Root Z-score Research Articles

Longitudinal echocardiography in pediatric patients with hypermobile Ehlers-Danlos syndrome.

Vascular Ehlers-Danlos, Marfan and Loeys-Dietz syndromes have increased risk of aortic dilation and dissection. Previous early studies showed hypermobile Ehlers-Danlos syndrome (hEDS) may also have increased risk, with echocardiography screening recommended; subsequent studies have not confirmed the risk or recommended echocardiography. This pediatric-based study assessed aortic dilation prevalence in those with hEDS by serial echocardiographic examinations and assessed family history for aortic dissections. We retrospectively identified individuals with hEDS who had echocardiography studies from the electronic medical records at one pediatric center. Aortic root Z-scores >2.0 were found in 15/225 subjects (average age 12.9 years) on initial echocardiograms, with no Z-score >3.0. Subsequent studies (n = 68) found statistically significant decline in aortic root Z-scores. Repeat echocardiography in those with initial aortic root Z-score >2.0 (n = 10) demonstrated a decline in Z score <2.0 in seven. On final examination, 9/225 (4.0%) had a Z-score >2.0, not statistically different from the general population. No aortic dissection occurred in first- or second-degree relatives. In conclusion, aortic root dilation rate in hEDS is likely not different from the general population. We propose that in the absence of other cardiac findings or suspicion for another disorder, echocardiography is not required in hEDS.

Extracardiac Manifestations Fail to Predict the Severity of Cardiac Phenotype in Children and Young Adults with Marfan Syndrome.

We performed a secondary analysis of the Pediatric Heart Network (PHN) Marfan Trial public-use database to evaluate associations between extracardiac features and cardiac and aortic phenotypes in study participants. Aortic aneurysm phenotype was defined as aortic root Z-score ≥4.5, aortic root growth rate ≥75th percentile, aortic dissection, and aortic surgery. Severe cardiac phenotype was defined as aortic dissection, aortic Z-score ≥4.5, aortic valve surgery, at least moderate mitral regurgitation, mitral valve surgery, left ventricular dysfunction, or death. Extracardiac manifestations were characterized by specific organ system involvement and by a novel aggregate extracardiac score (AES) that was created for this study based on the original Ghent nosology. Mixed effects logistic regression analysis compared AES and systems involvement to outcomes. Of 608 participants (60% male), the median age at enrollment was 10.8years (interquartile range: 6, 15.4). Aortic aneurysm phenotype was observed in 71% of participants and 64% had severe cardiac phenotype. On univariable analysis, skeletal (OR: 1.95, 95% CI: 1.01, 3.72; p = 0.05), skin manifestation (OR: 1.62, 95% CI: 1.13, 2.34; p = 0.01) and AES (OR: 1.17, 95% CI: 1.02, 1.34; p = 0.02) were associated with aortic aneurysm phenotype but were not significant in multivariable analysis. There was no association between extracardiac manifestations and severe cardiac phenotype. Thus, the severity of cardiac manifestations in Marfan syndrome (MFS) was independent of extracardiac phenotype and AES. Severity of extracardiac involvement did not appear to be a useful clinical marker for cardiovascular risk-stratification in this cohort of children and young adults with MFS.

Cardiac defects of hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorders: a retrospective cohort study.

Defective connective tissue structure may cause individuals with hypermobile Ehlers-Danlos syndrome (hEDS) or hypermobility spectrum disorders (HSD) to develop cardiac defects. We conducted a retrospective chart review of adult patients treated in the EDS Clinic from November 1, 2019, to June 20, 2022 to identify those with cardiac defects. Echocardiogram data were collected using a data collection service. All EDS Clinic patients were evaluated by a single physician and diagnosed according to the 2017 EDS diagnostic criteria. Patient demographic, family and cardiac history were extracted from self-reported responses from a REDCap clinical intake questionnaire. Patients with at least 1 available echocardiogram (ECHO) were selected for the study (n = 568). The prevalence of aortic root dilation in patients with hEDS was 2.7% and for HSD was 0.6%, with larger measurements for males than females and with age. Based on self-reported cardiac history that was verified from the medical record, patients with hEDS with bradycardia (p = 0.034) or brain aneurysm (p = 0.015) had a significantly larger average adult aortic root z-score. In contrast, patients with HSD that self-reported dysautonomia (p = 0.019) had a significantly larger average aortic root z-score. The prevalence of diagnosed mitral valve prolapse in patients with hEDS was 3.5% and HSD was 1.8%. Variants of uncertain significance were identified in 16 of 84 patients that received genetic testing based on family history. These data reveal a low prevalence of cardiac defects in a large cohort of well-characterized hEDS and HSD patients. Differences in cardiovascular issues were not observed between patients with hEDS vs. HSD; and our findings suggest that cardiac defects in patients with hEDS or HSD are similar to the general population.

Abstract 11817: Calculating Aortic Root Z- Scores With Ideal Body Weight Reclassifies Risk in Overweight and Obese Patients

Introduction: Indexing transthoracic echocardiography (TTE) aortic root diameter (AoR diam) measurements using body surface area (BSA) is important in children and small adults in whom non-indexed values may under detect dilation. However, the commonly used formula for expected AoR diam uses actual body weight, which may bias results in obese adults as AoR diam does not increase with body weight. Z-scores compare a patient’s AoR diam relative to an age, size, and sex specific population mean such that z- score = (observed AoR diam - expected AoR diam) /0.261. A normal AoR diam z-score is -2 ≤ z-score ≤2. Hypothesis: We hypothesize that using ideal body weight (IBW) in place of actual weight when calculating z-score reclassifies a significant proportion of overweight and obese patients with z-score &lt; 2 to z-score ≥2. Methods: We performed a retrospective review of all patients with a TTE at Tufts Medical Center in 2022 and Ao root diam ≥ 4 cm. We excluded patients &lt; 20 years old and those with inadequate TTE images or missing aortic measurements. Expected AoR diam and z-scores were calculated using both actual weight and IBW. A z-score difference, z diff = z actual weight - z ideal weight , was calculated. Results: 485 patients met our study criteria with a subset of 352 patients with BMI ≥ 25. The z diff was significantly different from zero across all BMI groups (p = 0.0003) and in the subset with BMI ≥ 25 (p&lt;0.001). 17.9% of patients with BMI ≥ 25 with z actual weight &lt; 2 were reclassified to z ideal weight ≥ 2 (p&lt;0.001) compared with 2.2% of patients with BMI &lt; 25 (p&lt;0.001). Among AoR diam subgroups of 4 - 4.5 cm, &gt; 4.5 - 5 cm, and &gt; 5 cm, all reclassification occurred in the 4 - 4.5 cm group. Within the 4 - 4.5 cm group, 24.1% of patients with z actual weight &lt; 2 reclassified to z ideal weight ≥ 2. Conclusions: Compared to current methods using actual weight, the use of IBW to calculate Ao root z-scores reclassifies nearly 2 in 10 patients with BMI ≥ 25 to Ao root dilation. Among patients with Ao root diam of 4 - 4.5 cm, nearly 1 in 4 are reclassified as dilated by z-scores calculated with IBW. Such reclassification would impact clinical decisions about increased surveillance and/or treatment. Further studies are needed to determine the optimal approach to indexing Ao root size and the implications for management.

Evaluating Variation in the Cardiac Management of Children with Hereditary Thoracic Aortic Disease in the United States.

Hereditary thoracic aortic diseases (HTAD) such as Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS), and vascular Ehlers-Danlos syndrome (VEDS) frequently result in complex cardiovascular pathology that can lead to premature death. However, given limited research and lack of detailed pediatric management guidelines, practice in the U.S. is largely guided by personal experience and/or advice from other professionals. A REDCap survey was composed that covered topics including genetic testing, imaging, and medication choice (all in children), among others. After piloting, the survey was distributed via email and advertised on PediHeartNet. Email addresses of providers were obtained through an established aortic research collaborative and a clinic directory offered through The Marfan Foundation. There were 64 survey responses (pediatric cardiologists 66%; geneticists 13%, genetic counselors 6%; the remaining 15% was comprised of a combination of cardiothoracic surgeons, adult cardiologists, adult congenital specialists, combined cardiology and genetics specialist, nurse practitioners, physician assistants, and nurse coordinators). The most supported indication for genetic evaluation in a child with mild aortic root dilation was family history of thoracic aortic dissection (100%), in contrast to mild root dilation with no other HTAD features (39% supported, 45% did not, 15% saying it would depend on other factors). The majority would start medical therapy in MFS at an aortic root z-score of 2, however differences existed regarding medication preferences for initiation (47% angiotensin receptor blockers, 36% beta blockers, 17% would not or cannot prescribe medication/defer medication choice to another provider). Variation existed for cross-sectional imaging indications and modality and for exercise restrictions, although on average respondents were more lenient than the Bethesda guidelines. While there are areas of general agreement in the cardiac management of children with HTAD, there are also several areas of considerable variation. This highlights the need for additional study in these areas with the ultimate goal of creating consensus guidelines.

Abnormal Left Ventricular Strain Correlates with Left Ventricular Dysfunction but not Aortic Pathology in Marfan Syndrome in Children.

Cardiomyopathy is a complication in adults with Marfan syndrome (MFS). Early recognition of MFS patients at high risk of cardiomyopathy could impact monitoring and treatment. Abnormal ventricular strain has been associated with impaired ventricular function among adults with MFS but remains understudied in children. We retrospectively analyzed a cohort of patients with MFS undergoing cardiac magnetic resonance imaging (CMR) performed in 2003-2018 at age < 19years. Correlations were evaluated between initial global circumferential strain (GCS) and global longitudinal strain (GLS) and the outcomes of left ventricular ejection fraction (LVEF), aortic root z-score, and vertebral artery tortuosity index corrected for height (VTI-h), all measured from CMR, using Spearman correlation. In those with serial CMR, the ability of ventricular strain to predict development of abnormal LVEF within a 5-year period was assessed. A total of 31 subjects were included (median age at initial CMR 13.5 years, Q1Q3 10.7-16.2 years), with 48% (n = 15) having LVEF < 55%. Worse GCS and worse GLS were associated with lower LVEF (ρ = - 0.629, p < 0.001 and ρ = - 0.411, p = 0.030, respectively). A clinical cutoff of GCS = - 34% predicted LVEF < 55% with sensitivity = 80% and specificity = 50%. Neither GCS nor GLS was associated with aortic root z-score (GCS: p = 0.524; GLS: p = 0.624) nor VTI-h (GCS: p = 0.949; GLS: p = 0.593). Of those with LVEF ≥ 55%, initial GCS and GLS did not differ between those with later normal versus abnormal LVEF (GCS: p = 0.505; GLS: p = 0.232). In this cohort, abnormal LV strain was associated with abnormal LVEF, but not with aortic dilation or low LVEF within the 5years post-CMR.

The Ross procedure in adult patients: a single-centre analysis of long-term results up to 28 years.

This study aimed to provide an in-depth insight into our single-centre experience with the Ross procedure. All adults who underwent the Ross procedure between 1991 and 2014 were included. Based on the total number of Ross procedures performed by each surgeon at our centre during this 24-year period, surgeon volume was classified as low (<25 procedures), intermediate (25-44 procedures) and high (≥45 procedures). Survival, complications and reinterventions were evaluated. A single cardiologist assessed the pulmonary autograft's function and the neoaortic root diameter by echocardiography. The outcomes of 224 patients {176 men, 48 women; mean age 37.2 [standard deviation (SD) 10.0] years} were analysed. Patients operated on by a low-volume surgeon had 7.22 times higher odds (P < 0.001) for a serious adverse event during the intraoperative or early postoperative course than patients operated on by a high-volume surgeon. Early mortality was 1.8%. Overall survival was 87.3% at 20 years. Compared with the demographically matched general population, the patients' survival was significantly lower (P = 0.002). The cumulative incidence of autograft and right ventricular outflow tract conduit reintervention was 21.5% and 5.9% at 20 years, respectively. Patients with preoperative aortic regurgitation had 6.25 times the subdistribution hazard of autograft reintervention (Bonferroni-adjusted P = 0.042) and a higher neoaortic root z-score [1.37 (SD 2.04) vs 0.17 (SD 1.81), P = 0.004] than patients with aortic stenosis. In patients with preoperative aortic regurgitation, autograft wrapping (remnant aortic wall and/or Vicryl® mesh) was associated with a 74% reduction in the subdistribution hazard of autograft reintervention (Bonferroni-adjusted P = 0.002) and with a reduced incidence of neoaortic root dilatation (P = 0.037). The Ross procedure performed by a specialized surgeon provides very satisfying long-term results. The higher risk of autograft reintervention in preoperative aortic regurgitation may be counteracted by supporting the autograft.

Aortic tortuosity in Turner syndrome is associated with larger ascending aorta.

Turner syndrome (TS) is associated with aortic coarctation, dissection and dilation/aneurysm. Predictors of dissection are not well delineated, making decisions regarding prophylactic root replacement challenging. In other disorders, arterial tortuosity is an imaging biomarker associated with increased risk for aortic dissection and adverse cardiovascular events. We aimed to determine if, in TS, arterial tortuosity was associated with aortic dilation or aortic events. We performed a retrospective cohort analysis of unselected women and children with TS who underwent cardiovascular magnetic resonance angiography (MRA) for a prior prospective study. We calculated tortuosity indices including vertebral artery tortuosity index, aortic arch tortuosity index, thoracic aortic tortuosity index (ATI-D), and aortic tortuosity index to the celiac artery (ATI-C). We compared tortuosity in TS patients against age and gender matched controls. We evaluated univariable and multivariable associations between the tortuosity indices and aortic root and ascending aorta size as defined by z-scores, which give a sense of how far a measurement deviates from the mean. We also studied associations between tortuosity and need for aortic root replacement or aortic dissection. Of 184 subjects, with median age 34years, mean general aortic root z-score was 0.1 ± 1.2 and mean general ascending aortic z-score was 0.4 ± 1.5. Three patients had aortic dissection, and one had prophylactic root replacement, which all occurred prior to first MRA. Vertebral tortuosity index, ATI-D, and ATI-C all increased with age (p < 0.0001) for all. ATI-C was associated with larger general ascending z-score. In multivariable analysis, ATI-C remained independently associated with larger ascending aortic z-scores. The relationship between aortic indices and surgery/dissection could not be evaluated since all were collected post-surgery/dissection. Thoracic aortic tortuosity as measured by ATI-C is independently associated with larger ascending aortic dimensions. In this population with only three aortic dissections occurring prior to imaging assessment, we could not assess for associations between aortic tortuosity and dissection. Studies including more patients with aortic dissection are needed to draw further conclusions.

Technique of Coronary Button Transfer Has no Impact on Neoaortic Root Size in Simple Transposition

We studied the effect of various coronary transfer techniques (CTT) on neo-aortic root size after an arterial switch operation (ASO) in simple transposition by excluding the impact of recognized predisposing factors. One hundred and seventy-eight patients with simple transposition were reviewed retrospectively (January 2004-December 2018) and grouped as Punch Hole (n=83/178), Nonpunch Hole (n=65/178; Trapdoor or Standard) and Mixed (n=30/178). Factors predicting the neo-aortic root z-scores- annulus, mid-sinus, and sinotubular junction (STJ) were analyzed by uni/multivariable linear regression. Follow-up was 6 years, Interquartile range (IQR) 3.4,10.6. Preoperative aortic (7.4 mm, IQR 6.9,8) and pulmonary annulus (7.5 mm, IQR 6.8,8.1) sizes were identical (P=0.831). The changes in preoperative, postoperative, and latest median z-scores for neo-aortic annulus (-0.2, IQR -1.2,0.9; 0.0, IQR -0.9,0.9; 0.9, IQR -0.4,2.6; P < 0.001), mid-sinus (1.1, IQR-0.1,2; 2.6, IQR 1.6,3.7; 2.9, IQR 1.8,4.3; P < 0.001) and STJ (-0.1, IQR -0.8,1.1; 2.1, IQR 0.7,3; 2.4, IQR 1,3.5; P < 0.001) were significant. On multivariate analysis, preoperative pulmonary annulus z-score predicted the latest neo-aortic annulus z-score [Beta estimate (BE)=0.32, 95% confidence interval (CI)=0.03,0.62; P=0.03] and STJ z-score (BE= 0.45, 95% CI= 0.20,0.70; P < 0.0001). CTT did not predict any of the latest neo-aortic z-scores (all P > 0.05). Mild plus neo-aortic regurgitation (neoAR) was not significantly different across CTT groups [punch hole 20% (n=15/74), mixed 37% (n=11/30), nonpunch hole 21% (n=13/62); Fisher-exact P=0.186], one patient required valve replacement for severe neoAR. The neo-aortic root enlarges significantly over time at all 3 levels following an ASO in simple transposition, however, this is not significantly influenced by the CTT utilized.

Magnetic resonance angiography derived predictors of progressive dilatation and surgery of the aortic root in Marfan syndrome.

BackgroundTo identify magnetic resonance (MR) angiography derived predictors of progressive dilatation and surgery of the aortic root in Marfan syndrome.Material and methodsWe retrospectively included 111 patients (32.7±16.5 years, range: 7–75 years) with a total of 446 MR angiographies. Aortic diameter growth rates of the entire thoracic aorta and Z-scores were estimated from annual diameter measurements. Aortic root shape was subdivided into three different types: (T0) normal; (T1) localized dilatation; (T2) generalized aortic root dilatation. Aortic diameter, Z-score, age, and aortic root shape at baseline were tested as predictors of aortic root dilatation using a multivariate logistic regression model.ResultsThe highest aortic growth rate was observed at the level of the sinuses of Valsalva. Higher aortic root diameters and Z-scores at baseline predicted an increased growth of the aortic root (p = 0.003 and p<0.001). Young age (<30 years) was a predictor for the increase of Z-scores when compared to patients ≥30 years (p = 0.019). 25/111 patients (22.5%) had a T0 aortic root shape, 59/111 patients (53.2%) had a T1 aortic root shape, and 27/111 patients (24.3%) had a T2 aortic root shape. Aortic root shape did not predict further aortic growth (p>0.05). However, significantly more patients undergoing surgery had a generalized aortic dilatation (19/28, 76.9%) than a localized aortic root dilatation (9/28, 32.1%) (p = 0.001).ConclusionLarger baseline aortic root diameter and Z-score as well as young age predict solely progressive aortic root dilatation in Marfan patients. MR angiography derived type of aortic root shape does not predict aortic growth, but patients with generalized aortic root dilatation are referred more frequently for aortic surgery.

Molecular characterization and investigation of the role of genetic variation in phenotypic variability and response to treatment in a large pediatric Marfan syndrome cohort

PurposeIn a large cohort of 373 pediatric patients with Marfan syndrome (MFS) with a severe cardiovascular phenotype, we explored the proportion of patients with MFS with a pathogenic FBN1 variant and analyzed whether the type/location of FBN1 variants was associated with specific clinical characteristics and response to treatment. Patients were recruited on the basis of the following criteria: aortic root z-score > 3, age 6 months to 25 years, no prior or planned surgery, and aortic root diameter < 5 cm. MethodsTargeted resequencing and deletion/duplication testing of FBN1 and related genes were performed. ResultsWe identified (likely) pathogenic FBN1 variants in 91% of patients. Ectopia lentis was more frequent in patients with dominant-negative (DN) variants (61%) than in those with haploinsufficient variants (27%). For DN FBN1 variants, the prevalence of ectopia lentis was highest in the N-terminal region (84%) and lowest in the C-terminal region (17%). The association with a more severe cardiovascular phenotype was not restricted to DN variants in the neonatal FBN1 region (exon 25-33) but was also seen in the variants in exons 26 to 49. No difference in the therapeutic response was detected between genotypes. ConclusionImportant novel genotype–phenotype associations involving both cardiovascular and extra-cardiovascular manifestations were identified, and existing ones were confirmed. These findings have implications for prognostic counseling of families with MFS.

Initial Angiotensin Receptor Blocker Response in Young Marfan Patients Decreases After 3 Years of Treatment

Marfan syndrome is caused by mutations of the fibrillin-1 gene, which weakens the connective tissue integrity. Since 2003, bioavailability regulations of TGF-ß through fibrillin alterations have been presumed of being the culprit mechanisms for aortic aneurysm development. We present the analysis of our single-center Marfan children and adolescents cohort to assess the influence of age, sex, degree of cardiovascular involvement and dosage on losartan effectivity. This prospective longitudinal registered echocardiographical investigation (EudraCT 2009-016139-36) of 49 patients with an average follow-up of 72 months focused on aortic root z-scores, elasticity, and yearly progression rates. The 33 patients under medication with losartan showed an aortic root z-score reduction during the first 36 months compared to 22 patients without medication presenting constant mild progression. Yet, results diminished under losartan thereafter, adding up to similar progressions over 72 months in both groups (0.07 ± 0.10/year versus 0.04 ± 0.11/year). Although male patients exhibited higher root z-scores, progression with and without medication was comparable to females and not age-dependent. In conclusion, losartan evoked a significant aortic root z-score regression in young Marfan patients over the first 3 years, but this effect mitigated thereafter. The initial improvement concurred with ameliorated elasticity; lower stiffness levels predicted better clinical outcome, but likewise only up to 36 months. Sex differences in dilatation severity were observed but neither age nor sex had significant influence on progression rates. Losartan dosages were gradually increased in more severely affected patients and provided an equal rate of root progression over 72 months in comparison to patients under losartan treatment with lesser baseline dilatation severity.

Aortic tortuosity is related to aortic phenotype in patients with bicuspid aortic valve: a CT scan study of 83 cases

Abstract Background Although the incidence of aortic dissection is higher in patients with bicuspid aortic valve (BAV) compared to tricuspid aortic valve (TAV), risk stratification remains unclear. Guidelines focus on ascending aorta diameters, regardless of the location, and do not take into account the morphology of the aorta. Aortic tortuosity (AT) is emerging as a novel biomarker associated with more severe aortopathy in patients with Marfan syndrome. AT has not been accuretely assessed in BAV. Our aim is to describe the relationship between AT and ascending aortic phenotype in patients with BAV. Methods 83 patients (43±16 years, 19 women) diagnosed with BAV and without significant aortic valve disease nor prior aortic intervention were included. CT scans were retrospectively analysed with measurements of aortic diameters and aortic tortuosity. For 61 patients with abdominal images available, descending and total aortic length and tortuosity were measured. Results In our cohort, 62 (75%) patients presented a typical BAV. Pathological aorta (Root and/or tubular Z-score &amp;gt;2) was found in 80 patients (96%) and 67 (81%) presented a tubular dilatation. The aortic phenotype, the maximal aortic diameters and aortic tortuosity index were similar in typical and atypical BAV. Total aortic tortuosity index was correlated to Z-score tubular diameter (r=0.31; p=0,014) but not with Z-score Valsalva diameter (p=0,55). In patients with tubular dilatation (Z score &amp;gt;2), total aortic tortuosity index was higher than in patient without tubular dilatation (2.01 vs 1.85; p=0,015). Conclusion Total aortic tortuosity is associated with tubular dilatation but not with root dilatation in BAV patients suggesting that tubular phenotype may be at higher risk of complication in BAV. Further studies evaluating the association between aortic tortuosity and clinical outcomes in BAV are needed. Funding Acknowledgement Type of funding sources: None.

Mitral annular disjunction and cardiovascular outcome in Marfan syndrome

Abstract Background Mitral annular disjunction (MAD) has received growing interest in patients with mitral valve prolapse (MVP), ventricular tachycardia (VT) and sudden cardiac death (SCD). The clinical significance of MAD in Marfan syndrome (MFS) remains largely unexplored. Purpose To define the prevalence of MAD and examine the relation with cardiovascular outcomes and arrhythmia in patients with MFS. Methods The presence of MAD was assessed by echocardiography and the extent of MAD was categorized in tertiles. Patients also underwent resting ECG and 24-hour Holter monitoring. Outcomes included aortic events (aortic dissection or prophylactic aortic surgery), arrhythmic events (VT/SCD) and mitral valve surgery. Results A total of 142 patients (median age 25 years [range 2–64], 51% women) were evaluated. Forty-eight (34%) patients had MAD. Patients with MAD had larger aortic root Z-scores (4.1 [2.8–5.7] vs. 3.0 [1.8–4.0], p&amp;lt;0.001) and more often showed MVP (71% vs. 15%, p&amp;lt;0.001), ventricular ectopy (42% vs. 21%, p=0.027) and non-sustained ventricular tachycardia (39% vs. 17%, p=0.014) than patients without MAD. During follow-up, aortic events occurred at similar rates in patients with vs. without MAD (35% vs. 25%, p=0.103), but patients in the upper MAD tertile (&amp;gt;10mm) showed a higher occurrence of aortic events (60% vs. 21%, p=0.011) compared to patients with MAD(+) ≤10mm. Arrhythmic events and a need for mitral valve surgery were observed exclusively in patients with MAD (p=0.004 and p&amp;lt;0.001, respectively). Conclusions MAD is associated with a higher need for mitral valve intervention, occurrence of arrhythmic events and, in patients with extensive MAD, more aortic events. Cardiac imaging in MFS should consider the assessment of MAD as a potential marker for adverse outcome. Funding Acknowledgement Type of funding sources: None. Cardiovascular outcome and arrhythmia

Relationship between the aortic root Z-score and degree of translamellar mucoid extracellular matrix accumulation.

A retrospective analysis was performed to compare the pathological findings and aortic root Z-score in patients with and without connective tissue disease (CTD). Twenty-two patients {47.5 [15-85] years old, 18 males} underwent surgery for aortic root dilatation without aortic dissection: 10 {40 [16-59] years old} with CTD and 12 {57.5 [15-85] years old} without CTD (non-CTD; p = 0.049). Systemic hypertension (p = 0.043) and the degree of preoperative aortic regurgitation (p = 0.017) were higher in the non-CTD patients than in the CTD patients. The diameters of the sinotubular junction (STJ) (p = 0.048) and ascending aorta (Asc.Ao.) (p = 0.020) and the Z-scores of the STJ (p = 0.027) and Asc.Ao. (p = 0.009) were significantly higher in the non-CTD patients than in the CTD patients. The degree of translamellar mucoid extracellular matrix accumulation (T-MEMA) of the Asc.Ao. was significantly higher in the non-CTD patients than in the CTD patients (p = 0.037) and was significantly correlated with the Z-scores of the aorta (R = 0.746, p < 0.01 in the sinus of Valsalva and R = 0.382, p = 0.031 in the Asc.Ao.), although there was no significant correlation between the diameter of the STJ and that of Asc.Ao. In non-CTD patients, not only the aortic root but also Asc.Ao. tended to dilate with age, and a significant correlation between the Z-scores of the aorta root and the Asc.Ao. and the degrees of T-MEMA was observed.

Comparability of different Z-score equations for aortic root dimensions in children with Marfan syndrome.

Aortic root dilation is a major complication of Marfan syndrome and is one of the most important criteria in establishing the diagnosis. Currently, different echocardiographic nomograms are used to calculate aortic root Z-scores. The aim of the present study was to assess the potential differences in aortic root measurements when aortic root Z-scores were obtained in a cohort of paediatric Marfan patients using several published nomograms. In a cohort of 100 children with Marfan syndrome, Z-scores for aortic root dimensions were calculated according to the nomograms of Pettersen et al, Gautier et al, Colan et al, and Lopez et al. Bland-Altman plots were used to estimate mean differences in Z-scores and to establish limits of agreement. The mean Z-score of the sinus of Valsalva for Lopez et al was significantly higher compared to Gautier et al (p < 0.01) and Pettersen et al (p = 0.03). The nomogram of Lopez et al resulted in substantially higher Z-scores in patients with a large sinus of Valsalva diameter. Thirty-five percentage of the studied patients would have a Z-score ≥ 2 using Lopez et al compared to 20% for Pettersen et al, 21% for Gautier et al, and 33% for Colan et al. The currently available nomograms for calculating Z-scores of aortic dilation in children with Marfan syndrome lead to clinically relevant differences in Z-scores, especially in children with a relative large aortic root diameter. This could have impact on both the diagnosis and treatment of patients with Marfan syndrome.

Central pulse pressure is inversely associated with proximal aortic remodelling.

Hypertension leads to aortic stiffening and dilatation but unexpected data from the Framingham Heart Study showed an inverse relationship between brachial pulse pressure and aortic diameter. Aortic dilatation would not only lead to lower pulse pressure but also to a worse prognosis (cardiac events, heart failure). Invasive pressure may be more informative but data are lacking. This study evaluated the relationship between invasively measured central blood pressure and proximal aortic diameter. In 71 consecutive patients referred to invasive haemodynamic study, proximal aortic remodelling was evaluated in terms of Z-score, comparing diameters measured at the sinus of Valsalva to the diameter expected according to patients' age, sex and body height. Pressures were recorded directly in the proximal aorta by means of a catheter before coronary assessment. The mean invasive aortic SBPs and DBPs were 146 ± 23 and 78 ± 13 mmHg, respectively, giving a central pulse pressure (cPP inv) of 68 ± 21 mmHg. Proximal aortic diameter was 34.9 ± 19.4 mm, whereas Z-score was -0.3 ± 1.7. Patients with higher cPPinv showed a significantly lower Z-score (-0.789 vs. 0.155, P = 0.001). cPPinv was inversely related to Z-score (R = -0.271, P = 0.022) independently from age, mean blood pressure and heart rate (β = -0.241, P = 0.011). Aortic root Z-score is inversely associated with invasively measured central pulse pressure in a cohort of patients undergoing invasive coronary assessment. Remodelling at the sinuses of Valsalva may be a compensatory mechanism to limit pulse pressure.

Is Aortic Z-score an Appropriate Index of Beneficial Drug Effect in Clinical Trials in Aortic Aneurysm Disease?

Aortic Z-score (Z-score) is utilized in clinical trials to monitor the effect of medications on aortic dilation rate in Marfan (MFS) patients. Z-scores are reported in relation to body surface area and therefore are a function of height and weight. However, an information void exists regarding natural, non-pharmacological changes in Z-scores as children age. We had concerns that Z-score decrease attributed to "therapeutic" effects of investigational drugs for Marfan disease connective tissue diseases might simply reflect normal changes ("filling out" of body contour) as children age. This investigation studies natural changes with age in Z-score in normal and untreated MFS children, teasing out normal effects that might erroneously be attributed to drug benefit. (1) We first compared body mass index (BMI) and Z-scores (Boston Children's Hospital calculator) in 361 children with "normal" single echo exams in four age ranges (0 to 1, 5 to 7, 10 to 12, 15 to 18 years). Regression analysis revealed that aging itself decreases ascending Z-score, but not root Z-score, and that increase in BMI with aging underlies the decreased Z-scores. (2) Next, we examined Z-score findings in both "normal" and Marfan children (all pharmacologically untreated) as determined on sequential echo exams over time. Of 27 children without aortic disease with sequential echos, 19 (70%) showed a natural decrease in root Z-score and 24 (89%) showed a natural decrease in ascending Z- score, over time. Of 25 untreated MFS children with sequential echos, 12 (40%) showed a natural decrease in root Z-score and 10 (33%) showed a natural decrease in ascending Z-score. Thus, Z-score is over time affected by natural factors even in the absence of any aneurysmal pathology or medical intervention. Specifically, Z-score decreases spontaneously as a natural phenomenon as children age and with fill out their BMI. Untreated Marfan patients often showed a spontaneous decrease in Z-score. In clinical drug trials in aneurysm disease, decreasing Z-score has been interpreted as a sign of beneficial drug effect. These data put such conclusions into doubt.

Growth Pattern of the Neo-Aorta after Arterial Switch Operation during Childhood.

Background and ObjectivesNeo-aortic root dilatation (ARD) and annular dilatation (AAD) tend to develop after arterial switch operation (ASO). However, the trend of neo-aortic growth has not been well established. This paper aims to identify this trend, its associated factors, and predictors of neo-aortic dilatation after ASO.MethodsWe analyzed the growth trend of the neo-aortic root, annulus, and sinotubular junction (STJ) z-scores using random coefficients model and the risk factors affecting neo-aortic dilatation in 163 patients who underwent ASO from 2006 to 2015.ResultsAmong 163 patients, 41 had a ventricular septal defect, and 11 had Taussig-Bing (TB) anomaly. The median follow-up duration was 6.61 years. The increased in the neo-aortic root z-score was different between the trapdoor and non-trapdoor coronary artery transfer techniques (0.149/year, p<0.001 vs. 0.311/year, p<0.001). Moreover, the neo-aortic annulus and STJ z-score significantly increased over time after ASO (0.067/year, p<0.001; 0.309/year, p<0.001). Pulmonary artery banding (PAB) was rather a negative affecting factor. The probabilities of freedom from ARD, AAD, and neo-aortic STJ dilatation at 10 years after ASO were 33.4%, 53.9%, and 65.4%. Neo- aortic regurgitation within 1 year was the predictor of ARD, AAD, and neo-aortic STJ dilatation. TB anomaly, PAB, and native pulmonary sinus z-score were other predictors for ARD.ConclusionThe growth of neo-aortic root, annulus, and STJ after ASO was greater than somatic growth during childhood. The coronary artery transfer technique affected the growth pattern of the neo-aortic root.

Abstract 14744: Native Bicuspid Pulmonary Valve in D-loop Transposition of the Great Arteries: Outcomes of the Neo-aortic Valve Function and Root Dilation After Arterial Switch Operation

Introduction: Neo-aortic root dilation (ARD) is common after arterial switch operation (ASO) for D-loop transposition of the great arteries (TGA). We sought to compare short and long-term outcomes for bicuspid native pulmonary valve (BNPV) patients to those with normal trileaflet variants (TNPV). Methods: A retrospective cohort of TGA patients undergoing ASO at Boston Children’s Hospital from 1989-2018 was analyzed, matching BNPV patients 1:3 with TNPV patients by year of ASO; those with &gt;mild subpulmonary stenosis or complex TGA were excluded. Categorical and continuous variables were compared using Fisher’s exact and Wilcoxon rank sum tests, respectively. Kaplan-Meier analyses with log-rank test compared groups for time to first reoperation on the neo-aortic valve, first occurrence of ≥moderate neo-aortic regurgitation (AR), and ARD defined as root z-score ≥4. Hazard ratios were estimated based on the Cox proportional hazards model. Results: A total of 83 BNPV patients were matched with 217 TNPV. BNPV patients were more likely to have a VSD (75% vs 44%, p &lt;0.001). Early surgical outcomes including hospital LOS (11 vs 10 days) and 30-day mortality (3.6% vs 2.8%) were similar. During median 10 years follow-up, neo-aortic valve reoperation occurred in 4 BNPV (6%) vs 6 TNPV (3%) patients, with no statistically significant difference in time to reoperation. More BNPV patients had AR at discharge (4.9% vs 0%, p=0.014) and during follow-up (13.4% vs 4.3%, HR 3.9, p=0.004), with shorter time to first occurrence of AR (Figure 1A); this remained significant after adjusting for presence of VSD. Similarly, ARD was more common in BNPV (45% vs 37%, HR 1.64, p=0.02) with shorter time to first occurrence (Figure 1B). Conclusions: While patients with BNPV have similar short-term ASO outcomes, AR and ARD occur more frequently and earlier compared with TNPV patients. Further long-term studies are needed to determine whether this results in greater need for neo-aortic valve reoperation.