Erika B. Rosenzweig

Long-Term Prostacyclin for Pulmonary Hypertension With Associated Congenital Heart Defects

BACKGROUND Although long-term prostacyclin (PGI2) has been shown to improve hemodynamics, quality of life, and survival in patients with primary pulmonary hypertension, its use in patients with pulmonary hypertension (PHT) and associated congenital heart defects (CHD) has not been evaluated. METHODS AND RESULTS Twenty patients (15+/-14 years) with PHT and associated CHD (9 atrial septal defect, 7 ventricular septal defect, 4 transposition of the great vessels, 3 patient ductus arteriosus, 3 partial anomalous pulmonary venous return, and 1 aortopulmonary window) who failed conventional therapy (including digitalis; diuretics; oxygen; warfarin; calcium channel blockade, if indicated; and surgery, if operable) were treated with chronic PGI2. Eleven patients had previous cardiac surgery at a median age of 3 years (range, 5 days to 47 years). Eleven of 20 patients had residual systemic to pulmonary shunts. Hemodynamics, NYHA functional class, and exercise capacity were measured at baseline and after 1 year of PGI2 therapy. None of the patients acutely responded to PGI2 administration. Despite lack of an acute response, mean pulmonary artery pressure decreased 21% on chronic PGI2: 77+/-20 to 61+/-15 mm Hg (P<0.01, n=16). Cardiac index and pulmonary vascular resistance also improved on long-term PGI2: 3. 5+/-2.0 to 5.9+/-2.7 L. min-1. m-2 (P<0.01, n=16), and 25+/-13 to 12+/-7 U.m2 (P<0.01, n=16), respectively. NYHA functional class improved from 3.2+/-0.7 to 2.0+/-0.9 (P<0.0001, n=19). Exercise capacity increased from 408+/-149 to 460+/-99 m (P=0.13, n=14) on long-term PGI2. CONCLUSIONS Chronic PGI2 improves hemodynamics and quality of life in patients with PHT and associated CHD who fail conventional therapy. As previously demonstrated in patients with primary pulmonary hypertension, long-term PGI2 may have an important role in the treatment of patients with PHT and associated CHD.

A Novel Channelopathy in Pulmonary Arterial Hypertension

BACKGROUND Pulmonary arterial hypertension is a devastating disease with high mortality. Familial cases of pulmonary arterial hypertension are usually characterized by autosomal dominant transmission with reduced penetrance, and some familial cases have unknown genetic causes. METHODS We studied a family in which multiple members had pulmonary arterial hypertension without identifiable mutations in any of the genes known to be associated with the disease, including BMPR2, ALK1, ENG, SMAD9, and CAV1. Three family members were studied with whole-exome sequencing. Additional patients with familial or idiopathic pulmonary arterial hypertension were screened for the mutations in the gene that was identified on whole-exome sequencing. All variants were expressed in COS-7 cells, and channel function was studied by means of patch-clamp analysis. RESULTS We identified a novel heterozygous missense variant c.608 G→A (G203D) in KCNK3 (the gene encoding potassium channel subfamily K, member 3) as a disease-causing candidate gene in the family. Five additional heterozygous missense variants in KCNK3 were independently identified in 92 unrelated patients with familial pulmonary arterial hypertension and 230 patients with idiopathic pulmonary arterial hypertension. We used in silico bioinformatic tools to predict that all six novel variants would be damaging. Electrophysiological studies of the channel indicated that all these missense mutations resulted in loss of function, and the reduction in the potassium-channel current was remedied by the application of the phospholipase inhibitor ONO-RS-082. CONCLUSIONS Our study identified the association of a novel gene, KCNK3, with familial and idiopathic pulmonary arterial hypertension. Mutations in this gene produced reduced potassium-channel current, which was successfully remedied by pharmacologic manipulation. (Funded by the National Institutes of Health.)

Pediatric pulmonary hypertension

Pulmonary hypertension (PH) is a rare disease in newborns, infants, and children that is associated with significant morbidity and mortality. In the majority of pediatric patients, PH is idiopathic or associated with congenital heart disease and rarely is associated with other conditions such as connective tissue or thromboembolic disease. Incidence data from the Netherlands has revealed an annual incidence and point prevalence of 0.7 and 4.4 for idiopathic pulmonary arterial hypertension and 2.2 and 15.6 for pulmonary arterial hypertension, respectively, associated with congenital heart disease (CHD) cases per million children. The updated Nice classification for PH has been enhanced to include a greater depth of CHD and emphasizes persistent PH of the newborn and developmental lung diseases, such as bronchopulmonary dysplasia and congenital diaphragmatic hernia. The management of pediatric PH remains challenging because treatment decisions continue to depend largely on results from evidence-based adult studies and the clinical experience of pediatric experts.

Outcomes in Children With Idiopathic Pulmonary Arterial Hypertension

Background—Treatment for idiopathic pulmonary arterial hypertension in children includes calcium channel blockade (CCB) for acute responders with vasodilator testing and chronic epoprostenol for nonresponders. We sought to determine parameters associated with survival and treatment success. Methods and Results—A previously identified cohort of 77 children diagnosed between 1982 and 1995 with idiopathic pulmonary arterial hypertension was followed up through 2002. For acute responders treated with CCB (n=31), survival at 1, 5, and 10 years was 97%, 97%, and 81%, respectively; treatment success was 84%, 68%, and 47%, respectively. Survival for all children treated with epoprostenol (n=35) at 1, 5, and 10 years was 94%, 81%, and 61%, respectively; treatment success was 83%, 57%, and 37%, respectively. Because of the inconsistent availability of epoprostenol before 1995, we defined a “recent medical era” subset by excluding children from the total 77 patient cohort for whom epoprostenol was recommended but was unavailable. Survival in the recent medical era (n=44) at 1, 5, and 10 years was 97%, 97%, and 78%; treatment success was 93%, 86%, and 60%, respectively. Treatment success on CCB decreased significantly when acute responders became nonresponders. Age at diagnosis predicted treatment success in the recent medical era. Conclusions—Survival for children with idiopathic pulmonary arterial hypertension has significantly improved with CCB and epoprostenol. Children who are acute responders are treated with CCB; they are treated with epoprostenol if they become nonresponders. The decrease in survival and in treatment success after 5 years in all children supports the role for transplant evaluation before treatment failure.

Whole Exome Sequencing to Identify a Novel Gene (Caveolin-1) Associated with Human Pulmonary Arterial Hypertension

Background— Heritable and idiopathic pulmonary arterial hypertension (PAH) are phenotypically identical and associated with mutations in several genes related to transforming growth factor (TGF) beta signaling, including bone morphogenetic protein receptor type 2, activin receptor-like kinase 1, endoglin, and mothers against decapentaplegic 9. Approximately 25% of heritable cases lack identifiable mutations in any of these genes. Methods and Results— We used whole exome sequencing to study a 3-generation family with multiple affected family members with PAH, but no identifiable TGF beta mutation. We identified a frameshift mutation in caveolin-1 (CAV1), which encodes a membrane protein of caveolae abundant in the endothelium and other cells of the lung. An independent de novo frameshift mutation was identified in a child with idiopathic PAH. Western blot analysis demonstrated a reduction in caveolin-1 protein, while lung tissue immunostaining studies demonstrated a reduction in normal caveolin-1 density within the endothelial cell layer of small arteries. Conclusions— Our study represents successful elucidation of a dominant Mendelian disorder using whole exome sequencing. Mutations in CAV1 are associated in rare cases with PAH. This may have important implications for pulmonary vascular biology, as well as PAH-directed therapeutic development.

Pediatric Pulmonary Hypertension Guidelines From the American Heart Association and American Thoracic Society

Pulmonary hypertension is associated with diverse cardiac, pulmonary, and systemic diseases in neonates, infants, and older children and contributes to significant morbidity and mortality. However, current approaches to caring for pediatric patients with pulmonary hypertension have been limited by the lack of consensus guidelines from experts in the field. In a joint effort from the American Heart Association and American Thoracic Society, a panel of experienced clinicians and clinician-scientists was assembled to review the current literature and to make recommendations on the diagnosis, evaluation, and treatment of pediatric pulmonary hypertension. This publication presents the results of extensive literature reviews, discussions, and formal scoring of recommendations for the care of children with pulmonary hypertension.

Pharmacologic Therapy for Pulmonary Arterial Hypertension in Adults: CHEST Guideline and Expert Panel Report

OBJECTIVE Choices of pharmacologic therapies for pulmonary arterial hypertension (PAH) are ideally guided by high-level evidence. The objective of this guideline is to provide clinicians advice regarding pharmacologic therapy for adult patients with PAH as informed by available evidence. METHODS This guideline was based on systematic reviews of English language evidence published between 1990 and November 2013, identified using the MEDLINE and Cochrane Library databases. The strength of available evidence was graded using the Grades of Recommendations, Assessment, Development, and Evaluation methodology. Guideline recommendations, or consensus statements when available evidence was insufficient to support recommendations, were developed using a modified Delphi technique to achieve consensus. RESULTS Available evidence is limited in its ability to support high-level recommendations. Therefore, we drafted consensus statements to address many clinical questions regarding pharmacotherapy for patients with PAH. A total of 79 recommendations or consensus statements were adopted and graded. CONCLUSIONS Clinical decisions regarding pharmacotherapy for PAH should be guided by high-level recommendations when sufficient evidence is available. Absent higher level evidence, consensus statements based upon available information must be used. Further studies are needed to address the gaps in available knowledge regarding optimal pharmacotherapy for PAH.

Hospitalization for pain in patients with sickle cell disease treated with sildenafil for elevated TRV and low exercise capacity

In adults with sickle cell disease (SCD), an increased tricuspid regurgitation velocity (TRV) by Doppler echocardiography is associated with increased morbidity and mortality. Although sildenafil has been shown to improve exercise capacity in patients with pulmonary arterial hypertension, it has not been evaluated in SCD. We therefore sought to determine whether sildenafil could improve exercise capacity in SCD patients with increased TRV and a low exercise capacity. A TRV ≥ 2.7 m/s and a 6-minute walk distance (6MWD) between 150 and 500 m were required for enrollment in this 16-week, double-blind, placebo-controlled sildenafil trial. After 74 of the screened subjects were randomized, the study was stopped early due to a higher percentage of subjects experiencing serious adverse events in the sildenafil arm (45% of sildenafil, 22% of placebo, P = .022). Subject hospitalization for pain was the predominant cause for this difference: 35% with sildenafil compared with 14% with placebo (P = .029). There was no evidence of a treatment effect on 6MWD (placebo-corrected effect -9 m; 95% confidence interval [95% CI] -56-38; P = .703), TRV (P = .503), or N-terminal pro-brain natriuretic peptide (P = .410). Sildenafil appeared to increase hospitalization rates for pain in patients with SCD. This study is registered at www.clinicaltrials.gov as NCT00492531.

Clinical Implications of Determining BMPR2 Mutation Status in a Large Cohort of Children and Adults With Pulmonary Arterial Hypertension

BACKGROUND Bone morphogenetic protein receptor type 2 (BMPR2) mutations occur in idiopathic and familial pulmonary arterial hypertension (IPAH, FPAH); however, the impact of these mutations on clinical assessment and disease severity remains unclear. We investigated the role of BMPR2 mutations on acute vasoreactivity and disease severity in IPAH/FPAH children and adults. METHODS BMPR2 mutation types were determined in 147 IPAH/FPAH patients. Hemodynamics were obtained at baseline and with acute vasodilator testing. RESULTS Of 147 patients (69 adults, 78 children; 114 with IPAH, 33 with FPAH), 124 (84%) were BMPR2 mutation-negative, and 23 (16%) were mutation-positive. BMPR2 mutation-positive patients were less likely to respond to acute vasodilator testing than mutation-negative patients (4% vs 33%; p < 0.003; n = 147). BMPR2 mutation-positive children also appeared less likely to respond to acute vasodilator testing than mutation-negative children. BMPR2-positive patients had lower mixed venous saturation (57 +/- 9% vs 62 +/- 10%; p < 0.05) and cardiac index (CI; 2.0 +/- 1.1 vs 2.4 +/- 1.5 liters/min; p < 0.05) than BMPR2-negative patients. CONCLUSIONS Patients with BMPR2 mutations are less likely to respond to acute vasodilator testing than mutation-negative patients and appear to have more severe disease at diagnosis. Determination of BMPR2 mutations appears to help identify IPAH/FPAH children and adults who are unlikely to respond to acute vasodilator testing and, thus, unlikely to benefit from calcium channel blockade (CCB) treatment.

An Official American Thoracic Society Clinical Practice Guideline: Diagnosis, Risk Stratification, and Management of Pulmonary Hypertension of Sickle Cell Disease

BACKGROUND In adults with sickle cell disease (SCD), an increased tricuspid regurgitant velocity (TRV) measured by Doppler echocardiography, an increased serum N-terminal pro-brain natriuretic peptide (NT-pro-BNP) level, and pulmonary hypertension (PH) diagnosed by right heart catheterization (RHC) are independent risk factors for mortality. METHODS A multidisciplinary committee was formed by clinician-investigators experienced in the management of patients with PH and/or SCD. Clinically important questions were posed, related evidence was appraised, and questions were answered with evidence-based recommendations. Target audiences include all clinicians who take care of patients with SCD. RESULTS Mortality risk stratification guides decision making. An increased risk for mortality is defined as a TRV equal to or greater than 2.5 m/second, an NT-pro-BNP level equal to or greater than 160 pg/ml, or RHC-confirmed PH. For patients identified as having increased mortality risk, we make a strong recommendation for hydroxyurea as first-line therapy and a weak recommendation for chronic transfusions as an alternative therapy. For all patients with SCD with elevated TRV alone or elevated NT-pro-BNP alone, and for patients with SCD with RHC-confirmed PH with elevated pulmonary artery wedge pressure and low pulmonary vascular resistance, we make a strong recommendation against PAH-specific therapy. However, for select patients with SCD with RHC-confirmed PH who have elevated pulmonary vascular resistance and normal pulmonary capillary wedge pressure, we make a weak recommendation for either prostacyclin agonist or endothelin receptor antagonist therapy and a strong recommendation against phosphodiesterase-5 inhibitor therapy. CONCLUSIONS Evidence-based recommendations for the management of patients with SCD with increased mortality risk are provided, but will require frequent reassessment and updating.