Search

OBJECTIVES Eosinophilic esophagitis (EoE) is characterized by remissions and relapses. Guidelines defining remission do not exist and therefore remission is inconsistently identified. We sought to define histology remission in EoE. METHODS Esophageal biopsies, obtained at the time the validated pediatric EoE symptoms scores v2.0 (PEESS v2.0) questionnaire was completed (N = 42), were scored using the validated EoE Histology Scoring System. An EoE Histology Remission Score (EoEHRS) was constructed and specified that in all esophageal sites sampled the peak eosinophil count was

OBJECTIVE. This study examined whether carrying dopamine-related “risk” genes—either the dopamine transporter (DAT1) 10-repeat allele or dopamine receptor-4 (DRD4) 7-repeat allele—moderated the association of family environment and executive function (EF) following traumatic brain injury in early childhood. METHOD. Caregivers of children with traumatic brain injury (TBI) or orthopedic injury (OI) completed the Behavior Rating Inventory of Executive Function (BRIEF) at post-injury visits. General linear models examined gene-environment interactions as moderators of the effects of TBI on EF at 12 months and 7 years post-injury. RESULTS. At 12 months, we did not find any significant gene by environment interactions. At 7 years, we found a significant 3-way interaction among combined carrier status, level of permissive parenting, and injury type. For children exposed to more optimal parenting, carriers of DAT1 and/or DRD4 risk alleles with TBI showed significantly worse parent-reported EF compared to carriers with OI. In those with less optimal parenting, carriers and non-carriers with TBI, as well as carriers with OI, showed significantly worse parent-reported EF compared to non-carriers with OI, with medium to large effect sizes. CONCLUSIONS. The findings highlight the importance of considering polygenetic and environmental factors in future studies of recovery following TBI and other injuries in childhood.

Hypertension is associated with left ventricular hypertrophy (LVH), a risk factor for cardiovascular events. Since cardiovascular events in youth are rare, hypertension has historically been defined by the 95th percentile of the normal blood pressure (BP) distribution in healthy children. The optimal BP percentile associated with LVH in youth is unknown. We aimed to determine the association of systolic BP (SBP) percentile, independent of obesity, on left ventricular mass index (LVMI), and to estimate which SBP percentile best predicts LVH in youth. We evaluated SBP, anthropometrics, and echocardiogram in 303 adolescents (mean age 15.6 years, 63% white, 55% male) classified by SBP as low-risk (L=141, 2.7 ; LVH: L=13%, M=21%, H=27%, all P 2.7 ). Abnormalities in cardiac structure in youth can be found at BP levels below those used to define hypertension.

Background Pediatric cardiomyopathy is a genetically heterogeneous disease with substantial morbidity and mortality. Current guidelines recommend genetic testing in children with hypertrophic, dilated, or restrictive cardiomyopathy, but practice variations exist. Robust data on clinical testing practices and diagnostic yield in children are lacking. This study aimed to identify the genetic causes of cardiomyopathy in children and to investigate clinical genetic testing practices. Methods and Results Children with familial or idiopathic cardiomyopathy were enrolled from 14 institutions in North America. Probands underwent exome sequencing. Rare sequence variants in 37 known cardiomyopathy genes were assessed for pathogenicity using consensus clinical interpretation guidelines. Of the 152 enrolled probands, 41% had a family history of cardiomyopathy. Of 81 (53%) who had undergone clinical genetic testing for cardiomyopathy before enrollment, 39 (48%) had a positive result. Genetic testing rates varied from 0% to 97% between sites. A positive family history and hypertrophic cardiomyopathy subtype were associated with increased likelihood of genetic testing ( P =0.005 and P =0.03, respectively). A molecular cause was identified in an additional 21% of the 63 children who did not undergo clinical testing, with positive results identified in both familial and idiopathic cases and across all phenotypic subtypes. Conclusions A definitive molecular genetic diagnosis can be made in a substantial proportion of children for whom the cause and heritable nature of their cardiomyopathy was previously unknown. Practice variations in genetic testing are great and should be reduced. Improvements can be made in comprehensive cardiac screening and predictive genetic testing in first‐degree relatives. Overall, our results support use of routine genetic testing in cases of both familial and idiopathic cardiomyopathy. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01873963.

Ambulatory blood pressure (BP) monitoring provides a more precise measure of BP status than clinic BP and is currently recommended in the evaluation of high BP in children and adolescents. However, ambulatory BP monitoring may not always be available. Our aim was to determine the clinic BP percentile most likely to predict ambulatory hypertension. We evaluated clinic and ambulatory BP in 247 adolescents (median age, 15.7 years; 63% white; 54% male). Clinic BP percentile (based on the fourth report and the 2017 American Academy of Pediatrics clinical practice guidelines) and ambulatory BP status (normal versus hypertension) were determined by age-, sex-, and height-specific cut points. Sensitivity and specificity of different clinic BP percentiles and cutoffs to predict ambulatory hypertension were calculated. Forty (16%) and 67 (27%) patients had systolic hypertension based on the fourth report and the 2017 guidelines, respectively, whereas 38 (15%) had wake ambulatory systolic hypertension. The prevalence of ambulatory wake systolic hypertension increased across clinic systolic BP percentiles, from 3% when clinic systolic BP was

Introduction: African origin coding variants in APOL1 , encoding apolipoprotein L1, are strongly associated with various kidney diseases in African Americans, with odds ratio ranging from 7 to 89 for two renal risk allele carriers. APOL1 renal risk genotypes may influence risk for cardiovascular disease and mortality, but findings have been inconsistent. Hypothesis: Given that African-American aging women are at high risk for cardiovascular disease and stroke, we asked whether APOL1 risk genotypes affect these outcomes. Methods: We used data from 11,137 African-American postmenopausal women who participated in the Women’s Health Initiative prospective cohort, followed from enrollment (1993-1998) to 2014. APOL1 genotypes were obtained directly or by imputation from whole exome sequencing data. Adjudicated outcomes were incident coronary heart disease, stroke and subtypes, heart failure and subtypes, and overall and cause-specific mortality obtained from hospital records and death certificates. End-stage renal disease status (ESRD) was obtained from the US Renal Data System. We estimated incident rates for each outcome and used Cox proportional hazard to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the associations of APOL1 high and low risk groups with outcomes. Results: Mean age was 61.7 years. APOL1 high risk carriers (12.3% of participants) had higher prevalence of hypertension, use of cholesterol lowering medication, and reduced estimated glomerular filtration rate (eGFR), defined as 2 . After 11 years mean follow-up APOL1 high risk subjects had a higher incident rate of ESRD and hospitalized heart failure with preserved ejection fraction (HFpEF) than low risk carriers, but showed no difference in the incident rates of other outcomes. In adjusted models, there were a significant 43% increased hazard of ESRD (95% CI 1.01, 2.02), and a 58% increased hazard of hospitalized HFpEF (95% CI 1.03, 2.41) among high risk compared to low risk APOL1 carriers. In sensitivity analyses restricted to the genome-wide association sample and accounting for population stratification (n=7,797), the associations remained significant for HFpEF. These associations were no longer significant after adjusting for eGFR. Conclusions: We identified novel associations of APOL1 high risk status with hospitalization for HFpEF among postmenopausal women, which are likely mediated by APOL1 -induced chronic kidney disease. We also showed lack of association of APOL1 with incident coronary heart disease, stroke and mortality.

Eosinophilic esophagitis (EoE) requires a peak count of 15 eosinophils per high-power field (hpf). Herein, the peak eosinophil count specified by a pathologist was compared with the second review of a research assistant. Of 477 biopsies, 106 had a peak count between 1 and 14 eosinophils/hpf cited in the pathology report, and 23/106 (22%) had ≥15 eosinophils/hpf on second review. The pathology report detected potential EoE with 99% specificity, but 80% sensitivity. As such, an additional review of esophageal biopsies yields higher eosinophil counts in ∼5% of cases. We propose that biopsies with a count between 1 and 14 eosinophils/hpf require further investigation because ∼22% may yield a potential EoE diagnosis.

OBJECTIVES: We hypothesized that common variants in the collagen genes COL4A1/COL4A2 are associated with sporadic forms of cerebral small vessel disease. METHODS: We conducted meta-analyses of existing genotype data among individuals of European ancestry to determine associations of 1,070 common single nucleotide polymorphisms (SNPs) in the COL4A1/COL4A2 genomic region with the following: intracerebral hemorrhage and its subtypes (deep, lobar) (1,545 cases, 1,485 controls); ischemic stroke and its subtypes (cardioembolic, large vessel disease, lacunar) (12,389 cases, 62,004 controls); and white matter hyperintensities (2,733 individuals with ischemic stroke and 9,361 from population-based cohorts with brain MRI data). We calculated a statistical significance threshold that accounted for multiple testing and linkage disequilibrium between SNPs (p < 0.000084). RESULTS: Three intronic SNPs in COL4A2 were significantly associated with deep intracerebral hemorrhage (lead SNP odds ratio [OR] 1.29, 95% confidence interval [CI] 1.14-1.46, p = 0.00003; r(2) > 0.9 between SNPs). Although SNPs associated with deep intracerebral hemorrhage did not reach our significance threshold for association with lacunar ischemic stroke (lead SNP OR 1.10, 95% CI 1.03-1.18, p = 0.0073), and with white matter hyperintensity volume in symptomatic ischemic stroke patients (lead SNP OR 1.07, 95% CI 1.01-1.13, p = 0.016), the direction of association was the same. There was no convincing evidence of association with white matter hyperintensities in population-based studies or with non-small vessel disease cerebrovascular phenotypes. CONCLUSIONS: Our results indicate an association between common variation in the COL4A2 gene and symptomatic small vessel disease, particularly deep intracerebral hemorrhage. These findings merit replication studies, including in ethnic groups of non-European ancestry./n© 2015 American Academy of Neurology. Kristiina Rannikmäe is supported by the Edinburgh and Lothians Health Foundation REMIND Fund and Stroke Research and Amenities Endowments Fund; Cathie Sudlow is supported by the Scottish Funding Council; Gail Davies is supported by The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (MR/K026992/1), BBSRC and Medical Research Council (MSRC). Tom Van Agtmael is supported by the Kidney Research UK project grant RP19/2012. Details of funding for the studies contributing to the ICH GWAS can be found in: Woo D, Falcone GJ, Devan WJ, et al. Meta-analysis of genome-wide association studies identifies 1q22 as a novel susceptibility locus for intracerebral hemorrhage. American Journal of Human Genetics 2014;pii: S0002-9297(14)00070-6. doi:10.1016/j.ajhg.2014.02.012. [Epub ahead of print]. Details of funding for the studies contributing to the ischaemic stroke GWAS can be found in: Traylor M, Farrall M, Holliday EG, et al. Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration): a meta-analysis of genome-wide association studies. Lancet Neurology 2012;11:951-962. Details of funding for the studies contributing to the WMH in ischaemic stroke GWAS can be found in: Adib-Samii P, Rost N, Traylor M, et al. 17q25 Locus Is Associated With White Matter Hyperintensity Volume in Ischaemic Stroke, But Not With Lacunar Stroke Status. Stroke 2013;44:1609-1615. Details of funding for the studies contributing to the WMH in population GWAS can be found in: Fornage M, Debette S, Bis JC, et al. Genome-Wide Association Studies of Cerebral White Matter Lesion Burden: The CHARGE Consortium. Annals of Neurology 2011;69:928-939. Martin Dichgans is supported by the Fondation Leducq (Transatlantic Network of Excellence on the Pathogenesis of Small Vessel Disease of the Brain); Guido J Falcone is supported by the NIH / NINDS grant P50NS061343; Chistopher D Anderson is supported by the American Brain Foundation Clinical Research Training Fellowship, NIH-NINDS K23NS086873, Massachusetts General Hospital Institute for Heart, Vascular, and Stroke Care SPARK award; Jonathan Rosand is supported by the NIH / NINDS grant R01NS059727.

Rationale: Mutations of the orphan transporter ABCC6 (ATP-binding cassette, subfamily C, member 6) cause the connective tissue disorder pseudoxanthoma elasticum. ABCC6 was thought to be located on the plasma membrane of liver and kidney cells. Objective: Mouse systems genetics and bioinformatics suggested that ABCC6 deficiency affects mitochondrial gene expression. We therefore tested whether ABCC6 associates with mitochondria. Methods and Results: We found ABCC6 in crude mitochondrial fractions and subsequently pinpointed its localization to the purified mitochondria-associated membrane fraction. Cell-surface biotinylation in hepatocytes confirmed that ABCC6 is intracellular. Abcc6-knockout mice demonstrated mitochondrial abnormalities and decreased respiration reserve capacity. Conclusions: Our finding that ABCC6 localizes to the mitochondria-associated membrane has implications for its mechanism of action in normal and diseased states.

Background— Disruption of the elastic lamina, as an early indicator of aneurysm formation, and vascular calcification frequently occur together in atherosclerotic lesions of humans. Methods and Results— We now report evidence of shared genetic basis for disruption of the elastic lamina (medial disruption) and medial calcification in an F 2 mouse intercross between C57BL/6J and C3H/HeJ on a hyperlipidemic apolipoprotein E ( ApoE −/− ) null background. We identified 3 quantitative trait loci (QTLs) on chromosomes 6, 13, and 18, which are common to both traits, and 2 additional QTLs for medial calcification on chromosomes 3 and 7. Medial disruption, including severe disruptions leading to aneurysm formation, and medial calcification were highly correlated and occurred concomitantly in the cross. The chromosome 18 locus showed a striking male sex-specificity for both traits. To identify candidate genes, we integrated data from microarray analysis, genetic segregation, and clinical traits. The chromosome 7 locus contains the Abcc6 gene, known to mediate myocardial calcification. Using transgenic complementation, we show that Abcc6 also contributes to aortic medial calcification. Conclusions— Our data indicate that calcification, though possibly contributory, does not always lead to medial disruption and that in addition to aneurysm formation, medial disruption may be the precursor to calcification.

Background— The biochemical differences between the 2 mammalian cardiac myosin heavy chains (MHCs), α-MHC and β-MHC, are well described, but the physiological consequences of basal isoform expression and isoform shifts in response to altered cardiac load are not clearly understood. Mature human ventricle contains primarily the β-MHC isoform. However, the α-MHC isoform can be detected in healthy human ventricle and appears to be significantly downregulated in failing hearts. The unique biochemical properties of the α-MHC isoform might offer functional advantages in a failing heart that is expressing only the β-MHC isoform. This hypothesis cannot be tested in mice or rats because both species express α-MHC as the predominant isoform. Methods and Results— To test the effects of persistent α-MHC expression on the background of β-MHC, we made transgenic (TG) rabbits that expressed rabbit α-MHC cDNA in the ventricle so that the endogenous myosin was partially replaced by the transgenically encoded species. Molecular, histological, and functional analyses showed no significant baseline effects in the TG rabbits compared with nontransgenic (NTG) littermates. To determine whether α-MHC expression afforded any advantages to stressed myocardium, a cohort of TG and NTG rabbits was subjected to rapid ventricular pacing. Although both the TG and NTG rabbits developed dilated cardiomyopathy, the TG rabbits had a higher shortening fraction, less septal thinning, and more normal ±dP/dt than paced NTG rabbits. Conclusions— Transgenic expression of α-MHC does not have any apparent detrimental effects under basal conditions and is cardioprotective in experimental tachycardia-induced cardiomyopathy.

We investigated the correlation of high density lipoprotein (HDL) and low density lipoprotein (LDL) particle size distributions in samples from >1100 participants in the San Antonio Family Heart Study. By use of analyses of individual correlations of each HDL fraction with each LDL fraction, we devised new metrics for particle size phenotype, termed ΔHDL and ΔLDL, to optimally reflect the size correlations. Confirming previous studies, we found that the 2 size phenotype variables were positively correlated ( r =0.51). Quantitative genetic analysis indicated that nearly half (44%) of the variance in ΔHDL and in ΔLDL was explained by the additive effects of genes. Bivariate genetic analyses indicated that a positive genetic correlation (ρ G =0.56) exists between them and suggested that the pleiotropic effects of a gene or group of genes account for ≈31% [ie, ρ G 2 =(0.56) 2 =0.31] of the genetic variance in the 2 traits. Triglyceride (TG) levels were negatively related to ΔHDL and ΔLDL, with phenotypic correlations of −0.48 and −0.58, respectively, and genetic correlations of −0.45 and −0.76, respectively, suggesting that genes exert significant pleiotropic effects on the covariation of TGs with each of the size variables. Finally, we evaluated a bivariate model for ΔHDL and ΔLDL in which TG level was included as a covariate. This analysis indicated that a small but significant genetic correlation remains for ΔHDL and ΔLDL, even after accounting for the effects of TGs. Thus, our study demonstrates that the phenotypic correlation of HDL and LDL sizes results in part from the pleiotropic actions of a set of genes, some of which also influence TG levels and some of which do not.

Pediatric heart disease, aka cardiovascular disease in the young, comprises varied phenotypes, including cardiovascular malformations, cardiomyopathies, vasculopathies (eg, Marfan syndrome), and cardiac arrhythmias. Cardiovascular malformations are a major component of pediatric heart disease and constitute a substantial portion of clinically significant birth defects, with a definition-dependent estimated incidence of 4 to 50 per 1000 live births.1,2 Despite advances in diagnosis and therapy, the morbidity and mortality associated with cardiovascular malformations and other forms of pediatric heart disease make them important clinical problems. Thus, there has been considerable interest in understanding their cause. Article see p 1313 Because of early recognition of environmental teratogens such as rubella, thalidomide, and high altitude, considerable attention was focused on environmental factors; however, in the Baltimore-Washington Infant Study,3 common risk factors identified for pediatric heart disease were positive family history and maternal diabetes mellitus. Numerous examples of increased risk of pediatric heart disease in family members of affected individuals have been published.4 The association of cardiovascular malformations and other birth defects with chromosomal abnormalities5 provides further support for a genetic origin. Based on studies of recurrence and transmission risks, a hypothesis of multifactorial origin was proposed.6 In this type of inheritance, an individual’s genetic predisposition interacts with other genes and/or environmental factors to cause heart disease. However, in the past 2 decades, mendelian inheritance models have been used to exploit molecular genetic and cytogenetic observations in multiplex families.7 The discovery that heterozygous mutation of the transcription factor NKX2.5 causes …

Background —Transgenesis using cardiac-specific expression has been valuable in exploring cardiac structure-function relationships. To date, cardiac-selective studies have been confined to the mouse. However, the utility of the mouse is limited in certain, possibly critical, aspects with respect to cardiovascular function. Methods and Results —To establish the potential validity of transgenic methodology for remodeling a larger mammalian heart, we explored cardiac-selective expression in transgenic rabbits. The murine α- and β-cardiac myosin heavy chain gene promoters were used to express a reporter gene, and transgene expression was quantified in cardiac, skeletal, and smooth muscles as well as in nonmuscle tissues. Although neither promoter exactly mimics endogenous patterns of myosin heavy chain expression, both are able to drive high levels of transgene expression in the cardiac compartment. Neither promoter is active in smooth muscle or nonmuscle tissues. Conclusions —Directed organ-specific expression is feasible in a larger animal with existing reagents, and cardiac-selective transgenic manipulation is possible in the rabbit.

Context: Intracranial bleeding is the most feared complication of antithrombotic use. Antiplatelet and anticoagulant drugs increase risk of intracerebral hemorrhage (ICH), yet in some instances, combinations of antiplatelet agents and anticoagulants are used without firm evidence of efficacy. Few studies have compared the risks of different agents and their combinations in a single population. We determined the risk of ICH associated with the most commonly used antiplatelet and anticoagulant drugs and their combinations in a population-based case-control study. Methods: This report includes data from subjects recruited from the Greater Cincinnati/Northern Kentucky area by the Genetic and Environmental Risk Factors for Hemorrhagic Stroke Study from 1997 to 2009. We compared individuals in different treatment groups to identify any differences in baseline covariates that could be associated with treatment assignment. As there were a number of statistically significant differences, we used multivariate matching to analyze risk for ICH conferred by different antithrombotic agents. Treatment effects on ICH were estimated using the matched samples while accounting for the dependence between matched individuals. Results: There were 733 subjects with ICH and 2555 controls included in this study period. Results are shown in the table. Use of aspirin, clopidogrel, or their combination was associated with a trend toward increased risk. Warfarin increased risk compared with no antithrombotic use (OR 3.98, p < 0.0001). The combination of warfarin and either aspirin or clopidogrel produced the greatest risk, compared with no antithrombic therapy (OR 4.92 p Conclusions: The combination of warfarin and an antiplatelet drug significantly increases risk of ICH compared with no antithrombotic therapy or warfarin monotherapy. The use of combination therapy requires careful consideration in clinical practice.

Background: Apolipoprotein E (ApoE) genotypes have been associated with lobar intracerebral hemorrhage (ICH), and HMG-CoA Reductase Inhibitors (statins) were associated with risk of ICH in a secondary prevention trial. Yet, large meta-analyses of statin use have not consistently identified an increased risk of ICH with statin use. We evaluated whether ApoE genotypes were differentially associated with ICH risk according to statin use. Methods: The Genetic and Environmental Risk Factors for Hemorrhagic Stroke study is a prospective ICH study which recruits cases and controls from the same population. Study physicians adjudicated cases and determined ICH location. Subjects were classified as normocholesterolemia (NC), hypercholesterolemia without statin (HC-NS), and hypercholesterolemia with statin use (HC-S) based on chart review. Genotyping for ApoE ( rs429358 and rs7412) was performed using standard methods. Statistical comparisons were performed using Fisher’s exact test and Mantel-Haenszel tests for homogeneity. Results: From 1997-2008, the study recruited 597 cases of ICH and 1,548 controls. Of these, 26 cases/ 8 controls were excluded for unknown history of hypercholesterolemia, and 13 cases/ 96 controls were excluded for missing ApoE result. Of the 554 cases included, 204 were lobar in location. For non-lobar ICH cases, no significant differences were observed in ApoE genotype and statin use between NC, HC-NS and HC-S cases and controls. However, for lobar ICH, a marked increased risk of ICH was seen in HC-S patients with Apo E4/E4 (OR=4.5; 95% CI 1.3-16; p=0.02) and E2/E4 (OR=11.3; 95%CI 2.0-64; p=0.005), and there was a trend for Apo E2/E3 (OR=2.8; 95% CI 1.1-7.5, p=0.06) compared with Apo E3/E3. Apo E4/E4 did not demonstrate an increased odds of ICH without statin use (OR=1.6; 95% CI 0.27-9.4; p=0.63). The p-value for heterogeneity of odds ratios did not reach statistical significance between the HC-NS vs. HC-S group. Conclusion: Our data support a gene-by-drug effect for lobar ICH and, if confirmed, may indicate a utility for ApoE genotyping to identify patients who would bear the highest risk of ICH with statin use. However, further study is required to determine if an interaction exists or if the finding is associative.

Introduction: CV risk-factor (CVRF) related increase in arterial stiffness is associated with adverse CV events in adults. Cross-sectional studies in youth show a relationship between CVRF and arterial stiffness. Longitudinal data are lacking. Hypothesis: CVRFs will predict decreased brachial artery distensibility (BrachD). Methods: Demographics, anthropometrics, BP, fasting glucose, insulin, lipids and BrachD were measured in 425 healthy youth in a school-based longitudinal cohort (age 17.4 +2.1 yrs, 41% male, 61% Caucasian). Anthropometrics, BP and BrachD were repeated 2.1 + 0.3 years later. Mean values for baseline and follow-up variables were evaluated by paired t-test. Characteristics of subjects with decrease in BrachD (N=167) were compared by t-test with subjects without BrachD decrease. The multivariable model to determine predictors of follow-up BrachD contained baseline and change of age, sex, BMI, MAP, HR, baseline lipids, glucose and insulin. Results: Over 2 years, the cohort increased in HT, WT, BMI, SBP and BrachD (all p2 = 0.36, model p 2 ) or increased more in MAP (0.8 vs −1.3 mmHg) and HR (1.1 vs −2.0 beats/min, all p Conclusions: Development of obesity with subsequent changes in BP and HR may lead to development of arterial dysfunction. Prevention of obesity may be the most important approach to improve the CV health of adolescents and young adults.