Mortality in Pulmonary Arterial Hypertension in the Modern Era: Early Insights From the Pulmonary Hypertension Association Registry.

Background Current mortality data for pulmonary arterial hypertension (PAH) in the United States are based on registries that enrolled patients prior to 2010. We sought to determine mortality in PAH in the modern era using the PHAR (Pulmonary Hypertension Association Registry). Methods and Results We identified all adult patients with PAH enrolled in the PHAR between September 2015 and September 2020 (N=935). We used Kaplan-Meier survival analysis and Cox proportional hazards models to assess mortality at 1, 2, and 3 years. Patients were stratified based on disease severity by 3 validated risk scores. In treatment-naïve patients, we compared survival based on initial treatment strategy. The median age was 56 years (44-68 years), and 76% were women. Of the 935 patients, 483 (52%) were ≤6 months from PAH diagnosis. There were 121 deaths (12.9%) during a median follow-up time of 489 days (281-812 days). The 1-, 2-, and 3-year mortality was 8% (95% CI, 6%-10%), 16% (95% CI, 13%-19%), and 21% (95% CI, 17%-25%), respectively. When stratified into low-, intermediate-, and high-risk PAH, the mortality at 1, 2, and 3 years was 1%, 4% to 6%, and 7% to 11% for low risk; 7% to 8%, 11% to 16%, and 18% to 20% for intermediate risk; and 12% to 19%, 22% to 38%, and 28% to 55% for high risk, respectively. In treatment-naïve patients, initial combination therapy was associated with better 1-year survival (adjusted hazard ratio, 0.43 [95% CI, 0.19-0.95]; P=0.037). Conclusions Mortality in the intermediate- and high-risk patients with PAH remains unacceptably high in the PHAR, suggesting the importance for early diagnosis, aggressive use of available therapies, and the need for better therapeutics.

Characterization of a caveolin-1 mutation associated with both pulmonary arterial hypertension and congenital generalized lipodystrophy.

Congenital generalized lipodystrophy (CGL) and pulmonary arterial hypertension (PAH) have recently been associated with mutations in the caveolin-1 ( CAV1 ) gene, which encodes the primary structural protein of caveolae. However, little is currently known about how these CAV1 mutations impact caveolae formation or contribute to the development of disease. Here, we identify a heterozygous F160X CAV1 mutation predicted to generate a C-terminally truncated mutant protein in a patient with both PAH and CGL using whole exome sequencing, and characterize the properties of CAV1 , caveolae-associated proteins and caveolae in skin fibroblasts isolated from the patient. We show that morphologically defined caveolae are present in patient fibroblasts and that they function in mechanoprotection. However, they exhibited several notable defects, including enhanced accessibility of the C-terminus of wild-type CAV1 in caveolae, reduced colocalization of cavin-1 with CAV1 and decreased stability of both 8S and 70S oligomeric CAV1 complexes that are necessary for caveolae formation. These results were verified independently in reconstituted CAV1 -/- mouse embryonic fibroblasts. These findings identify defects in caveolae that may serve as contributing factors to the development of PAH and CGL and broaden our knowledge of CAV1 mutations associated with human disease.

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.)

The relationship between the severity of hemolysis, clinical manifestations and risk of death in 415 patients with sickle cell anemia in the US and Europe.

The intensity of hemolytic anemia has been proposed as an independent risk factor for the development of certain clinical complications of sickle cell disease, such as pulmonary hypertension, hypoxemia and cutaneous leg ulceration. A composite variable derived from several individual markers of hemolysis could facilitate studies of the underlying mechanisms of hemolysis. In this study, we assessed the association of hemolysis with outcomes in sickle cell anemia. A hemolytic component was calculated by principal component analysis from reticulocyte count, serum lactate dehydrogenase, aspartate aminotransferase and total bilirubin concentrations in 415 hemoglobin SS patients. Association of this component with direct markers of hemolysis and clinical outcomes was assessed. As primary validation, both plasma red blood cell microparticles and cell-free hemoglobin concentration were higher in the highest hemolytic component quartile compared to the lowest quartile (P≤0.0001 for both analyses). The hemolytic component was lower with hydroxyurea therapy, higher hemoglobin F, and alpha-thalassemia (P≤0.0005); it was higher with higher systemic pulse pressure, lower oxygen saturation, and greater values for tricuspid regurgitation velocity, left ventricular diastolic dimension and left ventricular mass (all P<0.0001). Two-year follow-up analysis showed that a high hemolytic component was associated with an increased risk of death (hazard ratio, HR 3.44; 95% confidence interval, CI: 1.2-9.5; P=0.02). The hemolytic component reflects direct markers of intravascular hemolysis in patients with sickle cell disease and allows for adjusted analysis of associations between hemolytic severity and clinical outcomes. These results confirm associations between hemolytic rate and pulse pressure, oxygen saturation, increases in Doppler-estimated pulmonary systolic pressures and mortality (Clinicaltrials.gov identifier: NCT00492531).

Successful treatment of severe mechanical mitral valve thrombosis with tissue plasminogen activator in a 7-month-old infant.

Severe thrombosis of a mechanical valve is a rare complication in pediatric patients. Thrombolytic therapy as treatment of mechanical mitral valve thrombosis has rarely been reported in young infants. We report the successful treatment with recombinant tissue-type plasminogen activator of a mechanical mitral valve thrombus in a 7 month-old patient with trisomy 21, complete atrioventricular canal defect and pulmonary hypertension status post complete atrioventricular canal repair and subsequent prosthetic mitral valve replacement. He presented with respiratory decompensation and shock secondary to severe mechanical mitral valve stenosis. Serial echocardiograms showed significant resolution of the thrombus within 18 h of infusion with no major bleeding complications during the treatment course. Although a rare complication of mechanical valve placement in pediatrics, thrombosis of mechanical valves may result in severe hemodynamic and respiratory compromise. This case demonstrates that thrombolytic therapy is a feasible option for the treatment of critical thrombosis in pediatric patients after MVR.

Echocardiographic markers of elevated pulmonary pressure and left ventricular diastolic dysfunction are associated with exercise intolerance in adults and adolescents with homozygous sickle cell anemia in the United States and United Kingdom.

BACKGROUND: Noninvasively assessed pulmonary pressure elevations and left ventricular (LV) diastolic dysfunction are associated with increased mortality in adults with sickle cell disease, but their relationship to exercise intolerance has not been evaluated prospectively. METHODS AND RESULTS: Echocardiography, 6-minute walk distance, hemolytic rate, and serum concentrations of ferritin and erythropoietin were evaluated in a cohort of 483 subjects with homozygous hemoglobin S in the U.S. and U.K. Walk-Treatment of Pulmonary Hypertension and Sickle Cell Disease with Sildenafil Therapy (Walk-PHaSST) study. Tricuspid regurgitation velocity, which reflects systolic pulmonary artery pressure, was 2.7 to <3.0 m/s (mean±SD, 2.8±0.1) in 26% of the subjects and ≥3.0 m/s (mean±SD, 3.4±0.4) in 11%. The LV lateral E/e' ratio, which has been shown to reflect LV filling pressure in other conditions but has not been studied in sickle cell disease, was significantly higher in the groups with tricuspid regurgitation velocity ≥2.7 m/s. Increased hemolysis (P<0.0001), LV lateral E/e' ratio (P=0.0001), blood urea nitrogen (P=0.0002), and erythropoietin (P=0.002) were independently associated with an increased tricuspid regurgitation velocity. Furthermore, female sex (P<0.0001), older age (P<0.0001), LV lateral E/e' ratio (P=0.014), and tricuspid regurgitation velocity (P=0.019) were independent predictors of a shorter 6-minute walk distance. CONCLUSIONS: Echocardiography-estimated elevated pulmonary artery systolic pressure and LV lateral E/e' ratio were independently associated with poor exercise capacity in a large cohort of patients with sickle cell anemia. Controlled trials investigating whether strategies to prevent or delay pulmonary hypertension and/or LV diastolic dysfunction will improve exercise capacity and long-term outcomes in sickle cell anemia should be considered. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00492531.

Ambrisentan for pulmonary arterial hypertension due to congenital heart disease.

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 (S(a)O(2)), 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 S(a)O(2) (89 ± 7% vs 89% ± 6%, p=0.75, n=15), exercise S(a)O(2) (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, S(a)O(2), 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 S(a)O(2), 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.

Long-term outcomes in children with pulmonary arterial hypertension treated with bosentan in real-world clinical settings.

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.

Polymorphism in the angiotensin II type 1 receptor (AGTR1) is associated with age at diagnosis in pulmonary arterial hypertension.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Pulmonary hypertension in sickle cell disease.

Pulmonary hypertension (PH), a disorder characterized by elevated pulmonary artery pressure and pulmonary vascular resistance, is an increasingly recognized complication of sickle cell disease (SCD), with a prevalence of approximately 30% in adult patients. It confers a high risk of death, with 2-year mortality rates of 40-50%, even at modest elevations of pulmonary pressures. The pathogenesis of PH complicating SCD is probably heterogeneous, including hemolysis and its effect on nitric oxide bioavailability, asplenia, thrombosis, chronic lung disease, and iron overload. Clinical manifestations of PH are difficult to recognize in sickle cell patients as they overlap with signs and symptoms of chronic anemia. Doppler echocardiography is recommended for screening, using tricuspid regurgitant jet velocity (TRV) to estimate pulmonary artery systolic pressure, with PH defined as TRV of at least 2.5 m/s. Detection of an elevated TRV is followed by characterization of PH by various tests to confirm diagnosis, define hemodynamics, identify underlying causes or associated diseases, determine severity and prognosis, and select appropriate therapy. Current data on treatment of PH in SCD are limited. Recommendations include intensification of sickle cell-directed therapies, treatment of causal factors or associated diseases, general supportive measures, and use of PH-specific pharmacologic agents. Further knowledge of the pathobiology of this complication and clinical trials of effective therapy are needed to improve survival.

Effects of long-term bosentan in children with pulmonary arterial hypertension.

OBJECTIVES: This study investigated the long-term outcome of children with pulmonary arterial hypertension (PAH) treated with bosentan therapy, with or without concomitant prostanoid therapy. BACKGROUND: Bosentan, an oral endothelin ET(A)/ET(B) receptor antagonist, improves hemodynamics and exercise capacity in adults with PAH; however, limited data are available on its long-term effects in children. METHODS: In this retrospective study, 86 children with PAH (idiopathic, associated with congenital heart or connective tissue disease) started bosentan with or without concomitant intravenous epoprostenol or subcutaneous treprostinil therapy. Hemodynamics, World Health Organization (WHO) functional class, and safety data were collected. RESULTS: At the cutoff date, 68 patients (79%) were still treated with bosentan, 13 (15%) were discontinued, and 5 (6%) had died. Median exposure to bosentan was 14 months. In 90% of the patients (n = 78), WHO functional class improved (46%) or was unchanged (44%) with bosentan treatment. Mean pulmonary artery pressure and pulmonary vascular resistance decreased (64 +/- 3 mm Hg to 57 +/- 3 mm Hg, p = 0.005 and 20 +/- 2 U x m2 to 15 +/- 2 U x m2, p = 0.01, respectively; n = 49). Kaplan-Meier survival estimates at one and two years were 98% and 91%, respectively. The risk for worsening PAH was lower in patients in WHO functional class I/II at bosentan initiation than in patients in WHO class III/IV at bosentan initiation. CONCLUSIONS: These data suggest that bosentan, an oral endothelin ET(A)/ET(B) receptor antagonist, with or without concomitant prostanoid therapy, is safe and efficacious for the treatment of PAH in children.

Idiopathic pulmonary arterial hypertension in children.

PURPOSE OF REVIEW: Until recently, the diagnosis of idiopathic pulmonary arterial hypertension was virtually a death sentence, particularly for children. Although there is no cure for idiopathic pulmonary arterial hypertension, recent medical advances have dramatically changed the course of this disease in children. A review of some of the latest medical advances will provide the reader with a better understanding of the most current treatment options for children with idiopathic pulmonary arterial hypertension. RECENT FINDINGS: The literature reviewed demonstrate sustained clinical and hemodynamic improvement in children with various types of pulmonary arterial hypertension as well as increased survival in patients with idiopathic pulmonary arterial hypertension using current treatment strategies. SUMMARY: This article will provide an overview of how the current diagnostic and treatment strategies of idiopathic pulmonary arterial hypertension in children have advanced over the last several years and how this impacts on clinical practice.

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.

Pulmonary arterial hypertension in children.

Pulmonary arterial hypertension is a serious progressive condition with a poor prognosis if not identified and treated early. Because the symptoms are nonspecific and the physical findings can be subtle, the disease is often diagnosed in its later stages. Remarkable progress has been made in the field of pulmonary arterial hypertension over the past several decades. The pathology is now better defined, and significant advances have occurred in understanding the pathobiologic mechanisms. Risk factors have been identified, and the genetics have been characterized. Advances in technology allow earlier diagnosis as well as better assessment of disease severity. Therapeutic modalities such as new drugs, e.g., epoprostenol, treprostinil, and bosentan, and surgical/interventional options, e.g., transplantation and atrial septostomy, which were unavailable several decades ago, have had a significant impact on prognosis and outcome. Thus, despite our inability to cure pulmonary arterial hypertension, advances in medical treatments over the past two decades have resulted in significant improvement in outcomes for children with various forms of pulmonary arterial hypertension. This report is a review the current state of the art for pulmonary arterial hypertension in 2004, with an emphasis on childhood pulmonary arterial hypertension and specific recommendations for current practice and future directions.