Publications by authors named "Philip R Khoury"

100 Publications

Left Atrial Strain in the Repaired Tetralogy of Fallot Population: Comparisons to Biventricular Function, Native T1 Values, Exercise Parameters and Healthy Controls.

Pediatr Cardiol 2021 Mar 28. Epub 2021 Mar 28.

Heart Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, MLC 2003, Cincinnati, OH, 45229, USA.

Background: Non-invasive imaging markers in patients with repaired tetralogy of Fallot (rTOF) are still being investigated to inform clinical decision making. Atrial function is a prognostic indicator in many acquired and congenital heart diseases. We sought to examine the relationship between cardiac MRI (CMR)-derived indices of left atrial (LA) function, native left ventricular (LV) T1 values, biventricular systolic function, and exercise capacity in rTOF.

Methods: Sixty-six patients with rTOF without prior pulmonary valve replacement who underwent CMR (median age 18.5 years) were identified. Twenty-one adult rTOF patients (age range 19-32 years) were compared with 20 age-matched healthy volunteers (age range 19-34 years). LA reservoir, conduit, and pump global longitudinal strain (GLS) and strain rate (SR) were determined by tissue tracking. Native LV T1 values were measured on rTOF patients. Pearson correlations were performed to determine bivariate associations.

Results: Adult rTOF patients had higher pump GLS, pump:conduit, and pump:reservoir GLS ratios, and lower conduit:reservoir GLS ratio, LV ejection fraction (EF), and right ventricular EF compared to controls (p < 0.001 for each comparison). LA conduit:reservoir GLS and pump:reservoir GLS had correlations to native LV T1 (ρ = 0.26, p = 0.03 and ρ = - 0.26, p = 0.03, respectively). LA reservoir SR had positive correlation to RV EF (ρ = 0.27, p = 0.03). There were no statistically significant correlations between LA function and exercise capacity.

Conclusions: LA function is altered in adolescent and young adult patients with rTOF indicating worse diastolic function and relates to increasing native LV T1 values. Future studies are indicated to investigate the progression of adverse atrial-ventricular interactions and poor outcomes in this population.
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http://dx.doi.org/10.1007/s00246-021-02587-0DOI Listing
March 2021

Echocardiographic myocardial strain analysis describes subclinical cardiac dysfunction after craniospinal irradiation in pediatric and young adult patients with central nervous system tumors.

Cardiooncology 2021 Feb 2;7(1). Epub 2021 Feb 2.

Division of Cardiology, Department of Pediatrics, University of Cincinnati College of Medicine, and Heart Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, MLC 2003, Cincinnati, OH, 45229, USA.

Background: Craniospinal irradiation (CSI) is part of the treatment of central nervous system (CNS) tumors and is associated with cardiovascular disease in adults. Global myocardial strain analysis including longitudinal peak systolic strain (GLS), circumferential peak systolic strain (GCS), and radial peak systolic strain (GRS) can reveal subclinical cardiac dysfunction.

Methods: Retrospective, single-center study in patients managed with CSI vs. age-matched controls. Clinical data and echocardiography, including myocardial strain analysis, were collected at early (< 12 months) and late (≥ 12 months) time points after completion of CSI.

Results: Echocardiograms were available at 20 early and 34 late time points. Patients at the late time point were older (21.7 ± 10.4 vs. 13.3 ± 9.6 years) and further out from CSI (13.1 ± 8.8 vs. 0.2 ± 0.3 years). Standard echocardiographic parameters were normal for both groups. For early, CSI vs. control: GLS was - 16.8 ± 3.6% vs. -21.3 ± 4.0% (p = 0.0002), GCS was - 22.5 ± 5.2% vs. -21.3 ± 3.4% (p = 0.28), and GRS was 21.8 ± 11.0% vs. 26.9 ± 7.7% (p = 0.07). For late, CSI vs. control: GLS was - 16.2 ± 5.4% vs. -21.6 ± 3.7% (p < 0.0001), GCS was - 20.9 ± 6.8% vs. -21.9 ± 3.5% (p = 0.42), and GRS was 22.5 ± 10.0% vs. 27.3 ± 8.3% (p = 0.03). Radiation type (proton vs. photon), and radiation dose (< 30 Gy vs. ≥ 30 Gy) did not impact any parameter, although numbers were small.

Conclusions: Subclinical cardiac systolic dysfunction by GLS is present both early and late after CSI. These results argue for future studies to determine baseline cardiovascular status and the need for early initiation of longitudinal follow-up post CSI.
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http://dx.doi.org/10.1186/s40959-021-00093-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856804PMC
February 2021

Obese and Type 2 Diabetic Youth Have Increased Forward and Backward Wave Reflections.

Arterioscler Thromb Vasc Biol 2020 Dec 10:ATVBAHA120315317. Epub 2020 Dec 10.

Division of Cardiology, Cincinnati Children's Hospital Medical Center, OH. (A.H.T., P.R.K., E.M.U.).

Objective: Pulse wave analysis estimates arterial wave reflections relating to left ventricular dysfunction and cardiovascular event risk in adults. Forward and backward waves (Pf and Pb) may improve risk stratification for cardiovascular events. Data in youth are lacking. We hypothesized that a significant difference in wave reflections would be identified in young subjects with adverse cardiovascular risk factors. Approach and Results: Vital signs and labs were obtained in 551 patients aged 10 to 24 years who were lean (L=199), obese (O=173), or had type 2 diabetes (T=179). Wave separation was performed. Differences in cardiovascular risk factors and wave reflections were assessed using ANOVA. General linear models were constructed to elucidate independent predictors of wave reflections. O and T subjects had an adverse cardiovascular risk profile versus L. O and T subjects had higher Pf and Pb versus L (≤0.05). When adjusted for adiposity and other cardiovascular risk factors, reflection magnitude increased from L to O to T with higher T versus L values (≤0.05) and near-significant O versus L values (=0.06). Adiposity and blood pressure were major determinants of wave reflections. Pb influenced log left ventricular mass index, log E/e', and log composite carotid intima-media thickness.

Conclusions: Adolescents and young adults with obesity and type 2 diabetes have altered forward and backward wave reflections versus lean controls related to adiposity, BP, and insulin levels. These parameters may help risk stratify patients with adverse cardiovascular risk factors.
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http://dx.doi.org/10.1161/ATVBAHA.120.315317DOI Listing
December 2020

Progression of Vasculopathy in Young Individuals with Turner Syndrome.

Pediatr Cardiol 2021 Mar 26;42(3):481-491. Epub 2020 Nov 26.

Division of Endocrinology, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH, USA.

Vasculopathy has been identified in young individuals with Turner syndrome (TS). No studies in young individuals with TS have investigated whether this vasculopathy progresses over time. The objective of this study is to describe the changes in vasculopathy over time in a cohort of young individuals with TS. Repeat ultrasound and SphygmoCor CPV® (AtCor Medical) measurements of carotid thickness and peripheral arterial stiffness were performed. Vascular measurements were compared at baseline and follow-up. Follow-up measurements were also compared to historical lean (L) and obese (O) age-, race-, and sex-matched non-TS controls. Thirty-five individuals with TS were studied at a mean age of 19.4 years (range, 13.9-27.5). Mean time to follow-up was 7.2 years (range, 7.1-7.8). Carotid intima media thickness increased by 0.03 ± 0.07 mm (p < 0.01) over time, but was less than L and O controls at follow-up. Pulse wave velocity carotid-femoral increased by 0.51 ± 0.86 m/s (p < 0.01) over time, but was similar to L and less than O controls at follow-up. Augmentation index (AIx) remained unchanged (p = 0.09) over time, but was significantly higher at follow-up than both control groups (p < 0.01 for both). There were no identified differences between 45,X and other TS genotypes. We demonstrate evidence of vascular thickening and stiffening over 7 years in a cohort of young individuals with TS, as well as a persistently increased augmentation index compared to L and O non-TS controls. It is unclear whether the increase in vascular structure and function are related to normal aging or if TS is a risk factor. Higher body mass index seems to be a risk factor. Early estrogen replacement and longer exposure to growth hormone therapy need to be further explored as potential protective factors.
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http://dx.doi.org/10.1007/s00246-020-02505-wDOI Listing
March 2021

Dietary Approaches to Stop Hypertension Dietary Intervention Improves Blood Pressure and Vascular Health in Youth With Elevated Blood Pressure.

Hypertension 2021 Jan 16;77(1):241-251. Epub 2020 Nov 16.

Department of Pediatrics, Cincinnati Children's Hospital Medical Center (P.R.K., M. M. M., E.M.U.).

This randomized control trial assessed the post-intervention and 18-month follow-up effects of a 6-month dietary approaches to stop hypertension (DASH)-focused behavioral nutrition intervention, initiated in clinic with subsequent telephone and mail contact, on blood pressure (BP) and endothelial function in adolescents with elevated BP. Adolescents (n=159) 11 to 18 years of age with newly diagnosed elevated BP or stage 1 hypertension treated at a hospital-based clinic were randomized. DASH participants received a take-home manual plus 2 face-to-face counseling sessions at baseline and 3 months with a dietitian regarding the DASH diet, 6 monthly mailings, and 8 weekly and then 7 biweekly telephone calls focused on behavioral strategies to promote DASH adherence. Routine care participants received nutrition counseling with a dietitian consistent with pediatric guidelines established by the National High Blood Pressure Education Program. Outcomes, measured pre- and post-intervention and at 18-months follow-up, included change in BP, change in brachial artery flow-mediated dilation, and change in DASH score based on 3-day diet recalls. Adolescents in DASH versus routine care had a greater improvement in systolic BP (-2.7 mm Hg, = 0.03, -0.3 z-score, =0.03), flow-mediated dilation (2.5%, =0.05), and DASH score (13.3 points, <0.0001) from baseline to post-treatment and a greater improvement in flow-mediated dilation (3.1%, =0.03) and DASH score (7.4 points, =0.01) to 18 months. The DASH intervention proved more effective than routine care in initial systolic BP improvement and longer term improvement in endothelial function and diet quality in adolescents with elevated BP and hypertension. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00585832.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.16156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725858PMC
January 2021

Longitudinal Diet Quality Trajectories Suggest Targets for Diet Improvement in Early Childhood.

J Acad Nutr Diet 2020 Oct 24. Epub 2020 Oct 24.

Background: There is little information about how diet quality evolves in early childhood, whether children exhibit varying diet quality trajectories, or which components of diet quality should be targeted for intervention.

Objective: The goal of this study was to identify and evaluate trajectories of dietary quality in young children.

Design: This was a secondary analysis of an observational, longitudinal cohort study of non-Hispanic African American or White children and their parents from racially concordant households with 4 years of follow-up (up to 13 study visits). Data on mother, infant feeding, and body mass index were assessed at baseline. Diet was evaluated using 3-day diaries at each visit.

Participants/setting: Of 372 children enrolled, 349 children had at least 3 study visits with dietary data for this analysis. Participants were enrolled at age 3 years between March 2001 and August 2002 in Cincinnati, OH. Final study visits were conducted between February 2005 and June 2006.

Main Outcome Measure: The main outcome measure was the total Healthy Eating Index 2005 (HEI-2005) score and HEI-2005 component scores.

Statistical Analyses: Diet quality trajectories were modeled using group-based modeling techniques.

Results: The total HEI-2005 score was low at age 3 years (mean ± standard error = 55.1 ± 0.4 of maximum 100 points) and remained stable to age 7 years (mean ± standard error = 54.0 ± 0.6; P = 0.08 for trend). Five HEI-2005 trajectory groups were identified, of which 1 declined and 1 improved over time. HEI-2005 component scores, except milk intake and meat/beans scores, differed significantly (all, P ≤ 0.02) among trajectory groups at age 3 years, and most differences were maintained at age 7 years. Total vegetables, dark green and orange vegetables and legumes, and whole grains component scores were low for all trajectory groups. Whole fruit; total fruit; saturated fat; and calories from solid fats, alcoholic beverages, and added sugars (SoFAAS) were highly variable among trajectory groups. Children in the lowest diet quality trajectory group were less likely to be breastfed and more likely to have been regular consumers of soft drinks (e.g., powdered drink mixes, sport drinks, or soda pop) before age 3 years.

Conclusions: Young childhood diet quality was low at age 3 years and remained stable to age 7 years. Improving intake of vegetables and whole grains is needed for all children. Focused attention regarding increasing fruit intake and reducing SoFAAS may be needed for families at increased risk for low overall diet quality.
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http://dx.doi.org/10.1016/j.jand.2020.08.084DOI Listing
October 2020

Prevalence of ICU Delirium in Postoperative Pediatric Cardiac Surgery Patients.

Pediatr Crit Care Med 2021 Jan;22(1):68-78

University of California San Francisco, School of Nursing, San Francisco, CA.

Objectives: The objective of this study was to determine the prevalence of ICU delirium in children less than 18 years old that underwent cardiac surgery within the last 30 days. The secondary aim of the study was to identify risk factors associated with ICU delirium in postoperative pediatric cardiac surgical patients.

Design: A 1-day, multicenter point-prevalence study of delirium in pediatric postoperative cardiac surgery patients.

Setting: Twenty-seven pediatric cardiac and general critical care units caring for postoperative pediatric cardiac surgery patients in North America.

Patients: All children less than 18 years old hospitalized in the cardiac critical care units at 06:00 on a randomly selected, study day.

Interventions: Eligible children were screened for delirium using the Cornell Assessment of Pediatric Delirium by the study team in collaboration with the bedside nurse.

Measurement And Main Results: Overall, 181 patients were enrolled and 40% (n = 73) screened positive for delirium. There were no statistically significant differences in patient demographic information, severity of defect or surgical procedure, past medical history, or postoperative day between patients screening positive or negative for delirium. Our bivariate analysis found those patients screening positive had a longer duration of mechanical ventilation (12.8 vs 5.1 d; p = 0.02); required more vasoactive support (55% vs 26%; p = 0.0009); and had a higher number of invasive catheters (4 vs 3 catheters; p = 0.001). Delirium-positive patients received more total opioid exposure (1.80 vs 0.36 mg/kg/d of morphine equivalents; p < 0.001), did not have an ambulation or physical therapy schedule (p = 0.02), had not been out of bed in the previous 24 hours (p < 0.0002), and parents were not at the bedside at time of data collection (p = 0.008). In the mixed-effects logistic regression analysis of modifiable risk factors, the following variables were associated with a positive delirium screen: 1) pain score, per point increase (odds ratio, 1.3; 1.06-1.60); 2) total opioid exposure, per mg/kg/d increase (odds ratio, 1.35; 1.06-1.73); 3) SBS less than 0 (odds ratio, 4.01; 1.21-13.27); 4) pain medication or sedative administered in the previous 4 hours (odds ratio, 3.49; 1.32-9.28); 5) no progressive physical therapy or ambulation schedule in their medical record (odds ratio, 4.40; 1.41-13.68); and 6) parents not at bedside at time of data collection (odds ratio, 2.31; 1.01-5.31).

Conclusions: We found delirium to be a common problem after cardiac surgery with several important modifiable risk factors.
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http://dx.doi.org/10.1097/PCC.0000000000002591DOI Listing
January 2021

Left atrial strain and diastolic function abnormalities in obese and type 2 diabetic adolescents and young adults.

Cardiovasc Diabetol 2020 10 1;19(1):163. Epub 2020 Oct 1.

The Heart Institute, Cincinnati Children's Hospital Medical Center and the Department of Pediatrics, University of Cincinnati, Cincinnati, USA.

Background: Adults with obesity and type 2 diabetes mellitus (T2DM) related to obesity are at increased risk of heart failure with preserved ejection fraction (HFpEF). Whether left ventricular (LV) diastolic function abnormalities related to obesity and T2DM start in adolescence and early adulthood is unknown. We non-invasively evaluated the differences seen in LV diastolic and left atrial (LA) function in adolescents and young adults with obesity and T2DM.

Methods: We analyzed echocardiographic measures of LV diastolic function in patients with structurally normal hearts which were divided into 3 groups (normal weight, obese, and T2DM). Spectral and tissue Doppler and 2-D speckle tracking measurements of diastolic function were obtained. Logistic regression was performed to compare the prevalence of abnormalities in diastolic function based on the worst 25th percentile for each measure to determine the prevalence of diastolic and LA function abnormalities in obese and T2DM patients.

Results: 331 teenagers and young adults (median age 22.1 years) were analyzed (101 normal weight, 114 obese, 116 T2DM). Obese and T2DM group had lower E/A and higher E/e'. Obese and T2DM patients had significantly lower atrial reservoir, conduit, and booster strain and worse reservoir and conduit strain rate compared to normal patients (p < 0.001 for all measures). All patients had normal LA volumes. On multivariable analysis, conduit strain and reservoir and conduit strain rate were independently associated with having below the 25th percentile e'. Conduit strain rate was independently associated with having below the 25th percentile for mitral E/A ratio on multivariable analysis.

Conclusions: Abnormal indices of LV diastolic function are detected in adolescents and young adults with obesity and T2DM. LA function and strain analysis were able to detect evidence of decreased reservoir, conduit, and booster strain in these patients although LA volume was normal. The use of LA function strain may increase our ability to detect early diastolic function abnormalities in this population.
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http://dx.doi.org/10.1186/s12933-020-01139-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7531140PMC
October 2020

Variations in native T1 values in patients with Duchenne muscular dystrophy with and without late gadolinium enhancement.

Int J Cardiovasc Imaging 2021 Feb 20;37(2):635-642. Epub 2020 Sep 20.

Heart Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 2003, Cincinnati, OH, 45229, USA.

Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder leading to progressive skeletal and cardiac myopathy. Elevated myocardial T1 values correlate with fibrosis in most disease processes, but DMD skeletal and cardiac histopathology is defined by fibrofatty replacement that may result in a decrease in T1 values, due to the low T1 of fat. The study goal was to assess myocardial T1 values in DMD patients with and without late gadolinium enhancement (LGE). A retrospective analysis was performed on all patients with DMD referred for CMR at our institution from 7/5/2017 to 10/24/2018. T1 measurements were performed using breath-held modified Look Locker inversion recovery (MOLLI) sequences at the basal and mid-ventricular levels. The cohort was separated into patients without the presence of LGE (LGE-) and patients with current or previous LGE (LGE+). A total of 207 CMR studies were analyzed. The LGE- group comprised 88 patients while 119 patients were in the LGE+ group. The LGE+ group was older, had larger indexed LV end-diastolic volume and lower LV ejection fraction (LVEF) compared to the LGE- group. T1 values in the LGE+ group were lower compared to the LGE- group (mid T1 1012 ms vs. 1035 ms; p = 0.002), with 5 CMR studies demonstrating mid T1 values < 900 ms. There was no correlation between mid T1 and LVEF in the LGE- group. In the LGE+ cohort, lower T1 values correlated with worse LVEF (r = 0.34, p = 0.0002). The association between mid T1 values and LVEF remained statistically significant on multivariable analysis when accounting for number of LGE segments, LVEDVi, and age (p = 0.009). This is the largest study assessing native T1 values in patients with DMD. The results demonstrate that patients with LGE had lower T1 values than patients without LGE. In the LGE+ group, lower T1 values correlated with worse LV systolic function. These results are consistent with the evolving recognition of fibrofatty replacement in advanced stages of DMD myopathy. Furthermore, our study supports that there is not a simple linear relationship between increasing T1 values and advancing disease progression reported in most other cardiomyopathies.
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http://dx.doi.org/10.1007/s10554-020-02031-zDOI Listing
February 2021

Bone Mass and Density in Youth With Type 2 Diabetes, Obesity, and Healthy Weight.

Diabetes Care 2020 10 10;43(10):2544-2552. Epub 2020 Aug 10.

Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA

Objective: Youth-onset type 2 diabetes is an aggressive condition with increasing incidence. Adults with type 2 diabetes have increased fracture risk despite normal areal bone mineral density (aBMD), but the influence of diabetes on the growing skeleton is unknown. We compared bone health in youth with type 2 diabetes to control patients with obesity or healthy weight.

Research Design And Methods: Cross-sectional study of youth (56% African American, 67% female) ages 10-23 years with type 2 diabetes ( = 180), obesity (BMI >95th; = 226), or healthy weight (BMI <85th; = 238). Whole-body (less head) aBMD and lean mass as well as abdominal visceral fat were assessed via DXA. Lean BMI (LBMI) and aBMD SD scores ( scores) were computed using published reference data.

Results: We observed age-dependent differences in aBMD and LBMI scores between the healthy weight, obese, and type 2 diabetes groups. In children, aBMD and LBMI scores were greater in the type 2 diabetes group versus the obese group, but in adolescents and young adults, aBMD and LBMI scores were lower in the type 2 diabetes group versus the obese group (age interactions < 0.05). In the type 2 diabetes group and the obese group, aBMD was about 0.5 SDs lower for a given LBMI score compared with healthy weight control patients ( < 0.05). Further, aBMD was lower in those with greater visceral fat (β = -0.121, = 0.047).

Conclusions: These results suggest that type 2 diabetes may be detrimental to bone density around the age of peak bone mass. Given the increased fracture risk in adults with type 2 diabetes, there is a pressing need for longitudinal studies aimed at understanding the influence of diabetes on the growing skeleton.
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http://dx.doi.org/10.2337/dc19-2164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510020PMC
October 2020

Markers of cholesterol synthesis are elevated in adolescents and young adults with type 2 diabetes.

Pediatr Diabetes 2020 11 15;21(7):1126-1131. Epub 2020 Sep 15.

Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Background: Changes in cholesterol absorption and cholesterol synthesis may promote dyslipidemia and cardiovascular disease in individuals with type 2 diabetes mellitus (T2DM).

Objective: To assess cholesterol synthesis and absorption in lean individuals, obese individuals, and individuals with T2DM.

Methods: We measured lathosterol and lanosterol (markers of cholesterol synthesis) as well as campesterol and β-sitosterol (markers of cholesterol absorption) in the serum of 15 to 26 years old individuals with T2DM (n = 95), as well as their lean (n = 98) and obese (n = 92) controls.

Results: Individuals with T2DM showed a 51% increase in lathosterol and a 65% increase in lanosterol compared to lean controls. Similarly, obese individuals showed a 31% increase in lathosterol compared to lean controls. Lathosterol and lanosterol were positively correlated with body mass index, fasting insulin and glucose, serum triglycerides, and C-reactive protein, and negatively correlated with HDL-cholesterol. In contrast, campesterol and β-sitosterol were not altered in individuals with T2DM. Moreover, campesterol and β-sitosterol were negatively correlated with body mass index, fasting insulin, and C-reactive protein and were positively correlated with HDL-cholesterol.

Conclusions: Adolescents and young adults with T2DM show evidence of increased cholesterol synthesis compared to non-diabetic lean controls. These findings suggest that T2DM may promote cardiovascular disease by increasing cholesterol synthesis, and provide additional rationale for the use of cholesterol synthesis inhibitors in this group.
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http://dx.doi.org/10.1111/pedi.13097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855867PMC
November 2020

Protein QTL analysis of IGF-I and its binding proteins provides insights into growth biology.

Hum Mol Genet 2020 Aug;29(15):2625-2636

Division of Endocrinology, Children's National Hospital, Washington, DC 20010, USA.

The growth hormone and insulin-like growth factor (IGF) system is integral to human growth. Genome-wide association studies (GWAS) have identified variants associated with height and located near the genes in this pathway. However, mechanisms underlying these genetic associations are not understood. To investigate the regulation of the genes in this pathway and mechanisms by which regulation could affect growth, we performed GWAS of measured serum protein levels of IGF-I, IGF binding protein-3 (IGFBP-3), pregnancy-associated plasma protein A (PAPP-A2), IGF-II and IGFBP-5 in 838 children (3-18 years) from the Cincinnati Genomic Control Cohort. We identified variants associated with protein levels near IGFBP3 and IGFBP5 genes, which contain multiple signals of association with height and other skeletal growth phenotypes. Surprisingly, variants that associate with protein levels at these two loci do not colocalize with height associations, confirmed through conditional analysis. Rather, the IGFBP3 signal (associated with total IGFBP-3 and IGF-II levels) colocalizes with an association with sitting height ratio (SHR); the IGFBP5 signal (associated with IGFBP-5 levels) colocalizes with birth weight. Indeed, height-associated single nucleotide polymorphisms near genes encoding other proteins in this pathway are not associated with serum levels, possibly excluding PAPP-A2. Mendelian randomization supports a stronger causal relationship of measured serum levels with SHR (for IGFBP-3) and birth weight (for IGFBP-5) than with height. In conclusion, we begin to characterize the genetic regulation of serum levels of IGF-related proteins in childhood. Furthermore, our data strongly suggest the existence of growth-regulating mechanisms acting through IGF-related genes in ways that are not reflected in measured serum levels of the corresponding proteins.
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http://dx.doi.org/10.1093/hmg/ddaa103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471503PMC
August 2020

Accelerated Early Vascular Aging Among Adolescents With Obesity and/or Type 2 Diabetes Mellitus.

J Am Heart Assoc 2020 05 6;9(10):e014891. Epub 2020 May 6.

Cincinnati Children's Hospital Medical Center University of Cincinnati OH.

Background The normal rate of subclinical vascular aging from adolescence to young adulthood has not been well-characterized. We conducted a 5-year longitudinal study among adolescents with normal-weight, obesity, and/or type 2 diabetes mellitus to examine trajectories of early vascular aging. Methods and Results Adolescents (mean [SD] age 17.6 [3.5]; 35.3% male) had either normal weight (n=141), obesity (n=156), or type 2 diabetes mellitus (n=151) at baseline. Primary metrics used for early vascular aging included measures of vascular structure (carotid intima-media thickness [cIMT]; common, internal, and bulb) and arterial stiffness (carotid-femoral pulse wave velocity, and augmentation index). Longitudinal (5-year) outcomes were examined using generalized estimating equations adjusting for baseline value, sex, race, and age. Compared with participants with normal weight, those with obesity had greater positive change in common cIMT (0.05 mm [0.03, 0.06]; <0.001), bulb cIMT (0.02 mm [0.00, 0.05]; =0.033), internal cIMT (0.03 mm [0.01, 0.05]; <0.001), and pulse wave velocity carotid-femoral (0.38 m/sec [0.14, 0.61]; =0.001), and those with type 2 diabetes mellitus had greater positive change in common cIMT (0.05 mm [0.04, 0.07]; <0.001), bulb cIMT (0.06 mm [0.04, 0.09]; <0.001), internal cIMT (0.04 mm [0.02, 0.07]; <0.001), augmentation index (4.67% [2.20, 7.13]; <0.001), and pulse wave velocity carotid-femoral (0.74 m/sec [0.46, 1.02]; <0.001). Higher baseline systolic blood pressure was associated with greater positive change in common cIMT (0.007 mm [0.003, 0.011]; <0.001), bulb cIMT (0.009 mm [0.002, 0.016]; =0.01), internal cIMT (0.008 mm [0.003, 0.013]; =0.001), and pulse wave velocity carotid-femoral (0.066 m/sec [0.002, 0.130]; =0.042). Conclusions These longitudinal data support the hypothesis that the presence of obesity, type 2 diabetes mellitus, and elevated baseline systolic blood pressure in early life accelerates the progression of risk factors key in the development of early vascular aging.
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http://dx.doi.org/10.1161/JAHA.119.014891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660865PMC
May 2020

Pulmonary venous Doppler patterns and midterm outcomes in fetuses with left-sided obstructive lesions and restrictive atrial septum.

Prenat Diagn 2020 06 2;40(7):776-784. Epub 2020 Apr 2.

The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

Objective: To compare length of stay of the initial neonatal hospitalization and mortality across multiple stages of surgical palliation for infants with left-sided obstructive lesions and severely restrictive or intact atrial septum (I/RAS).

Methods: Retrospective cohort study of patients prenatally diagnosed with left-sided obstructive lesions and I/RAS, defined by fetal pulmonary venous Dopplers.

Results: We identified 76 fetal patients with 59 live born intending to pursue intervention. Those with I/RAS had longer durations of mechanical ventilation (P = .031) but no difference in intensive care unit or total length of stay. Survival to discharge from neonatal hospitalization was 41.7% in the I/RAS group and 80.7% in the unrestrictive group (P = .001). There was a higher proportion of deaths between stage 1 and stage 2 in the I/RAS group - 5/9 (55.6%) vs 9/50 (18%) in the unrestrictive group (P = .027). Beyond stage 2 palliation there was trend toward a difference in overall mortality (66.7% in I/RAS vs 35.7% in unrestrictive, P = .05) but no statistically significant difference in transplant-free survival (33.3% in I/RAS vs 53.5% in unrestrictive, P = .11).

Conclusion: The survival disadvantage conferred by prenatally diagnosed severe atrial septal restriction is most pronounced in the neonatal and early infancy period, with no detectable difference in late midterm transplant-free survival in our cohort.
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http://dx.doi.org/10.1002/pd.5682DOI Listing
June 2020

Anthropometric and biochemical correlates of PAPP-A2, free IGF-I, and IGFBP-3 in childhood.

Eur J Endocrinol 2020 Mar;182(3):363-374

Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

Objective: Pregnancy-associated plasma protein-A2 (PAPP-A2) is a metalloproteinase that cleaves IGFBP-3 and IGFBP-5. Human mutations in PAPPA2 result in short stature with a low percentage of free IGF-I. Little is known about PAPP-A2 levels and the regulation of free IGF-I throughout childhood. We examined PAPP-A2 and intact IGFBP-3 levels in childhood and explored associations between PAPP-A2, free and total IGF-I, and total and intact IGFBP-3 and their relationship to the percentage of free to total IGF-I and anthropometric factors.

Design: Cross-sectional study at a single center.

Methods: PAPP-A2, free IGF-I, and intact IGFBP-3 levels were measured in childhood (3-18 years old) and an evaluation of the relationship between these proteins and anthropometric factors.

Results: In 838 children, PAPP-A2 consistently decreased throughout childhood. In contrast, free IGF-I increased. A pubertal peak in free IGF-I was present in females but was less evident in males. Intact and total IGFBP-3 increased throughout childhood; however, intact IGFBP-3 had a more marked rise than total IGFBP-3. Percent free IGF-I decreased with no distinct pubertal peak. PAPP-A2 levels positively correlated with the percent free IGF-I (Male, Female; r = 0.18, 0.38; P < 0.001) and negatively with intact IGFBP-3 (Male, Female; r = -0.58, -0.65; P < 0.0001).

Conclusions: This is the first study to describe serum PAPP-A2 and intact IGFBP-3 in children between 3 and 18 years of age. Our correlative findings suggest that PAPP-A2 is an important regulator of the percent free IGF-I which can be a marker of perturbations in the GH/IGF-I axis.
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http://dx.doi.org/10.1530/EJE-19-0859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238294PMC
March 2020

Investigation of de novo variation in pediatric cardiomyopathy.

Am J Med Genet C Semin Med Genet 2020 03 8;184(1):116-123. Epub 2020 Jan 8.

The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

Pediatric cardiomyopathies can be caused by variants in genes encoding the sarcomere and cytoskeleton in cardiomyocytes. Variants are typically inherited in an autosomal dominant manner with variable expressivity. De novo variants have been reported, however their overall frequency is largely unknown. We sought to determine the rate of de novo, pathogenic and likely pathogenic (P/LP) variants in children with a diagnosis of hypertrophic, dilated, or restrictive cardiomyopathy (HCM, DCM, or RCM), and to compare disease outcomes between individuals with and without a de novo variant. A retrospective record review identified 126 individuals with HCM (55%), DCM (37%), or RCM (8%) ≤18 years of age who had genetic testing. Overall, 50 (40%) had positive genetic testing and 18% of P/LP variants occurred de novo. The rate of de novo variation in those with RCM (80%) was higher than in those with HCM (9%) or DCM (20%). There was evidence of germline mosaicism in one family with RCM. Individuals with de novo variants were more likely than those without to have a history of arrhythmia (p = .049), sudden cardiac arrest (p = .024), hospitalization (p = .041), and cardiac transplantation (p = .030). The likelihood of de novo variation and impact on family risk and screening should be integrated into genetic counseling.
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http://dx.doi.org/10.1002/ajmg.c.31764DOI Listing
March 2020

Type 1 diabetes is associated with an increase in cholesterol absorption markers but a decrease in cholesterol synthesis markers in a young adult population.

J Clin Lipidol 2019 Nov - Dec;13(6):940-946. Epub 2019 Sep 25.

Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address:

Background: To optimize treatment and prevent cardiovascular disease in subjects with type 1 diabetes, it is important to determine how cholesterol metabolism changes with type 1 diabetes.

Objective: The objective of the study was to compare plasma levels of campesterol and β-sitosterol, markers of cholesterol absorption, as well as lathosterol, a marker of cholesterol synthesis, in youth with and without type 1 diabetes.

Methods: Serum samples were obtained from adolescent subjects with type 1 diabetes (n = 175, mean age 15.2 years, mean duration of diabetes 8.2 years) and without diabetes (n = 74, mean age 15.4 years). Campesterol, β-sitosterol, and lathosterol, were measured using targeted liquid chromatography tandem mass spectrometry, compared between groups, and correlated with the available cardiometabolic variables.

Results: Campesterol and β-sitosterol levels were 30% higher in subjects with type 1 diabetes and positively correlated with hemoglobin A1c levels. In contrast, lathosterol levels were 20% lower in subjects with type 1 diabetes and positively correlated with triglycerides, body mass index, and systolic blood pressure.

Conclusion: Plasma markers suggest that cholesterol absorption is increased, whereas cholesterol synthesis is decreased in adolescent subjects with type 1 diabetes. Further studies to address the impact of these changes on the relative efficacy of cholesterol absorption and synthesis inhibitors in subjects with type 1 diabetes are urgently needed.
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http://dx.doi.org/10.1016/j.jacl.2019.09.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980756PMC
July 2020

Long-Term Burden of Increased Body Mass Index from Childhood on Adult Dyslipidemia: The i3C Consortium Study.

J Clin Med 2019 Oct 18;8(10). Epub 2019 Oct 18.

Department of Epidemiology, School of Public Health & Tropical Medicine, Tulane University, New Orleans, LA 70112, USA.

Data are limited regarding the association of cumulative burden and trajectory of body mass index (BMI) from early life with adult lipid disorders. The study cohort consisted of 5195 adults who had BMI repeatedly measured 4 to 21 times from childhood and had blood lipid measurements of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) and information on lipid-lowering medications in the last adult survey. The area under the curve (AUC) was calculated as a measure of long-term burden (total AUC) and trends (incremental AUC) of BMI. Participants with dyslipidemia, high LDL-C, low HDL-C and high TG had consistently and significantly higher BMI levels from childhood to adulthood compared to those with normal lipid levels. After adjusting for age, race, sex, and cohort, increased risk of adult dyslipidemia was significantly associated with higher values of childhood BMI, adulthood BMI, total AUC and incremental AUC, with odds ratio (95% confidence interval) = 1.22 (1.15-1.29), 1.85 (1.74-1.97), 1.61 (1.52-1.71), and 1.59 (1.50-1.69), respectively, and < 0.001 for all. The association patterns were similar in most race-sex subgroups. Adults with dyslipidemia versus normal lipid levels have consistently higher levels and distinct life-course trajectories of BMI, suggesting that the impact of excessive body weight on dyslipidemia originates in early life.
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http://dx.doi.org/10.3390/jcm8101725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832308PMC
October 2019

Comparison of Left Ventricular Mass Calculation Methods via Two-Dimensional Echocardiogram in Children, Adolescents, and Young Adults With Systemic Hypertension.

Am J Cardiol 2019 07 23;124(2):239-244. Epub 2019 Apr 23.

Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.

Left ventricular (LV) mass is a major determining tool for myocardial injury in hypertensive patients. Issues with LV mass calculations exist given that there are multiple methods to assess mass, including from the parasternal long axis (PLA), parasternal short axis (PSA), and 2-dimensional (2D) volumetric methods. The aim of this study was to compare the agreement of LV mass calculations using the PLA, PSA, and 2D volumetric methods. This study retrospectively reviewed 200 consecutive, initial echocardiograms for the indication of hypertension. A single reader calculated the LV mass in each patient via the PLA, PSA, and 2D volumetric methods. Percent differences for each study were calculated. LV mass threshold cutoffs of 51 g/m (cardiac organ injury) and 38.6 g/m (elevated LV mass) were used to compare categorical differences between the different measurement methods. Paired comparisons demonstrated an absolute mean percent difference of 8.46% to 9.41% among the different methods. LV mass calculated by the 2D volumetric method was less compared with PLA and PSA methods (31.64 vs 33.90 vs 35.51 g/m; p < 0.0001). Fewer patients were classified as having cardiac target organ injury or elevated LV mass via 2D volumetric calculation, compared with PLA and PSA methods (p = 0.02 and p = 0.03, respectively). In conclusion, there is a small but important difference in LV mass calculations for patients with hypertension. These results emphasize the need for consistency within echocardiography laboratories as surveillance studies are common in this patient population.
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http://dx.doi.org/10.1016/j.amjcard.2019.04.023DOI Listing
July 2019

Relation of Blood Pressure in Childhood to Self-Reported Hypertension in Adulthood.

Hypertension 2019 06;73(6):1224-1230

Division of Nephrology (A.S.), University of Minnesota Medical School, Minneapolis.

Blood pressure (BP) tracking (maintaining a BP percentile) across life is not well defined but is important in predicting which children will become hypertensive adults. We computed BP tracking in subjects with BP measured in childhood and adulthood and performed logistic regression to determine the ability of childhood BP to predict adult hypertension (N=5035, 46.7 years, 74.2% white, 17.7% black; 39.6% male). Prevalence of hypertension was 29%. Correlations between systolic BP for child and adolescent were r=0.48; for adolescent and young adult were r=0.40, and for child and young adult were r=0.24 (all P<0.0001). Participants self-reporting adult hypertension were less likely to be white (38.7% black, 27.6% white, 20.9% other; P<0.0001) and female (26.4% females, 32.9% male, P<0.0001). Participants with adult hypertension were more likely to have higher BP and adiposity by age 10 years and abnormal lipids and glucose by age 16 years. There was a graded increase in the frequency of self-reported adult hypertension across the BP change groups, even within the persistently normotensive group (X<0.0001) from 19% in children with a systolic BP% persistently below the median to 80% for individuals with elevated BP in both childhood and adolescence. Although our precision to predict which individual child is at risk of adult BP-related cardiovascular disease is weak, an increase in systolic BP and body mass index percentile from childhood to adolescence should signal a need for lifestyle intervention to prevent future sustained hypertension-related cardiovascular disease.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.118.12334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6510248PMC
June 2019

Left ventricular outflow tract obstruction: Uptake of familial cardiac screening and parental knowledge from a single tertiary care center.

J Genet Couns 2019 08 25;28(4):779-789. Epub 2019 Mar 25.

Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

Left ventricular outflow tract obstruction (LVOTO) malformations exhibit higher heritability than other cardiac lesions and cardiac screening is encouraged for first-degree relatives. This study sought to determine the uptake of familial cardiac screening in families with an infant with an LVOTO and assess parental knowledge regarding genetics and heritability of LVOTO. A chart review of the period 2010-2015 identified 69 families who received genetic counseling regarding a diagnosis of LVOTO in an infant. Surveys assessing familial cardiac screening and parental knowledge were completed by a parent in 24 families (completion rate of 35%). Forty percent (36/89) of all at-risk first-degree family members completed cardiac screening. The presence of additional congenital malformations in the affected infant was the only significant factor reducing the uptake of familial cardiac screening (p = 0.003). The reported uptake of screening for subsequent at-risk pregnancies was 11/12 (92%) compared to 25/77 (32%) of living at-risk relatives. Survey respondents answered seven knowledge questions with an average score of 5.2 and all correctly identified that LVOTO can run in families. Uptake of familial cardiac screening is occurring in less than half of at-risk individuals, despite parents demonstrating basic knowledge and receiving genetic counseling. Follow-up counseling in the outpatient setting to review familial screening recommendations should be considered to increase uptake and optimize outcomes.
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http://dx.doi.org/10.1002/jgc4.1117DOI Listing
August 2019

Ventricular force-frequency relationships during biventricular or multisite pacing in congenital heart disease.

Congenit Heart Dis 2019 Mar 15;14(2):201-206. Epub 2018 Oct 15.

The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

Background: Traditional indices to evaluate biventricular (BiV) pacing are load dependent, fail to assess dynamic changes, and may not be appropriate in patients with congenital heart disease (CHD). We therefore measured the force-frequency relationship (FFR) using tissue Doppler-derived isovolumic acceleration (IVA) to assess the dynamic adaption of the myocardium and its variability with different ventricular pacing strategies.

Methods: This was a prospective pilot study of pediatric and young adult CHD patients with biventricular or multisite pacing systems. Color-coded myocardial velocities were recorded at the base of the systemic ventricular free wall. IVA was calculated at resting heart rate and with incremental pacing. FFR curves were obtained by plotting IVA against heart rate for different ventricular pacing strategies.

Results: Ten patients were included (mean: 22 ± 7 years). The FFR identified a best and worst ventricular pacing strategy for each patient, based on the AUC at baseline, submaximal, and peak heart rates (P < .001). However, there was no single best ventricular pacing strategy that was optimal for all patients. Additionally, the best ventricular pacing strategy often differed within the same patient at different heart rates.

Conclusion: This novel assessment demonstrates a wide variability in optimal ventricular pacing strategy. These inherent differences may play a role in the unpredictable clinical response to BiV pacing in CHD, and emphasizes an individualized approach. Furthermore, the optimal ventricular pacing varies with heart rate within individuals, suggesting that rate-responsive ventricular pacing modulation may be required to optimize ventricular performance.
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http://dx.doi.org/10.1111/chd.12684DOI Listing
March 2019

Comparison of Native T1, Strain, and Traditional Measures of Cardiovascular Structure and Function by Cardiac Magnetic Resonance Imaging in Patients With Anderson-Fabry Disease.

Am J Cardiol 2018 09 22;122(6):1074-1078. Epub 2018 Jun 22.

Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. Electronic address:

Cardiovascular magnetic resonance imaging (CMR) has emerged as a powerful tool to illuminate cardiovascular pathology in Anderson-Fabry disease (AFD); however, further study is required to develop clinically useful monitoring paradigms. The objective of this study was to retrospectively evaluate strain, native septal T1 values, and standard CMR measurements in a cohort of AFD patients to characterize useful measures of cardiovascular dysfunction that may be derived from a CMR platform. Eighteen patients were identified (n = 8 males) and divided according to presence or absence of left ventricular hypertrophy (LVH). Biometric data were gathered and native T1 and strain values were measured for all patients. Patients with LVH were older and had significantly lower native T1 measured at the apical septal (893 ± 78 vs 1044 ± 217 ms, p = 0.035), midventricular septal (864 ± 76 vs 988 ± 67 ms, p = 0.016), and basal septal (867 ± 58 vs 1027 ± 84 ms, p = 0.006) regions. Circumferential strain was more positive in patients with LVH (-13.5% ± 5.0% vs -18.7% ± 2.7%, p = 0.042), but longitudinal strain was not significantly different between groups. Patients with LVH had higher stroke volumes (114.5 ± 9.7 vs 96.7 ± 17.8 ml, p = 0.050), but other standard CMR measures were not significantly different. In conclusion, AFD patients with LVH have reduced native T1 and more positive circumferential strain compared to those without. The basal septum may be an appropriate region for standard measure of native T1 in this population.
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http://dx.doi.org/10.1016/j.amjcard.2018.06.007DOI Listing
September 2018

Characteristics of hospital admissions associated with implantable cardioverter defibrillator placement among adults with congenital heart disease.

Int J Cardiol 2018 Oct 24;269:97-103. Epub 2018 Jul 24.

Division of Cardiology, University of Texas Southwestern Medical School, Dallas, TX, USA.

Background: Characteristics of hospitalizations including healthcare utilization for adult patients with congenital heart disease (ACHD) at the time of implantable cardioverter defibrillator (ICD) placement has not been well studied.

Methods: We analyzed data from the 2002-2014 United States National Inpatient Sample (NIS). ICD implantation, CHD, complications, and indications for admissions were determined based on diagnostic codes among adults. Propensity score matching was performed, based on age, sex and in-hospital mortality index with a 10:1 ratio between adults without CHD and those with CHD, to determine relative healthcare utilization attributable to CHD.

Results: ACHD accounted for 136,509 ± 3488 admissions of which 1451 ± 121 admissions (1.1 ± 0.06%) were associated with an ICD placement. ICD placement occurred most frequently among patients with TOF, VSD, and transposition complexes usually in the context of a dysrhythmia. Compared to those without CHD, ACHD patients had higher adjusted total hospital charges ($147,002 ± 5516 vs $132,455 ± 2182; p < 0.001), length of stay (6.2 ± 0.5 vs 5.2 ± 0.1 days; p < 0.001), lower readmission score (5.5 ± 0.5 vs 9.7 ± 0.1; p = 0.04) and a higher complication rate (13.4% vs 8.3%; p < 0.001). Dysrhythmias were more frequently the primary diagnosis for admission in the ACHD cohort (63% vs 38%; p < 0.001).

Conclusion: Compared to a matched non-CHD population, ACHD patients had greater healthcare utilization and had more frequent complications. The reasons underlying this difference bear investigation to improve care quality.
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http://dx.doi.org/10.1016/j.ijcard.2018.07.085DOI Listing
October 2018

Clinical Implications of the Revised AAP Pediatric Hypertension Guidelines.

Pediatrics 2018 08 5;142(2). Epub 2018 Jul 5.

Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio

Background And Objectives: New pediatric hypertension definitions were recently published in a clinical practice guideline (CPG). We evaluated the impact of the CPG, compared with the previous guideline ("Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents"), on the prevalence of hypertension and associations with target organ damage (TOD) in high-risk youth.

Methods: Participants (10-18 years old) undergoing an evaluation of the cardiovascular effects of obesity and type 2 diabetes mellitus in youth were studied. Blood pressure was categorized according to the 2 guidelines as normal, elevated, and hypertension (stages 1 and 2). Measures of TOD (carotid artery intima-media thickness, pulse wave velocity, left ventricular mass, and diastolic function) were obtained. Associations between blood pressure categories and TOD and the sensitivity of hypertension classification in identifying TOD were evaluated.

Results: Data were available for 364 participants (65% female sex; 15.1 ± 2.1 years of age). Hypertension was identified in 8% and 13% as defined in the Fourth Report and CPG, respectively ( = .007). The 2 guidelines revealed similar associations with TOD; however, the CPG demonstrated improved sensitivity of TOD detection in hypertensive participants. For example, the proportion of participants with an abnormal left ventricular mass categorized as hypertensive increased from 20% to 31% as defined in the Fourth Report and CPG, respectively ( < .001).

Conclusions: Incorporation of the CPG increased the prevalence of pediatric hypertension in a population of high-risk youth and improved the sensitivity of TOD identification in hypertensive participants.
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http://dx.doi.org/10.1542/peds.2018-0245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6317543PMC
August 2018

Preoperative Aortic Arch Size and Late Outcome After Coarctation Repair by Lateral Thoracotomy.

Ann Thorac Surg 2018 08 5;106(2):575-580. Epub 2018 May 5.

The Heart Institute, Division of Pediatric Cardiology, Cincinnati Children's Hospital and Medical Center, Cincinnati, Ohio.

Background: The approach (lateral thoracotomy versus median sternotomy) to repair coarctation of the aorta is frequently based on arch dimensions from the preoperative echocardiogram. Few studies have assessed the relationship between preoperative arch dimensions and late postoperative outcome. This study aimed to define how preoperative arch dimensions relate to late outcomes and identify long-term predictors of a successful operation.

Methods: We performed a retrospective review of 102 neonates and infants undergoing isolated coarctation repair by lateral thoracotomy between 2003 and 2012. Long-term surgical success was defined based on the following five factors: corrected arch gradient below 20 mm Hg, blood pressure cuff gradient below 15 mm Hg, systolic blood pressure below the 95th percentile during the clinic visit, no antihypertensive medication use, and freedom from reintervention. Regression analysis was performed to identify factors that would predict the need for reintervention and long-term success.

Results: At a median of 6 years of follow-up, long-term success was achieved in 63% (56 of 89) of patients, and 94% (96 of 102) were free of reintervention. Bivariate analysis showed that patients requiring reintervention had smaller absolute isthmus dimension (p = 0.04). No significant predictors for reintervention or long-term success could be identified, although a larger distal transverse arch dimension may play a role in long-term success (hazard ratio, 0.7; 95% confidence interval, 0.05 to 1.0; p = 0.06).

Conclusions: Aortic arches of various dimensions were successfully repaired by lateral thoracotomy. No significant predictors for reintervention or long-term success could be identified, although the distal transverse arch dimension may play a role in long-term success.
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http://dx.doi.org/10.1016/j.athoracsur.2018.03.084DOI Listing
August 2018

Association of Cardiomyopathy With MYBPC3 D389V and MYBPC3Δ25bpIntronic Deletion in South Asian Descendants.

JAMA Cardiol 2018 06;3(6):481-488

Heart, Lung and Vascular Institute, Department of Internal Medicine, University of Cincinnati, Cincinnati, Ohio.

Importance: The genetic variant MYBPC3Δ25bp occurs in 4% of South Asian descendants, with an estimated 100 million carriers worldwide. MYBPC3 Δ25bp has been linked to cardiomyopathy and heart failure. However, the high prevalence of MYBPC3Δ25bp suggests that other stressors act in concert with MYBPC3Δ25bp.

Objective: To determine whether there are additional genetic factors that contribute to the cardiomyopathic expression of MYBPC3Δ25bp.

Design, Setting, Andparticipants: South Asian individuals living in the United States were screened for MYBPC3Δ25bp, and a subgroup was clinically evaluated using electrocardiograms and echocardiograms at Loyola University, Chicago, Illinois, between January 2015 and July 2016.

Main Outcomes And Measures: Next-generation sequencing of 174 cardiovascular disease genes was applied to identify additional modifying gene mutations and correlate genotype-phenotype parameters. Cardiomyocytes derived from human-induced pluripotent stem cells were established and examined to assess the role of MYBPC3Δ25bp.

Results: In this genotype-phenotype study, individuals of South Asian descent living in the United States from both sexes (36.23% female) with a mean population age of 48.92 years (range, 18-84 years) were recruited. Genetic screening of 2401 US South Asian individuals found an MYBPC3Δ25bpcarrier frequency of 6%. A higher frequency of missense TTN variation was found in MYBPC3Δ25bp carriers compared with noncarriers, identifying distinct genetic backgrounds within the MYBPC3Δ25bp carrier group. Strikingly, 9.6% of MYBPC3Δ25bp carriers also had a novel MYBPC3 variant, D389V. Family studies documented D389V was in tandem on the same allele as MYBPC3Δ25bp, and D389V was only seen in the presence of MYBPC3Δ25bp. In contrast to MYBPC3Δ25bp, MYBPC3Δ25bp/D389V was associated with hyperdynamic left ventricular performance (mean [SEM] left ventricular ejection fraction, 66.7 [0.7%]; left ventricular fractional shortening, 36.6 [0.6%]; P < .03) and stem cell-derived cardiomyocytes exhibited cellular hypertrophy with abnormal Ca2+ transients.

Conclusions And Relevance: MYBPC3Δ25bp/D389V is associated with hyperdynamic features, which are an early finding in hypertrophic cardiomyopathy and thought to reflect an unfavorable energetic state. These findings support that a subset of MYBPC3Δ25bp carriers, those with D389V, account for the increased risk attributed to MYBPC3Δ25bp.
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http://dx.doi.org/10.1001/jamacardio.2018.0618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6054452PMC
June 2018

Infant Weight and Length Growth Trajectories Modeled Using Superimposition by Translation and Rotation Are Differentially Associated with Body Composition Components at 3 and 7 Years of Age.

J Pediatr 2018 05 7;196:182-188.e1. Epub 2018 Mar 7.

Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.

Objective: To evaluate how infant weigh and length growth trajectories associate with body composition at 3 and 7 years because previous studies have noted that rapid infant weight gain increases risk for high body mass index (BMI) in children.

Study Design: There were 322 children enrolled at 3 years of age with dual x-ray absorptiometry body composition data and pediatrician growth data for 0-2 years of age who were included in analysis. Superimposition by translation and rotation modeling was used to characterize infant weight and length trajectories in terms of size, tempo and velocity measures. Associations of these measures with fat mass, lean mass, percent body fat, bone mineral content, BMI z-score, and overweight prevalence at 3 and 7 years of age were determined.

Results: Infant growth trajectories differed by sex, race, and breastfeeding status. Higher overall weight size and weight velocity from 0 to 2 years of age were associated positively with all age 3 body composition and anthropometry outcomes. However, longer length size from 0 to 2 years of age was associated independently with higher bone mineral content and lean mass, but lower percent body fat, BMI z-score, and a lower odds of overweight at 3 years of age. By 7 years of age, later than average infant weight tempo was also associated with lower fat mass, lean mass, and BMI z-score.

Conclusions: Greater average weight size and greater weight velocity in infancy are markers for greater overall body size at 3 and 7 years of age. However, longer average lengths and later weight gain tempo between 0 and 2 years of age may help to establish a leaner body composition by 3 and 7 years of age.
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http://dx.doi.org/10.1016/j.jpeds.2017.12.077DOI Listing
May 2018

Risks and outcomes of direct current cardioversion in children and young adults with congenital heart disease.

Pacing Clin Electrophysiol 2018 05 17;41(5):472-479. Epub 2018 Apr 17.

Department of Pediatrics, Division of Pediatric Cardiology, The Heart Institute at Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

Objectives: Evaluate the efficacy, outcomes, and complications associated with direct current cardioversion (DCCV) in the treatment of arrhythmias in pediatric and adult congenital heart disease (CHD) populations and identify patient and procedural characteristics associated with adverse events.

Background: Pediatric and adult patients with CHD are at risk of atrial arrhythmias. DCCV is effective but is associated with potential complications.

Methods: In this single-center retrospective series, patients who underwent DCCV between January 2010 and May 2015 were identified and categorized as pediatric (<18 years) or adult (> 18 years). Records were reviewed for demographic, arrhythmic, and CHD-specific characteristics; acute efficacy; and 3-month arrhythmia recurrence. Complications were categorized as life-threatening (LT) or non-life-threatening (NLT). Univariate followed by multiple variable and logistic regression (LR) analyses were used to identify characteristics associated with complications.

Results: We identified 104 patients with 152 discrete DCCV events with median age 17.4 years (0.15-62.2). DCCV efficacy was 89% with 3-month recurrence of 46%. There were 52 complications among 24 patients, median age 17.7 years (0.15-49). Risks associated with NLT complications are as follows: moderate-severe systolic dysfunction (8/152 encounters, P = < 0.01) and more than one shock per DCCV encounter (P = < 0.01). Six of eight encounters with moderate-severe systolic dysfunction were <18 years (P = 0.1). Risks for LT complications included age >18 years and associated NLT complication. Adults had more frequent arrhythmia recurrence within 3 months than children (P = < 0.01).

Conclusions: DCCV is effective for arrhythmias but is associated with frequent recurrence, particularly in adult patients. Complications associated with DCCV may be greater than previously reported. Additional support and precautions should be in place for those at greatest risk.
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http://dx.doi.org/10.1111/pace.13315DOI Listing
May 2018

Arterial Thickness and Stiffness Are Independently Associated with Left Ventricular Strain.

J Am Soc Echocardiogr 2018 01 23;31(1):99-104. Epub 2017 Nov 23.

Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. Electronic address:

Background: The aim of this study was to examine the association between myocardial strain and arterial thickness and stiffness in young adults. Increased common carotid artery intima media thickness and peripheral arterial stiffness are known to precede coronary artery disease and cardiovascular (CV) events such as myocardial infarction and congestive heart failure. However, subclinical cardiac dysfunction can be detected in high-risk adults by myocardial strain echocardiography. The authors hypothesized that increased carotid artery intima media thickness would be associated with abnormal myocardial strain in young subjects who had obesity and type 2 diabetes mellitus.

Methods: CV risk factors were collected in 338 young adults participating in a prospective, cross-sectional study. The CV parameters collected included intima-media thickness, peripheral arterial stiffness by brachial distensibility, and myocardial strain and strain rate. General linear models were constructed to determine if vascular structure and function measures were independently associated with myocardial strain and strain rate.

Results: A linear relationship was found between global longitudinal strain obtained from the four-chamber view and global strain rate in systole and carotid intima-media thickness (four-chamber global longitudinal strain: β = 3.0, CV risk factor-adjusted R = 0.34; global strain rate in systole: β = 0.0053, R = 0.21; P ≤ .0001) and between four-chamber global longitudinal strain and lower brachial distensibility (β = -0.42, R = 0.22; P < .001).

Conclusions: Adverse changes in vascular structure and function are simultaneously present with reduced myocardial systolic function.
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http://dx.doi.org/10.1016/j.echo.2017.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5756686PMC
January 2018