Eisenmenger syndrome (ES) is a known complication of congenital heart disease associated with unrepaired systemic to pulmonary shunts. Evidence for use of targeted pulmonary arterial hypertension ...therapy in ES is limited. The early experience using ambrisentan was evaluated in a cohort of consecutive patients with ES who initiated ambrisentan at Columbia University's Pulmonary Hypertension Center from January 1, 2007, to August 1, 2008. Effects of ambrisentan on rest and exercise systemic arterial oxygen saturation (Sa O2 ), exercise capacity, functional status, hemoglobin levels, and hemodynamics were evaluated and compared using paired Student's t tests. Seventeen patients were evaluated at short-term (mean 163 ± 57 days) and longer term (mean 2.5 ± 0.5 years) follow-up. At short-term follow-up, there was an improvement in exercise capacity (6-minute walking distance 389 ± 74 vs 417 ± 77 m, p = 0.03, n = 11) and maintenance of rest Sa O2 (89 ± 7% vs 89% ± 6%, p = 0.75, n = 15), exercise Sa O2 (75 ± 15% vs 77% ± 15%, p = 0.33, n = 11), functional class (improvement in 2 patients, no change in 13), and hemoglobin (16.5 ± 2.8 vs 15.8 ± 1.8 g/dl, p = 0.11, n = 14). At longer term follow-up compared to baseline and short-term follow-up, there was stability of exercise capacity, Sa O2 , functional class, and hemoglobin. In conclusion, in this single-center cohort of patients with ES, ambrisentan was safe and was associated with increasing exercise capacity at short-term follow-up, with patients maintaining Sa O2 , functional class, and hemoglobin, and with no significant evidence of clinical deterioration at longer term follow-up. Additional studies are required to further assess the efficacy of ambrisentan in patients with ES.
Treatment algorithms in pediatric pulmonary arterial hypertension (PAH) are derived from clinical trials in adult populations and from clinical practice, but experience in children is limited. In ...this retrospective cohort study, we analyzed outcomes in a previously identified cohort of 86 consecutive children with PAH treated with bosentan as part of their treatment regimen. All children with idiopathic PAH or heritable PAH and PAH associated with congenital heart disease or connective tissue disease who started bosentan treatment from May 2001 to April 2003 in 2 tertiary pediatric referral centers were followed, with data collection ending August 2006. Eighty-six children (37 male, 49 female) 11 ± 5 years of age with idiopathic/heritable PAH (n = 36), PAH associated with congenital heart disease (n = 48), or PAH associated with connective tissue disease (n = 2) received bosentan as monotherapy (n = 42) or as an add-on to pre-existing continuous intravenous epoprostenol or subcutaneous treprostinil (n = 44). Median observation period was 39 months (range 2 to 60). Thirty-four patients (40%) received ≥1 additional PAH-specific therapy during follow-up. At end of data collection, 25 patients (29%) remained on bosentan, 43 (50%) had stopped bosentan, 11 (13%) had died while on bosentan, and 7 were lost to follow-up. At 4 years, the Kaplan-Meier estimate of disease progression in patients while on bosentan was 54% (7 patients at risk) with a survival estimate of 82% (16 patients at risk). Risk factors significantly associated with survival were World Health Organization functional class and indexed pulmonary vascular resistance. In conclusion, outcome in children with PAH managed with current treatment regimens appears favorable. However, despite current therapy options, disease progression remains a concern.
Pulmonary arterial hypertension (PAH) is a rare, lethal disease associated with single gene disorders, connective tissue disease, exposures to anorexigens, and often, idiopathic etiology. Genes can ...modify the risk of PAH: (1) monogenic disorders associated with PAH are incompletely penetrant, and (2) not all patients with associated conditions at increased risk for PAH develop the disease. The renin angiotensin aldosterone system (RAAS) provides a set of candidate genes that could modulate pulmonary vascular disease similar to its effects on renal and peripheral vasculature.
We studied 247 patients with PAH, comprising 177 with idiopathic PAH (IPAH), 63 with PAH/connective tissue disease (CTD), and 7 with PAH associated with anorexigens. Patients were genotyped for 5 common polymorphisms in angiotensinogen (AGT), angiotensin-converting enzyme (ACE), cardiac chymase A (CMA1), angiotensin II type 1 receptor (AGTR1), and aldosterone synthase (CYP11B2). Genotypes were tested for associations with age at diagnosis, hemodynamic parameters at diagnosis, and/or response to acute pulmonary vasodilator testing at diagnosis.
Associations were demonstrated for AGTR1 and age at diagnosis in IPAH (p = 0.005). Homozygotes for the 1166C allele (n = 13) were associated with an age at diagnosis 26 years later than those with A/A (n = 139) or A/C (n = 90) genotypes. No associations were demonstrated for AGT, ACE, CMA1, or CYP11B2.
The 1166C polymorphism in AGTR1 appears to be associated with a later age at diagnosis in IPAH, suggesting that this pathway could be involved in the biologic variability that is known to occur in PAH.
Objectives To compare registry and electronic health record (EHR) data mining approaches for cohort ascertainment in patients with pediatric pulmonary hypertension (PH) in an effort to overcome some ...of the limitations of registry enrollment alone in identifying patients with particular disease phenotypes. Study design This study was a single-center retrospective analysis of EHR and registry data at Boston Children's Hospital. The local Informatics for Integrating Biology and the Bedside (i2b2) data warehouse was queried for billing codes, prescriptions, and narrative data related to pediatric PH. Computable phenotype algorithms were developed by fitting penalized logistic regression models to a physician-annotated training set. Algorithms were applied to a candidate patient cohort, and performance was evaluated using a separate set of 136 records and 179 registry patients. We compared clinical and demographic characteristics of patients identified by computable phenotype and the registry. Results The computable phenotype had an area under the receiver operating characteristics curve of 90% (95% CI, 85%-95%), a positive predictive value of 85% (95% CI, 77%-93%), and identified 413 patients (an additional 231%) with pediatric PH who were not enrolled in the registry. Patients identified by the computable phenotype were clinically distinct from registry patients, with a greater prevalence of diagnoses related to perinatal distress and left heart disease. Conclusions Mining of EHRs using computable phenotypes identified a large cohort of patients not recruited using a classic registry. Fusion of EHR and registry data can improve cohort ascertainment for the study of rare diseases. Trial registration ClinicalTrials.gov : NCT02249923.
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