Connective Tissue Disease-associated Pulmonary Arterial Hypertension Research Articles

Endostatin and Vascular Endothelial Growth Factor-A165b May Contribute to Classification of Pulmonary Hypertension.

Background: Pulmonary hypertension (PH) is characterized by dysregulation of small pulmonary arteries. In addition to endostatin (ES), placenta growth factor (PlGF), vascular endothelial growth factor-A (VEGF-A), and the anti-angiogenesis isoform of VEGF-A (VEGF-A165b) are associated with PH. However, the usefulness of these biomarkers in PH in unknown. We investigated whether these 4 biomarkers are related to PH classification.Methods and Results: Between July 2015 and August 2017, 33 control patients and 107 PH patients were enrolled in the study. Among the PH patients, 48 had pulmonary arterial hypertension (PAH), 5 had left heart disease-associated PH (LHD-PH), 4 had lung disease-associated PH (LD-PH), and 50 had chronic thromboembolic PH (CTEPH). Among the PAH patients, 16 had idiopathic PAH (IPAH) and 17 had connective tissue disease-associated PAH (CTD-PAH). PlGF, total VEGF-A, and VEGF-A165b levels were measured in the control and PH groups. ES was only measured in the PH group. VEGF-A165b levels were significantly higher in the LD-PH group than in the PAH, LHD-PH, and CTEPH groups (all P<0.001). PlGF levels were significantly higher in the CTD-PAH group than in the IPAH and control groups. ES levels were significantly correlated with the 6-min walk distance (P<0.001), B-type natriuretic peptide (P<0.001), and pulmonary vascular resistance (P=0.008).Conclusions: ES could detect CTD-PAH in PAH and may be an indicator of PH severity. VEGF-A165b was useful in detecting LD-PH.

Abstract 14783: Association of Daily Step Count and Resting Heart Rate With Right Ventricular Function in Pulmonary Arterial Hypertension

Introduction: Remote activity monitoring may provide new insight into behavioral choices and exercise capacity in pulmonary arterial hypertension (PAH). Here, we report baseline data from a randomized behavioral intervention (NCT03069716) to increase step counts in PAH. Hypothesis: Higher daily step count and lower resting heart rate (RHR) are associated with better right ventricular (RV) function. Methods: We recruited functional class I-III patients with idiopathic, heritable, or connective tissue disease-associated PAH on stable therapy. Participants were provided a Fitbit Charge 3 device and monitored for two weeks as a run-in period to the trial. The 6MWD test and echocardiogram were performed at baseline. RV function was assessed by tricuspid annular plane systolic excursion (TAPSE) and fractional area change (FAC). We conducted linear regression to examine associations between daily step count and RHR with RV function, adjusted for age, sex, and BMI. Results: In total, 42 subjects completed the run-in period (48 ± 11 years, 86% female, 64% functional class II). PAH etiology was 76% idiopathic, 17% heritable, and 7% connective tissue disease. Average daily step count, RHR, and 6MWD were 4718 ± 3521 steps, 72 ± 10 beats per minute, and 424 ± 106 meters, respectively. Only 2.9% of days monitored had missing data. Daily step count (Beta 0.37mm per 1,000 steps; p = 0.039) and RHR (Beta -0.19mm per beat; p = 0.017) were associated with TAPSE ( Figure ), and daily step count was associated with FAC (Beta 1.1% per 1,000 steps; p = 0.01). The 6MWD was modestly associated with daily step count (r = 0.35; p = 0.028) but not associated with RV function (p &gt; 0.05). Conclusions: Remote activity monitoring is feasible in PAH and may provide important clinical information as an adjunct to clinic-based assessments of exercise capacity. Lower daily step count and a higher RHR are associated with poorer RV function. Interventions to increase daily activity warrant further investigation in PAH.

EmPHasis-10 health-related quality of life score predicts outcomes in patients with idiopathic and connective tissue disease-associated pulmonary arterial hypertension: results from a UK multicentre study

Health-related quality of life (HRQoL) scores assess symptom burden in pulmonary arterial hypertension (PAH) but data regarding their role in prognostication and risk stratification are limited. We assessed these relationships using the emPHasis-10 HRQoL measure.1745 patients with idiopathic PAH (IPAH), drug-induced PAH (DPAH), heritable PAH (HPAH) (collectively “(I/D/H)PAH”), or connective tissue disease-associated PAH (CTD-PAH), who had completed emPHasis-10 questionnaires at one of six UK referral centres between 2014 and 2017, were identified. Correlations with exercise capacity and World Health Organization (WHO) functional class were assessed, and exploratory risk stratification thresholds were tested.Moderate correlations were seen between emPHasis-10 scores and 6-min walk distance (r=−0.546), incremental shuttle walk distance (r=−0.504) and WHO functional class (r=0.497) (all p<0.0001). Distribution of emPHasis-10 score differed significantly between each WHO functional class (all p<0.0001). On multivariate analysis, emPHasis-10 score, but not WHO functional class, was an independent predictor of mortality. In a risk stratification approach, scores of 0–16, 17–33 and 34–50 identified incident patients with 1-year mortality of 5%, 10% and 23%, respectively. Survival of patients in WHO functional class III could be further stratified using an emPHasis-10 score ≥34 (p<0.01). At follow-up, patients with improved emPHasis-10 scores had improved exercise capacity (p<0.0001) and patients who transitioned between risk groups demonstrated similar survival to patients originally in those risk groups.The emPHasis-10 score is an independent prognostic marker in patients with (I/D/H)PAH or CTD-PAH. It has utility in risk stratification in addition to currently used parameters. Improvement in emPHasis-10 score is associated with improved exercise capacity.

Predictors of Long-term Outcomes in Patients With Connective Tissue Disease Associated With Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by increased pulmonary arterial pressure and pulmonary vascular resistance that can lead to right-sided heart failure. Connective tissue disease-associated PAH (CTD-PAH) often has poorer outcomes than idiopathic or hereditary PAH, suggesting the presence of non-PAH factors that could affect the prognoses. This cohort study aimed to identify prognostic factors for CTD-PAH management. Medical records from April 1999 to November 2014 were reviewed to determine the time from treatment initiation to the occurrence of a clinically worsening event and the time elapsed until death. Data at baseline and the final assessment were used to identify prognostic factors associated with events using univariate and multivariate analyses by the stepwise Cox regression method. In 36 patients with CTD-PAH analyzed, the proportions with no clinically worsening events at 1, 2, and 3 years after treatment initiation were 62%, 52%, and 45%, respectively, with survival rates of 88%, 77%, and 77%, respectively. The regression model showed that reduced hemoglobin at baseline, reduced qR pattern in electrocardiogram lead V1, increased 60-minute erythrocyte sedimentation rate, and increased mean pulmonary arterial pressure at the final assessment were risk factors that were significantly associated with clinical worsening. For survival, no prognostic factor was identifiable. Hemodynamic and non-PAH factors, such as anemia, nutritional status, and inflammatory activity of the underlying CTD, which are not listed in the risk assessment table of PAH guidelines, should be strictly controlled to improve the prognosis of patients with CTD-PAH. A more multifactorial treatment strategy should be developed.

Age-related differences in hemodynamics and functional status in pulmonary arterial hypertension: Baseline results from the Pulmonary Hypertension Association Registry

The age of patients with pulmonary arterial hypertension (PAH) has increased, with registries now reporting mean ages of 50 to 65 years old. Limited data exist on age-related differences in hemodynamic and functional assessments in PAH. Adults with PAH in the Pulmonary Hypertension Association Registry were divided into 3 groups (18-50, 51-65, and >65 years old). Analysis of variance and chi-square testing were used to assess for baseline differences. Linear regression was used to examine the association of age with continuous hemodynamic and functional variables. A total of 769 patients with mean age of 56 ± 16 years were included. Older patients had more connective tissue disease-associated PAH and less drug-associated PAH. In linear regression models, each year of increased age was associated with shorter 6-minute walk distance (-3.37 meters; 95% CI, -3.97 to -2.76), lower mean pulmonary arterial pressure (-0.21 mmHg; 95% CI, -0.27 to -0.15), and lower pulmonary vascular resistance (-0.06 Wood units; 95% CI, -0.09 to -0.04). Pulmonary arterial compliance, cardiac index, right ventricular stroke work index, and percent predicted 6-minute walk distance were unrelated to age; resistance-compliance time was negatively related to age (-3 milliseconds per year; 95% CI, -4 to -2). Relative to their pulmonary vascular resistance, older patients have lower pulmonary artery compliance and worse right ventricular performance. Based on these findings, we suspect that age influences right ventricular loading conditions and the response of the right ventricle to increased afterload.

Prognostic factors of pulmonary hypertension associated with connective tissue disease: pulmonary artery size measured by chest CT

Pulmonary artery enlargement is a common manifestation of chest CT in patients with pulmonary arterial hypertension (PAH). The exact clinical significance of this phenomenon has not been clarified in connective tissue disease (CTD)-associated PAH (CTD-PAH). We aimed to explore the association between the dilatation of pulmonary artery and prognosis of CTD-PAH patients. We retrospectively investigated 140 CTD-PAH patients diagnosed by echocardiography from 2009 to 2018. A chest multi-slice CT was performed on all the patients. Main pulmonary artery (MPA), right pulmonary artery (RPA), left pulmonary artery (LPA), ascending aorta (AAo) and descending aorta (DAo) diameters were measured. The ratios MPA/AAo and MPA/DAo were also calculated. The primary end point was all-cause mortality. During the observational period of 3.44 (0.23) years, 36 patients were followed to death. Cox univariate proportional hazard analysis showed that age, gender, MPA diameter, LPA diameter and RPA diameter were related to the risk of 5-year all-cause mortality in patients with CTD-PAH. In Cox multivariate proportional hazard analysis, MPA diameter and gender were predictors of all-cause mortality in CTD-PAH patients. An all-cause mortality risk prediction model revealed that baseline MPA diameter has the ability to predict 5-year all-cause mortality in CTD-PAH patients. Kaplan-Meier analysis showed that the 5-year survival rate was significantly lower in patients with MPA ≥37.70 mm (P ≤ 0.00012) compared with MPA ≤ 37.70 mm. MPA diameter ≥37.70 mm measured by chest multi-slice CT was a potential independent risk factor of the poor long-term prognosis in Chinese CTD-PAH patients.

Initial combination therapy of ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) in the modified intention-to-treat population of the AMBITION study: post hoc analysis

ObjectivesTo evaluate initial combination therapy with ambrisentan plus tadalafil (COMB) compared with monotherapy of either agent (MONO), and the utility of baseline characteristics and risk stratification in predicting outcomes, in...

Impact of race on survival in pulmonary arterial hypertension: Results from the REVEAL registry

Prior research has suggested that the prevalence and outcomes of pulmonary arterial hypertension (PAH) may vary by race or ethnicity. However, these studies have been limited by small sample size or methodological techniques relying on epidemiologic data. The purpose of this study is to evaluate the relationship between race/ethnicity and survival in a large U.S.-based prospective multicenter registry. Patients in the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL), a 5-year observational study of Group 1 PAH, were categorized by race/ethnicity. Baseline hemodynamic characteristics, clinical characteristics, and medication use was described. The relationship between race/ethnicity and outcome was evaluated by Kaplan-Meier and Cox proportional hazards modeling techniques. Left-truncation analysis, which adjusted for time from diagnosis to study enrollment, was used to minimize the effect of survivor bias. This analysis included 3,046 patients; 2,202 identified as white, 393 as black, 263 as Hispanic, 100 as Asian or Pacific Islander, and 88 as other. Unadjusted Kaplan-Meier survival analysis indicated that white patients had the lowest survival rates. After adjusting for variables of prognostic impact, race/ethnicity was no longer significantly associated with survival. Other results showed that black patients were more likely to have connective tissue disease-associated PAH, Hispanic patients were more likely to have portopulmonary hypertension, and Asian patients were more likely to have congenital heart disease-associated PAH. Analysis of the REVEAL registry did not find race/ethnicity to be a significant predictor of mortality. This is the largest analysis to date evaluating the role of race/ethnicity on outcomes in PAH.

TRANSITIONING FROM INHALED ILOPROST TO ORAL SELEXIPAG: A CASE REPORT

SESSION TITLE: Monday Medical Student/Resident Case Report Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/21/2019 02:30 PM - 03:15 PM INTRODUCTION: The TRANSIT-1 study looked into transition from inhaled Treprostinil to oral Selexipag (SXP) over the course of 16 weeks[1]. To our knowledge, similar published studies or case series regarding transition from inhaled Iloprost (ILO) to SXP are not yet available. We report the safe transition of a patient with connective tissue disease associated pulmonary arterial hypertension (CTD-PAH) from ILO over to SXP. CASE PRESENTATION: 52 y/o woman with SLE-SSc overlap, Raynauds syndrome, CTD-PAH, & resolved past APLA-related PEs on indefinite warfarin, had been on Bosentan 125mg BID & ILO 5mcg 6 inhalations a day for many years. Patient’s CTD-PAH had been stable at WHO FC 2. She had minimal adverse effects from her current medication regimen. Recently, patient expressed a preference for SXP over ILO. Transition was planned based on GRIPHON study[2] . Parallel up-titration of SXP with down-titration of ILO was performed, while patient continued to take Bosentan. For the 1st week, SXP was started at 200mcg BID in addition to usual 6 inhalations daily ILO. SXP was increased by 200mcg BID per week, while ILO was decreased by 3 inhalations per week. By 3rd week, patient took 600 mcg BID of SXP only, her highest tolerable dose. Throughout the transition, patient was in regular communication with the provider & a visiting specialty pharmacy nurse. Adverse reactions reported were nausea and episodic vomiting, which resolved with time & supportive care. Patient maintained her WHO FC & oxygenation, & had no clinical signs of right heart failure. DISCUSSION: The efficacy adverse profile for SXP against placebo is similar to ILO[2-4]. No head to head comparison is available for both drugs. TRANSIT-1 reported side-effect of muscle bleeding for a patient on warfarin. Our patient didn’t report any such event. TRANSIT-1 study continued their parallel titration for 8 weeks, followed by close monitoring for 4 weeks. In contrast, our patient safely stopped her ILO by the 2nd week, while continued the up-titration of SXP to tolerance. CONCLUSIONS: Our case report suggests that a relatively rapid & safe transition from ILO over to SXP is possible in clinically stable patients with CTD-PAH & relatively better preserved functional status. Reference #1: Frost, A., et al., Safety and tolerability of transition from inhaled treprostinil to oral selexipag in pulmonary arterial hypertension: Results from the TRANSIT-1 study. J Heart Lung Transplant, 2019. 38(1): p. 43-50. Reference #2: Sitbon, O., et al., Selexipag for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med, 2015. 373(26): p. 2522-33. Reference #3: Olschewski, H., et al., Inhaled Iloprost for Severe Pulmonary Hypertension. New Engl J Med, 2002. 347(5): p. 322-329. DISCLOSURES: No relevant relationships by Sajeer Bhura, source=Web Response No relevant relationships by William Gibbons, source=Web Response

Non-Cirrhotic Intrahepatic Portal Hypertension Induced Pulmonary Arterial Hypertension: Is it More Prevalent than we Think?

Introduction Porto-Pulmonary Hypertension (PoPH) belongs to WHO group I, Pulmonary Arterial Hypertension (PAH). It has a prevalence of 0.5-5% and is potentially curable with liver transplant. Non-cirrhotic intrahepatic portal hypertension (NCIPH) is a rare cause of PoPH that shares clinical features of advanced right heart failure. Based on review of the literature and Pulmonary Hypertension (PH) registries, most studies report the prevalence of patients with the liver cirrhosis with little to no data on the incidence of PoPH amongst the non-cirrhotic patient population. In this report, we describe the two cases of “missed” NCIPH and PoPH who were diagnosed in our institution within the span of six months. Case Reports The first patient was a 36 year old African American female who carried an initial diagnosis of SLE and ITP. She was on combination therapy with prostacyclin and endothelin receptor antagonist for the treatment of PAH. Her recurrent epistaxis from thrombocytopenia was refractory to therapy with prednisone, Rituximab, Romiplostim requiring multiple PRBC transfusions. Abdominal imaging revealed splenomegaly while liver biopsy demonstrated Nodular Regenerative Hyperplasia (NRH) without cirrhosis. The second patient, a 44 year old Chinese female, was initially diagnosed with idiopathic PAH. She was also identified to have ITP and showed no significant response to dexamethasone. On hospital admission, both patients presented with large volume ascites, splenomegaly and dependent edema. While in the ICU, they underwent RHC with assessment of Hepatic Venous Pressure Gradient (HVPG) demonstrating severely elevated pressures at 14 mmHg (Normally ≤ 5 mmHg) (Table 1). Liver biopsy was performed during the same procedure without complications. The pathology was consistent with NCIPH. Summary Our report illustrates the importance of considering the diagnosis of NCIPH in patients with PH and refractory ITP, particularly in the setting of splenomegaly and lack of overt cirrhosis. Due to an estimated 50% of patients with NCIPH that go on to develop portal hypertension, it is important to consider this diagnosis when evaluating patients with PH as the treatment strategy differs from idiopathic and connective tissue disease-associated PAH. Given the limited risk of HVPG measurement as part of the evaluation of patients with PAH, our single center experience would suggest screening for NCIPH in select patients and embracing this etiology in the differential.

Pulmonary arterial hypertension in a multi-ethnic Asian population: Characteristics, survival and mortality predictors from a 14-year follow-up study.

Pulmonary arterial hypertension (PAH) is a rare and fatal disease. Data from Asia are lacking compared with the West. We aim to describe disease characteristics in an ethnically diverse South-East Asian population and assess predictors for survival. We consecutively enrolled patients with PAH referred to our pulmonary hypertension specialty centre from January 2003 to December 2016. Baseline characteristics and survival were analysed. Based on a forward predictor selection procedure, a multi-level structural equation model was applied to identify predictors associated with mortality. Out of 148 patients enrolled, 77% were females and mean age was 50.8 ± 15.9 years. Racial distribution was consistent with our population census. The most common aetiologies were congenital heart disease-associated PAH (35.8%), idiopathic PAH (29.7%) and then connective tissue disease-associated PAH (24.3%). Most patients presented in World Health Organization (WHO) Functional Class (FC) II (48.6%), followed by FC III (28.8%). Majority of patients (54.1%) were on phosphodiesterase type 5 (PDE5) inhibitor monotherapy. Survival rates were 85.8% at the end of the first year, 70.9% at 3 years, 66.9% at 5 years, 61.5% at 7 years and 55.4% at 10 years. The Registry to Evaluate Early And Long-term PAH Disease Management (REVEAL) score (RS) was found to be the best predictor of mortality. A score > 6 was identified as a cut-off. Other predictors include mean right atrial pressure, heart rate, aetiology, age and N-terminal pro-brain natriuretic peptide. In this first registry study from a South-East Asian population, our survival rates are comparable with other national registries. The RS is validated in our population to be a good predictor of mortality.

Long-term survival in pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: Insights from a referral center in Portugal

ObjectivesThis study aims to assess the long-term survival of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) patients followed in a Portuguese pulmonary hypertension (PH) referral center. MethodsWe studied PAH and CTEPH patients diagnosed between January 2005 and December 2016. Cumulative survival was estimated using the Kaplan-Meier method. Survival trends were compared over two periods (2005-2010 vs. 2011-2016). ResultsOf the 142 studied PH patients (age 54±18 years; 31% male), 47 had CTEPH and 95 had group 1 PH. Most patients with CTEPH and idiopathic/heritable PAH (I/HPAH) were in NYHA III-IV at diagnosis (64% and 57%, respectively). At the time of death, 31% of patients with connective tissue disease (CTD)-associated PAH (CTD-PAH) and all I/HPAH patients were on double or triple combination therapy. No patient underwent lung transplantation. Pulmonary endarterectomy or angioplasty were performed in 36% of CTEPH patients. Age at diagnosis tended to increase over time in CTD-PAH (53±15 vs. 63±15 years; p=0.13) and I/HPAH (39±15 vs. 51±19 years; p=0.10). The five-year survival estimates for I/HPAH, CTD-PAH and CTEPH patients were 80%, 52%, and 81%, respectively. Over time, CTD-PAH and CTEPH showed better five-year survival (33 vs. 67% and 77 vs. 84%), but I/HPAH did not (84 vs. 75%). ConclusionsOur data indicate a trend toward improved survival over time of CTD-PAH and CTEPH patients treated at a Portuguese referral PH center. Earlier diagnosis, increasing use of parenteral prostanoids, and surgical treatment may further improve PH prognosis.

Prevalence of iron deficiency in different subtypes of pulmonary hypertension

ObjectivesIron deficiency (ID) prevalence in Chinese patients suffering from pulmonary hypertension (PH) is unclear so far. This study aimed to investigate ID prevalence in different subtypes of PH and its relevant factors. MethodsHospitalized patients diagnosed with PH from September 2015 to March 2017 were retrospectively enrolled. Patients were grouped based on etiology. Logistic regression analysis was performed to determine factors associated with ID. ResultsID was found in 38.25% of 251 PH patients; with the highest prevalence in connective tissue disease associated pulmonary arterial hypertension (CTD-PAH). Univariate logistic regression analysis showed that female sex, age, CTD-PAH diagnosis and high sensitive C reactive protein (hs-CRP) were associated with ID. After adjusting for age, sex and hs-CRP, the diagnosis of CTD-PAH was still associated with ID (OR = 3.01, 95%CI 1.02–8.90, P < 0.05). ConclusionsID is common in PH in China. CTD-PAH is independently associated with ID, after adjustment for age, sex, and hs-CRP.

Pulmonary arterial hypertension in the setting of scleroderma is different than in the setting of lupus: A review.

Pulmonary hypertension (PH) is a clinical syndrome that is subdivided into five groups per the World Health Organization (WHO) classification, based largely on hemodynamic and pathophysiologic criteria. WHO Group 1PH, termed pulmonary arterial hypertension (PAH), is a clinically progressive disease that can eventually lead to right heart failure and death, and it is hemodynamically characterized by pre-capillary PH and increased pulmonary vascular resistance in the absence of elevated left ventricular filling pressures. PAH can be idiopathic, heritable, or associated with a variety of conditions. Connective tissue diseases make up the largest portion of these associated conditions, most commonly systemic sclerosis (SSc), followed by mixed connective tissue disease and systemic lupus erythematous. These etiologies (namely SSc and Lupus) have been grouped together as connective tissue disease-associated PAH, however emerging evidence suggests they differ in pathogenesis, clinical course, prognosis, and treatment response. This review highlights the differences between SSc-PAH and Lupus-PAH. After introducing the diagnosis, screening, and pathobiology of PAH, we discuss connective tissue disease-associated PAH as a group, and then explore SSc-PAH and SLE-PAH separately, comparing these 2 PAH etiologies.

IL-13 enhances mesenchymal transition of pulmonary artery endothelial cells via down-regulation of miR-424/503 in vitro

Pulmonary arterial hypertension (PAH) has a major effect on life expectancy with functional degeneracy of the lungs and right heart. Interleukin-13 (IL-13), one of the type 2 cytokines mainly associated with allergic diseases, has recently been reported to be associated with Schistosomiasis-associated PAH which shares pathological features with other forms of PAH, such as idiopathic PAH and connective tissue disease-associated PAH. But a direct pathological role of IL-13 in the development of PAH has not been explored. We examined the effects of recombinant human IL-13 on the function of primary human pulmonary artery endothelial cells (HPAECs) to examine how IL-13 influences exacerbation of PAH. IL-13 increased the expression of Rictor, which is a key molecule of mammalian target of rapamycin complex 2. Treatment of IL-13 induced HPAEC migration via Rictor. Rictor was directly regulated by both miR-424 and 503 (miR-424/503). Therefore, IL-13 increases Rictor level by regulating miR-424/503, causing the increase of HPAEC migration. Since enhancement of HPAEC migration in the lung is thought to be associated with PAH, these data suggest that IL-13 takes some roles in exacerbating PAH.

A comprehensive risk stratification at early follow-up determines prognosis in pulmonary arterial hypertension.

Guidelines recommend a goal-oriented treatment approach in pulmonary arterial hypertension (PAH). The aim is to reach a low-risk profile, as determined by a risk assessment instrument. This strategy is incompletely validated. We aimed to investigate the bearing of such risk assessment and the benefit of reaching a low-risk profile. Five hundred and thirty PAH patients were included. Follow-up assessments performed after a median of 4 (interquartile range 3-5) months were available for 383 subjects. Patients were classified as 'Low', 'Intermediate', or 'High risk' and the benefit of reaching the 'Low risk' group was estimated. Survival differed (P < 0.001) between the risk groups at baseline and at follow-up. Survival was similar for patients who remained in or improved to the 'Low risk' group. Survival was similar for patients who remained in or worsened to the 'Intermediate risk' or 'High risk' groups. Irrespective of follow-up risk group, survival was better (P < 0.001) for patients with a higher proportion of variables at low risk. Results were unchanged after excluding patients with idiopathic PAH >65 years at diagnosis, and when patients with idiopathic or connective tissue disease-associated PAH were analysed separately. Patients in the 'Low risk' group at follow-up exhibited a reduced mortality risk (hazard ratio 0.2, 95% confidence interval 0.1-0.4 in multivariable analysis adjusted for age, sex and PAH subset), as compared to patients in the 'Intermediate risk' or 'High risk' groups. These findings suggest that comprehensive risk assessments and the aim of reaching a low-risk profile are valid in PAH.

Ambrisentan: a review of its use in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a progressive disease defined by an elevation in pulmonary arterial pressure that can lead to right heart failure and death. Ambrisentan is a selective endothelin receptor antagonist approved for the treatment of idiopathic, heritable PAH and connective tissue disease-associated PAH. Ambrisentan has been shown to improve exercise capacity and hemodynamics with an acceptable side-effect profile. It has also proven to be safely used in combination with other PAH-specific medications, especially with phosphodiesterase-5 inhibitors. In the recent randomized trial, AMBITION, it was shown that upfront combination therapy of ambrisentan and tadalafil significantly decreased the risk of clinical failure compared with monotherapy. This review describes the drug profile of ambrisentan and its safety and efficacy in the treatment of PAH.

Initial combination therapy with ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH): subgroup analysis from the AMBITION trial

BackgroundPatients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH), in particular systemic sclerosis (SSc), had an attenuated response compared with idiopathic PAH in most trials. Thus, there is uncertainty regarding...

Ambrisentan response in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) – A subgroup analysis of the ARIES-E clinical trial

ObjectivePulmonary arterial hypertension (PAH) is a condition which may lead to right ventricular failure and early mortality and is an important complication in patients with connective tissue disease (CTD). Previously, the endothelin A selective receptor antagonist, ambrisentan, demonstrated efficacy and safety in treating patients with PAH due to WHO Group I etiologies. These analyses describe the 3-year efficacy and safety of ambrisentan in patients specifically with CTD associated PAH (CTD-PAH). MethodsPatients with CTD-PAH participating in the ARIES-1 and -2 clinical trials and their long-term extension were evaluated. Efficacy evaluations including 6-min walk distance (6MWD), clinical worsening, and survival were collected at routine study visits. Additional analyses of 6MWD categorical (30 m) breakpoints were conducted to determine any relationship between 6MWD and a prognostic threshold for survival. Results124 patients with CTD-PAH were evaluated. 62.6%, 57.3%, and 58.2% of CTD-PAH patients treated with ambrisentan exhibited increases in 6MWD at 1-, 2-, and 3- years respectively. At 3 years, 64% of patients were free from clinical worsening and 76% of patients were still alive (Kaplan-Meier estimates). Identified factors holding prognostic relevance for survival include: baseline functional class, CTD-PAH subgroup, patient sex, improvement in 6MWD ≥30 m over the first 12 weeks of treatment, the most recent 6MWD, and a 6MWD absolute threshold of 222 m. ConclusionThese first analyses of the 3-year treatment of CTD-PAH patients with ambrisentan revealed fewer clinical worsening events and improved survival compared to historical controls. Key exercise parameters were also identified which appear important in guiding treatment.

Higher Estradiol and Lower Dehydroepiandrosterone-Sulfate Levels Are Associated with Pulmonary Arterial Hypertension in Men.

Recent studies have focused on the role of female sex and estradiol (E2) in pulmonary arterial hypertension (PAH), but it is not known whether sex hormones are risk factors for PAH in men. We performed a case-control study to determine whether hormone levels (E2, dehydroepiandrosterone-sulfate [DHEA-S], and testosterone) are associated with PAH in men. Plasma sex hormone levels in men with idiopathic, heritable, or connective tissue disease-associated PAH were compared with those from age- and body mass index-matched men without clinical cardiovascular disease. There were 23 cases with PAH (70% had idiopathic PAH, 65% were functional class III/IV) and 67 control subjects. Higher E2 and E2/testosterone levels were associated with the risk of PAH (odds ratio per 1 ln[E2:testosterone], 6.0; 95% confidence interval, 2.2-16.4; P = 0.001), whereas higher levels of DHEA-S were associated with a reduced risk (odds ratio per 1 ln[DHEA-S], 0.1; 95% confidence interval, 0.0-0.3; P = 0.001). E2 and DHEA-S levels were strong predictors of case status (C statistic for both, 0.82) but testosterone was not (C statistic, 0.53). Higher levels of E2 were associated with shorter 6-minute-walk distances (P = 0.03), whereas higher levels of DHEA-S were associated with lower right atrial pressure (P = 0.02) and pulmonary vascular resistance (P = 0.01) in men with PAH. Higher levels of E2 and lower levels of DHEA-S were associated with PAH in men. Sex-based differences in sex hormone processing and signaling may contribute to unique phenotypes in pulmonary vascular disease.