Lower Pulmonary Vascular Resistance Research Articles

Total Artificial Heart Incorporating Novel Stacked Motor; First In Vivo Results

The latest version of the continuous flow total artificial heart (CFTAH), which incorporates a novel stacked motor to improve passive self-regulation of pressure difference between the left and right atria, and reduce pump rotor over-excursion, was tested in vivo in a calf model to assess operational performance. The CFTAH was implanted in a calf and run at various pump operating conditions including mean pump speeds from 2400 to 3600 RPM, sinusoidal speed modulations from 0 to 25%, and speed modulation rates from 80 to 120 B.M. It was also tested under various combinations of simulated high and low systemic vascular resistance and pulmonary vascular resistance via outlet graft clamping and administration of a Nitroprusside respectively. The CFTAH responded to all control inputs and ran as expected during the experiment. The head curves of the right and left pumps generated from measured pressures, measured right flow and calculated left flow, were consistent with in vitro data on this pump. The passive atrial pressure regulation performed well in the normal operating range, and there were no signs of excessive rotor axial displacement during extreme pressure excursions as had been seen in the previous versions of the pump. The left atrial pressure was unusually low throughout most of the experiment and we believe that this may have been due to partial blockage of the of the left inflow cuff proximal to the pressure line tap. This led to several left inlet suction conditions and extreme pressure conditions. The replacement of the standard, single stack stator motor with the new dual stator stack motor resulted in better passive regulation of the pressure difference between the left and right atria. Also, the extreme pressure conditions resulting from left inlet suction events did not cause the pump's rotor to rub against the volute housing as had been seen in previous versions of the pump. Even though the self-regulation was acceptable, shifting of the regulation characteristic to increase the nominal LAP-RAP value will improve the regulation further, and this modification will be implemented prior to the next in vivo experiment.

Novel Mutations and Decreased Expression of the Epigenetic Regulator TET2 in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a lethal vasculopathy. Hereditary cases are associated with germline mutations in BMPR2 and 16 other genes; however, these mutations occur in <25% of patients with idiopathic PAH and are rare in PAH associated with connective tissue diseases. Preclinical studies suggest epigenetic dysregulation, including altered DNA methylation, promotes PAH. Somatic mutations of Tet-methylcytosine-dioxygenase-2 (TET2), a key enzyme in DNA demethylation, occur in cardiovascular disease and are associated with clonal hematopoiesis, inflammation, and adverse vascular remodeling. The role of TET2 in PAH is unknown. To test for a role of TET2, we used a cohort of 2572 cases from the PAH Biobank. Within this cohort, gene-specific rare variant association tests were performed using 1832 unrelated European patients with PAH and 7509 non-Finnish European subjects from the Genome Aggregation Database (gnomAD) as control subjects. In an independent cohort of 140 patients, we quantified TET2 expression in peripheral blood mononuclear cells. To assess causality, we investigated hemodynamic and histological evidence of PAH in hematopoietic Tet2-knockout mice. We observed an increased burden of rare, predicted deleterious germline variants in TET2 in PAH patients of European ancestry (9/1832) compared with control subjects (6/7509; relative risk=6; P=0.00067). Assessing the whole cohort, 0.39% of patients (10/2572) had 12 TET2 mutations (75% predicted germline and 25% somatic). These patients had no mutations in other PAH-related genes. Patients with TET2 mutations were older (71±7 years versus 48±19 years; P<0.0001), were more unresponsive to vasodilator challenge (0/7 versus 140/1055 [13.2%]), had lower pulmonary vascular resistance (5.2±3.1 versus 10.5±7.0 Wood units; P=0.02), and had increased inflammation (including elevation of interleukin-1β). Circulating TET2 expression did not correlate with age and was decreased in >86% of PAH patients. Tet2-knockout mice spontaneously developed PAH, adverse pulmonary vascular remodeling, and inflammation, with elevated levels of cytokines, including interleukin-1β. Long-term therapy with an antibody targeting interleukin-1β blockade resulted in regression of PAH. PAH is the first human disease related to potential TET2 germline mutations. Inherited and acquired abnormalities of TET2 occur in 0.39% of PAH cases. Decreased TET2 expression is ubiquitous and has potential as a PAH biomarker.

Bronchial-arterial-circulation-sparing Lung Preservation: A New Organ Protection Approach for Lung Transplantation.

Compromised microvasculature resulting from disrupted bronchial arterial circulation appears to trigger chronic lung allograft dysfunction. Maintaining the microvasculature throughout the transplant process could improve the long-term health of transplanted lungs. We recently developed a bronchial-arterial-circulation-sparing (BACS) lung preservation approach and tested whether this approach would decrease microvascular damage and improve allograft function. The lungs of Lewis rats were procured using either the BACS approach, where the bronchial and pulmonary arteries were synchronously perfused; a conventional approach, where only the pulmonary artery was perfused; or a conventional approach with a prostaglandin flush. After 4 hours of cold ischemia, physiologic function and vascular tone of the grafts were evaluated during ex vivo lung perfusion (EVLP), and microvasculature damage was assessed using 2-photon microscopy analysis. Lung function was compared after transplant among the groups. After 4 hours of cold ischemia, the BACS group exhibited significantly higher adenosine triphosphate levels and lower expression of phosphorylated myosin light chain, which is essential for vascular smooth muscle contraction. On EVLP, the BACS and prostaglandin groups showed lower pulmonary vascular resistance and less arterial stiffness. BACS attenuated microvasculature damage in the lung grafts when compared with conventional preservation. After transplantation, the lungs preserved with the BACS approach exhibited significantly better graft function and lower expression of phosphorylated myosin light chain. Our data suggest that BACS lung preservation protects the dual circulation inherent to the lungs, facilitating robust microvasculature in lung grafts after transplantation, leading to better posttransplant outcomes.

Schistosomiasis-associated pulmonary arterial hypertension: a systematic review

Schistosomiasis-associated pulmonary arterial hypertension (Sch-PAH) is a life-threatening complication of chronic hepatosplenic schistosomiasis. It is suggested to be the leading cause of pulmonary arterial hypertension (PAH) worldwide. However, pathophysiological data on Sch-PAH are scarce. We examined the hypothesis that there are pronounced similarities in pathophysiology, haemodynamics, and survival of Sch-PAH and idiopathic PAH (iPAH).This systematic review and meta-analysis was registered in the PROSPERO database (identifier CRD42018104066). A systematic search and review of the literature was performed according to PRISMA guidelines for studies published between 01 January 1990 and 29 June 2018.For Sch-PAH, 18 studies evaluating pathophysiological mechanisms, eight studies on haemodynamics (n=277), and three studies on survival (n=191) were identified. 16 clinical registries reporting data on haemodynamics and survival including a total of 5792 patients with iPAH were included for comparison. Proinflammatory molecular pathways are involved in both Sch-PAH and iPAH. The transforming growth factor (TGF)-β signalling pathway is upregulated in Sch-PAH and iPAH. While there was no difference in mean pulmonary artery pressure (54±17 mmHg versus 55±15 mmHg, p=0.29), cardiac output (4.4±1.3 L·min-1 versus 4.1±1.4 L·min-1, p=0.046), and cardiac index (2.6±0.7 L·min-1·m-2 versus 2.3±0.8 L·min-1·m-2, p<0.001) were significantly higher in Sch-PAH compared to iPAH, resulting in a lower pulmonary vascular resistance in Sch-PAH (10±6 Woods units versus 13±7 Woods units, p<0.001). 1- and 3-year survival were significantly better in the Sch-PAH group (p<0.001).Sch-PAH and iPAH share common pathophysiological mechanisms related to inflammation and the TGF-β signalling pathway. Patients with Sch-PAH show a significantly better haemodynamic profile and survival than patients with iPAH.

Idiopathic pulmonary arterial hypertension and co-existing lung disease: is this a new phenotype?

Patients classified as idiopathic pulmonary arterial hypertension (defined as Group 1 on European Respiratory Society (ERS)/European Cardiac Society (ESC) criteria) may have evidence of minor co-existing lung disease on thoracic computed tomography. We hypothesised that these idiopathic pulmonary arterial hypertension patients (IPAH lung disease) are a separate subgroup of idiopathic pulmonary arterial hypertension with different phenotype and outcome compared with idiopathic pulmonary arterial hypertension patients without co-existing lung disease (IPAH no lung disease). Patients with ‘IPAH lung disease’ have been eligible for all clinical trials of Group 1 patients because they have normal clinical examination and normal spirometry but we wondered whether they responded to treatment and had similar survival to patients with ‘IPAH no lung disease’. We described the outcome of the cohort of patients with ‘IPAH no lung disease’ in a previous paper. Here, we have compared incident ‘IPAH lung disease’ patients with ‘IPAH no lung disease’ patients diagnosed concurrently in all eight Pulmonary Hypertension centres in the UK and Ireland between 2001–2009. Compared with ‘IPAH no lung disease’ (n = 355), ‘IPAH lung disease’ patients (n = 137) were older, less obese, predominantly male, more likely to be current/ex-smokers and had lower six-minute walk distance, lower % predicted diffusion capacity for carbon monoxide, lower mean pulmonary arterial pressure and lower pulmonary vascular resistance index. After three months of pulmonary hypertension-targeted treatment, six-minute walk distance improved equally in ‘IPAH lung disease’ and ‘IPAH no lung disease’. However, survival of ‘IPAH lung disease’ was lower than ‘IPAH no lung disease’ (one year survival: 72% compared with 93%). This survival was significantly worse in ‘IPAH lung disease’ even after adjusting for age, gender, smoking history, comorbidities and haemodynamics. ‘IPAH lung disease’ patients had similar short-term improvement in six-minute walk distance with anti-pulmonary arterial hypertension therapy but worse survival compared with ‘IPAH no lung disease’ patients. This suggests that ‘IPAH lung disease’ are a separate phenotype and should not be lumped with ‘IPAH no lung disease’ in clinical trials of Group 1 pulmonary arterial hypertension.

Clinical characteristics of patients with chronic thromboembolic pulmonary hypertension

Objective: To investigate the clinical characteristics of patients with chronic thromboembolic pulmonary hypertension (CTEPH). Methods: CTEPH cases consecutively admitted into China-Japan Friendship Hospital from September 2015 to June 2019 were enrolled with prospective data collection. The medical histories, clinical characteristics, laboratory tests, imaging manifestation and hemodynamic parameters were analyzed. Patients were divided into high pulmonary vascular resistance (PVR) group and low PVR group according to the PVR level>1 000 dyn·s·cm(-5) or not, and clinical characteristics were compared between these two groups. Results: In the 148 cases of CTEPH, right heart catheterization was performed in 103 cases with mPAP (45.1±11.0) mmHg and PVR of (992±430) dyn·s·cm(-5). At diagnosis, 88 (59.5%) cases were in WHO functional class Ⅲ and 27 (18.2%) in class Ⅳ. Most common presenting symptoms were dyspnea (147, 99.3%), chest tightness (68, 45.9%), hemoptysis (42, 28.3%), syncope (30, 20.3%), and most common signs were P2 accentuation (95, 64.9%), edema (65, 43.9%), cyanosis (47, 31.8%), systolic murmur (44, 29.7%) and jugular vein distention (35, 23.6%). In 103 cases with right heart catheterization, 52 were in the low PVR group and 51 in high PVR group. Compared to the low PVR group, high PVR group patients had higher WHO functional class and more jugular vein distention (both P<0.05). In all the 148 cases, previous venous thromboembolism (VTE) was confirmed in 105 (70.9%) patients, with a higher prevalence of previous VTE in low PVR group than that in high PVR group (P<0.001). 30 (20.3%) patients had varicose veins of the lower extremities, and 21 (14.2%) had other thrombophilic disorders including antiphospholipid syndrome, protein C and S deficiency and antithrombin Ⅲ deficiency. Conclusions: Dyspnea, P2 accentuation and edema are the most common clinical presentation of CTEPH. Previous history of VTE is common in CTEPH patients with thrombophilia in some cases.

Effect of Pulmonary Hypertension on Transplant Outcomes in Patients With Ventricular Assist Devices

Although extremely high pulmonary vascular resistance (PVR) is a relative contraindication for heart transplantation (HTx), recent data with continuous-flow left ventricular assist devices (LVADs) indicate HTx outcomes may be different when high PVR is managed with an LVAD. This study clarifies the contemporary association between PVR at HTx and posttransplant survival in LVAD vs non-LVAD cohorts. We reviewed the United Network for Organ Sharing registry for adults who received a transplant from 2008 to 2015. In those with continuous-flow LVADs and those with no VADs at HTx, (non-VAD), we grouped patients by low PVR (PVR <3), intermediate PVR (PVR 3 to <6), and high PVR (PVR ≥6) groups. Adjusted hazard ratios (aHRs) for death after HTx were calculated by Cox regression. The non-LVAD cohort included 6270 patients (4385 in low, 1643 in intermediate, and 242 in high PVR), and the LVAD cohort included 4111 patients (3227 in low, 798 in intermediate, and 86 in high PVR). The high PVR LVAD group had the worst survival, which was not significant, likely to low power (P= .300). The aHR for death in non-LVAD was 1.047 (95% confidence interval, 1.010-1.088) and in LVAD was 1.063 (95% confidence interval, 1.010-1.119). Cubic spline analysis demonstrated nonlinear associations between PVR and the aHR, especially in the LVAD cohort. There was no significant evidence to conclude the effect of pretransplant PVR on posttransplant survival is higher in LVAD vs non-LVAD patients, based on analysis of the United Network for Organ Sharing database. However, further investigations are indicated to clarify HTx candidacy in those with extremely high PVR even after LVAD.

Early post-transplant elevated pulmonary artery pressure predicts adverse outcome in cardiac recipients

AimTo investigate the prognostic value of early post-transplant hemodynamic measurements on 5-year mortality in cardiac recipients (HTx). MethodsA right heart catheterization was performed in 290 heart transplantation (HTx) recipients at a one-year post-HTx evaluation. To study the effect of post-HTx hemodynamic variables on 5-year outcome, the cohort was stratified into several subgroups. For right atrial pressure (RAP), mean pulmonary artery pressure (MPAP), pulmonary artery wedge pressure (PAWP), and pulmonary vascular resistance (PVR), patients with values from the upper 10th percentile (high), were compared with those with values from the remaining lower 90th percentile (normal). For cardiac index (CI), patients with values from the lower 10th percentile (low) were compared with those with values from the remaining upper 90th percentile (normal). ResultsDeath or re-transplantation within 5 years after the one-year control occurred in 44 patients (13%). Of those, death or re-HTx was related to graft failure in 20 of cases (45%) and non-cardiac causes in 24 of cases (55%). The risk of death or re-HTx was higher in the subgroup with MPAP above 23 mmHg than those equal to or below this value [hazard ratio 3.22, 95% confidence interval (CI) 1.49–6.97; P = 0.003]. The association remained significant despite adjustment for several comorbidities. There were no differences in outcome between subgroups stratified with respect to high versus low RAP, PAWP, CI or PVR. ConclusionElevated pulmonary artery pressure at a first annual evaluation after HTx was the only hemodynamic variable that predicted impaired outcome in cardiac recipients.

P3680Baseline hemodynamics and its effect on survival in patients with idiopathic versus CTD-associated pulmonary arterial hypertension: data from the Swedish Pulmonary Arterial Hypertension Register

Abstract Background Patients with CTD-APAH have a worse prognosis than those with IPAH, despite having lower pulmonary vascular resistance at diagnosis. Purpose To compare the effect of baseline hemodynamics on one-year survival in incident CTD-APAH patients and IPAH patients. Methods Patients with IPAH and CTD-APAH reported to the SPAHR between January 2008 and December 2018 were analyzed. Clinical data, hemodynamic parameters, lung transplantation, and survival were extracted from SPAHR. The relation between baseline hemodynamics and one-year survival was assessed by Cox proportional regression. Results There was no difference in age, WHO-FC, and 6MWD. IPAH patients had more often hypertension and diabetes; CTD-APAH patients had worse DLCO. No difference was found regarding kidney function, atrial fibrillation, stroke, and thyroid dysfunction. For details regarding hemodynamics, see Table 1. One-year survival was similar in IPAH (84%) and CTD-APAH (82%, n.s.). After adjustment for age and gender, the only hemodynamic parameters that independently predicted survival were mRAP (CTD-APAH 1.06; 1.01–1.13, p=0.046 vs. IPAH 1.08; 1.01–1.15, p=0.048) and trans-pulmonary gradient, TPG (CTD-APAH 1.04; 1.01–1.07, p=0.008 vs. IPAH 1.02; 1.01–1.04, p=0.026). Patient characteristics at diagnosis IPAH (n=311) CTD-APAH (n=204) p-value Age (years) 63±16 65±13 NS Female gender (%) 57 79 &lt;0.001 WHO-FC III (%) 73 67 NS Hypertension (%) 50 38 0.014 Diabetes (%) 27 11 &lt;0.001 6MWD (m) 288 (180–382) 260 (180–393) 0.474 DLCO (%) 45 (31–62) 38 (31–49) 0.002 Hemoglobin (g/L) 147 (134–158) 131 (121–144) &lt;0.001 NTproBNP (ng/L) 1750 (758–4124) 1250 (351–3449) 0.003 mPAP (mmHg) 48 (41–55) 38 (31–45) &lt;0.001 mRAP (mmHg) 8 (5–11) 6 (3–10) &lt;0.001 PVR (WU) 9.4 (7.0–12.3) 6.8 (4.5–10.3) &lt;0.001 CI (L/min/m2) 2.2 (1.8–2.6) 2.5 (2.0–3.0) &lt;0.001 SvO2 (%) 60 (54–66) 64 (57–71) &lt;0.001 Conclusion Despite having better hemodynamic profile at baseline, CTD-APAH patients had similar one-year survival to IPAH patients; mRAP and TPG were independent predictors of survival in both groups.

P4690Effects of pulmonary artery wedge pressure on right ventricular pulsatile loading in pulmonary hypertension: a reappraisal based on pulmonary arterial isobaric stiffness

Abstract Background Pulmonary hypertension (PH) is associated with stiffening of pulmonary arteries. Previous studies have suggested that high pulmonary artery wedge pressure (PAWP) in postcapillary PH (Pc-PH) further augments PA stiffness at a given level of pulmonary vascular resistance as compared to pulmonary arterial hypertension (PAH). However, these studies do not take into account differences in distending pressure (mean PA pressure, mPAP), which has an effect on stiffness due to non-linear stress-strain behavior of arteries. Purpose To compare total PA stiffness between Pc-PH and idiopathic PAH (iPAH) studied at similar mPAP (isobaric stiffness). Methods This was an analysis of right heart catheterization results obtained in 112 Pc-PH and 112 iPAH patients extracted from the French PAH network registry and matched for mPAP (median 38 vs 39 mmHg, P=NS), age (70.5 years each) and sex (64% female each). Total PA stiffness was calculated as the ratio of PA pulse pressure to indexed stroke volume. Results Total PA stiffness (n=224) increased with mPAP (Spearman's rho = 0.66) and decreased with PAWP (rho = - 0.17) (each P&lt;0.01). The isobaric stiffness was lower in Pc-PH (median (IQR) = 0.91 (0.64–1.39) mmHg/mL/m2) than in iPAH (1.18 (0.83–1.62) mmHg/mL/m2, P&lt;0.01). The patients were then stratified according to their mPAP (25–35 mmHg, n=74 (37/37); 36–43 mmHg, n=75 (34/41); and 44–66 mmHg, n=75 (41/34)). The isobaric stiffness was lower in Pc-PH than iPAH in the 1st mPAP tertile (0.62 vs 0.83 mmHg/mL/m2, P=0.06), in the 2nd mPAP tertile (0.76 vs 1.22 mmHg/mL/m2, P&lt;0.01) and in the 3rd mPAP tertile (1.41 vs 1.77 mmHg/mL/m2, P&lt;0.01). The pulmonary vascular resistance was lower in Pc-PH than iPAH in every mPAP tertile (each P&lt;0.01). Finally, Pc-PH had a higher indexed stroke volume than iPAH (37 (29–48) vs 32 (27–40) mL/m2, P&lt;0.01) while systolic PA pressure and PA pulse pressure were similar. Conclusion Unexpectedly, the isobaric pulmonary arterial stiffness was lower in Pc-PH than iPAH patients. It is proposed that PAWP attenuates the increase in RV pulsatile loading in PH when the natural high-strain-induced stiffening was accounted for. This may contribute to a less impaired right ventricular-PA coupling leading to higher indexed stroke volume in Pc-PH than iPAH despite similar PA pressure. At every mPAP level, both the lower PA stiffness and lower pulmonary vascular resistance in Pc-PH than in iPAH may contribute to explain differences in the pressure overload-induced right ventricular adaptation between the two diseased groups, a point that deserves to be confirmed by further studies. Acknowledgement/Funding University regular funds

Clinical phenotypes and outcomes of precapillary pulmonary hypertension of sickle cell disease.

Precapillary pulmonary hypertension (PH) is a devastating complication of sickle cell disease (SCD). Little is known about the influence of the SCD genotype on PH characteristics. To describe clinical phenotypes and outcomes of precapillary PH due to SCD according to disease genotype. A nationwide multicentre retrospective study including all patients with SCD-related precapillary PH from the French PH Registry was conducted. Clinical characteristics and outcomes according to SCD genotype were analysed. 58 consecutive SCD patients with precapillary PH were identified, of whom 41 had homozygous for haemoglobin S (SS) SCD, three had S-β0 thalassaemia (S-β0 thal) and 14 had haemoglobin SC disease (SC). Compared to SC patients, SS/S-β0 thal patients were characterised by lower 6-min walk distance (p=0.01) and lower pulmonary vascular resistance (p=0.04). Mismatched segmental perfusion defects on lung scintigraphy were detected in 85% of SC patients and 9% of SS/S-β0 thal patients, respectively, and 50% of SS/S-β0 thal patients had heterogeneous lung perfusion without segmental defects. After PH diagnosis, 31 patients (53%) received medical therapies approved for pulmonary arterial hypertension, and chronic red blood cell exchange was initiated in 23 patients (40%). Four patients were managed for chronic thromboembolic PH by pulmonary endarterectomy (n=1) or balloon pulmonary angioplasty (n=3). Overall survival was 91%, 80% and 60% at 1, 3 and 5 years, respectively, without influence of genotype on prognosis. Patients with precapillary PH related to SCD have a poor prognosis. Thrombotic lesions appear as a major component of PH related to SCD, more frequently in SC patients.

Sex-specific differences and survival in patients with idiopathic pulmonary arterial hypertension 2008-2016.

BackgroundWomen with idiopathic pulmonary arterial hypertension (IPAH) have been found to have a worse haemodynamic status at diagnosis, but better survival than men. Over the past decade, demographics have changed and new treatments have become available. The objective of this study was to investigate sex differences in an incident IPAH population diagnosed between 2008 and 2016.MethodsDifferences in clinical characteristics of patients included in the Swedish Pulmonary Arterial Hypertension Register (SPAHR) were analysed at the time of diagnosis. Survival by sex was investigated using Cox proportional hazard regression and Kaplan–Meier curves.ResultsThe study included 271 patients diagnosed with IPAH, median age was 68 (1st–3rd quartiles 54–74) years and 56% were women. At diagnosis, women were younger, had lower pulmonary vascular resistance and fewer comorbidities and more often received a combination of PAH-targeted therapies than men. Men had worse survival rates than women (hazard ratio 1.49; CI 1.02–2.18; p=0.038), but this difference did not remain after adjustment for age (hazard ratio 1.30; CI 0.89–1.90; p=0.178).ConclusionsMen with incident IPAH have worse crude survival than women. This is due to women being younger with a less pronounced comorbidity burden than men at the time of diagnosis.

Physiologically based cord clamping improves cardiopulmonary haemodynamics in lambs with a diaphragmatic hernia

ObjectiveLung hypoplasia associated with congenital diaphragmatic hernia (CDH) results in respiratory insufficiency and pulmonary hypertension after birth. We have investigated whether aerating the lung before removing placental support (physiologically based...

The role of nitric oxide signaling in pulmonary circulation of high- and low-altitude newborn sheep under basal and acute hypoxic conditions

Nitric oxide (NO) is the main vasodilator agent that drives the rapid decrease of pulmonary vascular resistance for the respiratory onset during the fetal to neonatal transition. Nevertheless, the enhanced NO generation by the neonatal pulmonary arterial endothelium does not prevent development of hypoxic pulmonary hypertension in species without an evolutionary story at high altitude. Therefore, this study aims to describe the limits of the NO function at high-altitude during neonatal life in the sheep as an animal model without tolerance to perinatal hypoxia. We studied the effect of blockade of NO synthesis with l-NAME in the cardiopulmonary response of lowland (580 m) and highland (3600 m) newborn lambs basally and under an episode of acute hypoxia. We also determined the pulmonary expression of proteins that mediate the actions of the NO vasodilator pathway in the pulmonary vasoactive tone and remodeling. We observed an enhanced nitrergic function in highland lambs under basal conditions, evidenced as a markedly greater increase in basal mean pulmonary arterial pressure (mPAP) and resistance (PVR) under blockade of NO synthesis. Further, acute hypoxic challenge in lowland lambs infused with l-NAME markedly increased their mPAP and PVR to values greater than baseline, whilst in highland animals under NO synthesis blockade, these variables did not show additional increase in response to low PO2. Highland animals showed increased pulmonary RhoA expression, decreased PSer188-RhoA fraction, increased PSer311-p65-NFқβ fraction and up-regulated smooth muscle α-actin, relative to lowland controls. Taken together our data suggest that NO-mediated vasodilation is important to keep a low pulmonary vascular resistance under basal conditions and acute hypoxia at low-altitude. At high-altitude, the enhanced nitrergic signaling partially prevents excessive pulmonary hypertension but does not protect against acute hypoxia. The decreased vasodilator efficacy of nitrergic tone in high altitude lambs could be in part due to increased RhoA signaling that opposes to NO action in the hypoxic pulmonary circulation.

Riociguat, sildenafil and inhaled nitric oxide reduces pulmonary vascular resistance and improves right ventricular function in a porcine model of acute pulmonary embolism.

Pulmonary vasodilators as add-on to current treatment strategies in acute pulmonary embolism may improve right ventricular unloading and hence improve patient outcome. We aimed to investigate whether stimulation of the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway with riociguat, sildenafil or inhaled NO causes pulmonary vasodilation and improves right ventricular function in a porcine model of acute intermediate risk pulmonary embolism. Two large autologous blood clots were administered to the pulmonary circulation of 28 pigs (60 kg). Animals were randomized to four increasing, clinically equivalent doses of riociguat (n=6), sildenafil (n=6), inhaled NO (n=6) or vehicle (n=6). Sham animals (n=4) did not receive pulmonary embolism or treatment. Haemodynamic responses were evaluated at baseline, after pulmonary embolism and after each dose using invasive pressure measurements, transoesophageal echocardiography, respiratory parameters and blood analysis. Pulmonary embolism caused a three-fold increase in pulmonary vascular resistance compared with baseline (pulmonary embolism: 352±29 vs. baseline: 107±6 dynes, p<0.0001). All treatments lowered pulmonary vascular resistance compared with vehicle (riociguat: -158±35, sildenafil: -224±35, inhaled NO: -156±35 dynes, p<0.0001). Sildenafil, but neither inhaled NO nor riociguat, caused a decrease in systemic vascular resistance (sildenafil 678±41 vs. vehicle 1081±93 dynes, p=0.02) and increased cardiac output (sildenafil 8.8±0.8 vs. vehicle: 5.9±0.2 L/min, p<0.001). Systemic blood pressure was unaltered in all treatment groups. Stimulation of the NO-sGC-cGMP pathway by riociguat, sildenafil and inhaled NO reduces pulmonary vascular resistance in a porcine model of acute pulmonary embolism without lowering systemic blood pressure.

Isoform‐specific Pde3 knockout mice spontaneously develop pulmonary hypertension

Pulmonary hypertension (PH) is associated with vasoconstriction and vascular remodeling characterized by pulmonary artery smooth muscle cell (PASMC) and microvascular endothelial cell (PMVEC) proliferation and dysfunction. Phosphodiesterase 3 (PDE3), of which there are two isoforms (3A and 3B), hydrolyzes cAMP and cGMP, both critical cyclic nucleotides in cellular function. While both isoforms are present in the pulmonary vasculature, their specific contributions to the regulation of pulmonary vascular tone are unclear. Non‐selective PDE3 inhibitors have been used to treat PH for their vasodilatory effect, presumably by increasing cellular cAMP levels. We hypothesize that isoform‐selective knockout of PDE3 may reveal distinct roles in the regulation of pulmonary vascular tone and/or PH pathogenesis. Adult (8–10 weeks) Pde3a−/− (3A‐KO), Pde3b−/− (3B‐KO), and their respective wild type (WT) mice (3A‐WT, 3B‐WT) were exposed to normoxia or normobaric hypoxia (10% O2) for 28 days. Consistent with previous reports, we found that 3A‐WT and 3B‐WT mice exposed to 10% O2 for 28 days had right ventricular (RV) hypertrophy as evidenced by an increased RV/[left ventricle (LV)+septum (S)] weight ratio relative to mice exposed to 21% O2 [p &lt; 0.001; 0.38 ± 0.01 vs 0.25 ± 0.01 (3A) and 0.35 ± 0.01 vs 0.24 ± 0.01 (3B)]. In hypoxia, 3A‐WT and 3B‐WT mice had elevated pulmonary artery pressures estimated by 2D echocardiography measurements of pulmonary acceleration time/ejection time (PAT/PET) (p &lt; 0.0001; 0.21 ± 0.004 vs 0.29 ± 0.01 (3A) and 0.21 ± 0.01 vs 0.31 ± 0.01 (3B) relative to mice exposed to 21% O2. Interestingly, in normoxia both 3A‐KO (p = 0.012; 0.25 ± 0.004 vs 0.29 ± 0.01 and 3B‐KO (p = 0.023; 0.26 ± 0.01 vs 0.31 ± 0.01) mice had evidence of elevated pulmonary artery pressures relative to their respective WT mice, as evidenced by a lower PAT/PET via echocardiography. Consistent with these results, in normoxia RV/(LV+S) was higher in both 3A‐KO (0.29 ± 0.01 vs 0.25 ± 0.01, p = 0.0008) and 3B‐KO (0.31 ± 0.01 vs 0.24 ± 0.01, p &lt; 0.0001) than in their respective normoxiaexposed WT. Normoxia‐exposed 3B‐KO mice also had elevated right ventricular systolic pressure compared to normoxia‐exposed 3B‐WT (28.9 ± 0.7 mmHg vs 24.2 ± 1.2 mmHg, p = 0.0028). In hypoxia, there was no difference in RV/(LV+S) between 3A‐WT and 3A‐KO mice, although lower estimated pulmonary artery pressures were seen in the 3A‐KO mice (p = 0.0043). Conversely, in hypoxia there was a trend towards higher RV/(LV+S) in the 3B‐KO compared to 3B‐WT mice (p = 0.0532; 0.42 ± 0.02 vs 0.35 vs ± 0.01), but no difference was seen in pulmonary artery pressures between hypoxia‐exposed, 3B‐KO and 3B‐WT mice. Our data suggest a complex and isoform‐specific role of the Pde3 genes in the pathogenesis of PH associated with hypoxia. Furthermore, these data suggest a key role for each of the PDE3 isoforms in the maintenance of the low pulmonary vascular resistance found in normal lungs.Support or Funding Information5K08HL105677‐01A1, R01HL136963‐01A1This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Pulmonary Artery Banding in Post-tricuspid Congenital Cardiac Shunting Defects with High Pulmonary Vascular Resistance.

Reports of "treat and repair" of cardiac shunting lesions with inoperably high pulmonary vascular resistance (PVR) mostly concern pre-tricuspid defects; post-tricuspid lesions are different. We report our experience with pulmonary artery (PA) banding ± targeted pulmonary hypertension medications in five patients with a large VSD and inoperably high PVR, and review previous reports of PA banding with post-tricuspid defects. Three of our 5 patients had mean PAP > 50mmHg after banding and no or only a transient fall in PVR. Two patients had mean PAP < 50mmHg and lower PVR after banding; they had closure of their VSDs but have since had a progressive increase in PVR (follow-up after closure, 3.5 and 7.7years). Previous reports have also documented difficulty in achieving sufficient band gradient. Of previously reported patients, only one became operable only after banding and targeted therapy, and was repaired; follow-up after repair was short-term (16months). Our and previous experience demonstrate the difficulty in placing a PA band sufficiently tight to substantially reduce PA pressure. Reported attempts to "treat and repair" post-tricuspid defects are few and have met with limited success, and we found that PVR may increase significantly over time after repair. But more information is needed. Accurate interpretation of experience with "treat and repair" requires: careful characterization of the pulmonary circulation prior to "treating"; considering spontaneously reversible factors at pre-treatment catheterization before ascribing reduction in PVR to medical therapy; and long-term observation of PVR in patients who have had defect closure.

992: Physiologically based cord clamping improves pulmonary hemodynamics during neonatal transition in lambs with diaphragmatic hernia

Many infants with congenital diaphragmatic hernia (CDH) develop pulmonary hypertension during the neonatal period, due to underdeveloped lung vessels and an increased sensitivity to vasoactive triggers. The abnormal pulmonary vascular bed is not equipped to adapt to the rapid cardiovascular changes that occur immediately after umbilical cord clamping, exposing these lungs to increased arterial pressures. We hypothesised that delaying umbilical cord clamping until these hypoplastic lungs are fully aerated and optimally vasodilated could protect the vascular bed from these high pressures. A diaphragmatic hernia (DH) was surgically created at ≈80 days gestational age (GA; term≈147d) in 17 ovine fetuses. At ≈138d GA, all lambs were instrumented and then delivered via caesarean section. The umbilical cord was clamped either immediately prior to ventilation onset (immediate cord clamping, DH-ICC; n=6) or after achieving a target tidal volume of 4 mL/kg, with a maximum delay of 10 min (physiologically based cord clamping, DH-PBCC; n=11). Lambs were ventilated for a total of 120 min with real-time monitoring of physiological parameters. Pulmonary blood flow (PBF) gradually increased following ventilation onset in both groups, however to a greater degree in DH-PBCC lambs (Figure 1a). PBF was 2-fold greater in DH-PBCC compared to DH-ICC lambs at 15 min following ventilation onset (45 ± 9 vs. 22 ± 3 mL/min/kg; p=0.005), and by the end of the 120 min ventilation period was 3-fold greater (23 ± 4 vs 8 ± 2 mL/min/kg; p=0.048). Pulmonary arterial pressure increased more gradually and to a lesser degree in DH-PBCC lambs, reaching a maximum of 77 ± 5 mmHg in DH-ICC lambs at 10 min, and a maximum of 64 ± 3 mmHg in DH-PBCC lambs at 17 min (Figure 1b). Pulmonary vascular resistance (PVR) dramatically decreased following lung aeration in both groups, however subsequently increased in DH-ICC lambs after 60 min of ventilation (Figure 2). By the end of the 120 min ventilation period, PVR was 3-fold lower in DH-PBCC compared to DH-ICC lambs (2.2 ± 0.6 vs. 0.6 ± 0.1 mmHg/(L/min); p<0.001). In lambs with DH, PBCC reduced pulmonary arterial pressure during the initial neonatal transition and was associated with lower PVR and greater PBF throughout the first 120 min of neonatal life. These findings suggest that delaying cord clamping may improve the neonatal transition of infants with CDH.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Patient-Specific Multiscale Modeling of the Assisted Bidirectional Glenn

First-stage palliation of neonates with single-ventricle physiology is associated with poor outcomes and challenging clinical management. Prior computational modeling and invitro experiments introduced the assisted bidirectional Glenn (ABG), which increased pulmonary flow and oxygenation over the bidirectional Glenn (BDG) and the systemic-to-pulmonary shunt in idealized models. In this study, we demonstrate that the ABG achieves similar performance in patient-specific models and assess the influence of varying shunt geometry. In a small cohort of single-ventricle prestage 2 patients, we constructed three-dimensional in silico models and tuned lumped parameter networks to match clinical measurements. Each model was modified to produce virtual BDG and ABG surgeries. We simulated the hemodynamics of the stage 1 procedure, BDG, and ABG by using multiscale computational modeling, coupling a finite-element flow solver to the lumped parameter network. Two levels of pulmonary vascular resistances (PVRs) were investigated: baseline (low) PVR of the patients and doubled (high) PVR. The shunt nozzle diameter, anastomosis location, and shape were also manipulated. The ABG increased the pulmonary flow rate and pressure by 15% to 20%, which was accompanied by a rise in superior vena caval pressure (2 to 3 mm Hg) at both PVR values. Pulmonary flow rate and superior vena caval pressures were most sensitive to the shunt nozzle diameter. Patient-specific ABG performance was similar to prior idealized simulations and experiments, with good performance at lower PVR values in the range of measured clinical data. Larger shunt outlet diameters and lower PVR led to improved ABG performance.

Abstract 16732: Differential Association of Various Cardiac Hemodynamic Parameters With Renal Dysfunction in End-Stage Heart Failure Patients

Introduction: Decreased cardiac output is often thought to be the main determinant of renal dysfunction in patients with heart failure. However, large cohort studies are lacking to show these correlations in patients with end stage heart failure. Methods: We selected all adult patients between 2007-2016 who were listed for heart transplant (n=11,030) after excluding those on life support, inotropes, nitric oxide, total artificial heart, percutaneous mechanical or ECMO support, dialysis dependent, biventricular or only right ventricular assist device support and with prior heart or kidney transplant using the United Network for Organ Sharing database. We evaluated associations between renal function and three hemodynamic parameters: 1) cardiac index (CI), 2) mean pulmonary artery pressure (mPA) and 3) pulmonary vascular resistance (PVR) using robust regression models. Results: Average age of patients was 53.5±12.3 years (23% females) with mean estimated glomerular filtration rate (eGFR) of 71.7±26.2 mL/min/1.73m 2 . Nearly half (49%) of the patients had left ventricular assist devices (LVAD) with mPA pressure of 26.2±9.9 mmHg and average CI of 2.4±0.7. There was an inverse correlation between mPA pressure and eGFR (p&lt;0.001) however no association between CI and eGFR (p=0.853); or between PVR and eGFR (p=0.989). After multivariate adjustment, mPA pressure was inversely correlated with eGFR (p&lt;0.001). Subgroup analysis of individuals with LVADs (N=5,417) showed similar results with significant inverse relations between mPA and eGFR (p= 0.008) and no significant correlation between PVR or CI and eGFR (p&gt;0.2 for both). Analysis restricted to individuals with low CI (&lt; 1.8 L/min/m 2 ) and PVR &lt; 4 Woods Units (n=8376) also showed inverse linear correlation between mPA pressures up to 45 mmHg and eGFR (p&lt;0.001). Conclusions: Among patients with end stage heart failure, higher mPA pressure and not the lower cardiac index are cross-sectionally related to lower eGFR values.