Changes In Pulmonary Vascular Resistance Research Articles

Phosphodiesterase 9A inhibition improves aging-related increase in pulmonary vascular resistance in mice.

As individuals age, there is a gradual decline in cardiopulmonary function, often accompanied by cardiac pump dysfunction leading to increased pulmonary vascular resistance (PVR). Our study aims to investigate the changes in cardiac and pulmonary vascular function associated with aging. Additionally, we aim to explore the impact of phosphodiesterase 9A (PDE9A) inhibition, which has shown promise in treating cardiometabolic diseases, on addressing left ventricle (LV) dysfunction and elevated PVR in aging individuals. Young (3 months old) and aged (32 months old) male C57BL/6 mice were used. Aged mice were treated with the selective PDE9A inhibitor PF04447943 (1 mg/kg/day) through intraperitoneal injections for 10 days. LV function was evaluated using cardiac ultrasound, and PVR was assessed in isolated, ventilated lungs perfused under a constant flow condition. Additionally, changes in PVR were measured in response to perfusion of the endothelium-dependent agonist bradykinin or to nitric oxide (NO) donor sodium nitroprusside (SNP). PDE9A protein expression was measured by Western blots. Our results demonstrate the development of LV diastolic dysfunction and increased PVR in aged mice. The aged mice exhibited diminished decreases in PVR in response to both bradykinin and SNP compared to the young mice. Moreover, the lungs of aged mice showed an increase in PDE9A protein expression. Treatment of aged mice with PF04447943 had no significant effect on LV systolic or diastolic function. However, PF04447943 treatment normalized PVR and SNP-induced responses, though it did not affect the bradykinin response. These data demonstrate a development of LV diastolic dysfunction and increase in PVR in aged mice. We propose that inhibitors of PDE9A could represent a novel therapeutic approach to specifically prevent aging-related pulmonary dysfunction.

A PrOsPective Cohort Study on Interstitial Lung Disease-Associated Pulmonary Hypertension with a ParticulaR Focus on the Subset with Pulmonary Arterial Hypertension Features (POPLAR Study).

The pathogenesis and clinical profiles of patients with pulmonary hypertension (PH) associated with interstitial lung disease (ILD-PH) are poorly understood. Whether and to what extent pulmonary arterial hypertension (PAH)-specific therapy improves hemodynamic and outcome in ILD-PH are also unknown. This study aims to clarify the characteristics, clinical course and response to PAH-specific therapy of ILD and/or PH by enrolling three unique subsets: PAH, ILD-PH, and ILD. The proposed study is a retrospective and prospective, multi-centre, observational cohort study of patients treated at any of three university hospitals in the Hokkaido region of Japan who have any one of the following: PAH; ILD-PH with or without PAH features; or ILD without PH. We aim to enrol 250 patients in total. For the retrospective observation period, data obtained after 1 January 2010, will be analysed, and the prospective observation period will be 1year. We will compare the clinical data of patients with ILD-PH with those of patients with PAH and those of patients with ILD without PH in the real-world clinical setting. In addition, within the cohort of patients with ILD-PH, we will explore the subset with "ILD-PH with PAH features" and compare the response to PAH-specific therapy with that of PAH. The primary outcome will be the change in pulmonary vascular resistance from first treatment to follow-up in patients with PAH and ILD-PH with PAH features (excluding ILD-PH without PAH feature and ILD-no-PH for the primary outcome). The exploratory outcomes will include analyses of PH-associated biomarkers, right ventricular function and patient-reported outcomes. This is a protocol article and the results will be presented after data collection is completed. The POPLAR study will provide data that help better understand the pathophysiology of ILD-PH and improve the quality of life and outcome of patients with PH and/or ILD. Japan Registry of Clinical Trials: jRCT1010230018.

Right ventricular sizing and pulmonary vascular resistance: How much mass do you need?

ObjectiveRight ventricular (RV) donor-recipient sizing has been demonstrated to be a sensitive predictor for mortality after heart transplantation. We sought to understand the relationship between donor-recipient RV mass (RVM) ratio and pulmonary vascular resistance (PVR) on outcomes after heart transplantation. MethodsAdult heart transplant recipients from the United Network for Organ Sharing database were included (N = 42,594). The influence of RVM ratio and PVR on 1-year mortality was assessed by logistic regression after multivariable adjustment. ResultsAmong transplant recipients, median PVR was 2.4 Wood units (WU) (range, 1.7-3.3 WU) and median RVM ratio was 1.2 (1.0-1.3). Without considering PVR, RVM ratio was highly associated with postoperative dialysis (odds ratio [OR], 0.49; P < .001) and 1-year mortality (OR, 0.64; P < .001). Without considering RVM ratio, PVR was highly associated with 1-year mortality (OR, 1.05; P < .001), but not postoperative dialysis (OR, 0.98; P = .156). When considering both RVM ratio and PVR, the risk associated with each remained significant, but PVR did not modify the effect of RVM ratio on 1-year mortality (RVM ratio × PVR: OR, 0.99; P = .858). To maintain a consistent predicted 1-year mortality, RVM ratio would need to increase by 0.12 for each WU increase in PVR. Secondary analyses found that a 1 WU change in PVR was associated with an 11% increase in mortality risk in RVM ratio mismatched patients (RVM ratio < 1; P = .001), but only a 5% increase in RVM ratio matched patients (RVM ratio ≥ 1; P = .003). ConclusionsRVM ratio and recipient PVR are independent predictors of 1-year mortality. Still, a larger RV mass may be utilized to mediate the effects of an elevated PVR.

Changes in Pulmonary Vascular Resistance and Obstruction Score Following Acute Pulmonary Embolism in Pigs.

To investigate the contribution of mechanical obstruction and pulmonary vasoconstriction to pulmonary vascular resistance (PVR) in acute pulmonary embolism (PE) in pigs. Controlled, animal study. Tertiary university hospital, animal research laboratory. Female Danish slaughter pigs (n = 12, ~60 kg). None. PE was induced by infusion of autologous blood clots in pigs. CT pulmonary angiograms were performed at baseline, after PE (first experimental day [PEd0]) and the following 2 days (second experimental day [PEd1] and third experimental day [PEd2]), and clot burden quantified by a modified Qanadli Obstruction Score. Hemodynamics were evaluated with left and right heart catheterization and systemic invasive pressures each day before, under, and after treatment with the pulmonary vasodilators sildenafil (0.1 mg/kg) and oxygen (Fio2 40%). PE increased PVR (baseline vs. PEd0: 178 ± 54 vs. 526 ± 160 dynes; p < 0.0001) and obstruction score (baseline vs. PEd0: 0% vs. 45% ± 13%; p < 0.0001). PVR decreased toward baseline at day 1 (baseline vs. PEd1: 178 ± 54 vs. 219 ± 48; p = 0.16) and day 2 (baseline vs. PEd2: 178 ± 54 vs. 201 ± 50; p = 0.51). Obstruction score decreased only slightly at day 1 (PEd0 vs. PEd1: 45% ± 12% vs. 43% ± 14%; p = 0.04) and remained elevated throughout the study (PEd1 vs. PEd2: 43% ± 14% vs. 42% ± 17%; p = 0.74). Sildenafil and oxygen in combination decreased PVR at day 0 (-284 ± 154 dynes; p = 0.0064) but had no effects at day 1 (-8 ± 27 dynes; p = 0.4827) or day 2 (-18 ± 32 dynes; p = 0.0923). Pulmonary vasoconstriction, and not mechanical obstruction, was the predominant cause of increased PVR in acute PE in pigs. PVR rapidly declined over the first 2 days after onset despite a persistent mechanical obstruction of the pulmonary circulation from emboli. The findings suggest that treatment with pulmonary vasodilators might only be effective in the acute phase of PE thereby limiting the window for such therapy.

Hemodynamic response to inhaled nitric oxide in patients with pulmonary hypertension and chronic kidney disease: A retrospective cohort study.

Pulmonary hypertension (PH) associated with chronic kidney disease (CKD) (PH-CKD) affects approximately 20%-40% of CKD patients and is associated with increased morbidity and mortality. PH and CKD are both pathophysiologically associated with nitric oxide (NO) deficiency. The NO pathway, an important therapeutic domain in pulmonary arterial hypertension (PAH), is an intriguing but unexplored target in PH-CKD. We sought to improve understanding of the clinical significance of the NO pathway in patients with PH-CKD by assessing the hemodynamic response to inhaled NO (iNO) during right heart catheterization (RHC). In this retrospective cohort study, patients with diagnosis codes of PH and stage IV/V CKD or end-stage renal disease and estimated glomerular filtration rate < 60 mL/min/body surface areawho underwent RHC and hemodynamic drug study between July 2011 and June 2021 were eligible. Patients with mean pulmonary artery pressure (mPAP) > 20 mmHg and pulmonary vascular resistance (PVR) > 3Wood unitswere included. The final cohort included 37 patients (45.9% female, mean age 72.5 ± 9.7 years). A total of 56.7%of the cohort (21/37) had precapillary PH, while 43.2% (16/37) had combined precapillary postcapillary PH (Cpc-PH). Median survival was 3.1 years after RHC. iNO was associated with a significant decrease in both mPAP and PVR. Hemodynamic changes in mPAP and PVR were similar in precapillary and Cpc-PH groups. Among a small subset (n = 14) who were subsequently treated with PAH-targeted therapy, treatment response was mixed and did not reveal significant benefit. Further studies are warranted to better define the potential role of PAH therapy in PH-CKD.

Pulmonary Vasodilator Therapy in Severe Pulmonary Hypertension Due to Chronic Obstructive Pulmonary Disease (Severe PH-COPD): A Systematic Review and Meta-Analysis.

Background: Chronic obstructive pulmonary disease-associated pulmonary hypertension (PH-COPD) results in a significant impact on symptoms, quality of life, and survival. There is scant and conflicting evidence about the use of pulmonary hypertension (PH) specific therapy in patients with PH-COPD. Study Design and Methods: PubMed, OVID, CINAHL, Cochrane, Embase, and Web of Science were searched using various MESH terms to identify randomized controlled trials (RCTs) or observational studies investigating PH-specific therapies in patients with severe PH-COPD, defined by mean pulmonary artery pressure (mPAP) of more than 35 mm Hg or pulmonary vascular resistance (PVR) of more than 5 woods units on right heart catheterization. The primary outcome was a change in mPAP and PVR. Secondary outcomes were changes in six-minute walk distance (6MWD), changes in the brain-natriuretic peptide (BNP), New York Heart Association (NYHA) functional class, oxygenation, and survival. Results: Thirteen studies satisfied the inclusion criteria, including a total of 328 patients with severe PH-COPD. Out of these, 308 patients received some type of specific therapy for PH. There was a significant reduction in mPAP (mean difference (MD) -3.68, 95% CI [-2.03, -5.32], p < 0.0001) and PVR (MD -1.40 Wood units, 95% CI [-1.97, -0.82], p < 0.00001). There was a significant increase in the cardiac index as well (MD 0.26 L/min/m2, 95% CI [0.14, 0.39], p < 0.0001). There were fewer patients who had NYHA class III/lV symptoms, with an odds ratio of 0.55 (95% CI [0.30, 1.01], p = 0.05). There was no significant difference in the 6MWD (12.62 m, 95% CI [-8.55, 33.79], p = 0.24), PaO2 (MD -2.20 mm Hg, 95% CI [-4.62, 0.22], p = 0.08), or BNP or NT-proBNP therapy (MD -0.15, 95% CI [-0.46, 0.17], p = 0.36). Conclusion: The use of PH-specific therapies in severe PH-COPD resulted in a significant reduction in mPAP and PVR and increased CI, with fewer patients remaining in NYHA functional class III/IV. However, no significant difference in the 6MWD, biomarkers of right ventricular dysfunction, or oxygenation was identified, demonstrating a lack of hypoxemia worsening with treatment. Further studies are needed to investigate the use of PH medications in patients with severe PH-COPD.

Omics and Extreme Phenotyping Reveal Longitudinal Association Between Left Atrial Size and Pulmonary Vascular Resistance in Group 2 Pulmonary Hypertension.

Left heart disease is the most common cause of pulmonary hypertension (PH) and is frequently accompanied by increases in pulmonary vascular resistance. However, the distinction between phenotypes of PH due to left heart disease with a normal or elevated pulmonary vascular resistance-isolated postcapillary PH (IpcPH) and combined pre- and postcapillary PH (CpcPH), respectively-has been incompletely defined using unbiased methods. Patients with extremes of IpcPH versus CpcPH were identified from a single-center record of those who underwent right heart catheterization. Individuals with left ventricular ejection fraction <40% or with potential causes of PH beyond left heart disease were excluded. Medication usage in IpcPH and CpcPH was compared across Anatomical Therapeutic Chemical classes and identified vitamin K antagonists as the only medication with pharmacome-wide significance, being more commonly used in CpcPH and for an indication of atrial fibrillation in ≈90% of instances. Accordingly, atrial fibrillation prevalence was significantly higher in CpcPH in a phenome-wide analysis. Review of echocardiographic data most proximal to right heart catheterization revealed that left atrial diameter indexed to body surface area-known to be associated with atrial fibrillation-was increased in CpcPH regardless of the presence of atrial fibrillation. An independent cohort with serial right heart catheterizations and PH-left heart disease showed a significant positive correlation between change in left atrial diameter indexed to body surface area and change in pulmonary vascular resistance. Guided by pharmacomic and phenomic screens in a rigorously phenotyped cohort, we identify a longitudinal association between left atrial diameter indexed to body surface area and pulmonary vascular resistance with implications for the future development of diagnostic, prognostic, and therapeutic tools.

Macitentan tadalafil Fixed Dose Combination (FDC) in treatment-naive and prior monotherapy patients with Pulmonary Arterial Hypertension (PAH): insights from A DUE

Abstract Background Combination therapy is recommended for the management of pulmonary arterial hypertension (PAH). The A DUE study showed that M/T FDC, a fixed dose combination (FDC) of the endothelin receptor antagonist (ERA) macitentan 10mg (M) and the phosphodiesterase type 5 inhibitor (PDE5i) tadalafil 40mg (T), led to a clinically relevant improvement in pulmonary vascular resistance (PVR) vs macitentan and tadalafil monotherapies in PAH patients. A clinically meaningful trend for improvement in 6-minute walk distance (6MWD) in favor of M/T FDC vs macitentan and tadalafil was observed. Purpose Here we analysed the effect of M/T FDC in the subgroups of treatment-naïve and prior monotherapy patients. Methods In A DUE 187 adult PAH patients in WHO functional class II / III were randomised 2:1:1 to M/T FDC, macitentan or tadalafil if treatment-naïve, 2:1 to M/T FDC or macitentan if on prior ERA, and 2:1 to M/T FDC or tadalafil if on prior PDE5i. The treatment effect of M/T FDC vs macitentan and M/T FDC vs tadalafil was calculated using ANCOVA models for PVR (geometric mean ratios [95% CL]) and for 6MWD (mean change [95% CL]) in treatment-naïve patients and in patients on prior monotherapy (ERA or PDE5i) at randomisation. Results Treatment effects for M/T FDC versus macitentan and versus tadalafil on the change in PVR and 6MWD are reported in the table for each subgroup, along with those for the overall population. The safety profile of M/T FDC was in line with the safety profiles of macitentan and tadalafil. Conclusions In A DUE, the effect of M/T FDC vs both monotherapies on PVR and 6MWD in treatment-naïve and prior ERA/PDE5i patients was consistent with that observed in the overall population.

Changes in the levels of free sialic acid during ex vivo lung perfusion do not correlate with pulmonary function. Experimental model

BackgroundEx vivo lung perfusion (EVLP) constitutes a tool with great research potential due to its advantages over in vivo and in vitro models. Despite its important contribution to lung reconditioning, this technique has the disadvantage of incurring high costs and can induce pulmonary endothelial injury through perfusion and ventilation. The pulmonary endothelium is made up of endothelial glycocalyx (EG), a coating of proteoglycans (PG) on the luminal surface. PGs are glycoproteins linked to terminal sialic acids (Sia) that can affect homeostasis with responses leading to edema formation. This study evaluated the effect of two ex vivo perfusion solutions on lung function and endothelial injury.MethodsWe divided ten landrace swine into two groups and subjected them to EVLP for 120 min: Group I (n = 5) was perfused with Steen® solution, and Group II (n = 5) was perfused with low-potassium dextran-albumin solution. Ventilatory mechanics, histology, gravimetry, and sialic acid concentrations were evaluated.ResultsBoth groups showed changes in pulmonary vascular resistance and ventilatory mechanics (p < 0.05, Student’s t-test). In addition, the lung injury severity score was better in Group I than in Group II (p < 0.05, Mann–Whitney U); and both groups exhibited a significant increase in Sia concentrations in the perfusate (p < 0.05 t-Student) and Sia immunohistochemical expression.ConclusionsSia, as a product of EG disruption during EVLP, was found in all samples obtained in the system; however, the changes in its concentration showed no apparent correlation with lung function.

Cardiopulmonary interactions in left heart failure.

The primary impact of ventilation and ventilatory efforts on left ventricular (LV) function in left ventricular dysfunction relate to how changes in intrathoracic pressure (ITP) alter the pressure gradients for venous return into the chest and LV ejection out of the chest. Spontaneous inspiratory efforts by decreasing ITP increase both of these pressure gradients increasing venous blood flow and impeding LV ejection resulting in increased intrathoracic blood volume. In severe heart failure states when lung compliance is reduced, or airway resistance is increased these negative swings in ITP can be exacerbated leading to LV failure and acute cardiogenic pulmonary edema. By merely reversing these negative swings in ITP by the use of non-invasive continuous positive airway pressure (CPAP), these profoundly detrimental forces can be immediately reversed, and cardiovascular stability can be restored in moments. This forms the clinical rationale for the immediate use of CPAP for the treatment of acute cardiogenic pulmonary edema. Increasing ITP during positive pressure ventilation decreases the pressure gradients for venous return and LV ejection decreasing intrathoracic blood volume. In a hypovolemic patient even with LV dysfunction this can result in hypotension due to inadequate LV preload. Minor increases in ITP as occur using pressure-limited positive-pressure ventilation primarily reverse the increased LV afterload of negative swings in ITP and if fluid overload was already present, minimally alter cardiac output. The effect of changes in lung volume on LV function are related primarily to its effects on right ventricular (RV) function through changes in pulmonary vascular resistance and overdistention (hyperinflation). In acute lung injury with alveolar collapse, positive pressure ventilation may reduce pulmonary vascular resistance if alveolar recruitment predominates. Hyperinflation, however, impedes diastolic filling while simultaneously increasing pulmonary vascular resistance. Thus, increasing lung volume can reduce RV afterload by reversing hypoxic pulmonary vasoconstriction or increase afterload by overdistention. Hyperinflation can also impede RV filling. All of these processes can be readily identified at the bedside using echocardiography.

Heart-Lung Interactions.

The pulmonary and cardiovascular systems have profound effects on each other. Overall cardiac function is determined by heart rate, preload, contractility, and afterload. Changes in lung volume, intrathoracic pressure (ITP), and hypoxemia can simultaneously change all of these four hemodynamic determinants for both ventricles and can even lead to cardiovascular collapse. Intubation using sedation depresses vasomotor tone. Also, the interdependence between right and left ventricles can be affected by lung volume-induced changes in pulmonary vascular resistance and the rise in ITP. An increase in venous return due to negative ITP during spontaneous inspiration can shift the septum to the left and cause a decrease in left ventricle compliance. During positive pressure ventilation, the increase in ITP causes a decrease in venous return (preload), minimizing ventricular interdependence and will decrease left ventricle afterload augmenting cardiac output. Thus, positive pressure ventilation is beneficial in acute heart failure patients and detrimental in hypovolemic patients where it can cause a significant decrease in venous return and cardiac output. Recently, this phenomenon has been used to assess patient's volume responsiveness to fluid by measuring pulse pressure variation and stroke volume variation. Heart-lung interaction is very dynamic and changes in lung volume, ITP, and oxygen level can have various effects on the cardiovascular system depending on preexisting cardiovascular function and volume status. Heart failure and either hypo or hypervolemia predispose to greater effects of ventilation of cardiovascular function and gas exchange. This review is an overview of the basics of heart-lung interaction.

P98: Hemodynamic Effects of Minimally Invasive Mechanical Circulatory Support – Impella 5.5 versus Intra-Aortic Balloon Pump

Background: While the hemodynamic benefits of durable LVADs and intra-aortic balloon pumps (IABPs) in patients with acute-on-chronic heart failure are well described, the hemodynamic effects of the minimally-invasive Impella 5.5 in this patient population are not. Methods: Patient and hemodynamic data on all Impella 5.5 and IABP recipients between August 2020-November 2022 were extracted from a single-institutional database. Only patients with a history of decompensated chronic congestive heart failure were included. Patients requiring Impella support after myocardial infarction or immediately after cardiac surgery were excluded. The primary outcome was survival at 30 days after implantation. Secondary outcomes included changes in pulmonary vascular resistance (PVR), pulmonary capillary wedge pressure (PCWP), and cardiac index (CI) between device implantation and removal. Results: We identified 25 Impella 5.5 patients (12.0% female), 68 IABP patients (19.1% female), and 21 patients who had IABP exchanged for Impella 5.5 (14.2% female). There were no significant differences in baseline characteristics or hemodynamics between Impella 5.5 and isolated IABP patients (Table). Median support duration was significantly longer in the Impella 5.5 cohort (11 days vs. 8 days, p = 0.04). There was no significant difference in survival at 30 days between groups (Figure). PVR and PCWP significantly decreased in both cohorts, while CI significantly increased (Table). The percent increase in CI was significantly greater in Impella 5.5 patients than in IABP patients (67.8% vs 33.6%, p=0.01). However, only the IABP cohort demonstrated significantly decreased mean pulmonary artery pressure (PAP) (-7.0 mmHg, p<0.01) and central venous pressure (CVP) (-3.5 mmHg, p=0.03). Exchanging IABP to Impella 5.5 significantly improved PVR (-50.92 dynes sec cm-5, p=0.03), but not other hemodynamic parameters. Conclusion: Both IABP and Impella 5.5 improve hemodynamics by decreasing pulmonary congestion and increasing cardiac output. While only the IABP significantly decreased mean PAP and CVP, the Impella 5.5 provided greater improvements in CI, and exchanging IABP for Impella 5.5 provided further reductions in PVR.Figure 1. 30-day survival after Impella 5.5 or IABP. - IABP (n=68) Impella 5.5 (n=25) P-value Age 59.10 (47.12-64.97) 44.58 (40.3-63.2) 0.1824 Female 19.1% (13/68) 12.0% (3/25) 0.5442 ICM 30.9% (21/68) 40.3% (10/25) 0.4585 Pre-op PVR 240.0 (176.0-344.0) 231.0 (191.8-344.0) 0.4294 Pre-op PCWP 30.0 (26.0-34.0) 27.0 (20.5-34.0) 0.1186 Pre-op mean PAP 41.5 (37.8-48.0) 40.0 (32.5-49.3) 0.1964 Pre-op CVP 14.0 (10.0-12.5) 14.0 (10.0-22.0) 0.3746 Pre-op CO 3.6 (3.0-4.4) 3.6 (3.0-4.6) 0.3184 Pre-op CI 1.7 (1.5-2.1) 1.9 (1.5-2.2) 0.3184 IABP => Impella 5.5 Pre-exchange Pre-explant P-value PVR 184.4 (111.9-253.1) 148.2 (94.45-214.2) 0.0290 PCWP 23.0 (18.8-27.8) 22.0 (16.0-31.0) 0.3398 Mean PAP 34.5 (29.0-38.3) 35.0 (32.0-38.0) 0.2142 CVP 12.0 (7.50-20.5) 13.0 (9.8-18.8) 0.4431 CO 4.3 (3.3-5.4) 4.9 (4.0-6.1) 0.1832 CI 2.1 (1.6-2.8) 2.3 (2.1-2.6) 0.1526

Refined Balloon Pulmonary Angioplasty in Chronic Thromboembolic Pulmonary Hypertension: Initial Results of U.S. Regional Program

BackgroundBalloon pulmonary angioplasty (BPA) is rapidly evolving therapeutic option for patients with nonsurgical chronic thromboembolic pulmonary hypertension (CTEPH). There are few U.S. studies that have reported on the outcomes of this novel therapeutic option. ObjectivesThe authors sought to evaluate the efficacy and safety of refined BPA in the treatment of patients with CTEPH. MethodsThis is a retrospective study of CTEPH patients that underwent BPA. The primary efficacy endpoint was the change in pulmonary vascular resistance after BPA as compared to baseline and the primary safety endpoint was the rate of hemoptysis within 24 hours. Secondary endpoints included death, World Health Organization functional class, and 6-minute walk distance. Logistic regression was used to evaluate factors associated with a hemodynamic and functional response. ResultsA total of 211 BPA sessions were performed on 77 patients (average 2.7 ± 1.7 sessions/patient). After BPA the mean pulmonary vascular resistance improved by 26% (6.5 ± 3.4 WU to 4.8 ± 2.9 WU, P < 0.001). The mean 6-minute walk distance improved by 71.7 m (P < 0.001), and WHO functional class improved by 1 functional class (P < 0.001). There was one death related to reperfusion lung injury. Ten sessions (4.7%) were complicated by hemoptysis. Independent factors associated with improved functional and hemodynamic response included preprocedural use of riociguat, reduce baseline PA compliance, and >3 BPA sessions/patient. ConclusionsThis single center study from the United States showed that BPA with refined techniques in patients with CTEPH was relatively safe and was associated with significant improvements in pulmonary hemodynamics and functional capacity.

Phase 3 Trial of Sotatercept for Treatment of Pulmonary Arterial Hypertension

BackgroundPulmonary arterial hypertension is a progressive disease involving proliferative remodeling of the pulmonary vessels. Despite therapeutic advances, the disease-associated morbidity and mortality remain high. Sotatercept is a fusion protein that traps activins and growth differentiation factors involved in pulmonary arterial hypertension.MethodsWe conducted a multicenter, double-blind, phase 3 trial in which adults with pulmonary arterial hypertension (World Health Organization [WHO] functional class II or III) who were receiving stable background therapy were randomly assigned in a 1:1 ratio to receive subcutaneous sotatercept (starting dose, 0.3 mg per kilogram of body weight; target dose, 0.7 mg per kilogram) or placebo every 3 weeks. The primary end point was the change from baseline at week 24 in the 6-minute walk distance. Nine secondary end points, tested hierarchically in the following order, were multicomponent improvement, change in pulmonary vascular resistance, change in N-terminal pro–B-type natriuretic peptide level, improvement in WHO functional class, time to death or clinical worsening, French risk score, and changes in the Pulmonary Arterial Hypertension–Symptoms and Impact (PAH-SYMPACT) Physical Impacts, Cardiopulmonary Symptoms, and Cognitive/Emotional Impacts domain scores; all were assessed at week 24 except time to death or clinical worsening, which was assessed when the last patient completed the week 24 visit.ResultsA total of 163 patients were assigned to receive sotatercept and 160 to receive placebo. The median change from baseline at week 24 in the 6-minute walk distance was 34.4 m (95% confidence interval [CI], 33.0 to 35.5) in the sotatercept group and 1.0 m (95% CI, −0.3 to 3.5) in the placebo group. The Hodges–Lehmann estimate of the difference between the sotatercept and placebo groups in the change from baseline at week 24 in the 6-minute walk distance was 40.8 m (95% CI, 27.5 to 54.1; P<0.001). The first eight secondary end points were significantly improved with sotatercept as compared with placebo, whereas the PAH-SYMPACT Cognitive/Emotional Impacts domain score was not. Adverse events that occurred more frequently with sotatercept than with placebo included epistaxis, dizziness, telangiectasia, increased hemoglobin levels, thrombocytopenia, and increased blood pressure.ConclusionsIn patients with pulmonary arterial hypertension who were receiving stable background therapy, sotatercept resulted in a greater improvement in exercise capacity (as assessed by the 6-minute walk test) than placebo. (Funded by Acceleron Pharma, a subsidiary of MSD; STELLAR ClinicalTrials.gov number, NCT04576988.)

Learning curve and analysis of curative effects after balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension.

Learning curve and analysis of curative effects after balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension.

Treatment Response Evaluation by Computed Tomography Pulmonary Vasculature Analysis in Patients With Chronic Thromboembolic Pulmonary Hypertension.

To quantitatively assess the pulmonary vasculature using non-contrast computed tomography (CT) in patients with chronic thromboembolic pulmonary hypertension (CTEPH) pre- and post-treatment and correlate CT-based parameters with right heart catheterization (RHC) hemodynamic and clinical parameters. A total of 30 patients with CTEPH (mean age, 57.9 years; 53% female) who received multimodal treatment, including riociguat for ≥ 16 weeks with or without balloon pulmonary angioplasty and underwent both non-contrast CT for pulmonary vasculature analysis and RHC pre- and post-treatment were included. The radiographic analysis included subpleural perfusion parameters, including blood volume in small vessels with a cross-sectional area ≤ 5 mm² (BV5) and total blood vessel volume (TBV) in the lungs. The RHC parameters included mean pulmonary artery pressure (mPAP), pulmonary vascular resistance (PVR), and cardiac index (CI). Clinical parameters included the World Health Organization (WHO) functional class and 6-minute walking distance (6MWD). The number, area, and density of the subpleural small vessels increased after treatment by 35.7% (P < 0.001), 13.3% (P = 0.028), and 39.3% (P < 0.001), respectively. The blood volume shifted from larger to smaller vessels, as indicated by an 11.3% increase in the BV5/TBV ratio (P = 0.042). The BV5/TBV ratio was negatively correlated with PVR (r = -0.26; P = 0.035) and positively correlated with CI (r = 0.33; P = 0.009). The percent change across treatment in the BV5/TBV ratio correlated with the percent change in mPAP (r = -0.56; P = 0.001), PVR (r = -0.64; P < 0.001), and CI (r = 0.28; P = 0.049). Furthermore, the BV5/TBV ratio was inversely associated with the WHO functional classes I-IV (P = 0.004) and positively associated with 6MWD (P = 0.013). Non-contrast CT measures could quantitatively assess changes in the pulmonary vasculature in response to treatment and were correlated with hemodynamic and clinical parameters.

Pulmonary arterial compliance and exercise capacity after balloon pulmonary angioplasty in chronic thromboembolic pulmonary hypertension.

To determine whether changes in pulmonary vascular resistance (PVR) and changes in pulmonary artery compliance (C pa) are associated with changes in exercise capacity assessed either by changes in peak oxygen consumption (V'O2 ) or by changes in 6-min walk distance (6MWD) in patients with chronic thromboembolic pulmonary hypertension (CTEPH) undergoing balloon pulmonary angioplasty (BPA). Invasive haemodynamic parameters, peak V'O2 and 6MWD were measured within 24 h, before and after BPA (interval 3.1±2.4 months) in 34 CTEPH patients without significant cardiac and/or pulmonary comorbidities, of whom 24 received at least one pulmonary hypertension-specific treatment. C pa was calculated according to the pulse pressure method: C pa=((SV/PP)/1.76+0.1), where SV is the stroke volume and PP is the pulse pressure. The resistance-compliance (RC)-time of the pulmonary circulation was calculated as the PVR and C pa product. After BPA, PVR decreased (562±234 versus 290±106 dyn·s·cm-5; p<0.001); C pa increased (0.90±0.36 versus 1.63±0.65 mL·mmHg-1; p<0.001); but RC-time did not change (0.325±0.069 versus 0.321±0.083 s; p=0.75). There were improvements in peak V'O2 (1.11±0.35 versus 1.30±0.33 L·min-1; p<0.001) and in 6MWD (393±119 versus 432±100 m; p<0.001). After adjustment for age, height, weight and gender, changes in exercise capacity, assessed either by peak V'O2 or 6MWD, were significantly associated with changes in PVR, but not with changes in C pa. Contrary to what has been reported in CTEPH patients undergoing pulmonary endarterectomy, in CTEPH patients undergoing BPA, changes in exercise capacity were not associated with changes in C pa.

β3 adrenergic agonist treatment in chronic pulmonary hypertension associated with heart failure (SPHERE-HF): a double blind, placebo-controlled, randomized clinical trial.

Pulmonary hypertension (PH) associated with left heart disease is an increasingly prevalent problem, orphan of targeted therapies, and related to a poor prognosis, particularly when pre- and post-capillary PH combine. The current study aimed to determine whether treatment with the selective β3 adrenoreceptor agonist mirabegron improves outcomes in patients with combined pre- and post-capillary PH (CpcPH). The β3 Adrenergic Agonist Treatment in Chronic Pulmonary Hypertension Secondary to Heart Failure (SPHERE-HF) trial is a multicentre, randomized, parallel, placebo-controlled clinical trial that enrolled stable patients with CpcPH associated with symptomatic heart failure. A total of 80 patients were assigned to receive mirabegron (50 mg daily, titrated till 200 mg daily, n=39) or placebo (n=41) for 16 weeks. Of them, 66 patients successfully completed the study protocol and were valid for the main analysis. The primary endpoint was the change in pulmonary vascular resistance (PVR) on right heart catheterization. Secondary outcomes included the change in right ventricular (RV) ejection fraction by cardiac magnetic resonance or computed tomography, other haemodynamic variables, functional class, and quality of life. The trial was negative for the primary outcome (placebo-corrected mean difference of 0.62 Wood units, 95% confidence interval [CI] -0.38, 1.61, p=0.218). Patients receiving mirabegron presented a significant improvement in RV ejection fraction as compared to placebo (placebo-corrected mean difference of 3.0%, 95% CI 0.4, 5.7%, p=0.026), without significant differences in other pre-specified secondary outcomes. SPHERE-HF is the first clinical trial to assess the potential benefit of β3 adrenergic agonists in PH. The trial was negative since mirabegron did not reduce PVR, the primary endpoint, in patients with CpcPH. On pre-specified secondary outcomes, a significant improvement in RV ejection fraction assessed by advanced cardiac imaging was found, without differences in functional class or quality of life.

Pulmonary vascular reactivity to supplemental oxygen in Sherpa and lowlanders during gradual ascent to high altitude.

What is the central question of this study? How does hypoxic pulmonary vasoconstriction and the response to supplemental oxygen change over time at high altitude? What is the main finding and its importance? Lowlanders and partially de-acclimatized Sherpa both demonstrated pulmonary vascular responsiveness to supplemental oxygen that was maintained for 12days' exposure to progressively increasing altitude. An additional 2 weeks' acclimatization at 5050m altitude rendered the pulmonary vasculature minimally responsive to oxygen similar to the fully acclimatized non-ascent Sherpa. Additional hypoxic exposure at that time point did not augment hypoxic pulmonary vasoconstriction. Prolonged alveolar hypoxia leads to pulmonary vascular remodelling. We examined the time course at altitude, over which hypoxic pulmonary vasoconstriction goes from being acutely reversible to potentially irreversible. Study subjects were lowlanders (n=20) and two Sherpa groups. All Sherpa were born and raised at altitude. One group (ascent Sherpa, n=11) left altitude and after de-acclimatization in Kathmandu for ∼7days re-ascended with the lowlanders over 8-10days to 5050m. The second Sherpa group (non-ascent Sherpa, n=12) remained continuously at altitude. Pulmonary artery systolic pressure (PASP) and pulmonary vascular resistance (PVR) were measured while breathing ambient air and following supplemental oxygen. During ascent PASP and PVR increased in lowlanders and ascent Sherpa; however, with supplemental oxygen, lowlanders had significantly greater decrease in PASP (P=0.02) and PVR (P=0.02). After ∼14days at 5050m, PASP decreased with supplemental oxygen (mean decrease: 3.9mmHg, 95% CI 2.1-5.7mmHg, P<0.001); however, PVR was unchanged (P=0.49). In conclusion, PASP and PVR increased with gradual ascent to altitude and decreased via oxygen supplementation in both lowlanders and ascent Sherpa. Following ∼14days at 5050m altitude, there was no change in PVR to hypoxia or O2 supplementation in lowlanders or either Sherpa group. These data show that both duration of exposure and residential altitude influence the pulmonary vascular responses to hypoxia.

Abstract 13710: Acute Beneficial Effects of a Rho-Kinase Inhibitor, Fasudil in Patients With Pulmonary Hypertension Due to Left Heart Disease

Introduction: The prognosis of reactive pulmonary hypertension (PH) due to left heart disease is poor, and the pathogenesis of the disease is not well understood. Rho-Kinase inhibitor, fasudil dilates vascular smooth muscle and may improve pulmonary hypertension. We evaluated the acute effects of fasudil on hemodynamic parameters in patients with pulmonary hypertension due to left heart disease prospectively. Methods: From 2016 June to 2022 May, 100 consecutive patients requiring hospitalization for worsening chronic heart failure were enrolled. All patients underwent invasive hemodynamic measurement though right heart catheterization.In patients with mean pulmonary arterial pressure greater than 25 mmHg at baseline, 30 mg of fasudil was administered intravenously for 30 minutes. The hemodynamic measurements were performed at baseline and after 30 minutes of fasudil. PH due to left heart disease is defined as mean pulmonary arterial pressure (mPAP) ≥25mmHg and mean pulmonary capillary wedge pressure (mPCWP) &gt;15mmHg. Patients with PH were classified into 2 types, depending on the elevation of pulmonary vascular resistance (PVR) or the diastolic pressure gradient (DPG): Reactive-PH with elevated PVR (&gt;3.0 Wood units: WU) and/or DPG (&gt;7mmHg), and Passive-PH with normal PVR (≤3.0 WU) and DPG (≤7mmHg). Results: Fifty patients (mean age 70 years; 14 women and 36 men) received administration of fasudil. 30 patients had Passive-PH, and 20 patients had Reactive-PH. PVR significantly decreased after administration of fasudil in both Passive-PH and Reactive-PH group (1.7 to 1.4 WU, 3.5 to 2.7 WU, P&lt;0.001). The rate of change in PVR after administration of fasudil was significantly higher in the Reactive-PH group compared to the Passive-PH group (33% vs 21 %, P&lt;0.05). mPAP and cardiac index significantly improved in both Passive-PH (34±8.5 vs. 28±8.2 mmHg, 2.7±0.7 vs. 2.9±0.8 l/min/m 2 , p&lt;0.05) and Reactive-PH group (41±7.9 vs. 33±9.0 mmHg, 2.2±0.6 vs. 2.4±0.6 l/min/m 2 , p&lt;0.05). Mean blood pressure and arterial oxygen saturation were unaffected by fasudil (87 to 84 mmHg, 99 to 90 mmHg, 98 to 97%, 97 to 97%, not significant). Conclusions: Fasudil improves pulmonary hypertension due to left heart disease without any detrimental effects on hemodynamics.