Baseline Characteristics of the VANISH Cohort.

BACKGROUND: The VANISH trial (Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy) targeted young sarcomeric gene mutation carriers with early-stage hypertrophic cardiomyopathy (HCM) to test whether valsartan can modify disease progression. We describe the baseline characteristics of the VANISH cohort and compare to previous trials evaluating angiotensin receptor blockers. METHODS: Applying a randomized, double-blinded, placebo-controlled design, 178 participants with nonobstructive HCM (age, 23.3±10.1 years; 61% men) were randomized in the primary cohort and 34 (age, 16.5±4.9 years; 50% men) in the exploratory cohort of sarcomeric mutation carriers without left ventricular hypertrophy. RESULTS: In the primary cohort, maximal left ventricular wall thickness was 17±4 mm for adults and Z score 7.0±4.5 for children. Nineteen percent had late gadolinium enhancement on cardiac magnetic resonance. Mean peak oxygen consumption was 33 mL/kg per minute, and 92% of participants were New York Heart Association functional class I. New York Heart Association class II was associated with older age, MYH7 variants, and more prominent imaging abnormalities. Six previous trials of angiotensin receptor blockers in HCM enrolled a median of 24 patients (range, 19-133) with mean age of 51.2 years; 42% of patients were in New York Heart Association class ≥II, and sarcomeric mutations were not required. CONCLUSIONS: The VANISH cohort is much larger, younger, less heterogeneous, and has less advanced disease than prior angiotensin receptor blocker trials in HCM. Participants had relatively normal functional capacity and mild HCM features. New York Heart Association functional class II symptoms were associated with older age, more prominent imaging abnormalities, and MYH7 variants, suggesting both phenotype and genotype contribute to disease manifestations. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01912534.

Damaging Variants in Proangiogenic Genes Impair Growth in Fetuses with Cardiac Defects.

OBJECTIVE: To determine the impact of damaging genetic variation in proangiogenic pathways on placental function, complications of pregnancy, fetal growth, and clinical outcomes in pregnancies with fetal congenital heart defect. STUDY DESIGN: Families delivering a baby with a congenital heart defect requiring surgical repair in infancy were recruited. The placenta and neonate were weighed and measured. Hemodynamic variables were recorded from a third trimester (36.4 ± 1.7 weeks) fetal echocardiogram. Exome sequencing was performed on the probands (N = 133) and consented parents (114 parent-child trios, and 15 parent-child duos) and the GeneVetter analysis tool used to identify damaging coding sequence variants in 163 genes associated with the positive regulation of angiogenesis (PRA) (GO:0045766). RESULTS: In total, 117 damaging variants were identified in PRA genes in 133 congenital heart defect probands with 73 subjects having at least 1 variant. Presence of a damaging PRA variant was associated with increased umbilical artery pulsatility index (mean 1.11 with variant vs 1.00 without; P = .01). The presence of a damaging PRA variant was also associated with lower neonatal length and head circumference for age z score at birth (mean -0.44 and -0.47 with variant vs 0.23 and -0.05 without; P = .01 and .04, respectively). During median 3.1 years (IQR 2.0-4.1 years) of follow-up, deaths occurred in 2 of 60 (3.3%) subjects with no PRA variant and in 9 of 73 (12.3%) subjects with 1 or more PRA variants (P = .06). CONCLUSIONS: Damaging variants in proangiogenic genes may impact placental function and are associated with impaired fetal growth in pregnancies involving a fetus with congenital heart defect.

Availability of Automated External Defibrillators in Public High Schools.

OBJECTIVES: To assess automated external defibrillator (AED) distribution and cardiac emergency preparedness in Michigan secondary schools and investigate for association with school sociodemographic characteristics. STUDY DESIGN: Surveys were sent via electronic mail to representatives from all public high schools in 30 randomly selected Michigan counties, stratified by population. Association of AED-related factors with school sociodemographic characteristics were evaluated using Wilcoxon rank sum test and χ(2) test, as appropriate. RESULTS: Of 188 schools, 133 (71%) responded to the survey and all had AEDs. Larger student population was associated with fewer AEDs per 100 students (P < .0001) and fewer staff with AED training per AED (P = .02), compared with smaller schools. Schools with >20% students from racial minority groups had significantly fewer AEDs available per 100 students than schools with less racial diversity (P = .03). Schools with more students eligible for free and reduced lunch were less likely to have a cardiac emergency response plan (P = .02) and demonstrated less frequent AED maintenance (P = .03). CONCLUSIONS: Although AEDs are available at public high schools across Michigan, the number of AEDs per student varies inversely with minority student population and school size. Unequal distribution of AEDs and lack of cardiac emergency preparedness may contribute to outcomes of sudden cardiac arrest among youth.

Immune Abnormalities in Fontan Protein-Losing Enteropathy: A Case-Control Study.

OBJECTIVE: To comprehensively characterize the immunologic characteristics of patients with protein-losing enteropathy (PLE) post-Fontan and compare them with patients without PLE post-Fontan. STUDY DESIGN: Patients with PLE post-Fontan and age-matched controls post-Fontan were prospectively studied with laboratory markers of immune function. Infectious history was obtained by interview and chart review. The groups' demographics, cardiac history, immune characteristics, and infection history were compared using appropriate 2-group statistics. RESULTS: A total of 16 patients enrolled (8 patients with PLE and 8 controls). All patients with PLE had lymphopenia compared with 25% of controls (P = .01). All patients with PLE had markedly depressed CD4 T cell counts (median 58 cells/µL) compared with controls (median 450 cells/µL, P = .0002); CD4% was also low in the PLE group (12.3%) and normal in control (36.9%, P = .004). Both groups had mildly depressed CD8 T cells and normal to slightly elevated natural killer and B-cell subsets. A majority of patients with PLE (62.5%) had negative titers to measles, mumps, and rubella vaccination, compared with no control Fontan with a negative titer (P = .03). Despite profoundly low CD4 counts, the frequency of infection was not different between groups with no reported opportunistic infections. CONCLUSIONS: Patients with Fontan-associated PLE have extensive quantitative immune abnormalities, particularly CD4 deficiency. These immune abnormalities are similar to those found in non-Fontan patients with PLE caused by intestinal lymphangiectasia.

Fontan-associated protein-losing enteropathy and plastic bronchitis.

OBJECTIVE: To characterize the medical history, disease progression, and treatment of current-era patients with the rare diseases Fontan-associated protein-losing enteropathy (PLE) and plastic bronchitis. STUDY DESIGN: A novel survey that queried demographics, medical details, and treatment information was piloted and placed online via a Facebook portal, allowing social media to power the study. Participation regardless of PLE or plastic bronchitis diagnosis was allowed. Case control analyses compared patients with PLE and plastic bronchitis with uncomplicated control patients receiving the Fontan procedure. RESULTS: The survey was completed by 671 subjects, including 76 with PLE, 46 with plastic bronchitis, and 7 with both. Median PLE diagnosis was 2.5 years post-Fontan. Hospitalization for PLE occurred in 71% with 41% hospitalized ≥ 3 times. Therapy varied significantly. Patients with PLE more commonly had hypoplastic left ventricle (62% vs 44% control; OR 2.81, 95% CI 1.43-5.53), chylothorax (66% vs 41%; OR 2.96, CI 1.65-5.31), and cardiothoracic surgery in addition to staged palliation (17% vs 5%; OR 4.27, CI 1.63-11.20). Median plastic bronchitis diagnosis was 2 years post-Fontan. Hospitalization for plastic bronchitis occurred in 91% with 61% hospitalized ≥ 3 times. Therapy was very diverse. Patients with plastic bronchitis more commonly had chylothorax at any surgery (72% vs 51%; OR 2.47, CI 1.20-5.08) and seasonal allergies (52% vs 36%; OR 1.98, CI 1.01-3.89). CONCLUSIONS: Patient-specific factors are associated with diagnoses of PLE or plastic bronchitis. Treatment strategies are diverse without clear patterns. These results provide a foundation upon which to design future therapeutic studies and identify a clear need for forming consensus approaches to treatment.

Lower body symmetry and running performance in elite Jamaican track and field athletes.

In a study of degree of lower body symmetry in 73 elite Jamaican track and field athletes we show that both their knees and ankles (but not their feet) are-on average-significantly more symmetrical than those of 116 similarly aged controls from the rural Jamaican countryside. Within the elite athletes, events ranged from the 100 to the 800 m, and knee and ankle asymmetry was lower for those running the 100 m dashes than those running the longer events with turns. Nevertheless, across all events those with more symmetrical knees and ankles (but not feet) had better results compared to international standards. Regression models considering lower body symmetry combined with gender, age and weight explain 27 to 28% of the variation in performance among athletes, with symmetry related to about 5% of this variation. Within 100 m sprinters, the results suggest that those with more symmetrical knees and ankles ran faster. Altogether, our work confirms earlier findings that knee and probably ankle symmetry are positively associated with sprinting performance, while extending these findings to elite athletes.

Novel ryanodine receptor 2 mutation associated with a severe phenotype of catecholaminergic polymorphic ventricular tachycardia.

An adolescent girl with a history of anxiety associated seizure-like episodes was ultimately diagnosed with catecholaminergic polymorphic ventricular tachycardia. She tested positive for a novel mutation of the ryanodine receptor. The report underscores how genetic arrhythmia syndromes may be mistaken for neurologic disorders.