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Clinical Stratification of Pediatric Patients with Idiopathic Thoracic Aortic Aneurysm
Clinical Stratification of Pediatric Patients with Idiopathic Thoracic Aortic Aneurysm Benjamin J. Landis, MD1, Stephanie M. Ware, MD, PhD2, Jeanne James, MD1, Amy R. Shikany, MS1, Lisa J. Martin, PhD3, and Robert B. Hinton, MD1 Objectives To describe the global phenotypes of pediatric patients with thoracic aortic aneurysm (TAA) who do not have a clinical diagnosis of Marfan syndrome (MFS) or related connective tissue disorders. We hypothesized that the presence of noncardiovascular abnormalities correlate with TAA severity and that medical therapy reduces TAA progression. Study design This is a retrospective case series of patients with TAA age #21 years evaluated in a cardiovascular genetics clinic. Patients meeting clinical criteria for MFS or related disorders were excluded. Repeated measures analyses of longitudinal echocardiographic measurements of the aorta were used to test associations between TAA severity and noncardiovascular phenotype and to assess the impact of medical therapy. Results Sixty-nine patients with TAA at mean age 12.5 5.3 years were included. Noncardiovascular abnormalities, including skeletal (65%) or craniofacial (54%) findings, were frequently observed. Increased rate of aortic root enlargement was associated with ocular (P = .002) and cutaneous (P = .003) abnormalities, and increased rate of ascending aorta enlargement was associated with craniofacial (P < .001) abnormalities. Beta blocker or angiotensin receptor blocker therapy (n = 41) was associated with reduction in the rate of aortic root growth (P = .018). Conclusions Children with TAA not satisfying diagnostic criteria for MFS or related disorders frequently have noncardiovascular findings, some of which are associated with TAA progression. Because therapy initiation may reduce risk of progression and long-term complications, comprehensive assessment of noncardiovascular findings may facilitate early risk stratification and improve outcomes. (J Pediatr 2015;167:131-37). See editorial, p 14
T
horacic aortic aneurysm (TAA) is a subclinical aortopathy characterized by dilation of the proximal aorta. TAA is associated with severe acute complications such as aortic dissection and sudden cardiac death. There are an estimated 30 000 deaths per year in the US because of aneurysmal disease.1 Pediatric TAA is well recognized in connective tissue disorders (CTDs) such as Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS), but pediatric patients with TAA who do not meet diagnostic criteria for these conditions have not been well characterized. There is, however, mounting evidence to indicate that the aortopathy in these patients also has a genetic and developmental basis. The 2010 guidelines from the American Heart Association provide thresholds for prophylactic replacement of the aorta, based primarily on aortic diameter or rapid aortic enlargement.2 In these guidelines, the threshold for surgery is lower for patients with LDS than MFS and is lower for patients with MFS than “nonsyndromic” TAA, but the stratification of patients who do not have a diagnosis of a specific CTD is limited. In the context of increasing recognition of the genetic basis of TAA, there is a need to characterize this heterogeneous patient population with idiopathic TAA in order to develop risk classification paradigms to guide clinical management. Children with TAA may benefit from medical intervention to prevent disease progression, cardiac events, and need for surgery. We have performed deep phenotyping of cardiovascular and noncardiovascular characteristics in a pediatric cohort of patients with TAA who do not have the diagnosis of a specific CTD such as MFS or LDS. We aimed to generate a phenotype-based framework for risk classification and hypothesized that there are noncardiovascular abnormalities associated with TAA severity.
ARB BAV BB CTD CVM FTAAD LDS MFS MPA STJ TAA
Angiotensin II type 1 receptor blocker Bicuspid aortic valve Beta blocker Connective tissue disorder Cardiovascular malformation Familial thoracic aortic aneurysm or dissection Loeys-Dietz syndrome Marfan syndrome Main pulmonary artery Sinotubular junction Thoracic aortic aneurysm
From the 1Division of Cardiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH; 2Department of Pediatrics and Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN; and 3 Division Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH Supported by the American Heart Association (IRG 18830027 [to R.H.]) and the Cincinnati Children’s Hospital Medical Center’s Research Foundation (to R.H.). The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2015.02.042
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We additionally hypothesized that beta blocker (BB) or angiotensin II type 1 receptor blocker (ARB) therapy reduces the rate of aortic dilation. Consideration of the patient’s global phenotype may be useful to stratify risk and guide clinical interventions.
Methods This was a retrospective cohort study consisting of review of existing medical records; the local Institutional Review Board approved this study. Patients with TAA age 21 years or younger were identified by review of cardiovascular genetics clinic rosters from July 1, 2010, to December 31, 2012. TAA was defined as aortic root or ascending aorta z-score greater than +2 by transthoracic echocardiography.3 All patients underwent evaluation by a pediatric cardiologist, medical geneticist, and genetic counselor, which included comprehensive physical examination and detailed pedigree ascertainment. The patients evaluated in this clinic constitute a phenotypically and genetically heterogeneous spectrum including syndromic TAA (eg, MFS, LDS, Turner syndrome), familial TAA or dissection (FTAAD), patients with some concern for a CTD, and patients referred for coordinated management of isolated TAA. Patients with syndromic TAA were excluded. The included patients were further classified by a medical geneticist (S.W.) utilizing the systemic score of the revised Ghent nosology for MFS as having no or low (score 0-1), intermediate (score 2-4), or high (score 5-6) suspicion for MFS.4 In addition to excluding patients with the diagnosis of a specific CTD or syndrome associated with TAA, patients with complex cardiovascular malformations (CVMs) associated with aortic dilation (eg, tetralogy of Fallot) or at least moderate aortic valve stenosis or regurgitation were also excluded. Data collected from the electronic medical record included demographics, anthropomorphic data, vital signs, past medical history, family history, physical examination findings including Beighton score (hypermobility), noncardiovascular features of LDS, and systemic score of the revised Ghent nosology (MFS),4,5 medication use, and genetic testing. At each visit the patient was examined for the development of new findings, which were included in these analyses. Echocardiograms performed from May 1, 2003, to December 31, 2012 were reviewed. Data extracted included aorta and main pulmonary artery (MPA) diameters, aortic and mitral valve morphology and function, and presence of additional CVMs. To improve reliability, aortic dimensions were measured in triplicate by a single reader (B.L.) and 10% were re-measured by a second reader (R.H.). Aortic measurements were obtained with 2-dimensional echocardiography in the parasternal long axis in systole, according to consensus guidelines.2,6 Aortic annulus, aortic root, sinotubular junction (STJ), proximal ascending aorta, and MPA diameters were measured from inner edge to inner edge perpendicular to the long axis of the vessel at maximal expansion during systole. Absolute measurements were indexed to 132
Vol. 167, No. 1 body surface area, using the Haycock formula,7 and normalized to generate z-scores based on reference data from Boston Children’s Hospital for annulus and root8,9 and local data for STJ and ascending aorta. Intervals of therapy and doses were recorded. Atenolol was the prescribed BB in all but 1 patient (metoprolol), and losartan was the only ARB prescribed. Patients were divided into 2 groups: no therapy or therapy (BB or ARB). For exploratory subanalysis, the therapy group was subdivided into BB only or ARB only. Patients with reported noncompliance were considered as not receiving therapy. Statistical Analyses Analyses were performed using JMP statistical software package (SAS Institute, Cary, North Carolina). Continuous data were evaluated for distributional qualities. We examined the variability in the triplicate measures of echocardiographic data using coefficient of variation (cardiovascular). When triplicate values exceeded 5% cardiovascular, the 2 most similar measures were selected. Once consistency was evaluated, the maximum value of the retained replicated measure was used. In addition, 10% of studies were independently remeasured by a second reader (R.H.) with strong correlation (R2 > 0.95) between readers. Baseline characteristics of the cohort were described. For continuous variables distributed normally (eg, age), means and SDs are reported. For continuous variables that were non-normally distributed (eg, echocardiogram intervals, revised Ghent systemic score), medians, and IQRs are used. Categorical data are reported as frequencies. To identify differences between treatment groups, we utilized t tests for continuous normally distributed variables, Wilcoxon rank sum for continuous non-normally distributed variables, and contingency tables and c2 goodness of fit tests for categorical variables. To examine longitudinal changes in aortic dimensions from baseline study, repeated measures analysis (mixed models) was used on z-scores. For individuals in the no therapy group, the baseline study was considered the first echocardiogram. For individuals receiving BB or ARB, the baseline study was considered the last echocardiogram prior to therapy initiation. The primary outcome variables were zscores of the aortic root and ascending aorta. Time was the primary fixed effect with the individual as a random effect. Other covariates included age and presence of noncardiovascular or valvar abnormalities. As we considered 11 distinct noncardiovascular or valvar abnormalities, we employed a Bonferroni correction (a = 0.05/11 = 0.0045) for statistical significance of the rate of aortic root change for noncardiovascular and valvar abnormalities. To test whether there were differences in disease progression between untreated and treated individuals prior to the initiation of treatment, an interaction of treatment status and time was included with the analysis restricted to untreated and pretreatment treated individuals. To test whether initiation of treatment changed progression, we performed an analysis in treated individuals with an interaction term between pre-post Landis et al
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Results The medical history of each of the 128 pediatric patients with TAA who were evaluated in cardiovascular genetics clinic over the study period was reviewed. After excluding those diagnosed with a genetic syndrome associated with TAA (n = 48), complex CVM (n = 7), or worse than mild aortic valve stenosis or regurgitation (n = 4), there were 69 (53%) patients who comprised the study population (Figure 1). Referral indications for the study population were evaluation and management of suspected CTD or other genetic disorder in 45 (65%), evaluation and management of TAA without referring caregiver having clear concern for CTD in 18 (26%), and family history of TAA or dissection in 6 (9%) patients. There was a median of 2 (range 1-5) clinic visits and median of 4 (range 1-18) echocardiograms per subject. The study population consisted predominantly of white males in late childhood to adolescence (Table I). The population was slender with mean body mass index of 18 kg/m2 and included 15 (22%) patients exceeding 95th percentile for height. The median systemic score according to the revised Ghent nosology was 2 (IQR 1-4), which is below the diagnostic threshold of 7. Based upon individual systemic scores, there were 30 (43%) patients with low or no suspicion for MFS (score 0 or 1), 31 (45%) with intermediate suspicion for MFS (score 2-4), and 8 (12%) with high suspicion for MFS (score 5 or 6) (Figure 1 and Table II; Table II is available at www.jpeds.com). Although MFS was highly suspected in only a minority of the cohort,
Table I. Patient characteristics, cardiovascular, and noncardiovascular findings according to therapy group Patient characteristics
n (%) No therapy BB or ARB (N = 69) (N = 28) (N = 41)
Demographics Age at initial visit (y) 12.5 (5.3) Sex Male 60 (87) Female 9 (13) Race White 60 (87) Black 6 (9) Asian 1 (1) Other 2 (3) Ethnicity* Non-Hispanic 66 (97) Hispanic 3 (3) Anthropomorphic data, mean (SD) Height percentile 58 (33) Weight percentile 45 (30) BMI absolute 18 (2.6) BMI percentile 35 (26) BSA absolute 1.4 (0.5) Blood pressure, mean (SD) Systolic percentile 56 (27) Diastolic percentile 60 (23) Noncardiovascular abnormalities Skeletal 45 (65) Craniofacial 37 (54) Ocular 22 (32) Neurodevelopmental 17 (25) Cutaneous 13 (19) Gastrointestinal 7 (10) Pulmonary 3 (3) Cardiovascular abnormalities Aortic root z-score +2 to 3 22 (32) z-score +3 to 4 21 (30) z-score > +4 21 (30) Ascending aorta† z-score +2 to 3 18 (29) z-score +3 to 4 7 (11) z-score > +4 12 (19) BAV 17 (25) MVP 11 (16)
P
11.9 (5.9)
12.9 (4.9)
.51
21 (75) 7 (25)
39 (95) 2 (5)
.03
25 (89) 2 (7) 0 1 (4)
35 (85) 4 (10) 1 (2) 1 (2)
.73
27 (100) 0
39 (95) 2 (5)
.51
52 (35) 40 (32) 18 (2.5) 32 (26) 1.3 (0.5)
61 (32) 49 (29) 18 (2.6) 37 (27) 1.4 (0.4)
.27 .23 .74 .48 .48
55 (23) 61 (21)
57 (29) 60 (25)
.7 .9
16 (57) 16 (57) 9 (32) 7 (25) 3 (11) 2 (7) 2 (7)
29 (71) 21 (51) 13 (32) 10 (24) 10 (24) 5 (12) 1 (2)
.25 .63 .97 .95 .21 .69 .56
12 (43) 6 (21) 5 (18)
10 (24) 15 (37) 16 (39)
.18
6 (23) 1 (4) 4 (15) 7 (25) 4 (14)
12 (32) 6 (16) 8 (22) 10 (24) 7 (17)
.71 .95 .76
BMI, body mass index; BSA, body surface area; MVP, mitral valve prolapse. P represents comparison of no therapy vs BB or ARB. *One ethnicity not known. †Unable to measure ascending aorta dimension for 6 patients.
Figure 1. Distribution of patients with TAA in cardiovascular genetics clinic population. The clinic patient population with TAA (N = 128) was comprised of patients with syndromic TAA, CVM associated with TAA, moderate to severe aortic valve dysfunction, and the study cohort (n = 69). The study cohort (white) is subdivided with dashed lines into categories of high (H), intermediate (I), and low/no (L) suspicion for MFS AV, aortic valve.
noncardiovascular abnormalities were frequently observed even among patients who were not referred for a suspected CTD. Altogether, more than 90% of patients were observed to have at least 1 noncardiovascular abnormality, including 45 (65%) patients with skeletal abnormalities, 37 (54%) with craniofacial abnormalities, and 22 (32%) with ocular abnormalities (Tables I and III; Table III is available at www.jpeds.com). Joint hypermobility, defined as Beighton score of 5 or greater, was infrequently observed (n = 7, 10%); none met clinical criteria for hypermobility EhlersDanlos syndrome. Among the study cohort, FBN1, TGFBR1, and TGFBR2 sequencing was negative for pathogenic variants in 42 (61%) patients, and additional deletion/duplication testing was negative in 3 patients (Table II). The majority (77%)
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of patients in the study cohort who were determined to have intermediate or high suspicion for MFS had negative testing for FBN1, TGFBR1, and TGFBR2 mutations. At the time of last evaluation, 8 (12%) patients had a diagnosis of FTAAD based on confirmed family history of autosomal dominant TAA. Sequencing of ACTA2 and MYH11 was normal in 15 (22%) of the entire cohort. None of those with high suspicion for MFS or LDS was tested for ACTA2 and MYH11 mutations compared with 25% in the intermediate or low/no suspicion groups. These patterns indicate that over the study period, genetic testing was performed in a tiered manner based on suspicion for MFS or other CTD. Overall, the high frequency of noncardiovascular phenotype abnormalities in this collectively heterogeneous study cohort indicates that many pediatric patients with TAA have some degree of nonspecific systemic connective tissue involvement. The aortic root was dilated in 64 (93%) patients, but ascending aorta was dilated in 37 (59%) and annulus in only 3 patients (Table I). The mean z-score at baseline measurement was 3.1 1.1 (2.9 0.7 cm) for the aortic root and 2.0 1.7 (2.5 0.6 cm) for the ascending aorta (Figure 2). There were no cases of aortic dissection or surgical aortic replacement over the study period. Bicuspid aortic valve (BAV) was present in 17 (25%) patients, among whom 76% had fusion of the right and left coronary cusps, which is consistent with prior observations.10-12 Notably, 15 (88%) of the patients with BAV had aortic root dilation. In 11 of these cases of BAV, there was associated dilation of the ascending aorta; 2 patients had dilation restricted to the ascending aorta. Noncardiovascular abnormalities were also frequent in the BAV subset and similar to the overall cohort: 41% with skeletal, 53% with craniofacial, and 29% with ocular
Vol. 167, No. 1 abnormalities. The MPA was dilated in 19 (28%) patients, although image quality precluded measurement in a significant proportion of studies (43%), suggesting this may be an underestimate. All patients had normal left ventricular systolic function. Using longitudinal modeling (repeated measures), we observed significant associations between the rate of aortic enlargement and noncardiovascular abnormalities (Table IV). For example, ocular (P = .002) or cutaneous (P = .003) abnormalities were associated with an increased rate of aortic root dilation. Meanwhile, craniofacial (P < .001) abnormalities were associated with an increased rate of ascending aorta dilation. The severity of craniofacial dysmorphism, considered as the sum of craniofacial abnormalities in an individual, was also associated with rate of ascending aorta dilation (P < .001). There was no significant association between systemic score and rate of aortic enlargement or between BAV or mitral valve prolapse and the rate of aortic enlargement. When the cohort subset who had normal sequencing of FBN1, TGFBR1, and TGFBR2 were independently analyzed, the associations for cutaneous and craniofacial abnormalities with TAA progression remained significant, but ocular findings were no longer significant (Table V; available at www.jpeds.com). These observations provide a basis for stratifying the risk of TAA progression according to the pattern of a patient’s noncardiovascular abnormalities. BB or ARB therapy was initiated in 41 (59%) patients, including 24 (35%) on BB and 17 (25%) on ARB therapy. The mean age at therapy initiation was 12.9 4.9 years. The mean daily dose at the last follow up was 0.7 0.4 mg/kg for atenolol and 0.7 0.3 mg/kg for losartan (Table VI; available at www.jpeds.com). Although most patients were normotensive (Table I), 3 had systemic
Figure 2. A, Two-dimensional echocardiographic image of the proximal aorta. The aortic segments of interest are indicated by the double arrowhead lines and include: (1) aortic annulus; (2) aortic root; (3) STJ; and (4) ascending aorta. B, Bar plot demonstrating that the aortic root is more severely dilated at baseline compared with other aortic segments, and at baseline echocardiogram the patients who receive therapy have more severe aortic dilation than patients not receiving therapy. Bars represent mean z-score and error plots represent SDs from the mean. LA, left atrium; LV, left ventricle. 134
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Table IV. Noncardiovascular and cardiovascular factors impacting rate of aortic dilation
Affected systems Skeletal Craniofacial Craniofacial (sum) Ocular Neurodevelopmental Cutaneous Gastrointestinal Pulmonary Height >95th percentile Systemic score Cardiovascular BAV MVP
Relative change in rate of aortic root dilation 4 4 4 [[ 4 [[ 4 4 4 4 4 4
P
Relative change in rate of ascending aorta dilation
P
.4 .15 .54 .002 .88 .003 .10 .53 .37 .09
[ [[ [[ 4 4 Y 4 4 [ 4
.04 <.001 <.001 .90 .07 .04 .41 .07 .04 .28
.14 .78
Y 4
.01 .07
Double arrows ([[) indicate significant change. Single arrows ([ or Y) indicate change that does not reach statistical significance after multiple hypothesis correction (a = 0.0045).
hypertension treated with angiotensin converting enzyme inhibitors alone (1), with BB (1), or with ARB (1). Among patients on BB or ARB therapy, there was a median of 2 (IQR 1.98-4) echocardiograms obtained prior to initiation of therapy over a median interval of 14.4 (IQR 0.1-44) months. After therapy initiation, there was a median of 2 (IQR 1-3) echocardiograms obtained over 13.2 (IQR 7.817.8) months. Subjects in the no therapy group had median 3 (IQR 2-4) echocardiograms over 13.2 (IQR 6-78) months. These echocardiogram intervals exceed the recommended 6-month interval used to determine the rate of aortic enlargement clinically.2 Demographics including age and body surface area were similar between groups except for male predominance in the therapy group. The frequencies of noncardiovascular and valve abnormalities were similar between the therapy and no therapy groups (Table I). Patients in the therapy group had more severe dilation of the root, STJ, and ascending aorta, indicating provider tendency to treat more severely affected patients. There was no difference in the severity of aortic dilation between ARB and BB subgroups (Table I and Figure 2). Patients treated with BB or ARB had more rapidly progressive aortic root dilation before therapy was initiated compared with the no therapy group (P = .044), who presented with less severe root dilation at baseline study and collectively had stable z-scores over time. Among all patients treated with BB or ARB, the rate of root dilation post-therapy was significantly decreased compared with pretherapy trajectory (P = .018). This medication effect remained significant (P = .03) within the subset who had negative sequencing of FBN1, TGFBR1, and TGFBR2 and, thus, were least likely to have MFS. After therapy initiation, the root z-score trajectory stabilized to have a slope that was not statistically different from zero (P = .90). Because longitudinal aortic root measurements were obtained at different intervals and different time points relative to therapy initiation, the data are presented as a statistical model that collectively integrates all
measurements (Figure 3; available at www.jpeds.com). In contrast to the aortic root, the rate of ascending aorta enlargement was not impacted by therapy (P = .21). Exploratory subanalysis for the aortic root observed a significant interaction effect for BB therapy (P = .004) but not for ARB therapy (P = .20), but firm conclusions cannot be drawn from these data because of the low ARB dosage and smaller number of patients in these subgroups (Table VI). Overall, these data suggest that medical therapy (BB or ARB) may stabilize the rate of aortic enlargement by having the strongest impact on the aortic root.
Discussion The phenotypic heterogeneity of our clinic population reflects the diversity of patients seen by many pediatric cardiologists caring for children with TAA. One of the strengths of this study is that patients were serially evaluated in a multidisciplinary cardiovascular genetics clinic staffed by geneticists and cardiologists with expertise in the diagnostic evaluation and management of syndromic and “nonsyndromic” TAA. One limitation of the study is that not every patient had genetic testing. Genetic testing has an important role in establishing the diagnosis of MFS and related CTDs and can be especially useful in the pediatric population where age related onset of features can complicate clinical diagnosis.4,13,14 The reasons to withhold genetic testing were diverse and patient or family specific. To illustrate our clinical practice, after excluding patients with MFS or LDS, we subclassified the patients in the study cohort as having high, intermediate, or low/no suspicion of a CTD. In general, we recommend genetic testing in patients with high or intermediate suspicion for CTD, and in our cohort 30 of 39 (77%) of these individuals had sequencing of FBN1, TGFBR1, and TGFBR2. Among 30 patients with low/no suspicion for MFS, who were least frequently tested, 17 patients had no Ghent systemic features and 13 had a single systemic feature. Patients in this subgroup who had genetic testing were more likely to have more comprehensive TAA panels ordered. In some cases, these patients were followed clinically without the recommendation for genetic testing or with deferral of testing with a plan to pursue more comprehensive TAA testing at a future visit with newly emerging large panels. These sequencing panels, which include genes such as SMAD3, TGFB2, and MYLK, may be more likely to yield positive results for patients in certain clinical scenarios. For example positive results may be enriched in the setting of early degenerative osteoarthritis, LDS-like features such as an abnormal uvula (eg bifid), arterial tortuosity, or a positive family history of TAA.15-18 Approximately 5% of MFS is associated with FBN1 deletion, and, thus, deletion/duplication testing may be informative in cases where sequencing is normal. The diagnostic yield of this approach for other TAA genes is less well known. Deletion/duplication testing can increasingly be ordered at the time of sequencing without
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additional cost, but this was not the case during the timeframe of this study and thus testing was ordered in a tiered fashion. Despite excluding patients with a specific CTD diagnosis, we observed a high frequency of noncardiovascular abnormalities within the study population. These observations suggest that many pediatric patients with TAA, including those with BAV-associated aortopathy, may have nonspecific connective tissue findings reflective of systemic involvement. Indeed, 35% of patients in the study cohort were referred to our cardiovascular genetics clinic for evaluation and management of TAA or FTAAD without there being suspicion of a CTD by the referring caregiver, and upon evaluation 13 of these 24 (54%) patients were found to have at least 1 systemic feature using the current Ghent nosology. Together, this suggests that there is a genetic basis for all pediatric TAA, and phenotypic variability combined with genotype may distinguish new ways to classify patients and inform natural history in a clinically useful way. The 2010 American Heart Association guidelines for prophylactic surgical replacement of the aorta are based primarily on absolute aortic diameter or rapid aortic enlargement.2 However, size-based prediction of dissection risk is imperfect, and dissections at younger age have high mortality rates similar to dissection at older age.19,20 These are compelling reasons to seek better paradigms to classify risk including genotype-based and detailed phenotype-based stratification. Our data show that abnormalities in noncardiovascular structures, such as craniofacial, ocular, and cutaneous tissues, are associated with more rapid aortic enlargement. Interestingly, correlation between the severity of aortic disease and craniofacial malformation was also previously observed in LDS.21 We speculate that certain systemic features can identify a subset of patients that optimally benefit from early interventions such as activity restriction, strict avoidance of environmental cardiovascular risk factors, earlier surgical intervention, and medical therapy initiation in order to prevent progressive aortic dilation and reduce the long term risk of aortic complications such as dissection.2,22 We present preliminary evidence that BB or ARB therapy may reduce aortic root disease progression within this population at early follow-up time points. Cautious interpretation is necessary because medication dosages were low, the number of study patients was modest, and follow-up time was short. Future prospective trials are warranted to further delineate the efficacy of BB or ARB therapy in this population, including examination of dosing and dual therapy. The phenotype-based findings of this study may reflect the underlying dysregulation of common cellular and molecular pathways in the affected organ systems. Two prevailing paradigms of TAA pathogenesis are dysregulation of transforming growth factor-beta signaling and vascular smooth muscle cell dysfunction.23,24 Smooth muscle cells in different segments of the proximal aorta are derived from the cardiac neural crest or secondary heart field, 2 developmentally distinct lineages that are regulated by different molecular programs.25 It is intriguing that craniofacial abnormalities 136
Vol. 167, No. 1 were specifically associated with severity of dilation of the ascending aorta in this study because both are composed of cells derived from the neural crest.25 These observations highlight how different molecular mechanisms may correlate with specific manifestations of TAA or distinct natural histories, potentially informing diagnosis, risk stratification, and management.26 Further definition of pathways that contribute to the regulation of aortic development may help identify predictive biomarkers that distinguish patients with different risk profiles. Genetic variants in disease pathways may represent novel causes or major modifiers of TAA and enhance clinical stratification paradigms. These analyses are limited by the nature of retrospective data collection from a single center. Recognizing the short duration of follow-up, the inherent variability of echocardiography measurement despite the study’s quality control methods, and what is likely a genetically heterogeneous study group, these results should be considered preliminary and will require validation in larger populations over more extended periods of time. Rate of aortic dilation was the metric for aortic disease severity as there were no dissection events over the study period. Possible selection bias for noncardiovascular abnormalities because of referral patterns may limit generalizability to all pediatric TAA, but we highly suspect that noncardiovascular abnormalities may be more frequent in the general pediatric TAA population than is broadly recognized. A multidisciplinary approach incorporating longitudinal cardiology and genetics evaluation has the potential to contribute to risk stratification paradigms, uncover disease mechanisms, and improve outcomes. n We owe a debt of gratitude to the patients and families included in this study. Submitted for publication Jul 23, 2014; last revision received Jan 16, 2015; accepted Feb 12, 2015. Reprint requests: Robert B. Hinton, MD, Division of Cardiology, The Heart Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229. E-mail: [email protected]
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23.
24. 25. 26.
tions associated with mild systemic features of Marfan syndrome. Nat Genet 2012;44:916-21. Lindsay ME, Schepers D, Bolar NA, Doyle JJ, Gallo E, Fert-Bober J, et al. Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm. Nat Genet 2012;44:922-7. Milewicz DM, Regalado ES, Shendure J, Nickerson DA, Guo DC. Successes and challenges of using whole exome sequencing to identify novel genes underlying an inherited predisposition for thoracic aortic aneurysms and acute aortic dissections. Trends Cardiovasc Med 2014;24:53-60. van de Laar IM, van der Linde D, Oei EH, Bos PK, Bessems JH, BiermaZeinstra SM, et al. Phenotypic spectrum of the SMAD3-related aneurysms-osteoarthritis syndrome. J Med Genet 2012;49:47-57. Pape LA, Tsai TT, Isselbacher EM, Oh JK, O’Gara PT, Evangelista A, et al. Aortic diameter >or = 5.5 cm is not a good predictor of type A aortic dissection: observations from the International Registry of Acute Aortic Dissection (IRAD). Circulation 2007;116:1120-7. Januzzi JL, Isselbacher EM, Fattori R, Cooper JV, Smith DE, Fang J, et al. Characterizing the young patient with aortic dissection: results from the International Registry of Aortic Dissection (IRAD). J Am Coll Cardiol 2004;43:665-9. Loeys BL, Schwarze U, Holm T, Callewaert BL, Thomas GH, Pannu H, et al. Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med 2006;355:788-98. Maron BJ, Ackerman MJ, Nishimura RA, Pyeritz RE, Towbin JA, Udelson JE. Task Force 4: HCM and other cardiomyopathies, mitral valve prolapse, myocarditis, and Marfan syndrome. J Am Coll Cardiol 2005;45:1340-5. Milewicz DM, Guo DC, Tran-Fadulu V, Lafont AL, Papke CL, Inamoto S, et al. Genetic basis of thoracic aortic aneurysms and dissections: focus on smooth muscle cell contractile dysfunction. Annu Rev Genomics Hum Genet 2008;9:283-302. Lindsay ME, Dietz HC. Lessons on the pathogenesis of aneurysm from heritable conditions. Nature 2011;473:308-16. Majesky MW. Developmental basis of vascular smooth muscle diversity. Arterioscler Thromb Vasc Biol 2007;27:1248-58. Hinton RB. Bicuspid aortic valve and thoracic aortic aneurysm: three patient populations, two disease phenotypes, and one shared genotype. Cardiol Res Pract 2012;2012:926975.
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Figure 3. Statistical modeling of longitudinal aortic root dimensions demonstrates that prior to therapy initiation (dotted vertical line), the therapy group (solid line) has more rapid root dilation than the no therapy group (dashed line) (P = .04). After therapy initiation, the rate of root dilation decreases (P = .02). Symbols at top illustrate time interval from therapy initiation to last follow-up echocardiogram for individual patients (diamond represents BB and the mark represents ARB).
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Table II. Description of genetic testing status, systemic features, and family history
Age (y) High suspicion for MFS 19 17 17 15 15 15 18 12 Intermediate suspicion for MFS 17 17 17 16 14 14 14 13 8 7 20 20 19 18 17 16 11 20 20 20 19 18 17 16 15 15 13 12 12 10 9 Low or no suspicion for MFS 20 19 17 16 16 16 15 11 11 11 10 4 3 18 18 14 14 13 12 10
No. Skeletal Systemic No. CF additional feature score features CF score FBN1 TGFBR1 TGFBR2 ACTA2 MYH11 (Ghent) (Ghent) features (Ghent) Myopia Pneumothorax Striae MVP FTAAD
NT Neg Neg* NT Neg Neg Neg Neg
NT Neg Neg* NT Neg NT Neg Neg
NT Neg Neg* NT Neg NT Neg Neg
NT NT NT NT NT NT NT NT
NT NT NT NT NT NT NT NT
6 6 6 6 6 6 5 5
0 0 2a,c 0 3c,d,e 3a,c,e 1b 2c,e
0 0 1g 0 2g,i 1g 0 0
3l,m,s 5j,l,n,p,q 4l,m,n,r 4l,m,n,s 4l,m,n 4j,l,m 3j,n,p 5j,l,m,n,r
+ + + + +
Neg Neg Neg Neg Neg Neg Neg Neg NT NT NT Neg Neg Neg Neg Neg Neg Neg NT NT Neg NT Neg Neg Neg Neg Neg Neg Neg Neg Neg*
Neg Neg Neg Neg Neg Neg Neg Neg NT NT NT Neg Neg Neg Neg Neg Neg Neg NT NT Neg NT Neg Neg Neg Neg Neg Neg Neg Neg Neg*
Neg Neg Neg Neg Neg Neg Neg Neg NT NT NT Neg Neg Neg Neg Neg Neg Neg NT NT Neg NT Neg Neg Neg Neg Neg Neg Neg Neg Neg*
NT NT Neg NT NT NT Neg Neg NT NT NT NT NT Neg NT Neg NT NT NT NT NT NT Neg Neg NT NT Neg NT NT NT NT
NT NT Neg NT NT NT Neg Neg NT NT NT NT NT Neg NT Neg NT NT NT NT NT NT Neg Neg NT NT Neg NT NT NT NT
4 4 4 4 4 4 4 4 4 4 3 3 3 3 3 3 3 2 2 2 2 2 2 2 2 2 2 2 2 2 2
1c 1a 0 0 1c 0 0 0 0 0 2c,d c,d,e 3 2a,c 0 3a,c,e 1c 0 0 0 0 0 0 3a,c,e 1c 0 0 0 3a,c,d 0 0 0
1f 0 0 0 1g 0 0 0 1f 0 0 1g 0 0 0 0 0 1g 0 0 0 0 1g 0 0 0 0 1f 0 0 0
3m,n,o 3l,m,s 3k,n 3m,o 3j,m,n 2j,n 3k,n 4j,m,o 4k,o 3m,n,o 3m,n,q 1j 0s 2o,s 1l 1l 2n,o 1n 2j,n 1j 1l 0 1j 1p 1m 0 2j,n 0r 1l 1n 2o
+
Neg NT NT NT NT NT Neg NT NT Neg Neg NT Neg* NT Neg Neg Neg NT NT Neg
Neg NT NT NT Neg NT Neg NT NT Neg Neg NT Neg Neg Neg Neg Neg NT NT Neg
Neg NT NT NT Neg NT Neg NT NT Neg Neg NT Neg NT Neg Neg Neg NT NT Neg
NT NT NT Neg Neg NT NT NT NT Neg NT NT NT Neg Neg NT NT NT NT Neg
NT NT NT Neg Neg NT NT NT NT Neg NT NT NT NT Neg NT NT NT NT Neg
1 1 1 1 1 1 1 1 1 1 1 1 1 0 0 0 0 0 0 0
1c 0 2d,e 0 0 0 1c 1c 1c 0 2c,d 0 1c 0 0 2c,d 0 1c 0 0
0 1f 0 1f 0 0 0 0 2h,i 0 0 0 1g 0 0 0 0 1f 0 0
1l 1q 1q 1n 1p 0 0 0 1n 0 1j 0 1q 0 0 0 0 0 0 0
+
+
+ + + +
+
+ + + + + +
+
+ +
+ + + +
+
+ + +
+ + + + +
+ +
+
+
+ + + + +
+ + + + + + +
(continued )
Clinical Stratification of Pediatric Patients with Idiopathic Thoracic Aortic Aneurysm
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Table II. Continued
Age (y) 7 7 6 5 3 3 2 1 1 0.3
No. Skeletal Systemic No. CF additional feature score features CF score FBN1 TGFBR1 TGFBR2 ACTA2 MYH11 (Ghent) (Ghent) features (Ghent) Myopia Pneumothorax Striae MVP FTAAD Neg NT Neg Neg NT NT NT NT NT NT
Neg NT Neg Neg NT NT NT NT NT NT
Neg NT Neg Neg NT NT NT NT NT NT
NT NT Neg Neg NT NT NT NT NT NT
NT NT Neg Neg NT NT NT NT NT NT
0 0 0 0 0 0 0 0 0 0
0 0 1d 1d 2c,e 0 0 0 0 0
0 0 0 0 0 0 0 0 1f 0
0 0 0 0 0 0 0 0 0 0
+
CF, craniofacial; MVP, mitral valve prolapse; Neg, negative DNA sequencing; NT, not tested. The level of suspicion for MFS is based upon the patient’s revised Ghent nosology systemic score. All study patients had negative DNA sequencing or were not tested for mutations in the genes included in the table. Superscripts denote presence of specific craniofacial and skeletal features that are commonly observed in MFS or related CTDs and were absent if not indicated. The presence (+) or absence (blank space) of additional components of the revised Ghent nosology or presence of FTAAD (known affected first degree relative) is also provided. There are no unknown values for the phenotypic findings included. a. Dolichocephaly, b. Enophthalmos, c. Malar hypoplasia, d. Downslanting palpebral fissures, e. Retrognathia, f. Hypertelorism, g. High arched palate, h. Cleft palate, i. Broad uvula (none was bifid), j. Pectus excavatum, k. Pectus carinatum, l. Wrist sign, m. Thumb sign, n. Pes planus, o. Hindfoot valgus, p. Decreased elbow extension, q. Scoliosis, r. Reduced US/LS, s. Increased armspan/height. *Additional deletion/duplication testing negative.
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Table III. Expanded description of cardiovascular and noncardiovascular abnormalities in pediatric TAA population (N = 69) Patient characteristics Demographics Age at initial visit (y) Sex Male Female Race White Black Asian Other Ethnicity* Non-Hispanic Hispanic Anthropomorphic data, mean (SD) Height percentile Weight percentile BMI absolute BMI percentile BSA absolute Blood pressure, mean (SD) Systolic percentile Diastolic percentile Noncardiovascular abnormalities Skeletal Pes planus Thumb sign Wrist sign Arachnodactyly Pectus excavatum Scoliosis Hindfoot valgus Height >95th percentile Arm span/height >1.05 Low upper segment: lower segment (per Ghent criteria) Joint pain Pectus carinatum Decreased elbow extension Syndactyly Contractures Craniofacial Dolichocephaly Enophthalmos Downslanting palpebral fissures Malar hypoplasia Retrognathia Hypertelorism Palate abnormality Orthodontia Uvula abnormality Ear malformation Ocular Myopia Pupil/extraocular muscle abnormality Cutaneous Striae Easy bruising Abnormal scarring Gastrointestinal Inguinal hernia Eosinophilic esophagitis Pulmonary (pneumothorax) Cardiovascular abnormalities Aortic root z-score +2 to 3 z-score +3 to 4 z-score > +4
n (% of total)
No therapy (N = 28)
BB or ARB (N = 41)
BB (N = 24)
ARB (N = 17)
Pz
Px
12.5 (5.3)
11.9 (5.9)
12.9 (4.9)
13.1 (4.9)
12.5 (5.1)
.51 .026
.71 .17
60 (87) 9 (13)
21 (75) 7 (25)
39 (95) 2 (5)
24 (100) 0
15 (88) 2 (12) .73
.27
60 (87) 6 (9) 1 (1) 2 (3)
25 (89) 2 (7) 0 1 (4)
35 (85) 4 (10) 1 (2) 1 (2)
22 (92) 2 (8) 0 0
13 (76) 2 (12) 1 (6) 1 (6)
66 (97) 3 (3)
27 (100) 0
39 (95) 2 (5)
23 (96) 1 (4)
16 (94) 1 (6)
58 (33) 45 (30) 18 (2.6) 35 (26) 1.4 (0.5)
52 (35) 40 (32) 18 (2.5) 32 (26) 1.3 (0.5)
61 (32) 49 (29) 18 (2.6) 37 (27) 1.4 (0.4)
63 (32) 47 (30) 18 (2.2) 33 (27) 1.4 (0.4)
59 (33) 50 (28) 18 (3.1) 42 (27) 1.4 (0.5)
.27 .23 .74 .48 .48
.69 .76 .62 .27 .75
56 (27) 60 (23)
55 (23) 61 (21)
57 (29) 60 (25)
61 (33) 65 (23)
54 (25) 54 (27)
.7 .9
.49 .24
45 (65) 20 (29) 14 (20) 13 (19) 12 (17) 13 (19) 5 (7) 8 (12) 15 (22) 5 (7) 3 (4)
16 (57) 6 (21) 6 (21) 4 (14) 4 (14) 4 (14) 3 (11) 3 (11) 5 (18) 3 (11) 1 (4)
29 (71) 14 (34) 8 (20) 9 (22) 8 (20) 9 (22) 2 (5) 5 (12) 10 (24) 2 (5) 2 (5)
18 (75) 7 (29) 4 (17) 5 (21) 4 (17) 6 (25) 2 (8) 4 (17) 7 (29) 0 1 (4)
11 (65) 7 (41) 4 (24) 4 (24) 4 (24) 3 (17) 0 1 (6) 3 (17) 2 (12) 1 (6)
.25
.51
5 (7) 3 (4) 4 (6) 4 (6) 2 (3) 37 (54) 7 (10) 1 (1) 9 (13) 23 (33) 8 (12) 7 (10) 9 (13) 7 (10) 2 (3) 8 (12) 22 (32) 17 (25) 5 (7) 13 (19) 13 (19) 0 0 7 (10) 4 (6) 4 (6) 3 (4)
1 (4) 0 1 (4) 2 (7) 0 16 (57) 4 (14) 0 4 (14) 12 (43) 3 (11) 3 (11) 4 (14) 3 (11) 2 (7) 4 (14) 9 (32) 8 (29) 1 (4) 3 (11) 3 (11) 0 0 2 (7) 1 (4) 2 (7) 2 (7)
4 (10) 3 (7) 3 (7) 2 (5) 2 (5) 21 (51) 3 (7) 1 (2) 5 (12) 11 (27) 5 (12) 4 (10) 5 (12) 4 (10) 0 4 (10) 13 (32) 9 (22) 4 (10) 10 (24) 10 (24) 0 0 5 (12) 3 (7) 2 (5) 1 (2)
3 (13) 1 (4) 2 (8) 2 (8) 2 (8) 13 (54) 2 (8) 1 (4) 3 (13) 7 (29) 3 (13) 3 (13) 3 (13) 1 (4) 0 2 (8) 7 (29) 5 (21) 2 (8) 7 (29) 7 (29) 0 0 3 (12) 2 (8) 1 (4) 1 (4)
1 (6) 2 (12) 1 (6) 0 0 8 (47) 1 (6) 0 2 (12) 4 (24) 2 (12) 1 (6) 2 (12) 3 (18) 0 2 (12) 6 (35) 4 (24) 2 (12) 3 (18) 3 (18) 0 0 2 (12) 1 (6) 1 (6) 0
.63
.75
.97
.74
.21
.48
22 (32) 21 (30) 21 (30)
12 (43) 6 (21) 5 (18)
10 (24) 15 (37) 16 (39)
4 (17) 8 (33) 12 (50)
6 (35) 7 (41) 4 (24)
.51
Clinical Stratification of Pediatric Patients with Idiopathic Thoracic Aortic Aneurysm
1.0
.69
1.0
.56
1.0
.18 .11 (continued )
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Table III. Continued Patient characteristics
n (% of total)
No therapy (N = 28)
BB or ARB (N = 41)
BB (N = 24)
ARB (N = 17)
Pz
Px
.71 .95 .76
1.0 .79 .61
†
Ascending aorta z-score +2 to 3 z-score +3 to 4 z-score > +4 BAV MVP
18 (29) 7 (11) 12 (19) 17 (25) 11 (16)
6 (23) 1 (4) 4 (15) 7 (25) 4 (14)
12 (32) 6 (16) 8 (22) 10 (24) 7 (17)
7 (33) 4 (19) 5 (23) 5 (21) 3 (13)
5 (31) 2 (13) 3 (19) 5 (29) 4 (24)
BMI, body mass index; BSA, body surface area. *One ethnicity not known. †Unable to measure ascending aorta dimension for 6 patients. zNo therapy vs BB or ARB. xBB vs ARB.
Table VI. Therapy dosage of individual patients BB Age therapy started (y)
Table V. Non-cardiovascular and cardiovascular factors impacting rate of aortic dilation only among patients with negative testing for FBN1, TGFBR1, and TGFBR2
Affected systems Skeletal Craniofacial Craniofacial (sum) Ocular Neurodevelopmental Cutaneous Gastrointestinal Pulmonary Height >95th percentile Systemic score Cardiovascular BAV MVP
P
Relative change in rate of ascending aorta dilation
P
4 4 4 [ 4 [[ Y 4 4 4
.54 .96 .41 .03 .12 <.001 .04 .54 .62 .36
4 [[ [[ Y 4 Y 4 4 4 4
.24 <.001 <.001 .01 .10 .03 .77 .07 .29 .23
[ 4
.005 .09
4 4
.29 .34
Relative change in rate of aortic root dilation
Double arrows ([[) indicate significant change. Single arrows ([ or Y) indicate change that does not reach statistical significance after multiple hypothesis correction (a = 0.0045).
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Aortic root or ascending aorta z-score > +4 13 1.6 18 15 5 16 14* 5 7 6 19 12 9 Aortic root or ascending aorta zscore +2 to +4 9 12 14 17 15 8 14 7 17 16 6
ARB Age therapy started (y)
Maximum dosage (mg)
Maximum dosage (mg/kg)
25.0 100.0 75.0 6.0 50.0 25.0
0.4 1.3 1.1 0.8 0.8 0.5
25.0 12.5 25.0 25.0 50.0 25.0 25.0 25.0 50.0 25.0 25.0
1.1 0.5 0.6 0.3 1.1 0.8 0.4 0.7 0.8 0.8 0.7
Maximum dosage (mg)
Maximum dosage (mg/kg)
25.0 18.0 25.0 25.0 25.0 50.0 25.0 12.5 75.0 12.5 12.5 50.0 12.5
0.7 1.0 0.5 0.4 1.0 0.9 0.4 0.6 2.0 0.7 0.3 0.7 0.4
13 19 13 0.5 15 15
12.5 12.5 12.5 25.0 12.5 25.0 37.5 100.0 37.5 50.0 24.0
0.5 0.3 0.3 0.4 0.3 0.6 0.6 1.7 0.5 0.8 1.0
6 6 19 16 12 10 17 11 15 10 10
*BB therapy metoprolol.
Landis et al
T
horacic aortic aneurysm (TAA) is a subclinical aortopathy characterized by dilation of the proximal aorta. TAA is associated with severe acute complications such as aortic dissection and sudden cardiac death. There are an estimated 30 000 deaths per year in the US because of aneurysmal disease.1 Pediatric TAA is well recognized in connective tissue disorders (CTDs) such as Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS), but pediatric patients with TAA who do not meet diagnostic criteria for these conditions have not been well characterized. There is, however, mounting evidence to indicate that the aortopathy in these patients also has a genetic and developmental basis. The 2010 guidelines from the American Heart Association provide thresholds for prophylactic replacement of the aorta, based primarily on aortic diameter or rapid aortic enlargement.2 In these guidelines, the threshold for surgery is lower for patients with LDS than MFS and is lower for patients with MFS than “nonsyndromic” TAA, but the stratification of patients who do not have a diagnosis of a specific CTD is limited. In the context of increasing recognition of the genetic basis of TAA, there is a need to characterize this heterogeneous patient population with idiopathic TAA in order to develop risk classification paradigms to guide clinical management. Children with TAA may benefit from medical intervention to prevent disease progression, cardiac events, and need for surgery. We have performed deep phenotyping of cardiovascular and noncardiovascular characteristics in a pediatric cohort of patients with TAA who do not have the diagnosis of a specific CTD such as MFS or LDS. We aimed to generate a phenotype-based framework for risk classification and hypothesized that there are noncardiovascular abnormalities associated with TAA severity.
ARB BAV BB CTD CVM FTAAD LDS MFS MPA STJ TAA
Angiotensin II type 1 receptor blocker Bicuspid aortic valve Beta blocker Connective tissue disorder Cardiovascular malformation Familial thoracic aortic aneurysm or dissection Loeys-Dietz syndrome Marfan syndrome Main pulmonary artery Sinotubular junction Thoracic aortic aneurysm
From the 1Division of Cardiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH; 2Department of Pediatrics and Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN; and 3 Division Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH Supported by the American Heart Association (IRG 18830027 [to R.H.]) and the Cincinnati Children’s Hospital Medical Center’s Research Foundation (to R.H.). The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2015.02.042
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We additionally hypothesized that beta blocker (BB) or angiotensin II type 1 receptor blocker (ARB) therapy reduces the rate of aortic dilation. Consideration of the patient’s global phenotype may be useful to stratify risk and guide clinical interventions.
Methods This was a retrospective cohort study consisting of review of existing medical records; the local Institutional Review Board approved this study. Patients with TAA age 21 years or younger were identified by review of cardiovascular genetics clinic rosters from July 1, 2010, to December 31, 2012. TAA was defined as aortic root or ascending aorta z-score greater than +2 by transthoracic echocardiography.3 All patients underwent evaluation by a pediatric cardiologist, medical geneticist, and genetic counselor, which included comprehensive physical examination and detailed pedigree ascertainment. The patients evaluated in this clinic constitute a phenotypically and genetically heterogeneous spectrum including syndromic TAA (eg, MFS, LDS, Turner syndrome), familial TAA or dissection (FTAAD), patients with some concern for a CTD, and patients referred for coordinated management of isolated TAA. Patients with syndromic TAA were excluded. The included patients were further classified by a medical geneticist (S.W.) utilizing the systemic score of the revised Ghent nosology for MFS as having no or low (score 0-1), intermediate (score 2-4), or high (score 5-6) suspicion for MFS.4 In addition to excluding patients with the diagnosis of a specific CTD or syndrome associated with TAA, patients with complex cardiovascular malformations (CVMs) associated with aortic dilation (eg, tetralogy of Fallot) or at least moderate aortic valve stenosis or regurgitation were also excluded. Data collected from the electronic medical record included demographics, anthropomorphic data, vital signs, past medical history, family history, physical examination findings including Beighton score (hypermobility), noncardiovascular features of LDS, and systemic score of the revised Ghent nosology (MFS),4,5 medication use, and genetic testing. At each visit the patient was examined for the development of new findings, which were included in these analyses. Echocardiograms performed from May 1, 2003, to December 31, 2012 were reviewed. Data extracted included aorta and main pulmonary artery (MPA) diameters, aortic and mitral valve morphology and function, and presence of additional CVMs. To improve reliability, aortic dimensions were measured in triplicate by a single reader (B.L.) and 10% were re-measured by a second reader (R.H.). Aortic measurements were obtained with 2-dimensional echocardiography in the parasternal long axis in systole, according to consensus guidelines.2,6 Aortic annulus, aortic root, sinotubular junction (STJ), proximal ascending aorta, and MPA diameters were measured from inner edge to inner edge perpendicular to the long axis of the vessel at maximal expansion during systole. Absolute measurements were indexed to 132
Vol. 167, No. 1 body surface area, using the Haycock formula,7 and normalized to generate z-scores based on reference data from Boston Children’s Hospital for annulus and root8,9 and local data for STJ and ascending aorta. Intervals of therapy and doses were recorded. Atenolol was the prescribed BB in all but 1 patient (metoprolol), and losartan was the only ARB prescribed. Patients were divided into 2 groups: no therapy or therapy (BB or ARB). For exploratory subanalysis, the therapy group was subdivided into BB only or ARB only. Patients with reported noncompliance were considered as not receiving therapy. Statistical Analyses Analyses were performed using JMP statistical software package (SAS Institute, Cary, North Carolina). Continuous data were evaluated for distributional qualities. We examined the variability in the triplicate measures of echocardiographic data using coefficient of variation (cardiovascular). When triplicate values exceeded 5% cardiovascular, the 2 most similar measures were selected. Once consistency was evaluated, the maximum value of the retained replicated measure was used. In addition, 10% of studies were independently remeasured by a second reader (R.H.) with strong correlation (R2 > 0.95) between readers. Baseline characteristics of the cohort were described. For continuous variables distributed normally (eg, age), means and SDs are reported. For continuous variables that were non-normally distributed (eg, echocardiogram intervals, revised Ghent systemic score), medians, and IQRs are used. Categorical data are reported as frequencies. To identify differences between treatment groups, we utilized t tests for continuous normally distributed variables, Wilcoxon rank sum for continuous non-normally distributed variables, and contingency tables and c2 goodness of fit tests for categorical variables. To examine longitudinal changes in aortic dimensions from baseline study, repeated measures analysis (mixed models) was used on z-scores. For individuals in the no therapy group, the baseline study was considered the first echocardiogram. For individuals receiving BB or ARB, the baseline study was considered the last echocardiogram prior to therapy initiation. The primary outcome variables were zscores of the aortic root and ascending aorta. Time was the primary fixed effect with the individual as a random effect. Other covariates included age and presence of noncardiovascular or valvar abnormalities. As we considered 11 distinct noncardiovascular or valvar abnormalities, we employed a Bonferroni correction (a = 0.05/11 = 0.0045) for statistical significance of the rate of aortic root change for noncardiovascular and valvar abnormalities. To test whether there were differences in disease progression between untreated and treated individuals prior to the initiation of treatment, an interaction of treatment status and time was included with the analysis restricted to untreated and pretreatment treated individuals. To test whether initiation of treatment changed progression, we performed an analysis in treated individuals with an interaction term between pre-post Landis et al
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Results The medical history of each of the 128 pediatric patients with TAA who were evaluated in cardiovascular genetics clinic over the study period was reviewed. After excluding those diagnosed with a genetic syndrome associated with TAA (n = 48), complex CVM (n = 7), or worse than mild aortic valve stenosis or regurgitation (n = 4), there were 69 (53%) patients who comprised the study population (Figure 1). Referral indications for the study population were evaluation and management of suspected CTD or other genetic disorder in 45 (65%), evaluation and management of TAA without referring caregiver having clear concern for CTD in 18 (26%), and family history of TAA or dissection in 6 (9%) patients. There was a median of 2 (range 1-5) clinic visits and median of 4 (range 1-18) echocardiograms per subject. The study population consisted predominantly of white males in late childhood to adolescence (Table I). The population was slender with mean body mass index of 18 kg/m2 and included 15 (22%) patients exceeding 95th percentile for height. The median systemic score according to the revised Ghent nosology was 2 (IQR 1-4), which is below the diagnostic threshold of 7. Based upon individual systemic scores, there were 30 (43%) patients with low or no suspicion for MFS (score 0 or 1), 31 (45%) with intermediate suspicion for MFS (score 2-4), and 8 (12%) with high suspicion for MFS (score 5 or 6) (Figure 1 and Table II; Table II is available at www.jpeds.com). Although MFS was highly suspected in only a minority of the cohort,
Table I. Patient characteristics, cardiovascular, and noncardiovascular findings according to therapy group Patient characteristics
n (%) No therapy BB or ARB (N = 69) (N = 28) (N = 41)
Demographics Age at initial visit (y) 12.5 (5.3) Sex Male 60 (87) Female 9 (13) Race White 60 (87) Black 6 (9) Asian 1 (1) Other 2 (3) Ethnicity* Non-Hispanic 66 (97) Hispanic 3 (3) Anthropomorphic data, mean (SD) Height percentile 58 (33) Weight percentile 45 (30) BMI absolute 18 (2.6) BMI percentile 35 (26) BSA absolute 1.4 (0.5) Blood pressure, mean (SD) Systolic percentile 56 (27) Diastolic percentile 60 (23) Noncardiovascular abnormalities Skeletal 45 (65) Craniofacial 37 (54) Ocular 22 (32) Neurodevelopmental 17 (25) Cutaneous 13 (19) Gastrointestinal 7 (10) Pulmonary 3 (3) Cardiovascular abnormalities Aortic root z-score +2 to 3 22 (32) z-score +3 to 4 21 (30) z-score > +4 21 (30) Ascending aorta† z-score +2 to 3 18 (29) z-score +3 to 4 7 (11) z-score > +4 12 (19) BAV 17 (25) MVP 11 (16)
P
11.9 (5.9)
12.9 (4.9)
.51
21 (75) 7 (25)
39 (95) 2 (5)
.03
25 (89) 2 (7) 0 1 (4)
35 (85) 4 (10) 1 (2) 1 (2)
.73
27 (100) 0
39 (95) 2 (5)
.51
52 (35) 40 (32) 18 (2.5) 32 (26) 1.3 (0.5)
61 (32) 49 (29) 18 (2.6) 37 (27) 1.4 (0.4)
.27 .23 .74 .48 .48
55 (23) 61 (21)
57 (29) 60 (25)
.7 .9
16 (57) 16 (57) 9 (32) 7 (25) 3 (11) 2 (7) 2 (7)
29 (71) 21 (51) 13 (32) 10 (24) 10 (24) 5 (12) 1 (2)
.25 .63 .97 .95 .21 .69 .56
12 (43) 6 (21) 5 (18)
10 (24) 15 (37) 16 (39)
.18
6 (23) 1 (4) 4 (15) 7 (25) 4 (14)
12 (32) 6 (16) 8 (22) 10 (24) 7 (17)
.71 .95 .76
BMI, body mass index; BSA, body surface area; MVP, mitral valve prolapse. P represents comparison of no therapy vs BB or ARB. *One ethnicity not known. †Unable to measure ascending aorta dimension for 6 patients.
Figure 1. Distribution of patients with TAA in cardiovascular genetics clinic population. The clinic patient population with TAA (N = 128) was comprised of patients with syndromic TAA, CVM associated with TAA, moderate to severe aortic valve dysfunction, and the study cohort (n = 69). The study cohort (white) is subdivided with dashed lines into categories of high (H), intermediate (I), and low/no (L) suspicion for MFS AV, aortic valve.
noncardiovascular abnormalities were frequently observed even among patients who were not referred for a suspected CTD. Altogether, more than 90% of patients were observed to have at least 1 noncardiovascular abnormality, including 45 (65%) patients with skeletal abnormalities, 37 (54%) with craniofacial abnormalities, and 22 (32%) with ocular abnormalities (Tables I and III; Table III is available at www.jpeds.com). Joint hypermobility, defined as Beighton score of 5 or greater, was infrequently observed (n = 7, 10%); none met clinical criteria for hypermobility EhlersDanlos syndrome. Among the study cohort, FBN1, TGFBR1, and TGFBR2 sequencing was negative for pathogenic variants in 42 (61%) patients, and additional deletion/duplication testing was negative in 3 patients (Table II). The majority (77%)
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of patients in the study cohort who were determined to have intermediate or high suspicion for MFS had negative testing for FBN1, TGFBR1, and TGFBR2 mutations. At the time of last evaluation, 8 (12%) patients had a diagnosis of FTAAD based on confirmed family history of autosomal dominant TAA. Sequencing of ACTA2 and MYH11 was normal in 15 (22%) of the entire cohort. None of those with high suspicion for MFS or LDS was tested for ACTA2 and MYH11 mutations compared with 25% in the intermediate or low/no suspicion groups. These patterns indicate that over the study period, genetic testing was performed in a tiered manner based on suspicion for MFS or other CTD. Overall, the high frequency of noncardiovascular phenotype abnormalities in this collectively heterogeneous study cohort indicates that many pediatric patients with TAA have some degree of nonspecific systemic connective tissue involvement. The aortic root was dilated in 64 (93%) patients, but ascending aorta was dilated in 37 (59%) and annulus in only 3 patients (Table I). The mean z-score at baseline measurement was 3.1 1.1 (2.9 0.7 cm) for the aortic root and 2.0 1.7 (2.5 0.6 cm) for the ascending aorta (Figure 2). There were no cases of aortic dissection or surgical aortic replacement over the study period. Bicuspid aortic valve (BAV) was present in 17 (25%) patients, among whom 76% had fusion of the right and left coronary cusps, which is consistent with prior observations.10-12 Notably, 15 (88%) of the patients with BAV had aortic root dilation. In 11 of these cases of BAV, there was associated dilation of the ascending aorta; 2 patients had dilation restricted to the ascending aorta. Noncardiovascular abnormalities were also frequent in the BAV subset and similar to the overall cohort: 41% with skeletal, 53% with craniofacial, and 29% with ocular
Vol. 167, No. 1 abnormalities. The MPA was dilated in 19 (28%) patients, although image quality precluded measurement in a significant proportion of studies (43%), suggesting this may be an underestimate. All patients had normal left ventricular systolic function. Using longitudinal modeling (repeated measures), we observed significant associations between the rate of aortic enlargement and noncardiovascular abnormalities (Table IV). For example, ocular (P = .002) or cutaneous (P = .003) abnormalities were associated with an increased rate of aortic root dilation. Meanwhile, craniofacial (P < .001) abnormalities were associated with an increased rate of ascending aorta dilation. The severity of craniofacial dysmorphism, considered as the sum of craniofacial abnormalities in an individual, was also associated with rate of ascending aorta dilation (P < .001). There was no significant association between systemic score and rate of aortic enlargement or between BAV or mitral valve prolapse and the rate of aortic enlargement. When the cohort subset who had normal sequencing of FBN1, TGFBR1, and TGFBR2 were independently analyzed, the associations for cutaneous and craniofacial abnormalities with TAA progression remained significant, but ocular findings were no longer significant (Table V; available at www.jpeds.com). These observations provide a basis for stratifying the risk of TAA progression according to the pattern of a patient’s noncardiovascular abnormalities. BB or ARB therapy was initiated in 41 (59%) patients, including 24 (35%) on BB and 17 (25%) on ARB therapy. The mean age at therapy initiation was 12.9 4.9 years. The mean daily dose at the last follow up was 0.7 0.4 mg/kg for atenolol and 0.7 0.3 mg/kg for losartan (Table VI; available at www.jpeds.com). Although most patients were normotensive (Table I), 3 had systemic
Figure 2. A, Two-dimensional echocardiographic image of the proximal aorta. The aortic segments of interest are indicated by the double arrowhead lines and include: (1) aortic annulus; (2) aortic root; (3) STJ; and (4) ascending aorta. B, Bar plot demonstrating that the aortic root is more severely dilated at baseline compared with other aortic segments, and at baseline echocardiogram the patients who receive therapy have more severe aortic dilation than patients not receiving therapy. Bars represent mean z-score and error plots represent SDs from the mean. LA, left atrium; LV, left ventricle. 134
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Table IV. Noncardiovascular and cardiovascular factors impacting rate of aortic dilation
Affected systems Skeletal Craniofacial Craniofacial (sum) Ocular Neurodevelopmental Cutaneous Gastrointestinal Pulmonary Height >95th percentile Systemic score Cardiovascular BAV MVP
Relative change in rate of aortic root dilation 4 4 4 [[ 4 [[ 4 4 4 4 4 4
P
Relative change in rate of ascending aorta dilation
P
.4 .15 .54 .002 .88 .003 .10 .53 .37 .09
[ [[ [[ 4 4 Y 4 4 [ 4
.04 <.001 <.001 .90 .07 .04 .41 .07 .04 .28
.14 .78
Y 4
.01 .07
Double arrows ([[) indicate significant change. Single arrows ([ or Y) indicate change that does not reach statistical significance after multiple hypothesis correction (a = 0.0045).
hypertension treated with angiotensin converting enzyme inhibitors alone (1), with BB (1), or with ARB (1). Among patients on BB or ARB therapy, there was a median of 2 (IQR 1.98-4) echocardiograms obtained prior to initiation of therapy over a median interval of 14.4 (IQR 0.1-44) months. After therapy initiation, there was a median of 2 (IQR 1-3) echocardiograms obtained over 13.2 (IQR 7.817.8) months. Subjects in the no therapy group had median 3 (IQR 2-4) echocardiograms over 13.2 (IQR 6-78) months. These echocardiogram intervals exceed the recommended 6-month interval used to determine the rate of aortic enlargement clinically.2 Demographics including age and body surface area were similar between groups except for male predominance in the therapy group. The frequencies of noncardiovascular and valve abnormalities were similar between the therapy and no therapy groups (Table I). Patients in the therapy group had more severe dilation of the root, STJ, and ascending aorta, indicating provider tendency to treat more severely affected patients. There was no difference in the severity of aortic dilation between ARB and BB subgroups (Table I and Figure 2). Patients treated with BB or ARB had more rapidly progressive aortic root dilation before therapy was initiated compared with the no therapy group (P = .044), who presented with less severe root dilation at baseline study and collectively had stable z-scores over time. Among all patients treated with BB or ARB, the rate of root dilation post-therapy was significantly decreased compared with pretherapy trajectory (P = .018). This medication effect remained significant (P = .03) within the subset who had negative sequencing of FBN1, TGFBR1, and TGFBR2 and, thus, were least likely to have MFS. After therapy initiation, the root z-score trajectory stabilized to have a slope that was not statistically different from zero (P = .90). Because longitudinal aortic root measurements were obtained at different intervals and different time points relative to therapy initiation, the data are presented as a statistical model that collectively integrates all
measurements (Figure 3; available at www.jpeds.com). In contrast to the aortic root, the rate of ascending aorta enlargement was not impacted by therapy (P = .21). Exploratory subanalysis for the aortic root observed a significant interaction effect for BB therapy (P = .004) but not for ARB therapy (P = .20), but firm conclusions cannot be drawn from these data because of the low ARB dosage and smaller number of patients in these subgroups (Table VI). Overall, these data suggest that medical therapy (BB or ARB) may stabilize the rate of aortic enlargement by having the strongest impact on the aortic root.
Discussion The phenotypic heterogeneity of our clinic population reflects the diversity of patients seen by many pediatric cardiologists caring for children with TAA. One of the strengths of this study is that patients were serially evaluated in a multidisciplinary cardiovascular genetics clinic staffed by geneticists and cardiologists with expertise in the diagnostic evaluation and management of syndromic and “nonsyndromic” TAA. One limitation of the study is that not every patient had genetic testing. Genetic testing has an important role in establishing the diagnosis of MFS and related CTDs and can be especially useful in the pediatric population where age related onset of features can complicate clinical diagnosis.4,13,14 The reasons to withhold genetic testing were diverse and patient or family specific. To illustrate our clinical practice, after excluding patients with MFS or LDS, we subclassified the patients in the study cohort as having high, intermediate, or low/no suspicion of a CTD. In general, we recommend genetic testing in patients with high or intermediate suspicion for CTD, and in our cohort 30 of 39 (77%) of these individuals had sequencing of FBN1, TGFBR1, and TGFBR2. Among 30 patients with low/no suspicion for MFS, who were least frequently tested, 17 patients had no Ghent systemic features and 13 had a single systemic feature. Patients in this subgroup who had genetic testing were more likely to have more comprehensive TAA panels ordered. In some cases, these patients were followed clinically without the recommendation for genetic testing or with deferral of testing with a plan to pursue more comprehensive TAA testing at a future visit with newly emerging large panels. These sequencing panels, which include genes such as SMAD3, TGFB2, and MYLK, may be more likely to yield positive results for patients in certain clinical scenarios. For example positive results may be enriched in the setting of early degenerative osteoarthritis, LDS-like features such as an abnormal uvula (eg bifid), arterial tortuosity, or a positive family history of TAA.15-18 Approximately 5% of MFS is associated with FBN1 deletion, and, thus, deletion/duplication testing may be informative in cases where sequencing is normal. The diagnostic yield of this approach for other TAA genes is less well known. Deletion/duplication testing can increasingly be ordered at the time of sequencing without
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additional cost, but this was not the case during the timeframe of this study and thus testing was ordered in a tiered fashion. Despite excluding patients with a specific CTD diagnosis, we observed a high frequency of noncardiovascular abnormalities within the study population. These observations suggest that many pediatric patients with TAA, including those with BAV-associated aortopathy, may have nonspecific connective tissue findings reflective of systemic involvement. Indeed, 35% of patients in the study cohort were referred to our cardiovascular genetics clinic for evaluation and management of TAA or FTAAD without there being suspicion of a CTD by the referring caregiver, and upon evaluation 13 of these 24 (54%) patients were found to have at least 1 systemic feature using the current Ghent nosology. Together, this suggests that there is a genetic basis for all pediatric TAA, and phenotypic variability combined with genotype may distinguish new ways to classify patients and inform natural history in a clinically useful way. The 2010 American Heart Association guidelines for prophylactic surgical replacement of the aorta are based primarily on absolute aortic diameter or rapid aortic enlargement.2 However, size-based prediction of dissection risk is imperfect, and dissections at younger age have high mortality rates similar to dissection at older age.19,20 These are compelling reasons to seek better paradigms to classify risk including genotype-based and detailed phenotype-based stratification. Our data show that abnormalities in noncardiovascular structures, such as craniofacial, ocular, and cutaneous tissues, are associated with more rapid aortic enlargement. Interestingly, correlation between the severity of aortic disease and craniofacial malformation was also previously observed in LDS.21 We speculate that certain systemic features can identify a subset of patients that optimally benefit from early interventions such as activity restriction, strict avoidance of environmental cardiovascular risk factors, earlier surgical intervention, and medical therapy initiation in order to prevent progressive aortic dilation and reduce the long term risk of aortic complications such as dissection.2,22 We present preliminary evidence that BB or ARB therapy may reduce aortic root disease progression within this population at early follow-up time points. Cautious interpretation is necessary because medication dosages were low, the number of study patients was modest, and follow-up time was short. Future prospective trials are warranted to further delineate the efficacy of BB or ARB therapy in this population, including examination of dosing and dual therapy. The phenotype-based findings of this study may reflect the underlying dysregulation of common cellular and molecular pathways in the affected organ systems. Two prevailing paradigms of TAA pathogenesis are dysregulation of transforming growth factor-beta signaling and vascular smooth muscle cell dysfunction.23,24 Smooth muscle cells in different segments of the proximal aorta are derived from the cardiac neural crest or secondary heart field, 2 developmentally distinct lineages that are regulated by different molecular programs.25 It is intriguing that craniofacial abnormalities 136
Vol. 167, No. 1 were specifically associated with severity of dilation of the ascending aorta in this study because both are composed of cells derived from the neural crest.25 These observations highlight how different molecular mechanisms may correlate with specific manifestations of TAA or distinct natural histories, potentially informing diagnosis, risk stratification, and management.26 Further definition of pathways that contribute to the regulation of aortic development may help identify predictive biomarkers that distinguish patients with different risk profiles. Genetic variants in disease pathways may represent novel causes or major modifiers of TAA and enhance clinical stratification paradigms. These analyses are limited by the nature of retrospective data collection from a single center. Recognizing the short duration of follow-up, the inherent variability of echocardiography measurement despite the study’s quality control methods, and what is likely a genetically heterogeneous study group, these results should be considered preliminary and will require validation in larger populations over more extended periods of time. Rate of aortic dilation was the metric for aortic disease severity as there were no dissection events over the study period. Possible selection bias for noncardiovascular abnormalities because of referral patterns may limit generalizability to all pediatric TAA, but we highly suspect that noncardiovascular abnormalities may be more frequent in the general pediatric TAA population than is broadly recognized. A multidisciplinary approach incorporating longitudinal cardiology and genetics evaluation has the potential to contribute to risk stratification paradigms, uncover disease mechanisms, and improve outcomes. n We owe a debt of gratitude to the patients and families included in this study. Submitted for publication Jul 23, 2014; last revision received Jan 16, 2015; accepted Feb 12, 2015. Reprint requests: Robert B. Hinton, MD, Division of Cardiology, The Heart Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229. E-mail: [email protected]
References 1. Elefteriades JA, Farkas EA. Thoracic aortic aneurysm clinically pertinent controversies and uncertainties. J Am Coll Cardiol 2010;55:841-57. 2. Hiratzka LF, Bakris GL, Beckman JA, Bersin RM, Carr VF, Casey DE Jr, et al. 2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with Thoracic Aortic Disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine. Circulation 2010;121:e266-369. 3. Roman MJ, Devereux RB, Kramer-Fox R, O’Loughlin J. Two-dimensional echocardiographic aortic root dimensions in normal children and adults. Am J Cardiol 1989;64:507-12. 4. Loeys BL, Dietz HC, Braverman AC, Callewaert BL, De Backer J, Devereux RB, et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet 2010;47:476-85.
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July 2015 5. Beighton P, De Paepe A, Steinmann B, Tsipouras P, Wenstrup RJ. Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997. EhlersDanlos National Foundation (USA) and Ehlers-Danlos Support Group (UK). Am J Med Genet 1998;77:31-7. 6. Lopez L, Colan SD, Frommelt PC, Ensing GJ, Kendall K, Younoszai AK, et al. Recommendations for quantification methods during the performance of a pediatric echocardiogram: a report from the Pediatric Measurements Writing Group of the American Society of Echocardiography Pediatric and Congenital Heart Disease Council. J Am Soc Echocardiogr 2010;23:465-95. quiz 576-7. 7. Haycock GB, Schwartz GJ, Wisotsky DH. Geometric method for measuring body surface area: a height-weight formula validated in infants, children, and adults. J Pediatr 1978;93:62-6. 8. Colan SD, McElhinney DB, Crawford EC, Keane JF, Lock JE. Validation and re-evaluation of a discriminant model predicting anatomic suitability for biventricular repair in neonates with aortic stenosis. J Am Coll Cardiol 2006;47:1858-65. 9. Sluysmans T, Colan SD. Theoretical and empirical derivation of cardiovascular allometric relationships in children. J Appl Physiol (1985) 2005; 99:445-57. 10. Fernandes S, Khairy P, Graham DA, Colan SD, Galvin TC, Sanders SP, et al. Bicuspid aortic valve and associated aortic dilation in the young. Heart 2012;98:1014-9. 11. Calloway TJ, Martin LJ, Zhang X, Tandon A, Benson DW, Hinton RB. Risk factors for aortic valve disease in bicuspid aortic valve: a familybased study. Am J Med Genetics Part A 2011;155A:1015-20. 12. Tadros TM, Klein MD, Shapira OM. Ascending aortic dilatation associated with bicuspid aortic valve: pathophysiology, molecular biology, and clinical implications. Circulation 2009;119:880-90. 13. Lipscomb KJ, Clayton-Smith J, Harris R. Evolving phenotype of Marfan’s syndrome. Arch Dis Child 1997;76:41-6. 14. Faivre L, Masurel-Paulet A, Collod-Beroud G, Callewaert BL, Child AH, Stheneur C, et al. Clinical and molecular study of 320 children with Marfan syndrome and related type I fibrillinopathies in a series of 1009 probands with pathogenic FBN1 mutations. Pediatrics 2009;123: 391-8. 15. Boileau C, Guo DC, Hanna N, Regalado ES, Detaint D, Gong L, et al. TGFB2 mutations cause familial thoracic aortic aneurysms and dissec-
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tions associated with mild systemic features of Marfan syndrome. Nat Genet 2012;44:916-21. Lindsay ME, Schepers D, Bolar NA, Doyle JJ, Gallo E, Fert-Bober J, et al. Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm. Nat Genet 2012;44:922-7. Milewicz DM, Regalado ES, Shendure J, Nickerson DA, Guo DC. Successes and challenges of using whole exome sequencing to identify novel genes underlying an inherited predisposition for thoracic aortic aneurysms and acute aortic dissections. Trends Cardiovasc Med 2014;24:53-60. van de Laar IM, van der Linde D, Oei EH, Bos PK, Bessems JH, BiermaZeinstra SM, et al. Phenotypic spectrum of the SMAD3-related aneurysms-osteoarthritis syndrome. J Med Genet 2012;49:47-57. Pape LA, Tsai TT, Isselbacher EM, Oh JK, O’Gara PT, Evangelista A, et al. Aortic diameter >or = 5.5 cm is not a good predictor of type A aortic dissection: observations from the International Registry of Acute Aortic Dissection (IRAD). Circulation 2007;116:1120-7. Januzzi JL, Isselbacher EM, Fattori R, Cooper JV, Smith DE, Fang J, et al. Characterizing the young patient with aortic dissection: results from the International Registry of Aortic Dissection (IRAD). J Am Coll Cardiol 2004;43:665-9. Loeys BL, Schwarze U, Holm T, Callewaert BL, Thomas GH, Pannu H, et al. Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med 2006;355:788-98. Maron BJ, Ackerman MJ, Nishimura RA, Pyeritz RE, Towbin JA, Udelson JE. Task Force 4: HCM and other cardiomyopathies, mitral valve prolapse, myocarditis, and Marfan syndrome. J Am Coll Cardiol 2005;45:1340-5. Milewicz DM, Guo DC, Tran-Fadulu V, Lafont AL, Papke CL, Inamoto S, et al. Genetic basis of thoracic aortic aneurysms and dissections: focus on smooth muscle cell contractile dysfunction. Annu Rev Genomics Hum Genet 2008;9:283-302. Lindsay ME, Dietz HC. Lessons on the pathogenesis of aneurysm from heritable conditions. Nature 2011;473:308-16. Majesky MW. Developmental basis of vascular smooth muscle diversity. Arterioscler Thromb Vasc Biol 2007;27:1248-58. Hinton RB. Bicuspid aortic valve and thoracic aortic aneurysm: three patient populations, two disease phenotypes, and one shared genotype. Cardiol Res Pract 2012;2012:926975.
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Figure 3. Statistical modeling of longitudinal aortic root dimensions demonstrates that prior to therapy initiation (dotted vertical line), the therapy group (solid line) has more rapid root dilation than the no therapy group (dashed line) (P = .04). After therapy initiation, the rate of root dilation decreases (P = .02). Symbols at top illustrate time interval from therapy initiation to last follow-up echocardiogram for individual patients (diamond represents BB and the mark represents ARB).
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Table II. Description of genetic testing status, systemic features, and family history
Age (y) High suspicion for MFS 19 17 17 15 15 15 18 12 Intermediate suspicion for MFS 17 17 17 16 14 14 14 13 8 7 20 20 19 18 17 16 11 20 20 20 19 18 17 16 15 15 13 12 12 10 9 Low or no suspicion for MFS 20 19 17 16 16 16 15 11 11 11 10 4 3 18 18 14 14 13 12 10
No. Skeletal Systemic No. CF additional feature score features CF score FBN1 TGFBR1 TGFBR2 ACTA2 MYH11 (Ghent) (Ghent) features (Ghent) Myopia Pneumothorax Striae MVP FTAAD
NT Neg Neg* NT Neg Neg Neg Neg
NT Neg Neg* NT Neg NT Neg Neg
NT Neg Neg* NT Neg NT Neg Neg
NT NT NT NT NT NT NT NT
NT NT NT NT NT NT NT NT
6 6 6 6 6 6 5 5
0 0 2a,c 0 3c,d,e 3a,c,e 1b 2c,e
0 0 1g 0 2g,i 1g 0 0
3l,m,s 5j,l,n,p,q 4l,m,n,r 4l,m,n,s 4l,m,n 4j,l,m 3j,n,p 5j,l,m,n,r
+ + + + +
Neg Neg Neg Neg Neg Neg Neg Neg NT NT NT Neg Neg Neg Neg Neg Neg Neg NT NT Neg NT Neg Neg Neg Neg Neg Neg Neg Neg Neg*
Neg Neg Neg Neg Neg Neg Neg Neg NT NT NT Neg Neg Neg Neg Neg Neg Neg NT NT Neg NT Neg Neg Neg Neg Neg Neg Neg Neg Neg*
Neg Neg Neg Neg Neg Neg Neg Neg NT NT NT Neg Neg Neg Neg Neg Neg Neg NT NT Neg NT Neg Neg Neg Neg Neg Neg Neg Neg Neg*
NT NT Neg NT NT NT Neg Neg NT NT NT NT NT Neg NT Neg NT NT NT NT NT NT Neg Neg NT NT Neg NT NT NT NT
NT NT Neg NT NT NT Neg Neg NT NT NT NT NT Neg NT Neg NT NT NT NT NT NT Neg Neg NT NT Neg NT NT NT NT
4 4 4 4 4 4 4 4 4 4 3 3 3 3 3 3 3 2 2 2 2 2 2 2 2 2 2 2 2 2 2
1c 1a 0 0 1c 0 0 0 0 0 2c,d c,d,e 3 2a,c 0 3a,c,e 1c 0 0 0 0 0 0 3a,c,e 1c 0 0 0 3a,c,d 0 0 0
1f 0 0 0 1g 0 0 0 1f 0 0 1g 0 0 0 0 0 1g 0 0 0 0 1g 0 0 0 0 1f 0 0 0
3m,n,o 3l,m,s 3k,n 3m,o 3j,m,n 2j,n 3k,n 4j,m,o 4k,o 3m,n,o 3m,n,q 1j 0s 2o,s 1l 1l 2n,o 1n 2j,n 1j 1l 0 1j 1p 1m 0 2j,n 0r 1l 1n 2o
+
Neg NT NT NT NT NT Neg NT NT Neg Neg NT Neg* NT Neg Neg Neg NT NT Neg
Neg NT NT NT Neg NT Neg NT NT Neg Neg NT Neg Neg Neg Neg Neg NT NT Neg
Neg NT NT NT Neg NT Neg NT NT Neg Neg NT Neg NT Neg Neg Neg NT NT Neg
NT NT NT Neg Neg NT NT NT NT Neg NT NT NT Neg Neg NT NT NT NT Neg
NT NT NT Neg Neg NT NT NT NT Neg NT NT NT NT Neg NT NT NT NT Neg
1 1 1 1 1 1 1 1 1 1 1 1 1 0 0 0 0 0 0 0
1c 0 2d,e 0 0 0 1c 1c 1c 0 2c,d 0 1c 0 0 2c,d 0 1c 0 0
0 1f 0 1f 0 0 0 0 2h,i 0 0 0 1g 0 0 0 0 1f 0 0
1l 1q 1q 1n 1p 0 0 0 1n 0 1j 0 1q 0 0 0 0 0 0 0
+
+
+ + + +
+
+ + + + + +
+
+ +
+ + + +
+
+ + +
+ + + + +
+ +
+
+
+ + + + +
+ + + + + + +
(continued )
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Table II. Continued
Age (y) 7 7 6 5 3 3 2 1 1 0.3
No. Skeletal Systemic No. CF additional feature score features CF score FBN1 TGFBR1 TGFBR2 ACTA2 MYH11 (Ghent) (Ghent) features (Ghent) Myopia Pneumothorax Striae MVP FTAAD Neg NT Neg Neg NT NT NT NT NT NT
Neg NT Neg Neg NT NT NT NT NT NT
Neg NT Neg Neg NT NT NT NT NT NT
NT NT Neg Neg NT NT NT NT NT NT
NT NT Neg Neg NT NT NT NT NT NT
0 0 0 0 0 0 0 0 0 0
0 0 1d 1d 2c,e 0 0 0 0 0
0 0 0 0 0 0 0 0 1f 0
0 0 0 0 0 0 0 0 0 0
+
CF, craniofacial; MVP, mitral valve prolapse; Neg, negative DNA sequencing; NT, not tested. The level of suspicion for MFS is based upon the patient’s revised Ghent nosology systemic score. All study patients had negative DNA sequencing or were not tested for mutations in the genes included in the table. Superscripts denote presence of specific craniofacial and skeletal features that are commonly observed in MFS or related CTDs and were absent if not indicated. The presence (+) or absence (blank space) of additional components of the revised Ghent nosology or presence of FTAAD (known affected first degree relative) is also provided. There are no unknown values for the phenotypic findings included. a. Dolichocephaly, b. Enophthalmos, c. Malar hypoplasia, d. Downslanting palpebral fissures, e. Retrognathia, f. Hypertelorism, g. High arched palate, h. Cleft palate, i. Broad uvula (none was bifid), j. Pectus excavatum, k. Pectus carinatum, l. Wrist sign, m. Thumb sign, n. Pes planus, o. Hindfoot valgus, p. Decreased elbow extension, q. Scoliosis, r. Reduced US/LS, s. Increased armspan/height. *Additional deletion/duplication testing negative.
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Table III. Expanded description of cardiovascular and noncardiovascular abnormalities in pediatric TAA population (N = 69) Patient characteristics Demographics Age at initial visit (y) Sex Male Female Race White Black Asian Other Ethnicity* Non-Hispanic Hispanic Anthropomorphic data, mean (SD) Height percentile Weight percentile BMI absolute BMI percentile BSA absolute Blood pressure, mean (SD) Systolic percentile Diastolic percentile Noncardiovascular abnormalities Skeletal Pes planus Thumb sign Wrist sign Arachnodactyly Pectus excavatum Scoliosis Hindfoot valgus Height >95th percentile Arm span/height >1.05 Low upper segment: lower segment (per Ghent criteria) Joint pain Pectus carinatum Decreased elbow extension Syndactyly Contractures Craniofacial Dolichocephaly Enophthalmos Downslanting palpebral fissures Malar hypoplasia Retrognathia Hypertelorism Palate abnormality Orthodontia Uvula abnormality Ear malformation Ocular Myopia Pupil/extraocular muscle abnormality Cutaneous Striae Easy bruising Abnormal scarring Gastrointestinal Inguinal hernia Eosinophilic esophagitis Pulmonary (pneumothorax) Cardiovascular abnormalities Aortic root z-score +2 to 3 z-score +3 to 4 z-score > +4
n (% of total)
No therapy (N = 28)
BB or ARB (N = 41)
BB (N = 24)
ARB (N = 17)
Pz
Px
12.5 (5.3)
11.9 (5.9)
12.9 (4.9)
13.1 (4.9)
12.5 (5.1)
.51 .026
.71 .17
60 (87) 9 (13)
21 (75) 7 (25)
39 (95) 2 (5)
24 (100) 0
15 (88) 2 (12) .73
.27
60 (87) 6 (9) 1 (1) 2 (3)
25 (89) 2 (7) 0 1 (4)
35 (85) 4 (10) 1 (2) 1 (2)
22 (92) 2 (8) 0 0
13 (76) 2 (12) 1 (6) 1 (6)
66 (97) 3 (3)
27 (100) 0
39 (95) 2 (5)
23 (96) 1 (4)
16 (94) 1 (6)
58 (33) 45 (30) 18 (2.6) 35 (26) 1.4 (0.5)
52 (35) 40 (32) 18 (2.5) 32 (26) 1.3 (0.5)
61 (32) 49 (29) 18 (2.6) 37 (27) 1.4 (0.4)
63 (32) 47 (30) 18 (2.2) 33 (27) 1.4 (0.4)
59 (33) 50 (28) 18 (3.1) 42 (27) 1.4 (0.5)
.27 .23 .74 .48 .48
.69 .76 .62 .27 .75
56 (27) 60 (23)
55 (23) 61 (21)
57 (29) 60 (25)
61 (33) 65 (23)
54 (25) 54 (27)
.7 .9
.49 .24
45 (65) 20 (29) 14 (20) 13 (19) 12 (17) 13 (19) 5 (7) 8 (12) 15 (22) 5 (7) 3 (4)
16 (57) 6 (21) 6 (21) 4 (14) 4 (14) 4 (14) 3 (11) 3 (11) 5 (18) 3 (11) 1 (4)
29 (71) 14 (34) 8 (20) 9 (22) 8 (20) 9 (22) 2 (5) 5 (12) 10 (24) 2 (5) 2 (5)
18 (75) 7 (29) 4 (17) 5 (21) 4 (17) 6 (25) 2 (8) 4 (17) 7 (29) 0 1 (4)
11 (65) 7 (41) 4 (24) 4 (24) 4 (24) 3 (17) 0 1 (6) 3 (17) 2 (12) 1 (6)
.25
.51
5 (7) 3 (4) 4 (6) 4 (6) 2 (3) 37 (54) 7 (10) 1 (1) 9 (13) 23 (33) 8 (12) 7 (10) 9 (13) 7 (10) 2 (3) 8 (12) 22 (32) 17 (25) 5 (7) 13 (19) 13 (19) 0 0 7 (10) 4 (6) 4 (6) 3 (4)
1 (4) 0 1 (4) 2 (7) 0 16 (57) 4 (14) 0 4 (14) 12 (43) 3 (11) 3 (11) 4 (14) 3 (11) 2 (7) 4 (14) 9 (32) 8 (29) 1 (4) 3 (11) 3 (11) 0 0 2 (7) 1 (4) 2 (7) 2 (7)
4 (10) 3 (7) 3 (7) 2 (5) 2 (5) 21 (51) 3 (7) 1 (2) 5 (12) 11 (27) 5 (12) 4 (10) 5 (12) 4 (10) 0 4 (10) 13 (32) 9 (22) 4 (10) 10 (24) 10 (24) 0 0 5 (12) 3 (7) 2 (5) 1 (2)
3 (13) 1 (4) 2 (8) 2 (8) 2 (8) 13 (54) 2 (8) 1 (4) 3 (13) 7 (29) 3 (13) 3 (13) 3 (13) 1 (4) 0 2 (8) 7 (29) 5 (21) 2 (8) 7 (29) 7 (29) 0 0 3 (12) 2 (8) 1 (4) 1 (4)
1 (6) 2 (12) 1 (6) 0 0 8 (47) 1 (6) 0 2 (12) 4 (24) 2 (12) 1 (6) 2 (12) 3 (18) 0 2 (12) 6 (35) 4 (24) 2 (12) 3 (18) 3 (18) 0 0 2 (12) 1 (6) 1 (6) 0
.63
.75
.97
.74
.21
.48
22 (32) 21 (30) 21 (30)
12 (43) 6 (21) 5 (18)
10 (24) 15 (37) 16 (39)
4 (17) 8 (33) 12 (50)
6 (35) 7 (41) 4 (24)
.51
Clinical Stratification of Pediatric Patients with Idiopathic Thoracic Aortic Aneurysm
1.0
.69
1.0
.56
1.0
.18 .11 (continued )
137.e4
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Table III. Continued Patient characteristics
n (% of total)
No therapy (N = 28)
BB or ARB (N = 41)
BB (N = 24)
ARB (N = 17)
Pz
Px
.71 .95 .76
1.0 .79 .61
†
Ascending aorta z-score +2 to 3 z-score +3 to 4 z-score > +4 BAV MVP
18 (29) 7 (11) 12 (19) 17 (25) 11 (16)
6 (23) 1 (4) 4 (15) 7 (25) 4 (14)
12 (32) 6 (16) 8 (22) 10 (24) 7 (17)
7 (33) 4 (19) 5 (23) 5 (21) 3 (13)
5 (31) 2 (13) 3 (19) 5 (29) 4 (24)
BMI, body mass index; BSA, body surface area. *One ethnicity not known. †Unable to measure ascending aorta dimension for 6 patients. zNo therapy vs BB or ARB. xBB vs ARB.
Table VI. Therapy dosage of individual patients BB Age therapy started (y)
Table V. Non-cardiovascular and cardiovascular factors impacting rate of aortic dilation only among patients with negative testing for FBN1, TGFBR1, and TGFBR2
Affected systems Skeletal Craniofacial Craniofacial (sum) Ocular Neurodevelopmental Cutaneous Gastrointestinal Pulmonary Height >95th percentile Systemic score Cardiovascular BAV MVP
P
Relative change in rate of ascending aorta dilation
P
4 4 4 [ 4 [[ Y 4 4 4
.54 .96 .41 .03 .12 <.001 .04 .54 .62 .36
4 [[ [[ Y 4 Y 4 4 4 4
.24 <.001 <.001 .01 .10 .03 .77 .07 .29 .23
[ 4
.005 .09
4 4
.29 .34
Relative change in rate of aortic root dilation
Double arrows ([[) indicate significant change. Single arrows ([ or Y) indicate change that does not reach statistical significance after multiple hypothesis correction (a = 0.0045).
137.e5
Aortic root or ascending aorta z-score > +4 13 1.6 18 15 5 16 14* 5 7 6 19 12 9 Aortic root or ascending aorta zscore +2 to +4 9 12 14 17 15 8 14 7 17 16 6
ARB Age therapy started (y)
Maximum dosage (mg)
Maximum dosage (mg/kg)
25.0 100.0 75.0 6.0 50.0 25.0
0.4 1.3 1.1 0.8 0.8 0.5
25.0 12.5 25.0 25.0 50.0 25.0 25.0 25.0 50.0 25.0 25.0
1.1 0.5 0.6 0.3 1.1 0.8 0.4 0.7 0.8 0.8 0.7
Maximum dosage (mg)
Maximum dosage (mg/kg)
25.0 18.0 25.0 25.0 25.0 50.0 25.0 12.5 75.0 12.5 12.5 50.0 12.5
0.7 1.0 0.5 0.4 1.0 0.9 0.4 0.6 2.0 0.7 0.3 0.7 0.4
13 19 13 0.5 15 15
12.5 12.5 12.5 25.0 12.5 25.0 37.5 100.0 37.5 50.0 24.0
0.5 0.3 0.3 0.4 0.3 0.6 0.6 1.7 0.5 0.8 1.0
6 6 19 16 12 10 17 11 15 10 10
*BB therapy metoprolol.
Landis et al