Pulmonary Circulation

Pediatric pulmonary hypertension (PH) has high morbidity and mortality, with an estimated 5-year survival of 75% regardless of underlying cause. Pediatric PH most commonly affects infants born preterm who develop lung disease of prematurity as well as those with congenital heart disease. Current therapies have been adapted from the treatment of adult PH. One barrier to the study of pediatric PH is the lack of live tissue samples for research. In this manuscript, we describe the methods to obtain pulmonary endothelium from cardiac catheterization of pediatric patients with PH. We adapted methods previously described in adult patients undergoing isolated right heart catheterization to obtain viable pulmonary endothelium from three patients. Primary cells were grown using standard endothelial culture techniques, passaged, and analyzed with immunofluorescence and flow cytometry to confirm cell type. To our knowledge, this is the first published account of pulmonary endothelial culture from pediatric patients.

ELK3 is upregulated in blood and pulmonary vascular cells of PAH patients and may play a significant role in PAH potentially through modulating BMPR2 signaling.

Physical activity (PA) estimated by a wearable sensor may reflect clinical status in pediatric pulmonary hypertension (PH). Prior studies used research-grade hip-anchored sensors or commercial wrist sensors with proprietary scoring algorithms. Wrist sensors offer better acceptability in children, however, their ability to detect associations between PA and clinical characteristics is unknown. Youth 8-18 years with PH [Groups 1-4, functional class (FC) I-II] and healthy controls wore a GENEActiv accelerometer on the non-dominant wrist for 14 days. Raw acceleration data were processed using the open-source GGIR R-package. Participants completed a 6-minute walk distance (6MWD) and quality-of-life questionnaire. Muscle mass and strength were assessed by densitometry and handgrip dynamometry. Most recent cardiac testing was extracted from the medical record. Groups were compared by Fishers exact test, unpaired t-test, or Wilcoxon rank sum test. Multivariate regression models assessed for associations between PA and clinical metrics. Thirty PH participants (median 13.9 years, 57% female, 57% Group 1, 50% FC I) and 29 controls were included. Total PA was similar. PH participants demonstrated fewer and shorter bouts of moderate-to-vigorous PA [≥]10 minutes and more time spent at lower PA intensities. In PH participants, muscle mass was positively associated with PA but 6MWD was negatively associated with PA. PA was not associated with quality-of-life. Within the PH group, worse PA traits were associated with lower FC and worse clinical testing. Wrist sensors reveal deficits in PA traits including reduced moderate-to-vigorous activity bouts and lower intensity gradients in pediatric PH.

IntroductionCardiopulmonary exercise testing (CPET) quantifies exercise limitation and helps differentiate cardiovascular dysfunction from deconditioning in patients with exertional dyspnoea. In mild pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH), traditional CPET oxygen delivery parameters may not adequately distinguish cardiac limitation. We evaluated whether oxygen pulse (O2 pulse) kinetics and the ratio of ventilation-carbon dioxide slope to peak oxygen uptake (VEVCO2/peakVO2) improve identification of cardiovascular limitation and prognostication. MethodsWe retrospectively analysed 289 consecutive patients referred for CPET. Patients were categorised into pre-capillary PH, no PH, or "unclassified" PH based on haemodynamics. O2 pulse slopes were calculated across exercise phases, and qualitative curve patterns were classified. VEVCO2/peakVO2 was derived from standard CPET parameters. Logistic regression assessed predictors of cardiac dysfunction (peak O2 pulse <65% predicted). Survival was evaluated using Kaplan-Meier and Cox regression analyses. ResultsPre-capillary PH patients demonstrated more impaired aerobic capacity and ventilatory efficiency than those without PH. Abnormal O2 pulse patterns (early plateauing or down-sloping) were associated with shallower slopes, lower peak O2 pulse, and greater chronotropic index. A work-phase O2 pulse slope < 0.40 identified impaired oxygen delivery but was not independently predictive in multivariable analysis. VEVCO2/peakVO2 independently predicted cardiac dysfunction (OR 3.9 [2.6-6.2], p < 0.001) and showed strong discrimination (AUC 0.83). VEVCO2/peakVO2 [&ge;] 2.7 independently predicted mortality (HR 13.6, 95% CI 3.8-48.5, p<0.001) outperforming peak O2 pulse and VE/VCO2 slope. ConclusionO2 pulse kinetics, particularly a work-phase slope < 0.40 and plateauing or decreasing trajectories, are associated with cardiac dysfunction in patients with pre-capillary PH. VEVCO2/peakVO2 appears to be a marker of cardiovascular limitation and mortality and may aid differentiation between cardiac dysfunction and deconditioning in this population when conventional CPET parameters are inconclusive.

BackgroundLeft ventricular diastolic dysfunction in chronic thromboembolic pulmonary hypertension is classically attributed to the negative effects of pulmonary hypertension on left ventricular filling. Recent evidence, however, suggests diastolic dysfunction may exist independent of pulmonary hypertension and moreover may be masked by an under-filled left ventricle. MethodsConsecutive patients undergoing pulmonary endarterectomy (2007 - 2018) were included (n=1266). Left ventricular diastolic dysfunction was assessed using pulmonary arterial wedge pressure and in nested cohorts utilising multi-modal cardiac imaging. Diagnostic baseline, outcome data, and long-term mortality outcomes were assessed. Results135 individuals had a wedge pressure >15mmHg following surgery, of whom 60% had a normal wedge pressure pre-operatively. No patients had a formal diagnosis of heart-failure preserved ejection fraction. Haemodynamic, functional and patient-related outcomes were all worse in this patient subgroup and associated with a higher requirement for peri-operative non-invasive ventilation and impaired long-term survival. Post-operative cardiac imaging confirmed evidence of left ventricular diastolic dysfunction in patients with an elevated wedge pressure. Pre-operative left atrial dilatation alone predicted post-operative wedge elevation with accuracy (sensitivity 67%, specificity 100%), and was superior to echocardiography. ConclusionsLeft ventricular diastolic dysfunction is strongly associated with all pulmonary endarterectomy outcome measures, however the majority of patients do not have an elevated wedge pressure pre-operatively and are not diagnosed with heart failure. Standard pre-operative work-up should include assessment for diastolic dysfunction to aid risk categorisation and guide therapy decisions.

BackgroundThe efficacy of balloon pulmonary angioplasty (BPA) for chronic thromboembolic pulmonary disease (CTEPD) with or mild pulmonary hypertension (PH) or without PH remains unknown. Exercise pulmonary hypertension (Ex-PH) is associated with impaired exercise capacity and ventilatory efficiency, even under normalized pulmonary hemodynamics at rest. We hypothesized that patients with Ex-PH and/or hypoxemia would be candidates for BPA. We aimed to verify the prevalence and clinical profiles of Ex-PH and the effect of BPA on oxygenation and Ex-PH in patients with CTEPD with mean pulmonary arterial pressure (mPAP) < 25 mmHg. MethodsWe retrospectively reviewed 29 patients with CTEPD and mPAP < 25 mmHg at rest, who had undergone a cardiopulmonary exercise test with right heart catheterization (median age, 65 years; 38% male). Patients were divided into two groups: Ex-PH, defined as a cardiac output slope (mPAP/CO slope) > 3.0, and non-Ex-PH. ResultsOverall, six patients had mild PH (mPAP: 21-24 mmHg), and 16 and 13 were assigned to the Ex-PH and Non-Ex-PH groups, respectively. There were no significant differences in the clinical parameters, including hemodynamics at rest, blood gas analysis, and 6-minute walk distance, between the Ex-PH and Non-Ex-PH groups. Among the 16 patients with Ex-PH and/or long-term oxygen therapy (LTOT), BPA improved the World Health Organization-functional class (WHO-FC) and PaO2 in association with a decrease in the mPAP/CO slope. All nine patients discontinued LTOT after BPA. No significant complications were observed during each BPA session. ConclusionsEx-PH was common among patients with CTEPD and mPAP < 25 mmHg. BPA can improve symptoms, oxygenation, and exercise hemodynamics in patients with CTEPD and Ex-PH and/or hypoxemia. What is Known?O_LIBPA has been recommended for patients with non-operable CTEPH. C_LIO_LIAlthough there is still a small body of evidence, BPA for patients with CTEPD with mild PH (mPAP < 25 mmHg) or without PH can safely improve symptoms. C_LIO_LIThe prevalence of Ex-PH in CTEPD patients with or without PH is unknown. C_LI What the Study Adds?O_LIApproximately 50% of CTEPD patients with mild PH or without PH had Ex-PH. C_LI In patients with CTEPD with mPAP < 25 mmHg, BPA improves exercising hemodynamics, such as the mPAP/CO slope, which could be a parameter to determine the indication for BPA. O_FIG O_LINKSMALLFIG WIDTH=188 HEIGHT=200 SRC="FIGDIR/small/24303059v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@1332518org.highwire.dtl.DTLVardef@c860d0org.highwire.dtl.DTLVardef@14c0da1org.highwire.dtl.DTLVardef@12ea9f_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract.C_FLOATNO The distribution of exercise pulmonary hypertension (Ex-PH) in patients with chronic thromboembolic pulmonary disease (CTEPD) with mild pulmonary hypertension (PH) or without PH, and efficacy of balloon pulmonary angioplasty (BPA) for CTEPD with Ex-PH and/or hypoxemia. Blue person symbols mean Ex-PH, and white person symbols mean non-Ex-PH. C_FIG

The livers contribution to pulmonary arterial hypertension (PAH) pathogenesis remains unclear. We hypothesized that the liver promotes inflammatory injury to the pulmonary endothelium. PAH patients without liver disease with pulmonary artery endothelial cell (PAEC) biopsies were included. Liver serologies and imaging were analyzed by unsupervised classification and regression tree (CART) to identify subclinical liver dysfunction clusters. Two machine-learning models predicted cluster assignment and informed differential expression. PAEC transcriptomes were compared to liver and lung data from monocrotaline and Sugen-Hypoxia rats. Liver fibrosis was assessed in rat and human PAH livers. Among 25 PAH patients (76% female, median age 61 [30 - 84] years), CART identified clusters distinguished by Model for End-Stage Liver Disease Sodium (MELD-Na) [&ge;]12, predicting higher pulmonary vascular resistance ({beta}=0.5 Wood units per point increase in MELD-Na, 95% CI 0.2-0.8, p=0.005) after adjustment for right atrial pressure. Subjects with MELD-Na [&ge;]12 had decreased 6-minute walk distance (353 [120 - 576] m vs. 411[300 - 600] m, p=0.03), with upregulation of apelin, beta-catenin, and immune signaling. Rat lung ECs demonstrated survival and hepatic growth-factor signaling, while rat livers showed immune activation. Rat (20.8 vs 16.6 % area stained, p=0.09) and human PAH livers revealed fibrosis despite absent right ventricular failure, supporting a pathogenic lung-liver axis in PAH.

Disruption of the pulmonary endothelium by drugs, toxins, viruses (e.g., COVID-19), or bacterial sepsis can cause acute pulmonary vasculopathy leading to pulmonary hypertension and consequential heart failure. CD39 is a membrane-anchored ecto-enzyme expressed on endothelial cells (EC), integral in maintaining the antithrombotic profile of the endothelium. This ecto-enzyme works in concert with CD73 to hydrolyze both eATP (pro-inflammatory) and ADP (pro-thrombotic) ultimately to adenosine, which is anti-inflammatory, vasodilatory, and antithrombotic. CD39 activity and adenosine signalling are disrupted in idiopathic pulmonary arterial hypertension (PAH). In this work, we explored the efficacy of endothelial cell-targeted delivery of CD39 to prevent the development of acute toxin-induced PAH in a mouse model. We generated a novel therapeutic anti-VCAM-CD39 containing an scFv recognising VCAM-1 (a receptor expressed on activated EC) fused to the soluble form of extracellular human CD39. In a mouse model of endothelial cell-toxin-induced PAH, we show that a single administration of anti-VCAM-CD39 (0.4 mg/kg IV) prevented the development of PAH-- as reflected in the preservation of right ventricular systolic pressures and the absence of right ventricular hypertrophy at day 10 when compared with controls. This protection is conferred by multiple mechanisms: IL-10-driven potentiation of heme oxygenase (HO)-1, a known inhibitor of smooth muscle proliferation; VCAM-1 blockade reduces leukocyte adhesion to the endothelium; and cytoprotective effects through adenosine signalling. Thus, anti-VCAM-CD39 is a novel bifunctional therapeutic strategy for PAH.

BackgroundInternational guidelines recommend regular, hospital-based risk stratification to aid assessment and management of patients with pulmonary arterial hypertension. Technological advances enable daily, remote measurement of cardiopulmonary physiology and physical activity that have the potential to provide early evaluation of therapeutic efficacy and facilitate early intervention based on the physiological changes that precede clinical events. We sought to investigate the relationship between remote-monitored parameters and the COMPERA 2.0 4-strata risk score and evaluate physiological changes following therapeutic escalation and prior to clinical worsening events. MethodsEighty-seven patients with pulmonary arterial hypertension were implanted with insertable cardiac monitors including a nested set of twenty-eight patients also implanted with a pulmonary artery pressure monitor. Hospital measured and remote monitored physiological parameters were evaluated by 4-strata COMPERA 2.0 risk score. A time stratified bidirectional case-crossover study was undertaken to evaluate physiological changes at the time of therapy escalation and clinical worsening events in the nested group with insertable cardiac and pulmonary artery pressure monitors. A summary measure of remote physiological risk was calculated as the sum of the z-score of physical activity, heart rate reserve and total pulmonary resistance and applied to remote monitoring data. ResultsInsertable cardiac monitor-measured physical activity, heart rate variability and heart rate reserve were decreased and night heart rate increased in patients with increasing COMPERA 2.0 score (p<0.0001). Daily physical activity was related to incremental shuttle walk distance (p<0.0001) but not six-minute walk distance. Following therapeutic escalation mean pulmonary artery pressure and total pulmonary resistance were reduced and cardiac output, and physical activity increased at 7, 4, 22, and 42 days, respectively (p<0.05). Clinical worsening events were preceded by increased mean pulmonary artery pressure and total pulmonary resistance, reduced cardiac output and physical activity (p<0.05). Applying a remote physiological risk score to remote-monitored data demonstrated that following a clinically indicated increase in therapy, a reduction in physiological risk was identifiable at day three, and preceding a clinical worsening event, an increase in adverse physiology was observable at day - 16. ConclusionApproved devices accurately identify change in physiology in patients with pulmonary arterial hypertension following therapeutic intensification and before clinical worsening. A remote assessment of haemodynamic and cardiac monitoring may facilitate personalised, proactive medicine and innovative clinical study designs. Condensed AbstractTechnological advances provide the capacity to remotely measure cardiopulmonary physiology. In 87 patients with insertable cardiac monitors and a nested group 28 patients with pulmonary arterial hypertension implanted with pulmonary artery pressure monitors, significant improvements in cardiopulmonary function and physical activity were observed following therapeutic escalation and preceding clinical worsening events. The study highlights the potential of remote monitoring for personalised management, early therapeutic evaluation, and innovative clinical trial designs in patients with pulmonary hypertension. Twitter (X) post#PHPEEPS Remote monitoring shows improved cardiopulmonary function just 7 days after therapy adjustments, and adverse changes 12 days before a worsening event. The future of personalised care? Learning pointsPulmonary artery pressure monitor and insertable cardiac monitors offer safe and reliable data capture of physiological risk markers that change in response to therapy and preceding clinical worsening events. Remote monitored measures of physiology differ between patients with low, int-low, int-high and high risk of one-year mortality stratified by COMPERA 2.0 4-strata risk model. Remote risk evaluation may facilitate personalised medicine and proactive management for early evaluation of therapeutic efficacy and detection of clinical worsening. Plain Language SummaryThis study was undertaken in 87 patients diagnosed with pulmonary arterial hypertension (PAH). Treatments in PAH are based on a risk classification system with the aim of achieving a low-risk group. The usual in-hospital method uses the COMPERA 2.0 risk model which combines a field walk test, NT-proBNP (blood test) and World Health Organisation Functional Classification (WHO FC) which categorises level of breathlessness during everyday activity. The evidence for this is linked to risk of death, classified into four groups: low, intermediate-low, intermediate-high, and high risk. The aim of this study was to see whether newer medical technologies could grade risk in a remote setting. The two technologies used in this study are safe and approved for use. The first is a pulmonary artery pressure monitor (CardioMEMS) that measures the pressure in the lungs. It is implanted during right heart catheterisation (RHC). Measurements can be taken at home and sent securely to a medical database for the healthcare team to view. Please see the plain graphical summary figure for more information on the CardioMEMS device. The second technology is an insertable cardiac monitor (ICM), which is implanted under the skin using local anaesthetic, and sends remote readings such as physical activity and heart rate. Both technologies were implanted into a subgroup of patients to investigate whether these technologies could help classify risk from home, and whether they could detect response to new treatments, or signs that a condition may be getting worse. 28 patients with both these devices took part in the study and a further 59 had an ICM only. A remote risk score was calculated using 3 things: physical activity, heart rate reserve (HRR: difference between maximum heart rate for age and resting heart rate) from the ICM and total pulmonary resistance (TPR: a measure of the pressure and flow through the lungs) from the CardioMEMS. The results showed that these measures could classify risk as well as the in-hospital COMPERA 2.0 model. The remote risk score detected response to treatment as early as 6 days and clinical worsening as early as 12 days before an event (e.g. hospitalisation) in the group observed. Patient and Public Involvement and Engagement (PPIE)The study was developed following the 2017 Pulmonary Hypertension Association UK (PHA UK) survey in which 39% of patients reported difficulties attending hospital for appointments.1 A subsequent remote monitoring survey (2021) was positively received, with key themes highlighting benefits of improving [disease] understanding, personalising treatment, and reducing interruptions or unnecessary visits.2 Patients from the study and volunteers from PHA UK provided feedback on the results of the research. Amendments were made to the lay summary and a graphical summary was introduced following this feedback. There was universal agreement that participation in the study was beneficial to patients and future research. Participants involved in the study agreed the devices offer enhanced accessibility to non-invasive risk stratification and improvements in home-based care with minimal personal effort. Furthermore, the minimally invasive devices offered empowerment, confidence, and reassurance, with "opportunity to play an active role in [their] health and personal wellbeing" and "greater confidence with day-to-day living". No incentives were offered for the PPIE in this study. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/23289153v2_ufig1.gif" ALT="Figure 1"> View larger version (79K): org.highwire.dtl.DTLVardef@842d87org.highwire.dtl.DTLVardef@1c90abeorg.highwire.dtl.DTLVardef@1e063bdorg.highwire.dtl.DTLVardef@b41676_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOPlain Graphical Summary:C_FLOATNO CardioMEMS implantation covering frequently asked questions (FAQ). Created with BioRender.com C_FIG

Genome-wide association studies have identified rare and common mutations associated with increased risk of pulmonary arterial hypertension (PAH), but the mechanism by which impaired SOX17 expression increases PAH risk is not known. Notably, SOX17 plays a critical role in endothelial identity during development by suppressing RUNX1 through binding to its promoter and directing stem and progenitor cells toward an endothelial rather than a hematopoietic cell fate. RUNX1 functions as a key regulator of myeloid differentiation, aberrant angiogenesis and adverse cardiac remodeling. Previously, we found that RUNX1 inhibition reverses pulmonary hypertension (PH) in multiple animal models. Here, we hypothesize that impaired expression of SOX17 in PAH leads to endothelial cell (EC) dysfunction by failing to suppress RUNX1. METHODSHuman pulmonary artery endothelial cells (HPAECs) with stable SOX17 CRISPR/Cas9 knockout or RUNX1 overexpression were generated and examined for endothelial and hematopoietic gene expression, proliferation, migration, apoptosis, and angiogenesis. Immortalized lymphoblastoid cell lines (LCLs) from PAH patients with SOX17 mutations and healthy controls were reprogrammed into induced pluripotent stem cells (iPSCs) and differentiated into ECs. The effect of RUNX1 inhibition on Sugen/hypoxia-PH was examined in rats, SOX17 enhancer knockout (SOX17enhKO) mice, and Cdh5-CreERT2;Runx1(flox/flox);SOX17enhKO triple transgenic mice. SOX17 and RUNX1 expression were analyzed in peripheral blood samples from PAH patients (n=359). RESULTSHPAECs with SOX17 deletion or RUNX1 overexpression exhibited decreased expression of EC markers, enhanced proliferation and migration, defective angiogenesis, and decreased apoptosis. RUNX1 siRNA knockdown or RUNX1 inhibition by Ro5-3335 partially restored the endothelial properties in SOX17 KO HPAECs. ECs differentiated from SOX17 mutant PAH patient iPSCs exhibited upregulated RUNX1 expression and loss of endothelial identity, which was also partially restored by RUNX1 siRNA or Ro5-3335. In addition, SOX17enhKO mice had increased RUNX1 expression and susceptibility to Sugen/hypoxia-induced PH (SuHx-PH). Treatment with RUNX1 inhibitors or inducible endothelial-specific deletion of RUNX1 rescued SuHx-PH susceptibility in SOX17enhKO mice. RUNX1 inhibitors Ro5-3335 and Ro24-7429 also reversed SuHx-PH in wild-type rats. In addition, plasma RUNX1 expression was higher in PAH patients lacking detectable SOX17 expression than in patients with detectable SOX17 expression. CONCLUSIONSImpaired SOX17 expression increases the risk of PAH through insufficient suppression of RUNX1, leading to pulmonary endothelial dysfunction. RUNX1 inhibition mitigates PH associated with SOX17 deficiency and may represent a novel therapeutic strategy for PAH, especially those with rare or common SOX17 mutations.

BackgroundPulmonary arterial hypertension (PAH) is a devastating disease caused by loss of effective lung microvasculature for which there is no curative treatment. Evidence from preclinical models and human disease-causing genetic mutations point to endothelial cell (EC) injury and apoptosis as a central trigger for the initiation of PAH. However, how EC apoptosis leads to pulmonary hypertension (PH) and complex arteriolar remodeling is uncertain. MethodsRats were subjected to SU5416-hypoxia (SUHx) and EC apoptosis, pulmonary vascular remodeling and arterial volume was assessed by immunohistochemistry, histology and microCT, respectively. Left pulmonary artery banding (LPAB) was performed, either 1 week before (prevention) or 5 weeks after SU injection (reversal), to study the effect of hemodynamic offloading. ResultsIn the SUHx model, EC apoptosis was markedly increased as early as 3 days post-SU, persisting through PAH development, and this was associated with a profound arterial pruning with reduction in lung arterial volume ([~]80%). LPAB abrogated lung EC apoptosis in the banded left lung and prevented as well as reversed arteriolar pruning. Moreover, in the reversal protocol, removal of the band at 10 weeks resulted in improvement in pulmonary hemodynamics and RV function at 13 weeks. ConclusionThese data demonstrate that perturbed hemodynamic factors triggered by lung microvascular arteriolar loss play a requisite role in perpetuating endothelial injury in experimental PAH, leading to persistent arterial EC injury and disease progression. Importantly, vascular loss, arterial remodeling and PH are reversible once the cycle of perturbed hemodynamics and EC injury is broken by unilateral lung banding.

Surgically accessible lesions of chronic thromboembolic pulmonary hypertension (CTEPH) are classified as proximal or distal based on the distribution of thrombus burden in the pulmonary vasculature post operatively. Surgically accessible distal CTEPH lesions typically has a higher risk profile and worse clinical outcomes in less experienced centers, but the underlying molecular differences between proximal and distal CTEPH lesions remain unknown. Oxylipins, a diverse group of bioactive lipid mediators, have previously been implicated in a range of disorders including pulmonary hypertension. Therefore, we sought to characterize oxylipin profiles among patients with proximal and distal operable CTEPH lesions, as well as those with idiopathic pulmonary arterial hypertension (IPAH). We studied 271 patients with proximal operable CTEPH (n=123), distal operable CTEPH (n=74), or IPAH (n=74). Liquid chromatography-mass spectrometry was used to analyze oxylipin profiles in each patient. We found that patients with distal operable CTEPH had elevated levels of proinflammatory oxylipins while those with proximal CTEPH had an increase in procoagulant oxylipins. Notably, the proinflammatory oxylipins elevated in distal operable CTEPH were similarly elevated in IPAH. These findings suggest that distal operable and proximal CTEPH represent heterogenous disease processes. Furthermore, oxylipin profiles may be useful for potential risk stratification and therapeutic targeting in CTEPH.

AimsPulmonary hypertension (PH) is associated with significant morbidity and mortality and leads to progressive right heart failure. In patients with PAH, haemodynamic parameters measured at catheterisation relate to clinical worsening events, in patients with heart failure proactive pulmonary artery pressure based therapeutic intervention reduces hospitalisation. We therefore investigated use of a novel implanted pulmonary artery (PA) pressure monitor to detect clinically relevant changes in pressure in large animal models of pulmonary hypertension (PH). Methods and ResultsPrototype pulmonary artery pressure sensors (Endotronix) were implanted using standard interventional techniques. Acute PH was induced by infusion of thromboxane A2 in domestic swine. Over a physiological range pressure monitors remained concordant to reference catheter (bias -0.43, 95%CI-5.3-4.4). Chronic PH was induced by i.p. injection of monocrotaline. Implanted pressure sensors demonstrated a gradual rise in PA pressure over 30 days (baseline: 20.7+/-0.4 vrs day-30: 31.74+/-1.4, p<0.01). Pressure sensor derived readings matched reference catheter at baseline and day-30. Pressure sensors remained stable and no adverse events were identified by clinical and histological examination. ConclusionsThe development of PA pressure monitors provide long-term haemodynamic data that identified clinically meaningful changes in pulmonary artery pressure. In addition to proactive heart failure management, such devices may be used to optimise or personalize patient therapy, investigate aspects of physiology and pathology essential to the understanding of disease and provide the opportunity to assess therapeutic interventions in clinical studies.

Group 3 pulmonary hypertension (PH) patients have disproportionate right ventricular dysfunction (RVD) as compared to pulmonary arterial hypertension (PAH) patients, but the cause of the divergent RV phenotypes is unknown. One potential mechanism may be biological sex as females have better RV function than males. However, the combined effects of PH type and sex on RV function are unexplored. Therefore, we evaluated how sex and PH etiology modulated RVD in a single-center cohort study. Male sex was not associated with significant differences in RV function when comparing PH etiologies. However, female Group 3 patients had more pronounced RVD than female PAH patients. In particular, Group 3 females had marked reduction in RV function when pulmonary vascular resistance was matched. Group 3 females were older than PAH females, but the exaggerated RVD was still observed in postmenopausal (age[&ge;]55) Group 3 females. This suggests lung disease exacerbates RVD in Group 3 females.

BackgroundThe relationship between right atrial (RA) structural and functional remodeling and risk of atrial fibrillation/flutter (AF/AFL) in pulmonary arterial hypertension (PAH) is understudied. This is important due to the prognostic implications of AF/AFL in PAH. MethodsIn a multicenter cohort study comprised of 326 PAH patients with no prior history of AF/AFL, we evaluated how RA structure and function, as determined by echocardiography, were associated with AF/AFL. We calculated the incident rate (IR) of AF/AFL using time to event analysis. Cox proportional hazards analyses defined factors associated with incident AF/AFL and Harrells C-statistics compared the ability of different variables to predict incident AF/AFL. Survival decision tree and restricted cubic spline analyses identified thresholds associated with incident AF/AFL. ResultsIn the combined PAH cohort, the mean age was 51{+/-}15 years, 79% were female, and the mean REVEAL lite score was 7.4{+/-}2.9. Over a median follow-up of 6.1 years, 56 patients (17.1%) developed AF/AFL with an IR of 25.3 cases (95% CI: 19.5 - 32.8) per 1000 person-year. On multivariable Cox proportional hazards analysis, every 5% decrease in RA emptying fraction (RAEF, HR: 1.38, 95% CI: 1.03 - 1.86, p=0.030) and one centimeter increase in right ventricular (RV) basal diameter (HR: 1.55 95% CI: 1.18 - 2.05, p=0.002) were independently associated with 38% and 56% increased hazards of incident AF/AFL, respectively. The C-statistics of RAEF and RV basal diameter to predict incident AF/AFL were 0.62 and 0.65, respectively. Survival decision tree and restricted cubic spline analyses identified informative thresholds for RAEF at <17 and 45% and for RV basal diameter at [&ge;]5.4 cm for increased hazards of incident AF/AFL. ConclusionLower RAEF and higher RV basal diameter are associated with increased risk of incident AF/AFL in PAH patients. These data could help identify PAH patients at risk for AF/AFL.

Pulmonary arterial hypertension (PAH) is a progressive condition requiring precise measurement of pulmonary artery pressure (PAP), cardiac output (CO), and exercise capacity for diagnosis and therapeutic evaluation. Terminal digit preference, a form of observer bias favouring values ending in 0 and 5, has been reported in PAH clinical trials, potentially introducing significant measurement error. In the FIT-PH study (NCT04078243), we evaluated whether terminal digit preference occurs in remotely collected cardiopulmonary data from implanted monitors in 35 patients with PAH. Over 18,000 haemodynamic and 34,000 heart rate and activity measurements were analysed. No evidence of terminal digit preference was found in systolic or mean PAP, CO, heart rate, or physical activity. A non-uniform terminal digit distribution in diastolic PAP was observed but attributed to physiological constraints rather than rounding bias. These findings demonstrate that digital remote monitoring minimises observer-related bias, enhancing accuracy in PAH research and clinical care

Pulmonary arterial hypertension is a progressive, fatal disease driven by pathologic vascular remodeling including arterial medial hypertrophy, occlusive neointimal lesion formation, and venous muscularization. Current vasodilatory therapies improve hemodynamics but do not reverse established remodeling. Imatinib mesylate, a tyrosine kinase inhibitor targeting the PDGF-PDGFR signaling axis, has been proposed as an anti-remodeling therapy for pulmonary arterial hypertension and has demonstrated hemodynamic benefit in both preclinical models and clinical trials. However, prior preclinical models lack the neointimal lesions characteristic of human disease, effects on venous remodeling have not been examined, and direct histologic assessment in human trials is precluded by the invasiveness of serial lung biopsy. Here, leveraging the house dust mite mouse model of pulmonary hypertension, which recapitulates medial thickening, neointimal lesion formation, and venous muscularization, we rigorously evaluate the anti-remodeling and hemodynamic effects of imatinib during two defined remodeling stages: neointimal lesion growth and neointimal lesion maintenance. Imatinib treatment significantly reduced right ventricular systolic pressure at both stages. Despite this hemodynamic improvement, quantitative vessel-level analysis of over 1,700 arteries and 1,200 veins revealed no significant effect of imatinib on arterial medial thickness, neointimal lesion growth, neointimal lesion maintenance, or venous muscularization across any vessel size class. These findings dissociate imatinibs hemodynamic benefit from structural vascular remodeling and suggest that imatinib functions primarily as a pulmonary vasodilator rather than an anti-remodeling agent.

BackgroundDiagnosing pulmonary arterial hypertension (PAH) versus pulmonary hypertension associated with left hear disease (PH-LHD) can be challenging in patients with risk factors for both conditions. When resting pulmonary artery wedge pressure (PAWP) is proximate to a threshold of 15mmHg, exercise has been recommended to differentiate pre- versus post-capillary contributions to PH. To improve our understanding of this practice recommendation, we studied relationships between resting PAWP and the balance of pre- and post-capillary contributions to exercise PH. MethodsPatients suspected of PAH (n=29, 72{+/-}2y, 52% F) with risk factors for LHD were prospectively recruited to undergo cycle ergometry at time of diagnostic right-heart catheterization. Hemodynamic data, including pressure-flow slopes and contributions of transpulmonary gradient (TPG) and PAWP to mPAP, were analyzed to evaluate pre- and post-capillary contributions, respectively, at rest and during exercise. ResultsPAWP ranged from 0 to 20 mmHg. Exercise pressure-flow slopes demonstrated 62% with post-capillary PH, and 31% with pre-capillary PH only. The relationship between resting PAWP and the pre- versus post-capillary contributions to exercise PH was not straightforward. Of patients with PAWP<12mmHg, 67% had post-capillary contributions to exercise PH. Conversely, 50% of patients with PAWP>15mmHg had pre-capillary contributions to exercise PH. Exercise-associated increases in pulmonary artery pressures were more strongly associated with pre-capillary contributions regardless of post-capillary contributions or the value of resting PAWP. ConclusionIn this population, post-capillary contributions to exercise PH were commonly disclosed over a range of resting PAWP, including <12mmHg. The severity of exercise PH was determined by the pre-capillary contributions.

This study shows that the long non-coding RNA RGMB-AS1 is upregulated in the blood and pulmonary vascular cells of PAH patient and that it regulates BMPR2 signaling. Inhibiting RGMB-AS1 increases BMPR2 signaling and improves pulmonary vascular cell function.

AimsSeverity assessment for coarctation of the aorta (CoA) is challenging due to concomitant morphological anomalies (complex CoA) and inaccurate Doppler-based indices. Promising diagnostic performance has been reported for the continuous flow pressure gradient (CFPG), but it has not been studied in complex CoA. Our objective was to characterize the effect of complex CoA and associated hemodynamics on CFPG in a clinical cohort. Methods and ResultsRetrospective analysis identified discrete juxtaductal (n=25) and complex CoA (n=43; transverse arch and/or isthmus hypoplasia) patients with arm-leg systolic blood pressure gradients (BPG) within 24 hours of echocardiography for comparison to BPG by conventional Doppler indices (simplified Bernoulli equation and modified forms correcting for proximal kinetic energy and/or recovered pressure). Results were interpreted using the current CoA guideline (BPG [&ge;]20 mmHg) to compare diagnostic performance indicators including receiver operating characteristic curves, sensitivity, specificity, and diagnostic accuracy, among others. Echocardiography Z-scored aortic diameters were applied with computational stimulations from a preclinical CoA model to understand aspects of the CFPG driving performance differences. Diagnostic performance was substantially reduced from discrete to complex CoA for conventional Doppler indices calculated from patient data, and by hypoplasia and/or long segment stenosis in simulations. In contrast, diagnostic indicators for the CFPG only modestly dropped for complex vs discrete CoA. Simulations revealed differences in performance due to inclusion of the Doppler velocity index and diastolic pressure half-time in the CFPG calculation. ConclusionCFPG is less affected by aortic arch anomalies co-existing with CoA when compared to conventional Doppler indices.