Pulmonary Vascular Resistance In Patients Research Articles

Sleep-disordered breathing and nocturnal hypoxemia in chronic thromboembolic pulmonary disease.

Sleep-disordered breathing (SDB) and nocturnal hypoxemia were known to be present in patients with chronic thromboembolic pulmonary hypertension (CTEPH), but the difference betweenSDB and nocturnal hypoxemia in patients who have chronic thromboembolic pulmonary disease (CTEPD) with or without pulmonary hypertension (PH) at rest remains unknown. Patients who had CTEPH (n = 80) or CTEPD without PH (n= 40) and who had undergone sleep studies from July 2020 to October 2022 at Shanghai Pulmonary Hospital were enrolled. Nocturnal mean SpO2 (Mean SpO2) <90% was defined as nocturnal hypoxemia, and the percentage of time with a saturation below 90% (T90%) exceeding 10% was used to evaluate the severity of nocturnal hypoxemia. Logistic and linear regression analyses were performed to investigate the difference and potential predictor of SDB or nocturnal hypoxemia between CTEPH and CTEPD without PH. SDB was similarly prevalent in CTEPH and CTEPD without PH (P = 0.104), both characterised by obstructive sleep apnoea (OSA). Twenty-two patients with CTEPH were diagnosed with nocturnal hypoxemia, whereas only three were diagnosed with CTEPD without PH (P = 0.021). T90% was positively associated with mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance in patients with CTEPH and CTEPD without PH (P < 0.001); T90% was also negatively related to cardiac output in these patients. Single-breath carbon monoxide diffusing capacity, sex and mPAP were all correlated with nocturnal hypoxemia in CTEPH and CTEPD without PH (all P < 0.05). Nocturnal hypoxemia was worse in CTEPD with PH; T90%, but not SDB, was independently correlated with the hemodynamics in CTEPD with or without PH.

Pulmonary vascular resistance in patients with neuromuscular disorders

Pulmonary vascular resistance in patients with neuromuscular disorders

Assessment of pulmonary vascular resistance via doppler echocardiography in ischemic heart disease with reduced ejection fraction

Objectives: To determine pulmonary vascular resistance (PVR) by echocardiography - Doppler; and evaluate the correlation between pulmonary vascular resistance and some variables such as left ventricular EF, PASP, TAPSE, and tissue S-wave of the tricuspid valve in patients with ischemic heart disease. Method: Observational study on 82 heart failure patients with reduce ejection fraction brought upon by ischemic heart disease, at the Cardiology Department of the University of Medicine and Pharmacy from 04/2016 - 05/2017. Results: The average PVR is 3.91 ± 1.85 WU. There was not significant difference between age and gender groups (p &gt; 0.05), but there was a statistically significant difference of PVR in patients with NYHA III and IV compared to NYHA I, II (p &lt; 0.05). When EF &lt; 30%, the rate of increased PVR is higher than the normal value (35.4 % vs 4.9%). There is a strong correlation between LVEF and PVR (r = - 0.545, p &lt; 0.001), especially when PVR &lt; 8 WU (r = - 0.618, p &lt; 0.001). When the PASP increases, the rate of increased PVR is higher than normal value (54.9% vs. 9.8%, p &lt; 0.001), with an enough correlation coefficient (r = 0.361, p &lt; 0.001). In patients with RV systolic dysfunction evaluated by TAPSE and S’ wave, there was a significant difference in the rate of increased PVR from the normal value (41.5% vs 1.2%; 34.1 vs 8.5%, p 0.001). PVR is closely correlated with TAPSE (r = -0.590; p &lt; 0.001) and is inversely correlated with S’ wave (r = -0.590; p &lt; 0.001). Conclusions: Increased PVR is the primary mechanism for pulmonary hypertension and right ventricular dysfunction in patients with HFrEF brought upon by IHD. The evaluation of PVR in patients with left ventricular dysfunction by echocardiography is important in clinical practice

Abstract 17599: Sotatercept for the Treatment of Pulmonary Arterial Hypertension: A Systematic Review and Single-Arm Meta-Analysis

Introduction: Pulmonary arterial hypertension (PAH) is associated with progressive clinical worsening and a 50% 5-year survival rate with current PAH therapies. Sotatercept is a first-in-class fusion protein with promising results in preclinical trials, but clinical evidence on its role in treating PAH remains limited. Hypothesis: Sotatercept may provide clinical benefits for patients with symptomatic PAH. Aims: To assess the efficacy of sotatercept in addition to background PAH therapy in this population. Methods: We searched PubMed, Embase, Cochrane and Clinicaltrials.gov in April 2023 for clinical trials assessing efficacy outcomes of sotatercept in patients with PAH. Using a random-effects model, we performed a single-arm meta-analysis of proportions for binary outcomes and applied generic inverse variance weighting formulas to pool arithmetic means and least squares means for continuous outcomes. Statistical analyses were performed using Review Manager 5.4.1 and R software 4.2.2. Results: We included three clinical trials comprising 254 patients with WHO functional class II or III PAH. At 24 weeks, only 2% of patients on sotatercept experienced symptoms of clinical worsening (95% CI 1 to 5; Fig. 1A). Sotatercept was also associated with a reduction in pulmonary vascular resistance (mean change from baseline -199.92 dyn·sec·cm -5 ; 95% CI -256.83 to -143.0; Fig. 1B), while improving 6-minute walk distance (mean change from baseline 45.86 m; 95% CI 28.54 to 63.18; Fig. 1C). Conclusions: These findings suggest that sotatercept may improve exercise capacity while decelerating clinical worsening and attenuating pulmonary vascular resistance in patients with mild to moderate PAH.

CARC22: Automatic Monitoring of Pulmonary Vascular Resistance in Patients Eligible for Bridging to Candidacy while Supported by The Aeson Total Artificial Heart

Background: The pulsatile Aeson Total Artificial Heart (TAH) employs embedded sensors to autoregulate the response of the device to changing patient needs. These sensors are also used to monitor the Pulmonary Vascular Resistance (PVR) in patients supported by the TAH whose major contraindication to transplantation is an elevated PVR. The efficacy of this facility was evaluated during the course of a recent Bridge To Transplant study (NCT02962973). Methods: Pressure records from the right and left ventricular pressure sensors and pump output records are downloaded from the TAH and averaged at 30-day intervals. The effects of vasodilative medication provide guidance on the ongoing reversibility of the Trans Pulmonary Resistance (TPR), calculated as below. TPR = (mRightOutputPressure-mLeftInputPressure)/RightPumpOutput) This provides an estimate of the true PVR, as the measurements are made within the prosthesis, but the trends and responses to medication are helpful for medical decision-making (figure). Results: The BTT study comprised 3 patients aged 60, 35 and 54 years, with pre-implant Cardiac Index 2.1, 1.4 and 1.7 L/min/m2 and PVR values of 5.2, 4.4 and 6.0 Wood Units respectively. The average range of TAH outputs was 4.5 to 6.5 L/min. Patients were discharged at 68-, 48- and 48-days post implant and all experienced improved exercise capacities and resumed their daily activites. Medication included mild anticoagulation with enoxaparin 1 mg/kg and aspirin 100 mg daily. Implant durations were 243, 155, and 109 days, when all demonstrated a decrease in TPR and were considered transplant eligible (Table). The transplant procedures were uncomplicated. No right heart failure was observed. The first patient had late complications comprising pneumonia and multiorgan failure and died at 111 days post-transplant. The remaining two were doing well at 1 year follow-up. Conclusion: The integrated PVR monitoring system incorporated in the Aeson TAH provides a useful guide to manage patients with pulmonary hypertension and assess their transplant-eligibility. Table 1. - Transpulmonary Resistance Time Patient 1 Patient 2 Patient 3 Implant day 7.0 6.8 7.9 Post-implant day 30 5.6 5.5 7.0 Post-implant day 60 5.1 5.2 7.4 Post-implant day 90 5.5 5.1 6.5 Last day before Transplant 5.6 5.3 6.5 Values expressed in Wood Units

Clinical features and CT findings of fibrosing mediastinitis associated pulmonary hypertension

Objective: To investigate the clinical features and CT findings of pulmonary hypertension (PH) in patients with fibrosing mediastinitis (FM). Methods: Thirteen patients with FM diagnosed between September 2015 and June 2022 were studied retrospectively, including patients with PH (FM-PH group) and patients without PH (FM group) confirmed on right heart catheterization. The t test of two independent samples, Mann-Whitney U rank sum and Fisher's test were used to compare the general information, symptoms, laboratory examination, right ventricular and pulmonary artery measurement data and pulmonary artery CT findings between the two groups, respectively. Results: Compared with the 7 FM patients aged 28-79 (60.00±17.69) years, the 6 patients in the FM-PH group, aged from 60 to 82 (68.83±8.35) years, had more peripheral edema, lower percentage of PaO2, wider inner diameters of pulmonary artery and right ventricle, a higher ratio of right ventricle and left ventricular transverse diameter, faster tricuspid regurgitation velocity and higher estimated systolic pulmonary artery pressure (P<0.05). There were no differences in BNP levels and tricuspid annular plane systolic excursion between groups (P>0.05). Of the 6 patients with PH, 5 had precapillary PH and 1 had mixed PH. Except that the pulmonary vascular resistance in patients of the FM-PH group was significantly higher than that in the FM group (P<0.05), there were no significant differences in cardiac output, mixed venous oxygen saturation and pulmonary capillary wedge pressure between the two groups. CT pulmonary angiography (CTPA) showed pulmonary artery and vein stenosis. Patients in the FM-PH group had more severe stenosis and occlusion of pulmonary artery and pulmonary vein (P<0.05), and more involvement of multiple pulmonary veins (P<0.05). Conclusions: The clinical manifestation of FM complicated with PH is related to the degree of involvement of pulmonary artery, vein and airway. It is recommended that the disease be evaluated in combination with multiple parameters such as clinical manifestations, cardiac ultrasound, right cardiac catheter and CTPA.

Diet and Exercise Intervention in Pulmonary Hypertension

Current pharmacologic treatments for pulmonary arterial hypertension lead to vasodilation of the pulmonary arteries, increasing cardiac output and reducing pulmonary vascular resistance in patients with pulmonary arterial hypertension. Right ventricular failure is a leading cause of death in patients with pulmonary arterial hypertension, but there remain no promising leads in the treatment of right ventricular failure. Current research demonstrates that metabolic abnormalities, particularly regarding insulin resistance and glucose intolerance, may be pathologic in the development of right ventricular failure in patients with pulmonary arterial hypertension. In this review, we will address the potential role diet and exercise may play in improving right ventricular failure in patients with pulmonary arterial hypertension.

RASA3 is a candidate gene in sickle cell disease-associated pulmonary hypertension and pulmonary arterial hypertension.

Pulmonary hypertension (PH)is associated with significant morbidity and mortality. RASA3 is a GTPase activatingprotein integral to angiogenesis and endothelial barrier function. In this study, we explore the association of RASA3 genetic variation with PH risk in patients with sickle cell disease (SCD)-associatedPH and pulmonary arterial hypertension (PAH).Cis-expression quantitative trait loci (eQTL)were queried for RASA3 using whole genome genotype arrays and gene expression profiles derived from peripheral blood mononuclear cells (PBMC)of three SCD cohorts. Genome-wide single nucleotide polymorphisms (SNPs)near or in the RASA3 gene that may associate with lung RASA3 expression were identified, reduced to 9 tagging SNPs for RASA3 and associated with markers of PH. Associations between the top RASA3 SNP and PAH severity were corroborated using data from the PAH Biobank and analyzed based on European or African ancestry (EA,AA).We found that PBMC RASA3 expression was lower in patients with SCD-associated PH as defined by echocardiography and right heart catheterization and was associated with higher mortality. One eQTL for RASA3 (rs9525228) was identified, with the risk allele correlating with PH risk, higher tricuspid regurgitant jet velocity and higher pulmonary vascular resistance in patients with SCD-associated PH. rs9525228 associated with markers of precapillary PH and decreased survival in individuals of EA but not AA. In conclusion, RASA3 is a novel candidate gene in SCD-associated PH and PAH, with RASA3 expression appearing to be protective. Further studies are ongoing to delineate the role of RASA3 in PH.

Safety and efficacy of RT234 vardenafil inhalation powder on exercise parameters in pulmonary arterial hypertension: phase II, dose-escalation study design

BackgroundPulmonary arterial hypertension (PAH) is a progressive disease characterized by high mean pulmonary arterial pressure (≥ 20 mmHg) and remodeling of the vascular arteries. Approved therapies improve symptoms and delay clinical worsening in the long term, but they do not relieve acute exertional symptoms. RT234, a drug/device combination (Respira Therapeutics, Palo Alto, CA, USA) that delivers the phosphodiesterase 5 inhibitor vardenafil to the lungs via inhalation, has been shown to reduce pulmonary vascular resistance in patients with PAH. This study aims to evaluate whether RT234 can increase oxygen capacity during cardiopulmonary exercise testing (CPET) in patients with PAH.MethodsThis prospective, multi-center, open-label, two-cohort, dose-escalation, phase IIb trial in patients with PAH will evaluate the safety and efficacy of RT234 in improving exercise parameters. The trial began in September 2020 and is expected to be completed by early 2024. Patients eligible for enrollment will have a right heart catheterization–confirmed diagnosis of PAH, a 6-minute walking distance of ≥ 150 m, a minute ventilation/carbon dioxide production slope of ≥ 36, and will be on up to three stable oral and/or inhaled (not parenteral) PAH-specific background therapies. The estimated sample size is 86 patients, who will be divided into two dose cohorts. Cohort 1 will receive 0.5 mg RT234, and cohort 2 will receive 1.0 mg RT234. Each cohort will contain two subgroups based on the number of PAH background medications (up to two vs three). The trial will assess patients’ changes from baseline in peak oxygen consumption (VO2) during CPET 30 minutes after a single dose of 0.5 mg or 1.0 mg RT234, the change in the 6-minute walking distance, and the pharmacokinetics and safety profile of single doses of RT234.ConclusionThis is the first trial involving an as-needed medication for PAH. The trial will provide insights into the safety and efficacy of as-needed RT234 in treating the acute symptoms of PAH during exercise and will inform the design of further trials.Trial registration number: ClinicalTrials.gov identifier NCT04266197.

Pathophysiology and pathogenic mechanisms of pulmonary hypertension: role of membrane receptors, ion channels, and Ca2+ signaling.

The pulmonary circulation is a low-resistance, low-pressure, and high-compliance system that allows the lungs to receive the entire cardiac output. Pulmonary arterial pressure is a function of cardiac output and pulmonary vascular resistance, and pulmonary vascular resistance is inversely proportional to the fourth power of the intraluminal radius of the pulmonary artery. Therefore, a very small decrease of the pulmonary vascular lumen diameter results in a significant increase in pulmonary vascular resistance and pulmonary arterial pressure. Pulmonary arterial hypertension is a fatal and progressive disease with poor prognosis. Regardless of the initial pathogenic triggers, sustained pulmonary vasoconstriction, concentric vascular remodeling, occlusive intimal lesions, in situ thrombosis, and vascular wall stiffening are the major and direct causes for elevated pulmonary vascular resistance in patients with pulmonary arterial hypertension and other forms of precapillary pulmonary hypertension. In this review, we aim to discuss the basic principles and physiological mechanisms involved in the regulation of lung vascular hemodynamics and pulmonary vascular function, the changes in the pulmonary vasculature that contribute to the increased vascular resistance and arterial pressure, and the pathogenic mechanisms involved in the development and progression of pulmonary hypertension. We focus on reviewing the pathogenic roles of membrane receptors, ion channels, and intracellular Ca2+ signaling in pulmonary vascular smooth muscle cells in the development and progression of pulmonary hypertension.

Long-term prognostic impact of pulmonary vascular resistance in patients with rheumatic mitral stenosis undergoing percutaneous mitral balloon valvuloplasty

Abstract Background Pulmonary hypertension (PH) has a well-known impact on the prognosis of patients with rheumatic mitral stenosis (MS). Some patients can present pre-capillary PH, defined as a pulmonary vascular resistance (PVR) ≥3.0 woods, and there is few data regarding the prognostic value of invasive measures of PVR in this context. Purpose To assess the impact of PVR on the long-term outcomes of patients with rheumatic MS undergoing percutaneous mitral balloon valvuloplasty (PMBV). Methods Unicentric, retrospective study, including patients with rheumatic MS undergoing PMBV from 2016 to 2020. All patients underwent clinical and laboratorial evaluation, and transthoracic echocardiogram before and after the procedure. During PMBV, transesophageal echocardiogram and hemodynamic measures were performed. The composite endpoint included death, reintervention and persistent NYHA FC III–IV in long-term follow-up. Results 58 patients were included with a median age of 50.5 [42–60.5] years and 82.8% were female. Most important comorbidities were hypertension (55.2%), previous valvular intervention (22.4%), diabetes (20.7%), atrial fibrillation (18%), previous stroke/transient ischemic attack (3.4%), coronary artery disease (1.7%). Median mitral valve area was 1.2 [0.9–1.3] cm2, mean transmitral gradient was 8 [6–12] mmHg and pulmonary artery systolic pressure (PASP) was 42 [35–51] mmHg. Pre-procedure hemodynamic right atrium pressure (RAP) was 8 [6–10] mmHg, pulmonary artery mean pressure (mPAP) was 26 [21–31] mmHg, pulmonary capillary pressure (PCP) was 18 [15–22] mmHg and PVR was 2.15 [1.5–3.46] mmHg/min. Thirty-five (60.3%) patients underwent 1 balloon dilation, 10 (17.2%) 2 dilations, 3 (5.3%) 3 dilations and 1 (1.7%) 4 dilations. Only 1 (1.7%) case need conversion to open surgery. Post-procedure hemodynamic Δ mPAP was 4 [1–8] mmHg, Δ PCP was 5 [2–7] mmHg and Δ PVR was 0.03 [−0.072–0.99] mmHg/min. Median follow-up was 32.9 [20.2–43] months. Need for reintervention (surgery or PMBV) was 6.9%, mortality during follow-up was 1.7% and the composite endpoint occurred in 13 (22.4%) patients. By univariate analysis, echocardiographic PSAP (HR: 1.069, 95% CI 1.010–1.130, p=0.021), RAP (HR: 1.267, 95% CI 1.028–1.562, p=0.027), Δ hemodynamic PASP (HR: 0.927, 95% CI 0.866–0.991, p=0.026) and moderate or severe tricuspid regurgitation (HR: 6.318, 95% CI 1.734–23.023, p=0.005) were associated with the composite endpoint. By multivariate analysis adjusted by RVP, RAP (HR: 1.626, 95% CI 1.005–2.630, p=0.047) was the only independent predictor of the composite endpoint. The RAP cutoff found through the Youden index was 9.5 mmhg (Figure 1). Conclusion In patients with severe MS undergoing PMBV, RAP measurement in cardiac catheterization was the only independent predictor of combined outcome of death, reintervention and persistent NYHA FC III–IV in long-term follow-up. PVR had no impact on long-term outcomes. Funding Acknowledgement Type of funding sources: None.

Hemodynamic Effects of Cyclic Guanosine Monophosphate-Dependent Signaling Through β3 Adrenoceptor Stimulation in Patients With Advanced Heart Failure: A Randomized Invasive Clinical Trial.

β3-AR (β3-adrenergic receptor) stimulation improved systolic function in a sheep model of systolic heart failure (heart failure with reduced ejection fraction [HFrEF]). Exploratory findings in patients with New York Heart Association functional class II HFrEF treated with the β3-AR-agonist mirabegron supported this observation. Here, we measured the hemodynamic response to mirabegron in patients with severe HFrEF. In this randomized, double-blind, placebo-controlled trial we assigned patients with New York Heart Association functional class III-IV HFrEF, left ventricular ejection fraction <35% and increased NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels to receive mirabegron (300 mg daily) or placebo orally for a week, as add on to recommended HF therapy. Invasive hemodynamic measurements during rest and submaximal exercise at baseline, 3 hours after first study dose and repeated after 1 week's treatment were obtained. Predefined parameters for analyses were changes in cardiac- and stroke volume index, pulmonary and systemic vascular resistance, heart rate, and blood pressure. We randomized 22 patients (age 66±11 years, 18 men, 16, New York Heart Association functional class III), left ventricular ejection fraction 20±7%, median NT-proBNP 1953 ng/L. No significant changes were seen after 3 hours, but after 1 week, there was a significantly larger increase in cardiac index in the mirabegron group compared with the placebo group (mean difference, 0.41 [CI, 0.07-0.75] L/min/BSA; P=0.039). Pulmonary vascular resistance decreased significantly more in the mirabegron group compared with the placebo group (-1.6 [CI, -0.4 to -2.8] Wood units; P=0.02). No significant differences were seen during exercise. There were no differences in changes in heart rate, systemic vascular resistance, blood pressure, or renal function between groups. Mirabegron was well-tolerated. Oral treatment with the β3-AR-agonist mirabegron for 1 week increased cardiac index and decreased pulmonary vascular resistance in patients with moderate to severe HFrEF. Mirabegron may be useful in patients with worsening or terminal HF. URL: https://www. gov; Unique identifier: 2016-002367-34.

A simpler noninvasive method of predicting markedly elevated pulmonary vascular resistance in patients with chronic thromboembolic pulmonary hypertension.

Several echocardiographic methods to estimate pulmonary vascular resistance (PVR) have been proposed. So far, most studies have focused on relatively low PVR in patients with a nonspecific type of pulmonary hypertension. We aimed to clarify the clinical usefulness of a new echocardiographic index for evaluating markedly elevated PVR in chronic thromboembolic pulmonary hypertension (CTEPH). We studied 127 CTEPH patients. We estimated the systolic and mean pulmonary artery pressure using echocardiography (sPAPEcho, mPAPEcho) and measured the left ventricular internal diameter at end diastole (LVIDd). sPAPEcho/LVIDd and mPAPEcho/LVIDd were then correlated with invasive PVR. Using receiver operating characteristic curve analysis, a cutoff value for the index was generated to identify patients with PVR > 1000 dyn·s·cm−5. We analyzed pre‐ and postoperative hemodynamics and echocardiographic data in 49 patients who underwent pulmonary endarterectomy (PEA). In this study, mPAPEcho/LVIDd moderately correlated with PVR (r = 0.51, p < 0.0001). There was a better correlation between PVR and sPAPEcho/LVIDd (r = 0.61, p < 0.0001). sPAPEcho/LVIDd ≥ 1.94 had an 77.1% sensitivity and 75.4% specificity to determine PVR > 1000 dyn·s·cm−5 (area under curve = 0.804, p < 0.0001, 95% confidence interval [CI], 0.66–0.90). DeLong's method showed there was a statistically significant difference between sPAPEcho/LVIDd with tricuspid regurgitation velocity2/velocity–time integral of the right ventricular outflow tract (difference between areas 0.14, 95% CI, 0.00–0.27). The sPAPEcho/LVIDd and mPAPEcho/LVIDd significantly decreased after PEA (both p < 0.0001). The sPAPEcho/LVIDd and mPAPEcho/LVIDd reduction rate (ΔsPAPEcho/LVIDd and ΔmPAPEcho/LVIDd) was significantly correlated with PVR reduction rate (ΔPVR), respectively (r = 0.58, p < 0.01; r = 0.69, p < 0.05). In conclusion, the index of sPAPEcho/LVIDd could be a simpler and reliable method in estimating CTEPH with markedly elevated PVR and also be a convenient method of estimating PVR both before and after PEA.

End-Systolic Eccentricity Index Obtained by Enhanced Computed Tomography Is a Predictor of Pulmonary Vascular Resistance in Patients with Chronic Thromboembolic Pulmonary Hypertension.

The usefulness of the parameters of biventricular function simultaneously measured using enhanced multi-detector computed tomography (MDCT) pulmonary angiography in patients with chronic thromboembolic pulmonary hypertension (CTEPH) has not been clarified. This study aimed to verify the correlation between left and right ventricular (RV) parameters and pulmonary vascular resistance (PVR). Patients who underwent enhanced MDCT before diagnostic right heart catheterization at Nagoya University Hospital between October 2014 and April 2021 were enrolled. The correlation of biventricular function and volume parameters with PVR was assessed. Eighty patients were retrospectively analyzed. Patients’ mean age was 65 ± 13 years, mean PVR was 9.1 (range, 6.1–11.3) Wood units, and mean end-systolic eccentricity index (esEI) was 1.76 ± 0.50. RV end-systolic volume (ESV) (p = 0.007), RV cardiac output (CO) (p < 0.001), RV ejection fraction (p < 0.001), LV end-diastolic volume (EDV) (p < 0.001), left ventricular (LV) ESV (p = 0.006), LVCO (p < 0.001), end-diastolic EI (p < 0.001), and esEI (p < 0.001) were significantly correlated with PVR. The LVEDV (p = 0.001) and esEI (p < 0.009) were independent predictors of PVR. Systolic pulmonary arterial pressure (PAP) (p < 0.001), diastolic PAP (p < 0.001), mean PAP (p < 0.001), right atrial pressure (p < 0.023), and PVR (p < 0.001) were significantly higher in the high esEI group than in the low esEI group. The esEI was a simple predictor of CTEPH severity.

OR9. Association between Echocardiographic Pulmonary to Left Atrial Ratio (ePLAR) and Pulmonary Vascular Resistance in Patients with Adult Congenital Heart Diseases

Abstract Background and Aims Echocardiographic pulmonary to left atrial ratio (ePLAR) is a new echocardiographic valuable parameter for distinguishing precapillary and postcapillary PH. This study aims to determine the association between ePLAR and PVR in patients with ACHD. Methods and Results A total of 42 patients with ACHD who underwent RHC at Dr Moewardi General Hospital between May 2019 to February 2021 were included in this retrospective observational study. Transthoracic echocardiography and RHC were performed in all patients. The ePLAR then compared between the patient with PVR &amp;lt;5 WU and PVR &amp;gt;5 WU. There were 15 patients (median age 37.00 (24.00 - 64.00) in PVR &amp;lt;5WU group and 10 patients (median age 29.00 (24.00 – 49.00) in PVR &amp;gt;5 WU group. Mean ePLAR in PVR &amp;lt;5 WU group was 0.28 ±0.13 and 0.52 ±0.23 in patients with PVR &amp;gt;5 WU group. Statistical analysis has shown significant difference of ePLAR between the PVR &amp;lt;5 WU group and the PVR &amp;gt;5 WU group, p &amp;lt; 0.003. The ePLAR cut off value for PVR was 0.341 with sensitivity of 90.0% and specificity of 73.3% (AUC 0.827; p &amp;lt; 0.007). Patients with ePLAR value of &amp;gt;0.341 will significantly show higher PVR by RHC of &amp;gt; 5 WU (OR 24.7, (95% CI 2.333-262.5), p &amp;lt; 0.004). Conclusion Our study shows the association between ePLAR and PVR in patients with ACHD. The ePLAR value of &amp;gt;0.341 can predict PVR &amp;gt;5 WU with good sensitivity and specificity.

Abstract 12319: 16alpha-Hydroxyestrone Downregulates SOX17 During the Development of Pulmonary Arterial Hypertension

Introduction: Sexual dimorphism in pulmonary arterial hypertension (PAH) is attributed, in part, to estrogen signaling. 16α-hydroxyestrone (16αOHE) is considered a major contributor to PAH pathogenesis. Recent genetic studies have also suggested that deficiency of SOX17, an endothelial cell (EC)-specific transcription factor, contributes to PAH risk. While functional studies of SOX17 are absent, we hypothesized that 16αOHE contributes to PAH, in part, via, SOX17 downregulation. Methods/Results: Sox17 expression was reduced in 3 animal PAH models and in human pulmonary artery ECs (HPAECs) isolated from patients with PAH (vs controls). Inducible Tie2-specific Sox17 knockout ( Sox17 EC-/- ) mice exhibited increased right ventricular systolic pressure (RVSP), RV hypertrophy (RVH), and PA wall thickness (PAWT) after chronic hypoxia (CH) (Fig 1A). Inducible Tie2- Sox17 transgenic overexpressing ( Sox17 Tg ) mice attenuated CH-induced PH (Fig 1B). While not evident across murine sex, Sox17 expression was increased in baseline lungs from male compared to female rats. Supporting in silico evidence of estrogen response elements (ERE) on the SOX17 promoter, HPAECs exposed to 16αOHE reduced SOX17 expression and promoter luciferase activity via ERα, which was partly negated by serial ERE mutagenesis (Fig 1C ) . Lungs from ERα loss-of-function mutant rats (vs control) confirmed in vivo reductions of Sox17 expression. Sox17 Tg mice attenuated 16αOHE-mediated PH after CH (Fig 1D). To translate these data, we identified a functional coding SNP in the ESR1 gene (encoding ERα), rs746432, previously shown to reduce transcriptional activity of ERα. The SNP was associated with reduced pulmonary vascular resistance in patients with PAH (n=702, Fig 1E) in adjusted analyses. Conclusion: Validating genetic studies, SOX17 deficiency augments preclinical PAH. 16αOHE mediates PH development via downregulation of SOX17, linking SOX17 genetics with the observed sexual dimorphism.

Abstract 12358: Oral Iron Supplementation is Associated With Lower Pulmonary Vascular Resistance in Patients With Pulmonary Hypertension and Heart Failure With Preserved Ejection Fraction

Introduction: Pulmonary hypertension (PH) associated with left heart disease can be stratified as isolated post-capillary (IpcPH) or combined pre and postcapillary (CpcPH) on the basis of a normal or elevated pulmonary vascular resistance (PVR). While CpcPH carries a poor prognosis, the mechanistic determinants of PVR in this population remain undefined. We hypothesize that discrepant medication usage between hemodynamic extremes of IpcPH and CpcPH may underlie this phenotypic divergence. Methods: Invasive hemodynamics were obtained at UPMC between 2008 and 2018. 4,567 patients met diagnostic criteria for Group 2 PH (mean pulmonary artery pressure [mPAP] ≥ 25mmHg, pulmonary artery wedge pressure [PAWP] &gt; 15mmHg) based on the 2013 definition. Patients were classified as having extreme IpcPH (PVR&lt;2WU, N=414) or CpcPH (PVR&gt;4WU, N=172). Patients with overlapping PH diagnoses were excluded. Preserved ejection fraction was defined as a left ventricular EF &gt;40%. Follow-up analyses were conducted on an independent set of PH-HFpEF patients with two RHCs more than 90 days apart inclusive of all PVRs (N=46). Results: Compared to IpcPH (N=127), patients with CpcPH (N=47) were prescribed anticoagulants (53.19 vs. 19.69%, p&lt;0.001) more frequently and oral iron supplements less frequently (4.26 vs. 20.47%, p=0.010). Red cell distribution width (RDW), a marker of iron deficiency, was significantly higher in CpcPH (16.57 vs. 15.24%, p=0.007). In PH-HFpEF patients with successive RHCs, change in PVR correlated positively with change in RDW (p=0.002). Compared to iron naïve patients (N=30), iron initiation (N=7) between RHCs was associated with a lower change in PVR (-1.05 vs. +0.66WU, p=0.008). Conclusions: In a PH-HFpEF cohort, iron supplementation was associated with lower PVR, suggesting that iron deficiency may contribute to vascular remodeling in PH-HFpEF.

Pulmonary Vascular Resistance Estimated by Echocardiography in Dogs With Myxomatous Mitral Valve Disease and Pulmonary Hypertension Probability.

Post-capillary pulmonary hypertension (PH) is a life-threatening complication in dogs with myxomatous mitral valve disease (MMVD). An increase in pulmonary vascular resistance (PVR) is associated with post-capillary PH progression. In humans, PVR estimated by echocardiography (PVRecho) enables the non-invasive assessment of PVR in patients with PH. This study aimed to evaluate the clinical utility of PVRecho in dogs with MMVD, PH probability, and right-sided congestive heart failure (R-CHF). Dogs with MMVD and detectable tricuspid valve regurgitation were included in the study. Dogs were classified into three PH probability groups (low/intermediate/high) and according to the presence or absence of R-CHF. All dogs underwent echocardiographic measurements for right ventricular (RV) morphology and function. PVRecho was calculated by two methods using tricuspid valve regurgitation velocity and velocity–time integral of the pulmonary artery flow (PVRecho and PVRecho2). RV size indicators were significantly higher with a higher probability of PH. RV strain and velocity–time integral of the pulmonary artery flow in the high probability group were significantly lower than those in the other groups. Tricuspid valve regurgitation velocity, PVRecho, and PVRecho2 were significantly higher with an increase in PH probability. Logistic regression analysis revealed a significant association between the presence of R-CHF and increased PVRecho2 and end-diastolic RV internal dimension normalized by body weight. PVRecho and PVRecho2 showed significant differences among the PH probability groups. These non-invasive variables may be useful for the diagnosis and stratification of PH and the determination of the presence of R-CHF in dogs with MMVD.

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

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

Metabolic Syndrome Mediates ROS-miR-193b-NFYA-Dependent Downregulation of Soluble Guanylate Cyclase and Contributes to Exercise-Induced Pulmonary Hypertension in Heart Failure With Preserved Ejection Fraction.

Many patients with heart failure with preserved ejection fraction have metabolic syndrome and develop exercise-induced pulmonary hypertension (EIPH). Increases in pulmonary vascular resistance in patients with heart failure with preserved ejection fraction portend a poor prognosis; this phenotype is referred to as combined precapillary and postcapillary pulmonary hypertension (CpcPH). Therapeutic trials for EIPH and CpcPH have been disappointing, suggesting the need for strategies that target upstream mechanisms of disease. This work reports novel rat EIPH models and mechanisms of pulmonary vascular dysfunction centered around the transcriptional repression of the soluble guanylate cyclase (sGC) enzyme in pulmonary artery (PA) smooth muscle cells. We used obese ZSF-1 leptin-receptor knockout rats (heart failure with preserved ejection fraction model), obese ZSF-1 rats treated with SU5416 to stimulate resting pulmonary hypertension (obese+sugen, CpcPH model), and lean ZSF-1 rats (controls). Right and left ventricular hemodynamics were evaluated using implanted catheters during treadmill exercise. PA function was evaluated with magnetic resonance imaging and myography. Overexpression of nuclear factor Y α subunit (NFYA), a transcriptional enhancer of sGC β1 subunit (sGCβ1), was performed by PA delivery of adeno-associated virus 6. Treatment groups received the SGLT2 inhibitor empagliflozin in drinking water. PA smooth muscle cells from rats and humans were cultured with palmitic acid, glucose, and insulin to induce metabolic stress. Obese rats showed normal resting right ventricular systolic pressures, which significantly increased during exercise, modeling EIPH. Obese+sugen rats showed anatomic PA remodeling and developed elevated right ventricular systolic pressure at rest, which was exacerbated with exercise, modeling CpcPH. Myography and magnetic resonance imaging during dobutamine challenge revealed PA functional impairment of both obese groups. PAs of obese rats produced reactive oxygen species and decreased sGCβ1 expression. Mechanistically, cultured PA smooth muscle cells from obese rats and humans with diabetes or treated with palmitic acid, glucose, and insulin showed increased mitochondrial reactive oxygen species, which enhanced miR-193b-dependent RNA degradation of nuclear factor Y α subunit (NFYA), resulting in decreased sGCβ1-cGMP signaling. Forced NYFA expression by adeno-associated virus 6 delivery increased sGCβ1 levels and improved exercise pulmonary hypertension in obese+sugen rats. Treatment of obese+sugen rats with empagliflozin improved metabolic syndrome, reduced mitochondrial reactive oxygen species and miR-193b levels, restored NFYA/sGC activity, and prevented EIPH. In heart failure with preserved ejection fraction and CpcPH models, metabolic syndrome contributes to pulmonary vascular dysfunction and EIPH through enhanced reactive oxygen species and miR-193b expression, which downregulates NFYA-dependent sGCβ1 expression. Adeno-associated virus-mediated NFYA overexpression and SGLT2 inhibition restore NFYA-sGCβ1-cGMP signaling and ameliorate EIPH.