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 Sitaxsentan was voluntarily withdrawn from the market in late 2010 resulting in the need to quickly transition a large number of stable patients.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.     

Selexipag as Add-on Therapy for Patients with Pulmonary Arterial Hypertension Associated with Congenital Heart Disease: A Single-Center Retrospective Study

Purpose: This study examined the efficacy and safety of selexipag in treating pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD). Materials and Methods: We conducted a retrospective study of patients with CHD-associated PAH, treated with selexipag since December 2017. Thirteen adult patients (mean age, 45.4 years; women, 77%) were treated with selexipag as add-on therapy. Baseline characteristics, World Health Organization functional class, 6-minute walking distance (6MWD) test results, N-terminal pro-B-type natriuretic peptide levels, echocardiographic data, and incidence of side effects were assessed. Results: The majority of patients (12/13, 92.3%) experienced more than one treatment-associated complication; one patient dropped out of the study due to intolerable myalgia. The results of 6MWD test (from 299.2 ± 56.2 m to 363.8 ± 86.5 m, p = 0.039) and tricuspid regurgitation (TR) pressure gradient (from 84.7 ± 20.5 mmHg to 61.6 ± 24.0 mmHg, p = 0.018) improved and remained improved after selexipag treatment in 12 patients. Based on the results of a non-invasive risk assessment, 8 (66.7%) patients showed improvement, 3 (25.0%) showed no interval change, and the status of one patient (8.3%) deteriorated. Moreover, compared to patients treated with a low dosage, patients treated with a medium-to-high dosage showed a greater increase in 6MWD results (88.3 ± 26.4 m vs. 55.3 ± 27.6 m, p = 0.043) and a greater reduction in the TR pressure gradient (−33.7 ± 10.9 mmHg vs. −12.5 ± 12.0 mmHg, p = 0.015). Conclusion: Selexipag is an efficient pulmonary vasodilator as add-on therapy in treating CHD-associated PAH.     

先天性心脏病相关性肺动脉高压伴肺动脉血栓形成6例临床分析

目的:探讨先天性心脏病相关性肺动脉高压伴肺动脉血栓形成患者的临床特点,提高对该疾病的认识。方法:对6例患者病例资料回顾性分析及文献复习。结果:6例患者中,男性1例,女性5例,平均年龄43.5岁,均伴有重度肺动脉高压。所有患者均无静脉血栓形成的易患因素如:外伤、卧床等,且多普勒血管超声未发现下肢深静脉血栓形成。影像学特点表现为主肺动脉及左、右肺动脉显著扩张,近段肺动脉和(或)较大分支内层状附壁血栓形成。结论:先天性左向右分流性心脏病伴重度肺动脉高压可同时合并肺动脉血栓形成,临床上容易漏诊,肺动脉增强计算机断层摄影术或肺动脉造影是确诊的重要手段。     

Selexipag in Patients With Pulmonary Hypertension: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Despite the availability of treatments for all subgroups of pulmonary hypertension (PH), the prognosis for PH remains poor. This systematic review and meta-analysis aimed to determine the efficacy and safety of selexipag in patients with PH. A systematic search was made of PubMed, Embase, Cochrane Library, and clinicaltrials.gov, without language restrictions. Randomized controlled trials (RCTs) on treatment of PH with selexipag, compared with placebo or blank, were reviewed. Studies were pooled to weighted mean differences (WMDs) and risk ratios (RRs), with 95% confidence intervals (CIs). Selexipag was safe and significantly improved hospitalization for worsening of PH, WHO FC, mPAP, NT-proBNP, and cardiac index in patients with PH. Selexipag should be considered in patients with pulmonary arterial hypertension or chronic thromboembolic PH.     

Contractile Dysfunction of Left Ventricular Cardiomyocytes in Patients With Pulmonary Arterial Hypertension

Background

After lung transplantation, increased left ventricular (LV) filling can lead to LV failure, increasing the risk of post-operative complications and mortality. LV dysfunction in pulmonary arterial hypertension (PAH) is characterized by a reduced LV ejection fraction and impaired diastolic function.

Objectives

The pathophysiology of LV dysfunction in PAH is incompletely understood. This study sought to assess the contribution of atrophy and contractility of cardiomyocytes to LV dysfunction in PAH patients.

Methods

LV function was assessed by cardiac magnetic resonance imaging. In addition, LV biopsies were obtained in 9 PAH patients and 10 donors. The cross-sectional area (CSA) and force-generating capacity of isolated single cardiomyocytes was investigated.

Results

Magnetic resonance imaging analysis revealed a significant reduction in LV ejection fraction in PAH patients, indicating a reduction in LV contractility. The CSA of LV cardiomyocytes of PAH patients was significantly reduced (∼30%), indicating LV cardiomyocyte atrophy. The maximal force-generating capacity, normalized to cardiomyocyte CSA, was significantly reduced (∼25%). Also, a reduction in the number of available myosin-based cross-bridges was found to cause the contractile weakness of cardiomyocytes. This finding was supported by protein analyses, which showed an ∼30% reduction in the myosin/actin ratio in cardiomyocytes from PAH patients. Finally, the phosphorylation level of sarcomeric proteins was reduced in PAH patients, which was accompanied by increased calcium sensitivity of force generation.

Conclusions

The contractile function and the CSA of LV cardiomyocytes is substantially reduced in PAH patients. We propose that these changes contribute to the reduced in vivo contractility of the LV in PAH patients.     

Incidence and Significance of Pericardial Effusion in Patients With Pulmonary Arterial Hypertension

Background

The incidence of pericardial effusion (PEF) during long-term follow-up among patients with pulmonary arterial hypertension (PAH) is unknown. We aimed to determine the incidence and prognostic significance of developing a new PEF among PAH patients.

Methods

Records of consecutive patients diagnosed with PAH between January 1990 and May 2010 were reviewed. Patients had systematically undergone right heart catheterization, transthoracic echocardiography, and coronary angiography during their initial assessment as well as routine echocardiograms during follow-up. Effusions were graded as small (echo-free space in diastole <10 mm), moderate (10-20 mm), or large (≥ 20 mm).

Results

The entire cohort consisted of 154 patients. The prevalence of identified PEF during initial assessment was 28.6%. The incidence of PEF among patients with no effusions who had additional echocardiographic studies during follow-up (n = 102) was 44.1%. Patients who developed PEF during follow-up had no differences with respect to baseline characteristics, associated aetiologies, hemodynamic parameters, and extent of coronary disease. Among these 102 patients, survival estimates were 94.9%, 75.0%, and 62.4% at 1, 3, and 5 years, respectively. Development of a PEF that was at least moderate-sized at its first appearance was a predictor of mortality in univariate (hazard ratio, 6.85; 95% confidence interval, 2.60-18.10) as well as multivariate analysis (hazard ratio, 3.95; 95% confidence interval, 1.26-12.40).

Conclusions

PEF develops frequently in PAH patients. In patients with no PEF at baseline, the appearance of a new moderate-size or larger PEF is associated with increased mortality, whereas no significantly increased mortality was observed when a small PEF develops.