- Email: [email protected]
Clinical Significance of Late Gadolinium Enhancement in Patients <20 Years of Age With Hypertrophic Cardiomyopathy
Clinical Significance of Late Gadolinium Enhancement in Patients <20 Years of Age With Hypertrophic Cardiomyopathy Brandon M. Smith, MDa,*, Adam L. Dorfman, MDa,b, Sunkyung Yu, MSa, Mark W. Russell, MDa, Prachi P. Agarwal, MBBSc, Maryam Ghadimi Mahani, MDb, and Jimmy C. Lu, MDa,b Late gadolinium enhancement (LGE) on cardiovascular magnetic resonance imaging is associated with adverse events in adults with hypertrophic cardiomyopathy (HC). However, limited data exist on the extent and clinical significance of LGE in the pediatric population. In 30 patients (aged 14.1 – 3.2 years) with clinically diagnosed HC who underwent cardiovascular magnetic resonance imaging from 2007 to 2012, segments with hypertrophy and LGE were identified by 2 experienced readers blinded to outcome. Radial, circumferential, and longitudinal strains were evaluated using feature tracking software. The composite outcome was defined as cardiac death, nonsustained ventricular tachycardia, ventricular fibrillation, or appropriate implantable cardioverter-defibrillator discharge. LGE was present in 17 of 30 patients (57%), all in a midmyocardial pattern, with median 3 segments per patient (interquartile range [IQR] 2 to 5). No LGE was detected in patients without phenotypic hypertrophy. Segments with LGE had decreased radial (basal segments 20.7% vs 70.9%, p [ 0.01), circumferential (basal segments L23.2% vs L29.3%, p [ 0.04), and longitudinal strains (basal segments L13.8% vs L20.9%, p [ 0.04). After median follow-up of 26.9 months (IQR 7.5 to 34.3), 7 patients who had an adverse outcome (5 ventricular tachycardia, 1 appropriate implantable cardioverter-defibrillator discharge, and 1 death) had more segments of LGE (median 4, IQR 2 to 7 vs 0, IQR 0 to 2, p [ 0.01). One patient without LGE had ventricular tachycardia on exercise test. In conclusion, LGE occurs in a similar pattern in pediatric patients with HC as in adults, associated with hypertrophy, decreased myocardial strain, and adverse clinical outcomes. Further longitudinal studies are necessary to evaluate the rate of development of LGE and relation to outcomes in a larger cohort. Ó 2014 Elsevier Inc. All rights reserved. (Am J Cardiol 2014;113:1234e1239)
Hypertrophic cardiomyopathy (HC) is a heterogeneous cardiovascular condition characterized by myocardial disarray, hypertrophy, and fibrosis, with a prevalence of 1 in 500 and varied presentations from infancy through adulthood.1 HC is associated with adverse outcomes, including sudden cardiac death.1,2 Myocardial fibrosis can be detected by late gadolinium enhancement (LGE) on cardiovascular magnetic resonance (CMR) image in regions of hypertrophy and decreased myocardial deformation,3e6 and has been identified in adult cohorts as a risk factor for death, ventricular tachycardia and fibrillation, appropriate implantable cardioverter-defibrillator (ICD) discharge, and unplanned cardiac admission.2,7,8 However, there are few data on the prevalence and clinical significance of LGE in a pediatric population,9 and the relation with hypertrophy and strain have not been evaluated. This study aimed to further
a Division of Pediatric Cardiology, Department of Pediatrics and Communicable Diseases, bSection of Pediatric Radiology, Department of Radiology, and cDivision of Cardiothoracic Radiology, Department of Radiology, University of Michigan, Ann Arbor, Michigan. Manuscript received October 30, 2013; revised manuscript received and accepted December 16, 2013. See page 1238 for disclosure information. *Corresponding author: Tel: (734) 232-5431; fax: (734) 936-9470. E-mail address: [email protected] (B.M. Smith).
0002-9149/14/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2013.12.034
characterize the pattern of LGE and the association of LGE with strain and clinical outcomes in pediatric patients with HC. Methods This single-center retrospective study included all patients aged 21 years with phenotypic or genotypic HC who underwent clinically indicated CMR from 2007 to 2012. HC was defined as positive genetic testing result for a mutation known to be associated with HC or clinical characteristics of asymmetric septal hypertrophy or total left ventricular mass >2 SDs above the mean for body surface area without identifiable cause.1 Those with coexisting congenital heart disease or an underlying syndrome or storage condition predisposing to secondary HC were excluded. This study was approved by the institutional review board. Patient charts were reviewed for demographic data, ICD placement, and clinical outcome. A composite adverse outcome was defined as cardiac death, sustained or nonsustained ventricular tachycardia, ventricular fibrillation, or appropriate ICD discharge. Length of follow-up was defined as the time from CMR to the last clinical documentation. CMR was performed with a 1.5-T scanner (Achieva or Ingenia; Philips, Best, the Netherlands). Cine images were obtained with breath-held, electrocardiographic-gated, segmented k-space steady-state free precession, using 30 phases per cardiac www.ajconline.org
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Table 1 Demographics Age (yrs) 7.0 7.7 8.9 9.4 10.3 10.6 11.9 12.0 12.1 12.8 12.8 13.9 14.2 14.5 14.8 14.9 14.9 15.4 15.5 16.0 16.1 16.8 17.0 17.2 17.2 17.5 17.7 17.7 18.1 19.3
Gender
BSA (m2)
M F F M F M M M M M F F M F M F F M F M F M M F F M M F M M
0.98 1.08 1.6 1.9 1.24 1.5 1.23 1.77 1.37 1.9 1.46 1.38 1.81 1.85 2.03 1.78 1.6 1.93 1.91 1.98 1.52 1.73 1.78 1.8 1.93 2.16 1.83 1.53 1.76 1.98
Genotype
MYBPC3 MYH7
MYH7
MYBPC3 MYBPC3
MYH7 Negative MYBPC3 MYBPC3 MYBPC3 MYH7
MYBC3
Myectomy
LVOTO
NYHA
LVEDVi
LVESVi
LVMi
LGE
ICD
End Point
Yes No Yes Yes No No No No Yes No No No No No No No
Yes No Yes Yes No No No No Yes Yes No No Yes No No No No No Yes No No No No No No No No Yes No No
I I II II I I I I I I I I I I I I I II II I I I I I I I I I I I
97 57 72 118 77 95 65 85 88 112 72 85 92 77 134 106 82 108 78 92 84 102 87 83 69 90 92 84 96 88
31.6 13.0 11.4 25.8 29.0 27.3 21.1 22.6 30.6 30.5 24.6 31.1 27.6 33.0 47.8 38.8 25.6 40.4 24.1 28.3 27.0 43.3 28.6 27.2 28.0 40.7 24.0 25.5 34.6 39.9
134 72 164 125 37 45 44 181 98 159 84 45 101 56 158 83 47 86 137 53 65 64 62 51 73 67 79 102 77 91
2 0 3 4 0 1 0 5 2 1 3 0 0 0 7 2 0 3 4 0 0 0 2 0 3 0 2 8 0 0
Yes No Yes Yes No Yes No Yes Yes No Yes No No No Yes Yes Yes No Yes No No Yes No No No No No No Yes No
No No No No No VT No VF No No VT No No No VT No No Death VT No No No No No No No No No VT No
No No No No No No No No No No No No No
BSA ¼ body surface area; LVEDVi ¼ left ventricular end-diastolic volume (ml/m2); LVESVI ¼ left ventricular end-systolic volume (ml/m2); LVMi ¼ left ventricular mass (g/m2); LVOTO ¼ left ventricular outflow tract obstruction (gradient >30 mm Hg on echocardiography); NYHA ¼ New York Heart Association class; VF ¼ ventricular fibrillation; VT ¼ ventricular tachycardia.
cycle. LGE images were acquired with breath-held, phasesensitive inversion recovery in the 4-chamber and short-axis planes, 12 to 15 minutes after intravenous administration of 0.2 mmol/kg of gadoteridol (ProHance; Bracco, Monroe Township, New Jersey) or gadopentetate dimeglumine (Magnevist; Bayer, Leverkusen, Germany). Data were post-processed with QMass MR (Medis, Leiden, the Netherlands) and analyzed by 2 experienced readers blinded to patient outcome. Because of the range of patient age and size and the lack of pediatric CMR normative data for wall thickness, qualitatively hypertrophied segments were identified from short-axis images mapped on a 16-segment model and confirmed by a second reader. LGE was similarly evaluated qualitatively on a 16segment model, enabling better matching of segments with hypertrophy and LGE. Strain was measured with feature tracking software (TomTec, Unterschleissheim, Germany) on CMR images by manually drawing contours at the endocardial and epicardial borders, with visual evaluation to ensure adequate tracking. Basal (at the mitral valve), midventricular (at the papillary muscles), and apical (below the papillary muscles) shortaxis images were analyzed for circumferential and radial strains, which are reported by level, because of previous report of a base-to-apex gradient.4 Two-, 3-, and 4-chamber images were used for longitudinal strain.
Data are presented as frequency (percent) for categorical variables and mean SD or median (interquartile range [IQR]), as appropriate, for continuous variables. Association of LGE and hypertrophy was evaluated by generalized estimating equation to account for correlation across segments within patients. Similarly, repeated-measures analysis of variance was used to compare strain in segments with LGE versus segments without LGE and in segments with hypertrophy and LGE versus segments with hypertrophy alone. Clinical outcomes were compared between the patients with and without LGE using chi-square test or Fisher’s exact test for categorical variables and Wilcoxon rank sum test for continuous variables. Odds ratio (OR) and 95% confidence interval (CI) of having LGE for each outcome are reported. All analyses were performed using SAS, version 9.3 (SAS Institute Inc., Cary, North Carolina), with statistical significance set at a p value of <0.05 using 2sided test. Results Of 51 patients screened for possible HC, 30 were included in the study population (aged 14.1 3.2 years), with individual data given in Table 1. Of those excluded, 2 had associated congenital heart disease, 1 had secondary HC
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Figure 1. Example of LGE. This patient had enhancement (arrow) in a midmyocardial pattern in the area of greatest hypertrophy, seen in short-axis (A) and 4-chamber (B) images.
associated with a syndrome, and 18 lacked adequate phenotypic or genotypic evidence of HC. In this cohort, 2 patients were siblings, 11 of 12 patients with genetic testing had mutations associated with HC, and 6 patients were genotype positive without phenotypic evidence of hypertrophy. This cohort was largely asymptomatic, with no patients in clinical heart failure, and all patients had normal left ventricular systolic function (left ventricular ejection fraction 65.4 8.3%). Hypertrophy was identified in at least 1 segment in 24 patients (80%), with a median of 5 segments per patient (IQR 2 to 6). LGE was present in 17 patients (57% of the cohort; 71% of patients with phenotypic HC) with a median of 3 segments per patient (IQR 2 to 5). All LGE occurred in a midmyocardial pattern (Figure 1), most prevalent in the basal, midanterior and inferior septal segments (Figure 2). LGE was highly associated with hypertrophy; segments with LGE had an OR of 38.6 for being hypertrophied (95% CI 14.3 to 101, p <0.0001). No LGE was identified in patients without phenotypic hypertrophy. Segments with LGE had reduced radial, circumferential, and longitudinal strains in basal and mid segments (Figure 3). Apical segments were not compared because of few segments with LGE. Comparing all segments regardless of level, segments with LGE trended toward decreased radial strain versus segments with hypertrophy but no LGE (29.0 5.9 vs 44.7 5.7, p ¼ 0.07), although circumferential (26.0 1.7 vs 26.9 1.6, p ¼ 0.68) and longitudinal (10.7 1.2 vs 13.0 1.2, p ¼ 0.18) strains did not differ. After median follow-up of 26.9 months (IQR 0.8 to 34), patients with LGE were more likely to have subsequent ICD
placement (OR 22, 95% CI 2.3 to 213, p ¼ 0.002). An ICD was placed in 12 patients: 11 (65%) with LGE and 1 (8%) without LGE. Primary indications for ICD placement included 4 patients with marked septal hypertrophy, 3 with family history of sudden death, 2 with ventricular tachycardia, 2 with extensive LGE, and 1 with syncope. Excluding the 2 patients with ICD placement because of extensive LGE, the OR remained significant (OR 16.1, 95% CI 2.0 to 427, p ¼ 0.01). The composite end point was met by 7 patients (5 with ventricular tachycardia, 1 appropriate ICD discharge, and 1 cardiac death supported by autopsy with confirmed diagnosis of HC). One event occurred in a phenotypepositive patient without LGE (nonsustained ventricular tachycardia during an exercise test). Patients that met the composite end point had more segments of LGE than patients that did not have an adverse event (median 4 segments, IQR 2 to 7 vs 0 segments, IQR 0 to 2, p ¼ 0.01) with a trend toward increased odds of an adverse event in patients with LGE (OR 6.2, 95% CI 0.8 to 163, p ¼ 0.10). Excluding the 6 genotype-positive, phenotypenegative patients, those that met the composite end point continued to have more segments of LGE than patients without an adverse event (median 4 segments, IQR 2 to 7 vs 1 segment, IQR 0 to 2, p ¼ 0.04); however, the trend toward increased odds of an adverse event in patients with LGE decreased (OR 4.0, 95% CI 0.5 to 110, p ¼ 0.35), reflecting decreased power. Discussion We have demonstrated that in pediatric patients with HC, LGE is associated with areas of hypertrophy, decreased strain, and adverse clinical outcomes. These data demonstrate similarities between pediatric and adult cohorts, and help better characterize the pediatric population. Multiple studies in adult cohorts have demonstrated a prevalence of 59% to 81% for LGE, occurring primarily in a midmyocardial pattern,4,9,10 typically in hypertrophied areas in the anterior and inferior septal segments with minimal LGE in the lateral wall and apex.4,10 Chaowu et al9 reported a prevalence of 73% in a mostly symptomatic pediatric cohort in China (12.8 4.1 years, 31% in New York Heart Association class III to IV). LGE remains a common finding even in our largely asymptomatic cohort, with a similar nonischemic pattern and distribution, particularly in hypertrophied areas. Identification of LGE in pediatric patients may be limited by respiratory or motion artifact related to patient cooperation. The strong association with hypertrophy suggests that normal wall thickness is reassuring, as patients without hypertrophy had no LGE. However, HC is known to be a progressive disease, with varying onset of phenotypic hypertrophy.1 LGE has also been shown to develop over time in adults,11 and serial data are necessary to evaluate the rate of progression in the pediatric population. Decreased strain by tissue Doppler and speckle-tracking echocardiography has been associated with hypertrophy and LGE.3,12 However, few data are available on the use of feature tracking on CMR in this population. This technique does not require acquisition of additional myocardial tagged
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Figure 2. Prevalence of LGE by segment. This 16-segment model displays basal segments around the periphery and apical segments at the center. Data are presented as number of patients with LGE in a given segment and percentage of all patients.
images or use of echocardiographic specific software to evaluate CMR images13,14 and has been validated against myocardial tagged CMR images13,15 and speckle-tracking echocardiography16 in other populations. Our data demonstrate that differences in strain can also be detected by feature tracking on CMR, but additional study is necessary to determine whether strain by feature tracking in this population provides incremental prognostic value beyond LGE or when the presence of LGE is inconclusive. It is unclear whether myocardial deformation in segments with LGE is decreased beyond the effect of hypertrophy. Adult data suggest an association between decreased strain and LGE independent of hypertrophy,3,6 whereas our data only demonstrated a trend toward lower radial strain in segments with LGE versus segments with hypertrophy alone. An independent effect of LGE may be difficult to demonstrate because of power limitations and the close association of LGE and hypertrophy. Our data demonstrated an increased likelihood for ICD placement in patients with LGE, even after exclusion of patients referred primarily due to LGE. This retrospective study is limited in its ability to delineate whether the presence of LGE impacted the decision for ICD placement. This finding may reflect an association between LGE and other risk factors leading to ICD placement,17 or it may highlight clinicians’ reluctance to place an ICD in this population with a single risk factor and, thus, use of LGE to support placement. Patient selection for ICD placement can be particularly difficult in the pediatric and young adult population with reported complication rates of 32% to 41% in mid-term follow-up.18,19
Further prospective studies are necessary to clarify the role of LGE in ICD placement in this population. In adult patients with HC, LGE has been shown to be an independent risk factor for cardiac and all-cause mortality, unplanned cardiac admission, sustained ventricular tachycardia or ventricular fibrillation, and appropriate ICD discharge.2,7 The previous pediatric cohort showed an increased hazard ratio by LGE extent but did not reach significance in the amount of LGE in those with or without adverse events.9 Our data suggest that this association between LGE and outcomes persists in a less symptomatic pediatric population, and the finding of LGE on CMR may have important prognostic value even in asymptomatic adolescent patients. However, 1 episode of ventricular tachycardia occurred in a patient without LGE, which underscores the importance of careful monitoring in this population, as no current risk stratification model, including LGE, can be 100% sensitive. The small sample size of this study limits the granularity of analysis, including the relative contribution of hypertrophy versus LGE to outcome. Not all of the study population underwent genetic testing, thus limiting the ability to make genetic inferences. The retrospective nature limited the population to clinical referral for CMR, and the preference to avoid anesthesia may have led to underrepresentation of younger patients. Potential selection bias may help explain the high event rate; thus, we would not extrapolate the incidence of adverse outcomes to other cohorts. Because of the relatively short follow-up time, time-to-event analysis was not performed. In addition, the study design prevents
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Figure 3. Comparison of strain in segments with and without LGE. Radial (A), circumferential (B), and longitudinal (C) strains are presented by level.
speculation on rate of progression of fibrosis. Further longitudinal data with longer follow-up and larger sample size are needed in this population.
4.
Disclosures The authors have no conflicts of interest to disclose. 1. Gersh BJ, Maron BJ, Bonow RO, Dearani JA, Fifer MA, Link MS, Naidu SS, Nishimura RA, Ommen SR, Rakowski H, Seidman CE, Towbin JA, Udelson JE, Yancy CW. 2011 ACCF/AHA Guideline for the Diagnosis and Treatment of Hypertrophic Cardiomyopathy: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Developed in collaboration with the American Association for Thoracic Surgery, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2011;58:e212ee260. 2. Bruder O, Wagner A, Jensen CJ, Schneider S, Ong P, Kispert EM, Nassenstein K, Schlosser T, Sabin GV, Sechtem U, Mahrholdt H. Myocardial scar visualized by cardiovascular magnetic resonance imaging predicts major adverse events in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 2010;56:875e887. 3. Saito M, Okayama H, Yoshii T, Higashi H, Morioka H, Hiasa G, Sumimoto T, Inaba S, Nishimura K, Inoue K, Ogimoto A, Shigematsu Y, Hamada M, Higaki J. Clinical significance of global two-dimensional strain as a surrogate parameter of myocardial fibrosis and cardiac
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events in patients with hypertrophic cardiomyopathy. Eur Heart J Cardiovasc Imaging 2012;13:617e623. Popovic ZB, Kwon DH, Mishra M, Buakhamsri A, Greenberg NL, Thamilarasan M, Flamm SD, Thomas JD, Lever HM, Desai MY. Association between regional ventricular function and myocardial fibrosis in hypertrophic cardiomyopathy assessed by speckle tracking echocardiography and delayed hyperenhancement magnetic resonance imaging. J Am Soc Echocardiogr 2008;21:1299e1305. Chang SA, Lee SC, Choe YH, Hahn HJ, Jang SY, Park SJ, Choi JO, Park SW, Oh JK. Effects of hypertrophy and fibrosis on regional and global functional heterogeneity in hypertrophic cardiomyopathy. Int J Cardiovasc Imaging 2012;28(Suppl 2):133e140. Ghio S, Revera M, Mori F, Klersy C, Raisaro A, Raineri C, Serio A, Pasotti M, Visconti LO. Regional abnormalities of myocardial deformation in patients with hypertrophic cardiomyopathy: correlations with delayed enhancement in cardiac magnetic resonance. Eur J Heart Fail 2009;11:952e957. O’Hanlon R, Grasso A, Roughton M, Moon JC, Clark S, Wage R, Webb J, Kulkarni M, Dawson D, Sulaibeekh L, Chandrasekaran B, Bucciarelli-Ducci C, Pasquale F, Cowie MR, McKenna WJ, Sheppard MN, Elliott PM, Pennell DJ, Prasad SK. Prognostic significance of myocardial fibrosis in hypertrophic cardiomyopathy. J Am Coll Cardiol 2010;56:867e874. Moon JC, Reed E, Sheppard MN, Elkington AG, Ho SY, Burke M, Petrou M, Pennell DJ. The histologic basis of late gadolinium enhancement cardiovascular magnetic resonance in hypertrophic cardiomyopathy. J Am Coll Cardiol 2004;43:2260e2264. Chaowu Y, Shihua Z, Jian L, Li L, Wei F. Cardiovascular magnetic resonance characteristics in children with hypertrophic cardiomyopathy. Circ Heart Fail 2013;6:1013e1020.
Cardiomyopathy/LGE and Outcome in Pediatric and Adolescent HC 10. Choudhury L, Mahrholdt H, Wagner A, Choi KM, Elliott MD, Klocke FJ, Bonow RO, Judd RM, Kim RJ. Myocardial scarring in asymptomatic or mildly symptomatic patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 2002;40:2156e2164. 11. Todiere G, Aquaro GD, Piaggi P, Formisano F, Barison A, Masci PG, Strata E, Bacigalupo L, Marzilli M, Pingitore A, Lombardi M. Progression of myocardial fibrosis assessed with cardiac magnetic resonance in hypertrophic cardiomyopathy. J Am Coll Cardiol 2012;60: 922e929. 12. Ganame J, Mertens L, Eidem BW, Claus P, D’Hooge J, Havemann LM, McMahon CJ, Elayda MA, Vaughn WK, Towbin JA, Ayres NA, Pignatelli RH. Regional myocardial deformation in children with hypertrophic cardiomyopathy: morphological and clinical correlations. Eur Heart J 2007;28:2886e2894. 13. Harrild DM, Han Y, Geva T, Zhou J, Marcus E, Powell AJ. Comparison of cardiac MRI tissue tracking and myocardial tagging for assessment of regional ventricular strain. Int J Cardiovasc Imaging 2012;28:2009e2018. 14. Williams LK, Urbano-Moral JA, Rowin EJ, Jamorski M, BruchalGarbicz B, Carasso S, Pandian NG, Maron MS, Rakowski H. Velocity vector imaging in the measurement of left ventricular myocardial mechanics on cardiac magnetic resonance imaging: correlations with echocardiographically derived strain values. J Am Soc Echocardiogr 2013;26:1153e1162. 15. 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
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strain calculation with harmonic phase imaging analysis. JACC Cardiovasc Imaging 2010;3:144e151. Kempny A, Fernandez-Jimenez R, Orwat S, Schuler P, Bunck AC, Maintz D, Baumgartner H, Diller GP. Quantification of biventricular myocardial function using cardiac magnetic resonance feature tracking, endocardial border delineation and echocardiographic speckle tracking in patients with repaired tetralogy of fallot and healthy controls. J Cardiovasc Magn Reson 2012;14:32. Maron BJ, Spirito P, Shen WK, Haas TS, Formisano F, Link MS, Epstein AE, Almquist AK, Daubert JP, Lawrenz T, Boriani G, Estes NA 3rd, Favale S, Piccininno M, Winters SL, Santini M, Betocchi S, Arribas F, Sherrid MV, Buja G, Semsarian C, Bruzzi P. Implantable cardioverter-defibrillators and prevention of sudden cardiac death in hypertrophic cardiomyopathy. JAMA 2007;298:405e412. Maron BJ, Spirito P, Ackerman MJ, Casey SA, Semsarian C, Estes NA 3rd, Shannon KM, Ashley EA, Day SM, Pacileo G, Formisano F, Devoto E, Anastasakis A, Bos JM, Woo A, Autore C, Pass RH, Boriani G, Garberich RF, Almquist AK, Russell MW, Boni L, Berger S, Maron MS, Link MS. Prevention of sudden cardiac death with implantable cardioverter-defibrillators in children and adolescents with hypertrophic cardiomyopathy. J Am Coll Cardiol 2013;61: 1527e1535. Kamp AN, Von Bergen NH, Henrikson CA, Makhoul M, Saarel EV, Lapage MJ, Russell MW, Strieper M, Yu S, Dick M, Day SM, Bradley DJ. Implanted defibrillators in young hypertrophic cardiomyopathy patients: a multicenter study. Pediatr Cardiol 2013;34: 1620e1627.
Hypertrophic cardiomyopathy (HC) is a heterogeneous cardiovascular condition characterized by myocardial disarray, hypertrophy, and fibrosis, with a prevalence of 1 in 500 and varied presentations from infancy through adulthood.1 HC is associated with adverse outcomes, including sudden cardiac death.1,2 Myocardial fibrosis can be detected by late gadolinium enhancement (LGE) on cardiovascular magnetic resonance (CMR) image in regions of hypertrophy and decreased myocardial deformation,3e6 and has been identified in adult cohorts as a risk factor for death, ventricular tachycardia and fibrillation, appropriate implantable cardioverter-defibrillator (ICD) discharge, and unplanned cardiac admission.2,7,8 However, there are few data on the prevalence and clinical significance of LGE in a pediatric population,9 and the relation with hypertrophy and strain have not been evaluated. This study aimed to further
a Division of Pediatric Cardiology, Department of Pediatrics and Communicable Diseases, bSection of Pediatric Radiology, Department of Radiology, and cDivision of Cardiothoracic Radiology, Department of Radiology, University of Michigan, Ann Arbor, Michigan. Manuscript received October 30, 2013; revised manuscript received and accepted December 16, 2013. See page 1238 for disclosure information. *Corresponding author: Tel: (734) 232-5431; fax: (734) 936-9470. E-mail address: [email protected] (B.M. Smith).
0002-9149/14/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2013.12.034
characterize the pattern of LGE and the association of LGE with strain and clinical outcomes in pediatric patients with HC. Methods This single-center retrospective study included all patients aged 21 years with phenotypic or genotypic HC who underwent clinically indicated CMR from 2007 to 2012. HC was defined as positive genetic testing result for a mutation known to be associated with HC or clinical characteristics of asymmetric septal hypertrophy or total left ventricular mass >2 SDs above the mean for body surface area without identifiable cause.1 Those with coexisting congenital heart disease or an underlying syndrome or storage condition predisposing to secondary HC were excluded. This study was approved by the institutional review board. Patient charts were reviewed for demographic data, ICD placement, and clinical outcome. A composite adverse outcome was defined as cardiac death, sustained or nonsustained ventricular tachycardia, ventricular fibrillation, or appropriate ICD discharge. Length of follow-up was defined as the time from CMR to the last clinical documentation. CMR was performed with a 1.5-T scanner (Achieva or Ingenia; Philips, Best, the Netherlands). Cine images were obtained with breath-held, electrocardiographic-gated, segmented k-space steady-state free precession, using 30 phases per cardiac www.ajconline.org
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Table 1 Demographics Age (yrs) 7.0 7.7 8.9 9.4 10.3 10.6 11.9 12.0 12.1 12.8 12.8 13.9 14.2 14.5 14.8 14.9 14.9 15.4 15.5 16.0 16.1 16.8 17.0 17.2 17.2 17.5 17.7 17.7 18.1 19.3
Gender
BSA (m2)
M F F M F M M M M M F F M F M F F M F M F M M F F M M F M M
0.98 1.08 1.6 1.9 1.24 1.5 1.23 1.77 1.37 1.9 1.46 1.38 1.81 1.85 2.03 1.78 1.6 1.93 1.91 1.98 1.52 1.73 1.78 1.8 1.93 2.16 1.83 1.53 1.76 1.98
Genotype
MYBPC3 MYH7
MYH7
MYBPC3 MYBPC3
MYH7 Negative MYBPC3 MYBPC3 MYBPC3 MYH7
MYBC3
Myectomy
LVOTO
NYHA
LVEDVi
LVESVi
LVMi
LGE
ICD
End Point
Yes No Yes Yes No No No No Yes No No No No No No No
Yes No Yes Yes No No No No Yes Yes No No Yes No No No No No Yes No No No No No No No No Yes No No
I I II II I I I I I I I I I I I I I II II I I I I I I I I I I I
97 57 72 118 77 95 65 85 88 112 72 85 92 77 134 106 82 108 78 92 84 102 87 83 69 90 92 84 96 88
31.6 13.0 11.4 25.8 29.0 27.3 21.1 22.6 30.6 30.5 24.6 31.1 27.6 33.0 47.8 38.8 25.6 40.4 24.1 28.3 27.0 43.3 28.6 27.2 28.0 40.7 24.0 25.5 34.6 39.9
134 72 164 125 37 45 44 181 98 159 84 45 101 56 158 83 47 86 137 53 65 64 62 51 73 67 79 102 77 91
2 0 3 4 0 1 0 5 2 1 3 0 0 0 7 2 0 3 4 0 0 0 2 0 3 0 2 8 0 0
Yes No Yes Yes No Yes No Yes Yes No Yes No No No Yes Yes Yes No Yes No No Yes No No No No No No Yes No
No No No No No VT No VF No No VT No No No VT No No Death VT No No No No No No No No No VT No
No No No No No No No No No No No No No
BSA ¼ body surface area; LVEDVi ¼ left ventricular end-diastolic volume (ml/m2); LVESVI ¼ left ventricular end-systolic volume (ml/m2); LVMi ¼ left ventricular mass (g/m2); LVOTO ¼ left ventricular outflow tract obstruction (gradient >30 mm Hg on echocardiography); NYHA ¼ New York Heart Association class; VF ¼ ventricular fibrillation; VT ¼ ventricular tachycardia.
cycle. LGE images were acquired with breath-held, phasesensitive inversion recovery in the 4-chamber and short-axis planes, 12 to 15 minutes after intravenous administration of 0.2 mmol/kg of gadoteridol (ProHance; Bracco, Monroe Township, New Jersey) or gadopentetate dimeglumine (Magnevist; Bayer, Leverkusen, Germany). Data were post-processed with QMass MR (Medis, Leiden, the Netherlands) and analyzed by 2 experienced readers blinded to patient outcome. Because of the range of patient age and size and the lack of pediatric CMR normative data for wall thickness, qualitatively hypertrophied segments were identified from short-axis images mapped on a 16-segment model and confirmed by a second reader. LGE was similarly evaluated qualitatively on a 16segment model, enabling better matching of segments with hypertrophy and LGE. Strain was measured with feature tracking software (TomTec, Unterschleissheim, Germany) on CMR images by manually drawing contours at the endocardial and epicardial borders, with visual evaluation to ensure adequate tracking. Basal (at the mitral valve), midventricular (at the papillary muscles), and apical (below the papillary muscles) shortaxis images were analyzed for circumferential and radial strains, which are reported by level, because of previous report of a base-to-apex gradient.4 Two-, 3-, and 4-chamber images were used for longitudinal strain.
Data are presented as frequency (percent) for categorical variables and mean SD or median (interquartile range [IQR]), as appropriate, for continuous variables. Association of LGE and hypertrophy was evaluated by generalized estimating equation to account for correlation across segments within patients. Similarly, repeated-measures analysis of variance was used to compare strain in segments with LGE versus segments without LGE and in segments with hypertrophy and LGE versus segments with hypertrophy alone. Clinical outcomes were compared between the patients with and without LGE using chi-square test or Fisher’s exact test for categorical variables and Wilcoxon rank sum test for continuous variables. Odds ratio (OR) and 95% confidence interval (CI) of having LGE for each outcome are reported. All analyses were performed using SAS, version 9.3 (SAS Institute Inc., Cary, North Carolina), with statistical significance set at a p value of <0.05 using 2sided test. Results Of 51 patients screened for possible HC, 30 were included in the study population (aged 14.1 3.2 years), with individual data given in Table 1. Of those excluded, 2 had associated congenital heart disease, 1 had secondary HC
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Figure 1. Example of LGE. This patient had enhancement (arrow) in a midmyocardial pattern in the area of greatest hypertrophy, seen in short-axis (A) and 4-chamber (B) images.
associated with a syndrome, and 18 lacked adequate phenotypic or genotypic evidence of HC. In this cohort, 2 patients were siblings, 11 of 12 patients with genetic testing had mutations associated with HC, and 6 patients were genotype positive without phenotypic evidence of hypertrophy. This cohort was largely asymptomatic, with no patients in clinical heart failure, and all patients had normal left ventricular systolic function (left ventricular ejection fraction 65.4 8.3%). Hypertrophy was identified in at least 1 segment in 24 patients (80%), with a median of 5 segments per patient (IQR 2 to 6). LGE was present in 17 patients (57% of the cohort; 71% of patients with phenotypic HC) with a median of 3 segments per patient (IQR 2 to 5). All LGE occurred in a midmyocardial pattern (Figure 1), most prevalent in the basal, midanterior and inferior septal segments (Figure 2). LGE was highly associated with hypertrophy; segments with LGE had an OR of 38.6 for being hypertrophied (95% CI 14.3 to 101, p <0.0001). No LGE was identified in patients without phenotypic hypertrophy. Segments with LGE had reduced radial, circumferential, and longitudinal strains in basal and mid segments (Figure 3). Apical segments were not compared because of few segments with LGE. Comparing all segments regardless of level, segments with LGE trended toward decreased radial strain versus segments with hypertrophy but no LGE (29.0 5.9 vs 44.7 5.7, p ¼ 0.07), although circumferential (26.0 1.7 vs 26.9 1.6, p ¼ 0.68) and longitudinal (10.7 1.2 vs 13.0 1.2, p ¼ 0.18) strains did not differ. After median follow-up of 26.9 months (IQR 0.8 to 34), patients with LGE were more likely to have subsequent ICD
placement (OR 22, 95% CI 2.3 to 213, p ¼ 0.002). An ICD was placed in 12 patients: 11 (65%) with LGE and 1 (8%) without LGE. Primary indications for ICD placement included 4 patients with marked septal hypertrophy, 3 with family history of sudden death, 2 with ventricular tachycardia, 2 with extensive LGE, and 1 with syncope. Excluding the 2 patients with ICD placement because of extensive LGE, the OR remained significant (OR 16.1, 95% CI 2.0 to 427, p ¼ 0.01). The composite end point was met by 7 patients (5 with ventricular tachycardia, 1 appropriate ICD discharge, and 1 cardiac death supported by autopsy with confirmed diagnosis of HC). One event occurred in a phenotypepositive patient without LGE (nonsustained ventricular tachycardia during an exercise test). Patients that met the composite end point had more segments of LGE than patients that did not have an adverse event (median 4 segments, IQR 2 to 7 vs 0 segments, IQR 0 to 2, p ¼ 0.01) with a trend toward increased odds of an adverse event in patients with LGE (OR 6.2, 95% CI 0.8 to 163, p ¼ 0.10). Excluding the 6 genotype-positive, phenotypenegative patients, those that met the composite end point continued to have more segments of LGE than patients without an adverse event (median 4 segments, IQR 2 to 7 vs 1 segment, IQR 0 to 2, p ¼ 0.04); however, the trend toward increased odds of an adverse event in patients with LGE decreased (OR 4.0, 95% CI 0.5 to 110, p ¼ 0.35), reflecting decreased power. Discussion We have demonstrated that in pediatric patients with HC, LGE is associated with areas of hypertrophy, decreased strain, and adverse clinical outcomes. These data demonstrate similarities between pediatric and adult cohorts, and help better characterize the pediatric population. Multiple studies in adult cohorts have demonstrated a prevalence of 59% to 81% for LGE, occurring primarily in a midmyocardial pattern,4,9,10 typically in hypertrophied areas in the anterior and inferior septal segments with minimal LGE in the lateral wall and apex.4,10 Chaowu et al9 reported a prevalence of 73% in a mostly symptomatic pediatric cohort in China (12.8 4.1 years, 31% in New York Heart Association class III to IV). LGE remains a common finding even in our largely asymptomatic cohort, with a similar nonischemic pattern and distribution, particularly in hypertrophied areas. Identification of LGE in pediatric patients may be limited by respiratory or motion artifact related to patient cooperation. The strong association with hypertrophy suggests that normal wall thickness is reassuring, as patients without hypertrophy had no LGE. However, HC is known to be a progressive disease, with varying onset of phenotypic hypertrophy.1 LGE has also been shown to develop over time in adults,11 and serial data are necessary to evaluate the rate of progression in the pediatric population. Decreased strain by tissue Doppler and speckle-tracking echocardiography has been associated with hypertrophy and LGE.3,12 However, few data are available on the use of feature tracking on CMR in this population. This technique does not require acquisition of additional myocardial tagged
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Figure 2. Prevalence of LGE by segment. This 16-segment model displays basal segments around the periphery and apical segments at the center. Data are presented as number of patients with LGE in a given segment and percentage of all patients.
images or use of echocardiographic specific software to evaluate CMR images13,14 and has been validated against myocardial tagged CMR images13,15 and speckle-tracking echocardiography16 in other populations. Our data demonstrate that differences in strain can also be detected by feature tracking on CMR, but additional study is necessary to determine whether strain by feature tracking in this population provides incremental prognostic value beyond LGE or when the presence of LGE is inconclusive. It is unclear whether myocardial deformation in segments with LGE is decreased beyond the effect of hypertrophy. Adult data suggest an association between decreased strain and LGE independent of hypertrophy,3,6 whereas our data only demonstrated a trend toward lower radial strain in segments with LGE versus segments with hypertrophy alone. An independent effect of LGE may be difficult to demonstrate because of power limitations and the close association of LGE and hypertrophy. Our data demonstrated an increased likelihood for ICD placement in patients with LGE, even after exclusion of patients referred primarily due to LGE. This retrospective study is limited in its ability to delineate whether the presence of LGE impacted the decision for ICD placement. This finding may reflect an association between LGE and other risk factors leading to ICD placement,17 or it may highlight clinicians’ reluctance to place an ICD in this population with a single risk factor and, thus, use of LGE to support placement. Patient selection for ICD placement can be particularly difficult in the pediatric and young adult population with reported complication rates of 32% to 41% in mid-term follow-up.18,19
Further prospective studies are necessary to clarify the role of LGE in ICD placement in this population. In adult patients with HC, LGE has been shown to be an independent risk factor for cardiac and all-cause mortality, unplanned cardiac admission, sustained ventricular tachycardia or ventricular fibrillation, and appropriate ICD discharge.2,7 The previous pediatric cohort showed an increased hazard ratio by LGE extent but did not reach significance in the amount of LGE in those with or without adverse events.9 Our data suggest that this association between LGE and outcomes persists in a less symptomatic pediatric population, and the finding of LGE on CMR may have important prognostic value even in asymptomatic adolescent patients. However, 1 episode of ventricular tachycardia occurred in a patient without LGE, which underscores the importance of careful monitoring in this population, as no current risk stratification model, including LGE, can be 100% sensitive. The small sample size of this study limits the granularity of analysis, including the relative contribution of hypertrophy versus LGE to outcome. Not all of the study population underwent genetic testing, thus limiting the ability to make genetic inferences. The retrospective nature limited the population to clinical referral for CMR, and the preference to avoid anesthesia may have led to underrepresentation of younger patients. Potential selection bias may help explain the high event rate; thus, we would not extrapolate the incidence of adverse outcomes to other cohorts. Because of the relatively short follow-up time, time-to-event analysis was not performed. In addition, the study design prevents
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Figure 3. Comparison of strain in segments with and without LGE. Radial (A), circumferential (B), and longitudinal (C) strains are presented by level.
speculation on rate of progression of fibrosis. Further longitudinal data with longer follow-up and larger sample size are needed in this population.
4.
Disclosures The authors have no conflicts of interest to disclose. 1. Gersh BJ, Maron BJ, Bonow RO, Dearani JA, Fifer MA, Link MS, Naidu SS, Nishimura RA, Ommen SR, Rakowski H, Seidman CE, Towbin JA, Udelson JE, Yancy CW. 2011 ACCF/AHA Guideline for the Diagnosis and Treatment of Hypertrophic Cardiomyopathy: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Developed in collaboration with the American Association for Thoracic Surgery, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2011;58:e212ee260. 2. Bruder O, Wagner A, Jensen CJ, Schneider S, Ong P, Kispert EM, Nassenstein K, Schlosser T, Sabin GV, Sechtem U, Mahrholdt H. Myocardial scar visualized by cardiovascular magnetic resonance imaging predicts major adverse events in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 2010;56:875e887. 3. Saito M, Okayama H, Yoshii T, Higashi H, Morioka H, Hiasa G, Sumimoto T, Inaba S, Nishimura K, Inoue K, Ogimoto A, Shigematsu Y, Hamada M, Higaki J. Clinical significance of global two-dimensional strain as a surrogate parameter of myocardial fibrosis and cardiac
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