Association of left ventricular hypertrophy and stage of hypertension by ambulatory blood pressure monitor

Hypertension in adults is defined by risk for cardiovascular morbidity and mortality, but in children, hypertension is defined using population norms. The diagnosis of hypertension in children and adolescents requires only casual blood pressure measurements, but the use of ambulatory blood pressure monitoring to further evaluate patients with elevated blood pressure has been recommended in the Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents. The aim of this study is to assess the association between stage of hypertension (using both casual and 24 hour ambulatory blood pressure measurements) and target organ damage defined by left ventricular hypertrophy (LVH) in a sample of children and adolescents in Houston, TX. A retrospective analysis was performed on the primary de-identified data from the combination of participants in two, IRB approved, cross-sectional studies. The studies collected basic demographic data, height, weight, casual blood pressures, ambulatory blood pressures, and left ventricular measurements by echocardiography on children age 8 to 18 years old. Hypertension was defined and staged using the criteria for ambulatory blood pressure reported by Lurbe et al. [1] with some modification. Left ventricular hypertrophy was defined using left ventricular mass index (LVMI) criteria specific for children and adults. The pediatric criterion was LVMI2.7 > 95th percentile for gender and the adult criterion was LVMI2.7 > 51g/m2.7. Participants from the original studies were included in this analysis if they had complete demographic information, anthropometric measures, casual blood pressures, ambulatory blood pressures, and echocardiography data. There were 241 children and adolescents included: 19.1% were normotensive, 17.0% had white coat hypertension, 11.6% had masked hypertension, and 52.4% had confirmed hypertension. Of those with hypertension, 22.4% had stage 1 hypertension, 5.8% had stage 2 hypertension, and 24.1% had stage 3 hypertension. Participants with confirmed hypertension were more likely to have LVH by pediatric criterion than those who were normotensive [OR 2.19, 95% CI (1.04–4.63)]; LVH defined by adult criterion did not differ significantly in normotensives compared with hypertensives [OR 2.08, 95% CI (0.58–7.52)]. However, there was a significant trend in the increased prevalence of LVH across the six blood pressure categories for LVH defined by both pediatric and adult criteria (p < 0.001 and p = 0.02, respectively). Additionally, the mean LVM indexed by height 2.7 had a significantly increased trend across blood pressure stages from normal to stage 3 hypertension (p < 0.02). Pediatric hypertension is defined using population norms, and although children with mild hypertension are not at increased odds of having target organ damage defined by LVH, those with severe hypertension are more likely to have LVH. Staging hypertension by ambulatory blood pressure further describes an individual's risk for LVH target organ damage. ^

Secondary left ventricular ejection fraction response to beta blocker therapy in heart failure patients

Chronic β-blocker treatment improves survival and left ventricular ejection fraction (LVEF) in patients with systolic heart failure (HF). Data on whether the improvement in LVEF after β-blocker therapy is sustained for a long term or whether there is a loss in LVEF after an initial gain is not known. Our study sought to determine the prevalence and prognostic role of secondary decline in LVEF in chronic systolic HF patients on β-blocker therapy and characterize these patients. Retrospective chart review of HF hospitalizations fulfilling Framingham Criteria was performed at the MEDVAMC between April 2000 and June 2006. Follow up vital status and recurrent hospitalizations were ascertained until May 2010. Three groups of patients were identified based on LVEF response to beta blockers; group A with secondary decline in LVEF following an initial increase, group B with progressive increase in LVEF and group C with progressive decline in LVEF. Covariate adjusted Cox proportional hazard models were used to examine differences in heart failure re-hospitalizations and all cause mortality between the groups. Twenty five percent (n=27) of patients had a secondary decline in LVEF following an initial gain. The baseline, peak and final LVEF in this group were 27.6±12%, 40.1±14% and 27.4±13% respectively. The mean nadir LVEF after decline was 27.4±13% and this decline occurred at a mean interval of 2.8±1.9 years from the day of beta blocker initiation. These patients were older, more likely to be whites, had advanced heart failure (NYHA class III/IV) more due to a non ischemic etiology compared to groups B & C. They were also more likely to be treated with metoprolol (p=0.03) compared to the other two groups. No significant differences were observed in combined risk of all cause mortality and HF re-hospitalization [hazard ratio 0.80, 95% CI 0.47 to 1.38, p=0.42]. No significant difference was observed in survival estimates between the groups. In conclusion, a late decline in LVEF does occur in a significant proportion of heart failure patients treated with beta blockers, more so in patients treated with metoprolol.^

The epidemiology of left ventricular outflow tract obstruction defects in Texas, 2002-2008: An update and assessment of effect heterogeneity

Left ventricular outflow tract (LVOT) defects are an important group of congenital heart defects (CHDs) because of their associated mortality and long-term complications. LVOT defects include aortic valve stenosis (AVS), coarctation of aorta (CoA), and hypoplastic left heart syndrome (HLHS). Despite their clinical significance, their etiology is not completely understood. Even though the individual component phenotypes (AVS, CoA, and HLHS) may have different etiologies, they are often "lumped" together in epidemiological studies. Though "lumping" of component phenotypes may improve the power to detect associations, it may also lead to ambiguous findings if these defects are etiologically distinct. This is due to potential for effect heterogeneity across component phenotypes. ^ This study had two aims: (1) to identify the association between various risk factors and both the component (i.e., split) and composite (i.e., lumped) LVOT phenotypes, and (2) to assess the effect heterogeneity of risk factors across component phenotypes of LVOT defects. ^ This study was a secondary data analysis. Primary data were obtained from the Texas Birth Defect Registry (TBDR). TBDR uses an active surveillance method to ascertain birth defects in Texas. All cases of non complex LVOT defects which met our inclusion criteria during the period of 2002–2008 were included in the study. The comparison groups included all unaffected live births for the same period (2002–2008). Data from vital statistics were used to evaluate associations. Statistical associations between selected risk factors and LVOT defects was determined by calculating crude and adjusted prevalence ratio using Poisson regression analysis. Effect heterogeneity was evaluated using polytomous logistic regression. ^ There were a total of 2,353 cases of LVOT defects among 2,730,035 live births during the study period. There were a total of 1,311 definite cases of non-complex LVOT defects for analysis after excluding "complex" cardiac cases and cases associated with syndromes (n=168). Among infant characteristics, males were at a significantly higher risk of developing LVOT defects compared to females. Among maternal characteristics, significant associations were seen with maternal age > 40 years (compared to maternal age 20–24 years) and maternal residence in Texas-Mexico border (compared to non-border residence). Among birth characteristics, significant associations were seen with preterm birth and small for gestation age LVOT defects. ^ When evaluating effect heterogeneity, the following variables had significantly different effects among the component LVOT defect phenotypes: infant sex, plurality, maternal age, maternal race/ethnicity, and Texas-Mexico border residence. ^ This study found significant associations between various demographic factors and LVOT defects. While many findings from this study were consistent with results from previous studies, we also identified new factors associated with LVOT defects. Additionally, this study was the first to assess effect heterogeneity across LVOT defect component phenotypes. These findings contribute to a growing body of literature on characteristics associated with LVOT defects. ^

Analyzing left-truncated right-censored data with uncertain onset time with parametric models

Prevalent sampling is an efficient and focused approach to the study of the natural history of disease. Right-censored time-to-event data observed from prospective prevalent cohort studies are often subject to left-truncated sampling. Left-truncated samples are not randomly selected from the population of interest and have a selection bias. Extensive studies have focused on estimating the unbiased distribution given left-truncated samples. However, in many applications, the exact date of disease onset was not observed. For example, in an HIV infection study, the exact HIV infection time is not observable. However, it is known that the HIV infection date occurred between two observable dates. Meeting these challenges motivated our study. We propose parametric models to estimate the unbiased distribution of left-truncated, right-censored time-to-event data with uncertain onset times. We first consider data from a length-biased sampling, a specific case in left-truncated samplings. Then we extend the proposed method to general left-truncated sampling. With a parametric model, we construct the full likelihood, given a biased sample with unobservable onset of disease. The parameters are estimated through the maximization of the constructed likelihood by adjusting the selection bias and unobservable exact onset. Simulations are conducted to evaluate the finite sample performance of the proposed methods. We apply the proposed method to an HIV infection study, estimating the unbiased survival function and covariance coefficients. ^

Genetic analysis of Pitx2 in left -right asymmetry and cardiovascular development

Pitx2, a paired-related homeobox gene that is mutated in human Rieger Syndrome, plays a key role in transferring the early asymmetric signals to individual organs. Pitx2 encodes three isoforms, Pitx2a, Pitx2b and Pitx2c. I found that Pitx2c was the Pitx2 isoform for regulating left-right asymmetry in heart, lung and the predominant isoform in guts. Previous studies suggested that the generation of left-right asymmetry within individual organs is an all or none, random event. Phenotypic analysis of various Pitx2 allelic combinations, that encode graded levels of Pitx2c, reveals an organ-intrinsic mechanism for regulating left-right asymmetric morphogenesis based on differential response to Pitx2c levels. The heart needs low Pitx2c levels, while the lungs and duodenum require higher doses of Pitx2c. In addition, the duodenal rotation is under strict control of Pitx2c activity. Left-right asymmetry development for aortic arch arteries involves complex vascular remodeling. Left-sided expression of Pitx2c in these developing vessels implied its potential function in this process. In order to determine if Pitx2c also can regulate the left-right asymmetry of the aortic arch arteries, a Pitx2c-specific loss of function mutation is generated. Although in wild type mice, the direction of the aortic arch is always oriented toward the left side, the directions of the aortic arches in the mutants were randomized, showing that Pitx2c also determined the left-right asymmetry of these vessels. I have further showed that the cardiac neural crest wasn't involved in this vascular remodeling process. In addition, all mutant embryos had Double Outlet Right Ventricle (DORV), a common congenital heart disease. This study provided insight into the mechanism of Pitx2c-mediated late stages of left-right asymmetry development and identified the roles of Pitx2c in regulation of aortic arch remodeling and heart development. ^

Left, right and interval bivariate censored data: Evaluating screening mammography in the presence of lead -time bias, length bias and over-detection

Of the large clinical trials evaluating screening mammography efficacy, none included women ages 75 and older. Recommendations on an upper age limit at which to discontinue screening are based on indirect evidence and are not consistent. Screening mammography is evaluated using observational data from the SEER-Medicare linked database. Measuring the benefit of screening mammography is difficult due to the impact of lead-time bias, length bias and over-detection. The underlying conceptual model divides the disease into two stages: pre-clinical (T0) and symptomatic (T1) breast cancer. Treating the time in these phases as a pair of dependent bivariate observations, (t0,t1), estimates are derived to describe the distribution of this random vector. To quantify the effect of screening mammography, statistical inference is made about the mammography parameters that correspond to the marginal distribution of the symptomatic phase duration (T1). This shows the hazard ratio of death from breast cancer comparing women with screen-detected tumors to those detected at their symptom onset is 0.36 (0.30, 0.42), indicating a benefit among the screen-detected cases. ^