Cardiac disease is now the leading cause of death in Duchenne muscular dystrophy (DMD). Clinical evaluations over time have demonstrated asymptomatic cardiac troponin elevations and acute elevations ...are associated with symptoms and cardiac dysfunction in DMD. Clinicians require a better understanding of the relationship of symptoms, troponin levels and progression of cardiac disease in DMD. As clinical trials begin to assess novel cardiac therapeutics in DMD, troponin levels in DMD are important for safety monitoring and outcome measures. The Parent Project Muscular Dystrophy convened an expert panel of cardiologists, scientists, and regulatory and industry specialists on 16 December 2019 in Silver Spring, Maryland and reviewed published and unpublished data from their institutions. The panel recommended retrospective troponin data analyses, prospective longitudinal troponin collection using high-sensitivity cardiac troponin I assays, inclusion of troponin in future clinical trial outcomes and future development of clinical guidelines for monitoring and treating troponin elevations in DMD.
Current approaches to stratify the risk for disease progression in thoracic aortic aneurysm (TAA) lack precision, which hinders clinical decision making. Connective tissue phenotyping of children ...with TAA previously identified the association between skin striae and increased rate of aortic dilation. The objective of this study was to analyze associations between connective tissue abnormalities and clinical endpoints in adults with aortopathy. Participants with TAA or aortic dissection (TAD) and trileaflet aortic valve were enrolled from 2016 to 2019 in the setting of cardiothoracic surgical care. Data were ascertained by structured interviews with participants. The mean age among 241 cases was 61 ± 13 years. Eighty (33%) had history of TAD. While most participants lacked a formal syndromic diagnosis clinically, connective tissue abnormalities were identified in 113 (47%). This included 20% with abdominal hernia and 13% with skin striae in atypical location. In multivariate analysis, striae and hypertension were significantly associated with TAD. Striae were associated with younger age of TAD or prophylactic aortic surgery. Striae were more frequent in TAD cases than age- and sex-matched controls. Thus, systemic features of connective tissue dysfunction were prevalent in adults with aortopathy. The emerging nexus between striae and aortopathy severity creates opportunities for clinical stratification and basic research.
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.
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.
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.
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.
The objective of this study is to investigate cognitive and attentional function in adolescents and young adults with operated congenital heart disease. Previous research has indicated that children ...with congenital heart disease have deficits in broad areas of cognitive function. However, less attention has been given to survivors as they grow into adolescence and early adulthood. The participants were 18 non-syndromic adolescents and young adults with tetralogy of Fallot and d-transposition of the great arteries that required cardiac surgery before the age of 5 years, and 18 healthy, unaffected siblings (11-22 years of age for both groups). Cases with congenital heart disease and their siblings were administered Wechsler Intelligence scales and reported attention problems using the Achenbach System of Empirically Based Assessments. Cases were compared to both healthy siblings and established norms. Cases performed significantly lower than siblings on full scale IQ and processing speed, and significantly lower than norms on perceptual reasoning. Cases also reported more attention problems compared to both siblings and norms. Effect sizes varied with medium-to-large effects for processing speed, perceptual reasoning, working memory, and attention problems. Findings suggest that neurocognitive function may continue to be affected for congenital heart disease survivors in adolescence and young adulthood, and that comparisons to established norms may underestimate neurocognitive vulnerabilities.
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.
Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene, which codes for the dystrophin protein. While progress has been made in defining the molecular basis and pathogenesis of DMD, ...major gaps remain in understanding mechanisms that contribute to the marked delay in cardiac compared to skeletal muscle dysfunction.
To address this question, we analyzed cardiac and skeletal muscle tissue microarrays from golden retriever muscular dystrophy (GRMD) dogs, a genetically and clinically homologous model for DMD. A total of 15 dogs, 3 each GRMD and controls at 6 and 12 months plus 3 older (47-93 months) GRMD dogs, were assessed.
GRMD dogs exhibited tissue- and age-specific transcriptional profiles and enriched functions in skeletal but not cardiac muscle, consistent with a "metabolic crisis" seen with DMD microarray studies. Most notably, dozens of energy production-associated molecules, including all of the TCA cycle enzymes and multiple electron transport components, were down regulated. Glycolytic and glycolysis shunt pathway-associated enzymes, such as those of the anabolic pentose phosphate pathway, were also altered, in keeping with gene expression in other forms of muscle atrophy. On the other hand, GRMD cardiac muscle genes were enriched in nucleotide metabolism and pathways that are critical for neuromuscular junction maintenance, synaptic function and conduction.
These findings suggest differential metabolic dysfunction may contribute to distinct pathological phenotypes in skeletal and cardiac muscle.
Duchenne muscular dystrophy leads to cardiomyopathy. The objective of this study was to estimate the association of body mass index with cardiomyopathy onset. Cardiomyopathy was defined as left ...ventricular ejection fraction <55% or left ventricular fractional shortening <28%. Overall, 48% met the criteria for cardiomyopathy. We were unable to demonstrate an association between body mass index Z score and age of cardiomyopathy onset (hazard ratio 0.79, 95% confidence interval 0.57-1.11, P = .17) after adjusting for covariates. Duration of corticosteroid use (P = .01), but not loss of ambulatory ability (P = .47), was associated with age of cardiomyopathy onset. We were unable to detect a significant difference in median body mass index Z scores in corticosteroid-treated boys compared with corticosteroid-naïve boys (1.11, 95% confidence interval 0.25-1.95, vs 1.05, 95% confidence interval 0.01-1.86, P = .69). No association was detected between the body mass index Z scores of Duchenne muscular dystrophy subjects and age of cardiomyopathy onset.
Background The Pediatric Heart Network designed a clinical trial to compare aortic root growth and other short-term cardiovascular outcomes in children and young adults with Marfan syndrome ...randomized to receive atenolol or losartan. We report here the characteristics of the screened population and enrolled subjects. Methods and results Between 2007 and 2011, 21 clinical sites randomized 608 subjects, aged 6 months to 25 years who met the original Ghent criteria and had a body surface area–adjusted aortic root diameter z-score >3.0. The mean age at study entry was 11.2 years, 60% were male, and 25% were older teenagers and young adults. The median aortic root diameter z-score was 4.0. Aortic root diameter z-score did not vary with age. Mitral valve prolapse and mitral regurgitation were more common in females. Among those with a positive family history, 56% had a family member with aortic surgery, and 32% had a family member with a history of aortic dissection. Conclusions Baseline demographic, clinical, and anthropometric characteristics of the randomized cohort are representative of patients in this population with moderate to severe aortic root dilation. The high percentage of young subjects with relatives who have had aortic dissection or surgery illustrates the need for more definitive therapy; we expect that the results of the study and the wealth of systematic data collected will make an important contribution to the management of individuals with Marfan syndrome.
Fontan-associated liver disease universally affects adults with single ventricle heart disease. Chronic kidney disease is also highly prevalent in adult Fontan patients. In this study, we evaluate ...the relationship of Fontan hemodynamics invasively and noninvasively with extra-cardiac dysfunction as measured by MELD and MELD-XI.
We hypothesize that invasive and noninvasive measures of Fontan circuit congestion and ventricular dysfunction are associated with increased MELD and MELD-XI scores.
Single-center data from adults with Fontan palliation who had ongoing care, including cardiac catheterization, were retrospectively collected. Hemodynamic data from cardiac catheterization and echocardiographic assessment of ventricular and atrioventricular valve function were tested for association with serum creatinine, MELD, and MELD-XI. Linear regression was used to perform multivariable analysis in the echocardiogram cohort.
Fifty-seven patients had congruent lab and catheterization data for analysis. Sixty-three and sixty-nine patients had congruent lab and echocardiogram data for MELD and MELD-XI, respectively. Of the hemodynamic variables analyzed, only decreased systemic oxygen saturation had significant correlation with elevated MELD and MELD-XI (P = .045). Patients with moderately or severely reduced ejection fraction by echocardiogram had significantly higher MELD and MELD-XI scores compared to those with normal or mildly depressed systolic ventricular function (P = .008 and P < .001 for MELD and MELD-XI, respectively). Significant differences in creatinine were also found among the ventricular dysfunction groups (P = .02).
In adults following Fontan palliation, systolic ventricular dysfunction and decreased oxygen saturation were associated with hepatic and renal dysfunction as assessed by elevated serum creatinine, MELD, and MELD-XI scores.
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