Design of a multi-institutional neurocognitive discovery study in adult congenital heart disease (MINDS-ACHD).

BACKGROUND: Neurocognitive dysfunction (NCD) is a common comorbidity among children with congenital heart disease (CHD). However, it is unclear how underlying CHD and its sequelae combine with genetics and acquired cardiovascular and neurological disease to impact NCD and outcomes across the lifespan in adults with CHD. METHODS: The Multi-Institutional Neurocognitive Discovery Study in Adults with Congenital Heart Disease (MINDS-ACHD) is a partnership between the Pediatric Heart Network (PHN) and the Adult Alliance for Research in Congenital Cardiology (AARCC) that examines objective and subjective neurocognitive function and genetics in young ACHD. This multicenter cross-sectional pilot study is enrolling 500 young adults between 18 and 30 years with moderate or severe complexity CHD at 14 centers in North America. Enrollment includes 4 groups (125 participants each): (1) d-looped Transposition of the Great Arteries (d-TGA); (2) Tetralogy of Fallot (TOF); (3) single ventricle (SV) physiology; and (4) "other moderately or severely complex CHD." Participants complete the standardized tests from the NIH Toolbox Cognitive Battery, the NeuroQoL, the Hospital Anxiety and Depression Scale, and the PROMIS Global QoL measure. Clinical and demographic variables are collected by interview and medical record review, and an optional biospecimen is collected for genetic analysis. Due to the COVID-19 pandemic, participation may be done remotely. Tests are reviewed by a Neurocognitive Core Laboratory. CONCLUSIONS: MINDS-ACHD is the largest study to date characterizing NCD in young adults with moderate or severely complex CHD in North America. Its results will provide valuable data to inform screening and management strategies for NCD in ACHD and improve lifelong care.

Comprehensive cardiac magnetic resonance T1, T2, and extracellular volume mapping to define Duchenne cardiomyopathy.

BACKGROUND: Cardiomyopathy is the leading cause of death in Duchenne muscular dystrophy (DMD). Cardiac magnetic resonance (CMR) parametric mapping sequences offer insights into disease pathophysiology. We propose a novel approach by leveraging T2 mapping in conjunction with T1 and extracellular volume (ECV) mapping to perform a virtual myocardial biopsy. While previous work has attempted to describe myocardial changes in DMD, our inclusion of T2 mapping enables comprehensive categorization of myocardial tissue characteristics of fibrosis, edema, and fat to better understand the pathological composition of the myocardium with disease progression. METHODS: DMD patients (n = 49; median: 12 years-old) underwent CMR, including T1, T2, and ECV. Categories were defined as normal, isolated high T1 (normal ECV, high T1, normal T2), fibrosis (high ECV, normal or high T1, normal T2), edema (normal or high ECV, normal or high T1, high T2), fat (normal ECV, low T1, high T2) or fibrofatty (high ECV, low T1, high T2). RESULTS: Median left ventricular ejection fraction (LVEF) was 59% with 27% having LVEF < 55%. Those with normal LVEF and no late gadolinium enhancement (37%) were younger in age (10.5 ± 2.6 vs. 15.0 ± 4.3 years-old, p < 0.001). Native T1 was elevated in at least one slice in 82% of patients. Those with high T2 at any slice (27%) were older (p = 0.005) and had lower LVEF (p = 0.005) compared with subjects with normal T2 (73%). The most common myocardial characterization was fibrosis (43%) followed by isolated high T1 (24%). Of the 13 with high T2, ten were categorized as edema, two as fibrofatty, and one as fat. CONCLUSION: CMR parametric mapping sequences offer insights into Duchenne cardiomyopathy pathophysiology, which should drive development of therapeutic interventions aimed at these targets. Myocardial fibrosis is common in DMD. Patients with elevated T2 were older and had lower LVEF. Though fat infiltration was present, the majority of subjects with elevated T2 met criteria for myocardial edema.

Localized strain characterization of cardiomyopathy in Duchenne muscular dystrophy using novel 4D kinematic analysis of cine cardiovascular magnetic resonance.

BACKGROUND: Cardiomyopathy (CMP) is the most common cause of mortality in Duchenne muscular dystrophy (DMD), though the age of onset and clinical progression vary. We applied a novel 4D (3D + time) strain analysis method using cine cardiovascular magnetic resonance (CMR) imaging data to determine if localized strain metrics derived from 4D image analysis would be sensitive and specific for characterizing DMD CMP. METHODS: We analyzed short-axis cine CMR image stacks from 43 DMD patients (median age: 12.23 yrs [10.6-16.5]; [interquartile range]) and 25 male healthy controls (median age: 16.2 yrs [13.3-20.7]). A subset of 25 male DMD patients age-matched to the controls (median age: 15.7 yrs [14.0-17.8]) was used for comparative metrics. CMR images were compiled into 4D sequences for feature-tracking strain analysis using custom-built software. Unpaired t-test and receiver operator characteristic area under the curve (AUC) analysis were used to determine statistical significance. Spearman's rho was used to determine correlation. RESULTS: DMD patients had a range of CMP severity: 15 (35% of total) had left ventricular ejection fraction (LVEF) > 55% with no findings of myocardial late gadolinium enhancement (LGE), 15 (35%) had findings of LGE with LVEF > 55% and 13 (30%) had LGE with LVEF < 55%. The magnitude of the peak basal circumferential strain, basal radial strain, and basal surface area strain were all significantly decreased in DMD patients relative to healthy controls (p < 0.001) with AUC values of 0.80, 0.89, and 0.84 respectively for peak strain and 0.96, 0.91, and 0.98 respectively for systolic strain rate. Peak basal radial strain, basal radial systolic strain rate, and basal circumferential systolic strain rate magnitude values were also significantly decreased in mild CMP (No LGE, LVEF > 55%) compared to a healthy control group (p < 0.001 for all). Surface area strain significantly correlated with LVEF and extracellular volume (ECV) respectively in the basal (rho = - 0.45, 0.40), mid (rho = - 0.46, 0.46), and apical (rho = - 0.42, 0.47) regions. CONCLUSION: Strain analysis of 3D cine CMR images in DMD CMP patients generates localized kinematic parameters that strongly differentiate disease from control and correlate with LVEF and ECV.

Duchenne muscular dystrophy patients: troponin leak in asymptomatic and implications for drug toxicity studies.

BACKGROUND: Cardiomyopathy is the leading cause of death in Duchenne muscular dystrophy (DMD), but studies suggest heart failure biomarkers correlate poorly with cardiomyopathy severity. DMD clinical trials have used troponin I (cTnI) as a biomarker of toxicity, but it is unclear if asymptomatic DMD patients have elevated cTnI. We longitudinally evaluated cTnI, brain natriuretic peptide (BNP), and N-terminal pro-BNP (NT-proBNP) in a DMD cohort. METHODS: DMD patients were prospectively enrolled and followed for 3 years. Serum was drawn at the time of cardiac magnetic resonance (CMR). Normal biomarker values were derived from healthy subjects. Biomarkers were correlated with CMR markers. RESULTS: All subjects were asymptomatic at the time of enrollment. Several DMD subjects had transiently elevated cTnI. Those with elevated cTnI were more likely to have late gadolinium enhancement on baseline CMR. NT-proBNP correlated with indexed left ventricular end diastolic and maximum left atrial volumes. Otherwise, standard cardiac biomarkers did not correlate with CMR markers of cardiomyopathy. CONCLUSIONS: CTnI, BNP, and NT-proBNP do not correlate with CMR assessment of cardiomyopathy progression. A subset of DMD patients have asymptomatic cTnI leak of uncertain clinical significance, though of critical importance if cTnI is used to assess for cardiac toxicity in future drug trials. IMPACT: Asymptomatic patients with Duchenne muscular dystrophy (DMD) exhibit transient troponin I leak. NT-proBNP correlated with indexed left ventricular end diastolic volume and indexed maximum left atrial volume. Other cardiac biomarkers did not correlate with cardiac magnetic resonance (CMR) markers of cardiomyopathy.

Novel Cardiac Imaging Risk Score for Mortality Prediction in Duchenne Muscular Dystrophy.

Cardiovascular disease is the leading cause of death in patients with Duchenne Muscular Dystrophy (DMD), but there is significant cardiomyopathy phenotypic variability. Some patients demonstrate rapidly progressive disease and die at a young age while others survive into the fourth decade. Criteria to identify DMD subjects at greatest risk for early mortality could allow for increased monitoring and more intensive therapy. A risk score was created describing the onset and progression of left ventricular dysfunction and late gadolinium enhancement in subjects with DMD. DMD subjects prospectively enrolled in ongoing observational studies (which included cardiac magnetic resonance [CMR]) were used to validate the risk score. A total of 69 subjects had calculable scores. During the study period, 12 (17%) died from complications of DMD. The median risk score was 3 (IQR [2,5]; range [0,9]). The overall risk score applied at the most recent imaging age was associated with mortality at a median age of 17 years (IQR [16,20]) (HR 2.028, p < 0.001). There were no deaths in subjects with a score of less than two. Scores were stable over time. An imaging-based risk score allows risk stratification of subjects with DMD. This can be quickly calculated during a clinic visit to identify subjects at greatest risk of early death.

Non-contrast cardiovascular magnetic resonance detection of myocardial fibrosis in Duchenne muscular dystrophy.

BACKGROUND: Duchenne muscular dystrophy (DMD) leads to progressive cardiomyopathy. Detection of myocardial fibrosis with late gadolinium enhancement (LGE) by cardiovascular magnetic resonance (CMR) is critical for clinical management. Due to concerns of brain deposition of gadolinium, non-contrast methods for detecting and monitoring myocardial fibrosis would be beneficial. OBJECTIVES: We hypothesized that native T1 mapping and/or circumferential (εcc) and longitudinal (εls) strain can detect myocardial fibrosis. METHODS: 156 CMRs with gadolinium were performed in 66 DMD boys and included: (1) left ventricular ejection fraction (LVEF), (2) LGE, (3) native T1 mapping and myocardial tagging (εcc-tag measured using harmonic phase analysis). LGE was graded as: (1) presence/absence by segment, slice, and globally; (2) global severity from 0 (no LGE) to 4 (severe); (3) percent LGE using full width half maximum (FWHM). εls and εcc measured using feature tracking. Regression models to predict LGE included native T1 and either εcc-tag or εls and εcc measured at each segment, slice, and globally. RESULTS: Mean age and LVEF at first CMR were 14 years and 54%, respectively. Global εls and εcc strongly predicted presence or absence of LGE (OR 2.6 [1.1, 6.0], p = 0.029, and OR 2.3 [1.0, 5.1], p = 0.049, respectively) while global native T1 did not. Global εcc, εls, and native T1 predicted global severity score (OR 2.6 [1.4, 4.8], p = 0.002, OR 2.6 [1.4, 6.0], p = 0.002, and OR 1.8 [1.1, 3.1], p = 0.025, respectively). εls correlated with change in LGE by severity score (n = 33, 3.8 [1.0, 14.2], p = 0.048) and εcc-tag correlated with change in percent LGE by FWHM (n = 34, OR 0.2 [0.1, 0.9], p = 0.01). CONCLUSIONS: Pre-contrast sequences predict presence and severity of LGE, with εls and εcc being more predictive in most models, but there was not an observable advantage over using LVEF as a predictor. Change in LGE was predicted by εls (global severity score) and εcc-tag (FWHM). While statistically significant, our results suggest these sequences are currently not a replacement for LGE and may only have utility in a very limited subset of DMD patients.

Characterization of the Rate of Aortic Dilation in Young Patients with Thoracic Aortic Aneurysm.

Longitudinal changes in aortic diameters of young patients with thoracic aortic aneurysm (TAA) have not been completely described, particularly over long periods of follow-up. This retrospective study sought to characterize the rates of proximal aortic dilation in young patients, identify risk factors for TAA progression, and evaluate the predictive utility of early echocardiographic follow-up. Inclusion criteria were: (1) TAA or TAA-predisposing genetic diagnosis, (2) age < 25 years at first echocardiogram, and (3) minimum of 5 years of echocardiographic follow-up. Proximal aortic diameters were measured by echocardiography and Z-scores calculated to index for body surface area. TAA severity was classified as no TAA (Z-score < 2), mild (Z-score 2 to 4), or at least moderate (Z-score > 4). Among 141 included patients, mean age at first echocardiogram was 7.3 ± 3.5 years. Mean follow-up duration was 9.8 ± 3.5 years. Fifty five patients had a genetic syndrome, and 38 of the non-syndromic patients had bicuspid aortic valve (BAV). The rate of aortic dilation was significantly higher at the ascending aorta than other aortic segments. BAV and age > 10 years at first echocardiogram were associated with increased rate of ascending aorta dilation. At the ascending aorta, over 25% of patients had categorical increase in TAA severity between first and last echocardiograms, and such patients demonstrated higher rate of dilation within their first 2 years of follow-up. These longitudinal findings highlight progressive ascending aorta dilation in young patients, which may worsen around adolescence. This may help determine timing of follow-up and target ages for clinical trials.

Cognitive and Attentional Function in Children with Hypoplastic Left Heart Syndrome: A Pilot Study.

While survival for children with hypoplastic left heart syndrome (HLHS) has improved, compromised cardiac output and oxygen delivery persist, and children show cognitive deficits. Most research has assessed young children on broad cognitive indices; less is known about specific indices in older youth. In this pilot study, cognitive function and attention in youth ages 8 to 16 years with HLHS (n = 20) was assessed with the Wechsler Intelligence Scale for Children - Fifth Edition (WISC-V) and NIH Toolbox Cognition Battery (NTCB); parents completed the Child Behavior Checklist. Children scored significantly lower than normative means on the WISC-V Full Scale IQ, Verbal Comprehension, Visual Spatial, Working Memory, and Processing Speed indices, and the NTCB Fluid Cognition Composite; effect sizes ranged from medium to large. Attention problems had a large significant effect. Child age corresponded to lower visual spatial scores. Findings highlight the importance of assessing multiple cognitive indices for targeted intervention and investigating age and disease factors as potential correlates in larger samples.

Variants in ADRB1 and CYP2C9: Association with Response to Atenolol and Losartan in Marfan Syndrome.

OBJECTIVE: To test whether variants in ADRB1 and CYP2C9 genes identify subgroups of individuals with differential response to treatment for Marfan syndrome through analysis of data from a large, randomized trial. STUDY DESIGN: In a subset of 250 white, non-Hispanic participants with Marfan syndrome in a prior randomized trial of atenolol vs losartan, the common variants rs1801252 and rs1801253 in ADRB1 and rs1799853 and rs1057910 in CYP2C9 were analyzed. The primary outcome was baseline-adjusted annual rate of change in the maximum aortic root diameter z-score over 3 years, assessed using mixed effects models. RESULTS: Among 122 atenolol-assigned participants, the 70 with rs1801253 CC genotype had greater rate of improvement in aortic root z-score compared with 52 participants with CG or GG genotypes (Time × Genotype interaction P = .005, mean annual z-score change ± SE -0.20 ± 0.03 vs -0.09 ± 0.03). Among participants with the CC genotype in both treatment arms, those assigned to atenolol had greater rate of improvement compared with the 71 of the 121 assigned to losartan (interaction P = .002; -0.20 ± 0.02 vs -0.07 ± 0.02; P < .001). There were no differences in atenolol response by rs1801252 genotype or in losartan response by CYP2C9 metabolizer status. CONCLUSIONS: In this exploratory study, ADRB1-rs1801253 was associated with atenolol response in children and young adults with Marfan syndrome. If these findings are confirmed in future studies, ADRB1 genotyping has the potential to guide therapy by identifying those who are likely to have greater therapeutic response to atenolol than losartan.

Recruitment, retention, and adherence in a clinical trial: The Pediatric Heart Network's Marfan Trial experience.

BACKGROUND/AIMS: The Pediatric Heart Network Marfan Trial was a randomized trial comparing atenolol versus losartan on aortic root dilation in 608 children and young adults with Marfan syndrome. Barriers to enrollment included a limited pool of eligible participants, restrictive entry criteria, and a diverse age range that required pediatric and adult expertise. Retention was complicated by a 3-year commitment to a complex study and medication regimen. The Network partnered with the Marfan Foundation, bridging the community with the research. The aims of this study are to report protocol and medication adherence and associated predictive factors, and to describe recruitment and retention strategies. METHODS: Recruitment, retention, and adherence to protocol activities related to the primary outcome were measured. Retention was measured by percentage of enrolled participants with 3-year outcome data. Protocol adherence was calculated by completion rates of study visits, ambulatory electrocardiography (Holter monitoring), and quarterly calls. Medication adherence was assessed by the number of tablets or the amount of liquid in bottles returned. Centers were ranked according to adherence (high, medium, and low tertiles). Recruitment, retention, and adherence questionnaires were completed by sites. Descriptive statistics summarized recruitment, retention, and adherence, as well as questionnaire results. Regression modeling assessed predictors of adherence. RESULTS: Completion rates for visits, Holter monitors, and quarterly calls were 99%, 94%, and 96%, respectively. Primary outcome data at 3 years were obtained for 88% of participants. The mean percentage of medication taken was estimated at 89%. Site and age were associated with all measures of adherence. Young adult and African American participants had lower levels of adherence. Higher adherence sites employed more strategies; had more staffing resources, less key staff turnover, and more collaboration with referring providers; utilized the Foundation's resources; and used a greater number of strategies to recruit, retain, and promote protocol and medication adherence. CONCLUSION: Overall adherence was excellent for this trial conducted within a National Institutes of Health-funded clinical trial network. Strategies specifically targeted to young adults and African Americans may have been beneficial. Many strategies employed by higher adherence sites are ones that any site could easily use, such as greeting families at non-study hospital visits, asking for family feedback, providing calendars for tracking schedules, and recommending apps for medication reminders. Additional key learnings include adherence differences by age, race, and site, the value of collaborative learning, and the importance of partnerships with patient advocacy groups. These lessons could shape recruitment, retention, and adherence to improve the quality of future complex trials involving rare conditions.

The BDNF rs6265 Polymorphism is a Modifier of Cardiomyocyte Contractility and Dilated Cardiomyopathy.

Brain-derived neurotrophic factor (BDNF) is a neuronal growth and survival factor that harbors cardioprotective qualities that may attenuate dilated cardiomyopathy. In ~30% of the population, BDNF has a common, nonsynonymous single nucleotide polymorphism rs6265 (Val66Met), which might be correlated with increased risk of cardiovascular events. We previously showed that BDNF correlates with better cardiac function in Duchenne muscular dystrophy (DMD) patients. However, the effect of the Val66Met polymorphism on cardiac function has not been determined. The goal of the current study was to determine the effects of rs6265 on BDNF biomarker suitability and DMD cardiac functions more generally. We assessed cardiovascular and skeletal muscle function in human DMD patients segregated by polymorphic allele. We also compared echocardiographic, electrophysiologic, and cardiomyocyte contractility in C57/BL-6 wild-type mice with rs6265 polymorphism and in mdx/mTR (mDMD) mouse model of DMD. In human DMD patients, plasma BDNF levels had a positive correlation with left ventricular function, opposite to that seen in rs6265 carriers. There was also a substantial decrease in skeletal muscle function in carriers compared to the Val homozygotes. Surprisingly, the opposite was true when cardiac function of DMD carriers and non-carriers were compared. On the other hand, Val66Met wild-type mice had only subtle functional differences at baseline but significantly decreased cardiomyocyte contractility. Our results indicate that the Val66Met polymorphism alters myocyte contractility, conferring worse skeletal muscle function but better cardiac function in DMD patients. Moreover, these results suggest a mechanism for the relative preservation of cardiac tissues compared to skeletal muscle in DMD patients and underscores the complexity of BDNF signaling in response to mechanical workload.

Health-Related Quality of Life in Children and Young Adults with Marfan Syndrome.

OBJECTIVE: To assess health-related quality of life (HRQOL) in a large multicenter cohort of children and young adults with Marfan syndrome participating in the Pediatric Heart Network Marfan Trial. STUDY DESIGN: The Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Scales were administered to 321 subjects with Marfan syndrome (5-25 years). PedsQL scores were compared with healthy population norms. The impact of treatment arm (atenolol vs losartan), severity of clinical features, and number of patient-reported symptoms on HRQOL was assessed by general linear models. RESULTS: Mean PedsQL scores in children (5-18 years) with Marfan syndrome were lower than healthy population norms for physical (P ≤ .003) and psychosocial (P < .001) domains; mean psychosocial scores for adults (19-25 years) were greater than healthy norms (P < .001). HRQOL across multiple domains correlated inversely with frequency of patient-reported symptoms (r = 0.30-0.38, P < .0001). Those <18 years of age with neurodevelopmental disorders (mainly learning disability, attention-deficit/hyperactivity disorder) had lower mean PedsQL scores (5.5-7.4 lower, P < .04). A multivariable model found age, sex, patient-reported symptoms, and neurodevelopmental disorder to be independent predictors of HRQOL. There were no differences in HRQOL scores by treatment arm, aortic root z score, number of skeletal features, or presence of ectopia lentis. CONCLUSIONS: Children and adolescents with Marfan syndrome were at high risk for impaired HRQOL. Patient-reported symptoms and neurodevelopmental disorder, but not treatment arm or severity of Marfan syndrome-related physical findings, were associated with lower HRQOL.

The Role of Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases in Duchenne Muscular Dystrophy Cardiomyopathy.

BACKGROUND: Cardiomyopathy is the leading cause of death in Duchenne muscular dystrophy (DMD). Standard cardiac biomarkers are poor indicators of DMD cardiovascular disease. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) regulate collagen turnover. Given the cardiac fibrosis seen in DMD, we hypothesized that MMPs and TIMPs correlate with severity of DMD cardiomyopathy. METHODS AND RESULTS: Prospectively enrolled DMD subjects (n = 42) underwent cardiac magnetic resonance imaging for function and late gadolinium enhancement (LGE), including LGE severity from 0 (no LGE) to 4 (severe). Serum from DMD and healthy male control subjects (n = 15) analyzed for MMPs 1, 2, 3, 7, 9, and 10 and TIMPs 1-4. MMP1, MMP7, and MMP10 were higher in DMD than in control (respectively, median 5080 pg/mL vs 2120 pg/mL [P = .007], 2170 pg/mL vs 1420 pg/mL [P < .001], and 216 pg/mL vs 140pg/mL [P = .040]); TIMP4 was lower in DMD (124 pg/mL vs 263 pg/mL; P = .046). Within DMD, MMP7 correlated inversely with left ventricular ejection fraction (r = -0.40; P = .012) and directly with strain (r = 0.54; P = .001) and LGE severity (r = 0.47; P = .003). MMP7 was higher in DMD patients with LGE compared with those without LGE and control subjects (P < .001). CONCLUSIONS: Multiple MMPs are elevated in DMD compared with control subjects. MMP7 is related to DMD cardiac dysfunction and myocardial fibrosis, possibly through remodeling of the extracellular matrix.

Creation of a novel algorithm to identify patients with Becker and Duchenne muscular dystrophy within an administrative database and application of the algorithm to assess cardiovascular morbidity.

BACKGROUND: Outcome analyses in large administrative databases are ideal for rare diseases such as Becker and Duchenne muscular dystrophy. Unfortunately, Becker and Duchenne do not yet have specific International Classification of Disease-9/-10 codes. We hypothesised that an algorithm could accurately identify these patients within administrative data and improve assessment of cardiovascular morbidity. METHODS: Hospital discharges (n=13,189) for patients with muscular dystrophy classified by International Classification of Disease-9 code: 359.1 were identified from the Pediatric Health Information System database. An identification algorithm was created and then validated at three institutions. Multi-variable generalised linear mixed-effects models were used to estimate the associations of length of stay, hospitalisation cost, and 14-day readmission with age, encounter severity, and respiratory disease accounting for clustering within the hospital. RESULTS: The identification algorithm improved identification of patients with Becker and Duchenne from 55% (code 359.1 alone) to 77%. On bi-variate analysis, left ventricular dysfunction and arrhythmia were associated with increased cost of hospitalisation, length of stay, and mortality (p<0.001). After adjustment, Becker and Duchenne patients with left ventricular dysfunction and arrhythmia had increased length of stay with rate ratio 1.4 and 1.2 (p<0.001 and p=0.004) and increased cost of hospitalization with rate ratio 1.4 and 1.4 (both p<0.001). CONCLUSIONS: Our algorithm accurately identifies patients with Becker and Duchenne and can be used for future analysis of administrative data. Our analysis demonstrates the significant effects of cardiovascular disease on length of stay and hospitalisation cost in patients with Becker and Duchenne. Better recognition of the contribution of cardiovascular disease during hospitalisation with earlier more intensive evaluation and therapy may help improve outcomes in this patient population.

Management of Cardiac Involvement Associated With Neuromuscular Diseases: A Scientific Statement From the American Heart Association.

For many neuromuscular diseases (NMDs), cardiac disease represents a major cause of morbidity and mortality. The management of cardiac disease in NMDs is made challenging by the broad clinical heterogeneity that exists among many NMDs and by limited knowledge about disease-specific cardiovascular pathogenesis and course-modifying interventions. The overlay of compromise in peripheral muscle function and other organ systems, such as the lungs, also makes the simple application of endorsed adult or pediatric heart failure guidelines to the NMD population problematic. In this statement, we provide background on several NMDs in which there is cardiac involvement, highlighting unique features of NMD-associated myocardial disease that require clinicians to tailor their approach to prevention and treatment of heart failure. Undoubtedly, further investigations are required to best inform future guidelines on NMD-specific cardiovascular health risks, treatments, and outcomes.

Atenolol versus losartan in children and young adults with Marfan's syndrome.

BACKGROUND: Aortic-root dissection is the leading cause of death in Marfan's syndrome. Studies suggest that with regard to slowing aortic-root enlargement, losartan may be more effective than beta-blockers, the current standard therapy in most centers. METHODS: We conducted a randomized trial comparing losartan with atenolol in children and young adults with Marfan's syndrome. The primary outcome was the rate of aortic-root enlargement, expressed as the change in the maximum aortic-root-diameter z score indexed to body-surface area (hereafter, aortic-root z score) over a 3-year period. Secondary outcomes included the rate of change in the absolute diameter of the aortic root; the rate of change in aortic regurgitation; the time to aortic dissection, aortic-root surgery, or death; somatic growth; and the incidence of adverse events. RESULTS: From January 2007 through February 2011, a total of 21 clinical centers enrolled 608 participants, 6 months to 25 years of age (mean [±SD] age, 11.5±6.5 years in the atenolol group and 11.0±6.2 years in the losartan group), who had an aortic-root z score greater than 3.0. The baseline-adjusted rate of change in the mean (±SE) aortic-root z score did not differ significantly between the atenolol group and the losartan group (-0.139±0.013 and -0.107±0.013 standard-deviation units per year, respectively; P=0.08). Both slopes were significantly less than zero, indicating a decrease in the aortic-root diameter relative to body-surface area with either treatment. The 3-year rates of aortic-root surgery, aortic dissection, death, and a composite of these events did not differ significantly between the two treatment groups. CONCLUSIONS: Among children and young adults with Marfan's syndrome who were randomly assigned to losartan or atenolol, we found no significant difference in the rate of aortic-root dilatation between the two treatment groups over a 3-year period. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT00429364.).

Loss-of-function mutations in the X-linked biglycan gene cause a severe syndromic form of thoracic aortic aneurysms and dissections.

PURPOSE: Thoracic aortic aneurysm and dissection (TAAD) is typically inherited in an autosomal dominant manner, but rare X-linked families have been described. So far, the only known X-linked gene is FLNA, which is associated with the periventricular nodular heterotopia type of Ehlers-Danlos syndrome. However, mutations in this gene explain only a small number of X-linked TAAD families. METHODS: We performed targeted resequencing of 368 candidate genes in a cohort of 11 molecularly unexplained Marfan probands. Subsequently, Sanger sequencing of BGN in 360 male and 155 female molecularly unexplained TAAD probands was performed. RESULTS: We found five individuals with loss-of-function mutations in BGN encoding the small leucine-rich proteoglycan biglycan. The clinical phenotype is characterized by early-onset aortic aneurysm and dissection. Other recurrent findings include hypertelorism, pectus deformity, joint hypermobility, contractures, and mild skeletal dysplasia. Fluorescent staining revealed an increase in TGF-ß signaling, evidenced by an increase in nuclear pSMAD2 in the aortic wall. Our results are in line with those of prior reports demonstrating that Bgn-deficient male BALB/cA mice die from aortic rupture. CONCLUSION: In conclusion, BGN gene defects in humans cause an X-linked syndromic form of severe TAAD that is associated with preservation of elastic fibers and increased TGF-ß signaling.Genet Med 19 4, 386-395.

Synthetic hematocrit derived from the longitudinal relaxation of blood can lead to clinically significant errors in measurement of extracellular volume fraction in pediatric and young adult patients.

BACKGROUND: Extracellular volume fraction (ECV) is altered in pathological cardiac remodeling and predicts death and arrhythmia. ECV can be quantified using cardiovascular magnetic resonance (CMR) T1 mapping but calculation requires a measured hematocrit (Hct). The longitudinal relaxation of blood has been used in adults to generate a synthetic Hct (estimate of true Hct) but has not been validated in pediatric populations. METHODS: One hundred fourteen children and young adults underwent a total of 163 CMRs with T1 mapping. The majority of subjects had a measured Hct the same day (N = 146). Native and post-contrast T1 were determined in blood pool, septum, and free wall of mid-LV, avoiding areas of late gadolinium enhancement. Synthetic Hct and ECV were calculated and intraclass correlation coefficient (ICC) and linear regression were used to compare measured and synthetic values. RESULTS: The mean age was 16.4 ± 6.4 years and mean left ventricular ejection fraction was 59% ± 9%. The mean measured Hct was 41.8 ± 3.0% compared to the mean synthetic Hct of 43.2% ± 2.9% (p < 0.001, ICC 0.46 [0.27, 0.52]) with the previously published model and 41.8% ± 1.4% (p < 0.001, ICC 0.28 [0.13, 0. 42]) with the locally-derived model. Mean measured mid-free wall ECV was 30.5% ± 4.8% and mean synthetic mid-free wall ECV of local model was 29.7% ± 4.6% (p < 0.001, ICC 0.93 [0.91, 0.95]). Correlations were not affected by heart rate and did not significantly differ in subpopulation analysis. While the ICC was strong, differences between measured and synthetic ECV ranged from -8.4% to 4.3% in the septum and -12.6% to 15.8% in the free wall. Using our laboratory's normal cut-off of 28.5%, 59 patients (37%) were miscategorized (53 false negatives, 6 false positives) with published model ECV. The local model had 37 miscategorizations (20 false negatives, 17 false positives), significantly fewer but still a substantial number (23%). CONCLUSIONS: Our data suggest that use of synthetic Hct for the calculation of ECV results in miscategorization of individual patients. This difference may be less significant once synthetic ECV is calculated and averaged over a large research cohort, making it potentially useful as a research tool. However, we recommend formal measurement of Hct in children and young adults for clinical CMRs.