Pulmonary Vasodilator Therapy Research Articles

Chronic thromboembolic pulmonary hypertension and the post-pulmonary embolism (PE) syndrome.

Over a third of patients surviving acute pulmonary embolism (PE) will experience long-term cardiopulmonary limitations. Persistent thrombi, impaired gas exchange, and altered hemodynamics account for aspects of the postpulmonary embolism syndrome that spans mild functional limitations to debilitating chronic thromboembolic pulmonary hypertension (CTEPH), the most worrisome long-term consequence. Though pulmonary endarterectomy is potentially curative for the latter, less is understood surrounding chronic thromboembolic disease (CTED) and post-PE dyspnea. Advances in pulmonary vasodilator therapies and growing expertise in balloon pulmonary angioplasty provide options for a large group of patients ineligible for surgery, or those with persistent postoperative pulmonary hypertension. In this clinical review, we discuss epidemiology and pathophysiology as well as advances in diagnostics and therapeutics surrounding the spectrum of disease that may follow months after acute PE.

Pulmonary vasodilator therapy in sarcoidosis-associated pulmonary hypertension may decrease lung function decline and mortality.

The efficacy of treating sarcoidosis-associated pulmonary hypertension (SAPH) with pulmonary vasodilator therapy is unclear. The INCREASE trial showed improvement in 6-minute walk distance (6MWD) and in decline in functional vital capacity (FVC) in patients with interstitial lung disease and pulmonary hypertension. We hypothesize that patients with SAPH treated with pulmonary vasodilators have reduced decline in FVC. We retrospectively analyzed patients with SAPH who underwent lung transplantation evaluation. The primary objective was to compare change in FVC between patients with SAPH who received pulmonary vasodilators (treated) and those who did not (untreated). Secondary objectives were to compare the change in 6MWD, change in oxygen requirement, transplant rates, and mortality between treated and untreated SAPH patients. We identified 58 patients with SAPH; 38 patients received pulmonary vasodilator therapy, and 20 patients did not. Treated SAPH patients had significantly less decline in FVC than untreated SAPH patients (+54 mL vs. -357 mL, p < 0.01). Treated SAPH patients had significantly higher survival than untreated SAPH patients. Receiving PH therapy was significantly associated with a change in FVC (estimate 0.36 ± 0.07, p < 0.01) and decreased mortality (hazard ratio 0.29, confidence interval 0.12-0.67, p < 0.01). Among patients with SAPH, those who received pulmonary vasodilator therapy had significantly less decline in FVC and increased survival. Receiving pulmonary vasodilator therapy was significantly associated with FVC change and decreased mortality. These study findings point towards potential benefit of pulmonary vasodilator therapy in SAPH patients. Further prospective studies are required to fully elucidate the benefits of pulmonary vasodilator therapy in SAPH.

Predictors of hospitalization for respiratory failure among patients with sarcoidosis-associated pulmonary hypertension.

Pulmonary hypertension leads to significant morbidity and mortality in patients with sarcoidosis. In this study, we examined clinical factors associated with the risk of respiratory failure-related hospitalization in 58 patients with sarcoidosis-associated pulmonary hypertension. Pulmonary vasodilator therapy and spirometry were associated with reduced risk of hospitalization in this cohort.

A Canadian, retrospective, multicenter experience with selexipag for a heterogeneous group of pediatric pulmonary hypertension patients.

Selexipag, an oral nonprostanoid prostaglandin receptor agonist, has led to reduced morbidity and mortality in adults with pulmonary arterial hypertension (PAH). While the adult literature has been extrapolated to suggest selexipag as an oral treatment for severe pediatric pulmonary hypertension (PH), longitudinal, multicenter data on the benefits of selexipag in this population are lacking. The purpose of this study is to present a longitudinal, multicentre experience with selexipag in a relatively large cohort of pediatric PH patients and add to the existing selexipag literature. We performed a retrospective, multicenter review describing the clinical outcomes of pediatric PH patients receiving selexipag in addition to standard oral pulmonary vasodilator therapy across three Canadian centers between January 2005 and June 2021. Twenty-four pediatric patients (fifteen female) with a mean age of 9.7 (range 2.0-15.5) years were included. Of this cohort, eighteen (75.0%) were in group 1, one (4.2%) was in group 2, four (16.7%) were in group 3, and one (4.2%) was in group 4. Twenty-two (91.7%) patients were on dual PH therapy after six months. Dosing was targeted to achieve 20-30 mcg/kg/dose orally every twelve hours. Median dose after twelve months was 30 mcg/kg/dose. Twelve months following selexipag initiation, median decreases of 0.2 cm in tricuspid annular plane systolic excursion, 3.5 mmHg in right-ventricular systolic pressure, and 6.1 mmHg in mean pulmonary arterial pressure were observed; none of these changes were statistically significant. Three patients died, one clinically deteriorated and required admission to a pediatric intensive care unit, ten had gastrointestinal symptoms, and three had flushing. Selexipag appears to be a safe and effective adjunctive therapy for pediatric PH patients and has a tolerable adverse effect profile aside from gastrointestinal disturbances. Additional prospective studies of changes in hemodynamics and functional classification over a longer period and with a larger sample are needed. Future research should aim to identify subgroups that stand to benefit from the addition of selexipag as well as optimal timing and dosing for the pediatric population.

Pulmonary vasodilator therapies in pulmonary arterial hypertension associated with CHD: a systematic review and network meta-analysis.

The optimal treatment strategy using pulmonary vasodilators in pulmonary arterial hypertension associated with CHD (PAH-CHD) remains controversial. We aimed to compare the efficacy and safety of pulmonary vasodilators in PAH-CHD. PubMed and EMBASE databases were searched through May 2022 and a network meta-analysis was conducted. The primary outcomes were mean difference of changes in 6-minute walk distance, NYHA functional class, and N-terminal pro-brain natriuretic peptide. The secondary outcomesincluded pulmonary vascular resistance, mean pulmonary arterial pressure, and resting oxygen saturation. We identified 14 studies, yielding 807 patients with PAH-CHD. Bosentan and sildenafil were associated with a significant increase in 6-minute walk distance from baseline compared with placebo (MD 48.92 m, 95% CI 0.32 to 97.55 and MD 59.70 m, 95% CI 0.88 to 118.53, respectively). Bosentan, sildenafil, and combination of bosentan and sildenafil were associated with significant improvement in NYHA functional class compared with placebo (MD -0.33, 95% CI -0.51 to -0.14, MD -0.58, 95% CI -0.75 to -0.22 and MD -0.62, 95% CI -0.92 to -0.31, respectively). Bosentan and sildenafil were also associated with significant improvements in secondary outcomes. These findings were largely confirmed in the subgroup analysis. Various adverse events were reported; however, serious adverse event rates were relatively low (4.8-8.7%), including right heart failure, acute kidney injury, respiratory failure, hypotension, and discontinuation of pulmonary vasodilators. In conclusion, bosentan and sildenafil were the most effective in improving prognostic risk factor such as 6-minute walk distance and NYHA class. Overall, pulmonary vasodilators were well tolerated in PAH-CHD.

A canadian retrospective multicenter experience with selexipag in a heterogeneous group of pediatric pulmonary hypertension patients

Abstract Funding Acknowledgements Type of funding sources: None. Background The introduction of the oral prostanoid selexipag for treating severe adult pulmonary arterial hypertension (PH) has contributed to reduced rates of death and secondary complications in PAH. Pediatric physicians have extrapolated from the adult literature to utilize this medication to treat severe pediatric pulmonary hypertension. However, longitudinal, multicenter data on the therapeutic benefits of selexipag for pediatric patients is lacking. Materials and Methods We performed a retrospective review describing the clinical outcomes of pediatric PH patients receiving selexipag for pulmonary hypertension (PH) therapy in addition to standard pulmonary vasodilator therapy across three North American pediatric PH centers between January 2005 and June 2021. Results Across three Canadian centers, 24 patients (15 female) with a mean age at diagnosis of 5.4 (0.9) years were included. Of this cohort, 19 (79.2%) had group 1 PAH, 4 (16.7%) had group 3 PH, and 1 (4.2%) had group 4 PH. Genetic syndromes were noted in 7 (29.2%) patients. Dosing was targeted to achieve 20–30 mcg/kg/dose orally every 12 hours; the mean dosage after 12 months was 31.2 (10.3) mcg/kg/dose. Twelve months following selexipag initiation, a median increase of 71.5 m (p = 0.44) in six-minute walk test distance was observed together with median decreases of 0.2 cm (p = 0.17) in tricuspid annular plane systolic excursion, 3.5 mmHg (p = 0.95) in right ventricle systolic pressure, and 6.1 mmHg (p = 0.09) in mean pulmonary artery pressure. 2 patients (8.3%) died, 1 (4.2%) was referred for a heart transplant, and 1 (4.2%) received an atrial flow regulator. One patient (4.2%) required admission to a pediatric intensive care unit during their treatment course this was related to profound desaturation, six (25.0%) had gastrointestinal symptoms, and two (8.3%) had facial flushing. Conclusion Selexipag appears to be a beneficial adjunctive therapy for selected pediatric PH patients and has a tolerable adverse effect profile aside from gastrointestinal disturbances. Further prospective studies of changes in hemodynamics and functional classification over a longer period and with a larger sample are needed.

POINT: Is It Time to Lower the Cut-off for Increased Pulmonary Vascular Resistance? Yes

Background For decades, pulmonary hypertension (PH) used to be defined by a mean pulmonary artery pressure (mPAP) ≥25 mm Hg; however, this criterion was not based on data that were systematically collected. With the availability of contemporary datasets however, it was evident that the upper limit of normal mPAP was ∼20 mm Hg, which is also the level of mPAP above which adverse outcomes increase. In addition, it is now evident that the specificity of mPAP &amp;gt;20 mm Hg to denote precapillary pulmonary vascular disease could be enhanced by adding pulmonary vascular resistance (PVR) to the precapillary PH definition. Finally, after characterizing large groups of normal individuals, akin to observations for mPAP, it was recently demonstrated that a PVR of ∼2.0 Wood units (WU) is the upper limit of normal, and the lower level associated with all-cause mortality in at-risk patients. Clinical Implications The current hemodynamic criteria for PH are positioned to capture more patients compared to the classical definition, with particular implications for earlier diagnosis. Importantly, pulmonary vasodilator therapies have not been tested adequately in patients with mPAP &amp;lt;25 mm Hg or PVR between 2 to 3 WU and, thus, should not be administered in these patients. Mild PH is an active focus of clinical trial design; at present, these patients should be referred to expert PH centers earlier for individualized therapeutic planning. Conclusions The revised definition of precapillary PH uses a PVR threshold of &amp;gt;2 WU. This value is evidence-based, and exceeding this threshold is associated with adverse clinical outcomes. This revision places focus on early diagnosis, close monitoring, and consideration for certain treatments. Further studies are needed that test the efficacy and safety of pulmonary arterial hypertension-specific therapy in precapillary PH patients with PVR 2 to 3 WU.

Outpatient prescription of pulmonary vasodilator therapy to preterm children with bronchopulmonary dysplasia.

The use of pulmonary vasodilator therapy in children born preterm is largely unknown. Our aim was to map prescription patterns in children with bronchopulmonary dysplasia in Sweden. This was a descriptive national registry-based study of children <7 years who had been prescribed a pulmonary vasodilator during 2007-2017, were born preterm and classified as having bronchopulmonary dysplasia. Information on prescriptions, patient characteristics and comorbidities were retrieved from the Swedish Prescribed Drug Register and linked to other national registers. The study included 74 children, 54 (73%) born at 22-27 weeks' gestation and 20 (27%) at 28-36 weeks. Single therapy was most common, n=64 (86.5%), and sildenafil was prescribed most frequently, n=69 (93%). Bosentan, iloprost, macitentan and/or treprostinil were used mainly for combination therapies, n=10 (13.5%). Patent ductus arteriosus or atrial septal defect were present in 29 (39%) and 25 (34%) children, respectively, and 20 (69%) versus 3 (12%) underwent closure. Cardiac catheterisation was performed in 19 (26%) patients. Median duration of therapy was 4.6 (1.9-6.8, 95% CI) months. Mortality was 9%. Preterm children with bronchopulmonary dysplasia were prescribed pulmonary vasodilators, often without prior catheterisation. Sildenafil was most commonly used. Diagnostic tools, effects, and drug safety need further evaluation.

Novel and emerging therapies in pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH), defined as a mean pulmonary artery pressure exceeding 20 mmHg with a pulmonary vascular resistance of 3 or more Wood units, is an incurable and progressive condition. The cornerstone of PAH treatment is pulmonary vasodilators, which act on the pulmonary vasculature to reduce pulmonary pressures and pulmonary vascular resistance and prevent progression to right heart failure. The number of available pulmonary vasodilator therapies has grown markedly in the last 10 years, alongside a rapidly expanding body of literature establishing strategies for their use. Up-front combination therapy, typically with two pulmonary vasodilator medications, has become the standard of care based on landmark trials showing superior outcomes over single therapies alone. Complex risk stratification matrices have begun to see widespread use as tools with which to guide changes in PAH therapies for individual patients. Strategies for using the pulmonary vasodilators in common use continue to be evaluated in trials exploring concepts such as up-front triple combination therapy and substitution of vasodilators for patients not meeting therapeutic goals. Alongside established pulmonary vasodilator therapies for PAH, there is a broad spectrum of experimental therapies that are being studied for the disease. These include both more conventional medications that act on pathways targeted by existing vasodilator therapies as well as non-vasodilator treatments with novel methods of action, that may act both to vasodilate and to address the detrimental changes of pulmonary arterial and right ventricular remodeling. Many of these emerging medications are the focus of active phase 2 and 3 trials. Finally, there has been significant interest in therapeutic pathways that are well established in left heart failure, with the hope of adapting strategies that may be efficacious in PAH and right heart failure as well. These include explorations of pathways treated by goal-directed medical therapy as well as device therapies such as pacing, resynchronization therapy, and cardiac monitoring devices. Many of these options show promise and may represent a complementary approach to treatment of PAH, allowing for multimodal therapy alongside pulmonary vasodilators to improve patient outcomes.

Association Between Copayment and Adherence to Medications for Pulmonary Arterial Hypertension.

Background Pharmacologic treatment for pulmonary arterial hypertension (PAH) improves exercise capacity, functional class, and hemodynamic indexes. However, monthly prescription costs often exceed $4000. We examined associations between (1) medication copayment and (2) annual household income with adherence to pulmonary vasodilator therapy among individuals with PAH. Methods and Results We used administrative claims data from an insured population in the United States to identify individuals diagnosed with PAH between 2015 and 2020. All individuals had ≥1 medication claim for endothelin receptor antagonists, phosphodiesterase type-5 inhibitors, prostanoids or prostacyclin receptor agonists, or the soluble guanylate cyclase stimulator riociguat. We defined copayments as low, medium, or high, as determined by their distributions for each medication class. Annual household income was categorized as <$40 000, $40 000 to $74 999, and ≥$75 000. The primary outcome was medication adherence, defined by proportion of days covered ≥80%. We studied 4025 adults (aged 65.9±13.3 years; 71.2% women). Compared with those with annual household income ≥$75 000, individuals in the <$40 000 and $40 000 to $74 999 categories had no significant differences in medication adherence. Compared with those with low copayments, individuals with high copayments had decreased adherence to prostanoids (odds ratio [OR], 0.36 [95% CI, 0.20-0.65]; P<0.001) and combination therapy with endothelin receptor antagonist and phosphodiesterase type-5 inhibitor (OR, 0.61 [95% CI, 0.38-0.97]; P=0.03). Conclusions We identified associations between copayment and adherence to prostanoids and combination therapy among individuals with PAH. Copayment may be a structural barrier to medication adherence and merits inclusion in studies examining access to pharmacotherapy among individuals with PAH.

Selective Use of Pulmonary Vasodilators in Patients with Fontan Physiology.

Fontan-associated liver disease is a well-known sequela following the Fontan procedure for patients living with single-ventricle heart disease. Pulmonary vasodilators, such as phosphodiesterase type 5 inhibitors, have emerged as a potential therapeutic option for lowering central venous pressures by reducing pulmonary vascular resistance. We performed a single-center retrospective review of Fontan patients who were placed on pulmonary vasodilator therapy with prehemodynamic and posthemodynamic, MR elastography, and histologic assessments. A total of 125 patients with Fontan circulation underwent surveillance with cardiac catheterization during the review period. Fifty-three (42%) patients who did not have increased end-diastolic pressures at the time of cardiac catheterization were started on phosphodiesterase type 5 inhibitor therapy. Nine patients (17%) underwent posttherapy follow-up catheterization. The mean Fontan pressure decreased from 15.4 ± 3.3 mmHg to 13.3 ± 2.5 mmHg (p=0.026), after initiation of pulmonary vasodilatory therapy. There was no change in end-diastolic pressure, transpulmonary gradient, wedge pressure, pulmonary vascular resistance, cardiac index, or saturation. Eleven patients (21%) underwent pretherapy MR elastography testing with posttherapy follow-up MR elastography. We found no improvement in liver stiffness score following the application of pulmonary vasodilators. Three patients underwent pretherapy and posttherapy liver biopsies, with variable histological changes observed within the hepatic parenchyma. These data demonstrate indeterminate results for the selective use of pulmonary vasodilators but highlight the need for large prospective randomized control trials of pulmonary vasodilator therapies to fully assess the benefit of such therapies in Fontan-associated liver disease.

Abstract 10753: Phosphodiesterase Type 5 Inhibition and C-c Chemokine Receptor-2 Disruption Synergistically Protect Against Pulmonary Arterial Hypertension in Monocrotaline-Treated Rats: Potential Synergism of Anti-inflammatory Agents and Pulmonary Vasodilator Therapy

BACKGROUND: Whether conventional pulmonary vasodilator therapy and anti-inflammatory agents synergistically protect against pulmonary arterial hypertension (PAH) is unknown. Hypothesis: We tested the hypothesis that a phosphodiesterase type 5 (PDE5) inhibitor and disruption of C-C chemokine receptor (CCR)-2, a receptor for MCP-1, synergistically protect against PAH in monocrotaline (MCT)-treated rats. Methods: Study1:Seven-week-old male Ccr2 (-/-) rats, generated by using the CRISPAR/ Cas9 genome editing technology, or wild-type littermates, treated with MCT (60mg/kg) or vehicle, were subjected to hemodynamic, morphometric and immunohistochemical analyses and mRNA and protein expression studies on day21 (n=40, 4 groups). Study 2: Tadarafil (10mg/kg/d), a PDE5 inhibitor, or vehicle was administered in Ccr2 (-/-) or wild-type MCT rats on days 21-42 (n=71, 4 groups) for evaluating survival and were evaluated hemodynamically on day28. Results: Study1: MCT treatment increased right ventricular systolic pressure (RVSP), an index of right ventricular hypertrophy (Fulton index), indices of pulmonary vascular diseases (%medial wall thickness, %muscularization) and the number of perivascular CD68-positive macrophages in WT rats, all of which were decreased by Ccr2 (-/-) (p&lt;.05). Similarly, an increase in mRNA expression of inflammatory cytokines (IL6 ,TNFa, MCP1, IL1b, TGFb) and a decrease in BMPR2 pathways (BMPR2, pSmad1/5/9 and ID1) as well as an increase in endothelial apoptosis (% cleaved Caspase 3 positive CD31 cells) and a decrease in NO pathways (eNOS and phospho-eNOS/eNOS) in lungs in wild-type MCT rats were reversed by Ccr2 (-/-) on day21 (p&lt;.05) with comparable PDE5 expression. Study2: Tadarafil administration or CCR2(-/-)(p=.03 and p=.02) alone improved the survival in wild type MCT rats. A double intervention synergistically improved the survival in separately treated groups (p=.02 vs CCR2(-/-), p=.04 vs Tadarafil) in MCT rats. Tadarafil treatment on days21-28 decreased RVSP and Fulton index in CCR2(-/-) MCT rats (p&lt;.05). Conclusions PDE5 inhibition and CCR-2 disruption synergistically protect against PAH in MCT-treated rats, suggesting an adjunctive role of a CCR2 inhibitor on top of administering a PDE5 inhibitor for PAH.

Abstract 11386: Double Whammy Complicating Management of Pulmonary Hypertension

Introduction: When presented with challenging cardiac cases, in addition to obvious diagnoses, it is critical to maintain high level of suspicion about other subtle conditions. We describe one such case of pulmonary arterial hypertension (PAH) from severe mitral stenosis (MS) and another less obvious congenital cardiac condition that significantly impacted the clinical course. Case: 32-year-old immigrant male with known heart murmur presented with palpitations due to atrial fibrillation. His resting oxygen saturation was 95% in all extremities and he had no clubbing. He had pectus carinatum and scoliosis, prominent right ventricular lift, normal S1, loud S2, opening snap, rumbling diastolic murmur at the apex, and an ejection systolic murmur at the left upper sternal border. Echocardiogram revealed normal biventricular size and function, severely enlarged left atrium, rheumatic severe MS, moderate mitral regurgitation, a restrictive ventricular septal defect (VSD), and elevated right ventricular systolic pressure. Cardiac catheterization demonstrated mixed pre- and post-capillary PAH with mean pulmonary artery pressure of 80 mmHg, wedge pressure 30 mm Hg and pulmonary vascular resistance of 3.0 woods unit which was underestimated. Since pre-capillary component of the PAH could not be entirely explained by the small VSD, a congenital cardiac CT was performed revealing moderate sized patent ductus arteriosus (PDA). Further management decisions were complicated since MS was not amenable to percutaneous intervention and surgical risks were high given severe pre-capillary PAH- management of which with pulmonary vasodilators was itself high risk in the setting of severe MS and high wedge pressures. After optimal medical management, a multidisciplinary team carefully considered the risks and benefits of multiple interventions. Ultimately, the patient underwent surgical mitral valve replacement, fenestrated patch closure of the PDA, and then initiation of pulmonary vasodilators. The patient continues to do well on oral pulmonary vasodilator therapy 6 months after surgery. Conclusion: We describe an astute critical thought process of a multidisciplinary team utilized to manage a challenging case of mixed PAH from severe rheumatic MS and PDA.

Comprehensive Review of Pulmonary Hypertension and Treatment Options in the Paediatric Population

Pulmonary hypertension (PH) is a complex condition that can occur as a result of a wide range of disorders, including left heart disease, lung disease, and chronic pulmonary thromboembolism. Multiple improvements have been made in the diagnosis and treatment of pulmonary arterial hypertension (PAH)including a greater understanding of the involvement of extrapulmonary vascular organ systems, validated point of care, clinical assessment tools, and a focus on the initial exposure of numerous pharmacotherapeutics in the appropriate level of care. To achieve a minimal symptom burden, improve the patient's biochemical, hemodynamic, and functional profile, and reduce adverse impact, early diagnosis of PAH is a key objective today. The preferred method of management for thromboembolic PH, which is chronic, is pulmonary endarterectomysince the majority of affected patients are operable. The timing of pulmonary endarterectomy should never be delayed for medical reasons, and risk stratification can enable us to select patients who have a high chance of success. Patients who are not qualified for endarterectomy should be referred for drug trials. Even though there are more effective ways to guarantee a sufficient, long-lasting septostomy, atrial septostomy is promising but undervalued. The procedure's indications remain the sameand needto be taken into account more frequently. Class III or IV patients who are not improving need to be consulted at a transplant centre as soon as possible as they may be candidates for potential recipients of bilateral sequential lung or heart-lung transplants, which is a significant choice for some people. PH is rarely linked to other conditions like connective tissue or thromboembolic disease. It is either idiopathic or linked to congenital heart disease. Infants and children with PH are more frequently recognised in conjunction with a congenital diaphragmatic hernia and developmental lung diseases like bronchopulmonary dysplasia. Although the underlying disease has not yet been treated and advanced structural changes have not yet been reversed, the value of natural life and survival have suggestively increased. Children's haemodynamic and functional outcomes have improved as a result of endothelin receptor antagonists, prostacyclin analogues, and phosphodiesterase type 5 inhibitors, which are examples of targeted pulmonary vasodilator therapies. The health maintenance of paediatric PH is still difficult because treatment decisions are largely based on the findings of adult studies that have been supported by evidence and the clinical expertise of paediatric specialists.

Predicting the response to pulmonary vasodilator therapy in systemic sclerosis with pulmonary hypertension by using quantitative chest CT.

Systemic sclerosis (SSc) is associated with pulmonary vascular disease and interstitial lung disease, making it difficult to differentiate pulmonary arterial hypertension and pulmonary hypertension (PH) due to lung diseases and/or hypoxia and to decide treatments. We aimed to predict the response to pulmonary vasodilators in patients with SSc and PH. Eighty-four SSc patients were included with 47 having PH. Chest computed tomography was evaluated using software to calculate the abnormal lung volume (ALV). To define the response to vasodilators, Δ mean pulmonary artery pressure (mPAP)/basal mPAP was used (cut-off value: 10%). The predictive value was evaluated by using the receiver operating characteristic curve. The mean (±standard deviation) value of ALV was 26.8 (±32.2) %. A weak correlation was observed between ALV and forced vital capacity (FVC) (R = -0.46). The predictive value of ALV [area under curve (AUC) = 0.74] was superior to that of FVC (AUC = 0.62) for the response to vasodilators. No hemodynamic parameters differed between patients with high and low ALV, whereas survival was worse in high ALV. Quantitative chest computed tomography well predicted the response to vasodilators in patients with SSc and PH. Our results suggest its utility in differentiating the dominance of pulmonary vascular disease or interstitial lung disease.

P9.49: Efficacy and Long-term Prognosis of Liver Transplantation For Porto-Pulmonary Hypertension

Objective: Porto-pulmonary hypertension (PoPH) refers to pulmonary hypertension based on severe portal hypertension. Severe PoPH has a very high perioperative mortality rate and is still considered a contraindication for liver transplantation (LT). We analyze efficacy and long-term prognosis of liver transplantation for porto-pulmonary hypertension from our center. Methods: A retrospective analysis was performed on 5 patients with PoPH who received liver transplantation in Beijing Friendship Hospital from Jan. 2013 to March 2022, in order to analyze postoperative follow-up results and long-term survival. Results: Five patients with PoPH with a mean age of 35.6 ± 18.6 years (60% females), were included in the analysis. Their primary diseases were hepatic spongiosis, Caroli disease, hepatitis B cirrhosis, drug-induced cirrhosis and primary sclerosing cholangitis. All patients were measured by Swan-Ganz catheterization of right heart, among them, the mean of the highest mean pulmonary artery pressure(mPAP) level before LT were 46.6mmHg(27-58mmHg). The mean of their highest systolic pulmonary artery pressure(SPAP) level measured under echocardiography was 101.36mmHg(51-154mmHg) before LT. The median Model for End-Stage Liver Disease (MELD) score was 16(14-20) at PoPH diagnosis. All patients had been on pulmonary vasodilator therapy(including ambrisentan, remodulin and sildenafil) for more than six months to lower pulmonary artery pressure to mPAP<35mmHg, that can achieve surgical indications before LT. The operations went smoothly, except in one case where pulmonary artery pressure suddenly increased during surgery ended smoothly after the addition of remodulin. Two patients underwent a second liver transplant at 6 months and 65 months postoperatively, and one patient died of acute heart failure after the second transplantation, while the remaining four patients survived. The follow-up time of the survived patients were 29.7, 46.9, 56, 85.2 months. The longest follow-up among them was over seven years. SPAP of them decreased 15.4, 129, 65.3, 20mmHg after LT. Two patient was discontinued pulmonary arterial pressure medications within 1 year after surgery because SPAP were down to normal, and other patients still on medication. Conclusion: Patients with pulmonary vasodilator therapy before LT can have excellent long-term outcomes post-transplant. Oral pulmonary vasodilator therapy can be effective treatment to qualify patients for LT.

Acute vasodilator response testing in the adult Fontan circulation using non-invasive 4D Flow MRI: a proof-of-principle study.

Pulmonary vasodilator therapy in Fontan patients can improve exercise tolerance. We aimed to assess the potential for non-invasive testing of acute vasodilator response using four-dimensional (D) flow MRI during oxygen inhalation. Six patients with well-functioning Fontan circulations were prospectively recruited and underwent cardiac MRI. Ventricular anatomical imaging and 4D Flow MRI were acquired at baseline and during inhalation of oxygen. Data were compared with six age-matched healthy volunteers with 4D Flow MRI scans acquired at baseline. All six patients tolerated the MRI scan well. The dominant ventricle had a left ventricular morphology in all cases. On 4D Flow MRI assessment, two patients (Patients 2 and 6) showed improved cardiac filling with improved preload during oxygen administration, increased mitral inflow, increased maximum E-wave kinetic energy, and decreased systolic peak kinetic energy. Patient 1 showed improved preload only. Patient 5 showed no change, and patient 3 had equivocal results. Patient 4, however, showed a decrease in preload and cardiac filling/function with oxygen. Using oxygen as a pulmonary vasodilator to assess increased pulmonary venous return as a marker for positive acute vasodilator response would provide pre-treatment assessment in a more physiological state - the awake patient. This proof-of-concept study showed that it is well tolerated and has shown changes in some stable patients with a Fontan circulation.

A systematic review of clinical study evidence for pulmonary vasodilator therapy following surgery with cardiopulmonary bypass in children with CHD.

Complications from pulmonary hypertension are one of the leading contributors to morbidity and mortality post-cardiopulmonary bypass surgery in children with CHD. Pulmonary vasodilator therapies are commonly used post-operatively, but the optimal target patient population, therapy choice, timing of therapy initiation, and duration of therapy are not well defined. We used PubMed and EMBASE to identify studies from 2000 to 2020 investigating the use of pulmonary vasodilator therapy post-cardiopulmonary bypass in children aged 0-18 years. To ensure eligibility criteria, studies were systematically reviewed by two independent reviewers. We identified 26 studies of 42,971 children across four medication classes; 23 were single centre, 14 were prospective, and 11 involved randomisation (four of which employed a placebo-control arm). A disproportionate number of children were from a single retrospective study of 41,872 patients. Definitions varied, but change in pulmonary haemodynamics was the most common primary outcome, used in 14 studies. Six studies had clinical endpoints, with mortality the primary endpoint for two studies. Treatment with inhaled nitric oxide, iloprost, and sildenafil all resulted in improved haemodynamics in specific cohorts of children with post-operative pulmonary hypertension, although improved outcomes were not consistently demonstrated across all treated children. Iloprost may be a cheaper alternative to inhaled nitric oxide with similar haemodynamic response. Studies were predominantly single-centre, a control arm was rarely used in randomised studies, and haemodynamic endpoints varied significantly. Further research is needed to reduce post-operative morbidity and mortality from pulmonary hypertension in children with CHD.

Prevalence of aortic stenosis and TAVR outcomes in patients with systemic sclerosis-associated pulmonary hypertension.

There is little known about performing transcatheter aortic valve replacement (TAVR) in patients with group 1 pulmonary arterial hypertension (PAH) on advanced pulmonary vasodilator therapy. Retrospective cohort study among 90 patients with systemic sclerosis‐associated pulmonary arterial hypertension and systemic sclerosis‐associated pulmonary hypertension (SSc‐PAH/PH) evaluated at a tertiary PH center. The SSc‐PAH/PH cohort was stratified by the presence or absence of aortic stenosis (AS) to identify differences in baseline characteristics, hemodynamics, and long‐term outcomes. Of the 90 SSc‐PAH/PH patients, 13 patients were diagnosed with AS at PH diagnosis and another 6 patients developed AS during the study period. The period prevalence of AS was 21.1% (19/90, 95% confidence interval: 13.2%–30.1%) of which 94.7% was mild (18/19) at diagnosis with mean age at AS diagnosis of 66.3 + 2.2 years. Among AS patients, 31.6% (6/19) progressed to severe AS, five of which underwent TAVR (median age: 70 years) while on advanced PAH therapy. One of the five TAVR patients developed worsening pulmonary hypertension post‐TAVR. The 5‐year survival rate for all AS patients from diagnosis date was 37.2%. There was a high prevalence of AS in this cohort of SSc‐PAH/PH patients, with mean age of onset younger than patients with nonbicuspid aortic valve stenosis. This is the largest series of SSc‐PAH/PH patients on advanced pulmonary vasodilator therapy who underwent TAVR with acceptable early outcomes.

Guest Editors’ Memo

Chronic thromboembolic pulmonary hypertension (CTEPH) is unique among the many etiologies of pulmonary hypertension (PH), in that it can be treated very effectively, even cured, with the surgical extraction of occlusive thrombo-fibrotic lesions via pulmonary thromboendarterectomy (PTE) surgery. More recently, balloon pulmonary angioplasty (BPA) has emerged as a viable option for patients who cannot or should not be operated upon, and for those with residual disease after PTE. Arguably, BPA is one of the major advancements in pulmonary vascular disease over the past 2 decades, although surgical therapy with PTE remains the treatment of choice whenever feasible. Effective PH-targeted medical therapy is also available, and increasingly multimodality approaches including a combination of these treatment options are being utilized in expert centers to achieve the best outcomes. And yet, CTEPH remains a vastly under-recognized disease, with considerable delays and confusion in its diagnosis. As a result, many patients are still not being effectively treated. This issue of Advances in Pulmonary Hypertension represents an effort to update our readers on the key current diagnostic and therapeutic approaches for CTEPH.In “Post-Pulmonary Embolism Follow-Up and Epidemiology of Chronic Thromboembolic Pulmonary Hypertension”, Jasuja and colleagues provide a comprehensive framework of the many issues that need to be addressed in follow-up after an acute pulmonary embolism (PE). In addition, the authors review the available evidence and challenges on the epidemiology and risk factors for CTEPH, as well as the evolving understanding of the post-PE syndrome.In the article “Diagnostic Evaluation of CTEPH”, Vaidya and Forfia describe the multiple steps and testing needed to arrive at the correct diagnosis of CTEPH, including several chest imaging studies that can accurately identify and quantify chronic thrombo-fibrotic occlusive disease of pulmonary arteries, as well as detailed imaging and hemodynamic studies that measure the impact of occlusive disease on right ventricular afterload.The article “Pulmonary Thromboendarterectomy: Patient Selection, Techniques, Outcomes, and Recent Advances” by Madani and Higgins provides a discussion on the current role of surgical therapy for CTEPH, which remains the treatment of choice for a majority of patients.In “Balloon Pulmonary Angioplasty for Chronic Thromboembolic Pulmonary Hypertension” Serfas and Krasuski share an expert insight into patient selection, procedural technique and complications of this relatively novel interventional treatment modality for CTEPH, which is gaining an increasingly important role in management of CTEPH in expert centers.In “Medical Management of Chronic Thromboembolic Pulmonary Hypertension” Goyanes and Heresi review the medical management of CTEPH, including lifelong anticoagulation to prevent recurrent PE and PH-targeted therapy (pulmonary vasodilators) directed at the concomitant microscopic vasculopathy. The authors detail the available literature and current knowledge gaps regarding choice of anticoagulant, patient selection for pulmonary vasodilator therapy, and the place of PH therapy in the context of PTE and BPA.Finally, in the round table discussion, Co-editors Drs. Heresi and Krasuski gather Drs. Auger, Tapson and Lang for a lively conversation on the practical aspects and current challenges in the diagnosis of CTEPH, including recognition of CTEPH after acute PE, and the use of detailed and precise imaging and hemodynamic techniques to phenotype CTEPH.We are confident our readers will find this issue informative and we sincerely thank all the contributors for their efforts and time devoted to this issue.