- Email: [email protected]
Left Ventricular Function in Children and Adolescents With Arrhythmogenic Right Ventricular Cardiomyopathy
Left Ventricular Function in Children and Adolescents With Arrhythmogenic Right Ventricular Cardiomyopathy Paweena Chungsomprasong, MDa, Robert Hamilton, MDa, Wietske Luining, BSca, Meena Fatah, HBSca, Shi-Joon Yoo, MDa,b, and Lars Grosse-Wortmann, MDa,b,* The aim of this study was to determine if left ventricular (LV) contractility is reduced in children with arrhythmogenic right ventricular cardiomyopathy (ARVC). For this retrospective study, children and adolescents undergoing a workup for ARVC were characterized according to the revised Task Force Criteria (rTFC). LV strain, rotation, and torsion were measured by feature-tracking cardiovascular magnetic resonance imaging (CMR). Of 142 pediatric patients, 41% had no, 23% possible, 20% borderline, and 16% definite ARVC. LV ejection fraction (EF) did not differ between rTFC categories. Patients in higher rTFC categories had lower right ventricular (RV) EF z-scores (Z-), higher Z-RV end-diastolic volumes (EDVs) and larger Z-LVEDVs (p <0.001, p [ 0.002 and 0.013, respectively). LV global circumferential strain was lower in higher rTFC categories (p [ 0.018). Z-LVEDV correlated with Z-RVEDV, and Z-LVEF correlated with Z-RVEF (r [ 0.69 and r [ 0.55, both p <0.001). Z-LVEF and Z-RVEF correlated with LV global circumferential strain (r [ 0.48 and r [ 0.46, both p <0.001). Forty-eight patients (34%) underwent follow-up CMR investigations after a mean of 3.2 – 1.9 (0.4 to 8.4) years. A decrease of Z-LVEF over time correlated with that of Z-RVEF (r [ 0.35), and Z-LVEDV increase correlated with Z-RVEDV increase (r [ 0.57). In conclusion, LV myocardial dysfunction is present in young patients with suspected ARVC. Progressive LV dysfunction assessed by conventional CMR and feature-tracking and enlargement over time parallel adverse remodeling of the RV. Ó 2016 Elsevier Inc. All rights reserved. (Am J Cardiol 2016;-:-e-) Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically determined, progressive condition and a cause of potentially fatal tachyarrhythmia. As suggested by its name, ARVC has traditionally been regarded as a predominantly right ventricular (RV) disease. However, involvement of the left ventricle (LV) is increasingly recognized in adults with ARVC1,2 in whom LV dysfunction appears to be a risk factor for heart failure and ventricular arrhythmias.3,4 In contrast, it is unclear whether pediatric patients are affected.5,6 Signs and symptoms of ARVC are generally less advanced in children compared with adults.7 We hypothesized that children with ARVC harbor abnormalities of LV systolic function and that the detection of these abnormalities require more sensitive measures of myocardial contractility than ejection fraction (EF). The objective of this study was to assess LV global function and myocardial mechanics in children who underwent a diagnostic workup for ARVC and to assess whether they predict adverse ventricular remodeling in the future.
a Department of Paediatrics, Labatt Family Heart Centre and bDepartment of Diagnostic Imaging, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. Manuscript received September 9, 2016; revised manuscript received and accepted November 10, 2016. See page 6 for disclosure information. *Corresponding author: Tel: (þ1) 416-813-7418; fax: (þ1) 416-8135857. E-mail address: [email protected] (L. Grosse-Wortmann).
0002-9149/16/$ - see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2016.11.020
Methods This retrospective study was approved by the institutional research ethics board and complies with the Declaration of Helsinki. The data of consecutive children and adolescents who underwent a workup for ARVC at a single institution from 2005 to 2009 were reviewed for this retrospective study. Using the patients’ family history, results of cardiovascular magnetic resonance imaging (CMR), electrocardiogram (ECG), signal-averaged ECG, echocardiogram, Holter monitoring, endomyocardial biopsy, and genetic test results, patients were classified as having “no,” “possible,” “borderline,” or “definite” ARVC according to the revised Task Force Criteria (rTFC).8 Patients with concomitant congenital heart disease other than a hemodynamically insignificant interatrial communication and those with insufficient axial or short-axis cine imaging were excluded. Patients who lacked information in more than 2 of the rTFC criteria categories were also excluded. Some of the results in this cohort were previously published under a different objective.9 The family history and genetic information was updated following our previous report on this cohort, leading to recategorization in a small number of patients. Forty-eight patients (34%) of study patients underwent repeat CMR examinations and were reviewed for a change in LV/RV EF and end-diastolic volumes (EDVs). CMR scans were performed on a 1.5-T CMR scanner (Signa CV/I; General Electric Medical Systems, Milwaukee, Wisconsin or Avanto; Siemens Medical Solutions, Erlangen, Germany). Details regarding the scan protocol can be found elsewhere.10,11 In summary, the protocol included www.ajconline.org
2
The American Journal of Cardiology (www.ajconline.org)
Table 1 Right and left ventricular function Variable
Z-RVEDV Z-LVEDV Z-RVEF Z-LVEF Presence of RV RWMAs (%) PR at apex( )* PR at base( )* GCS (%) - base - mid - apex - IVS - FW GCS rate (%/s) - base - mid - apex - IVS - FW Torsion ( )
All N¼142
No ARVC N¼56 (39%)
Possible N¼33 (23%)
Borderline N¼29 (20%)
Definite N¼24 (18%)
P value across all groups (ANOVA)
P value (‘no’ versus ‘definite’ ARVC)
0.21.6 0.31.8 -1.51.7 -0.41.5 52 (36.6) 10.3 (4.4-21.6) -8.54.7 -24.74.3 -23.53.5 -22.13.9 -28.27.2 -24.23.8 -26.15.0 -1.60.4 -1.40.3 -1.30.3 -2.00.8 -0.90.7 -1.80.5 8.43.0
-0.31.3 0.02 1.5 -1.11.7 -0.31.5 9 (16) 10.6 (5.5-27.6) -8.84.9 -25.34.5 -24.03.4 -22.64.3 -29.78.2 -24.73.6 -26.94.9 -1.60.4 -1.40.3 -1.40.4 -2.10.8 -1.00.9 -1.60.4 8.83.4
-0.11.8 -0.042.0 -1.41.5 -0.41.5 10 (30.3) 10.2 (4.9-21.1) -8.44.5 -25.54.0 -23.72.7 -22.42.8 -28.85.6 -24.52.8 -27.05.0 -1.60.3 -1.40.3 -1.40.3 -2.00.8 -1.00.6 -1.80.4 8.22.6
0.81.4 1.01.7 -1.31.2 -0.051.24 14 (48.3) 9.4 (4.4-21.0) -8.95.7 -24.83.8 -24.43.4 -22.73.4 -27.26.9 -24.23.9 -25.85.0 -1.60.3 -1.40.3 -1.40.3 -1.90.6 -1.00.7 -1.90.4 8.02.8
1.01.7 0.42.1 -2.72.1 -0.91.8 19 (79.2) 9.4 (5.1-20.8) -7.42.4 -22.14.1 -21.04.2 -19.84.0 -24.86.0 -21.34.3 -23.35.3 -1.40.4 -1.20.3 -1.20.2 -1.70.8 -0.80.7 -1.90.5 8.33.2
<0.001 0.052 0.002 0.251 <0.001 0.392 0.811 0.01 0.006 0.018 0.037 0.02 0.042 0.058 0.080 0.049 0.157 0.726 0.062 0.829
0.001 0.422 0.003 0.192 <0.001 0.210 0.349 0.004 0.01 0.008 0.005 0.05 0.016 0.024 0.019 0.003 0.045 0.389 0.061 0.639
The statistically significant p values are in bold. EDV ¼ end-diastolic volume; EF ¼ ejection fraction; FW ¼ LV free wall; GCS ¼ global circumferential strain; IVS ¼ intraventricular septum; LV ¼ left ventricle; PR ¼ peak rotation; RV ¼ right ventricle; RWMAS ¼ regional wall motion abnormalities; Z ¼ z-score. * Higher values denote greater counterclockwise rotation. Lower (more negative) values reflect stronger clockwise rotation.
ECG-gated cine imaging in the axial, short axis, and 2-chamber planes using the steady-state free precession (SSFP) technique, with a temporal resolution sufficient to acquire 20 true phases per cardiac cycle. Ventricular volumes and EFs were derived from a cine short-axis stack in the routine clinical fashion, using commercially available software (Mass Analysis; Medis Medical Imaging Systems, Leiden, the Netherlands). EDVs and EFs of both ventricles were converted into Z-scores (Z-) according to published normative data for different ages and genders.12 The differences between the initial and the last available CMR Z-scores were divided by the follow-up duration to obtain the rates of progression. Left ventricular (LV) myocardial mechanics were quantified using the aforementioned standard SSFP cine images and feature-tracking software (2D Cardiac Performance Analysis MR; TomTec, Unterschleissheim, Germany). The feature-tracking approach is described in detail elsewhere.13 In brief, the endocardium/blood border was manually defined at one phase within the cardiac cycle. This contour was then propagated to the remaining cardiac phases using an automated border-tracking algorithm.13 LV global circumferential strain (GCS) and strain rate were measured at 3 short-axis levels. Rotation was quantified at the basal and apical levels. By convention, clockwise rotation is expressed as negative angles and counterclockwise rotation as positive angles.14 The base typically rotates clockwise and the apex counterclockwise. Torsion was calculated as follows15: Torsion ¼ (PRapex PRbase) (rapex þ rbase)/ (2 L) where PR ¼ peak rotation at the basal and apical
levels, L ¼ LV length (measured in the 2-chamber view at end diastole) and r ¼ LV radius at the basal and apical levels (measured in short axis at end diastole). Gadolinium was administrated for enhancement imaging to assess for myocardial scars. Continuous variables are presented as means SDs if distributed normally and as medians and ranges otherwise. Normality of distribution was tested using the Shapiro-Wilk test. Categorical data are reported as n (%). Continuous variables were compared across 4 diagnostic categories by analysis of variance and by Kruskal-Wallis tests for normally and nonnormally distributed data, respectively. Categorical variables were compared using the chi-square test. Correlation was assessed by the Pearson and Spearman rank correlation coefficient if distributed normally and not normally, respectively. Patients in the “possible” and “borderline” rTFC categories may or may not have ARVC, potentially blurring the differences between health and disease. Therefore, patients with “no” ARVC according to the rTFC were contrasted to the ones with “definite” ARVC using unpaired Student t tests. For all analyses, p values <0.05 were regarded as statistically significant. SPSS version 20.0 (IBM, Armonk, New York) was used for all statistical analyses. Results The diagnostic tests of 213 consecutive patients referred for the first time evaluation ARVC, including CMR, were reviewed. Twenty-eight patients were excluded because of
Cardiomyopathy/LV Function in Pediatric ARVC
3
Figure 1. Correlation of baseline right with LV volumes and EFs and of progression of left and RV volumes and EFs. LV EDV (A) and EF (B), expressed as z-scores, correlate with RVEDV and RVEF. Similarly, the rates of increase of ventricular size (C) and decline in EF (D) correlate between the LV and RV. EDV ¼ end diastolic volume; EF ¼ ejection fraction; LV ¼ left ventricle; RV ¼ right ventricle; Z ¼ z-score.
incomplete or poor-quality cine imaging on CMR, 23 due to concomitant significant congenital heart disease, and 20 because of missing data in 3 or more rTFC criteria. The remaining 142 patients (80 male [56%]) were enrolled (Table 1). Reasons for referral (some patients had more than one) included family history in 67 patients (47%), cardiac symptoms in 55 (38%), ventricular arrhythmias in 49 (35%), incidentally discovered abnormal electrocardiographic findings in 3 (2%), and incidental abnormal echocardiographic findings in 5 (4%). Their median age at the first evaluation was 14.6 years (3.0 to 18.0; medians of 14.3, 14.1, 15.3, and 15.2 years in the no, possible, borderline, and definite ARVC groups, respectively, p ¼ 0.17). Patients in higher rTFC categories had lower Z-RVEF and higher ZRVEDV. Z-LVEF did not differ between rTFC categories; there was a trend toward larger LVs in patients in higher rTFC categories. The differences and similarities between the 4 diagnostic groups by analysis of variance test were mirrored by the t test results between the “no” and “definite” ARVC groups. Z-LVEDV correlated with Z-RVEDV and Z-LVEF correlated with Z-RVEF (Figure 1). No late gadolinium enhancement in the LV myocardium was detected
in this study. A total of 39 children had undergone genetic testing, and 8 had mutations which are reportedly associated with ARVC (5 plakophilin-2, 1 desmocollin-2, 1 desmoplakin, and 1 transmembrane protein-43). Patients with a pathogenic mutation did not differ from confirmed gene negative patients with regards to ventricular size and EF. Cardiac magnetic resonance feature tracking was successful in all patients. The results for LV myocardial circumferential strain, rotation, and torsion are provided in Table 1. Patients in greater rTFC categories had worse LV GCS (Figure 2). There was a trend toward lower LV GCS rate in patients in greater rTFC categories. LV GCS and GCS rate were reduced in patients with “definite” ARVC compared with those with “no” ARVC. When applying published normal values for GCS by CMR feature tracking in children and defining values > mean þ 2 SDs as a cutoff for decreased GCS, 5 patients (9%) with no, 1 (3%) with possible, 2 (7%) with borderline, and 6 (26%) with definite ARVC had abnormally low circumferential strain, p ¼ 0.034.16 Worse circumferential strains in the intraventricular septum and in the LV free wall were found in patients with greater rTFC categories and were worse in the “definite” compared with
4
The American Journal of Cardiology (www.ajconline.org)
Figure 2. Circumferential strain (A), strain rate (B), Z-LVEF, and Z-LVEDV (C) in the 4 diagnostic categories of the rTFC. Circumferential strain (A) and circumferential strain rate (B) are worse in patients with a “definite” diagnosis of ARVC than in those with “no” ARVC. At the apex, these parameters show a progressive decline with increasing diagnostic certainty, that is, from “no” to “possible” to “borderline” to “definite” ARVC. Z-LVEF and LVEDV did not differ between rTFC categories. EDV ¼ end-diastolic volume; EF ¼ ejection fraction; LV ¼ left ventricle; Z ¼ z-score.
Cardiomyopathy/LV Function in Pediatric ARVC
the “no” ARVC group. There was a trend toward worse strain rate within the free wall across all groups and between “definite” and “no” ARVC. There was a trend toward weaker GCS rate in patients with RVEF < 2 (p ¼ 0.085). Patients with LVEF t-2 had worse LV GCS, LV GCS rate, and LV peak apical rotation (21.3 3.6% vs 25.3 4.1%, p <0.001, 1.4 0.3%/s vs 1.6 0.4%/s, p ¼ 0.014 and 9.7 1.5( ) vs 11.6 4.7( ), p ¼ 0.001, respectively). Higher peak apical rotation, that is, stronger counterclockwise rotation, correlated with smaller Z-RVEDV and smaller Z-LVEDV and with better Z-LVEF (r ¼ 0.26, 0.19 and 0.23, p ¼ 0.005, 0.04 and 0.01, respectively). There was a trend toward a correlation of torsion with Z-LVEF and Z-RVEF (r ¼ 0.21, p ¼ 0.06 for both). LV GCS, GCS rate, rotation, and torsion did not differ between gene positive and negative patients. RV WMAs were more prevalent in higher rTFC categories (p 0.001). Patients with RV WMAs had worse LV GCS (22.5 3.7% vs 23.9 3.3%, p ¼ 0.028). LV GCS correlated with Z-LVEF (r ¼ 0.48, p <0.001) and Z-RVEF (r ¼ 0.46, p <0.001; shown in Figure 3). Strain rate correlated with Z-LVEF (r ¼ 0.38, p <0.001) and with Z-RVEF (r ¼ 0.28, p ¼ 0.02). Forty-eight patients (34%) underwent follow-up CMR investigations after a mean of 3.2 1.9 (0.4 to 8.4) years. The rate of deterioration of biventricular Z-EF or of chamber enlargement did not differ between rTFC categories (Table 2). The rate of decrease of Z-LVEF over time correlated with that of Z-RVEF (r ¼ 0.349, p ¼ 0.015), and the rate of Z-LVEDV increase correlated with that of Z-RVEDV increase (r ¼ 0.566, p <0.001). Basal and mid circumferential strain, global, mid, and apical circumferential strain rate, peak apical and basal rotation, and torsion did not correlate with progression of RV or LV systolic dysfunction or dilation. The incidence of adverse outcomes including death, heart transplantation, aborted sudden cardiac death, and documented sustained ventricular tachycardia was too low to evaluate their association with markers of ventricular and myocardial function.
Discussion The involvement of the LV in adults with ARVC is increasingly appreciated.17 However, the phenotype is typically milder during childhood and adolescence, and little is known about the prevalence and extent of adverse LV remodeling in youths with suspected ARVC. Our previous observation of LV enlargement in pediatric patients prompted us to investigate LV function in more detail.9 The present study, which represents the largest cohort of ARVC patients of any age group who were examined for LV myocardial mechanics, adds the following information to our understanding of LV integrity in ARVC: (1) LV systolic function is reduced in children and adolescents with ARVC; (2) advanced rTFC categories are characterized by impaired LV circumferential strain and strain rate but not by decreased LVEF; (3) lower LV circumferential strain and strain rate predict more rapid future decline in LVEF; (4) progressive enlargement and dysfunction in the LV parallel changes in the RV.
5
Figure 3. Left (A) and right (B) ventricular EF versus LV GCS. GCS correlates inversely not only with LV (A) but also with RV (B) EF, that is, better strain is associated with better EF. EF ¼ ejection fraction; GCS ¼ global circumferential strain; LV ¼ left ventricle; RV ¼ right ventricle; Z ¼ z-score.
Although right-sided heart signs and symptoms predominate in most patients and in the reports, up to 76% of pathology specimens of patients with ARVC show some degree of LV involvement.3 The presence of biventricular dysfunction is a stronger predictor of adverse outcomes including death and the need for heart transplantation than RV dysfunction alone.18 Using CMR, Sen-Chowdhry et al19 found evidence of LV myocardial scarring and fatty infiltration in affected adults and El Ghannudi et al6 demonstrated an association of LV scarring by late gadolinium enhancement CMR with reduced LVEF, presence of LV wall motion abnormalities, and LV dilatation. In our cohort, there was a close relation of RV and LV remodeling: LV size and EF correlated with RV size and EF at baseline and both ventricles deteriorated “in parallel” over time. Whether both ventricles are independently affected by the same primary disease process or whether these associations are causal through ventricular-ventricular interactions is unclear.20 Reports of isolated LV involvement in ARVC21 suggest that LV remodeling can be the primary expression of the disease. “Left-sided ARVC” is now regarded as a separate entity by some.22 Ejection fraction is commonly used to gauge ventricular systolic function. However, EF is a relatively crude measure of contractility. Strain rate has been shown to be less
6
The American Journal of Cardiology (www.ajconline.org)
Table 2 Progression of biventricular ejection fraction and size between the first and last magnetic resonance study Variable
All N¼48
No ARVC N¼10 (21%)
Interval between the initial and 2.65 (0.44-8.39) 2.49 the last CMR Z-RVEDV change (per year) -0.64 (-2.55- 3.99) 0.14 Z-LVEDV change (per year) 0.03 (-2.3 -6.45) 0.31 Z-RVEF change (per year) 0.98 (-2.52 e 1.8) 0.19 Z-LVEF change (per year) -0.28 (-6.1 -1.7) -0.15
(0.81-6.1)
Possible N¼13 (9%)
Borderline N¼12 (25%)
Definite N¼13 (27%)
2.34 (0.44-6.54)
3.12 (0.71-6.85)
3.15 (0.75-8.39)
(-0.85-1.07) -0.12 (-1.48-3.99) -0.13 (-1.7- 0.09) 0.01 (-0.53- 0.7) 0.15 (-0.29- 6.45) -0.18 (-1.48- 0.4) 0.24 (-1.11-1.64) 0.71 (-2.52-1.87) 0.10 (-0.4 -1.43) 0.27 (-1.32 -1.21) -0.22 (-0.29 -6.45) -0.18 (-1.48- 0.4) 0.024
(-2.55-0.64) (-2.29- 1.5) (-0.58 -1.34) (-2.29-1.51)
P value P value across (‘no’ all versus groups ‘definite’ (ANOVA) ARVC) 0.766
0.235
0.836 0.143 0.836 0.550
0.455 0.421 0.988 0.693
Results are presented as medians and (ranges). CMR ¼ cardiac magnetic resonance; EDV ¼ end-diastolic volume; EF ¼ ejection fraction; LV ¼ left ventricle; RV ¼ right ventricle; Z ¼ z-score.
affected by loading conditions than EF and has been shown to be a more sensitive indicator of functional decline than EF.23 In dilated cardiomyopathy, for example, LV strain, measured by CMR, is an independent predictor of survival.24 In the pediatric patients examined for this study, LVEF did not discriminate between the four rTFC groups, as opposed to circumferential strain and strain rate (Figure 2). Jain et al,2 using CMR tagging, revealed reduced circumferential strain in adults with “definite” or “borderline” ARVC. Using CMR feature tracking, similar to our approach, Heermann et al25 demonstrated reduced global longitudinal and basal circumferential strain rates in adult patients with ARVC. The present study illustrates that functional compromise of the LV is not confined to adult patients but that it is already present during childhood and adolescence, as evidenced by reduced circumferential strain and strain rate as well as a trend toward LV enlargement. Aneq et al26 demonstrated a reduction of LV longitudinal strain in adult patients with ARVC by echocardiographic speckle tracking even at an early disease stage. Paralleling their results, we found a gradual reduction in circumferential strain and strain rate from “no” to “definite” ARVC. Recently, Mast et al found that only 16% of adults with ARVC had reduced LVEF by echocardiography, whereas 55% had reduced strain. In their study, only LV myocardial deformation imaging and RV enlargement, but not LVEF, were predictors of adverse outcomes.4 Magnetic resonance feature tracking has been shown to measure circumferential strain with high reproducibility and reliability.27 An important advantage of feature tracking over tagging is its applicability to standard SSFP cine images and, at least at 1.5 T, the superior myocardial tracking.13 Feature-tracking analysis was successful in all patients analyzed in the present study. Previous studies showed excellent reproducibility, including in children.28 Although the present study reports the largest pediatric population evaluated for LV involvement in ARVC, the number of patients in each rTFC group was modest and longitudinal studies with a larger number of adverse outcomes are needed to assess the prognostic value of feature tracking in ARVC. The characterization of myocardial deformation would have been more complete with the inclusion of radial and longitudinal strain. However, radial strain lacks reproducibility by both echocardiography and
CMR which is why it was not included here, and no suitable cine images were available for longitudinal strain analysis. However, GCS is considered to be more representative of the outer, subepicardial fibers of the LV myocardium than longitudinal strain; and it is the subepicardial region which has been identified as the origin of the pathological changes of ARVC.29 The quantification of strain rate by CMR is hampered by the relatively poor temporal resolution of cine CMR compared with echocardiography. We conclude that LV myocardial dysfunction is present in children. Abnormal strain may be useful to detect early LV involvement despite initially preserved LVEF. Therefore, children and adolescents with suspected or confirmed ARVC should be monitored for LV dysfunction especially in those who show signs of adverse RV remodeling. Disclosures Dr. Chungsomprasong was funded by Siriraj Hospital Faculty of Medicine, Mahidol University, Thailand. None of the authors have conflicts of interest to disclose. 1. Saguner AM, Brunckhorst C, Duru F. Arrhythmogenic ventricular cardiomyopathy: a paradigm shift from right to biventricular disease. World J Cardiol 2014;6:154e174. 2. Jain A, Shehata ML, Stuber M, Berkowitz SJ, Calkins H, Lima JA, Bluemke DA, Tandri H. Prevalence of left ventricular regional dysfunction in arrhythmogenic right ventricular dysplasia: a tagged MRI study. Circ Cardiovasc Imaging 2010;3:290e297. 3. Corrado D, Basso C, Thiene G, McKenna WJ, Davies MJ, Fontaliran F, Nava A, Silvestri F, Blomstrom-Lundqvist C, Wlodarska EK, Fontaine G, Camerini F. Spectrum of clinicopathologic manifestations of arrhythmogenic right ventricular cardiomyopathy/dysplasia: a multicenter study. J Am Coll Cardiol 1997;30:1512e1520. 4. Mast TP, Teske AJ, Vd Heijden JF, Groeneweg JA, Te Riele AS, Velthuis BK, Hauer RN, Doevendans PA, Cramer MJ. Left ventricular involvement in arrhythmogenic right ventricular dysplasia/cardiomyopathy assessed by echocardiography predicts adverse clinical outcome. J Am Soc Echocardiogr 2015;28:1103e1113; e1109. 5. Pinamonti B, Sinagra G, Salvi A, Di Lenarda A, Morgera T, Silvestri F, Bussani R, Camerini F. Left ventricular involvement in right ventricular dysplasia. Am Heart J 1992;123:711e724. 6. El Ghannudi S, Nghiem A, Germain P, Jeung MY, Gangi A, Roy C. Left ventricular involvement in arrhythmogenic right ventricular cardiomyopathy - a cardiac magnetic resonance imaging study. Clin Med Insights Cardiol 2014;8(Suppl 4):27e36. 7. Hamilton RM, Fidler L. Right ventricular cardiomyopathy in the young: an emerging challenge. Heart Rhythm 2009;6:571e575.
Cardiomyopathy/LV Function in Pediatric ARVC 8. Marcus FI, McKenna WJ, Sherrill D, Basso C, Bauce B, Bluemke DA, Calkins H, Corrado D, Cox MG, Daubert JP, Fontaine G, Gear K, Hauer R, Nava A, Picard MH, Protonotarios N, Saffitz JE, Sanborn DM, Steinberg JS, Tandri H, Thiene G, Towbin JA, Tsatsopoulou A, Wichter T, Zareba W. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the Task Force Criteria. Eur Heart J 2010;31:806e814. 9. Etoom Y, Govindapillai S, Hamilton R, Manlhiot C, Yoo SJ, Farhan M, Sarikouch S, Peters B, McCrindle BW, Grosse-Wortmann L. Importance of CMR within the task force criteria for the diagnosis of ARVC in children and adolescents. J Am Coll Cardiol 2015;65:987e995. 10. Windram JD, Benson LN, Dragelescu A, Yoo SJ, Mertens L, Wong D, Grosse-Wortmann L. Distribution of hypertrophy and late gadolinium enhancement in children and adolescents with hypertrophic cardiomyopathy. Congenit Heart Dis 2015;10:E258eE267. 11. Grosse-Wortmann L, Dragulescu A, Drolet C, Chaturvedi R, Kotani Y, Mertens L, Taylor K, La Rotta G, van Arsdell G, Redington A, Yoo SJ. Determinants and clinical significance of flow via the fenestration in the Fontan pathway: a multimodality study. Int J Cardiol 2013;168: 811e817. 12. Buechel EV, Kaiser T, Jackson C, Schmitz A, Kellenberger CJ. Normal right- and left ventricular volumes and myocardial mass in children measured by steady state free precession cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2009;11:19. 13. Hor KN, Gottliebson WM, Carson C, Wash E, Cnota J, Fleck R, Wansapura J, Klimeczek P, Al-Khalidi HR, Chung ES, Benson DW, Mazur W. Comparison of magnetic resonance feature tracking for strain calculation with harmonic phase imaging analysis. JACC Cardiovasc Imaging 2010;3:144e151. 14. Opdahl A, Helle-Valle T, Remme EW, Vartdal T, Pettersen E, Lunde K, Edvardsen T, Smiseth OA. Apical rotation by speckle tracking echocardiography: a simplified bedside index of left ventricular twist. J Am Soc Echocardiogr 2008;21:1121e1128. 15. Young AA, Cowan BR. Evaluation of left ventricular torsion by cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2012;14:49. 16. Eichhorn JG, Buss S, Foell A, Helling A, Robbers-Visser D, Pieterman E, Bossers S, Lossnitzer D, Gorenflo M, Helbing WA. Quantification of left ventricular regional myocardial function using MRI feature tracking in healthy children - a dual-center study. J Cardiovasc Magn Reson 2013;15(Suppl 1):O42. 17. Tandri H, Saranathan M, Rodriguez ER, Martinez C, Bomma C, Nasir K, Rosen B, Lima JA, Calkins H, Bluemke DA. Noninvasive detection of myocardial fibrosis in arrhythmogenic right ventricular cardiomyopathy using delayed-enhancement magnetic resonance imaging. J Am Coll Cardiol 2005;45:98e103. 18. Pinamonti B, Dragos AM, Pyxaras SA, Merlo M, Pivetta A, Barbati G, Di Lenarda A, Morgera T, Mestroni L, Sinagra G. Prognostic predictors in arrhythmogenic right ventricular cardiomyopathy: results from a 10-year registry. Eur Heart J 2011;32:1105e1113.
7
19. Sen-Chowdhry S, Syrris P, Ward D, Asimaki A, Sevdalis E, McKenna WJ. Clinical and genetic characterization of families with arrhythmogenic right ventricular dysplasia/cardiomyopathy provides novel insights into patterns of disease expression. Circulation 2007;115:1710e1720. 20. Szymanski P, Klisiewicz A, Spiewak M, Szumowski L, Walczak F, Hoffman P. Left dominant arrhythmogenic cardiomyopathyea newly defined clinical entity. Int J Cardiol 2012;156:e60ee61. 21. De Pasquale CG, Heddle WF. Left sided arrhythmogenic ventricular dysplasia in siblings. Heart 2001;86:128e130. 22. Norman M, Simpson M, Mogensen J, Shaw A, Hughes S, Syrris P, Sen-Chowdhry S, Rowland E, Crosby A, McKenna WJ. Novel mutation in desmoplakin causes arrhythmogenic left ventricular cardiomyopathy. Circulation 2005;112:636e642. 23. Dahle GO, Stangeland L, Moen CA, Salminen PR, Haaverstad R, Matre K, Grong K. The influence of acute unloading on left ventricular strain and strain rate by speckle tracking echocardiography in a porcine model. Am J Physiol Heart Circ Physiol 2016;310:H1330eH1339. 24. Buss SJ, Breuninger K, Lehrke S, Voss A, Galuschky C, Lossnitzer D, Andre F, Ehlermann P, Franke J, Taeger T, Frankenstein L, Steen H, Meder B, Giannitsis E, Katus HA, Korosoglou G. Assessment of myocardial deformation with cardiac magnetic resonance strain imaging improves risk stratification in patients with dilated cardiomyopathy. Eur Heart J Cardiovasc Imaging 2015;16:307e315. 25. Heermann P, Hedderich DM, Paul M, Schulke C, Kroeger JR, Baessler B, Wichter T, Maintz D, Waltenberger J, Heindel W, Bunck AC. Biventricular myocardial strain analysis in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) using cardiovascular magnetic resonance feature tracking. J Cardiovasc Magn Reson 2014;16:75. 26. Aneq MA, Engvall J, Brudin L, Nylander E. Evaluation of right and left ventricular function using speckle tracking echocardiography in patients with arrhythmogenic right ventricular cardiomyopathy and their first degree relatives. Cardiovasc Ultrasound 2012;10:37. 27. Taylor RJ, Moody WE, Umar F, Edwards NC, Taylor TJ, Stegemann B, Townend JN, Hor KN, Steeds RP, Mazur W, Leyva F. Myocardial strain measurement with feature-tracking cardiovascular magnetic resonance: normal values. Eur Heart J Cardiovasc Imaging 2015;16:871e881. 28. Smith BM, Dorfman AL, Yu S, Russell MW, Agarwal PP, Ghadimi Mahani M, Lu JC. Relation of strain by feature tracking and clinical outcome in children, adolescents, and young adults with hypertrophic cardiomyopathy. Am J Cardiol 2014;114:1275e1280. 29. Te Riele AS, James CA, Philips B, Rastegar N, Bhonsale A, Groeneweg JA, Murray B, Tichnell C, Judge DP, Van Der Heijden JF, Cramer MJ, Velthuis BK, Bluemke DA, Zimmerman SL, Kamel IR, Hauer RN, Calkins H, Tandri H. Mutation-positive arrhythmogenic right ventricular dysplasia/cardiomyopathy: the triangle of dysplasia displaced. J Cardiovasc Electrophysiol 2013;24: 1311e1320.
a Department of Paediatrics, Labatt Family Heart Centre and bDepartment of Diagnostic Imaging, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. Manuscript received September 9, 2016; revised manuscript received and accepted November 10, 2016. See page 6 for disclosure information. *Corresponding author: Tel: (þ1) 416-813-7418; fax: (þ1) 416-8135857. E-mail address: [email protected] (L. Grosse-Wortmann).
0002-9149/16/$ - see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2016.11.020
Methods This retrospective study was approved by the institutional research ethics board and complies with the Declaration of Helsinki. The data of consecutive children and adolescents who underwent a workup for ARVC at a single institution from 2005 to 2009 were reviewed for this retrospective study. Using the patients’ family history, results of cardiovascular magnetic resonance imaging (CMR), electrocardiogram (ECG), signal-averaged ECG, echocardiogram, Holter monitoring, endomyocardial biopsy, and genetic test results, patients were classified as having “no,” “possible,” “borderline,” or “definite” ARVC according to the revised Task Force Criteria (rTFC).8 Patients with concomitant congenital heart disease other than a hemodynamically insignificant interatrial communication and those with insufficient axial or short-axis cine imaging were excluded. Patients who lacked information in more than 2 of the rTFC criteria categories were also excluded. Some of the results in this cohort were previously published under a different objective.9 The family history and genetic information was updated following our previous report on this cohort, leading to recategorization in a small number of patients. Forty-eight patients (34%) of study patients underwent repeat CMR examinations and were reviewed for a change in LV/RV EF and end-diastolic volumes (EDVs). CMR scans were performed on a 1.5-T CMR scanner (Signa CV/I; General Electric Medical Systems, Milwaukee, Wisconsin or Avanto; Siemens Medical Solutions, Erlangen, Germany). Details regarding the scan protocol can be found elsewhere.10,11 In summary, the protocol included www.ajconline.org
2
The American Journal of Cardiology (www.ajconline.org)
Table 1 Right and left ventricular function Variable
Z-RVEDV Z-LVEDV Z-RVEF Z-LVEF Presence of RV RWMAs (%) PR at apex( )* PR at base( )* GCS (%) - base - mid - apex - IVS - FW GCS rate (%/s) - base - mid - apex - IVS - FW Torsion ( )
All N¼142
No ARVC N¼56 (39%)
Possible N¼33 (23%)
Borderline N¼29 (20%)
Definite N¼24 (18%)
P value across all groups (ANOVA)
P value (‘no’ versus ‘definite’ ARVC)
0.21.6 0.31.8 -1.51.7 -0.41.5 52 (36.6) 10.3 (4.4-21.6) -8.54.7 -24.74.3 -23.53.5 -22.13.9 -28.27.2 -24.23.8 -26.15.0 -1.60.4 -1.40.3 -1.30.3 -2.00.8 -0.90.7 -1.80.5 8.43.0
-0.31.3 0.02 1.5 -1.11.7 -0.31.5 9 (16) 10.6 (5.5-27.6) -8.84.9 -25.34.5 -24.03.4 -22.64.3 -29.78.2 -24.73.6 -26.94.9 -1.60.4 -1.40.3 -1.40.4 -2.10.8 -1.00.9 -1.60.4 8.83.4
-0.11.8 -0.042.0 -1.41.5 -0.41.5 10 (30.3) 10.2 (4.9-21.1) -8.44.5 -25.54.0 -23.72.7 -22.42.8 -28.85.6 -24.52.8 -27.05.0 -1.60.3 -1.40.3 -1.40.3 -2.00.8 -1.00.6 -1.80.4 8.22.6
0.81.4 1.01.7 -1.31.2 -0.051.24 14 (48.3) 9.4 (4.4-21.0) -8.95.7 -24.83.8 -24.43.4 -22.73.4 -27.26.9 -24.23.9 -25.85.0 -1.60.3 -1.40.3 -1.40.3 -1.90.6 -1.00.7 -1.90.4 8.02.8
1.01.7 0.42.1 -2.72.1 -0.91.8 19 (79.2) 9.4 (5.1-20.8) -7.42.4 -22.14.1 -21.04.2 -19.84.0 -24.86.0 -21.34.3 -23.35.3 -1.40.4 -1.20.3 -1.20.2 -1.70.8 -0.80.7 -1.90.5 8.33.2
<0.001 0.052 0.002 0.251 <0.001 0.392 0.811 0.01 0.006 0.018 0.037 0.02 0.042 0.058 0.080 0.049 0.157 0.726 0.062 0.829
0.001 0.422 0.003 0.192 <0.001 0.210 0.349 0.004 0.01 0.008 0.005 0.05 0.016 0.024 0.019 0.003 0.045 0.389 0.061 0.639
The statistically significant p values are in bold. EDV ¼ end-diastolic volume; EF ¼ ejection fraction; FW ¼ LV free wall; GCS ¼ global circumferential strain; IVS ¼ intraventricular septum; LV ¼ left ventricle; PR ¼ peak rotation; RV ¼ right ventricle; RWMAS ¼ regional wall motion abnormalities; Z ¼ z-score. * Higher values denote greater counterclockwise rotation. Lower (more negative) values reflect stronger clockwise rotation.
ECG-gated cine imaging in the axial, short axis, and 2-chamber planes using the steady-state free precession (SSFP) technique, with a temporal resolution sufficient to acquire 20 true phases per cardiac cycle. Ventricular volumes and EFs were derived from a cine short-axis stack in the routine clinical fashion, using commercially available software (Mass Analysis; Medis Medical Imaging Systems, Leiden, the Netherlands). EDVs and EFs of both ventricles were converted into Z-scores (Z-) according to published normative data for different ages and genders.12 The differences between the initial and the last available CMR Z-scores were divided by the follow-up duration to obtain the rates of progression. Left ventricular (LV) myocardial mechanics were quantified using the aforementioned standard SSFP cine images and feature-tracking software (2D Cardiac Performance Analysis MR; TomTec, Unterschleissheim, Germany). The feature-tracking approach is described in detail elsewhere.13 In brief, the endocardium/blood border was manually defined at one phase within the cardiac cycle. This contour was then propagated to the remaining cardiac phases using an automated border-tracking algorithm.13 LV global circumferential strain (GCS) and strain rate were measured at 3 short-axis levels. Rotation was quantified at the basal and apical levels. By convention, clockwise rotation is expressed as negative angles and counterclockwise rotation as positive angles.14 The base typically rotates clockwise and the apex counterclockwise. Torsion was calculated as follows15: Torsion ¼ (PRapex PRbase) (rapex þ rbase)/ (2 L) where PR ¼ peak rotation at the basal and apical
levels, L ¼ LV length (measured in the 2-chamber view at end diastole) and r ¼ LV radius at the basal and apical levels (measured in short axis at end diastole). Gadolinium was administrated for enhancement imaging to assess for myocardial scars. Continuous variables are presented as means SDs if distributed normally and as medians and ranges otherwise. Normality of distribution was tested using the Shapiro-Wilk test. Categorical data are reported as n (%). Continuous variables were compared across 4 diagnostic categories by analysis of variance and by Kruskal-Wallis tests for normally and nonnormally distributed data, respectively. Categorical variables were compared using the chi-square test. Correlation was assessed by the Pearson and Spearman rank correlation coefficient if distributed normally and not normally, respectively. Patients in the “possible” and “borderline” rTFC categories may or may not have ARVC, potentially blurring the differences between health and disease. Therefore, patients with “no” ARVC according to the rTFC were contrasted to the ones with “definite” ARVC using unpaired Student t tests. For all analyses, p values <0.05 were regarded as statistically significant. SPSS version 20.0 (IBM, Armonk, New York) was used for all statistical analyses. Results The diagnostic tests of 213 consecutive patients referred for the first time evaluation ARVC, including CMR, were reviewed. Twenty-eight patients were excluded because of
Cardiomyopathy/LV Function in Pediatric ARVC
3
Figure 1. Correlation of baseline right with LV volumes and EFs and of progression of left and RV volumes and EFs. LV EDV (A) and EF (B), expressed as z-scores, correlate with RVEDV and RVEF. Similarly, the rates of increase of ventricular size (C) and decline in EF (D) correlate between the LV and RV. EDV ¼ end diastolic volume; EF ¼ ejection fraction; LV ¼ left ventricle; RV ¼ right ventricle; Z ¼ z-score.
incomplete or poor-quality cine imaging on CMR, 23 due to concomitant significant congenital heart disease, and 20 because of missing data in 3 or more rTFC criteria. The remaining 142 patients (80 male [56%]) were enrolled (Table 1). Reasons for referral (some patients had more than one) included family history in 67 patients (47%), cardiac symptoms in 55 (38%), ventricular arrhythmias in 49 (35%), incidentally discovered abnormal electrocardiographic findings in 3 (2%), and incidental abnormal echocardiographic findings in 5 (4%). Their median age at the first evaluation was 14.6 years (3.0 to 18.0; medians of 14.3, 14.1, 15.3, and 15.2 years in the no, possible, borderline, and definite ARVC groups, respectively, p ¼ 0.17). Patients in higher rTFC categories had lower Z-RVEF and higher ZRVEDV. Z-LVEF did not differ between rTFC categories; there was a trend toward larger LVs in patients in higher rTFC categories. The differences and similarities between the 4 diagnostic groups by analysis of variance test were mirrored by the t test results between the “no” and “definite” ARVC groups. Z-LVEDV correlated with Z-RVEDV and Z-LVEF correlated with Z-RVEF (Figure 1). No late gadolinium enhancement in the LV myocardium was detected
in this study. A total of 39 children had undergone genetic testing, and 8 had mutations which are reportedly associated with ARVC (5 plakophilin-2, 1 desmocollin-2, 1 desmoplakin, and 1 transmembrane protein-43). Patients with a pathogenic mutation did not differ from confirmed gene negative patients with regards to ventricular size and EF. Cardiac magnetic resonance feature tracking was successful in all patients. The results for LV myocardial circumferential strain, rotation, and torsion are provided in Table 1. Patients in greater rTFC categories had worse LV GCS (Figure 2). There was a trend toward lower LV GCS rate in patients in greater rTFC categories. LV GCS and GCS rate were reduced in patients with “definite” ARVC compared with those with “no” ARVC. When applying published normal values for GCS by CMR feature tracking in children and defining values > mean þ 2 SDs as a cutoff for decreased GCS, 5 patients (9%) with no, 1 (3%) with possible, 2 (7%) with borderline, and 6 (26%) with definite ARVC had abnormally low circumferential strain, p ¼ 0.034.16 Worse circumferential strains in the intraventricular septum and in the LV free wall were found in patients with greater rTFC categories and were worse in the “definite” compared with
4
The American Journal of Cardiology (www.ajconline.org)
Figure 2. Circumferential strain (A), strain rate (B), Z-LVEF, and Z-LVEDV (C) in the 4 diagnostic categories of the rTFC. Circumferential strain (A) and circumferential strain rate (B) are worse in patients with a “definite” diagnosis of ARVC than in those with “no” ARVC. At the apex, these parameters show a progressive decline with increasing diagnostic certainty, that is, from “no” to “possible” to “borderline” to “definite” ARVC. Z-LVEF and LVEDV did not differ between rTFC categories. EDV ¼ end-diastolic volume; EF ¼ ejection fraction; LV ¼ left ventricle; Z ¼ z-score.
Cardiomyopathy/LV Function in Pediatric ARVC
the “no” ARVC group. There was a trend toward worse strain rate within the free wall across all groups and between “definite” and “no” ARVC. There was a trend toward weaker GCS rate in patients with RVEF < 2 (p ¼ 0.085). Patients with LVEF t-2 had worse LV GCS, LV GCS rate, and LV peak apical rotation (21.3 3.6% vs 25.3 4.1%, p <0.001, 1.4 0.3%/s vs 1.6 0.4%/s, p ¼ 0.014 and 9.7 1.5( ) vs 11.6 4.7( ), p ¼ 0.001, respectively). Higher peak apical rotation, that is, stronger counterclockwise rotation, correlated with smaller Z-RVEDV and smaller Z-LVEDV and with better Z-LVEF (r ¼ 0.26, 0.19 and 0.23, p ¼ 0.005, 0.04 and 0.01, respectively). There was a trend toward a correlation of torsion with Z-LVEF and Z-RVEF (r ¼ 0.21, p ¼ 0.06 for both). LV GCS, GCS rate, rotation, and torsion did not differ between gene positive and negative patients. RV WMAs were more prevalent in higher rTFC categories (p 0.001). Patients with RV WMAs had worse LV GCS (22.5 3.7% vs 23.9 3.3%, p ¼ 0.028). LV GCS correlated with Z-LVEF (r ¼ 0.48, p <0.001) and Z-RVEF (r ¼ 0.46, p <0.001; shown in Figure 3). Strain rate correlated with Z-LVEF (r ¼ 0.38, p <0.001) and with Z-RVEF (r ¼ 0.28, p ¼ 0.02). Forty-eight patients (34%) underwent follow-up CMR investigations after a mean of 3.2 1.9 (0.4 to 8.4) years. The rate of deterioration of biventricular Z-EF or of chamber enlargement did not differ between rTFC categories (Table 2). The rate of decrease of Z-LVEF over time correlated with that of Z-RVEF (r ¼ 0.349, p ¼ 0.015), and the rate of Z-LVEDV increase correlated with that of Z-RVEDV increase (r ¼ 0.566, p <0.001). Basal and mid circumferential strain, global, mid, and apical circumferential strain rate, peak apical and basal rotation, and torsion did not correlate with progression of RV or LV systolic dysfunction or dilation. The incidence of adverse outcomes including death, heart transplantation, aborted sudden cardiac death, and documented sustained ventricular tachycardia was too low to evaluate their association with markers of ventricular and myocardial function.
Discussion The involvement of the LV in adults with ARVC is increasingly appreciated.17 However, the phenotype is typically milder during childhood and adolescence, and little is known about the prevalence and extent of adverse LV remodeling in youths with suspected ARVC. Our previous observation of LV enlargement in pediatric patients prompted us to investigate LV function in more detail.9 The present study, which represents the largest cohort of ARVC patients of any age group who were examined for LV myocardial mechanics, adds the following information to our understanding of LV integrity in ARVC: (1) LV systolic function is reduced in children and adolescents with ARVC; (2) advanced rTFC categories are characterized by impaired LV circumferential strain and strain rate but not by decreased LVEF; (3) lower LV circumferential strain and strain rate predict more rapid future decline in LVEF; (4) progressive enlargement and dysfunction in the LV parallel changes in the RV.
5
Figure 3. Left (A) and right (B) ventricular EF versus LV GCS. GCS correlates inversely not only with LV (A) but also with RV (B) EF, that is, better strain is associated with better EF. EF ¼ ejection fraction; GCS ¼ global circumferential strain; LV ¼ left ventricle; RV ¼ right ventricle; Z ¼ z-score.
Although right-sided heart signs and symptoms predominate in most patients and in the reports, up to 76% of pathology specimens of patients with ARVC show some degree of LV involvement.3 The presence of biventricular dysfunction is a stronger predictor of adverse outcomes including death and the need for heart transplantation than RV dysfunction alone.18 Using CMR, Sen-Chowdhry et al19 found evidence of LV myocardial scarring and fatty infiltration in affected adults and El Ghannudi et al6 demonstrated an association of LV scarring by late gadolinium enhancement CMR with reduced LVEF, presence of LV wall motion abnormalities, and LV dilatation. In our cohort, there was a close relation of RV and LV remodeling: LV size and EF correlated with RV size and EF at baseline and both ventricles deteriorated “in parallel” over time. Whether both ventricles are independently affected by the same primary disease process or whether these associations are causal through ventricular-ventricular interactions is unclear.20 Reports of isolated LV involvement in ARVC21 suggest that LV remodeling can be the primary expression of the disease. “Left-sided ARVC” is now regarded as a separate entity by some.22 Ejection fraction is commonly used to gauge ventricular systolic function. However, EF is a relatively crude measure of contractility. Strain rate has been shown to be less
6
The American Journal of Cardiology (www.ajconline.org)
Table 2 Progression of biventricular ejection fraction and size between the first and last magnetic resonance study Variable
All N¼48
No ARVC N¼10 (21%)
Interval between the initial and 2.65 (0.44-8.39) 2.49 the last CMR Z-RVEDV change (per year) -0.64 (-2.55- 3.99) 0.14 Z-LVEDV change (per year) 0.03 (-2.3 -6.45) 0.31 Z-RVEF change (per year) 0.98 (-2.52 e 1.8) 0.19 Z-LVEF change (per year) -0.28 (-6.1 -1.7) -0.15
(0.81-6.1)
Possible N¼13 (9%)
Borderline N¼12 (25%)
Definite N¼13 (27%)
2.34 (0.44-6.54)
3.12 (0.71-6.85)
3.15 (0.75-8.39)
(-0.85-1.07) -0.12 (-1.48-3.99) -0.13 (-1.7- 0.09) 0.01 (-0.53- 0.7) 0.15 (-0.29- 6.45) -0.18 (-1.48- 0.4) 0.24 (-1.11-1.64) 0.71 (-2.52-1.87) 0.10 (-0.4 -1.43) 0.27 (-1.32 -1.21) -0.22 (-0.29 -6.45) -0.18 (-1.48- 0.4) 0.024
(-2.55-0.64) (-2.29- 1.5) (-0.58 -1.34) (-2.29-1.51)
P value P value across (‘no’ all versus groups ‘definite’ (ANOVA) ARVC) 0.766
0.235
0.836 0.143 0.836 0.550
0.455 0.421 0.988 0.693
Results are presented as medians and (ranges). CMR ¼ cardiac magnetic resonance; EDV ¼ end-diastolic volume; EF ¼ ejection fraction; LV ¼ left ventricle; RV ¼ right ventricle; Z ¼ z-score.
affected by loading conditions than EF and has been shown to be a more sensitive indicator of functional decline than EF.23 In dilated cardiomyopathy, for example, LV strain, measured by CMR, is an independent predictor of survival.24 In the pediatric patients examined for this study, LVEF did not discriminate between the four rTFC groups, as opposed to circumferential strain and strain rate (Figure 2). Jain et al,2 using CMR tagging, revealed reduced circumferential strain in adults with “definite” or “borderline” ARVC. Using CMR feature tracking, similar to our approach, Heermann et al25 demonstrated reduced global longitudinal and basal circumferential strain rates in adult patients with ARVC. The present study illustrates that functional compromise of the LV is not confined to adult patients but that it is already present during childhood and adolescence, as evidenced by reduced circumferential strain and strain rate as well as a trend toward LV enlargement. Aneq et al26 demonstrated a reduction of LV longitudinal strain in adult patients with ARVC by echocardiographic speckle tracking even at an early disease stage. Paralleling their results, we found a gradual reduction in circumferential strain and strain rate from “no” to “definite” ARVC. Recently, Mast et al found that only 16% of adults with ARVC had reduced LVEF by echocardiography, whereas 55% had reduced strain. In their study, only LV myocardial deformation imaging and RV enlargement, but not LVEF, were predictors of adverse outcomes.4 Magnetic resonance feature tracking has been shown to measure circumferential strain with high reproducibility and reliability.27 An important advantage of feature tracking over tagging is its applicability to standard SSFP cine images and, at least at 1.5 T, the superior myocardial tracking.13 Feature-tracking analysis was successful in all patients analyzed in the present study. Previous studies showed excellent reproducibility, including in children.28 Although the present study reports the largest pediatric population evaluated for LV involvement in ARVC, the number of patients in each rTFC group was modest and longitudinal studies with a larger number of adverse outcomes are needed to assess the prognostic value of feature tracking in ARVC. The characterization of myocardial deformation would have been more complete with the inclusion of radial and longitudinal strain. However, radial strain lacks reproducibility by both echocardiography and
CMR which is why it was not included here, and no suitable cine images were available for longitudinal strain analysis. However, GCS is considered to be more representative of the outer, subepicardial fibers of the LV myocardium than longitudinal strain; and it is the subepicardial region which has been identified as the origin of the pathological changes of ARVC.29 The quantification of strain rate by CMR is hampered by the relatively poor temporal resolution of cine CMR compared with echocardiography. We conclude that LV myocardial dysfunction is present in children. Abnormal strain may be useful to detect early LV involvement despite initially preserved LVEF. Therefore, children and adolescents with suspected or confirmed ARVC should be monitored for LV dysfunction especially in those who show signs of adverse RV remodeling. Disclosures Dr. Chungsomprasong was funded by Siriraj Hospital Faculty of Medicine, Mahidol University, Thailand. None of the authors have conflicts of interest to disclose. 1. Saguner AM, Brunckhorst C, Duru F. Arrhythmogenic ventricular cardiomyopathy: a paradigm shift from right to biventricular disease. World J Cardiol 2014;6:154e174. 2. Jain A, Shehata ML, Stuber M, Berkowitz SJ, Calkins H, Lima JA, Bluemke DA, Tandri H. Prevalence of left ventricular regional dysfunction in arrhythmogenic right ventricular dysplasia: a tagged MRI study. Circ Cardiovasc Imaging 2010;3:290e297. 3. Corrado D, Basso C, Thiene G, McKenna WJ, Davies MJ, Fontaliran F, Nava A, Silvestri F, Blomstrom-Lundqvist C, Wlodarska EK, Fontaine G, Camerini F. Spectrum of clinicopathologic manifestations of arrhythmogenic right ventricular cardiomyopathy/dysplasia: a multicenter study. J Am Coll Cardiol 1997;30:1512e1520. 4. Mast TP, Teske AJ, Vd Heijden JF, Groeneweg JA, Te Riele AS, Velthuis BK, Hauer RN, Doevendans PA, Cramer MJ. Left ventricular involvement in arrhythmogenic right ventricular dysplasia/cardiomyopathy assessed by echocardiography predicts adverse clinical outcome. J Am Soc Echocardiogr 2015;28:1103e1113; e1109. 5. Pinamonti B, Sinagra G, Salvi A, Di Lenarda A, Morgera T, Silvestri F, Bussani R, Camerini F. Left ventricular involvement in right ventricular dysplasia. Am Heart J 1992;123:711e724. 6. El Ghannudi S, Nghiem A, Germain P, Jeung MY, Gangi A, Roy C. Left ventricular involvement in arrhythmogenic right ventricular cardiomyopathy - a cardiac magnetic resonance imaging study. Clin Med Insights Cardiol 2014;8(Suppl 4):27e36. 7. Hamilton RM, Fidler L. Right ventricular cardiomyopathy in the young: an emerging challenge. Heart Rhythm 2009;6:571e575.
Cardiomyopathy/LV Function in Pediatric ARVC 8. Marcus FI, McKenna WJ, Sherrill D, Basso C, Bauce B, Bluemke DA, Calkins H, Corrado D, Cox MG, Daubert JP, Fontaine G, Gear K, Hauer R, Nava A, Picard MH, Protonotarios N, Saffitz JE, Sanborn DM, Steinberg JS, Tandri H, Thiene G, Towbin JA, Tsatsopoulou A, Wichter T, Zareba W. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the Task Force Criteria. Eur Heart J 2010;31:806e814. 9. Etoom Y, Govindapillai S, Hamilton R, Manlhiot C, Yoo SJ, Farhan M, Sarikouch S, Peters B, McCrindle BW, Grosse-Wortmann L. Importance of CMR within the task force criteria for the diagnosis of ARVC in children and adolescents. J Am Coll Cardiol 2015;65:987e995. 10. Windram JD, Benson LN, Dragelescu A, Yoo SJ, Mertens L, Wong D, Grosse-Wortmann L. Distribution of hypertrophy and late gadolinium enhancement in children and adolescents with hypertrophic cardiomyopathy. Congenit Heart Dis 2015;10:E258eE267. 11. Grosse-Wortmann L, Dragulescu A, Drolet C, Chaturvedi R, Kotani Y, Mertens L, Taylor K, La Rotta G, van Arsdell G, Redington A, Yoo SJ. Determinants and clinical significance of flow via the fenestration in the Fontan pathway: a multimodality study. Int J Cardiol 2013;168: 811e817. 12. Buechel EV, Kaiser T, Jackson C, Schmitz A, Kellenberger CJ. Normal right- and left ventricular volumes and myocardial mass in children measured by steady state free precession cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2009;11:19. 13. Hor KN, Gottliebson WM, Carson C, Wash E, Cnota J, Fleck R, Wansapura J, Klimeczek P, Al-Khalidi HR, Chung ES, Benson DW, Mazur W. Comparison of magnetic resonance feature tracking for strain calculation with harmonic phase imaging analysis. JACC Cardiovasc Imaging 2010;3:144e151. 14. Opdahl A, Helle-Valle T, Remme EW, Vartdal T, Pettersen E, Lunde K, Edvardsen T, Smiseth OA. Apical rotation by speckle tracking echocardiography: a simplified bedside index of left ventricular twist. J Am Soc Echocardiogr 2008;21:1121e1128. 15. Young AA, Cowan BR. Evaluation of left ventricular torsion by cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2012;14:49. 16. Eichhorn JG, Buss S, Foell A, Helling A, Robbers-Visser D, Pieterman E, Bossers S, Lossnitzer D, Gorenflo M, Helbing WA. Quantification of left ventricular regional myocardial function using MRI feature tracking in healthy children - a dual-center study. J Cardiovasc Magn Reson 2013;15(Suppl 1):O42. 17. Tandri H, Saranathan M, Rodriguez ER, Martinez C, Bomma C, Nasir K, Rosen B, Lima JA, Calkins H, Bluemke DA. Noninvasive detection of myocardial fibrosis in arrhythmogenic right ventricular cardiomyopathy using delayed-enhancement magnetic resonance imaging. J Am Coll Cardiol 2005;45:98e103. 18. Pinamonti B, Dragos AM, Pyxaras SA, Merlo M, Pivetta A, Barbati G, Di Lenarda A, Morgera T, Mestroni L, Sinagra G. Prognostic predictors in arrhythmogenic right ventricular cardiomyopathy: results from a 10-year registry. Eur Heart J 2011;32:1105e1113.
7
19. Sen-Chowdhry S, Syrris P, Ward D, Asimaki A, Sevdalis E, McKenna WJ. Clinical and genetic characterization of families with arrhythmogenic right ventricular dysplasia/cardiomyopathy provides novel insights into patterns of disease expression. Circulation 2007;115:1710e1720. 20. Szymanski P, Klisiewicz A, Spiewak M, Szumowski L, Walczak F, Hoffman P. Left dominant arrhythmogenic cardiomyopathyea newly defined clinical entity. Int J Cardiol 2012;156:e60ee61. 21. De Pasquale CG, Heddle WF. Left sided arrhythmogenic ventricular dysplasia in siblings. Heart 2001;86:128e130. 22. Norman M, Simpson M, Mogensen J, Shaw A, Hughes S, Syrris P, Sen-Chowdhry S, Rowland E, Crosby A, McKenna WJ. Novel mutation in desmoplakin causes arrhythmogenic left ventricular cardiomyopathy. Circulation 2005;112:636e642. 23. Dahle GO, Stangeland L, Moen CA, Salminen PR, Haaverstad R, Matre K, Grong K. The influence of acute unloading on left ventricular strain and strain rate by speckle tracking echocardiography in a porcine model. Am J Physiol Heart Circ Physiol 2016;310:H1330eH1339. 24. Buss SJ, Breuninger K, Lehrke S, Voss A, Galuschky C, Lossnitzer D, Andre F, Ehlermann P, Franke J, Taeger T, Frankenstein L, Steen H, Meder B, Giannitsis E, Katus HA, Korosoglou G. Assessment of myocardial deformation with cardiac magnetic resonance strain imaging improves risk stratification in patients with dilated cardiomyopathy. Eur Heart J Cardiovasc Imaging 2015;16:307e315. 25. Heermann P, Hedderich DM, Paul M, Schulke C, Kroeger JR, Baessler B, Wichter T, Maintz D, Waltenberger J, Heindel W, Bunck AC. Biventricular myocardial strain analysis in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) using cardiovascular magnetic resonance feature tracking. J Cardiovasc Magn Reson 2014;16:75. 26. Aneq MA, Engvall J, Brudin L, Nylander E. Evaluation of right and left ventricular function using speckle tracking echocardiography in patients with arrhythmogenic right ventricular cardiomyopathy and their first degree relatives. Cardiovasc Ultrasound 2012;10:37. 27. Taylor RJ, Moody WE, Umar F, Edwards NC, Taylor TJ, Stegemann B, Townend JN, Hor KN, Steeds RP, Mazur W, Leyva F. Myocardial strain measurement with feature-tracking cardiovascular magnetic resonance: normal values. Eur Heart J Cardiovasc Imaging 2015;16:871e881. 28. Smith BM, Dorfman AL, Yu S, Russell MW, Agarwal PP, Ghadimi Mahani M, Lu JC. Relation of strain by feature tracking and clinical outcome in children, adolescents, and young adults with hypertrophic cardiomyopathy. Am J Cardiol 2014;114:1275e1280. 29. Te Riele AS, James CA, Philips B, Rastegar N, Bhonsale A, Groeneweg JA, Murray B, Tichnell C, Judge DP, Van Der Heijden JF, Cramer MJ, Velthuis BK, Bluemke DA, Zimmerman SL, Kamel IR, Hauer RN, Calkins H, Tandri H. Mutation-positive arrhythmogenic right ventricular dysplasia/cardiomyopathy: the triangle of dysplasia displaced. J Cardiovasc Electrophysiol 2013;24: 1311e1320.