Outcomes In Pulmonary Hypertension Research Articles

Implication of heart rhythm complexity in predicting long-term outcomes in pulmonary hypertension

Pulmonary hypertension (PH) is a serious disease, however simple tools to predict outcomes are lacking. In our previous investigation, we found that heart rate variability (HRV) and heart rhythm complexity (HRC) were associated with the detection and severity of PH, however their association with PH mortality remains unclear.The aim of this study was to investigate these metrics as a tool for determining long-term outcomes in PH patients. We enrolled 74 Asian PH patients with WHO PH group 1 or 4 at a single hospital in Taiwan between March 2012 and June 2018. After a median follow-up duration of 58 months (to January 2023), 22 patients had died. The patients who died had a significantly lower lean body mass index (BMI), impaired renal function, higher N-terminal pro B-type natriuretic peptide (NT-proBNP) level, lower very low-frequency (VLF), lower short-term detrended fluctuation analysis α1 (DFAα1), and lower multiscale entropy scale 5 value. In multivariable analysis, BMI, VLF and multiscale entropy scale 5 were significantly associated with survival. The best cut-off VLF and scale 5 values were 115.13 and 0.738, respectively. We then categorized the study population into three groups: both elevated VLF/scale 5 (group 1), either depressed VLF or depressed scale 5 (group 2), and both depressed VLF/scale 5 (group 3). The results showed that group 1 had the best outcomes, whereas group 3 had the worst survival (P < 0.001).Combining HRV and HRC metrics appears to be a good non-invasive tool to predict the long-term outcomes of patients with PH.

Clinical features, hemodynamics, and outcomes of pulmonary hypertension in adults with coarctation of aorta

BackgroundPulmonary hypertension (pH) and secondary right ventricle dysfunction is present in 20 % of adults with coarctation of aorta (COA) based on echocardiographic studies. There are limited data about invasive hemodynamic characterization of PH in COA. The purpose of this study was to delineate the clinical features, hemodynamics, and outcomes of PH in COA. MethodRetrospective cohort study of adults with repaired COA that underwent right heart catheterization (RHC). PH was defined as pulmonary artery (PA) mean pressure > 20 mmHg, and PH was classified as isolated precapillary PH and combined pre/postcapillary PH. ResultsOf 99 COA patients that underwent RHC, 57 (58 %) had PH. Of the patients with PH, 14 (25 %) had isolated precapillary PH while 43 (75 %) had postcapillary PH with or without precapillary disease. The correlates of PH were PA compliance (adjusted OR 0.79, 95 % CI 0.71–0.86 per 1 ml/mmHg), left atrial reservoir strain (adjusted OR 0.95, 95 % CI 0921–0.98 per 1 %), and atrial fibrillation (adjusted OR 2.18, 95 % CI 1.20–13.5). Higher PA mean pressure was associated with risk of cardiovascular events (adjusted HR 1.04, 95 % CI 1.02–1.06 per 1 mmHg) and all-cause mortality (adjusted HR 1.05, 95 % CI 1.02–1.08 per 1 mmHg). ConclusionsPH was present in over half of adults with COA referred for RHC, and one-quarter of the patients with PH presented with isolated precapillary PH suggesting an underlying PA vascular dysfunction as a contributing mechanism. Further studies are required to determine optimal therapies and strategies for prevention and treatment of PH in this population. Clinical summaryOf 99 adults with repaired coarctation of aorta (COA) that underwent right heart catheterization, 57 % had pulmonary hypertension (pH). Of the patients with PH, 25 % had isolated precapillary PH while 75 % had combined pre/postcapillary PH. The correlates of PH were pulmonary artery (PA) compliance, left atrial reservoir strain and atrial fibrillation. PH was associated with cardiovascular events and all-cause mortality. These data suggest PA vascular dysfunction in addition to left-sided heart disease as potential etiologies for PH in this population. Further studies are required to determine optimal therapies and strategies for prevention and treatment of PH in this population.

Asymmetric right ventricular myocardial work correlates with gold standard measurements of cardiac function in pulmonary hypertension.

Right ventricular (RV) (dys)function determines outcomes in pulmonary hypertension (PH). We previously found that asymmetric RV myocardial work (MW) corresponds with inefficient RV function in experimental PH models. We therefore aimed to investigate regional distribution of RV MW and its correlation with catheter hemodynamics in children with PH. RV MW was calculated by longitudinal strain and simultaneous catheter pressure measurements in 14 patients with PH. Wasted MW was defined as the ratio of inappropriate myocardial lengthening to favorable shortening work. Segment-wise and averaged MW and wasted MW were evaluated at baseline and during pulmonary vasodilation therapy with oxygen and nitric oxide, and their relationship to hemodynamic measurements was analyzed. We found that MW was higher for the lateral wall than the septum: 1013 ± 374 mmHg · % versus 532 ± 190 mmHg · % at baseline. Wasted MW ratio did not differ significantly between wall regions. Pulmonary vasodilators slightly reduced mean pulmonary artery pressure and was accompanied by a more symmetrical MW distribution. Averaged MW correlated with the rate of RV pressure development (dP/dt maximum) and decay (dP/dt minimum) at all conditions (p 0.047). The results suggest that MW contribute to, and may be used as a marker of, systolic and diastolic efficiency in the PH RV.

Association of Cardiopulmonary Hemodynamics and Outcomes in Pulmonary Hypertension Following Kidney Transplantation: A Multicenter Retrospective Cohort Study

BackgroundPulmonary Hypertension (PH) frequently complicates the evaluation of kidney transplant (KT) candidates, and is associated with increased adverse outcomes (mortality, delayed graft function (DGF), and major adverse cardiovascular events (MACE)) following KT. Research QuestionWhat is the relationship between cardiopulmonary hemodynamics and post-KT outcomes? Study Design and MethodsWe conducted a multicenter retrospective cohort study of adults undergoing KT between 10/1/11 and 10/1/21, who underwent right heart catheterization (RHC) to assess cardiopulmonary hemodynamics within a year of transplantation. Frailty models and logistic regression models were used to evaluate the association between cardiopulmonary hemodynamics and outcomes (mortality, DGF, MACE) following KT. ResultsA total of 117 patients were included in the final analysis, predominantly male (72%), with a median age of 57 years. PH, defined as mean pulmonary artery pressure (mPAP) > 20mmHg, was present in the majority of the cohort (N=93, 79%). The cohort was followed for a median of 29.9 months post-KT, during which about one-fourth experienced mortality (23%) or DGF (25%) events, and approximately one-third (34%) experienced MACE. Though echocardiographic measures of pulmonary artery pressure failed to identify post-KT outcomes, a mPAP of ≥ 30mmHg on RHC was associated with post-KT MACE (Hazard Ratio 2.60, 95% Confidence Interval [1.10, 6.10]) and more prevalent in those experiencing post-KT mortality (63% vs 32%, p=0.001). Pre-capillary pulmonary hypertension was also associated with post-KT mortality (Hazard Ratio 3.71, 95% Confidence Interval [1.07, 12.90]). InterpretationPre-capillary pulmonary hypertension and a mPAP of ≥ 30mmHg on RHC, but not echocardiographic evidence of PH, was associated with mortality and MACE following KT. These data suggest that RHC hemodynamics are superior to echocardiographic measures of PH in associating with outcomes following KT, and RHC-derived mPAP in particular may have value in predicting MACE and mortality post-KT.

Prevalence, Predictors, and Outcomes of Pulmonary Hypertension in Patients with Lupus Nephritis.

Background and Objectives: This study aimed to assess the prevalence, predictors, and outcomes of pulmonary hypertension (PH) in patients with lupus nephritis (LN). Materials and Methods: Baseline characteristics and clinical outcomes of 387 patients with LN were retrospectively collected from 2007 to 2017. PH was defined as pulmonary artery systolic pressure ≥40 mmHg assessed by resting transthoracic echocardiography. The primary endpoint was all-cause mortality. The secondary endpoint was renal events, defined as the doubling of baseline serum creatinine or end-stage renal disease. Associations between PH and outcomes were analyzed by Cox regression models. Results: A total of 15.3% (59/387) of patients with LN were diagnosed with PH, and the prevalence of PH was higher for patients with an estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 compared to those with an eGFR ≥ 30 mL/min/1.73 m2 (31.5% vs. 12.6%). Higher mean arterial pressure, lower hemoglobin, and lower triglyceride levels were associated with greater odds of having PH. After adjusting for relevant confounding variables, PH was independently associated with a higher risk for death (HR: 2.01; 95% CI: 1.01-4.00; p = 0.047) and renal events (HR: 2.07; 95% CI: 1.04-4.12; p = 0.039). Conclusions: PH is an independent risk factor for all-cause mortality and adverse renal outcomes in patients with LN.

Pulmonary hypertension in the intensive care unit after pediatric allogeneic hematopoietic stem cell transplant: incidence, risk factors, and outcomes.

To determine the incidence, risk factors, and outcomes of pulmonary hypertension (PH) in the pediatric intensive care unit (PICU) after pediatric hematopoietic stem cell transplant (HCT). This was a retrospective study of pediatric patients who underwent allogeneic HCT between January 2008-December 2014 at a center contributing to the Center for International Blood and Marrow Transplant Research data registry. Incidence of PH was assessed from PICU diagnostic codes from records merged from the Virtual Pediatric Systems database. Regression and survival analyses identified factors associated with post-HCT PH. Additional post-HCT morbidities and survival after PH were also assessed. Among 6,995 HCT recipients, there were 29 cases of PH, a cumulative incidence of 0.42% (95% CI 0.27%-0.57%) at 60 months post-HCT. In the sub-cohort of 1,067 patients requiring intensive care after HCT, this accounted for a PH prevalence of 2.72% (95% CI 1.74-3.69%). There was an increased risk of developing PH associated with Black/African American race, metabolic disorders, partially HLA-matched or cord blood allografts, graft-versus-host prophylaxis regimen, and lower pre-HCT functional status. Patients who developed PH had significant PICU comorbidities including heart failure, pulmonary hemorrhage, respiratory failure, renal failure, and infections. Survival at 6 months after diagnosis of post-HCT PH was 51.7% (95% CI 32.5%-67.9%). PH is a rare but serious complication in the pediatric post-HCT population. A significant burden of additional comorbidities, procedural interventions, and risk of mortality is associated with its development. Close monitoring and prompt intervention for this severe complication are necessary in this vulnerable population.

CAMP enriched EVs mediates hypoxic pulmonary hypertension

Our lab reported the novel finding that stimulation of pulmonary endothelial cells with a beta-agonist and a phosphodiesterase inhibitor induced enrichment of cyclic adenosine monophosphate (cAMP) in EVs. cAMP protects the pulmonary vasculature by regulation of permeability, vasoreactivity and proliferation. Extracellular vesicles provide a protected environment for circulating cAMP. Thus, we hypothesized that administration of cAMP, in the protected environment of an EV, could deliver cAMP to improve outcomes in pulmonary hypertension. Briefly, male Sprague Dawley rats, maintained in normoxic or hypoxic conditions for 3 weeks, received 50 ug of cAMP-enriched EVs (cAMP-EVs) per day over 3 days via tail vein injection. cAMP-EV injections improved the Fulton index (non-injected hypoxia rat 0.37 ± 0.039 versus injected hypoxia rat 0.32 ± 0.019, p value 0.032 n = 5) and echocardiography revealed PH rats that received cAMP-EVs had a significant increase in PAAT/PAET ratio compared to those that did not (non-injected hypoxia rat 0.27 ± 0.056 versus injected hypoxia rat 0.32 ± 0.04, p value 0.04, n = 6). Using IVIS analysis of isolated tissues to detect PKH-labeled EVs we found that cAMP-enriched EVs accumulated in the lung but were not detectable in the heart. To confirm this was not strictly a vasoreactivity effect, we also examined PCNA, a marker of proliferation, in histological sections and found it was decreased in the presence of cAMP-EVs. Pulmonary arterial thickness was also significantly improved in the presence of cAMP-EVs. To understand the underlying mechanism for cAMP-EV based signaling, we studied the phosphorylation status of endothelial nitric oxide synthase (eNOS) in isolated paraffn fixed lung slices. We found increased phosphorylation of eNOS in PH rats which received cAMP EVs compared to non-injected PH or control rats. Combined these data suggest that cAMP-EVs may decrease right ventricular hypertrophy, improve pulmonary arterial function, and repair hypoxic vascular injury. Future investigations will determine whether the observed response is cAMP dependent and further evaluate the specificity of pulmonary vascular uptake of cAMP-EVs. 1R01HL133066-01A1 (Bauer). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Maternal and Fetal Outcomes in Pulmonary Hypertension During Pregnancy: A Contemporary Nationwide Analysis

BackgroundPulmonary hypertension (PH) disproportionately affects women, presenting challenges during pregnancy. Historically, patients with PH are advised to avoid pregnancy; however, recent reports have indicated that the incidence of adverse events in pregnant females with PH may be lower than previously reported. MethodsWe conducted a retrospective cohort study in pregnant patients with PH using the National Readmission Database from January 1, 2016, to December 31, 2020. PH was categorized according to the World Health Organization (WHO) classification. Primary endpoints include maternal mortality and 30-day non-elective readmission rate. Other adverse short term maternal (cardiovascular and obstetric) and fetal outcomes were also analyzed. ResultsAmong 9,922,142 pregnant women, 3,532 (0.04%) had pulmonary hypertension (PH), with Group 1 PH noted in 1,833 (51.9%), Group 2 PH in 676 (19.1%), Group 3 PH in 604 (17.1%), Group 4 PH in 23 (0.7%), Group 5 PH in 98 (2.8%), and multifactorial PH in 298 (8.4%). PH patients exhibited higher rates of adverse cardiovascular events (15.7% vs. 0.3% without PH, p < 0.001) and mortality (0.9% vs. 0.01% without PH, p < 0.001). Mixed PH and Group 2 PH had the highest prevalence of adverse cardiovascular events among WHO PH groups. Patients with PH had a significantly higher non-elective 30-day readmission rate (10.4% vs. 2.3%) and maternal adverse obstetric events (24.2% vs. 9.1%) compared to those without PH (p < 0.001) (Figure 1). ConclusionPregnant women with PH had significantly higher adverse event rates, including in-hospital maternal mortality (85-fold), compared to those without PH.

Complexities and Outcomes of Pulmonary Hypertension in Kidney Transplant Patients: A Comprehensive Review

Complexities and Outcomes of Pulmonary Hypertension in Kidney Transplant Patients: A Comprehensive Review

Clinical Profile and Outcome of Pulmonary Hypertension With and Without Interstitial Lung Disease in Scleroderma

Background: Scleroderma associated pulmonary arterial hypertension and interstitial lung disease (ILD) with pulmonary hypertension are considered to be separate pathological processes with different approach to management. In this study, we looked at the demographics, clinical features, and outcome of patients with both type of pulmonary hypertension in systemic sclerosis Methods: Patients diagnosed with scleroderma and with pulmonary hypertension as per transthoracic ECHO in the time period between 2010 and 2023 were retrospectively identified enrolled in the study. They were divided into two groups-isolated PAH and ILD-PH. ECHO parameters, clinical data were recorded Results: There were 800 patients with a diagnosis of systemic sclerosis during this period. In total, 49 incident scleroderma PH cases were identified (6.13%); 25 with diffuse cutaneous SSc (51.02%), 19 with limited cutaneous SSc (38.78%), and 5 with sine scleroderma (10.2%). Among the study group, 39 (79.59%) patients had ILD with PH and 10 (20.4%) had isolated PH (Table 1). Though the baseline ECHO parameters were similar in both the groups, features of severe PH - Right atrial and ventricular dilatation with Right ventricular dysfunction was more in Isolated PH than ILD-PH (50% vs 23%). Other clinical features were similar in both the groups (Table 2). Isolated PH was treated with vasodilatory therapy and all patients with ILD -PAH were treated with immunosuppression along with vasodilatory therapy. Follow up of ECHO parameters of the two groups at the end of 2 years showed better improvement in the ILD-PH group. Unsatisfactory long-term outcome as defined by clinical NYHA progression, hospitalization and need for long term oxygen therapy was similar in both isolated PH and PH-ILD (40% vs 41%). 1 year survival was 95.9% (2/49 lost to follow up). Conclusions: The prevalence of Pulmonary Hypertension in our scleroderma cohort of a tertiary care center was 6.13%. ILD-PH was 4 times more prevalent than isolated PH.46.94% of all our PH patients had it at presentation. The one-year survival of our cohort was 95.9% almost equivalent to other international cohorts

Abstract 15082: Novel Imaging/Hemodynamic Based Right Ventricular Phenotypes in Patients With Pulmonary Hypertension

Introduction: Right ventricular function and ventricular dynamics associate with outcomes in pulmonary hypertension (PH). Measures of RV strain describe ventricular mechanics but are not included in RV function assessments. This study aimed to develop novel RV imaging-hemodynamic phenotypes using unsupervised machine learning. Methods: Participants with cardiac magnetic resonance (CMR) and right heart catheterization data were identified from The Ohio State University CMR PH registry (n=81). RV areas were segmented from CMR 4-chamber images and used to determine RV free wall (RVFW) and septal strain. K-medoids clustering was used on imaging features, RV hemodynamics, and RV function (Figure A). Correlation analysis was used to reduce collinearity. Significance was measured with Kruskal Wallis and chi-squared tests. A p-value &lt; 0.05 was considered significant. Results: Participants were assigned to three clusters and top contributors to cluster assignment were RVEF, RVFW strain, and Ea. RV phenotypes progress from mild/no RV dysfunction (Cluster 1) to severe RV dysfunction (Cluster 3) (Figure A). Cluster 1 had normal RV function with high RVEF and PA compliance, preserved LVEF, low RVSP, and low Eed. Compared to cluster 1, cluster 2 demonstrates more RV dysfunction with reduced RVEF, stroke volume, and PA compliance with an increase in RVSP but no change in Eed. In addition to more RV dysfunction (decreased RVEF and stroke volume), cluster 3 had increased RA pressure and Eed. In terms of RV strain, (Figure B), cluster 2 had less negative RVFW and septal strain compared to cluster 1. In cluster 3, RV septal strain is similar to cluster 2 but with decreased RVFW strain. Conclusions: Imaging and hemodynamic RV variables contribute to identification of novel RV-centric phenotypes and should be included in phenotyping efforts to better describe altered ventricular dynamics contributing to RV dysfunction in PH.

Do Patients With Low-Risk Pulmonary Arterial Hypertension Really Benefit From Upfront Combination Therapy?: Insight From the AMBITION Trial

Based on results of the Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) trial, upfront combination therapy is recommended for treatment-naive patients with low-risk pulmonary arterial hypertension (PAH). However, conflicting data exist whether adopting this treatment strategy in this risk group is beneficial or well tolerated. Do patients with low-risk PAH really benefit from upfront combination therapy? Using the data from the original AMBITION trial, patients with PAH were classified as low, intermediate, or high risk using the Registry to Evaluate Early and Long-term PAH Disease Management 2.0 (REVEAL 2.0) score and the Pulmonary Hypertension Outcomes and Risk Assessment (PHORA) tool. The primary end point was time to clinical worsening (including death, hospitalization for PAH worsening, and disease progression) censored at 1- and 3-year post-enrollment. Side effects that led to withdrawal of treatment were also considered. Patients with low-risk PAH categorized by REVEAL 2.0 and PHORA did not see a statistically significant benefit of upfront combination therapy vsmonotherapy for time to clinical worsening at 1 and 3 years' post-enrollment using Cox proportional analysis (3-year hazard ratio of 0.40 [95%CI, 0.15-1.06; P= .07] and 0.55 [95%CI, 0.26-1.18; P= .12] for REVEAL 2.0 and PHORA, respectively) or considering time to clinical worsening or side effects (3-year hazard ratio of 0.75 [95%CI, 0.39-1.47; P= .4] and 0.87 [95%CI, 0.49-1.54; P= .63] for REVEAL 2.0 and PHORA). Patients with low-risk PAH on upfront combination therapy experienced a higher but not significant incidence of side effects using REVEAL 2.0 and PHORA. In contrast, patients at intermediate or high risk saw a statistically significant benefit of upfront combination therapy considering each of the end points regardless of side effects. This analysis suggests that perhaps some patients with low-risk PAH should be further stratified using other modalities prior to committing to upfront combination therapy, especially when the occurrence of side effects is considered. Further prospective data are needed to validate this hypothesis prior to changes in current guideline directed therapy are contemplated.

Emphysema and interstitial lung disease in systemic sclerosis-related pulmonary hypertension

Pulmonary hypertension (PH) is a major cause of morbidity and mortality among patients with systemic sclerosis (SSc) [ [1] Steen V.D. Medsger T.A. Changes in causes of death in systemic sclerosis, 1972-2002. Ann. Rheum. Dis. 2007 Feb 2; 66 (PMCID: PMC1955114): 940-944 Crossref PubMed Scopus (1174) Google Scholar ]. Patients with SSc-PH and concomitant interstitial lung disease (ILD) have worse clinical outcomes compared to those with SSc-PH, alone [ 2 Chauvelot L. Gamondes D. Berthiller J. Nieves A. Renard S. Catella-Chatron J. Ahmad K. Bertoletti L. Camara B. Gomez E. Launay D. Montani D. Mornex J.F. Prévot G. Sanchez O. Schott A.M. Subtil F. Traclet J. Turquier S. Zeghmar S. Habib G. Reynaud-Gaubert M. Humbert M. Cottin V. Hemodynamic response to treatment and outcomes in pulmonary hypertension associated with interstitial lung disease versus pulmonary arterial hypertension in systemic sclerosis: data from a study identifying prognostic factors in pulmonary hypertension associated with interstitial lung disease. Arthritis Rheumatol Hoboken NJ. 2021 Feb; 73 (PMID: 32892515): 295-304 Google Scholar , 3 Le Pavec J. Girgis R.E. Lechtzin N. Mathai S.C. Launay D. Hummers L.K. Zaiman A. Sitbon O. Simonneau G. Humbert M. Hassoun P.M. Systemic sclerosis-related pulmonary hypertension associated with interstitial lung disease: impact of pulmonary arterial hypertension therapies. Arthritis Rheum. 2011 Aug; 63 (PMID: 21538327): 2456-2464 Crossref PubMed Scopus (102) Google Scholar , 4 Mathai S.C. Hummers L.K. Champion H.C. Wigley F.M. Zaiman A. Hassoun P.M. Girgis R.E. Survival in pulmonary hypertension associated with the scleroderma spectrum of diseases: impact of interstitial lung disease. Arthritis Rheum. 2009 Feb; 60 (PMID: 19180517): 569-577 Crossref PubMed Scopus (208) Google Scholar ]. In patients with increasing ILD severity, as assessed by forced vital capacity (FVC), there is a trend toward increased all-cause mortality [ [5] Sangani R.A. Lui J.K. Gillmeyer K.R. Trojanowski M.A. Bujor A.M. LaValley M.P. Klings E.S. Clinical Characteristics and outcomes in pulmonary manifestations of systemic sclerosis: contribution from pulmonary hypertension and interstitial lung disease severity. Pulm. Circ. 2022 Jul 16; (pul2.12117) Crossref Scopus (0) Google Scholar ]. Common in restrictive lung diseases including ILD [ [5] Sangani R.A. Lui J.K. Gillmeyer K.R. Trojanowski M.A. Bujor A.M. LaValley M.P. Klings E.S. Clinical Characteristics and outcomes in pulmonary manifestations of systemic sclerosis: contribution from pulmonary hypertension and interstitial lung disease severity. Pulm. Circ. 2022 Jul 16; (pul2.12117) Crossref Scopus (0) Google Scholar ], reduced FVC also occur in obstructive lung diseases, including chronic obstructive pulmonary disease (COPD), which can also affect SSc patients. To date, little is known about the impact of concurrent obstructive lung disease in SSc-PH which may both confound FVC on pulmonary function testing (PFT) used as a marker for ILD severity [ [5] Sangani R.A. Lui J.K. Gillmeyer K.R. Trojanowski M.A. Bujor A.M. LaValley M.P. Klings E.S. Clinical Characteristics and outcomes in pulmonary manifestations of systemic sclerosis: contribution from pulmonary hypertension and interstitial lung disease severity. Pulm. Circ. 2022 Jul 16; (pul2.12117) Crossref Scopus (0) Google Scholar ], and its contribution to overall mortality [ [6] Koo B.S. Park K.Y. Lee H.J. Kim H.J. Ahn H.S. Yim S.Y. Jun J.B. Effect of combined pulmonary fibrosis and emphysema on patients with connective tissue diseases and systemic sclerosis: a systematic review and meta-analysis. Arthritis Res. Ther. 2021 Apr 6; 23 (PMCID: PMC8022385): 100 Crossref Scopus (4) Google Scholar , [7] Ariani A. Silva M. Bravi E. Parisi S. Saracco M. De Gennaro F. Caimmi C. Girelli F. De Santis M. Volpe A. Lumetti F. Hax V. Bredemeier M. Alfieri V. Santilli D. Bodini F.C. Lucchini G. Mozzani F. Seletti V. Bacchini E. Arrigoni E. Giuggioli D. Chakr R. Idolazzi L. Bertorelli G. Imberti D. Michieletti E. Paolazzi G. Fusaro E. Chetta A.A. Scirè C.A. Sverzellati N. Overall mortality in combined pulmonary fibrosis and emphysema related to systemic sclerosis. RMD Open. 2019; 5 (PMCID: PMC6397433)e000820 Crossref Scopus (14) Google Scholar ]. Our goal in this study was to characterize the impact of FVC on clinical outcomes in SSc-PH when adjusted for radiologic ILD/emphysema. We hypothesized that FVC decline in any hypoxic lung disease, regardless of etiology, was associated with increased transplant-free, all-cause mortality in SSc-PH.

Elevated Pulmonary Arterial Compliance Is Associated with Survival in Pulmonary Hypertension: Results from a Novel Network Medicine Analysis.

Rationale: Predictors of adverse outcome in pulmonary hypertension (PH) are well established; however, data that inform survival are lacking. Objectives: We aim to identify clinical markers and therapeutic targets that inform the survival in PH. Methods: We included data from patients with elevated mean pulmonary artery pressure (mPAP) diagnosed by right heart catheterization in the U.S. Veterans Affairs system (October 1, 2006-September 30, 2018). Network medicine framework was used to subgroup patients when considering an N of 79 variables per patient. The results informed outcome analyses in the discovery cohort and a sex-balanced validation right heart catheterization cohort from Vanderbilt University (September 24, 1998-December 20, 2013). Measurements and Main Results: From an N of 4,737 complete case patients with mPAP of 19-24 mm Hg, there were 21 distinct subgroups (network modules) (all-cause mortality range = 15.9-61.2% per module). Pulmonary arterial compliance (PAC) drove patient assignment to modules characterized by increased survival. When modeled continuously in patients with mPAP ⩾19 mm Hg (N = 37,744; age, 67.2 yr [range = 61.7-73.8 yr]; 96.7% male; median follow-up time, 1,236 d [range = 570-1,971 d]), the adjusted all-cause mortality hazard ratio was <1.0 beginning at PAC ⩾3.0 ml/mm Hg and decreased progressively to ∼7 ml/mm Hg. A protective association between PAC ⩾3.0 ml/mm Hg and mortality was also observed in the validation cohort (N = 1,514; age, 60.2 yr [range = 49.2-69.1 yr]; 48.0% male; median follow-up time, 2,485 d [range = 671-3,580 d]). The association was strongest in patients with precapillary PH at the time of catheterization, in whom 41% (95% confidence interval, 0.55-0.62; P < 0.001) and 49% (95% confidence interval, 0.38-0.69; P < 0.001) improvements in survival were observed for PAC ⩾3.0 versus <3.0 ml/mm Hg in the discovery and validation cohorts, respectively. Conclusions: These data identify elevated PAC as an important parameter associated with survival in PH. Prospective studies are warranted that consider PAC ⩾3.0 ml/mm Hg as a therapeutic target to achieve through proven interventions.

Functional and molecular determinants of right ventricular response to severe pulmonary hypertension in a large animal model.

Right ventricular (RV) failure is the major determinant of outcome in pulmonary hypertension (PH). Calves exposed to 2-wk hypoxia develop severe PH and unlike rodents, hypoxia-induced PH in this species can lead to right heart failure. We, therefore, sought to examine the molecular and structural changes in the RV in calves with hypoxia-induced PH, hypothesizing that we could identify mechanisms underlying compensated physiological function in the face of developing severe PH. Calves were exposed to 14 days of environmental hypoxia (equivalent to 4,570 m/15,000 ft elevation, n = 29) or ambient normoxia (1,525 m/5,000 ft, n = 25). Cardiopulmonary function was evaluated by right heart catheterization and pressure volume loops. Molecular and cellular determinants of RV remodeling were analyzed by cDNA microarrays, RealTime PCR, proteomics, and immunochemistry. Hypoxic exposure induced robust PH, with increased RV contractile performance and preserved cardiac output, yet evidence of dysregulated RV-pulmonary artery mechanical coupling as seen in advanced disease. Analysis of gene expression revealed cellular processes associated with structural remodeling, cell signaling, and survival. We further identified specific clusters of gene expression associated with 1) hypertrophic gene expression and prosurvival mechanotransduction through YAP-TAZ signaling, 2) extracellular matrix (ECM) remodeling, 3) inflammatory cell activation, and 4) angiogenesis. A potential transcriptomic signature of cardiac fibroblasts in RV remodeling was detected, enriched in functions related to cell movement, tissue differentiation, and angiogenesis. Proteomic and immunohistochemical analysis confirmed RV myocyte hypertrophy, together with localization of ECM remodeling, inflammatory cell activation, and endothelial cell proliferation within the RV interstitium. In conclusion, hypoxia and hemodynamic load initiate coordinated processes of protective and compensatory RV remodeling to withstand the progression of PH.NEW & NOTEWORTHY Using a large animal model and employing a comprehensive approach integrating hemodynamic, transcriptomic, proteomic, and immunohistochemical analyses, we examined the early (2 wk) effects of severe PH on the RV. We observed that RV remodeling during PH progression represents a continuum of transcriptionally driven processes whereby cardiac myocytes, fibroblasts, endothelial cells, and proremodeling macrophages act to coordinately maintain physiological homeostasis and protect myocyte survival during chronic, severe, and progressive pressure overload.

248: EPIDEMIOLOGY AND OUTCOMES OF PULMONARY HYPERTENSION AMONG PATIENTS WITH TAKAYASU ARTERITIS

Introduction: According to a study published in Journal of Rheumatology, the reported prevalence of secondary pulmonary hypertension (PHTN) in patients with takayasu’s arteritis (TA) varies 13.3% to 61.7% with 7 times higher risk of mortality. But the accurate US national data predicting outcomes of PHTN with TA were limited. Aims: Primary aim of our study was to identify national prevalence and outcomes of PHTN amongst patients with TA. Methods: A population-based cross-sectional study was performed in adult US hospitalizations from the nationwide inpatient sample (NIS-2016-2018). We identified patients with TA and sub-grouped into patients with and without PHTN using ICD-10 codes. Univariate analysis was performed using unpaired students’ t-test and chi-square test to identify prevalence, epidemiology, and outcomes of PHTN amongst TA patients. Mix effects multivariate survey logistic regression analyses weighted for variables were performed to identify outcomes (adjusted odds ratio [aOR] and 95% confidence interval [95%CI]) of PTHN amongst TA. p value < 0.05 was considered as significant. Results: Out of 3560 patients with TA, prevalence of PHTN was 6.04%. PHTN patients were older (58 vs 52 years-old) and highly prevalent in age group >75 years (9.3% vs 18-50 years: 3.55%), female (6.82% vs male:2.88%), Native American (40% and Asian:13.51% vs Black:6.19% vs White: 5.57%), and in emergency admissions (7% vs elective:0.89%). (p< 0.0001) Patients with PTHN had a higher frequency of mortality (4.86% vs 2.12%), morbidity (11.49% vs 5.06%), discharge to non-home (55.79% vs 33.22%), disability (81.82% vs 34.91%), and risk of mortality on discharge (69.67% vs 26.11%).(p< 0.0001) In regression analysis, we found TA as an effect modifier to PHTN for increasing odds of disability [aOR 9.10, 95%CI 3.75-22.12, p=0.0274] and risk of mortality [15.26, 6.17-37.70, p< 0.0001]. Conclusions: Poor outcomes and high disability related burden warrants early identification and risk mitigation of secondary pulmonary hypertension amongst patients with takayasu’s arteritis.

Prediction and prognosis of adverse maternal and foetal/neonatal outcomes in pulmonary hypertension: an observational study and nomogram construction

BackgroundPregnant women with pulmonary hypertension (PH) have higher mortality rates and poor foetal/neonatal outcomes. Tools to assess these risk factors are not well established.MethodsPredictive and prognostic nomograms were constructed using data from a “Development” cohort of 420 pregnant patients with PH, recorded between January 2009 and December 2018. Logistic regression analysis established models to predict the probability of adverse maternal and foetal/neonatal events and overall survival by Cox analysis. An independent “Validation” cohort comprised data of 273 consecutive patients assessed from January 2019 until May 2022. Nomogram performance was evaluated internally and implemented with online software to increase the ease of use.ResultsType I respiratory failure, New York Heart Association functional class, N-terminal pro-brain natriuretic peptide ge 1400 ng/L, arrhythmia, and eclampsia with pre-existing hypertension were independent risk factors for maternal mortality or heart failure. Type I respiratory failure, arrhythmia, general anaesthesia for caesarean section, New York Heart Association functional class, and N-terminal pro-brain natriuretic peptide ge 1400 ng/L were independent predictors of pulmonary hypertension survival during pregnancy. For foetal/neonatal adverse clinical events, type I respiratory failure, arrhythmia, general anaesthesia for caesarean section, parity, platelet count, fibrinogen, and left ventricular systolic diameter were important predictors. Nomogram application for the Development and Validation cohorts showed good discrimination and calibration; decision curve analysis demonstrated their clinical utility.ConclusionsThe nomogram and its online software can be used to analyse individual mortality, heart failure risk, overall survival prediction, and adverse foetal/neonatal clinical events, which may be useful to facilitate early intervention and better survival rates.

Abstract 15182: Recruiting Super-Relaxed Myosin to Restore Contractility in Human Right Heart Failure

Intro: Right ventricular (RV) dysfunction worsens outcomes in pulmonary hypertension (PH) due to heart failure with reduced ejection fraction (HF), yet underlying mechanisms are unknown. We previously reported RV myofilament max calcium-activated tension (T max ) is reduced in human PH-HF. Here, we reveal that this decline is due to more myosin heads in the super-relaxed (SRX) state which lack force-production due to low ATP turnover. Methods: Frozen RV myocardium from 25 PH-HF and 9 control patients were permeabilized and myocyte mechanics and small angle X-ray diffraction measured. Results: RV T max (16±4 vs. 23±3 mN/mm 2 , p&lt;1x10 -15 ) and peak power (0.06±0.01 vs. 0.11±0.03, p=7.9x10 -5 ) were 50% lower in HF. Unsupervised machine learning (infinite mixture Dirichlet process) using mechanics identified two HF subgroups distinguished by RV T max : Group 1 with slightly reduced T max (19±1 mN/mm 2 , p=3.8x10 -6 ) and Group 2 with 40% reduced T max (14±3 mN/mm 2 , p&lt;1x10 -15 ), with Group 2 exhibiting clinically overt RV failure vs. Group 1 (right atrial pressure, RAP 14±6 vs. 9±4, p=0.01; RAP/pulmonary capillary wedge ratio 0.7±0.3 vs. 0.4±0.2, p=0.047). To test if low RV T max was associated with more SRX myosin, X-ray diffraction patterns from RV myofibers were used to determine the equatorial intensity ratio (I 1,1 /I 1,0 ), an indicator of myosin proximity to the thick filament backbone. The ratio was lower (more SRX), which was associated with reduced myosin ATP turnover in Group 2 vs. both 1 (p=9.0x10 -7 ) and controls (p=1.8x10 -9 ). We then tested the effect of SRX on T max by perturbing the proportion of SRX myosin using mavacamten (M), a myosin inhibitor that stabilizes the SRX state, and deoxy-ATP (dATP), a nucleotide that destabilizes SRX. In group 2, dATP augmented T max by 30% (p=0.0002) while M had no effect (p=0.1); meanwhile in group 1, M suppressed T max by 30% (p=0.0002) while dATP had no effect (p=0.9). Finally, a myosin activator EMD-57033, which increases probability of actin-myosin binding, augmented T max (correlation between ΔSRX-ΔT max r=-0.55, p=0.01). Conclusion: We find increased SRX myosin contributes to RV myofilament and chamber-level failure in PH-HF. Small molecules that recruit SRX myosin may have therapeutic benefit in patients with RV dysfunction.

Prevalence and survival associated with pulmonary hypertension after mitral valve replacement: National echocardiography database of Australia study.

The specific prevalence and outcome of pulmonary hypertension after mitral valve replacement (MVR) is not well documented. The aim of the study was to determine the prevalence and prognostic impact of pulmonary hypertension after MVR. In addition, we sought to determine the threshold of mortality risk according to echocardiography derived pulmonary pressures and those echocardiographic characteristics that are associated with increased mortality. Using the National Echocardiography Database of Australia, patients who had undergone MVR were identified with estimated right ventricular systolic pressure (eRVSP) assessed and linked to patient mortality during mean follow up of 1917 days. Classification and regression tree analysis was used to identify the most powerful predictors of mortality. A total of 10,994 patients who had undergone echocardiography following MVR (mean age 65.2 ± 16, 44.8% women) were studied (mean follow‐up 1917 days). The prevalence of PH (defined as eRSVP ≥40 mmHg) was 64.1% (7042/10,994). Severe PH (eRVSP ≥60 mmHg) was seen in 42.3% (4671/10,994). Mortality in individuals with PH was greater than amongst individuals without PH (41.1% vs. 26.3%). Age, tricuspid regurgitation and left ventricular dysfunction were also associated with mortality. There is a high prevalence of PH after MVR which confers an adverse prognosis. Improved therapeutic approaches to mitral valve disease and the subsequent development of PH are essential.

The clinical characteristics and outcomes of patients with pulmonary hypertension in association with hyperthyroid state: A systematic review.

Background:Pulmonary hypertension (PHTN) may occur in thyroid disorders, especially in hypothyroidism. However, there is increasing evidence of PHTN in hyperthyroidism (HTH). The etiology, clinical course, management, and factors associated with outcomes of PHTN in the setting of HTH are unascertained. This systematic review consolidates available evidence on patients with HTH who developed PHTN.Methods:We conducted a systematic review on English articles from PubMed, Scopus, and Google Scholar reporting PHTN in patients with hyperthyroidism. Data were analyzed and reported in Microsoft Excel 2020, SPSS version 26, and Jamovi version 1.2.Results:We identified 589 patients with PHTN in the setting of HTH. Etiologies included Grave disease 66.7%), toxic multinodular goiter (TMNG) (16.8%), drug-induced HTH (0.3%), thyroiditis(0.8%), and toxic adenoma(0.1%). Most patients did not receive any specific management for PHTN and were managed by antithyroid treatment (97.4%). Outcomes of PHTN were reported in 181 patients, with a 94% recovery rate. Pulmonary artery pressures (PAP) before and after HTH management ranged from 22.5 to 75 mm Hg and from 24 to 50 mm Hg, respectively. Outcome analysis performed on data from case reports and series with individually identifiable data revealed a 67.6% female preponderance. An estimated 73.5% of the patients had PHTN at the initial presentation of HTH, which was associated with a better resolution rate of PHTN(OR: 12, P-value: 0.048). TRAB was positive in 47% patients with no clinical difference in outcomes. antiTG AB was reported positive in 29.4%, all of whom had an improvement, compared to an 83.3% improvement rate in those with negative antiTG AB. Various etiologies and treatments did not have any significant differences in the outcome of PHTN.Conclusions:PHTN can be present at the initial diagnosis of HTH, which is associated with better outcomes of PHTN. There is a clear female preponderance in the development of PHTN. However, resolution rates seem to be better in males. Although TRAB is associated with the development of PHTN, it does not seem to affect the outcomes. PHTN in patients with HTH does not need any specific management, with >90% resolution with antithyroid therapy. Whether any specific antithyroid therapy has a better outcome in PHTN needs to be explored prospectively.