Ambulatory Systolic Blood Pressure and Obesity are Independently Associated with Left Ventricular Hypertrophic Remodeling in Children

Background: Children with obesity have hypertrophic cardiac remodeling. Hypertension is common in pediatric obesity, and may independently contribute to hypertrophy. We hypothesized that both the degree of obesity and ambulatory blood pressure (ABP) would independently associate with measures of hypertrophic cardiac remodeling in children. Methods: Children, aged 8–17 years, prospectively underwent cardiovascular magnetic resonance (CMR) and ABP monitoring. Left ventricular (LV) mass indexed to height2.7(LVMI), myocardial thickness and end-diastolic volume were quantified from a 3D LV model reconstructed from cine balanced steady state free precession images. Categories of remodeling were determined based on cutoff values for LVMI and mass/volume. Principal component analysis was used to define a “hypertrophy score” to study the continuous relationship between concentric hypertrophy and ABP. Results: Seventy-two children were recruited, and 68 of those (37 healthy weight and 31 obese/overweight) completed both CMR and ABP monitoring. Obese/overweight children had increased LVMI (27 ± 4 vs 22 ± 3 g/m2.7, p \u3c 0.001), myocardial thickness (5.6 ± 0.9 vs 4.9 ± 0.7 mm, p \u3c 0.001), mass/volume (0.69 ± 0.1 vs 0.61 ± 0.06, p \u3c 0.001), and hypertrophy score (1.1 ± 2.2 vs −0.96 ± 1.1, p \u3c 0.001). Thirty-five percent of obese/overweight children had concentric hypertrophy. Ambulatory hypertension was observed in 26% of the obese/overweight children and none of the controls while masked hypertension was observed in 32% of the obese/overweight children and 16% of the controls. Univariate linear regression showed that BMI z-score, systolic BP (24 h, day and night), and systolic load correlated with LVMI, thickness, mass/volume and hypertrophy score, while 24 h and nighttime diastolic BP and load also correlated with thickness and mass/volume. Multivariate analysis showed body mass index z-score and systolic blood pressure were both independently associated with left ventricular mass index (β=0.54 [p \u3c 0.001] and 0.22 [p = 0.03]), thickness (β=0.34 [p \u3c 0.001] and 0.26 [p = 0.001]) and hypertrophy score (β=0.47 and 0.36, both p \u3c 0.001). Conclusions: In children, both the degree of obesity and ambulatory blood pressures are independently associated with measures of cardiac hypertrophic remodeling, however the correlations were generally stronger for the degree of obesity. This suggests that interventions targeted at weight loss or obesity-associated co-morbidities including hypertension may be effective in reversing or preventing cardiac remodeling in obese children

Cardiac Remodeling and Dysfunction in Childhood Obesity: A Cardiovascular Magnetic Resonance Study

Background: Obesity affects nearly one in five children and is associated with increased risk of premature death. Obesity-related heart disease contributes to premature death. We aimed to use cardiovascular magnetic resonance (CMR) to comprehensively characterize the changes in cardiac geometry and function in obese children. Methods and results: Forty-one obese/overweight (age 12 ± 3 years, 56 % female) and 29 healthy weight children (age 14 ± 3 years, 41 % female) underwent CMR, including both standard cine imaging and displacement encoded imaging, for a complete assessment of left ventricular (LV) structure and function. After adjusting for age, LV mass index was 23 % greater (27 ± 4 g/m2.7 vs 22 ± 3 g/m2.7, p \u3c 0.001) and the LV myocardium was 10 % thicker (5.6 ± 0.8 mm vs 5.1 ± 0.8 mm, p \u3c 0.001) in the obese/overweight children. This evidence of cardiac remodeling was present in obese children as young as age 8. Twenty four percent of obese/overweight children had concentric hypertrophy, 59 % had normal geometry and 17 % had either eccentric hypertrophy or concentric remodeling. LV mass index, thickness, ejection fraction and peak longitudinal and circumferential strains all correlated with epicardial adipose tissue after adjusting for height and gender (all p \u3c 0.05). Peak longitudinal and circumferential strains showed a significant relationship with the type of LV remodeling, and were most impaired in children with concentric hypertrophy (p \u3c 0.001 and p = 0.003, respectively). Conclusions: Obese children show evidence of significant cardiac remodeling and dysfunction, which begins as young as age 8. Obese children with concentric hypertrophy and impaired strain may represent a particularly high risk subgroup that demands further investigation

Impaired right ventricular contractile function in childhood obesity and its association with right and left ventricular changes: a cine DENSE cardiac magnetic resonance study

Abstract Background Pediatric obesity is a growing public health problem, which is associated with increased risk of cardiovascular disease and premature death. Left ventricular (LV) remodeling (increased myocardial mass and thickness) and contractile dysfunction (impaired longitudinal strain) have been documented in obese children, but little attention has been paid to the right ventricle (RV). We hypothesized that obese/overweight children would have evidence of RV remodeling and contractile dysfunction. Methods One hundred and three children, ages 8–18 years, were prospectively recruited and underwent cardiovascular magnetic resonance (CMR), including both standard cine imaging and displacement encoding with stimulated echoes (DENSE) imaging, which allowed for quantification of RV geometry and function/mechanics. RV free wall longitudinal strain was quantified from the end-systolic four-chamber DENSE image. Linear regression was used to quantify correlations of RV strain with LV strain and measurements of body composition (adjusted for sex and height). Analysis of variance was used to study the relationship between RV strain and LV remodeling types (concentric remodeling, eccentric/concentric hypertrophy). Results The RV was sufficiently visualized with DENSE in 70 (68%) subjects, comprising 36 healthy weight (13.6 ± 2.7 years) and 34 (12.1 ± 2.9 years) obese/overweight children. Obese/overweight children had a 22% larger RV mass index (8.2 ± 0.9 vs 6.7 ± 1.1 g/m2.7, p < 0.001) compared to healthy controls. RV free wall longitudinal strain was impaired in obese/overweight children (−16 ± 4% vs −19 ± 5%, p = 0.02). Ten (14%) out of 70 children had LV concentric hypertrophy, and these children had the most impaired RV longitudinal strain compared to those with normal LV geometry (−13 ± 4% vs −19 ± 5%, p = 0.002). RV longitudinal strain was correlated with LV longitudinal strain (r = 0.34, p = 0.004), systolic blood pressure (r = 0.33, p = 0.006), as well as BMI z-score (r = 0.28, p = 0.02), waist (r = 0.31, p = 0.01), hip (r = 0.40, p = 0.004) and abdominal (r = 0.38, p = 0.002) circumference, height and sex adjusted. Conclusions Obese/overweight children have evidence of RV remodeling (increased RV mass) and RV contractile dysfunction (impaired free wall longitudinal strain). Moreover, RV longitudinal strain correlates with LV longitudinal strain, and children with LV concentric hypertrophy show the most impaired RV function. These results suggest there may be a common mechanism underlying both remodeling and dysfunction of the left and right ventricles in obese/overweight children

A Wearable Multimodal Sensing System for Tracking Changes in Pulmonary Fluid Status, Lung Sounds, and Respiratory Markers

Heart failure (HF) exacerbations, characterized by pulmonary congestion and breathlessness, require frequent hospitalizations, often resulting in poor outcomes. Current methods for tracking lung fluid and respiratory distress are unable to produce continuous, holistic measures of cardiopulmonary health. We present a multimodal sensing system that captures bioimpedance spectroscopy (BIS), multi-channel lung sounds from four contact microphones, multi-frequency impedance pneumography (IP), temperature, and kinematics to track changes in cardiopulmonary status. We first validated the system on healthy subjects (n = 10) and then conducted a feasibility study on patients (n = 14) with HF in clinical settings. Three measurements were taken throughout the course of hospitalization, and parameters relevant to lung fluid status&mdash;the ratio of the resistances at 5 kHz to those at 150 kHz (K)&mdash;and respiratory timings (e.g., respiratory rate) were extracted. We found a statistically significant increase in K (p &lt; 0.05) from admission to discharge and observed respiratory timings in physiologically plausible ranges. The IP-derived respiratory signals and lung sounds were sensitive enough to detect abnormal respiratory patterns (Cheyne&ndash;Stokes) and inspiratory crackles from patient recordings, respectively. We demonstrated that the proposed system is suitable for detecting changes in pulmonary fluid status and capturing high-quality respiratory signals and lung sounds in a clinical setting

The Potential Role of DNA Methylation in Abdominal Aortic Aneurysms

Abdominal aortic aneurysm (AAA) is a complex disorder that has a significant impact on the aging population. While both genetic and environmental risk factors have been implicated in AAA formation, the precise genetic markers involved and the factors influencing their expression remain an area of ongoing investigation. DNA methylation has been previously used to study gene silencing in other inflammatory disorders and since AAA has an extensive inflammatory component, we sought to examine the genome-wide DNA methylation profiles in mononuclear blood cells of AAA cases and matched non-AAA controls. To this end, we collected blood samples and isolated mononuclear cells for DNA and RNA extraction from four all male groups: AAA smokers (n = 11), AAA non-smokers (n = 9), control smokers (n = 10) and control non-smokers (n = 11). Methylation data were obtained using the Illumina 450k Human Methylation Bead Chip and analyzed using the R language and multiple Bioconductor packages. Principal component analysis and linear analysis of CpG island subsets identified four regions with significant differences in methylation with respect to AAA: kelch-like family member 35 (KLHL35), calponin 2 (CNN2), serpin peptidase inhibitor clade B (ovalbumin) member 9 (SERPINB9), and adenylate cyclase 10 pseudogene 1 (ADCY10P1). Follow-up studies included RT-PCR and immunostaining for CNN2 and SERPINB9. These findings are novel and suggest DNA methylation may play a role in AAA pathobiology

Electronic Health Record Phenotype in Subjects with Genetic Variants Associated with Arrhythmogenic Right Ventricular Cardiomyopathy: A Study in 30,716 Subjects with Exome Sequencing: Genotype-Phenotype Association in Incidental ARVC Genetic Findings

Purpose Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart disease. Clinical follow-up of incidental findings in ARVC-associated genes is recommended. We aimed to determine the prevalence of disease thus ascertained. Methods: 30,716 individuals underwent exome sequencing. Variants in PKP2, DSG2, DSC2, DSP, JUP, TMEM43, or TGFβ3 that were database-listed as pathogenic or likely pathogenic were identified and evidence-reviewed. For subjects with putative loss-of-function (pLOF) variants or variants of uncertain significance (VUS), electronic health records (EHR) were reviewed for ARVC diagnosis, diagnostic criteria, and International Classification of Diseases (ICD-9) codes. Results: 18 subjects had pLOF variants; none had an EHR diagnosis of ARVC. Of 14 patients with an electrocardiogram (ECG), one had a minor diagnostic criterion, 13 were normal. 184 subjects had VUSs; none had an ARVC diagnosis. In subjects with VUSs, there was no difference in the proportion with major (4%) or minor (13%) ECG diagnostic criteria compared to variant-negative controls. ICD-9 codes showed no difference in defibrillator utilization, electrophysiologic abnormalities or non-ischemic cardiomyopathies in patients with pLOF or VUSs compared to controls. Conclusion: pLOF variants in an unselected cohort were not associated with ARVC phenotypes based on EHR review. The negative predictive value of EHR review remains uncertain

Electronic health record phenotype in subjects with genetic variants associated with arrhythmogenic right ventricular cardiomyopathy: a study of 30,716 subjects with exome sequencing

PurposeArrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart disease. Clinical follow-up of incidental findings in ARVC-associated genes is recommended. We aimed to determine the prevalence of disease thus ascertained.MethodsIndividuals (n = 30,716) underwent exome sequencing. Variants in PKP2, DSG2, DSC2, DSP, JUP, TMEM43, or TGFβ3 that were database-listed as pathogenic or likely pathogenic were identified and evidence-reviewed. For subjects with putative loss-of-function (pLOF) variants or variants of uncertain significance (VUS), electronic health records (EHR) were reviewed for ARVC diagnosis, diagnostic criteria, and International Classification of Diseases (ICD-9) codes.ResultsEighteen subjects had pLOF variants; none of these had an EHR diagnosis of ARVC. Of 14 patients with an electrocardiogram, one had a minor diagnostic criterion; the rest were normal. A total of 184 subjects had VUS, none of whom had an ARVC diagnosis. The proportion of subjects with VUS with major (4%) or minor (13%) electrocardiogram diagnostic criteria did not differ from that of variant-negative controls. ICD-9 codes showed no difference in defibrillator use, electrophysiologic abnormalities or nonischemic cardiomyopathies in patients with pLOF or VUSs compared with controls.ConclusionpLOF variants in an unselected cohort were not associated with ARVC phenotypes based on EHR review. The negative predictive value of EHR review remains uncertain