Pulmonary Arterial Resistance Research Articles

Peripheral Vascular Ageing in Pulmonary Arterial Hypertension as Assessed by Common Carotid Artery Intima Thickness and Intima/Media Thickness Ratio: An Investigation Using Non-Invasive High-Resolution Ultrasound.

Pulmonary arterial hypertension (PAH; WHO Group 1) is associated with increased pulmonary arterial pressure and resistance, with pulmonary vascular remodelling. The vascular anatomy of the systemic arteries has been less well studied. Nineteen (19) patients with PAH, confirmed by right heart catheterisation (RHC), 14 patients with left ventricular heart failure with reduced ejection fraction (LVrEF), and 30 healthy subjects were enrolled. Common carotid artery (CCA) intima thickness, intima/media (I/M) thickness ratio, and intima-media thickness (IMT) were assessed using non-invasive ultrasound (22 MHz centre frequency). The CCA intima thickness was correlated with several RHC variables (all p<0.05). The intima was 56% thicker (+0.05 mm; 95% CI 0.03, 0.06; p<0.0001) and the I/M thickness ratio was 128% greater (+0.21; 95% CI 0.13, 0.28; p<0.0001) in patients with PAH than healthy subjects. These values were also significantly higher than in patients with LVrEF. In ROC curve analysis, the c-values for CCA intima thickness (0.92) and I/M ratio (0.87), but not for IMT, correctly indicated which individuals belonged to the PAH or healthy control groups. The CCA IMT showed no corresponding significant group differences or associations and was of no use according to receiver operating curve analysis. Patients with PAH displayed signs of peripheral vascular remodelling, challenging the common opinion that vascular changes in PAH are restricted to the lung vasculature. Correlations with cardiopulmonary variables from RHC support peripheral vascular coupling and the association with vascular ageing. Results from this pilot study warrant further confirmation.

Characteristics, treatments and survival of pulmonary arterial hypertension associated with congenital heart disease in China: Insights from a national multicenter prospective registry

The purpose of this registry was to provide insights into the characteristics, treatments and survival of patients with PAH-CHD in China. Patients diagnosed with PAH-CHD were enrolled in this national multicenter prospective registry. Baseline and follow-up data on clinical characteristics, PAH-targeted treatments and survival were collected. A total of 1060 PAH-CHD patients (mean age 31 years; 67.9% females) were included, with Eisenmenger syndrome (51.5%) being the most common form and atrial septal defects (37.3%) comprising the most frequent underlying defect. Approximately 33.0% of the patients were in World Health Organization functional class III to IV. The overall mean pulmonary arterial pressure and pulmonary vascular resistance were 67.1 (20.1) mm Hg and 1112.4 (705.9) dyn/s/cm5, respectively. PAH-targeted therapy was utilized in 826 patients (77.9%), and 203 patients (19.1%) received combination therapy. The estimated 1-, 3-, 5-, and 10-year survival rates of the overall cohort were 96.9%, 92.9%, 87.6% and 73.0%, respectively. Patients received combination therapy had significantly better survival than those with monotherapy (p=0.016). NT-proBNP >1400 pg/ml, SvO2 ≤ 65% and Borg dyspnea index ≥ 3 and PAH-targeted therapy were independent predictors of mortality. Hemoglobin > 160g/L was a unique predictor for mortality in Eisenmenger syndrome. Chinese PAH-CHD patients predominantly exhibit Eisenmenger syndrome and have significantly impaired exercise tolerance and right ventricular function at diagnosis, which are closely associated with long-term survival. PAH-targeted therapy including combination therapy showed a favorable effect on survival in PAH-CHD. The long-term survival of Chinese CHD-PAH patients remains to be improved.

Procedural Sedation in Congenital Heart Disease

AbstractProcedural sedation in patients with congenital heart disease (CHD) is associated with significant morbidity and mortality. It is vital for the practitioner to fully understand the complexity of lesions, their hemodynamics, and the impact of medications commonly used for procedural sedation on the stability of systemic vascular resistance and pulmonary flow. According to the literature, we explain the interaction of the systemic vascular resistance and pulmonary flow in such lesions and divide them into five categories outlined in this article: (1) CHDs with left-to-right shunt with normal pulmonary arterial pressure and resistance, (2) CHD with left-to-right shunt and moderate to severe elevation of pulmonary arterial pressure with near-normal pulmonary vascular resistance, (3) CHD with pulmonary flow dependent on systemic vascular resistance, (4) patients with congenital coronary stenosis and coronary anomalies, and 5) aortic obstructive lesions.

Serum Biomarkers in Connective Tissue Disease-Associated Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a life-threatening complication of connective tissue diseases (CTDs) characterised by increased pulmonary arterial pressure and pulmonary vascular resistance. CTD-PAH is the result of a complex interplay among endothelial dysfunction and vascular remodelling, autoimmunity and inflammatory changes, ultimately leading to right heart dysfunction and failure. Due to the non-specific nature of the early symptoms and the lack of consensus on screening strategies-except for systemic sclerosis, with a yearly transthoracic echocardiography as recommended-CTD-PAH is often diagnosed at an advanced stage, when the pulmonary vessels are irreversibly damaged. According to the current guidelines, right heart catheterisation is the gold standard for the diagnosis of PAH; however, this technique is invasive, and may not be available in non-referral centres. Hence, there is a need for non-invasive tools to improve the early diagnosis and disease monitoring of CTD-PAH. Novel serum biomarkers may be an effective solution to this issue, as their detection is non-invasive, has a low cost and is reproducible. Our review aims to describe some of the most promising circulating biomarkers of CTD-PAH, classified according to their role in the pathophysiology of the disease.

Which is more accurate measuring pulmonary artery resistance index or 4D lung volume for prediction of neonatal respiratory distress in preterm pregnancies?

BackgroundNeonatal respiratory distress syndrome (RDS) is a leading cause of neonatal respiratory failure and neonatal mortality. It is frequent in preterm infants, because deficient surfactant needed to keep the airways (alveoli) open to assist infants breathe after birth. Nonetheless, it was also seen in full-term pregnancies. Noninvasive approaches for predicting the development of neonatal respiratory distress (RD) in preterm newborns include comparing the prenatal clinical outcome with the pulmonary artery resistance index (PA-RI) and fetal lung capacity as assessed by the virtual organ computer-aided analysis (VOCAL). Our study aimed to estimate optimal cutoff values and compare measurements of fetal pulmonary artery resistance index (PA-RI) and fetal lung volume (LV) assessed by VOCAL as noninvasive measures to predict neonatal RD development in preterm pregnancies to show which is more accurate.ResultsOut of the examined 147 women who delivered 147 living newborns, 59 of newborn (40.1%) developed neonatal RD. PA-RI has a higher value in 45 (76.27%), while fetal lung volume (FLV) was significantly lower in 43 (72.88%) of neonates who developed RD. Combining both measurements of PA-RI and FLV could predict all cases of RDS 59 (100%). Thirty of RDS neonates had mechanical ventilation and died (50.85%). Cutoff values of PA-RI ≥ 0.75 with 76.27% sensitivity, 82.95% specificity and 81.5% accuracy, whereas a cutoff of FLV ≤ 28 cm3 with sensitivity of 72.88%, specificity of 65.91% and accuracy of 74.8%, for prediction of RDS. Combining both cutoffs generated a more accurate detection 100%, specificity of 65.91% and 66.3% positive predictive value (PPV) and 100% negative predictive value (NPV) and 83% accuracy.ConclusionsBoth PA-RI and FLV are promising noninvasive tools which help in predicting RD fetuses with high sensitivity and specificity. PA-RI is more accurate than FLV cm3 in prediction of neonatal RDS. Combining these parameters increases the predictive value.

Elevation of Pulmonary Artery Pressure in Newborns from High-Altitude Pregnancies Complicated by Preeclampsia.

We hypothesized that fetal exposure to the oxidative stress induced by the combined challenge of preeclampsia (PE) and high altitude would induce a significant impairment in the development of pulmonary circulation. We conducted a prospective study in La Paz (Bolivia, mean altitude 3625 m) in which newborns from singleton pregnancies with and without PE were compared (PE group n = 69, control n = 70). We conducted an echocardiographic study in these infants at the median age of two days. The percentage of cesarean deliveries and small for gestational age (SGA) infants was significantly higher in the PE group. Heart rate, respiratory rate, and oxygen saturation did not vary significantly between groups. Estimated pulmonary arterial pressure and pulmonary vascular resistance were 30% higher in newborns exposed to PE and high altitude compared with those exposed only to high altitude. We also detected signs of right ventricular hypertrophy in infants subjected to both exposures. In conclusion, this study provides evidence that the combination of PE and pregnancy at high altitude induces subclinical alterations in the pulmonary circulation of the newborn. Follow-up of this cohort may provide us with valuable information on the potential increased susceptibility to developing pulmonary hypertension or other pulmonary and cardiovascular disorders.

Multicenter review of a tadalafil suspension formulation in infants and children with pulmonary hypertension: a north american experience

Abstract Funding Acknowledgements Type of funding sources: None. Background Pulmonary arterial hypertension (PAH) is a disease characterised by an increase in pulmonary vascular resistance and pulmonary artery pressure. Phosphodiesterase type 5 (PDE5) inhibitors, with sildenafil the earliest among them, are widely used in the management of pediatric PAH. There has more recently been a transition to once-daily tadalafil suspensions. Herein, we present a multicenter experience detailing safety, tolerability and haemodynamic data utilizing tadalafil suspension alone or in combination for the management of pediatric PAH. Methods and materials We performed a retrospective review of all infants and children at two North American paediatric PH centres between December 2013 and April 2022. We included all patients less than 9 years of age who were treated with a tadalafil suspension after an initial treatment with sildenafil. Demographic, clinical, imaging, and laboratory data were collected. Results Over the study period, 158 children were treated with tadalafil therapy: 41 (25.9%) had group 1 PAH, 81 (51.3%) had group 3 PH, and 33 (20.9%) had group 5 PH. The median initial dose of tadalafil was 1.0 mg/kg once daily with a median time to maximum dose of 1 day. The majority of patients required the suspension formulation due to an inability to take oral tablets or the need for nasogastric or nasojejunal feeding. We observed improvements in median echocardiographic parameters in the six months following initiation, namely, in RVFAC from 34.7% (Q1 = 31.0%, Q3 = 42.0%) to 37.0% (Q1 = 31.0%, Q3 = 44.0%) and in TAPSE from 1.0 (Q1 = 0.8, Q3 = 1.7) cm to 1.3 (Q1 = 1.0, Q3 = 1.7) cm. We observed median decreases in RVSp from 51.0 (Q1 = 35.0, Q3 = 69.0) mmHg to 37.0 (Q1 = 30.0, Q3 = 50.0) mmHg and in NT pro BNP levels from 439.0 (Q1 = 217.0, Q3 = 2051.0) ng/L to 313.0 (Q1 = 193.0, Q3 = 1110.0) ng/L. Tadalafil therapy was well tolerated over the six-month period: at baseline, only four patients (2.5%) reported gastrointestinal side effects, two (1.3%) reported adverse skin adverse effects (i.e., rash and flushing), and one (0.6%) reported adverse neurological effects. At six months, 150 patients (94.9%) reported no adverse effects. Conclusion Tadalafil, a long-acting PDE5 inhibitor, when administered in a suspension formulation, has a safe and tolerable adverse effect profile once patients are established on sildenafil therapy. Following 6 months of once daily tadalafil suspension, alone or in combination, showed a trend towards improvement in clinical parameters, echocardiographic measurements, and laboratory results for pediatric PAH. All patient adverse effects were managed with non pharmacological measures and there was good patient compliance.

Single-Center Experience of Pulmonary Endarterectomy for Chronic Thromboembolic Pulmonary Hypertension: The Results from the Tabriz University Medical Sciences (TUMS) CTEPH Program.

Pulmonary endarterectomy (PEA) remains the preferred and potentially curative option for patients with chronic thromboembolic pulmonary hypertension (CTEPH). This study aimed to report the results of PEA for CTEPH in a tertiary center in Tabriz, Iran. We analyzed the results of 42 CTEPH patients undergoing PEA, who were enrolled in the Tabriz University of Medical Sciences (TUMS-CTEPH) from January 2016 to October 2020. The main outcome measures included the New York Heart Association (NYHA) functional classification, the 6-Minute Walk Distance, hemodynamic measures in right heart catheterization, morbidity, and mortality. There was a significant improvement in the NYHA function class (2.6 ± 0.5 vs 1.1 ± 0.34), mean pulmonary arterial pressure (47.1 ± 13 vs 27.9 ± 8 mm Hg), cardiac output (4.3 ± 1.06 vs 5.9 ± 1.2 L/min), and pulmonary vascular resistance (709.4 ± 297.5 vs 214 ± 77 dyn s/cm5). Fifteen patients (35%) developed complications. The most common complication (10 [23%]) was reperfusion injury. Also, postsurgical mortality was 4% during hospital admission and 1-year follow-up. This is the first single-center report of PEA from Iran. Post-PEA and 1-year survival were acceptable as a referral center. PEA can be performed safe with low mortality. Greater awareness of PEA and patients' access to experienced CTEPH centers are important issues.

Transcription factors in the pathogenesis of pulmonary arterial hypertension-Current knowledge and therapeutic potential.

Pulmonary arterial hypertension (PAH) is a disease characterized by elevated pulmonary vascular resistance and pulmonary artery pressure. Mortality remains high in severe cases despite significant advances in management and pharmacotherapy. Since currently approved PAH therapies are unable to significantly reverse pathological vessel remodeling, novel disease-modifying, targeted therapeutics are needed. Pathogenetically, PAH is characterized by vessel wall cell dysfunction with consecutive remodeling of the pulmonary vasculature and the right heart. Transcription factors (TFs) regulate the process of transcribing DNA into RNA and, in the pulmonary circulation, control the response of pulmonary vascular cells to macro- and microenvironmental stimuli. Often, TFs form complex protein interaction networks with other TFs or co-factors to allow for fine-tuning of gene expression. Therefore, identification of the underlying molecular mechanisms of TF (dys-)function is essential to develop tailored modulation strategies in PAH. This current review provides a compendium-style overview of TFs and TF complexes associated with PAH pathogenesis and highlights their potential as targets for vasculoregenerative or reverse remodeling therapies.

PS-C05-3: ESTIMATION OF PULMONARY PULSATILE ARTERIAL LOAD IN PATIENTS UNDERGOING INVESTIGATION FOR PULMONARY HYPERTENSION

Objective: Diagnosis of pulmonary hypertension (PH) is typically confirmed by elevation of the pulmonary artery (PA) pressure and/or pulmonary vascular resistance (PVR). However, PVR may overlook the pulsatile component of RV hydraulic work which involves the dynamic interplay between PA resistance and compliance. PA vascular impedance (PVZ) offers a more comprehensive assessment of RV and PA load. This study aims to apply a method of PA pulsatile load as PVZ determination in a cohort of patients referred for PH evaluation. Design and Methods: Fifty-eight participants (71% females, mean 53 ± 18 years) were recruited, and underwent right heart catheterisation (RHC) to measure systolic (sPAP), diastolic (dPAP), mean (mPAP), and PA wedge pressures (PAWP), cardiac output (CO) and PVR; classified as precapillary PH (PrecPH), isolated postcapillary PH (IpcPH), combined PH (CpcPH) and control group. PA flows were recorded using 3T cardiac magnetic resonance (CMR); RV volume (V) were obtained by contouring endocardial and epicardial borders on the short axis at end diastolic (ED) and end systolic (ES) phases, and ejection fraction (RVEF) was calculated as (RVEDV - RVESV)/RVEDVx100. Volumetric flow was measured using phase-contrast velocity quantification using 3T cardiac magnetic resonance (CMR). PVZ was expressed as the relationship of pulsatile pressure to pulsatile flow in the frequency domain. Results: 76% of patients had evidence of PH on RHC (8 PrecPH, 17 IpcPH, 9 CpcPH). CpcPH and PrecPH patients tended to show poorer RV contractility compared with control and IpcPH groups, albeit not statistically significant. PVZ was highest in patients with PrecPH and CpcPH, while lowest in those with IpcPH. A correlation analysis was performed to seek association between mPAP, PVR and PVZ and other variables thought to be related to PH. In PrecPH, increased mPAP was found to be associated with raised PVR (p &lt; 0.001; R = 0.94) and PVZ (p &lt; 0.001; R = 0.78). However, there was no association between elevated mPAP and PVZ in IpcPH and CpcPH, despite a significant correlation with PVR (IpcPH P = 0.03, R = 0.55; CpcPH P = 0.01, R = 0.77). Conclusion: We describe a straightforward method to measure and compare pulsatile vascular load of the systemic and pulmonary circulations simultaneously, allowing further quantification of systemic/pulmonary vascular interactions. Further research is required to evaluate small-vessel contributions to the arterial circulation, especially in the pulmonary system.

An electrochemical nitric oxide generator for in-home inhalation therapy in pulmonary artery hypertension

BackgroundInhaled NO is a selective pulmonary vasodilator proven to be therapeutic for patients with pulmonary artery hypertension (PAH). The most common NO delivery system in clinical practice is cylinder-based, but unfortunately limited by its high costs, complicated delivery, and the requirement of an extensive supply chain, leaving vast unmet medical needs globally.MethodsTo address the need for rapid, affordable, and safe production of nitric oxide (NO) for in-home inhalation therapy in patients with PAH. We developed a novel portable device to derive NO from a nitrite complex solution with a copper(II)-ligand catalyst, and further examined its effectiveness in a porcine model of PAH. This model was established by using female Bama miniature pig and induced by monocrotaline (MCT) administration.ResultsThis generator could rapidly and safely produce therapeutic NO at concentrations ranging from 0 to 100 parts per million (ppm) with the least disproportionated nitrogen dioxide (NO2) and byproducts. It could effectively alleviate pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR) in piglets with PAH, without causing major physiologic disruptions.ConclusionsOur electrochemical NO generator is able to produce the desired NO doses for pulmonary vasodilation in a safe and sustainable way, with low costs, which paves the way for its subsequent clinical trials in the patient with PAH and other common cardiopulmonary conditions with a high disease burden around the world.

Pathogenic Mechanisms of Pulmonary Arterial Hypertension: Homeostasis Imbalance of Endothelium-Derived Relaxing and Contracting Factors.

Pulmonary arterial hypertension (PAH) is a progressive and fatal disease. Sustained pulmonary vasoconstriction and concentric pulmonary vascular remodeling contribute to the elevated pulmonary vascular resistance and pulmonary artery pressure in PAH. Endothelial cells regulate vascular tension by producing endothelium-derived relaxing factors (EDRFs) and endothelium-derived contracting factors (EDCFs). Homeostasis of EDRF and EDCF production has been identified as a marker of the endothelium integrity. Impaired synthesis or release of EDRFs induces persistent vascular contraction and pulmonary artery remodeling, which subsequently leads to the development and progression of PAH. In this review, the authors summarize how EDRFs and EDCFs affect pulmonary vascular homeostasis, with special attention to the recently published novel mechanisms related to endothelial dysfunction in PAH and drugs associated with EDRFs and EDCFs.

Temporal Trends in Portopulmonary Hypertension Model for End-stage Liver Disease Exceptions and Outcomes.

Using data from the Organ Procurement and Transplantation Network database, we describe the frequency of POPH MELD exceptions between 2006 and 2019, compare baseline patient characteristics, and characterize trends in liver disease and POPH severity' as well as POPH treatment and outcomes' over time. To facilitate comparison, we divided this 14-y period into 3 "eras" (2006-2010, 2011-2015, and 2016-2019). Between 2006 and 2019, 504 unique POPH MELD exceptions were granted. Both liver disease severity and patient age have increased over time (P = 0.04 and P = 0.006, respectively). Posttreatment hemodynamic values (mean pulmonary arterial pressure and pulmonary vascular resistance) have significantly improved (P < 0.001 and P = 0.008, respectively). Treatment with endothelin receptor antagonists has become more prevalent, whereas use of parenteral therapy and monotherapy regimens has decreased (P < 0.001). Neither waitlist nor liver transplant mortality outcomes have significantly changed over the eras analyzed. In conclusion, 504 patients have received POPH MELD exceptions between 2006 and 2019. Since 2010, nearly all patients granted POPH MELD exceptions have met hemodynamic criteria for POPH. Over time, there has been a trend toward older age and higher MELD scores with significant changes in pulmonary arterial hypertension treatment patterns and an improvement in posttreatment hemodynamics without major change in outcomes.

Pulmonary arterial compliance in patients of CHD with increased pulmonary blood flow.

Pulmonary arterial compliance, the dynamic component of pulmonary vasculature, remains inadequately studied in patients with left to right shunts. We sought to study the pulmonary arterial compliance in patients with left to right shunt lesions and its utility in clinical decision-making. In this single-centre retrospective study, we reviewed cardiac catheterisation data of consecutive patients of left to right shunt lesions catheterised over one year. In addition to the various other parameters, pulmonary arterial compliance was calculated, as indexed pulmonary flow (Qpi) / (Heart rate × pulse pressure in the pulmonary artery). RC time was also calculated, as the product of pulmonary arterial compliance and pulmonary vascular resistance index. Patients were divided into "operable," "borderline," and "inoperable" based on the decision of the treating team, and the pulmonary arterial compliance values were evaluated in these groups to study if it can be utilised to refine the operability decision. 298 patients (Median age 16 years, 56% <18 years) with various acyanotic shunt lesions were included. Overall, the pulmonary arterial compliance varied with Qpi, pulmonary artery mean pressure, and pulmonary vascular resistance index, but did not vary with age, type of lesion, or transpulmonary gradients. The median pulmonary arterial compliance in patients with normal pulmonary artery pressure (Mean pulmonary artery pressure less than 20 mmHg) was 4.1 ml/mmHg/m2 (IQR 3.2). The median pulmonary arterial compliance for operable patients was 2.67 ml/mmHg/m2 (IQR 2.2). Median pulmonary arterial compliance was significantly lower in both inoperable (0.52 ml/mmHg/m2, IQR 0.34) and borderline (0.80 ml/mmHg/m2, IQR 0.36) groups when compared to operable patients (p < 0.001). A pulmonary arterial compliance value lower than 1.18 ml/mmHg/m2 identified inoperable patients with high sensitivity and specificity (95%, AUC 0.99). However, in borderline cases, assessment by this value did not agree with empirical clinical assessment.The median RC time for the entire study population was 0.47 S (IQR 0.30). RC time in operable patients was significantly lower than that in the inoperable patients (Median 0.40 IQR 0.23 in operable, 0.73 0.25 in inoperable patients (p < 0.001). Addition of pulmonary arterial compliance to the routine haemodynamic assessment of patients with shunt lesions may improve our understanding of the pulmonary circulation and may have clinical utility.

Balloon pulmonary angioplasty can be an effective and safe therapeutic option in non-surgical elderly patients.

Advanced age, frailty, and age-related comorbidities are the major causes of pulmonary endarterectomy disqualification in patients with chronic thromboembolic pulmonary hypertension (CTEPH). Balloon pulmonary angioplasty (BPA) is an attractive and less invasive therapy for elderly patients. However, information about the safety, procedure tolerance, and effectiveness of BPA in elderly patients is limited. We aimed to analyze the safety, tolerance, and efficacy of BPA in CTEPH patients aged ≥70 years. This observational, descriptive, and retrospective series included consecutive patients aged ≥70 years, who underwent completed or interrupted BPA programs at a pulmonary hypertension reference center between May 2013 and May 2022. We enrolled 155 patients in our institution's BPA program. Among these, 33 patients were aged ≥70 years (mean age, 76.4 years; women, 75.8%) and had finished or interrupted BPA programs. In this cohort, we performed 116 BPA procedures (average, 3.6 ± 1.8 sessions/patient). Among the 33 patients, 19 (57.6%) completed treatment for all lobes, while the BPA program was interrupted in the remaining 14 (42.4%). Among all 33 patients, BPA was associated with a significant reduction in mean pulmonary arterial pressure (39.2 ± 9.3 vs. 32.8 ± 8.8 mmHg; p < 0.001) and pulmonary vascular resistance (6.7 ± 3.1 vs. 4.4 ± 2.0 WU; p < 0.001), along with an improvement in the cardiac index (2.5 ± 0.6 vs. 2.8 ± 0.7 L/min/m2; p = 0.04) with significant reductions in the N-terminal prohormone of brain natriuretic peptide level (pre-BPA, 353 pg/mL [207-1,960 pg/mL] vs. post-BPA, 167 pg/mL [73-629 pg/mL]; p = 0.03). The patients' functional class improved, and pulmonary hypertension-targeting drug requirements were significantly reduced. The pulmonary injury appeared in 3.4% of the 116 procedures, of which 50% were of grade 2. No patient of ≥70 years had grade 5 pulmonary injury. One periprocedural mortality was recorded (3%), and the median follow-up period was 2.8 years. The survival rate of the entire cohort at 1 and 3 years was 90.5 and 82.8%, respectively. BPA is an effective and safe approach in patients aged ≥70 years. It significantly improves patients' functional class, hemodynamic, and biomarkers, and reduces their pulmonary hypertension-targeting medical therapy requirements. These successes were achieved even though a significant percentage of patients did not complete the therapy. The rates of procedural complications and periprocedural mortality were low. Survival at 1 and 3 years was good in comparison to that of younger patients undergoing BPA.

Chronic thromboembolic pulmonary hypertension and mortality after venous thromboembolism: a nationwide population-based cohort study

Abstract Background One of the ultimate long-term complications of venous thromboembolism (VTE) is chronic thromboembolic pulmonary hypertension (CTEPH). CTEPH is a condition defined as an increased mean pulmonary arterial pressure of at least 25 mmHg at rest and abnormal pulmonary artery resistance measured by right heart catheterization. To our knowledge, no study has compared mortality in VTE patients developing CTEPH to those who do not. Purpose We aimed to investigate the influence of CTEPH on long-term VTE mortality, by examining how receiving any pulmonary hypertension (PH) diagnosis following VTE influenced mortality. Methods We conducted a population-based cohort study of all adult Danish patients with an incident in or outpatient VTE diagnosis from 1995 through 2016. We excluded patients with a previous PH diagnosis. We defined CTEPH as receiving any PH diagnosis within two years following VTE. We categorized VTE by type (deep venous thrombosis [DVT] or pulmonary embolism [PE]) and provoking risk factors. We followed patients from two years after VTE until the first of death, emigration, or 31 December 2016. We calculated mortality rates and standardized mortality rate ratios (SMRs) of the association between PH and all-cause mortality and cause-specific mortality due to cancer and cardiovascular diseases. We also stratified the analyses by baseline presence of comorbidity (congestive heart failure, chronic pulmonary disease, and/or interstitial pulmonary disease). Results In 89,062 VTE patients alive two years after their VTE, 724 developed PH. The mortality rate per 1,000 person-years was 121 (95% confidence interval [CI]: 110–134) in patients with PH and 48 (95% CI: 47–48) in patients without PH. The SMR was 2.05 (95% CI: 1.77–2.37) for all VTE patients, 2.20 (95% CI: 1.53–3.16) for DVT patients, and 1.72 (95% CI: 1.47–2.01) for PE patients. The SMR was 1.79 (95% CI: 1.28–2.51) in VTE patients with a provoking VTE risk factor and 2.15 (95% CI: 1.83–2.53) in VTE patients without a provoking VTE risk factor. PH was associated with increased cause-specific mortality due to cardiovascular diseases (SMR=2.31, 95% CI: 1.75–3.06), but not cancer (SMR=0.94, 95% CI: 0.64–1.38). The SMR was 2.36 (95% CI: 2.06–2.71) in patients with comorbidity and 1.80 (95% CI: 1.45–2.24) in patients without comorbidity. Conclusion Development of PH, as a measure of CTEPH, within two years following incident VTE was associated with two-fold increased mortality in two-year VTE survivors. The increase in mortality was driven by cardiovascular causes. Funding Acknowledgement Type of funding sources: None.

Efficacy and safety of oral pulmonary vasodilators in pulmonary veno-occlusive disease.

Pulmonary veno-occlusive disease (PVOD) or pulmonary capillary hemangiomatosis (PCH) is a rare subtype of pulmonary hypertension with dismal prognosis. Limited data are available on the efficacy and safety of orally administered pulmonary vasodilators for PVOD/PCH. Whether and how systemic sclerosis (SSc) affects the clinical outcomes of PVOD/PCH is also unknown. This study aimed to determine the clinical and hemodynamic efficacy and safety of oral pulmonary vasodilators for PVOD/PCH and clarify the possible effects of SSc on the clinical presentation of PVOD/PCH. We retrospectively analyzed the clinical data of 15 patients with PVOD/PCH treated with oral pulmonary vasodilators in our department since 2001. Six of them had SSc. Oral pulmonary vasodilators were administered either as single agents (n = 10) or in combination (n = 5). Treatment improved the functional class of five patients, and pulmonary arterial pressure and pulmonary vascular resistance decreased by 10 ± 12 mmHg and 36 ± 19%, respectively (p < 0.05 for both, n = 13), whereas pulmonary edema developed in three patients. The mean survival was 3.9 years, and the 1- and 3-year survival rates were 93% and 65%, respectively. The clinical presentation, including survival, was similar between patients with and without SSc. In our PVOD/PCH cohort, oral pulmonary vasodilators caused pulmonary edema in 20% of patients, but more than 80% of patients experienced significant pulmonary vasodilatory effects, and the overall prognosis was better than that previously reported. SSc does not adversely affect the clinical outcomes of PVOD/PCH.

Salusin-β, a TOR2A gene product, promotes proliferation, migration, fibrosis, and calcification of smooth muscle cells and accelerates the imbalance of vasomotor function and vascular remodeling in monocrotaline-induced pulmonary hypertensive rats.

Purpose: The hyper-proliferation, promoted migration, fibrosis, and calcification of pulmonary arterial smooth muscle cells (PASMCs) play critical roles in pulmonary artery (PA) continuous contraction and vascular remodeling, leading to elevated pulmonary arterial resistance and pulmonary hypertension (PH). In this study, we sought to ascertain the effects of a TOR2A gene product, salusin-β, on PASMCs’ proliferation, migration, fibrosis, calcification, and the imbalance of vasomotor function as well as pulmonary vascular remodeling in monocrotaline (MCT)-induced PH rats and their underlying mechanisms. Methods: Knockdown or overexpression of salusin-β in rats or PASMCs was performed through tail vein injection or cell transfection of virus. The right ventricular systolic pressure (RVSP) of the rat was measured by right ventricle catheterization. Sodium nitroprusside (SNP) or acetylcholine (ACh)-induced dose-dependent relaxation was used to evaluate the vasodilatation function. Primary PASMCs were isolated from the PAs of control and PH rats. Results: The salusin-β protein expressions were significantly increased in PAs and PASMCs isolated from PH rats compared with control rats. Knockdown of salusin-β in rats decreased high K+ solution-induced contraction, RVSP and RV hypertrophy index, improved SNP or ACh-induced vascular relaxation of PAs, and relieved vascular remodeling and calcification of PAs from PH rats. Silencing salusin-β in PASMCs isolated from PH rats alleviated the proliferation, migration, fibrosis, and calcification, as well as the NAD(P)H oxidase activity and reactive oxygen species (ROS) level. Overexpression of salusin-β exerted the opposite effects on vasomotor function and vascular remodeling, and PASMCs proliferation, migration, fibrosis and calcification. Conclusion: Increased salusin-β activity in PAs from PH rats contributes to PASMCs proliferation, migration, fibrosis, and calcification, leading to the imbalance of vascular contraction and relaxation and vascular remodeling through stimulating the production of NAD(P)H oxidase derived ROS.

Saluisn-β contributes to endothelial dysfunction in monocrotaline-induced pulmonary arterial hypertensive rats

BackgroundThe endothelial dysfunction and the consequent attenuated pulmonary vasodilatation are the major causes of elevated pulmonary arterial resistance and pressure in pulmonary arterial hypertension (PAH). Current study aimed to explore the effects of a TOR2A gene product, salusin-β, on endothelium-dependent vascular relaxation and the progression of PAH in monocrotaline (MCT)-induced PAH rats as well as the relevant signaling pathway. MethodsAcetylcholine (ACh)-induced dose-dependent relaxation was used to evaluate the endothelium-dependent vasodilatation function. ResultsThe salusin-β level in plasma and pulmonary artery (PA) in MCT-PAH rats were significantly increased, while the ACh-induced endothelium-dependent vasodilatation was attenuated. After salusin-β incubation or overexpression of salusin-β gene, the endothelium-dependent relaxation was further deteriorated, while anti-salusin-β IgG incubation or knockdown of salusin-β improved it in PAH rats. The superoxide anions scavenger NAC or the antioxidant apocynin inhibited the effect of salusin-β, while the SOD inhibitor DETC further enhanced it. The nitric oxide (NO) synthase inhibitor L-NAME almost blocked the effect of anti-salusin-β IgG. Silencing of salusin-β in PAH rats decreased right ventricular (RV) systolic pressure, RV hypertrophy index, NAD(P)H oxidase activity and ROS level, and increased the eNOS activity and NO level of PA. Overexpression of salusin-β played opposite roles. ConclusionsThe elevated saluisn-β level in PAH rats plays important roles in the reduction of endothelium-dependent vasodilatation and participates in the progression of PAH through stimulating NAD(P)H oxidase-ROS production and inhibiting eNOS-NO release.

Microrna-486-5P Regulates Human Pulmonary Artery Smooth Muscle Cell Migration via Endothelin-1

Pulmonary arterial hypertension (PAH) is a fatal or life-threatening disorder characterized by elevated pulmonary arterial pressure and pulmonary vascular resistance. Abnormal vascular remodeling, including the proliferation and phenotypic modulation of pulmonary artery smooth muscle cells (PASMCs), represents the most critical pathological change during PAH development. Previous studies showed that miR-486 could reduce apoptosis in different cells; however, the role of miR-486 in PAH development or HPASMC proliferation and migration remains unclear. After 6 h of hypoxia treatment, miR-486-5p was significantly upregulated in HPASMCs. We found that miR-486-5p could upregulate the expression and secretion of ET-1. Furthermore, transfection with a miR-486-5p mimic could induce HPASMC proliferation and migration. We also found that miRNA-486-5p could downregulate the expression of SMAD2 and the phosphorylation of SMAD3. According to previous studies, the loss of SMAD3 may play an important role in miRNA-486-5p-induced HPASMC proliferation. Although the role of miRNA-486-5p in PAH in in vivo models still requires further investigation and confirmation, our findings show the potential roles and effects of miR-486-5p during PAH development.