Elevated Pulmonary Vascular Resistance Research Articles

Extracorporeal Membrane Oxygenation Support After Heart Transplantation in Children-Outcomes of a Single Center Cohort.

Extracorporeal membrane oxygenation is used for postcardiotomy low cardiac output but is less established following heart transplantation. We characterized outcomes for children supported with extracorporeal membrane oxygenation after heart transplantation. Single-center retrospective study. Large pediatric cardiac referral center. All patients who received heart transplantation and were cannulated to extracorporeal membrane oxygenation between 1995 and 2016. Primary outcome measure was mortality 12 months postextracorporeal membrane oxygenation. Patient characteristics were analyzed for association with outcome according to early graft failure (extracorporeal membrane oxygenation ≤ 7 d after heart transplantation), or late graft failure. There were 246 heart transplants during the study period and 50 extracorporeal membrane oxygenation runs in 44 patients. Median time from transplant to extracorporeal membrane oxygenation was 1 day (range, 0-11.7 yr), with early graft failure in 28 patients (median 1, range 0-2 d) and 22 extracorporeal membrane oxygenation runs in 20 late graft failure patients (median, 0.8 yr; range, 8 d to 11.7 yr), including four patients with prior extracorporeal membrane oxygenation for early graft failure. Twenty-six patients (59%) survived to hospital discharge, and survival 12 months postextracorporeal membrane oxygenation was 24 patients (55%), lower in those with late graft failure (40% vs 67%; p 0.02). Independent risk factors for 12-month mortality were congenital heart disease, higher pulmonary vascular resistance indexed to body surface area (> 2.2 Woods U/m), and higher creatinine. Higher panel reactive antibody levels were associated with 12-month mortality in the late graft failure group only. Extracorporeal membrane oxygenation can be effectively used to rescue patients with graft dysfunction after heart transplantation but is associated with high early mortality. Factors associated with mortality within 12 months include presence of congenital heart disease, renal dysfunction, elevated pulmonary vascular resistance indexed to body surface area and in those supported with extracorporeal membrane oxygenation late after heart transplantation, significant human leukocyte antigen sensitization.

Calcium Homeostasis Modulator (CALHM1/2) and Pulmonary Arterial Hypertension

RATIONALEConcentric pulmonary vascular remodeling is a major cause for the elevated pulmonary vascular resistance (PVR) and pulmonary arterial pressure (PAP) in patients with pulmonary arterial hypertension (PAH). Excessive PASMC proliferation and inhibited PASMC apoptosis have been implicated in the development and progression of pulmonary vascular wall thickening in PAH. Transition from the contractile phenotype to the synthetic or proliferative phenotype of PASMC is thus an important pathogenic process that promotes vascular remodeling. An increase in cytosolic free Ca2+ concentration ([Ca2+]cyt) in PASMC is not only a trigger for PASMC contraction (and pulmonary vasoconstriction), but also an important stimulus for PASMC proliferation. Calcium homeostasis modulators (CALHM), CALHM1/2, are membrane Ca2+ channels that are allosterically regulated by voltage and extracellular Ca2+. CALHM1/2 are closed at the resting membrane potential but can be opened by strong membrane depolarization. Reduction of extracellular [Ca2+] increases CALHM open probability, which allows the channel to be activated at negative potential. We aimed to study whether CALHM1/2 are involved in the phenotypical transition of PASMC and whether CALHM1/2 are upregulated in highly proliferative PASMC from patients with PAH.METHODSFreshly isolated pulmonary artery with the endothelium removed (as contractile PASMC) and primary cultured PASMC (as synthetic or proliferative PASMC) from rats were used for this study. Western blot analysis was used to compare protein expression levels of CALHM1 and CALHM2 in fresh PA tissue and cultured PASMC derived from the same rats. In addition, we compared protein expression levels of CALHM1/2 in PASMC from normal subjects and PAH patients.RESULTSThe protein expression level of CALHM2 in proliferative PASMC (the primary cultured PASMC in growth factor‐containing medium) was significantly higher than in contractile PASMC (the freshly isolated PA tissue). The increased CALHM2 in proliferative PASMC was indeed associated with a significantly increased expression of PCNA, a cell proliferation marker, and a significantly decreased expression of MHC and TGLN4, markers for contractile phenotype of SMC. Furthermore, we also observed that mRNA expression level of CALHM2 was significantly higher in PASMC isolated from PAH patients than in PASMC from normal subjects.CONCLUSIONUpregulation of CALHM2 may play an important role in the phenotypical transition of PASMC from the contractile phenotype to the synthetic or proliferative phenotype. Ca2+ influx through voltage‐ and extracellular Ca2+‐regulated CALHM2 in the plasma membrane of PASMC is an important trigger for PASMC proliferation and may play an important role in stimulating PASMC proliferation in patients with PAH.Support or Funding InformationNIH

Impact of Mechanical Circulatory Support on Pediatric Heart Transplant Candidates with Elevated Pulmonary Vascular Resistance

With the new era of more effective medicines and increasing use of mechanical circulatory support (MCS) in children, seemingly more patients with elevated pulmonary vascular resistance (PVR) are having positive outcomes. The purpose of this study is to define the effect of MCS on pediatric patients listed for heart transplant with an elevated PVR. The United Network for Organ Sharing (UNOS) database was used to identify patients ages 0-18 at time of listing for heart transplant between 2010 and 2019 who had PVR documented. Patients were divided into MCS (LVAD, RVAD, BiVAD, and TAH) and No-MCS groups, then divided by indexed PVR (PVRi) at time of listing: <3, 3-6, and >6 Wood units. Positive waitlist outcome was defined as reaching transplant or delisted because of clinical improvement. Negative waitlist outcome was defined as death or delisted because too sick to transplant. 2081 pediatric patients were listed for heart transplant between 2010 and 2019. MCS was used in 20% overall (n=426); 57% of those with PVRi <3, 27% with PVRi 3-6, and 16% with PVRi >6. Median MCS duration was 68 days (IQR 30-142). In all three PVRi groups, MCS patients had a significantly higher incidence of positive waitlist outcome compared to No-MCS patients (Table 1). Within the No-MCS group, patients with a PVRi >6 had a higher incidence of negative waitlist outcome compared to PVRi <3 (17 vs 10%, p=0.002). This was not true in the MCS group (5 vs 6%, p=0.693). No significant differences in post-transplant survival were found between the subgroups. Patients supported with MCS had a significantly higher chance of a positive waitlist outcome than those without such support regardless of PVR status. With better waitlist survival and equivalent post-transplant survival compared to No-MCS patients, MCS patients had better overall survival from listing regardless of PVR.

Size Does Not Matter: The Outdated Practice of Using Oversized Organs for Recipients with Elevated PVR

Elevated pulmonary vascular resistance (PVR) continues to pose challenges in heart transplantation, but does the common belief that implanting a larger organ when the PVR is high actually affect outcomes? The purpose of this study is to assess post-transplantation outcomes in recipients with increased PVR in relation to donor organ size. The United Network for Organ Sharing (UNOS) database was used to identify patients ages 0-18 years at time of listing who underwent transplantation between 2010 and 2019 and for whom cardiac catheterization and donor-recipient weight data was available. Patients were divided by listing PVR into <3, 3-6, and >6 Wood units. Donor-Recipient weight ratio was categorized as undersized (≤0.80), mid-size (0.81-1.2), and oversized (>1.2). Subgroup analysis was done with an additional supersized group (>2.0). 1491 patients met study criteria. Median age [years (IQR)] 10 (3-15) and 45% female. 4% of heart transplantation cases used undersized, 45% used mid-size, and 51% used oversized organs. More patients with PVR>6 were transplanted with an oversized organ compared to patients with PVR<3 [59% (148/252) vs 48% (430/894), p=0.003). There was no difference in survival between the organ size groups regardless of PVR; this includes patients with PVR>6 at listing who were transplanted with an oversized organ versus those transplanted with an undersized (p=0.359) or mid-sized (p=0.956) organ. In subgroup analysis, even in patients transplanted with a supersized organ, there was no survival difference noted regardless of PVR. Despite a persistent practice pattern to transplant high PVR patients with oversized organs, there remains no difference in post-transplantation survival between these patients and those transplanted with smaller organs. Therefore, transplants in patients with high PVR should not be delayed by waiting for larger organs.

Extended Pig-to-Baboon Lung Xenograft Survival

In baboons, lungs from galactosyl transferase knock-out (GTKO) pigs expressing human complement regulatory proteins (hCPRP: hCD46, hCD55) exhibit elevated pulmonary vascular resistance and loss of vascular barrier function within hours. Here we summarize efforts over ten years to understand and prevent these phenomena. Orthotopic left single lung transplantation was performed using GTKO.hCPRP lungs with additional expression of one or more thromboregulatory (hEPCR, hTBM, hTFPI, hCD39) and anti-inflammatory genes (HO-1, HLA-E, hCD47), and β4Gal carbohydrate xenoantigen knock-down (KD), in various combinations. Anti-inflammatory drugs (steroids, sC1Inh, anti-histamine, anti-thromboxane, A1AT, sTNFR, αIL-6, αIL-8, PSGL-1, αMac1), antibody adsorption (AbAds) using donor pig kidneys, and donor pretreatment with chlodronate liposomes were progressively added in recent years. Transient life-supporting GTKO.hCD46 lung function was consistently observed with either hEPCR (alone [n=6] or with hCD55 [6], HO-1 [2], or hCD47 [1]); with hTBM (alone [3] or with HO-1 [1] or CD47 [1]); or with hCD55.hTFPI.CD47 [11]. Although recipient survival was occasionally extended to 2 [n=6] or even 8 days [1], loss of xenograft vascular barrier function and systemic inflammation typically occurred within 24-48 hours. Consistent recipient survival beyond 12 hours was only observed with hEPCR and hTBM co-expression [n=12] in combination with one or more additional genetic modifications (HO-1 [2], CD47.HO-1 [3], hCD55 [2], hCD55.hCD39 [3], or β4GalKD.hCD47 [2]), including 7 and 9 day survivals with selectin/integrin blockade, A1AT, and liposomes. β4GalKD.hCD47, liposome pretreatment, recipient splenectomy, and AbAds were associated with prolonged recipient survival to 31 days in one instance. Graft demise beyond 2 days was association with elaboration of anti-non-Gal antibody whether using conventional or αCD40-based immunosuppression. Consistent life-supporting lung xenograft function and increasingly frequent recipient survival >2d reflect significant progress in understanding the remaining barriers to clinical translation. We identify a pivotal role for dysregulated coagulation and multiple proinflammatory mechanisms in the loss of vascular barrier function which is associated with lung xenograft failure, and the need for more effective immunosuppression.

Short-Term Outcomes of Infants and Children Receiving Selexipag for Pulmonary Hypertension

Selexipag is a long acting, immediate release, prostacyclin IP receptor agonist used to treat pulmonary hypertension (PH). Little is known about its use in infants and children. Our study reports short-term outcomes in pediatric patients receiving selexipag. We reviewed pediatric PH patients who received selexipag at our hospital. Previously published dosing/titration recommendations from our group were followed. Nine children (3 infants, 1 toddler, & 5 adolescents) received selexipag since Feb. 2018. Median age and weight at initiation were 10 years (97 days to 18.6 years) and 34 kg (3.4-162 kg). The 4 youngest subjects were transitioned from intravenous treprostinil to selexipag and 5 subjects initiated de novo. Transitions from treprostinil were uneventful, with one infant requiring slower titration due to asymptomatic hypotension. Three adolescents required selexipag dose reduction, with two unable to achieve target dose. Median duration of therapy was 322 days (54-600 days) with five subjects remaining on selexipag. Two subjects remain on PH therapy after discontinuation of selexipag. One subject's follow up catheterization showed elevated pulmonary vascular resistance after discontinuing selexipag, thus it was re-initiated. A subject with worsening PH required transition to subcutaneous treprostinil while undergoing lung transplant evaluation. Children with a variety of other disease processes have received selexipag, including one with single ventricle anatomy status post BT shunt, one awaiting heart transplant with ventricular assist device support, and one status post heart transplant receiving treprostinil. There were no deaths and side effects mirror those seen in adults [Figure]. Administration of selexipag in infants and children appears safe, and is a viable alternative to other forms of prostacyclin administration in stable patients. Selexipag may also have a role as tertiary adjunct therapy for those who do not improve on dual oral therapy.

Exercise intolerance in heart failure: The important role of pulmonary hypertension

What is the topic of this review? This review concerns the negative impact of pulmonary hypertension (PH) on the pulmonary haemodynamic and gas exchange responses to exercise, considering the mechanisms by which PH plays a role in exercise intolerance in heart failure (HF) patients. What advances does it highlight? The hallmark limited pulmonary vascular 'reserve' and impaired pulmonary gas exchange responses to exercise in HF are worsened by the development of PH; these are key determinants of exercise intolerance. Even HF patients who present with 'normal' pulmonary vascular function experience exercise-induced PH, which plays a role in exercise intolerance. Patients with heart failure universally complain of exertional intolerance, but the underlying cause(s) of this intolerance may differ between patients with different disease phenotypes. Exercise introduces an impressive stress to the lungs, where elevations in venous return and cardiac output engender substantial increases in pulmonary blood volume and flow. Relative to healthy individuals, the pulmonary vascular reserve to accept this increase in pulmonary perfusion is compromised in heart failure, with a growing body of evidence suggesting that the development of pulmonary hypertension (PH), and in particular a precapillary component of PH, worsens the pulmonary haemodynamic response to exercise in these patients. Characterized by an exaggerated increase in pulmonary arterial pressure and an elevation in pulmonary vascular resistance, this dysfunctional pulmonary haemodynamic response plays a role in exercise intolerance, probably through an impairment of right ventricular function, underperfusion of the pulmonary circulation and a subsequent reduction in systemic blood flow and oxygen delivery. The hallmark abnormalities in ventilatory and pulmonary gas exchange that accompany heart failure, including a greater ventilatory equivalent for carbon dioxide, are also worsened by the development of PH. This raises the possibility that measures of exercise pulmonary gas exchange might help to 'describe' underlying PH in heart failure; however, several fundamental issues and questions need to be addressed before such gas exchange measures could truly be considered efficacious measures used to differentiate the type of PH and track the severity of PH in heart failure. exercise intolerance, heart failure, pulmonary gas exchange, pulmonary haemodynamics, pulmonary hypertension.

Heterotopic Cardiac Transplantation: Long-term Results and Fate of the Native Heart

The long-term results of heterotopic cardiac transplantation have not been well defined. Patient survival rates and the fate of the native heart remain unclear. This study is a retrospective review of all 46 heterotopic cardiac transplantations performed at a single institution, the Texas Heart Institute in Houston, Texas, between 1982 and 2017. Four patients who underwent heterotopic transplantation as an emergency procedure for cardiogenic shock were excluded. Three of the procedures were repeat transplantations in patients who had previously undergone heterotopic transplantation; the 3 repeat transplantations were excluded, but the original procedures were not. Follow-up was 100% complete for mortality and 77% complete (30 of 39 patients) for assessment of preoperative indication for surgery and postoperative cardiac function. For the 39 patients, the 1-year, 5-year, and 10-year survival rates were 69%, 36%, and 21%, respectively. One patient remains alive 25 years after the transplantation procedure. The most frequent indication for heterotopic transplantation was pulmonary vascular resistance greater than 4 Wood units (n= 11), followed by weight greater than 112.5 kg (n= 7). In most patients, native heart left ventricular ejection fraction stabilized over time to between 10% and 30%. Sinus rhythm was preserved in 87% (26 of 30) of native hearts at long-term follow-up. Heterotopic cardiac transplantation is an acceptable procedure that should be considered for obese patients (especially those heavier than 112.5 kg) and patients with elevated pulmonary vascular resistance (especially those with pulmonary vascular resistance >4.0 Wood units). After heterotopic transplantation, native cardiac function appears to stabilize, and there is potential for native heart recovery.

Elevated pre-transplant pulmonary vascular resistance is associated with early post-transplant atrial fibrillation and mortality.

AimsSeverely elevated pre‐transplant pulmonary vascular resistance (PVR) has been linked to adverse effects after heart transplantation (HTX). The impact of a moderately increased PVR before HTX on post‐transplant outcomes remains uncertain. The aim of this study was to investigate the effects of an elevated pre‐transplant PVR ≥ 300 dyn·s·cm−5 (≥3.75 Wood units) on outcomes after HTX.Methods and resultsThis observational retrospective single‐centre study included 561 patients receiving HTX at Heidelberg Heart Center between 1989 and 2015. Patients were stratified by degree of pre‐transplant PVR. Analyses covered demographics, post‐transplant medication, mortality and causes of death after HTX, early post‐transplant atrial fibrillation (AF), and length of the initial hospital stay after HTX. Ninety‐four patients (16.8%) had a PVR ≥ 300 dyn·s·cm−5 (≥3.75 Wood units). These patients had a higher rate of early post‐transplant AF [20.2 vs. 10.7%, difference: 9.5%, 95% confidence interval (CI): 0.9–18.1%, P = 0.01] and an increased 30 day post‐transplant mortality (25.5 vs. 6.4%, hazard ratio: 4.4, 95% CI: 2.6–7.6, P < 0.01), along with a higher percentage of death due to transplant failure (21.2 vs. 4.1%, difference: 17.1%, 95% CI: 8.7–25.5%, P < 0.01). Multivariate analysis revealed a PVR ≥ 300 dyn·s·cm−5 (≥3.75 Wood units) as a significant risk factor for increased 30 day mortality after HTX (hazard ratio: 4.4, 95% CI: 2.5–7.6, P < 0.01). Kaplan–Meier estimator showed a lower 2 year survival after HTX (P < 0.01) in patients with a PVR ≥ 300 dyn·s·cm−5 (≥3.75 Wood units).ConclusionsElevated pre‐transplant PVR ≥ 300 dyn·s·cm−5 (≥3.75 Wood units) is associated with early post‐transplant AF and increased mortality after HTX.

Exercise Performance at Increased Altitude After Fontan Operation: Comparison to Normal Controls and Correlation with Cavopulmonary Hemodynamics.

Exercise performance declines as patients who have undergone Fontan operation enter adolescence. However, the effect of altitude on functional capacity after Fontan remains inadequately studied. Our aim was to describe exercise performance in a cohort of patients with Fontan physiology living at increased altitude and compare to a normal control group and relate these data to invasively derived hemodynamics. We hypothesized that peak oxygen consumption ([Formula: see text]) would be decreased, in association with elevated mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVRi). Patients were evaluated in a multidisciplinary clinic for patients with Fontan physiology. Evaluation included cardiopulmonary exercise test and cardiac catheterization at predetermined intervals. Descriptive statistics were calculated. Associations of catheterization and exercise testing measures with [Formula: see text] were estimated with Spearman correlation coefficients. One hundred patients with age- and gender-matched controls were included in the analysis. The mean age was 13.3 ± 3.9years, with mean weight of 47.1 ± 18.4kg. The mean [Formula: see text] was 29.0 ± 7.8ml/kg/min, significantly lower than the control group, 40.2 ± 8.4ml/kg/min (p < 0.0001). There was no statistically significant linear correlation between [Formula: see text] and mPAP or PVRi. We characterized exercise performance in a large cohort with Fontan physiology living at increased altitude and showed a decrease in [Formula: see text] compared to controls. Our data do not support the hypothesis that moderately increased altitude has a detrimental effect on exercise performance, nor is there a substantial link between poor cavopulmonary hemodynamics and exercise in this setting.

Clinical Utility of Echocardiography in Former Preterm Infants with Bronchopulmonary Dysplasia

The clinical utility of echocardiography for the diagnosis of pulmonary vascular disease (PVD) in former preterm infants with bronchopulmonary dysplasia (BPD) is not established. Elevated pulmonary vascular resistance (PVR) rather than pulmonary artery pressure (PAP) is the hallmark of PVD. We evaluated the utility of echocardiography in infants with BPD in diagnosing pulmonary hypertension and PVD (PVR >3 Wood units×m2) assessed by cardiac catheterization. A retrospective single center study of 29 infants born ≤29weeks of gestational age with BPD who underwent cardiac catheterization and echocardiography was performed. PVD was considered present by echocardiography if the tricuspid valve regurgitation jet peak velocity was >2.9m/sec, post-tricuspid valve shunt systolic flow velocity estimated a right ventricular systolic pressure >35mm Hg, or systolic septal flattening was present. The utility (accuracy, sensitivity, and positive predictive value [PPV]) of echocardiography in the diagnosis of PVD was tested. Subgroup analysis in patients without post-tricuspid valve shunts was performed. Echocardiographic estimations of right ventricular pressure, dimensions, function, and pulmonary flow measurements were evaluated for correlation with PVR. The duration between echocardiography and cardiac catheterization was a median of 1day (interquartile range, 1-4days). Accuracy, sensitivity, and PPV of echocardiography in diagnosing PVD were 72%, 90.5%, and 76%, respectively. Accuracy, sensitivity, and PPV increased to 93%, 91.7%, and 100%, respectively, when infants with post-tricuspid valve shunts were excluded. Echocardiography had poor accuracy in estimating the degree of PAP elevation by cardiac catheterization. In infants without post-tricuspid valve shunts, there was moderate to good correlation between indexed PVR and right ventricular myocardial performance index (rho=0.89, P=.005), systolic to diastolic time index (0.84, P<.001), right to left ventricular diameter ratio at end systole (0.66, P=.003), and pulmonary artery acceleration time (0.48, P=.05). Echocardiography performs well in screening for PVD in infants with BPD and may be diagnostic in the absence of a post-tricuspid valve shunt. However, cardiac catheterization is needed to assess the degree of PAP elevation and PVR. The diagnostic utility of echocardiographic measurements that correlate with PVR should be evaluated prospectively in this patient population.

Pathophysiological roles of TRPC6 channels in pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a progressive and lethal disease of the pulmonary artery. The pathogenesis of PAH is mainly sustained vasoconstriction and vascular remodeling of the pulmonary artery. These pathogeneses cause progressive elevations in pulmonary vascular resistance and pulmonary arterial pressure in PAH patients. Elevated pulmonary arterial pressure leads to right heart failure and finally death. The vascular remodeling is caused by the enhanced proliferation and reduced apoptosis of pulmonary arterial smooth muscle cells (PASMCs). Excitable abnormality in the pulmonary artery of PAH patients is mostly mediated by an elevated cytosolic Ca2+ concentration. PASMCs express several Ca2+-permeable channels including voltage-dependent Ca2+ channels, store-operated Ca2+ (SOC) channels, and receptor-operated Ca2+ (ROC) channels. The activation and upregulation of these Ca2+ channels have been reported in PASMCs from PAH patients. Here, we analyzed pathophysiological functions of enhanced Ca2+ signaling mediated by SOC and ROC channels using PASMCs from idiopathic PAH patients and animal PAH models. Notch signal enhanced transient receptor potential canonical 6 (TRPC6) "SOC" channels via direct (non-genomic and stimulatory) and indirect (genomic and upregulating) effects in PAH. On the other hand, the activation of Ca2+-sensing receptors evoked Ca2+ influx through TRPC6 "ROC" channels in PAH. In addition, TRPC6 channel blocker and TRPC6 gene deletion inhibited the development of PAH. Specifically, TRPC6 channels potentially form both ROC and SOC channels in PASMCs, which are involved in the pathophysiological events in PAH. Therefore, targeting TRPC6 channels in PASMCs may help develop novel therapeutic approach for PAH.

Pulmonary hypertension in patients with end stage renal disease undergoing hemodialysis.

Pulmonary hypertension (PH) is a serious cardiovascular complication in patients with end stage renal disease (ESRD) undergoing hemodialysis (HD) via arterio-venous fistulas (AVF). The aim of this study was to assess pulmonary vascular resistance (PVR), AVF flow volume (AVF-FV) and cardiac output (CO) and to highlight the impact of their augmentation, as well as of the duration of HD, on the occurrence of PH in patients with ESRD. Our study group consisted of 51 dialyzed patients, with ESRD, without history of PH. We determined by ultrasonography the systolic pulmonary arterial pressure (PAPs), the left ventricular ejection fraction (EF), the cardiac output (CO), PVR and AVF-FV. We documented PH in 27 (52.94%) patients. All had elevated PVR, higher AVF-FV and CO comparing to patients without PH. They were undergoing HD for a longer period and had lower EF than those without PH. For all patients, we documented strong correlations between PAPs and PVR (r = 0.933, P < 0.001) and the duration of HD (r = 0.702, P < 0.001), but moderate ones with AVF-FV (r = 0.583, P < 0.001) and CO (r = 0.519, P < 0.001). In patients with ESRD undergoing HD, PH was a common finding being associated with increased PVR, a longer duration of HD and chronic glomerulonephritis as etiology for ESRD. The majority of patients with PH had altered left ventricular systolic function, predisposing them to an increased risk to develop heart failure.

Circulating NEDD9 is increased in pulmonary arterial hypertension: A multicenter, retrospective analysis

Pulmonary arterial hypertension (PAH) is a highly morbid disease characterized by elevated pulmonary vascular resistance (PVR) and pathogenic right ventricular remodeling. Endothelial expression of the prometastatic protein NEDD9 is increased in fibrotic PAH arterioles, and NEDD9 inhibition decreases PVR in experimental PAH. We hypothesized that circulating NEDD9 is increased in PAH and informs the clinical profile of patients. Clinical data and plasma samples were analyzed retrospectively for 242 patients from 5 referral centers (2010-2017): PAH (n = 139; female 82%, 58 [48-67] years), non-PAH pulmonary hypertension (PH) (n = 54; female 56%, 63.4 ± 12.2 years), and dyspnea non-PH controls (n = 36; female 75%, 54.2 ± 14.0 years). Compared with controls, NEDD9 was increased in PAH by 1.82-fold (p < 0.0001). Elevated NEDD9 correlated with PVR in idiopathic PAH (ρ = 0.42, p < 0.0001, n = 54), connective tissue disease (CTD)-PAH (ρ = 0.53, p < 0.0001, n = 53), and congenital heart disease-PAH (ρ = 0.68, p < 0.0001, n = 10). In CTD-PAH, NEDD9 correlated with 6-minute walk distance (ρ = -0.35, p = 0.028, n = 39). In contrast to the PAH biomarker N-terminal pro-brain natriuretic peptide (n = 38), NEDD9 correlated inversely with exercise pulmonary artery wedge pressure and more strongly with right ventricular ejection fraction (ρ = -0.41, p = 0.006, n = 45) in a mixed population. The adjusted hazard ratio for lung transplant-free survival was 1.12 (95% confidence interval [CI], 1.02-1.22, p = 0.01) and 1.75 (95% CI, 1.12-2.73, p = 0.01) per 1 ng/ml and 5 ng/ml increase in plasma NEDD9, respectively, by Cox proportional hazard model. In PAH, plasma NEDD9 is increased and associates with key prognostic variables. Prospective studies that include hard end points are warranted to validate NEDD9 as a novel PAH biomarker.

O-GlcNAc Transferase Regulates Angiogenesis in Idiopathic Pulmonary Arterial Hypertension.

Idiopathic pulmonary arterial hypertension (IPAH) is considered a vasculopathy characterized by elevated pulmonary vascular resistance due to vasoconstriction and/or lung remodeling such as plexiform lesions, the hallmark of the PAH, as well as cell proliferation and vascular and angiogenic dysfunction. The serine/threonine hydroxyl-linked N-Acetylglucosamine (O-GlcNAc) transferase (OGT) has been shown to drive pulmonary arterial smooth muscle cell (PASMC) proliferation in IPAH. OGT is a cellular nutrient sensor that is essential in maintaining proper cell function through the regulation of cell signaling, proliferation, and metabolism. The aim of this study was to determine the role of OGT and O-GlcNAc in vascular and angiogenic dysfunction in IPAH. Primary isolated human control and IPAH patient PASMCs and pulmonary arterial endothelial cells (PAECs) were grown in the presence or absence of OGT inhibitors and subjected to biochemical assessments in monolayer cultures and tube formation assays, in vitro vascular sprouting 3D spheroid co-culture models, and de novo vascularization models in NODSCID mice. We showed that knockdown of OGT resulted in reduced vascular endothelial growth factor (VEGF) expression in IPAH primary isolated vascular cells. In addition, specificity protein 1 (SP1), a known stimulator of VEGF expression, was shown to have higher O-GlcNAc levels in IPAH compared to control at physiological (5 mM) and high (25 mM) glucose concentrations, and knockdown resulted in decreased VEGF protein levels. Furthermore, human IPAH PAECs demonstrated a significantly higher degree of capillary tube-like structures and increased length compared to control PAECs. Addition of an OGT inhibitor, OSMI-1, significantly reduced the number of tube-like structures and tube length similar to control levels. Assessment of vascular sprouting from an in vitro 3D spheroid co-culture model using IPAH and control PAEC/PASMCs and an in vivo vascularization model using control and PAEC-embedded collagen implants demonstrated higher vascularization in IPAH compared to control. Blocking OGT activity in these experiments, however, altered the vascular sprouting and de novo vascularization in IPAH similar to control levels when compared to controls. Our findings in this report are the first to describe a role for the OGT/O-GlcNAc axis in modulating VEGF expression and vascularization in IPAH. These findings provide greater insight into the potential role that altered glucose uptake and metabolism may have on the angiogenic process and the development of plexiform lesions. Therefore, we believe that the OGT/O-GlcNAc axis may be a potential therapeutic target for treating the angiogenic dysregulation that is present in IPAH.

The revised definition of pulmonary hypertension: exploring the impact on patient management.

At the 6th World Symposium on Pulmonary Hypertension (PH), it was proposed that the mean pulmonary arterial pressure (mPAP) threshold used to define PH should be lowered from ≥25 mmHg to >20 mmHg. The rationale for this change is that the ≥25 mmHg threshold is arbitrary, whereas the revised threshold is based on scientific evidence. For the definition of all forms of pre-capillary PH, the inclusion of a pulmonary vascular resistance (PVR) ≥3 Wood Units was also proposed, placing greater emphasis on an elevated PVR to identify pulmonary vascular disease. Here, we discuss the possible impact of the revised definition of PH on future clinical management. This change may facilitate earlier PH detection, particularly in at-risk patient groups that are already undergoing screening programmes, e.g. those with systemic sclerosis or mutations associated with PH. As an mPAP above the upper limit of normal (>20 mmHg) but <25 mmHg is associated with increased risk of morbidity and mortality compared with a normal mPAP, early identification of patients in this group is important to enable close monitoring and timely treatment initiation once clinically indicated. Treatments currently approved for PH are not necessarily suitable for patients with an mPAP 21–24 mmHg, as the management of this group has not been widely examined. The revised definition may facilitate inclusion of these patients in prospective trials, allowing the evaluation of appropriate management strategies.

Inhaled Iloprost and Oral Sildenafil Combination Therapy: Is it a Chance for Heart Transplant Candidacy?

Severe pulmonary hypertension is a risk factor for mortality, due to increased postoperative right ventricular failure, in a heart transplant patient. Elevated pulmonary vascular resistance (PVR) in heart transplant candidates can be reduced using a left ventricular assist device or medical therapy. This study analysed the effect of inhaled iloprost and oral sildenafil combination therapy (ilo-sil) on pulmonary haemodynamic parameters in patients with secondary pulmonary hypertension. Between May 2011 and April 2014, 25 patients who were unresponsive to reversibility test and PVR >3.5 Wood units (WU) during right heart catheterisation were included in this study. After 6 months of oral sildenafil (3 × 20 mg/day) and inhaled iloprost (6 × 5 μg/day) combination therapy, second right heart catheterisations were performed and eligibility for heart transplant was evaluated. Repeat right heart catheterisation revealed that there was a significant decrease in the PVR from 5.4± 1.6 WU to 3.54± 2.5 WU (p<0.001), with trans-pulmonary gradient from 13.7± 5.6 to 11.46± 6.64 (p=0.042), and mean cardiac index (CI) increasing non-significantly from 1.45± 0.51 L/min/m2 to 1.82± 0.60 (p=0.157). The mean sPAP was initially 57.54± 14.79 mmHg and fell to 52.93± 16.83 mm Hg (p=0.03). Twenty (20) (80%) patients were enrolled in the waiting list since their PVR values decreased to <3.5 WU. Of these 20 patients, one had undergone heart transplant and four were bridged to transplant with mechanical circulatory support devices. After a decrease in PVR with ilo-sil combination therapy for patients with severe pulmonary hypertension, these patients may become candidates for heart transplant without bearing additional risk. Ilo-sil combination therapy could be a viable option with which to evaluate the reversibility of PVR.

Utilization of inhaled nitric oxide after surgical repair of truncus arteriosus: A multicenter analysis.

Elevated pulmonary vascular resistance (PVR) is common following repair of truncus arteriosus. Inhaled nitric oxide (iNO) is an effective yet costly therapy that is frequently implemented postoperatively to manage elevated PVR. We aimed to describe practice patterns of iNO use in a multicenter cohort of patients who underwent repair of truncus arteriosus, a lesion in which recovery is often complicated by elevated PVR. We also sought to identify patient and center factors that were more commonly associated with the use of iNO in the postoperative period. Retrospective cohort study. 15 tertiary care pediatric referral centers. All infants who underwent definitive repair of truncus arteriosus without aortic arch obstruction between 2009 and 2016. Descriptive statistics were used to demonstrate practice patterns of iNO use. Bivariate comparisons of characteristics of patients who did and did not receive iNO were performed, followed by multivariable mixed logistic regression analysis using backward elimination to identify independent predictors of iNO use. We reviewed 216 patients who met inclusion criteria, of which 102 (46%) received iNO in the postoperative period: 69 (68%) had iNO started in the operating room and 33 (32%) had iNO initiated in the ICU. Median duration of iNO use was 4 days (range: 1-21 days). In multivariable mixed logistic regression analysis, use of deep hypothermic circulatory arrest (odds ratio: 3.2; 95% confidence interval: 1.2, 8.4) and center (analyzed as a random effect, p=.02) were independently associated with iNO use. In this contemporary multicenter study, nearly half of patients who underwent repair of truncus arteriosus received iNO postoperatively. Use of iNO was more dependent on individual center practice rather than patient characteristics. The study suggests a need for collaborative quality initiatives to determine optimal criteria for utilization of this important but expensive therapy.

Pediatric Pulmonary Hypertension on the World Stage: Do We Need Separate Neonatal Guidelines?

Pediatric Pulmonary Hypertension on the World Stage: Do We Need Separate Neonatal Guidelines?

DIAGNOSIS OF PULMONARY VENO-OCCLUSIVE DISEASE BY CRYOBIOPSY

SESSION TITLE: Pulmonary Vascular Disease SESSION TYPE: Fellow Case Reports PRESENTED ON: 10/22/2019 3:45 PM - 4:45 PM INTRODUCTION: Pulmonary capillary hemangiomatosis (PCH) and pulmonary veno-occlusive disease (PVOD) are rare disorders that are characterized by vascular proliferation of alveolar capillaries and pulmonary venules, respectively. Proliferation leads to vessel obstruction, elevated pulmonary vascular resistance and right heart failure. Given their identical clinical course, similar pathologic changes, and shared genetic mutation, they are now considered the same disease. Definitive diagnosis is made histologically. Patients with severe right heart failure are high-risk candidates for surgical lung biopsy, making pathologic confirmation prior to autopsy or explant is rare. Clinical recognition is crucial due to the dismal prognosis and risk for clinical worsening with vasodilators. CASE PRESENTATION: A 76-year-old woman presented to the emergency room with dyspnea. She was previously active until a few weeks prior when she developed shortness of breath, a 5-pound weight gain and new leg edema. She completed treatment for breast cancer several years prior. Her oxygen saturation was 93% breathing ambient air, and her chest X-ray showed vascular congestion. She was admitted for suspected heart failure exacerbation. An echocardiogram showed normal left ventricular systolic function, normal right ventricular systolic function, with an elevated right ventricular systolic pressure at 73 mmHg. A right heart catheterization showed a mean pulmonary artery pressure of 32mmHg, a pulmonary artery occlusion pressure of 5mmHg, with a pulmonary vascular resistance of 4.7 woods units, consistent with pulmonary arterial hypertension. A CT of the chest demonstrated intralobular septal thickening and ground glass opacities, multiple peripheral nodules, and bilateral mediastinal and hilar lymphadenopathy. An endobronchial ultrasound-guided biopsy was planned for her lymph nodes. Because of her pulmonary edema in the setting of pre-capillary pulmonary hypertension in the absence of left heart disease, PVOD was suspected and a cryobiopsy of the lung was also performed. No significant bleeding was noted. Pathology results of her lymph nodes were negative for malignancy, and the cryobiopsy of her lung parenchyma demonstrated septal capillary proliferation consistent with PCH. DISCUSSION: Cryobiopsy a less-invasive alternative to surgical lung biopsy. A larger lung sample with more intact architecture is obtained as compared to traditional transbronchial biopsy. Cryobiopsy has gained attention for diagnosis of interstitial lung disease in patients who are too high-risk to undergo surgery. Our case illustrates the first known case of PCH/PVOD diagnosed by cryobiopsy, and was achieved without significant bleeding. CONCLUSIONS: Diagnosis of patients with suspected PCH/PVOD is crucial to guide management, but they are often unable to undergo surgical lung biopsy for diagnosis. Cryobiopsy may be a safer alternative. Reference #1: Montani D, Lau EM, Dorfmüller P, Girerd B, Jaïs X, Savale L, Perros F, Nossent E, Garcia G, Parent F, Fadel E, Soubrier F, Sitbon O, Simonneau G, Humbert M. Pulmonary Veno-occlusive disease. European Respiratory Journal, May 2016, 47 (5) 1518-1534 DISCLOSURES: No relevant relationships by Isabel Bazan, source=Web Response No relevant relationships by Inderjit Singh, source=Web Response