inducible ventricular tachycardia, impaired exercise capacity and potentially extensive RV scarring on late gadolinium cardiac magnetic
https://doi.org/10.1016/j.ijcard.2018.04.005 0167-5273/© 2018 Published by Elsevier B.V.
Please cite this article as: P. Kalaitzidis, et al., Biventricular dyssynchrony on cardiac magnetic resonance imaging and its correlation with myocardial deformation, ventricular func..., Int J Cardiol (2018), https://doi.org/10.1016/j.ijcard.2018.04.005
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Maximum wall delay 222 ms
Fig. 1. Illustration of the measurement of maximum wall motion delay on feature tracking cardiac magnetic resonance imaging.
resonance imaging (CMR) have been related to outcome in this cohort [5–8]. Beyond non-invasive imaging, elevated left ventricular enddiastolic pressures on cardiac catheterization have also been identified as a major prognostic marker in this setting [8]. While the utility of regular transthoracic echocardiography in predicting outcome has been established [9], CMR has emerged as the gold standard imaging modality for assessing ventricular volumes in ToF patients. It has only recently, however, become possible to quantify mechanical dyssynchrony on CMR using standard CMR cine images. This is due to the introduction of CMR feature tracking (FT) analysis - a technique for the quantification of myocardial strain using standard steady-state-free precession (SSFP) images [10]. We have reported on the feasibility of using FT analysis for measuring myocardial deformation and its potential prognostic value [11,12]. However, information on the potential clinical utility of FT derived parameters of mechanical dyssynchrony are limited in contemporary ToF patients [13,14]. The pathophysiologic rationale for the evaluation of measures of mechanical dyssynchrony is provided by the observation that electrical dyssynchrony is a prognostic marker in ToF patients and by previous studies suggesting an association between mechanical asynchrony and outcome [6,14,21,30]. The current study was designed to evaluate the potential association between biventricular mechanical dyssynchrony on FT-CMR with parameters of biventricular mechanics, exercise capacity, clinical data and outcome in a large multicenter cohort of ToF patients. 2. Materials and methods The current study included patients enrolled in a nationwide, prospective study of ToF patients run by the German Competence Network for Congenital Heart Defects as described before [15]. In essence, patients with repaired ToF older than 8 years were recruited at various German centers (24 centers overall) between 2005 and 2008. All patients without contraindications for CMR (such as implanted pacemakers or ICD devices) were invited to participate. All enrolled ToF-patients underwent CMR investigations (avoiding sedation) using a standardized CMR protocol. Acquired datasets were stored on a central archiving database in a pseudonymized format. Further details on the CMR protocol, quality assurance measures and conventional (volumetric) analysis have been reported [15–17]. Feature tracking analysis was performed prospectively on all digitally archived datasets by using the TomTec 2D CPA MR software (TomTec, Unterschleissheim, Germany, Version 1.1.2.36-B) by GD and SO. There was no difference image quality between the right and left ventricle. Analysis was performed separately for both ventricles by delineating the endocardial border followed by automatic FT computation. For all analysis the quality and adequacy of myocardial displacement and the tracking contour was
controlled visually and the analysis repeated if required. Longitudinal and radial deformation parameters of the LV and RV were assessed in a four chamber view. Circumferential parameters of both LV and RV were assessed in the short axis view at the level of the papillary muscles. Additional details of the FT algorithm have been published by us and others [18–21]. Data on reproducibility of the FT-method in the setting of ToF has also been provided by our group [22]. As described previously [12], available clinical characteristics included the NYHA (New York Heart Association) functional class, the QRS duration on standard 12-lead ECG, as well as details of previous interventional and surgical procedures. Patients also were subjected to symptom-limited cardiopulmonary exercise testing on a treadmill or bicycle ergometer at the time of CMR [23]. Mechanical dyssynchrony was assessed by quantifying the maximum wall delay of the longitudinal, radial (both in a long axis and short axis view) as well as circular contraction of the right and left ventricle. The method of assessment of maximum wall delay is illustrated in Fig. 1. Follow-up was secured by using competence network infrastructure and/or by contacting local institutions or residents' registration office if required. As an endpoint of the study we chose a composite of documented ventricular tachycardia (sustained or non-sustained) or cardiac death, which included aborted cardiac death. The study protocol has been approved by the relevant ethics committee and all patients/guardians gave informed consent before recruitment/inclusion in the study.
2.1. Statistics Depending on data distribution parameter values are given as mean and standard deviation or median and interquartile range (25th and 75th percentile). Categorical variables are shown as frequencies and percentages. The association between parameters of mechanical dyssynchrony, myocardial deformation parameters, conventional volumetric markers of ventricular function and clinical status was assessed by Spearman's rank regression analysis. In addition, the potential association with outcome was studied by Cox proportional-hazard analysis. Due to the limited number of events no multivariate analyses were performed. For all analyses, a 2-tailed p-value b0.05 was used as the criterion for statistical significance. Statistical analyses were performed using MedCalc 17.6 (MedCalc Software, Mariakerke, Belgium) and R version 3.3.0 (The R Foundation for Statistical Computing).
3. Results Overall, adequate CMR images for FT assessment of mechanical dyssynchrony were available in 345 patients (56% male, mean age 17.5 ± 8.3 years, RV end-diastolic volume index 121 ± 33 ml/m2, RV ejection fraction 50 ± 9%; LV ejection fraction 57 ± 9%). Values of the measures of mechanical dyssynchrony are provided in Table A (Online Appendix). The majority of patients were asymptomatic and the objective exercise capacity as assessed by cardiopulmonary exercise testing
Please cite this article as: P. Kalaitzidis, et al., Biventricular dyssynchrony on cardiac magnetic resonance imaging and its correlation with myocardial deformation, ventricular func..., Int J Cardiol (2018), https://doi.org/10.1016/j.ijcard.2018.04.005
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same anatomical position and strain orientation (longitudinal, radial or circumferential). This is shown by the significant values (shaded areas in grey) on the diagonal of the correlation matrix provided in Fig. 2.
Table 1 Demographic and baseline characteristics. Parameter Demographic parameters Number of patients Gender Age at CMR Age at correction Previous palliation Transannular patch Previous pulmonary valve replacement Functional class NYHA class (I/II/III) Arrhythmia and ECG parameters Sinus rhythm at CMR Antiarrhythmic medication at CMR QRS duration Objective exercise capacity Peak VO2 Peak VO2 at anaerobic threshold % pred. peak VO2 Peak heart rate Selected conventional CMR measurements LVEDVi LVESVi LV EF LV mass RVEDVi RVESVi RV EF RV mass Pulmonary regurgitation fraction
3
345 193 male 17.5 ± 8.3 years 2.4 ± 3.6 years 71 69 52 66/32/2% 99.70% 2% 146 ± 24 ms 31.9 ± 9.2 ml/kg/min 25.1 ± 10.3 ml/kg/min 80 ± 22% 168 ± 21 beats per minute 81 ± 17 mL/m2 35 ± 13 mL/m2 57 ± 9% 64.6 ± 14.0 g/m2 121 ± 33 mL/m2 62 ± 24 mL/m2 50 ± 9% 36.5 ± 14.1 g/m2 27 ± 19%
CMR = cardiac magnetic resonance imaging, LV = left ventricle, RV = right ventricle. EDVi = end diastolic volume index, ESVi = end systolic volume index, EF = ejection fraction.
was – on average – only mildly reduced. Further details on demographic and clinical information at presentation are given in Table 1. 3.1. Correlation between parameters of mechanical dyssynchrony and CMR strain Wall motion delay correlated significantly with myocardial displacement assessed by myocardial strain as illustrated in Fig. 2. As expected wall motion delay was negatively correlated to strain measures in the
3.2. Relationship between parameters of mechanical dyssynchrony, biventricular function and exercise capacity Wall motion delay parameters correlated significantly with left and right ventricular ejection fraction as shown in Fig. 3. In addition, circumferential LV and RV dyssynchrony was negatively correlated with objective exercise capacity (Fig. 3). In addition, RV short axis circumferential strain was found to correlate with symptoms (i.e. NYHA class N1) on logistic regression analysis (odds ratio 6.21 [95% CI 1.34–28.91]/%, p = 0.02). 3.3. Relationship between parameters of mechanical dyssynchrony and outcome During a median follow up time of 4.7 years (interquartile range 2.1–5.4 years), 10 patients experienced an event. This included 3 cardiac deaths, 2 aborted cardiac deaths with successful resuscitation and 5 documented non-sustained ventricular tachycardias. Table B (Online supplement) presents the results of the (univariate) Cox-proportional hazards analysis for conventional volumetric CMR parameters, myocardial deformation (strain measured by FT CMR), QRS duration and exercise parameters. None of the studied CMR-FT mechanical dyssynchrony markers correlated significantly with the risk of the pre-specified composite endpoint (p N 0.05 for all). 4. Discussion The current study illustrates the feasibility of assessing intraventricular mechanical dyssynchrony in patients with repaired tetralogy Fallot. Parameters of mechanical dyssynchrony were found to correlate with symptoms, exercise capacity and conventional parameters of biventricular function as well as with myocardial displacement. Despite the fact that the degree of correlation with clinical markers was not very pronounced, these novel physiologic parameters that can be derived from conventional CMR cine images might point to a potential value
Fig. 2. Correlation matrix illustrating the association between parameters of mechanical dyssynchrony and myocardial function (measured by myocardial strain). As expected the significant associations are mainly located on the diagonal of the matrix corresponding to similar anatomical position and geometric orientation of contraction. Circ. = circular, CS = circumferential strain, LAX = long axis, long. = longitudinal, LS = longitudinal strain, LV = left ventricle, rad. = radial, RV = right ventricle, RS = radial strain, SAX = short axis. Significant correlations are presented in grey.
Please cite this article as: P. Kalaitzidis, et al., Biventricular dyssynchrony on cardiac magnetic resonance imaging and its correlation with myocardial deformation, ventricular func..., Int J Cardiol (2018), https://doi.org/10.1016/j.ijcard.2018.04.005
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Fig. 3. Correlation matrix illustrating the association between parameters of mechanical dyssynchrony and biventricular ejection fraction as well as peak oxygen consumption (% of predicted) based on the results of Spearman's rank correlation analysis. Circ. = circumferential, EF = ejection fraction, Long = longitudinal, LV = left ventricle, RV = right ventricle, VO2 = oxygen uptake. Significant correlations are presented in grey.
of assessing CMR based mechanical myocardial dyssynchrony in ToF patients in future. Tetralogy of Fallot has been one of the prime focus areas of research in congenital heart disease in the last decades for various reasons. Firstly, ToF represents the most common form of cyanotic heart disease at birth. Secondly, despite initially successful surgical repair ToF patients are far from being cured [24]. Late complications include pulmonary regurgitation, heart failure symptoms and especially malignant arrhythmias associated with sudden cardiac death (SCD). Risk stratification algorithms have been developed but predicting individual risk of sudden cardiac death in ToF patients remains an unsolved problem. While survived SCD is a clear indication for secondary prevention implantation of an implantable cardioverter/defibrillator (ICD), identifying patients likely to benefit from such a device for primary prevention remains challenging. This is, in part, mediated by the low annual incidence rate of SCD. In addition, it has become obvious that multimodal assessment, integrating different clinical, electrical, invasive and imaging parameters into risk scores is required to identify patients at risk. Gatzoulis et al. have established a prolonged QRS-duration, exceeding 180 ms as a risk factor in this setting [6]. In isolation, however, this parameter is insufficiently discriminative to guide primary prevention ICD implantation. Interestingly, due to earlier repair and improved surgical expertise it now appears from more recent studies that prolongation of QRS duration is lower in more contemporary ToF patients. Although in part speculative, it seems that lower cut-off value for QRS duration, therefore, should be employed when assessing the risk of sudden cardiac death. Consistent with these data is the observation that only 9 patients (2.6%) included in the current study had a QRS duration above 180 ms. Khairy and colleagues have proposed a risk score based on medical history, QRS duration, the results of electrophysiological assessment (ventricular stimulation) and invasive measurements of LV enddiastolic pressures [8,25]. The need for invasive assessment remains one of the major drawbacks of this published risk score and limits its clinical uptake in routine practice. Left ventricular systolic dysfunction has been suggested as a surrogate for LV end-diastolic pressures in this setting but its clinical utility remains to be established [9,26,27]. The exact etiology of LV dysfunction in the setting of ToF, however, remains unclear and is likely related to the adverse impact of RV dilation/dysfunction on LV function (ventriculo–ventricular interaction) [28]. Ultimately, therefore, RV dysfunction and dyssynchrony remain central to the onset of malignant arrhythmia in ToF patients. We hypothesized that CMR based quantification of dyssynchrony could add to echocardiographic assessment by providing a wider field of view and allowing for free choice of imaging plane. In fact, CMR based parameters of dyssynchrony were found to be correlated with exercise capacity, electrical dyssynchrony as well as biventricular function in the current study. We could not establish a direct relationship between
CMR markers of mechanical dyssynchrony and outcome in a young cohort of largely asymptomatic ToF patients, however. The lack of an association is not entirely explained by the young population and the low event rate, as various other parameters were found to be significantly related to the combined end-point in our study (see Table B). Potentially, the inability of this novel CMR based technique to quantify RV outflow tract dyssynchrony limits its predictive value. Therefore, further efforts are required to implement software algorithms for the quantification of RV outflow tract disease in the commercially available FT software packages. This should be technically possible and could further supplement conventional CMR imaging describing functional impairment, wall motion abnormalities, aneurysms and myocardial fibrosis. As available data suggests that arrhythmias originate mainly in the RV outflow tract correlating outflow tract dyssynchrony with electrophysiological and outcome data appears promising and further research along this line is recommended [29]. Available data on the prognostic value of mechanical dyssynchrony in ToF is conflicting so far. While Ortega et al. have reported an association between LV dyssynchrony and outcome in 39 ToF patients, two later reports by Moon and Jing failed to confirm a significant relationship between CMR derived mechanical dyssynchrony and adverse outcome or clinical deterioration in 48 and 153 ToF patients, respectively [14,21,30]. The major strength of our dataset compared to the available literature is the large number of patients included. Given the results of over 300 patients investigated here, it appears that – using available technology – assessing mechanical dyssynchrony on CMR is unlikely to add significantly to established risk markers in contemporary ToF patients. Nonetheless, recording wall motion delay on CMR might in future add to clinical decision as part of the multimodal patient assessment and potentially highlighting the need for electrophysiological consultation in selected patients. 4.1. Limitations of the study The current study – despite its sizable patient population included – was not specifically (and a priori) powered to assess the prognostic value of novel FT parameters in ToF patients. The results of this study should, therefore, be regarded as hypothesis generating and be considered primarily as proof of feasibility and physiological relevance of the assessed FT parameters. Interventricular dyssynchrony was not assessed as part of the current study but could yield additional physiologic and prognostic value. As patients with implantable cardioverter defibrillators - the subset of patients deemed at particularly high risk of sudden cardiac death - had to be excluded from the study cohort, the studied population includes a selection bias, presumably favoring lower risk ToF patients.
Please cite this article as: P. Kalaitzidis, et al., Biventricular dyssynchrony on cardiac magnetic resonance imaging and its correlation with myocardial deformation, ventricular func..., Int J Cardiol (2018), https://doi.org/10.1016/j.ijcard.2018.04.005
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5. Conclusions Biventricular mechanical dyssynchrony can be quantified based on conventional cine CMR imaging using feature tracking techniques. Ventricular wall motion delay is associated with biventricular dysfunction, electrical dyssynchrony and exercise intolerance in contemporary ToF patients. Our data underscore the pathological importance of assessing the degree of dyssynchrony in ToF patients but questions its prognostic value at present. Due to the weak degree of correlation the clinical significance of these findings remains to be clarified by further studies before the inclusion of parameters of mechanical dyssynchrony in routine CMR assessment can be recommended.
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Conflicts of interest The authors report no relationships that could be construed as a conflict of interest. Acknowledgements This study was supported by a research grant from the EMAH Stiftung Karla Voellm, Krefeld, Germany. This study conducted by the Competence Network for Congenital Heart Defects was funded by the German Federal Ministry of Education and Research (BMBF), FKZ 01G10210 and 01GI0601.
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Appendix A. Supplementary data
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Please cite this article as: P. Kalaitzidis, et al., Biventricular dyssynchrony on cardiac magnetic resonance imaging and its correlation with myocardial deformation, ventricular func..., Int J Cardiol (2018), https://doi.org/10.1016/j.ijcard.2018.04.005