Therapy For Pulmonary Hypertension Research Articles

Impact of COVID-19 pandemics upon pulmonary hypertension patients: insights from BNP-PL national database

Abstract Introduction COVID-19 pandemic has caused not only an increase in overall and cardiovascular mortality, but also hindered access to health care, diagnosis and treatment of diseases other than coronavirus infection. Aim Assessment of the impact of the SARS-CoV-2 pandemic on the rate of diagnosis and therapy of pulmonary hypertension (PH) in Poland, along with an analysis of the incidence and course of COVID-19 among patients (pts) diagnosed with PH, treated under the National Health Fund program, registered in the national BNP-PL database. Methods The records of the complete population of Polish pts treated under the National Drug Program of PH (PAH and CTEPH), registered in the national database of BNP-PL, updated on an ongoing basis by all PH centers, were analyzed. The frequency of SARS-CoV-2 infections, the clinical severity of their course and the mortality were reviewed, taking into account the specific therapies used. The basic clinical characteristics of the group of sick and deceased patients were compared to the remaining patients registered in the BNP-PL database. The rate of increase of new diagnoses ended with inclusion in the Drug Program between March and December 2020, compared to the corresponding periods of the previous year, and the change in the treatment profile were compared. Results The analysis included 1704 pts (PAH 1134, CTEPH 570). The incidence of SARS-CoV-2 infections was 3.8% (n=65), including PAH 2.7% (n=46) and CTEPH 3,2% (n=18). 32 patients (49%) required hospitalization. Mortality rate was 28% (18/65) – including 7/18 outside of hospital. Those who died due to COVID-19 were older (mean age 68.4±15.8 vs. 50.8±18.8 yrs; p<0,001), had higher WHO class and more cardiovascular comorbidities (4±2,06 vs. 2,66±1,8; p=0,01) (Table 1). During the pandemic the number of new diagnoses of PH markedly decreased compared to the corresponding period in 2019 (total 150 vs. 203, PAH 90 vs. 123, CTEPH 60 vs. 80, respectively). A significant increase in total mortality was also observed in the PH group (9,72 vs. 5,85%). Moreover, escalation of specific PH therapy decreased significantly (14,7% vs. 21,6%). Incidence of COVID-19 study group was lower than estimated for general Polish adult population (3,8% vs. 6,5%). Conclusions COVID-19 pandemic deeply influenced the diagnostic and therapeutic process of pulmonary hypertension by reducing the number of new diagnoses, escalation therapy and increased overall mortality in this population. This may be due in part to the conversion of some PAH centers into hospitals treating patients infected with SARS-CoV-2, as well as to patients' fear of admitting to hospital despite clinical deterioration. Pulmonary hypertension is linked to markedly increased mortality in COVID-19, similarly for PAH and CTEPH. Intriguing finding of lower infection rate may be linked to protective lifestyle or specific therapies. Funding Acknowledgement Type of funding sources: None.

Comparison of 2-years follow-up of optimal medical therapy versus balloon pulmonary angioplasty for inoperable chronic thromboembolic pulmonary hypertension

Abstract Introduction Balloon pulmonary angioplasty (BPA) has emerged as a therapeutic option for chronic thromboembolic pulmonary hypertension (CTEPH) considered ineligible for pulmonary endarterectomy (PEA). The initial publications showed very good short-term outcomes for the technique, but there are limited data regarding medium-term outcomes and its comparison with optimal medical treatment (OMT). Objectives To evaluate and compare the medium-term outcomes of OMT versus (vs) BPA in inoperable CTEPH. Methods Retrospective study of consecutive patients (pts) with CTEPH followed in a referral centre for Pulmonary Hypertension. Selected those pts considered ineligible for PEA and with at least 2 years of follow-up. Comparison between two treatment strategies: OMT alone [maximum tolerated doses of pulmonary vasodilator drugs (PVD), as indicated] vs BPA (pts who completed the program with or without OMT). Endpoint was a composite of all-cause death and unplanned right heart failure admission at 2-year. Results From 62 pts, 19 pts were included (11 pts were excluded due to recent diagnosis; 32 were submitted to EAP): mean age 65.0±15.3 years, 89.5% female. At diagnosis, all pts had functional capacity limitation and elevated serum NTproBNP levels (median value 1255.0 pg/mL). Mean pulmonary arterial pressure (mPAP) was 46.2±9.3 mmHg and pulmonary vascular resistance (PVR) 15.3±8.3 Wood units (WU). Concerning treatment, 12 pts (63.2%) underwent OMT alone. These pts had higher NTproBNP levels (2670.0 vs 538.0 pg/mL, p<0.01) and PVR values (19.7±7.6 vs 9.7±5.4 WU, p=0.01) and lower CI (1.6±0.3 vs 2.4±0.5 L/min/m2, p<0.01), at baseline; the remaining basal features didn't differ among groups (Fig.A). At 2-year follow-up, pts submitted to BPA were under PVD in 71.4% of cases with a mean of 1±0.8 drugs per patient and no difference compared to OMT group (83.3%, 1.7±0.9 drugs per patient), although oxygen therapy was higher in medical group (50% vs 0%, p=0.04). A significant overall improvement was observed in BPA group (Table – A): all pts were in functional class I (p<0.01), no one had right ventricular dysfunction (p<0.01) and mPAP decreased to 25.1±6.7 mmHg (p=0.01) and RVP to 2.9±0.8 WU (p=0.01). Inversely, no change was observed in pts under OMT alone (p>0.05 in all, Table – A). Endpoint rate was 31.6% with all adverse events occurring in the OMT group (50% vs 0%, p=0.04). After adjustment by Cox regression, no difference in baseline or follow-up features besides treatment influenced the outcome. Kaplan-Meier analysis (Graphic – B) confirmed significant benefit of BPA in 2-year outcome occurrence (long rank 4.6, p=0.03). Conclusions BPA strategy seems to improve medium-term functional capacity, right ventricular function and haemodynamics and decrease oxygen therapy dependence in inoperable CTEPH. Pts under OMT alone have a poor prognosis. These data encourage the development and implementation of the technique for inoperable CTEPH. Funding Acknowledgement Type of funding sources: None.

PH Roundtable: Conundrums and Controversies in PH-ILD: To Treat or Not to Treat—Identifying Optimal Treatment Candidates

PH Roundtable: Conundrums and Controversies in PH-ILD: To Treat or Not to Treat—Identifying Optimal Treatment Candidates

Riociguat therapy for pulmonary hypertension: a systematic review and meta-analysis.

Riociguat therapy has been recommended for pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH), and it might have therapeutic significance for other types of pulmonary hypertension (PH). Our purpose was to evaluate the specific impact of riociguat on all types of PH. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing the safety and efficacy of riociguat treatment for PH through databases of the Cochrane Library, PubMed, Embase, and Web of Science from inception to the present. Duplicate publications, studies with no full text, incomplete information or inability to extract data, animal experiments and reviews, and systematic reviews were excluded. The software RevMan 5.4 was used for data synthesis. There were 8 RCTs included in our study, involving 1,606 participants. For PAH and CTEPH patients, riociguat treatment extended 6-minute walk distance (6MWD) by 39.84 meters, decreased mean pulmonary arterial pressure (PAP) by 4.20 mmHg, lowered pulmonary vascular resistance (PVR) by 218.76 dynes/sec/cm-5, cut down right atrial pressure (RAP) by 0.9 mmHg, increased cardiac index (CI) by 0.49 L/min/m2, improved cardiac output (CO) by 0.89 L/min, reduced N-terminal pro-type B natriuretic peptide (NT-proBNP) by 436.21 pg/mL, and decreased adverse events and clinical worsening as compared with placebo. For other types of PH including PH due to left heart disease and PH due to lung disease, riociguat was reported as having improved CI by 0.42 L/min/m2 and CO was increased by 0.92 L/min compared with placebo. Other efficacy outcomes and safety outcomes did not attain statistical difference in other types of PH. For PAH and CTEPH, riociguat treatment is safe and effective, but for other types of PH, it can only improve some hemodynamic parameters.

Vasodilator therapy for pulmonary hypertension in children: a national study of patient characteristics and current treatment strategies.

Pulmonary vasodilator therapy is still often an off-label treatment for pulmonary hypertension in children. The aim of this nationwide register-based study was to assess patient characteristics and strategies for pulmonary vasodilator therapy in young Swedish children. Prescription information for all children below seven years of age at treatment initiation, between 2007 and 2017, was retrieved from the National Prescribed Drug Register, and medical information was obtained by linkage to other registers. All patients were categorized according to the WHO classification of pulmonary hypertension. In total, 233 patients had been prescribed pulmonary vasodilators. The treatment was initiated before one year of age in 61% (N = 143). Sildenafil was most common (N = 224 patients), followed by bosentan (N = 29), iloprost (N = 14), macitentan (N = 4), treprostinil (N = 2) and riociguat (N = 2). Over the study period, the prescription rate for sildenafil tripled. Monotherapy was most common, 87% (N = 203), while 13% (N = 20) had combination therapy. Bronchopulmonary dysplasia (N = 82, 35%) and/or congenital heart defects (N = 156, 67%) were the most common associated conditions. Eight percent (N = 18) of the patients had Down syndrome. Cardiac catheterization had been performed in 39% (N = 91). Overall mortality was 13% (N = 30) during the study period. This study provides an unbiased overview of national outpatient use of pulmonary vasodilator therapy in young children. Few cases of idiopathic pulmonary arterial hypertension were found, but a large proportion of pulmonary hypertension associated with congenital heart defects or bronchopulmonary dysplasia. Despite treatment, mortality was high, and additional pediatric studies are needed for a better understanding of underlying pathologies and evidence of treatment effects.

Assessment of Clinical Usefulness of Resting Electrocardiogram (PH-ECG Score) in Monitoring the Efficacy of Balloon Pulmonary Angioplasty (BPA) in Patients with Chronic Thromboembolic Pulmonary Hypertension (CTEPH).

Background: Balloon pulmonary angioplasty (BPA) is a form of therapy for chronic thromboembolic pulmonary hypertension (CTEPH). The study objective is to assess the clinical usefulness of resting ECG (PH-ECG score) in monitoring the efficacy of BPA in CTEPH patients. Methods and results: Ninety-four (n = 94) CTEPH patients were included in the analysis. A standard 12-lead-ECG was performed before the first BPA session and after completion of treatment. The whole analysed population (n = 94) was divided into the following two groups: derivation cohort (n = 41) and validation cohort (n = 53). The derivation cohort was divided into the following two subgroups: patients with mean pulmonary artery pressure (mPAP) after the completion of therapy < 25 mmHg (n = 21) and patients with mPAP after the completion of therapy ≥ 25 mmHg (n = 20). In the first subgroup, four (R-wave V1 + S-wave V5/V6 > 10.5 mm, QRS-wave axis > 110 degrees, R-wave V1 > S-wave V1, SIQIII pattern) of the six ECG parameters of overload of the right cardiac chambers showed statistically significant differences (p < 0.005). That was followed by a determination of the sensitivity and specificity, positive (PPV) and negative predictive value (NPV), and ROC curve (AUC 0.9; 95% CI: 0.792–1.000) for the variable that was a sum of the above four ECG parameters (PH-ECG score). The absence of all of the four ECG parameters at rest (PH-ECG score = 0) well reflected patients with mPAP < 25 mmHg (sensitivity, 100%; specificity, 80%; PPV, 84%; NPV, 100%). In the validation cohort with mPAP < 25 mmHg and PH-ECG score = 0, sensitivity, specificity, PPV, and NPV were 86%, 77%, 73%, and 89%, respectively. Conclusions: Resting ECG trace is clinically useful in the monitoring of therapeutical effects of BPA in CTEPH patients.

Optimization of specific therapy for pulmonary hypertension: the possibilities of riociguat

Pulmonary hypertension (PH) is a severe and often rapidly progressive disease with fatal outcome. Endothelial dysfunction in PH is associated with decreased nitric oxide production. After reviewing the mechanisms of action and the evidence base for specific therapy with phosphodiesterase 5 inhibitors (PDE-5) and soluble guanylate cyclase stimulators, a reseach review on switching from PDE-5 to riociguat is conducted. A potential advantage of riociguat is its independence from endogenous nitric oxide and from the other (besides PDE-5) isoenzymes of phosphodiesterases. The favorable efficacy profile of sildenafil has been proven for the main forms of pulmonary arterial hypertension, of riociguat for the main forms of pulmonary arterial hypertension and chronic thromboembolic PH. The clinical efficacy of replacing PDE-5 with riociguat has been demonstrated in uncontrolled trials and in the randomized controlled study REPLACE. The possibility of therapy optimization by switching from IFDE-5 to riociguat is fixed in the Russian (class and level of evidence B-3) and Eurasian (class and level of evidence IIb-B) clinical guidelines, as well as in the materials of the Cologne Expert Consensus. An additional argument for switching is the lower cost as compared to combination therapy in the Russian Federation. According to the Russian and Eurasian guidelines for PH and the Russian instructions for the use of riociguat, the drug should be taken at least 24 hours after sildenafil discontinuation.

Piperlongumine attenuates vascular remodeling in hypoxic pulmonary hypertension by regulating autophagy

ObjectiveThe aim of this study was to determine the therapeutic effect of piperlongumine on hypoxic pulmonary hypertension. MethodsA hypoxic pulmonary hypertension rat model was constructed, primary rat pulmonary artery smooth muscle cells (PASMCs) were isolated, and the proliferation of PASMCs was measured by Cell Counting Kit‑8 assay. The expression of autophagic proteins microtubule-associated protein 1 light chain 3B (LC3B) and P62 were examined by western blot. Autophagic flux in PASMCs was detected by tandem mRFP-GFP-LC3 fluorescence analysis. ResultsHypoxia-induced proliferation of PASMCs was significantly inhibited by piperlongumine exposure. Treatment with piperlongumine elevated LC3B II/LC3B I protein ratio and decreased the expression of P62 protein in both PASMCs and rat lung tissues. Tandem mRFP-GFP-LC3 fluorescence analysis showed that piperlongumine increased autophagic flux in PASMCs. Inhibition of autophagy using 3-methyladenine (3-MA) attenuated the inhibitory effect of piperlongumine on proliferation of PASMCs. Chronic hypoxia exposure led to a significant increase in rat right ventricle systolic pressure, right ventricular hypertrophy, wall thickness and area of pulmonary artery, and muscularization of pulmonary arterioles, which was obviously suppressed by administration of piperlongumine. 3-MA attenuated the alleviating effects of piperlongumine on pulmonary vascular remodeling. ConclusionsPiperlongumine attenuates vascular remodeling in hypoxic pulmonary hypertension by regulating autophagy. Piperlongumine treatment may serve as a promising therapy for hypoxic pulmonary hypertension.

Vasodilator use in precapillary pulmonary hypertension with end stage kidney disease: A single center experience

Background and objectivesPulmonary hypertension is commonly seen in end stage kidney disease and is most commonly due to elevated left heart pressures. There is limited data about vasodilator use during the management of Group 1 pulmonary arterial hypertension in the context of those who also have or later developed end stage kidney disease. The objective of this study was to determine safety and efficacy of vasodilator therapy in precapillary pulmonary hypertension requiring renal replacement therapy. DesignThis was a single-center retrospective case series. Patients were identified from our Pulmonary Hypertension Clinic using a historical roster from 2012 to 2020. Patients were included if they >18 years of age, had Group 1 or Group 4 (precapillary) pulmonary hypertension on right heart catheterization, and also had end stage kidney disease requiring either intermittent hemodialysis or peritoneal dialysis. Results18 patients were identified with invasively confirmed Group 1 or Group 4 pulmonary hypertension and end stage kidney disease on renal replacement therapy. Scleroderma was the most common etiology for renal failure. 17 patients were treated with vasodilator therapy. Fifteen patients had paired right heart catheterizations that showed a significant decrease in mean pulmonary artery pressure and pulmonary vascular resistance. Therapy was relatively well tolerated but hypotension was common and midodrine was often helpful. Two patients had successful renal transplantation after starting vasodilator therapy. ConclusionWe found vasodilator therapy was reasonably well tolerated and associated with a drop in mean pressure and pulmonary vascular resistance in patients with end stage kidney disease on dialysis.

Comparative Efficacy and Safety of Targeted Therapies for Chronic Thromboembolic Pulmonary Hypertension: A Systematic Review and Network Meta-Analysis.

Background There is significant controversy relating to whether chronic thromboembolic pulmonary hypertension (CTEPH) can be treated with pulmonary arterial hypertension- (PAH-) targeted therapies and which therapy is the optimal choice for patients. A large number of randomized controlled trials (RCTs) have compared PAH-targeted therapies with placebo or conventional therapies. In this study, we aimed to compare all of the PAH-targeted medications that are used to treat CTEPH and rank their efficacy by the application of network meta-analysis (NMA). Methods We searched PubMed, EMBASE, Web of Science, the Cochrane Central Register, https://clinicaltrials.gov, and who.int/trialsearch/, for relevant RCTs published up to January 2020. In addition to traditional meta-analysis, we also performed NMA in our systematic review, as deployed in a previous protocol (PROSPERO: CRD42020173765). Results Our study identified eight eligible RCTs that evaluated seven PAH-targeted therapies in 703 patients with CTEPH. NMA revealed that riociguat was ranked first as the most optimized therapy for ameliorating the 6-minute walk distance with a probability of 80.4%. Bosentan was significantly better than others with regard to reducing brain natriuretic peptide/N-terminal pro-B-type natriuretic peptide with a probability of 84.3%. Sildenafil was identified as the best drug in terms of improving the New York Heart Association/World Health Organization functional class with a probability of 87.3%. Treprostinil and macitentan were more beneficial than other drugs in reducing pulmonary vascular resistance and lowering the incidence of clinical worsening with probabilities of 86.2% and 79.2%, respectively. Conclusion Analysis revealed positive advantages for the use of PAH-targeted drugs in patients with CTEPH. Overall, treprostinil and riociguat were superior to all other PAH-targeted medications in most of the outcomes investigated.

A randomized, double-blind, placebo-controlled study to evaluate sildenafil, ambrisentan combination therapy in pulmonary hypertension, particularly of Eisenmenger syndrome

Pulmonary arterial hypertension (PAH) - a complex and progressive disease that carries significant morbidity and mortality despite optimal medical treatment. Combination therapy for PAH can be more effective than monotherapy. The present randomized trial compared the safety and efficacy of sildenafil ambrisentan combination therapy with sildenafil monotherapy. Twenty-two patients of Eisenmenger syndrome and five patients of idiopathic PAH were randomized to two arms. There was a significant improvement in NYHA functional class and mean pulmonary artery pressure, while an insignificant improving trend was observed for 6-min walk distance and oxygen saturation, following the 12 weeks of combination therapy. An upfront combination therapy was found to be safe and effective in the management of PAH patients.

Stable Gastric Pentadecapeptide BPC 157 Therapy for Monocrotaline-Induced Pulmonary Hypertension in Rats Leads to Prevention and Reversal.

Background. Monocrotaline selectively injures the lung’s vascular endothelium and induces pulmonary arterial hypertension. The stable gastric pentadecapeptide BPC 157 acts as a prototype cytoprotective agent that maintains endothelium, and its application may be a novel therapy. Besides, BPC 157 prevents and reverses thrombosis formation, maintains platelet function, alleviates peripheral vascular occlusion disturbances, and has anti-arrhythmic and anti-inflammatory effects. Monocrotaline-induced pulmonary arterial hypertension in rats (wall thickness, total vessel area, heart frequency, QRS axis deviation, QT interval prolongation, increase in right ventricle systolic pressure and bodyweight loss) can be counteracted with early or delayed BPC 157 therapy. Methods and Results. After monocrotaline (80 mg/kg subcutaneously), BPC 157 (10 μg/kg or 10 ng/kg, days 1–14 or days 1–30 (early regimens), or days 14–30 (delayed regimen)) was given once daily intraperitoneally (last application 24 h before sacrifice) or continuously in drinking water until sacrifice (day 14 or 30). Without therapy, the outcome was the full monocrotaline syndrome, marked by right-side heart hypertrophy and massive thickening of the precapillary artery’s smooth muscle layer, clinical deterioration, and sometimes death due to pulmonary hypertension and right-heart failure during the 4th week after monocrotaline injection. With all BPC 157 regimens, monocrotaline-induced pulmonary arterial hypertension (including all disturbed parameters) was counteracted, and consistent beneficial effects were documented during the whole course of the disease. Pulmonary hypertension was not even developed (early regimens) as quickly as the advanced pulmonary hypertension was rapidly attenuated and then completely eliminated (delayed regimen). Conclusions. Thus, pentadecapeptide BPC 157 prevents and counteracts monocrotaline-induced pulmonary arterial hypertension and cor pulmonale in rats.

Current strategies for managing chronic thromboembolic pulmonary hypertension: results of the worldwide prospective CTEPH Registry.

BackgroundPulmonary endarterectomy (PEA), pulmonary arterial hypertension (PAH) therapy and balloon pulmonary angioplasty (BPA) are currently accepted therapies for chronic thromboembolic pulmonary hypertension (CTEPH). This international CTEPH Registry identifies clinical characteristics of patients, diagnostic algorithms and treatment decisions in a global context.Methods1010 newly diagnosed consecutive patients were included in the registry between February 2015 and September 2016. Diagnosis was confirmed by right heart catheterisation, ventilation–perfusion lung scan, computerised pulmonary angiography and/or invasive pulmonary angiography after at least 3 months on anticoagulation.ResultsOverall, 649 patients (64.3%) were considered for PEA, 193 (19.1%) for BPA, 20 (2.0%) for both PEA and BPA, and 148 (14.7%) for PAH therapy only. Reasons for PEA inoperability were technical inaccessibility (n=235), comorbidities (n=63) and patient refusal (n=44). In Europe and America and other countries (AAO), 72% of patients were deemed suitable for PEA, whereas in Japan, 70% of patients were offered BPA as first choice. Sex was evenly balanced, except in Japan where 75% of patients were female. A history of acute pulmonary embolism was reported for 65.6% of patients. At least one PAH therapy was initiated in 35.8% of patients (26.2% of PEA candidates, 54.5% of BPA candidates and 54.1% of those not eligible for either PEA or BPA). At the time of analysis, 39 patients (3.9%) had died of pulmonary hypertension-related causes (3.5% after PEA and 1.8% after BPA).ConclusionsThe registry revealed noticeable differences in patient characteristics (rates of pulmonary embolism and sex) and therapeutic approaches in Japan compared with Europe and AAO.

Critical Care Management of Decompensated Right Heart Failure in Pulmonary Arterial Hypertension Patients - An Ongoing Approach.

Despite substantial advancements in diagnosis and specific medical therapy in pulmonary arterial hypertension patients’ management, this condition continues to represent a major cause of mortality worldwide. In pulmonary arterial hypertension, the continuous increase of pulmonary vascular resistance and rapid development of right heart failure determine a poor prognosis. Against targeted therapy, patients inexorable deteriorate over time. Pulmonary arterial hypertension patients with acute right heart failure who need intensive care unit admission present a complexity of the disease pathophysiology. Intensive care management challenges are multifaceted. Awareness of algorithms of right-sided heart failure monitoring in intensive care units, targeted pulmonary hypertension therapies, and recognition of precipitating factors, hemodynamic instability and progressive multisystem organ failure requires a multidisciplinary pulmonary hypertension team. This paper summarizes the management strategies of acute right-sided heart failure in pulmonary arterial hypertension adult cases based on recently available data.

Prevalence of new coronavirus infection COVID-19 in patients undergoing pulmonary thromboendarterectomy (data from a single-center registry)

Aim. To assess the prevalence and clinical and functional features of a new coronavirus infection (COVID-19) in patients who underwent pulmonary thromboendarterectomy (PTE) using data from a single-center registry. Methods. This study included 127 patients with chronic thromboembolic pulmonary hypertension who underwent PTE from January 2016 to March 2020 and were included in a follow-up group. The follow-up after surgery was 6 or more months. The prevalence of COVID-19 and clinical and functional properties of the cardiorespiratory system were assessed in the study group. Results. The average follow-up period after PTE in the study group was 2.5 ± 0.9 years. 14 (11%) deaths not associated with COVID-19 were reported during this period. 5 cases of COVID-19 were detected among the remaining 113 patients. In one case, the infection was asymptomatic, while other patients had the typical clinical symptoms and developed bilateral polysegmental pneumonia. No patients required mechanical ventilation or died of COVID-19. All patients who underwent PTE were compliant with anticoagulation therapy and PAH-specific therapy for residual pulmonary hypertension. No adjustment of PAH-specific and anticoagulation therapy was required during COVID-19. Conclusion. The prevalence of COVID-19 in patients who underwent PTE was 4.4%, no deaths were recorded. Outpatient follow-up and timely informing of patients undergoing PTE allow keeping the COVID-19 morbidity and mortality in the studied group at the general population level. Evaluation of the impact of chronic anticoagulants and PAH-specific therapy on the outcome of COVID-19 deserves further research.

Inhaled nitric oxide improves pulmonary hypertension and organ functions after adult heart valve surgeries.

Pulmonary hypertension during cardiac surgery is associated with increased morbidity and mortality. Inhaled nitric oxide serves as a selective pulmonary vasodilator and has other potential extrapulmonary protective roles. Its effects on pulmonary hypertension and organ functions after adult valve surgeries were evaluated. From April 2017 to March 2000, 30 patients received inhaled nitric oxide therapy for pulmonary hypertension during weaning from cardiopulmonary bypass in valvular surgery (iNO group). The group was compared with a control group of 65 patients who developed pulmonary hypertension during weaning from cardiopulmonary bypass in valvular surgery and received conventional therapy from April 2014 to March 2017. Intraoperative hemodynamic changes and postoperative Sequential Organ Failure Assessment (SOFA) score were evaluated. The inhalation of nitric oxide lowered the pulmonary-to-systemic pressure ratio (Pp/Ps) (p < 0.0001) in the iNO group, and this ratio after the inhalation was significantly lower than that in the control group (p = 0.015). Moreover, norepinephrine requirement was lower in the iNO group than in the control group (p = 0.0060). The SOFA total scores, respiratory scores, coagulation scores, and the increase of renal scores within postoperative 2 days were lower in the iNO group than in the control group (p < 0.0001, p = 0.0002, p = 0.0013, and p = 0.037). Inhaled nitric oxide therapy ameliorated pulmonary hypertension and improved postoperative respiratory, coagulation, and renal functions in adult valve surgeries.

Haemodynamic effects of PAH-targeted therapies in pulmonary hypertension due to lung disease: A systematic review and meta-analysis

BackgroundPulmonary hypertension (PH) is a negative predictor in patients with lung disease and/or hypoxia (group 3 PH). Current guidelines do not endorse the use of targeted therapies for pulmonary arterial hypertension (PAH) in patients with group 3 PH, due to lack of strong evidence. However, a variety of studies have examined the effect of PAH-targeted therapies in group 3 PH with mixed methods and conflicting results. ObjectiveTo evaluate the effect of PAH-targeted therapies on haemodynamic parameters as assessed by right heart catheterization in patients with group 3 PH. MethodsSearch strategy included PubMed and CENTRAL databases for randomized controlled trials from inception until Jan 30, 2020. We hand searched review articles, clinical trial registries and reference lists of retrieved articles. The primary outcome was the effect of PAH-targeted therapies on haemodynamic parameters [mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), cardiac index (CI) and right atrial pressure (RAP)] in patients with group 3 PH, while secondary outcomes were 6-min walking distance (6MWD), brain natriuretic peptide (BNP) and quality of life (QoL). ResultsFive studies with a total of 140 patients were included. PAH-targeted therapies improved significantly mPAP [mean difference (MD) −4.02 mmHg, 95% CI -7.95;-0.09], and PVR [standardized mean difference (SMD) −0.29, 95% CI -0.50;-0.07], but not CI (SMD 0.23, 95% CI -0.23; 0.70) or RAP (MD 0.26 mmHg, 95% CI -18.75; 19.27). PAH-targeted therapies significantly increased the 6MWD by 38.5 m (95% CI 17.6; 59.4), while they did not manage to improve QoL (SMD -3.42, 95% CI -14.74; 7.91) or BNP values. There was no effect of oxygenation by the PAH-targeted therapies compared to placebo. ConclusionPAH-targeted therapies slightly improved mPAP and PVR in group 3 PH, without affecting CI. Larger RCTs targeted in specific subpopulations are needed to extract more robust conclusions. Protocol registrationOpen Science Framework 10.17605/OSF.IO/56FDW.

Inhibition of mTOR by rapamycin does not improve hypoxic pulmonary hypertension-induced right heart failure in old mice.

Inhibition of the mammalian target of rapamycin (mTOR) by rapamycin attenuates heart failure (HF) and age-associated changes in left ventricular (LV) function. Rapamycin has also been suggested as a therapy for pulmonary hypertension (PH) and concomitant right heart failure (PH-RHF) based on reports of elevated mTOR signaling in young models with PH. However, rapamycin has yet to be tested in the setting of aging, PH, and right heart disease despite the fact that RV function predicts survival in both age-related HF as well as several pulmonary disease states including PH. Thus we tested the hypothesis that rapamycin treatment would attenuate hypoxic PH-RHF in old mice using a mouse model of hypobaric hypoxia (HH)-induced PH and right ventricular (RV) remodeling. Exposure to HH resulted in significant loss of body weight which was exacerbated by rapamycin. HH elevated lung and RV weight, RV wall thickness as well as RV systolic dysfunction as evidenced by RV stroke volume and cardiac output. While rapamycin rescued pulmonary artery acceleration time in males, it generally did not improve other indexes cardiopulmonary remodeling or function. As expected, HH induced expression of hypoxia-regulated genes in the RV and the lungs; however, this transcriptional activation was attenuated by rapamycin, representing a potential mechanism by which rapamycin is detrimental in the aged RV in the setting of chronic hypoxia. Together, we demonstrate that rapamycin is not a viable therapeutic in hypoxic PH in old mice, likely due to exacerbated loss of body weight in this setting. We suggest that future efforts should take into consideration the differences between the RV and LV and the interaction between mTOR and hypoxia in the setting of age-related disease.

Stereological Lung Parameters After Fetoscopic Abdominal Decompression of Congenital Diaphragmatic Hernia in an Ovine Model: A Pilot Study.

Background: Fetoscopic endoluminal tracheal occlusion (FETO) improves lung maturation in severe cases of congenital diaphragmatic hernia (CDH) but it does not ameliorate lung compression by herniated abdominal organs. Surgically opening the fetal abdomen (abdominal decompression [AD]) reduces the intrathoracic pressure by diverting the abdominal organs into the amniotic cavity-a probable causal therapy for lung hypoplasia and pulmonary hypertension in CDH. Open surgical abdominal decompression has been reported: we describe a minimally invasive approach in an ovine model of CDH as a probable fetoscopic intervention. Materials and Methods: Eight fetuses were included, 2 were kept as HEALTHY controls. A CDH (left side, liver down) was created by open fetal surgery at midgestation in 6 fetuses, 2 were taken as CDH controls. Fetoscopic abdominal decompression (fAD) was performed 21 days later in 4 animals. The fetuses were retrieved at the end of gestation and evaluated by lung stereology. Results: fAD led to a near total evacuation of the thoracic cavity in 2 of the 4 animals. Fetuses with CDH had a lower total volume and fraction of alveolar air space, a lower volume fraction of the parenchyma, and an increase of the volume fraction of the alveolar septa and atelectasis, as well as an increased mean thickness of alveolar septa compared with HEALTHY fetuses. Fetuses treated with abdominal decompression showed an improvement of stereological parameters. Conclusions: In spite of relevant limitations (pilot study, small groups, spontaneous closure of the abdominal incision) we were able to demonstrate that abdominal decompression for CDH can be performed by fetoscopy. Our results support the hypothesis of causally improving lung development by abdominal decompression, thus implying increased survival in extreme cases of CDH. A refinement of the fetoscopic techniques and direct comparison to FETO appears warranted.

Evidence for the Management of Bronchopulmonary Dysplasia in Very Preterm Infants.

Background: Very preterm birth often results in the development of bronchopulmonary dysplasia (BPD) with an inverse correlation of gestational age and birthweight. This very preterm population is especially exposed to interventions, which affect the development of BPD. Objective: The goal of our review is to summarize the evidence on these daily procedures and provide evidence-based recommendations for the management of BPD. Methods: We conducted a systematic literature research using MEDLINE/PubMed on antenatal corticosteroids, surfactant-replacement therapy, caffeine, ventilation strategies, postnatal corticosteroids, inhaled nitric oxide, inhaled bronchodilators, macrolides, patent ductus arteriosus, fluid management, vitamin A, treatment of pulmonary hypertension and stem cell therapy. Results: Evidence provided by meta-analyses, systematic reviews, randomized controlled trials (RCTs) and large observational studies are summarized as a narrative review. Discussion: There is strong evidence for the use of antenatal corticosteroids, surfactant-replacement therapy, especially in combination with noninvasive ventilation strategies, caffeine and lung-protective ventilation strategies. A more differentiated approach has to be applied to corticosteroid treatment, the management of patent ductus arteriosus (PDA), fluid-intake and vitamin A supplementation, as well as the treatment of BPD-associated pulmonary hypertension. There is no evidence for the routine use of inhaled bronchodilators and prophylactic inhaled nitric oxide. Stem cell therapy is promising, but should be used in RCTs only.