Eric D. Austin

EIF2AK4 Mutations in Pulmonary Capillary Hemangiomatosis

BACKGROUNDnPulmonary capillary hemangiomatosis (PCH) is a rare disease of capillary proliferation of unknown cause and with a high mortality. Families with multiple affected individuals with PCH suggest a heritable cause although the genetic etiology remains unknown.nnnMETHODSnWe used exome sequencing to identify a candidate gene for PCH in a family with two affected brothers. We then screened 11 unrelated patients with familial (n = 1) or sporadic (n = 10) PCH for mutations.nnnRESULTSnUsing exome sequencing, we identified compound mutations in eukaryotic translation initiation factor 2 α kinase 4 (EIF2AK4) (formerly known as GCN2) in both affected brothers. Both parents and an unaffected sister were heterozygous carriers. In addition, we identified two EIF2AK4 mutations in each of two of 10 unrelated individuals with sporadic PCH. EIF2AK4 belongs to a family of kinases that regulate angiogenesis in response to cellular stress.nnnCONCLUSIONSnMutations in EIF2AK4 are likely to cause autosomal-recessive PCH in familial and some nonfamilial cases.

Prostanoids But Not Oral Therapies Improve Right Ventricular Function in Pulmonary Arterial Hypertension

OBJECTIVESnThis study hypothesized that right ventricular stroke work index (RVSWI) and pulmonary capacitance (PC) would increase after treatment for pulmonary arterial hypertension (PAH) and that prostanoids would have a stronger effect than oral therapy.nnnBACKGROUNDnRight ventricular (RV) function is a major determinant of outcome in patients with PAH. Little is known about the response of RV function or its hemodynamic determinants to PAH-specific therapy.nnnMETHODSnWe reviewed hemodynamic and health data on 58 patients from an institutional registry and analyzed changes in hemodynamic status between diagnostic and first repeat catheterization after initiation of therapy for PAH.nnnRESULTSnThe RVSWI and PC increased significantly after therapy (p = 0.007 and p = 0.02, respectively). Improvement in RV function was limited to patients treated with prostanoid-only therapy (p = 0.04); no improvement was found in patients treated with oral therapy (p = 0.25). Patients with the poorest baseline RV function (lowest tertile) had the greatest improvement post-therapy (p = 0.005 and p < 0.001 vs. middle and highest tertiles). The major determinant of RVSWI was change in stroke volume (r(s) = 0.54, p < 0.001), indicating RVSWI is an accurate reflection of RV function.nnnCONCLUSIONSnRight ventricular function improves after therapy with regimens including prostanoids but not oral-only regimens. Patients with the least compensated RV function at diagnosis might derive the most benefit from therapy. Larger studies are needed to determine whether changes in RVSWI after therapy are associated with outcomes.

Haemodynamic characterisation and heart catheterisation complications in children with pulmonary hypertension: Insights from the Global TOPP Registry (tracking outcomes and practice in paediatric pulmonary hypertension)

BACKGROUNDnThe TOPP Registry has been designed to provide epidemiologic, diagnostic, clinical, and outcome data on children with pulmonary hypertension (PH) confirmed by heart catheterisation (HC). This study aims to identify important characteristics of the haemodynamic profile at diagnosis and HC complications of paediatric patients presenting with PH.nnnMETHODS AND RESULTSnHC data sets underwent a blinded review for confirmation of PH (defined as mean pulmonary arterial pressure ≥ 25 mmHg, pulmonary capillary wedge pressure ≤ 12 mmHg and pulmonary vascular resistance index [PVRI] of >3 WU × m(2)). Of 568 patients enrolled, 472 who fulfilled the inclusion criteria and had sufficient data from HC were analysed. A total of 908 diagnostic and follow-up HCs were performed and complications occurred in 5.9% of all HCs including five (0.6%) deaths. General anaesthesia (GA) was used in 53%, and conscious sedation in 47%. Complications at diagnosis were more likely to occur if GA was used (p=0.04) and with higher functional class (p=0.02). Mean cardiac index (CI) was within normal limits at diagnosis when analysed for the entire group (3.7 L/min/m(2); 95% confidence interval 3.4-4.1), as was right atrial pressure despite a severely increased PVRI (16.6 WU × m(2,) 95% confidence interval 15.6-17.76). However, 24% of the patients had a CI of <2.5L/min/m(2) at diagnosis. A progressive increase in PVRI and decrease in CI was observed with age (p<0.001).nnnCONCLUSIONnIn TOPP, haemodynamic assessment was remarkable for preserved CI in the majority of patients despite severely elevated PVRI. HC-related complication incidence was 5.9%, and was associated with GA and higher functional class.

Shorter survival in familial versus idiopathic pulmonary arterial hypertension is associated with hemodynamic markers of impaired right ventricular function

Although individuals with familial pulmonary arterial hypertension (FPAH) have more severe hemodynamics, compared to individuals with idiopathic PAH (IPAH), it is unclear whether this translates into a survival difference. The influence of right ventricular (RV) function on survival in these groups is also unknown. We reviewed hemodynamic data and health information from a prospective institutional database of 57 FPAH and 66 IPAH patients registered with the Vanderbilt Pulmonary Hypertension Research Cohort. We compared hemodynamics at the time of diagnosis between the two groups and calculated pulmonary arteriolar capacitance (PC) and RV stroke work index (RVSWI). Using survival analysis, we compared freedom from a 5-year composite of death or lung transplantation in FPAH and IPAH patients. The composite outcome of death or transplant at 5 years from diagnosis was significantly increased in FPAH (log rank P < 0.001). PC and RVSWI were significantly decreased in FPAH, compared to IPAH (P < 0.001 for both). In univariate analysis, PC (odds ratio [OR]: 0.17 [95% confidence interval (95% CI): 0.03–0.83]) and RVSWI (OR: 0.86 [95% CI: 0.77–0.95]) were predictors of mortality, as were cardiac index (OR: 0.17 [95% CI: 0.06–0.51]) and PVR (OR: 1.1 [95% CI: 1.01–1.12]). Among FPAH patients, RVSWI was lower in those who died or received a transplant than in survivors (P = 0.006), while PC was not (P = 0.5). We found significantly worse event-free survival and significantly lower PC and RVSWI in FPAH than in IPAH. In FPAH patients who died or underwent transplantation, RVSWI was lower than that in survivors, suggesting disproportionate RV dysfunction.

A Computable Phenotype Improves Cohort Ascertainment in a Pediatric Pulmonary Hypertension Registry

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 Childrens 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.

Treatment initiation in paediatric pulmonary hypertension : insights from a multinational registry

Different treatment options for pulmonary hypertension have emerged in recent years, and evidence-based management strategies have improved quality of life and survival in adults. In children with pulmonary vascular disease, therapeutic algorithms are not so clearly defined; this study determined current treatment initiation in children with pulmonary hypertension in participating centres of a registry. Through the multinational Tracking Outcomes and Practice in Pediatric Pulmonary Hypertension registry, patient demographics, diagnosis, and treatment as judged and executed by the local physician were collected. Inclusion criteria were >3 months and <18 years of age and diagnostic cardiac catheterisation consistent with pulmonary hypertension (mean pulmonary arterial pressure ⩾25 mmHg, pulmonary vascular resistance index ⩾3 Wood units×m2, and mean pulmonary capillary wedge pressure ⩽12 mmHg). At diagnostic catheterisation, 217/244 patients (88.9%) were treatment naïve for pulmonary hypertension-targeted therapy. Targeted therapy was initiated after catheterisation in 170 (78.3%) treatment-naïve patients. A total of 19 patients received supportive therapy, 28 patients were not started on therapy, and 26 patients (10.7%) were on targeted treatment before catheterisation. Among treatment-naïve subjects, treatment was initiated with one targeted drug (n=112, 51.6%), dual therapy (n=39, 18%) or triple-therapy (n=5, 2.3%), and calcium channel blockers with one targeted medication in one patient (0.5%). Phosphodiesterase inhibitors type 5 were used frequently; some patients with pulmonary hypertension related to lung disease received targeted therapy. There is a diverse therapeutic approach for children with pulmonary hypertension with a need of better-defined treatment algorithms based on paediatric consensus for different aetiologies including the best possible diagnostic workup.