Intravenous epoprostenol treatment of patients with connective tissue disease and pulmonary arterial hypertension at a single center

Objective

To assess the efficacy of epoprostenol treatment in Japanese patients with pulmonary arterial hypertension (PAH) associated with connective tissue disease (CTD).

Methods

Sixteen patients with PAH–CTD treated with continuous intravenous epoprostenol at a single center between 2000 and 2009 were enrolled. Baseline characteristics, short-term and long-term outcomes, predictors of mortality, and safety profiles were evaluated. For survival analysis, 16 controls were selected who matched the underlying CTD, World Health Organization functional class, and use of PAH drugs, except for epoprostenol.

Results

Six patients had systemic lupus erythematosus, five had mixed CTD, four had systemic sclerosis, and one had primary Sjögren’s syndrome. The mean pulmonary arterial pressure (mPAP), cardiac index (CI), pulmonary vascular resistance, and functional class were significantly improved during the first 6 months of epoprostenol treatment. Cumulative survival rates at 1, 2, and 3 years in epoprostenol-treated patients were 69, 69, and 55 %, respectively, and were significantly better than those of the controls. Functional class, CI at baseline, and reduction of mPAP at 6 months were identified as predictors of survival. Adverse events, including flushing and catheter-related infection, were frequent, but all patients tolerated the treatment.

Conclusion

Based on the improvements in both short-term and long-term outcomes among our patient cohort, epoprostenol is an effective treatment for CTD patients with advanced PAH.     

Anti-endothelial cell antibodies in connective tissue diseases associated with pulmonary arterial hypertension

Objective

To investigate the prevalence of anti-endothelial cell antibodies (AECA) in connective tissue diseases (CTD) associated with pulmonary arterial hypertension (PAH) and to corroborate the pathologic function of AECA in PAH-associated CTDs.

Methods

AECA were detected by cellular enzyme-linked immunosorbent assay (ELISA) in sera of 19 PAH-associated CTD patients, 22 CTD patients without PAH involvement, and 20 age- and sex-matched healthy individuals as controls. Using IgG purified from the sera of AECA-positive, AECA-negative, and healthy subjects, the effects of AECA on the expression of ICAM-1 and the chemokine regulated upon activation normal T-cell expressed and secreted (RANTES) in cultured endothelial cells were also evaluated.

Results

A total of 12 of the 19 (63.2%) CTD patients with PAH, 9 of the 22 (40.9%) CTD patients without PAH, and 1 of the 20 (5%) healthy controls were positive for AECA, which were calculated as ELISA ratio (ER) values. ER values in PAH-associated CTD patients were significantly higher than those with CTD without PAH (3.68±2.05 versus 1.67±1.07, P<0.001). IgG purified from AECA-positive sera induced a significantly increased level of ICAM-1 expression after 48 h incubation (795.2±32.5 pg/mL) compared with AECA-negative or healthy control IgG (231.5±27.1 and 192.8±33.4 pg/mL, respectively; P<0.001). In addition, RANTES production by cultured human pulmonary arterial endothelial cells (HPAECs) increased in both a time- and concentration-dependent manner in response to incubation with purified AECA-positive IgG.

Conclusions

AECA could be involved in CTD and might participate in the pathogenesis of PAH-associated CTD.     

Ferric carboxymaltose improves exercise capacity and quality of life in patients with pulmonary arterial hypertension and iron deficiency: A pilot study

Background

Pulmonary arterial hypertension (PAH) is a progressive condition harboring a poor prognosis. Iron deficiency in PAH correlates with disease severity and mortality. While replacement therapy may be beneficial, dietary iron absorption is impaired in PAH patients by hepcidin, a key regulatory protein of iron homoeostasis. We therefore assessed the therapeutic potential and safety of intravenous iron supplementation in patients with PAH and iron deficiency.

Methods

20 patients with PAH and iron deficiency, who were on stable targeted PAH therapy, received a single infusion of ≤ 1000 mg ferric carboxymaltose. All patients were assessed at baseline and two months after iron treatment. Exercise capacity was evaluated based on the 6-minute-walking distance (6MWD), and quality of life (QoL) was assessed by the SF-36 questionnaire (100 point scale). The effects were compared to 20 matched patients with stable PAH without iron deficiency who did not receive ferric carboxymaltose.

Results

In iron deficient patients, iron supplementation led to a marked improvement of iron status (serum iron 5.7 ± 0.4 to 11.1 ± 1.1 μmol/L, ferritin 29.3 ± 6.3 to 145.2 ± 25.4 μg/L, transferrin saturation 7.5 ± 0.7 to 19.3 ± 2.3%, all p ≤ 0.001). Iron-deficient patients receiving ferric carboxymaltose showed a significant increase of the 6MWD from 346.5 ± 28.3 to 374.0 ± 25.5 m (p = 0.007), whereas no significant changes were found in the control group not receiving iron supplementation (6MWD 389.9 ± 25.3 to 379.6 ± 26.2 m; n.s.), resulting in a net increase in the 6MWD of 37.8 m (p = 0.003). This was associated with an improvement in QoL (SF-36 score from 44.3 ± 3.7 to 50.6 ± 3.6; p = 0.01). Only minimal side-effects were reported.

Conclusions

These data indicate that parenteral iron supplementation with ferric carboxymaltose significantly improves exercise capacity and QoL and is well tolerated in patients with PAH and iron deficiency, and when administered in addition to targeted PAH therapies. Our results provide proof of concept for further studies evaluating the potential of iron as an adjunct in PAH treatment on a larger scale.     

Hemodynamic Stability After Transitioning Between Endothelin Receptor Antagonists in Patients With Pulmonary Arterial Hypertension

Background

Maintenance of a favourable hemodynamic profile is central to therapeutic success in pulmonary arterial hypertension (PAH). There is little information about the safety of transitioning patients between oral therapies for PAH. Endothelin receptor antagonists (ERAs) have been a therapeutic mainstay in PAH, providing benefit to many patients. Three ERAs, bosentan, sitaxsentan, and ambrisentan have been approved for clinical use. Sitaxsentan was voluntarily withdrawn from the market in late 2010 resulting in the need to quickly transition a large number of stable patients.

Methods

We transitioned 30 clinically stable patients to either ambrisentan or bosentan. Patients underwent a right heart catheterization, measurement of serum N-terminal pro-brain natriuretic peptide (NT-proBNP), and assessment of functional class before changing ERA and again 4 months later. We present a retrospective analysis of those data.

Results

Of the 30 patients transitioned (15 to ambrisentan, 15 to bosentan), 23 had complete hemodynamic data. No significant change was observed in the groups in right atrial, mean pulmonary artery, and pulmonary artery wedge pressures, or in cardiac output, pulmonary vascular resistance, or NT-proBNP levels. There was no change in World Health Organization functional class. Four ambrisentan and 2 bosentan-treated patients reported fluid retention, and 3 bosentan-treated patients had elevation of hepatic transaminases. Two of the patients had a right atrial pressure increase of ≥5 mm Hg, and 4 had pulmonary artery wedge pressure increase of ≥5 mm Hg.

Conclusions

Transitioning between ERAs in stable PAH patients does not result in hemodynamic or clinical deterioration during the first 4 months posttransition. A minority of patients have developed increased cardiac filling pressures.     

Calidad de vida relacionada con la salud en una cohorte nacional de pacientes con hipertensión arterial pulmonar o hipertensión pulmonar tromboembólica crónica

Background

Patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) experience impaired health-related quality of life (HRQL). The objective of this study was to evaluate HRQL in a nation-wide sample.

Patients and methods

This is a prospective, multicenter, non-interventional study of HRQL including 139 (89%) PAH and 17 (11%) CTEPH patients (women 70.5%; mean age, 52.2) recruited from 21 Spanish hospitals. 55% had idiopathic PAH, 34% other PAH and 11% CTEPH. HRQL was measured using the Short Form 36 Health Survey (SF-36) and EuroQoL-5D (baseline and after 6 months).

Results

HRQL in the patients with PAH or CTEPH was impaired. The physical component of SF-36 and the EuroQol-5D correlated with the functional class (FC). Mean EuroQol-5D visual analogical scale (EQ-5D VAS) scores were 73.5 ± 18.4, 62.9 ± 20.7 and 51.3 ± 16.0 (P < .0001) in patients with FC I, II and III, respectively. Every increase of one FC represented a loss of 4.0 on the PCS SF-36 and a loss of 9.5 on the EQ-5D VAS. Eight patients who died or received a transplant during the study period presented poorer initial HRQL compared with the rest of the population. No significant changes in HRQL were observed in survivors after 6 months of follow-up.

Conclusions

HRQL is impaired in this population, especially in PAH/CTEPH patients near death. HRQL measurements could help predict the prognosis in PAH and CTPH and provide additional information in these patients.     

Long-term results from the EARLY study of bosentan in WHO functional class II pulmonary arterial hypertension patients

Background

The double-blind phase of the EARLY study of bosentan remains the only randomized controlled trial of a PAH-targeted therapy in World Health Organization functional class (FC) II patients. We report on the efficacy, safety, disease worsening, survival and prognostic factors in mildly symptomatic pulmonary arterial hypertension (PAH) patients treated with bosentan in the open-label extension phase of the EARLY study.

Methods

Exploratory efficacy outcomes included 6-minute walk distance (6MWD) and WHO FC. Adverse events were recorded. Kaplan–Meier analysis was used to estimate time to first PAH worsening event (death, initiation of intravenous or subcutaneous prostanoids, atrial septostomy or lung transplantation) and survival. Cox regression analysis determined factors prognostic of survival.

Results

Median exposure to bosentan (n = 173) was 51 months. At the end of the bosentan-treatment assessment period, 77.8% of patients were in WHO FC I/II. Adverse events led to discontinuation of bosentan in 20.2% of patients. Aminotransferase elevations > 3 × upper limit of normal occurred in 16.8%. Four-year PAH-event-free survival and survival were 79.5% (95% confidence intervals [95% CI] 73.4, 85.6) and 84.8% [95% CI 79.4, 90.2], respectively. Low 6MWD, low mixed venous oxygenation, high N-terminal pro hormone of brain natriuretic peptide levels and PAH associated with connective tissue disease were associated with a higher risk of death.

Conclusions

The majority of patients exposed to long-term bosentan maintained or improved their functional class. Approximately 20% of the patients discontinued treatment because of adverse events, which were most commonly PAH worsening and elevated liver enzymes.     

Acute hemodynamic response of infused fasudil in patients with pulmonary arterial hypertension: A randomized,controlled, crossover study

Background

The Rho-kinase pathway has been shown to be involved in the pathogenesis of PAH. As yet, however, the acute effects of the Rho-kinase inhibitor fasudil have not been compared with established pulmonary selective vasodilators in patients with PAH. We compared the acute effects of intravenous fasudil with inhaled iloprost in patients with pulmonary arterial hypertension (PAH).

Methods

Using a crossover design, 50 patients with PAH (idiopathic PAH, PAH associated with repaired left-to-right cardiac shunts, or connective tissue disease) were randomized to iloprost inhalation (5 μg) and intravenous fasudil (30 mg over 30 min). Hemodynamic data were collected at baseline and during acute drug exposure.

Results

Comparable decreases were observed in mean pulmonary artery pressure (− 4.6 ± 4.3 mm Hg vs. − 4.8 ± 4.2 mm Hg) and pulmonary vascular resistance (− 3.0 ± 3.0 Wood U vs. − 2.2 ± 2.7 Wood U) with fasudil infusion and iloprost inhalation, respectively, during acute challenge. However, fasudil infusion resulted in a more pronounced increase in mean cardiac output and mixed venous oxygen saturation compared with iloprost inhalation (13.7 ± 17.1% vs. 6.9 ± 15.0%; p = 0.044 and 4.5 ± 5.3% vs. 2.7 ± 8.2%; p = 0.044, respectively). Whereas inhaled iloprost resulted in a non-significant increase in mean systemic arterial oxygen saturation (0.8 ± 3.6%), infused fasudil resulted in a non-significant reduction (− 0.6 ± 1.1%).

Conclusion

Infused fasudil improved pulmonary hemodynamics in patients with PAH without significant toxicity.     

Addition of sildenafil in patients with pulmonary arterial hypertension with inadequate response to bosentan monotherapy

BACKGROUND:

Pulmonary arterial hypertension (PAH) remains a progressive disease despite improvement when using one of three medication classes: prostanoids, endothelin receptor antagonists or phosphodiesterase-5 inhibitors. Combination therapy has been proposed for patients with unsatisfactory response to monotherapy.

OBJECTIVES:

To examine the effect of adding sildenafil to bosentan on 6 min walk distance (6MWD) and New York Heart Association (NYHA) classification in patients with PAH who achieved inadequate improvement with bosentan monotherapy.

METHODS:

Patients with idiopathic PAH or connective tissue disease-associated PAH, and who had either self-reported inadequate improvement in exercise tolerance or a decline in 6MWD after initial improvement, were included in the study (n=10). Data on 6MWD and NYHA class at baseline (before initiation of bosentan), three and six months after baseline, second baseline (before initiation of combination therapy with sildenafil), and three and six months after second baseline were analyzed for any changes.

RESULTS:

Mean time from initiation of bosentan monotherapy to initiation of combination therapy was 558 days (range 150 to 900 days). Six months after initiation of bosentan, 6MWD increased by 57.2 m above the baseline of 314.4 m. Six months after combination therapy, 6MWD was 62.80 m higher than the baseline before initiation of combination therapy of 339 m (P<0.02). The overall increase in 6MWD six months after combination therapy was higher than the first baseline by 87.4 m (P not significant). NYHA functional class did not improve with combination therapy in all patients.

DISCUSSION:

Initiating combination therapy in patients who achieve an inadequate improvement in exercise tolerance with mono-therapy may result in further improvement in exercise tolerance.     

Blood biomarkers and their potential role in pulmonary arterial hypertension associated with congenital heart disease. A systematic review

Background

The development of pulmonary arterial hypertension (PAH) in patients with congenital heart disease (CHD) is multifactorial with a number of biomarkers serving as mediators of neurohormonal activation [B-type natriuretic peptide (BNP) and its N-terminal-pro-fragment (NT-proBNP)], endothelial dysfunction [asymmetric dimethylarginine (ADMA)] and cellular proliferation [vascular endothelial growth factor (VEGF)].

Methods

We systematically reviewed the literature for trials studying the role of these biomarkers in the clinical evaluation, prognosis and management of patients with PAH related to CHD (CHD–PAH).

Results

Twenty-six studies were included in the systematic review, involving a total of 1113 patients with CHD–PAH. These patients had higher BNP, NT-proBNP and ADMA levels and higher VEGF expression when compared with healthy controls. Baseline and serial values of plasma levels of natriuretic peptides were shown to be significant predictors of survival. ADMA concentration was elevated in patients with CHD–PAH when compared with patients with simple CHD without PAH, whereas VEGF expression was particularly high in patients with CHD and persistent PAH after corrective surgery of the underlying heart disease.

Conclusion

Right heart dysfunction, endothelial inflammation and proliferation are mirrored by plasma levels of the corresponding biomarkers among patients with CHD–PAH. There is early evidence to suggest that natriuretic peptides, in particular, may be a simple and effective tool for determining prognosis and timing for therapeutic interventions in patients with CHD–PAH.     

Six-minute walk test distance and resting oxygen saturations but not functional class predict outcome in adult patients with Eisenmenger syndrome

Background

Eisenmenger syndrome (ES) represents the extreme manifestation of pulmonary arterial hypertension in patients with congenital heart disease, associated with significant exercise intolerance and mortality. Even though of six-minute-walk-test (6MWT) is routinely used in these patients, little is known about its prognostic value in comparison to functional class.

Methods and results

We included 210 adult patients with ES who underwent a total of 822 6MWTs. Median walking distance (6MWD) was 330 m [IQR 260–395], oxygen saturation (SO₂) at baseline 86% [IQR 82–91%] and SO₂ at peak-exercise 69% [IQR 60–80%]. In patients commenced on advanced therapy for pulmonary hypertension, but not in the reminder, there was a significant improvement in walking distance (297 ± 97 m vs. 325 ± 87 m,P = 0.0019), SO₂ at rest (84.9 ± 7.1 vs. 86.8 ± 5.9%,P = 0.003), SO₂ at peak exercise (69.1 ± 12.7 vs. 72.3 ± 12.2%,P = 0.04) and NYHA functional class (P = 0.0047).During a follow up of 3.3 years, 29 patients died. On time-dependent Cox analysis, 6MWD (HR 0.94 per 10 m, 95%CI: 0.91–0.97,P < 0.001) and baseline SO₂ (HR 0.90, 95%CI:0.86–0.94,P < 0.0001) were predictors of death. In contrast, age, functional class, peak-exercise SO₂ and SO₂ change were not related to mortality. A three-fold increased risk of death was identified in patients not reaching a 6MWD of 350 m or with baseline SO₂ below 85%.

Conclusions

The 6MWD and resting SO₂, but not functional class were predictive of outcome in this contemporary cohort of Eisenmenger patients and should be incorporated in both risk stratification and management algorithms for these patients.     

口服伐地那非治疗肺动脉高压的临床观察

目的：观察口服伐地那非对肺动脉高压患者的临床疗效及其量效关系。方法：采用前瞻性、开放性、随机对照研究方法,入选的48例肺动脉高压患者被均分为5mg治疗组、10mg治疗组及20mg治疗组,疗程6个月,观察患者治疗前后6min步行距离（6MWD）、WHO肺动脉高压功能分级和血流动力学指标的变化,以及药物的安全性。结果：口服不同剂量伐地那非6月后,各组患者6MwD显著增加,WHO肺动脉高压功能分级改善,活动耐量增加,肺动脉收缩压（PASP）明显下降（P均〈0．05）;与5mg治疗组比较,10mg和20mg治疗组治疗后的6MWD增量[（46．9±14．7）m比（80．8±17．2）m、（81．9±19．6）m]和PASP减少量[（14．1±3．6）mmHg比（26．4±4．5）mmHg、（27．8±5．7）mmHg]均显著增加（P〈0．05）,10mg与20mg治疗组相比,其6MWD增量和减少量、PASP差异无显著性;但治疗后三组的6MWD、PASP值无显著差异。口服伐地那非不良反应小,耐受性好。结论：口服伐地那非可以降低肺动脉收缩压,提高肺动脉高压患者的活动耐量,并呈一定程度的量效关系。     

The Combination of Exercise and Respiratory Training Improves Respiratory Muscle Function in Pulmonary Hypertension

Purpose

Increased dyspnea and reduced exercise capacity in pulmonary arterial hypertension (PAH) can be partly attributed to impaired respiratory muscle function. This prospective study was designed to assess the impact of exercise and respiratory training on respiratory muscle strength and 6-min walking distance (6MWD) in PAH patients.

Methods

Patients with invasively confirmed PAH underwent 3 weeks of in-hospital exercise and respiratory training, which was continued at home for another 12 weeks. Medication remained constant during the study period. Blinded observers assessed efficacy parameters at baseline (I) and after 3 (II) and 15 weeks (III). Respiratory muscle function was assessed by twitch mouth pressure (TwPmo) during nonvolitional supramaximal magnetic phrenic nerve stimulation.

Results

Seven PAH patients (4 women; mean pulmonary artery pressure 45 ± 11 mmHg, median WHO functional class 3.1 ± 0.4, idiopathic/associated PAH n = 5/2) were included. The training program was feasible and well tolerated by all patients with excellent compliance. TwPmo was I: 0.86 ± 0.37 kPa, II: 1.04 ± 0.29 kPa, and III: 1.27 ± 0.44 kPa, respectively. 6MWD was I: 417 ± 51 m, II: 509 ± 39 m, and III: 498 ± 39 m, respectively. Both TwPmo (+0.41 ± 0.34 kPa, +56 ± 39 %) and 6MWD (+81 ± 30 m, +20 ± 9 %) increased significantly in the period between baseline and the final assessment (pairwise comparison: p = 0.012/<0.001; RM-ANOVA considering I, II, III: p = 0.037/<0.001).

Conclusions

Exercise and respiratory training as an adjunct to medical therapy may be effective in patients with PAH to improve respiratory muscle strength and exercise capacity. Future, randomized, controlled trials should be carried out to further investigate these findings.     

Elevated NT-proBNP levels should be interpreted in elderly patients presenting with dyspnea

Background

B-type natriuretic peptide (BNP) assay is a useful tool in order to diagnose dyspnea due to congestive heart failure (CHF). On the other hand many other diseases could affect BNP levels. The aim of this study was to investigate a group of elderly patients admitted to an Internal Medicine unit because of dyspnea.

Patients and methods

NT-proBNP was assessed in 132 consecutive patients aged 80 ± 6 years because of dyspnea. History data, anthropometric, clinical and biochemical parameters were collected. Renal function was assessed by the CKD-EPI formula. Diagnosis of pulmonary disease such as infections and chronic obstructive disease was considered and was analyzed as a single parameter. Statistical analysis was carried out dividing patients with high NT-proBNP from those with normal NT-proBNP according to the Januzzi cut-off.

Results

NT-proBNP was higher than the normal reference values in 68.7% of patients and its levels increased in the 5 different stages of chronic kidney disease. Subjects with high NT-proBNP had lower haemoglobin levels (11.6 ± 2.1 vs 12.8 ± 1.9 g/dl, p = 0.003), higher prevalence of atrial fibrillation (54.3 vs 25%, p = 0.001), and lower prevalence of pulmonary diseases (29.7 vs 57.5%, p = 0.005). Logistic regression analysis showed that NT-proBNP levels were independently associated with haemoglobin (OR 1.307 95% CI 1.072-1.593, p = 0.008) and pulmonary diseases (OR 3.069 95% CI 1.385-6.801, p = 0.006).

Conclusions

A disease different from CHF appears to affect NT-proBNP plasma levels. Therefore, determination of its levels does not seem to help clinicians in the definition of dyspnea in elderly people with different comorbidities.     

Clinical characteristics and risk factors of pulmonary hypertension associated with chronic respiratory diseases: a retrospective study

Background

Chronic respiratory disease-associated pulmonary hypertension (PH) is an important subtype of PH, which lacks clinical epidemiological data in China.

Methods

Six hundred and ninety three patients hospitalized from 2010 to 2013 were classified by echocardiography according to pulmonary arterial systolic pressure (PASP): mild (36≤ PASP <50 mmHg); moderate (50≤ PASP <70 mmHg) and severe (PASP ≥70 mmHg).

Results

Dyspnea (93.51%) was the most common symptom. Hemoptysis observed in the severe group (6.42%) was significantly higher than the other two groups (P<0.05). COPD (78.35%), lung bullae (44.16%), tuberculosis (including obsolete pulmonary tuberculosis) (38.82%), and bronchiectasis (30.45%) were frequently present. Mild group occupied the highest proportion (84.7%) in COPD, while severe group occupied the highest proportion (19.3%) in pulmonary embolism (P<0.01). Age, partial pressure of oxygen (PaO₂), hematocrit (HCT), partial pressure of carbon dioxide (PaCO₂), increase of N-terminal pro brain natriuretic peptide (NT-proBNP) and right ventricular (RV) diameter (>20 mm) were associated with moderate-to-severe PH, while RV [odds ratio (OR) =3.53, 95% CI, 2.17–5.74], NT-proBNP (OR=2.44, 95% CI, 1.51–3.95), HCT (OR=1.03, 95% CI, 1.00–1.07) and PaCO₂ (OR=1.01, 95% CI, 1.00–1.03) were independent risk factors.

Conclusions

PH related to respiratory diseases is mostly mild to moderate, and the severity is associated with the category of respiratory disease. Increased HCT can be an independent risk factor for PH related to chronic respiratory diseases.     

Screening and diagnostic modalities for connective tissue disease-associated pulmonary arterial hypertension: A systematic review

Objective

Pulmonary arterial hypertension (PAH) is a frequent complication in connective tissue diseases (CTD), especially in systemic sclerosis (SSc), and is associated with a high degree of morbidity and mortality. We undertook a systematic review for the screening tests for CTD-PAH.

Methods

A systematic literature search of PAH in CTD was performed in available databases through June 2012. Our evaluation of diagnostic tests was focused on patients with PAH confirmed by right heart catheterization (RHC).

Results

The search resulted in 2805 titles and 838 abstracts. Our final inclusion encompassed 22 articles—six of which were case–control studies and 16 were cohort studies. Twelve studies assessed the tricuspid regurgitation velocity (VTR) or equivalent right ventricular systolic pressure (RVSP) using transthoracic echocardiogram (TTE) as a threshold for RHC in patients suspected as having PAH. The screening threshold for RHC was VTR from >2.73 to >3.16 m/s without symptoms or 2.5–3.0 m/s with symptoms and resulted in 20–67% of patients having RHC-proven PAH. Three studies looked at pulmonary function tests and found that a low lung diffusing capacity for carbon monoxide (DLCO) (45–70% of predicted) is associated with a 5.6–7.4% development of PAH, and a decline in DLCO% is associated with an increase in the specificity (for DLCO ≤60%, spec = 45%; and for DLCO ≤50%, spec = 90%) for PAH. Five studies assessed N-terminal prohormone of brain natriuretic peptide (NT-ProBNP), where a cutoff >239 pg/ml had a sensitivity of 90–100%.

Conclusions

Our systematic review revealed that most evidence exists for TTE, pulmonary function tests, and NT-ProBNP for screening and diagnosis of SSc-PAH; however, more robust studies are needed.     

Prevalence and severity of ventricular dysfunction in patients with HIV-related pulmonary arterial hypertension

Objectives

To evaluate the occurrence of ventricular systolic dysfunction in human immunodeficiency virus (HIV)-related pulmonary arterial hypertension (PAH).

Background

Patients with HIV-related PAH may develop ventricular systolic dysfunction both as a consequence of PAH progression or of the myocardial involvement from the HIV infection itself.

Methods

Cardiac magnetic resonance imaging was applied to measure ejection fraction for the left ventricle and the right ventricle in patients with HIV-related PAH (n = 27) and in patients with PAH from other aetiologies (n = 115).

Results

In HIV-related PAH, ejection fraction values were lower and a higher proportion of patients presented with an advanced stage of ventricular dysfunction (55% vs. 25%; p = 0.009). In a multivariate model, PAH related to HIV infection remained independently associated with advanced ventricular dysfunction (p = 0.011).

Conclusions

Patients with HIV-related PAH have more prevalent and severe ventricular systolic dysfunction compared to patients with PAH from other aetiologies.     

The Role of Noninvasive Endpoints in Predicting Long-Term Outcomes in Pulmonary Arterial Hypertension

Background

Until recently, many clinical trials in patients with pulmonary arterial hypertension (PAH) evaluated exercise capacity with 6-minute walk distance (6MWD) as the primary endpoint. Common secondary endpoints include PAH functional class (FC), which assesses symptoms, and either brain natriuretic peptide (BNP) or the inactive N-terminal cleavage product of its prohormone (NT-proBNP), which assesses cardiac function.

Objective

Examine the relationships among 6MWD, FC, and BNP/NT-proBNP measured at baseline or follow-up with long-term outcomes in PAH studies.

Methods

Relevant literature from January 1990 to April 2018 were obtained by searching PubMed, Embase, and Cochrane. Articles in English reporting on associations between 6MWD, FC, or BNP/NT-proBNP and outcomes in PAH were identified. Each endpoint was evaluated individually. Prespecified inclusion and exclusion criteria were applied at level 1 (titles/abstracts) and level 2 (full-text review).

Results

The database search yielded 836 unique records; 65 full-text articles were reviewed. Twenty-five studies were eligible for inclusion. Findings supported the importance of measuring PAH noninvasive endpoints in predicting long-term outcomes. Patients with shorter or decreased 6MWD, poor (III/IV) or declining FC (e.g., from II to III), or elevated or increasing BNP/NT-proBNP had a higher risk of death and costly events (e.g., hospitalization, lung transplant). FC also predicted health care resource utilization and costs. Collectively, these endpoints establish risk groups that predict likelihood of complications from PAH or death.

Conclusion

Assessment of 6MWD, FC, and BNP/NT-proBNP provides low-cost, efficient, and noninvasive means of predicting long-term health and economic outcomes in patients with PAH.

     

Hemodynamics of patients developing pulmonary arterial hypertension after shunt closure

Background

Pulmonary arterial hypertension (PAH) after shunt closure is associated with a poor prognosis. The aim of this study was to assess retrospectively the hemodynamics of patients developing PAH after shunt closure.

Methods

Hemodynamic data obtained by right heart catheterization (RHC) performed at baseline and after shunt closure were analyzed.

Results

Twenty-two patients, 13 with atrial septal defect (ASD), 6 with ventricular septal defect (VSD), 1 with patent ductus arteriosus, 1 with both ASD and VSD, and 1 with complete atrio-ventricular canal have been considered. The mean age at closure was 25.3 ± 20.1 years (range of 3 months to 56.7 years), and the mean age at PAH diagnosis was 37.0 ± 20.8 years (range of 5 to 61.2 years). The time delay between shunt closure and PAH diagnosis was 140.2 ± 100.2 months. At baseline RHC, hemodynamic data were as follows: pulmonary vascular resistance (PVR) of 8.6 ± 2.6 Wood units, PVR index (PVRi) of 10.1 ± 2.7 Wood units ∗ m², mean pulmonary arterial pressure of 43.7 ± 9.7 mm Hg, PVR to systemic vascular resistance ratio (PVR/SVR) of 0.70 ± 0.23, and Qp/Qs of 1.6 ± 0.4. In particular, 18/22 (81%) had PVR ≥ 5 Wood units, 21/22 (95%) PVRi ≥ 6 Wood units ∗ m², 21/22 (95%) PVR/SVR ≥ 0.33, and 11/22 (50%) Qp/Qs ≤ 1.5. During the follow-up, 5/22 (22%) patients died and one patient underwent successful double lung transplantation.

Conclusions

High baseline values of PVR (≥ 5 Wood units), PVRi (≥ 6 Wood units ∗ m²) and PVR/SVR (≥ 0.33) are common findings in patients who develop PAH late after shunt closure. Large prospective clinical trials are needed to establish the safe limits for shunt closure.     

Initial Riociguat Monotherapy and Transition from Sildenafil to Riociguat in Patients with Idiopathic Pulmonary Arterial Hypertension: Influence on Right Heart Remodeling and Right Ventricular–Pulmonary Arterial Coupling

Purpose

To evaluate the influence of riociguat on World Health Organization functional class (WHO FC), 6-min walk distance (6MWD), right heart remodeling, and right ventricular–pulmonary arterial (RV–PA) coupling in patients with idiopathic pulmonary arterial hypertension (IPAH) who are treatment-naïve or who have failed to achieve treatment goals with sildenafil therapy.

Methods

Twenty patients with IPAH were enrolled: 12 had not previously received PAH-targeted therapy (treatment-naïve subgroup) and 8 had been receiving sildenafil therapy but failed to achieve treatment goals; on entering this pilot study these 8 patients were switched from sildenafil to riociguat therapy (treatment-switch subgroup). Patients received riociguat individually dose-adjusted up to a maximum of 2.5 mg three times daily. After 12 weeks, patients were assessed for WHO FC, 6MWD, right heart remodeling, and RV–PA coupling.

Results

Riociguat significantly improved WHO FC in treatment-naïve patients (from 0/4/8/0 patients in WHO I/II/III/IV at baseline to 1/6/5/0 at week 12) and in treatment-switch patients (from 0/4/4/0 patients in WHO I/II/III/IV at baseline to 1/4/3/0 at week 12). Additionally, treatment-naïve and treatment-switch patients showed significant improvements at week 12 versus baseline in 6MWD (increases of +?76.8 m and +?71.6 m, respectively), RV systolic function, and RV–PA coupling.

Conclusion

These results support the proven efficacy of riociguat in patients with IPAH, including treatment-naïve patients and those switching to riociguat following failure to achieve treatment goals with sildenafil, and suggest that it may be possible to delay disease progression in this patient group.