BACKGROUND:The metabolic mechanisms underlying right ventricular (RV) dysfunction are poorly understood, particularly outside of group 1 pulmonary hypertension (PH). We aimed to identify metabolites and pathways associated with RV systolic function and explored whether associations differed by pulmonary vascular resistance, PH group 1 status, and sex. METHODS:We analyzed data from the multicenter PVDOMICS (Pulmonary Vascular Disease Phenomics) cohort. RV systolic function metrics included fractional area change (echo), global longitudinal strain (echo), and ejection fraction (cardiac magnetic resonance). We used linear regression adjusted for age, sex, body mass index, and PH group to assess associations between metabolites and RV function. Pathway enrichment analyses were used to identify pathways significantly associated with RV function. Interaction terms were assessed to determine whether metabolite associations were modified by pulmonary vascular resistance, group 1 PH status, or sex. Least absolute shrinkage and selection operator regression was used to develop metabolite-based scores for RV function, and prognostic performance was assessed. RESULTS:There were 979 participants with plasma metabolomics and RV function data. Linear regression identified 170 metabolites that were significantly associated with all 3 RV metrics. Androgenic steroid, gamma-glutamyl amino acid, polyamine, vitamin A, fatty acid, and sterol pathways are most strongly associated with RV systolic function. Two metabolites interacted with group 1 PH status, and 6 interacted with pulmonary vascular resistance. Four androgenic steroids are associated more strongly with RV systolic function in women compared with men. Metabolite-based scores were prognostically equivalent to RV systolic function metrics and less accurate than REVEAL Lite 2 scores. CONCLUSIONS:We provide a blueprint of metabolites and metabolic pathways associated with RV systolic function across the spectrum of PH. Novel links to vitamin A and glutathione metabolites were observed. We detected few metabolites that associated with RV systolic function differentially by group 1 PH status or degree of pulmonary vascular resistance elevation. Androgenic steroids may associate more strongly with RV systolic function in women compared with men.

Pulmonary hypertension (PH) is a progressive condition characterized by elevated mean pulmonary arterial pressures (mPAP; mPAP >20mmHg). If left untreated, PH can progress to right heart failure and premature death. While pharmacological treatment is currently the primary means of management, lifestyle interventions are increasingly recognized as helpful adjuvant strategies for PH symptom management. Inspiratory muscle strength training (IMST) has emerged as a potential therapeutic strategy to reduce common PH symptoms such as dyspnea, exercise intolerance, and respiratory muscle weakness. However, no studies have assessed the effects of an IMST intervention on central cardiopulmonary pressures or hemodynamics in PH patients. The purpose of this study was to evaluate the feasibility and effects of four-weeks of IMST (30 resisted efforts, 5 days/week, 50-55% maximal inspiratory pressure [PImax]) in a 41-year-old female patient with severe idiopathic pulmonary arterial hypertension. We hypothesized the training would be well-tolerated and coupled with improvements in invasive cardiopulmonary hemodynamics, respiratory muscle strength (i.e., PImax), and functional capacity. Methods: Invasive cardiopulmonary testing with right heart catheterization (RHC) during rest and hemodynamic provocation (i.e., passive leg raise) was conducted as part of her standard of care five months pre-IMST and again immediately post-IMST. During RHC, we assessed cardiopulmonary pressures, cardiac output (CO) determined via direct Fick, blood oxygen content, and peripheral pulse oximetry. Further, we evaluated PImax, spirometry, grip strength, blood pressure, six-minute walk distance (6MWT) pre- and post IMST. The participant reported daily sleep and physical activity, which were averaged weekly. Results: The participant completed 18 of the 20 prescribed IMST sessions (55% PImax; 48 cmH 2 O) at home with weekly virtual supervision. Post IMST, we noted pre to post reductions in resting mPAP (i.e., 55 vs. 47 mmHg), pulmonary capillary wedge pressure (16 vs. 12 mmHg), right atrial pressure (14 vs. 11 mmHg), and superior vena cava pressure (15 vs. 8 mmHg). We noted similar declines in mPAP during the hemodynamic provocation test (58 vs. 49 mmHg). We report pre-post improvements in pulmonary arterial resting blood oxygen saturation (i.e., SaO 2 , 70 to 77%) and peripheral pulse oximetry (SaO 2 , 89 to 93%). The participant’s inspiratory strength improved post IMST (i.e., -87 to -95 cmH 2 O) as did sleep duration (+1.8 hr/night) and physical activity (+240 min/week). Conversely, we saw no change in cardiac output (5.71 vs 6.02 L/min), systemic blood pressure (105/68 vs. 103/71), spirometry (FEV1/FVC: 75.2 vs. 76.7%), grip strength (Dominant: 27 vs. 28 kg), or performance on the 6MWT (461 vs. 464 m). Conclusion: These preliminary findings highlight improvements in cardiopulmonary pressures during rest and hemodynamic provocation following 4-weeks of time-efficient, moderate intensity IMST. Funding: This research was supported by the National Institutes of Health T32 training grant (T32HL007249) to J.L.M. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

BACKGROUND:Long-term effect of COVID-19 (Long COVID) may persist for months or years after SARS-CoV-2 infection, but longer-term cardiopulmonary manifestations have not been previously reported. OBJECTIVES:The objective of the study was to characterize cardiopulmonary function after SARS-CoV-2 infection in a digital health substudy of the nationwide Researching COVID-19 to Enhance Recovery Adult Cohort Study. METHODS:Associations between wearable sensor device measures of cardiopulmonary fitness and survey-derived Long COVID symptoms were estimated over a 6-month window at least 6 months after infection using linear regression models adjusted for wear time, age, sex, race/ethnicity, and body mass index. RESULTS:Among 1,475 participants (72% female, 65% non-Hispanic White) a median of 21 months (IQR: 15-31 months) after infection, 498 (34%) had high symptom burden as characterized by the Researching COVID-19 to Enhance Recovery Long COVID Research Index (LCRI). High LCRI (vs low LCRI) was associated with significantly lower heart rate variability (-4.4 ms; 95% CI: -6.5 to -2.4; P < 0.001), higher resting heart rate (+1.5 beats/min [+0.7 to +2.4]; P < 0.001), fewer metabolic equivalent of task minutes (-96.3 [-128.8 to -63.8]; P < 0.001), lower step counts (-1,624 steps/day [-1,952 to -1,296]; P < 0.001), and lower activity levels (-7.9 minutes/day very or fairly active [-10.9 to -5.0]; P < 0.001). Hierarchal clustering analysis identified two subphenotypes with abnormal cardiovascular measures associated with low quality of life scores. CONCLUSIONS:Long COVID is associated with worse cardiovascular fitness. Additional studies are needed to determine if Long COVID is a novel risk factor for incident cardiovascular disease.

Background:Pulmonary arterial hypertension (PAH) is characterized by circulating metabolic alterations, but whether these reflect disease-specific metabolic programs or reorganization of normal metabolic architecture, and how they relate to right ventricular-pulmonary vascular function (RV-PV), remains unclear. We hypothesized that the PAH metabolome is organized into biologically coherent, co-regulated metabolic modules whose relationships to RV-PV function would provide insight into known and novel metabolic pathways. Methods:We applied weighted gene co-expression network analysis (WGCNA) to untargeted metabolomic data from 412 PAH patients enrolled in the multicenter PVDOMICS study. Module preservation analysis was performed in 85 healthy controls, with external replication in an independent single-center pulmonary hypertension cohort of 89 patients. Results:WGCNA identified 16 distinct metabolic modules organized around biologically coherent programs. A coherent fatty acid axis, spanning substrate pools, β-oxidation intermediates, and conjugated fatty acid disposal products, formed a central organizing structure, with downstream fatty acid oxidation modules strongly associated with adverse hemodynamics and worse RV-pulmonary artery (PA) coupling. Acylcholine-enriched and 5α-reduced androgen metabolite modules were associated with favorable hemodynamic indices. Module architecture was largely preserved in healthy controls, with subtle disease-associated modular reorganization, rather than emergence of novel modules, observed in PAH. Core modules were recovered in the replication cohort with conserved hub metabolites. Conclusions:These findings establish a systems-level framework demonstrating that PAH involves structured intensification and reorganization of interconnected metabolic programs associated with favorable and adverse RV-PV phenotypes. This work provides new insight into the metabolic architecture underlying PAH and identifies coordinated metabolic pathways linked to pulmonary vascular and right ventricular function.

BACKGROUND:Some symptomatic patients manifest pulmonary hypertension (PH), despite normal pulmonary vascular resistance and pulmonary artery wedge pressure-a condition termed unclassified PH. Although hypothesized to reflect increased flow as seen in congenital heart disease, broader clinical implications remain unknown. METHODS:The current analysis included pulmonary vascular disease phenomics participants with either no PH or unclassified PH who underwent dynamic right heart catheterization and transpulmonary metabolomics. In a validation cohort, patients with no PH or unclassified PH underwent exercise right heart catheterization. In exploratory cohorts to understand the impact of increased flow, the prevalence of unclassified PH was assessed in (1) adult congenital heart disease and (2) high output heart failure. RESULTS:The overall prevalence of unclassified PH in pulmonary vascular disease phenomics (n=1046) and the validation cohort (n=1202) was 7.8% (175/2248), which was comparable to the 6.6% (66/1005) prevalence in adult congenital heart disease (n=1005), and lower than high output heart failure (n=159, prevalence 14.5% [23/159]; P=0.006). Increased flow occurred in a minority of unclassified PH from both pulmonary vascular disease phenomics (28%; 15/53) and the validation cohort (11%; 13/122). Unclassified PH (n=53) was associated with greater adiposity, higher heart failure with preserved ejection fraction (HFpEF)-age, body mass index, atrial fibrillation score probability, and more left heart remodeling compared with those with no PH (n=216). Metabolomics revealed lower glycine metabolites in unclassified PH indicative of metabolic dysfunction. Left heart remodeling, quality of life, exercise capacity, and glycine levels were all abnormal in unclassified PH relative to healthy controls (n=96). In the validation cohort, pulmonary artery wedge pressure, pulmonary vascular resistance, and pulmonary artery compliance were subtly abnormal at rest in unclassified PH (n=122) compared with no PH (n=312). With exercise testing, 59% (72/122) with unclassified PH had exertional pulmonary artery wedge pressure elevation consistent with undiagnosed HFpEF. CONCLUSIONS:The presence of PH without obvious cause most often reflects subclinical left heart and metabolic dysfunction consistent with unrecognized early-stage HFpEF. Dynamic provocation during right heart catheterization can unmask unrecognized HFpEF in over half of unclassified PH, which may help guide appropriate initiation of proven HFpEF therapies to improve symptoms and functional status. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT02980887.

BACKGROUND:With pulmonary hypertension (PH), a pulmonary artery wedge pressure (PAWP)>15 mm Hg is used to diagnose left heart dysfunction, but some patients with adjudicated group 1 PH demonstrate PAWP>15 mm Hg. The primary objective of the study was to evaluate group 1 PH with high PAWP>15 mm Hg. METHODS:Patients with adjudicated group 1 PH from PVDOMICS between 2016 and 2019 were separated into high PAWP(>15 mm Hg) or normal PAWP and compared with adjudicated combined pre- and postcapillary (Cpc) PH related to heart failure with preserved ejection fraction (HFpEF). Participants underwent dynamic right heart catheterization and metabolomics. Findings were validated in 3 independent cohorts with adjudicated group 1 PH (validation cohorts 1 and 2 with exercise right heart catheterization and validation cohort 3 with resting right heart catheterization). RESULTS:Of 325 patients with group 1 PH (73% women, mean age 53.0±14.3 years), 15% (n=48) had high PAWP. Group 1 PH+high PAWP demonstrated greater obesity, left ventricular hypertrophy (P<0.0002), left ventricular strain impairment (P<0.0001), and decreased left ventricular compliance (P<0.0001) compared with group 1 PH+normal PAWP, with changes comparable to Cpc-PH HFpEF (n=75). Compared with Cpc-PH HFpEF, left atrial function was better in group 1 PH+high PAWP with lower PAWP V wave, higher left atrial compliance, and left atrial ejection fraction (P<0.0001 for all). Metabolomics demonstrated little difference between group 1 PH with high versus normal PAWP but large differences between group 1 PH+high PAWP versus Cpc-PH HFpEF (100 metabolites altered at false discovery rate P<0.05). Elevated PAWP was also observed in 18% of group 1 PH in the validation cohort 1 (n=402), with exercise PAWP response intermediately abnormal in group 1 PH+high PAWP relative to Cpc-PH HFpEF and group 1 PH+normal PAWP (interaction P<0.0001). Elevated PAWP was similarly observed in 22% and 19% of group 1 PH in validation cohorts 2 (n=55) and 3 (n=787), respectively. CONCLUSIONS:Approximately 1 in 5 adjudicated patients with group 1 PH has elevation in resting PAWP despite severe pulmonary vascular dysfunction and metabolomics consistent with traditionally defined group 1 PH. Despite resting PAWP elevation, these patients with group 1 PH were metabolomically and biologically distinct from Cpc PH HFpEF, with better left atrial function and diastolic reserve during exercise. These data emphasize the limitations of using resting PAWP alone to separate group 1 PH from HFpEF and call for development of more integrated clinical diagnostic criteria.

Background:World Symposium on Pulmonary Hypertension (WSPH) Group 2 pulmonary hypertension (PH) is a clinically integrated phenotype attributed to left heart disease, whereas pre- versus post-capillary classification is operationalized primarily by pulmonary capillary wedge pressure (PCWP). Although current recommendations emphasize contextual interpretation and provocative testing for intermediate PCWP values, the relationship between PCWP-based classification and underlying phenotype has not been systematically evaluated. We aim to quantify phenotype-hemodynamic discordance across the PCWP spectrum and evaluate a staged physiology-guided framework incorporating inhaled nitric oxide (iNO), ventricular geometry, and provocative testing. Methods:We studied 1,032 participants from the NHLBI-sponsored PVDOMICS cohort with multidisciplinary adjudicated phenotypes integrating clinical, imaging, physiologic, and hemodynamic data. Stage-specific PCWP thresholds classified pre- versus post-capillary physiology at rest, during iNO, and during provocation (fluid challenge or invasive cardiopulmonary exercise testing [iCPET]). Echocardiographic right ventricular-to-left ventricular (RV/LV) ratio was evaluated as a marker of ventricular interdependence. Restricted cubic spline and staged concordance analyses defined certainty-based PCWP ranges and incremental diagnostic yield. Results:Adjudicated Group 2 PH was present in 37.0% of participants. Resting PCWP demonstrated good discrimination (AUC 0.86), but substantial bidirectional phenotype-hemodynamic discordance persisted across intermediate PCWP ranges. At a resting PCWP of 12 mmHg, 25% of participants classified as pre-capillary had adjudicated Group 2 PH, whereas at 18 mmHg, 35% classified as post-capillary remained discordant non-Group 2. Concordance did not approach 90% until PCWP values were <9 mmHg or >24 mmHg. Dynamic testing incrementally improved concordance within these overlap zones. Nearly half of adjudicated Group 2 PH participants (46.5%) were not identified by resting PCWP alone; incorporation of iNO and provocative testing increased cumulative Group 2 identification by 63.4% and improved sensitivity from 79.9% to 83.7%. Model discrimination improved from an AUC of 0.863 to 0.908 (likelihood-ratio P<0.001). iNO increased PCWP in discordant Pre/G2 participants, unmasking latent left-sided limitation, while lowering PCWP in discordant Post/NonG2 participants, consistent with ventricular interdependence. RV/LV ratio ≥0.94 reduced discordant Post/NonG2 classification by 70.5%, and incorporation of PCWP/cardiac output slope improved physiologic specificity during exercise. Conclusions:Group 2 PH is a dynamic, load-dependent phenotype inadequately characterized by resting PCWP alone. Intermediate PCWP values represent continuous probabilities of bidirectional discordance rather than discrete diagnostic states. A staged physiology-guided approach integrating iNO, ventricular geometry, and provocative testing improves concordance between hemodynamic classification and clinically integrated phenotype assignment. Clinical Perspective:What Is New?: In the deeply phenotyped PVDOMICS cohort, resting pulmonary capillary wedge pressure demonstrated good overall discrimination for adjudicated Group 2 (left heart disease) pulmonary hypertension, yet intermediate values frequently either concealed latent left-heart disease or overclassified patients without intrinsic left-heart diseaseResting pulmonary capillary wedge pressure should be viewed as a continuous probability signal rather than a binary threshold, allowing additional physiologic testing to be targeted according to the degree of diagnostic uncertainty a clinician is willing to accept.A staged physiology-guided approach incorporating inhaled nitric oxide, ventricular geometry, and provocative testing improved concordance with adjudicated PH category and pre or post-capillary classification.What Are the Clinical Implications?: Pre- versus post-capillary classification should be interpreted within the broader clinical and physiologic context rather than relying on a single resting pulmonary capillary wedge pressure threshold.Intermediate pulmonary capillary wedge pressure values should prompt consideration of additional physiologic evaluation, with inhaled nitric oxide providing a practical intermediate step and provocative testing providing the greatest incremental diagnostic yield.Exercise pulmonary capillary wedge pressure/cardiac output slope and markers of ventricular interdependence may provide complementary information for resolving uncertainty when resting and dynamic hemodynamics are discordant.

INTRODUCTION/BACKGROUND:Oral imatinib, a tyrosine kinase inhibitor, demonstrated efficacy in pulmonary arterial hypertension (PAH) studies but was poorly tolerated. We report here the findings of a study using a dry powder inhaled version of imatinib (AV-101). AIMS AND OBJECTIVES:IMPAHCT (NCT05036135) was designed to assess the efficacy, safety, tolerability, and optimal dose of AV-101 as an add-on treatment for PAH, using a novel phase 2b/3 adaptive study design. Here we report the phase 2b results. METHODS:The phase 2b part assessed 3 doses of AV-101 (10 mg, 35 mg, and 70 mg), administered twice a day, vs placebo for 24 weeks as an add-on treatment in adults with PAH. Change in pulmonary vascular resistance (PVR) was the primary endpoint. Secondary endpoints included the change in other hemodynamic variables, 6-minute walk distance (6MWD), World Health Organization functional class, Registry to Evaluate Early and Long-Term PAH Disease Management Lite 2 risk score, clinical worsening, clinical improvement, N-terminal proB-type natriuretic peptide, quality of life, safety, and tolerability. RESULTS:In total, 202 patients were randomized. Baseline characteristics were broadly well balanced between groups. There were no significant improvements vs placebo in PVR (42.8 dyn·s·cm-5 in the AV-101 10-mg group, -5.5 dyn·s·cm-5 in the AV-101 35-mg group, -57.0 dyn·s·cm-5 in the AV-101 70-mg group, and 19.5 dyn·s·cm-5 in the placebo group), 6MWD, or other secondary endpoints at any dose. Pharmacokinetic measures supported delivery of drug to the lung and into the plasma. The incidence of cough increased with dose. No safety concerns were identified. CONCLUSIONS:Add-on dry powder inhaled imatinib (AV-101) was not effective in lowering PVR at any of the studied doses in patients with PAH. The phase 3 part of the IMPAHCT study was halted.

BACKGROUND:Pulmonary vasodilators increase cardiac output (CO) in group 1 pulmonary hypertension (PH) and can cause high CO with unclear implications. Our objective was to describe the pathophysiology of high CO in group 1 PH. METHODS:Clinical characteristics were compared among PVDOMICS group 1 PH participants by low (cardiac index (CI) <2.2 L·min-1·m-2), normal or high output (CO ≥8 L·min-1 or CI ≥4 L·min-1·m-2). RESULTS:Of 449 group 1 PH participants, 23% (n=103) had low output, 68% (n=304) had normal CO and 9% (n=42) had high output. Increasing CO was associated with more intensive vasodilator use (triple therapy 11% versus 19% versus 33%, respectively; p=0.0008), with progressively lower pulmonary vascular resistance (p<0.0001). High output was associated with the lowest systemic vascular resistance (p<0.0001), with greater left ventricular (LV) and left atrial enlargement (p<0.001 for all). High flow resulted in an increase in LV and right ventricular (RV) work at rest, and absolute/relative RV work during exercise (p<0.0001 for all). Despite greater exercise oxygen delivery (p<0.0001), peripheral oxygen utilisation was impaired by oxygen extraction ratio (p=0.001) and arteriovenous oxygen difference (p=0.005), without incremental functional or survival benefit compared to normal output PH. After adjusting for baseline risk, high output had increased risk of death/transplantation compared to normal output (adjusted hazard ratio 2.1, 95% CI 1.2-3.7; p=0.007). In a validation cohort (n=37), 93% had normal CO at diagnosis, with the high output state developing in follow-up after vasodilator initiation. CONCLUSIONS:Around one in 10 patients with group 1 PH has a high output state, which is most common in prevalent PH and related to vasodilator intensity, with adverse cardiac remodelling and myocardial workload. Further studies are needed to determine optimal vasodilator dosing with high output and therapeutic interaction with vasodilator-sparing therapies such as sotatercept.

There is a limited understanding of how pulmonary hypertension (PH) patients are managed worldwide. The Pulmonary Vascular Research Institute (PVRI) Innovative Drug Discovery Initiative (IDDI) global survey attempted to obtain insights into access to PH care in diverse international regions to pave future action plans. Responses from 151 centers (19.9% from Europe, 3.9% Middle East, 6% South Asia, 17.9% East Asia, 2% Sub-Saharan Africa, 31.8% Latin America, and 18.5% North America) were received. Most respondents had access to electrocardiography, echocardiography, and right heart catheterization but less availability to pulmonary function tests, ventilation/perfusion scans, and genetic testing. Phosphodiesterase type 5 (PDE-5) inhibitors were available in almost all centers but there was limited access to oral, inhaled, and parenteral prostacyclin therapy, riociguat, and selexipag. Cluster analysis of middle-high- and high income countries demonstrated significant variability in PH care delivery and disparities in therapeutic resources across the three clusters. The most common limitations identified that contribute to delayed PH diagnosis were insufficient financial resources, insufficient staff, and limited time. Survey respondents requested access to webinars with content experts (45%), access to content experts for consultation and review of complex cases via video chat (55%), resources to attend a conference (67.5%), and provision of a mentorship program (33.1%) along with greater availability of medications, remote conference access, clinical trial availability, and increased advocacy for patients. Survey results suggest significant disparities across the globe. Further research is needed to understand access to PH care and therapies in non-expert/academic centers and regional disparities within countries.

Introduction: PH increases RV afterload, often leading to RV systolic and diastolic failure. The metabolic mechanisms underlying RV dysfunction remain poorly understood and are largely unexplored across non-PAH forms of PH. Aims: We aimed to identify which metabolites and metabolic pathways associated with imaging measures of RV systolic function. Methods: We analyzed data from the multi-center PVDOMICS cohort, which includes echo, CMR, invasive hemodynamics, clinical phenotyping, and untargeted plasma metabolomics (via Metabolon). RV systolic function metrics selected as the outcome measures for this study were fractional area change (echo), global longitudinal strain (echo), and RVEF (CMR). Associations between non-xenobiotic, named metabolites and RV function measures were assessed using linear regression adjusted for age, sex, BMI, and PH group, with significance defined by FDR <0.05. Metabolite set enrichment analysis (MSEA) was performed to identify significantly enriched pathways (FDR <0.20). To complement MSEA, we conducted mean-aggregation analysis: we averaged metabolite concentrations within each pathway and tested associations with RV function using the same covariate adjustments (FDR <0.05). Results: We identified 979 participants with plasma metabolomics and at least one available outcome measure (317 Group 1 PH; 106 Group 2 PH; 140 Group 3 PH; 51 Group 4 PH; 26 Group 5 PH; 81 Healthy Controls; 258 Disease Comparators). Linear regression identified 170 metabolites from the 647 named metabolites significantly associated with all 3 RV metrics (Top 10 by average ranked p-value displayed in Image 1 ). MSEA revealed seven enriched pathways across all RV metrics: Androgenic Steroids, Pregnenolone Steroids, Progestin Steroids, Fatty Acid Metabolism (Acyl Choline), Histidine metabolism, Vitamin A metabolism, Gamma-glutamyl Amino Acid ( Image 2) . Mean aggregation analysis showed that higher concentrations of Androgenic/Pregnenolone Steroids and Vitamin A metabolites strongly associated with improved RV function, while higher levels of Fatty Acid Metabolism (Acyl Carnitine) and Acetylated Peptides associated with worse function ( Image 3 ). Conclusions: Using data from the multi-institutional PVDOMICS cohort, we provide a blueprint of metabolites and metabolic pathways associated with RV systolic function across the spectrum of PH. Steroid hormones as well as Vitamin A and fatty acid metabolites emerged as central to RV systolic function.