Transcriptional profiles of pulmonary artery endothelial cells in pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is characterized by endothelial cell (EC) dysfunction. There are no data from living patients to inform whether differential gene expression of pulmonary artery ECs (PAECs) can discern disease subtypes, progression and pathogenesis. We aimed to further validate our previously described method to propagate ECs from right heart catheter (RHC) balloon tips and to perform additional PAEC phenotyping. We performed bulk RNA sequencing of PAECs from RHC balloons. Using unsupervised dimensionality reduction and clustering we compared transcriptional signatures from PAH to controls and other forms of pulmonary hypertension. Select PAEC samples underwent single cell and population growth characterization and anoikis quantification. Fifty-four specimens were analyzed from 49 subjects. The transcriptome appeared stable over limited passages. Six genes involved in sex steroid signaling, metabolism, and oncogenesis were significantly upregulated in PAH subjects as compared to controls. Genes regulating BMP and Wnt signaling, oxidative stress and cellular metabolism were differentially expressed in PAH subjects. Changes in gene expression tracked with clinical events in PAH subjects with serial samples over time. Functional assays demonstrated enhanced replication competency and anoikis resistance. Our findings recapitulate fundamental biological processes of PAH and provide new evidence of a cancer-like phenotype in ECs from the central vasculature of PAH patients. This "cell biopsy" method may provide insight into patient and lung EC heterogeneity to advance precision medicine approaches in PAH.

Effects of COVID-19 pandemic on the management of pulmonary hypertension.

The coronavirus of 2019 (COVID-19) disrupted delivery of healthcare. Patients with pulmonary hypertension (PH), especially pulmonary arterial hypertension (PAH), require significant resources for both diagnosis and management and are at high risk for decompensation due to disruption in their care. A survey consisting of 47 questions related to the care of patients with PH was designed by the American College of Chest Physicians 2020-2021 Pulmonary Vascular Disease (PVD) NetWork Steering Committee and sent to all members of the PVD NetWork, as well as the multiple other professional networks for PH. Participation was voluntary and anonymous. Responses were collected from November 2020 through February 2021. Ninety-five providers responded to this survey. The majority (93%) believe that care of PH patients has been affected by the pandemic. Sixty-seven percent observed decreased referrals for PH evaluation. Prior to the pandemic, only 15% used telemedicine for management of PH patients compared to 84% during the pandemic. Telemedicine was used most for follow up of selected low-risk patients (49%). While 22% respondents were completely willing to prescribe new PAH therapy via telemedicine, 11% respondents were completely unwilling. Comfort levels differed based on type of medication being prescribed. Over 90% of providers experienced disruptions in obtaining testing and 31% experienced disruptions in renewal or approval of medications. Overall, providers perceived that the COVID-19 pandemic caused significant disruption of care for PH patients. Telemedicine utilization increased but was used mostly in low-risk patients. Some providers had a decreased level of comfort prescribing PAH therapy via telemedicine encounters.

Utilization of risk assessment tools in management of PAH: A PAH provider survey.

Pulmonary arterial hypertension (PAH) is a chronically progressive fatal disease. A goal-oriented approach to achieve low risk status has been associated with improved survival. A variety of risk stratification tools are available, but use is low. We conducted a survey to assess potential reasons for under-utilization. We conducted a survey-based study of global PAH disease specialists with a goal of assessing risk assessment utilization and identifying modifiable barriers to use. The survey was designed by the American College of Chest Physicians' Pulmonary Vascular Diseases (PVD) NetWork. Respondents were global members of the PVD NetWork and Pulmonary Hypertension Association. Survey invitations were sent electronically to all members. Participation was anonymous and no provider or patient level data was collected. Participants from four countries responded with the majority (84%) being from the United States. Our survey found suboptimal use of any risk stratification tool with 71/112 (63%) reporting use. A total of 85% of the respondents had more than 5 years of experience in managing PAH. REVEAL 2.0 and European Society of Cardiology/European Respiratory Society risk tools were the most commonly used. A total of 44 (65%) surveyed felt that use of risk tools led to change in PAH therapies. Only 6 (9%) felt they prompted additional testing or changed the frequency of follow-up. A total of 5 (7%) reported they prompted goals of care/palliative care discussions and 2 (3%) that they triggered lung transplant referral. The vast majority indicated that incorporation of risk tools into electronic medical records (EMR) would improve utilization. PAH risk assessment tools remain under-utilized. Most respondents were experienced PAH clinicians. More than one-third were not routinely using risk tools. Most felt that risk tools led to PAH therapy changes but few reported impacts on other aspects of care. The most commonly identified barriers to use were time constraints and lack of integration with EMR.

Right ventricular function as assessed by cardiac magnetic resonance imaging-derived strain parameters compared to high-fidelity micromanometer catheter measurements.

Right ventricular function has prognostic significance in patients with pulmonary hypertension. We evaluated whether cardiac magnetic resonance-derived strain and strain rate parameters could reliably reflect right ventricular systolic and diastolic function in precapillary pulmonary hypertension. End-systolic elastance and the time constant of right ventricular relaxation tau, both derived from invasive high-fidelity micromanometer catheter measurements, were used as gold standards for assessing systolic and diastolic right ventricular function, respectively. Nineteen consecutive precapillary pulmonary hypertension patients underwent cardiac magnetic resonance and right heart catheterization prospectively. Cardiac magnetic resonance data were compared with those of 19 control subjects. In pulmonary hypertension patients, associations between strain- and strain rate-related parameters and invasive hemodynamic parameters were evaluated. Longitudinal peak systolic strain, strain rate, and early diastolic strain rate were lower in PAH patients than in controls; peak atrial-diastolic strain rate was higher in pulmonary hypertension patients. Similarly, circumferential peak systolic strain rate was lower and peak atrial-diastolic strain rate was higher in pulmonary hypertension. In pulmonary hypertension, no correlations existed between cardiac magnetic resonance-derived and hemodynamically derived measures of systolic right ventricular function. Regarding diastolic parameters, tau was significantly correlated with peak longitudinal atrial-diastolic strain rate (r = -0.61), deceleration time (r = 0.75), longitudinal systolic to diastolic time ratio (r = 0.59), early diastolic strain rate (r = -0.5), circumferential peak atrial-diastolic strain rate (r = -0.52), and deceleration time (r = 0.62). Strain analysis of the right ventricular diastolic phase is a reliable non-invasive method for detecting right ventricular diastolic dysfunction in PAH.

Diagnosis of Pulmonary Hypertension.

Pulmonary hypertension (PH) is a chronic disease of elevated pulmonary artery pressure that can result from pulmonary vascular diseases or complicate left heart and lung disease. Pulmonary arterial hypertension (PAH) is a rare pulmonary artery vasculopathy that leads to progressive right heart failure and death. Timely and accurate diagnosis of PH is paramount, given the increased morbidity and mortality, but can be challenging given the nonspecific nature of the presenting symptoms and the many potential causative or contributing conditions. The diagnosis of PH remains clinical and the initial workup uses history, physical exam, and echocardiography to evaluate likelihood of disease, followed by characterization of left heart and lung disease and the appropriate evaluation for chronic thromboembolic disease. A right heart catheterization is requisite for the diagnosis and thus early referral to a PH expert center is strongly recommended, particularly for patients with high-risk features and in high-risk populations.

Experimental design of the Effects of Dehydroepiandrosterone in Pulmonary Hypertension (EDIPHY) trial.

Pulmonary arterial hypertension (PAH) remains life-limiting despite numerous approved vasodilator therapies. Right ventricular (RV) function determines outcome in PAH but no treatments directly target RV adaptation. PAH is more common in women, yet women have better RV function and survival as compared to men with PAH. Lower levels of the adrenal steroid dehydroepiandrosterone (DHEA) and its sulfate ester are associated with more severe pulmonary vascular disease, worse RV function, and mortality independent of other sex hormones in men and women with PAH. DHEA has direct effects on nitric oxide (NO) and endothelin-1 (ET-1) synthesis and signaling, direct antihypertrophic effects on cardiomyocytes, and mitigates oxidative stress. Effects of Dehydroepiandrosterone in Pulmonary Hypertension (EDIPHY) is an on-going randomized double-blind placebo-controlled crossover trial of DHEA in men (n = 13) and pre- and post-menopausal women (n = 13) with Group 1 PAH funded by the National Heart, Lung and Blood Institute. We will determine whether orally administered DHEA 50 mg daily for 18 weeks affects RV longitudinal strain measured by cardiac magnetic resonance imaging, markers of RV remodeling and oxidative stress, NO and ET-1 signaling, sex hormone levels, other PAH intermediate end points, side effects, and safety. The crossover design will elucidate sex-based phenotypes in PAH and whether active treatment with DHEA impacts NO and ET-1 biosynthesis. EDIPHY is the first clinical trial of an endogenous sex hormone in PAH. Herein we present the study's rationale and experimental design.

Critical Care Management of the Patient with Pulmonary Hypertension.

Pulmonary hypertension patients admitted to the intensive care unit have high mortality, and right ventricular failure typically is implicated as cause of or contributor to death. Initial care of critically ill pulmonary hypertension patients includes recognition of right ventricular failure, appropriate monitoring, and identification and treatment of any inciting cause. Management centers around optimization of cardiac function, with a multipronged approach aimed at reversing the pathophysiology of right ventricular failure. For patients who remain critically ill or in shock despite medical optimization, mechanical circulatory support can be used as a bridge to recovery or lung transplantation.

Insights from the Menstrual Cycle in Pulmonary Arterial Hypertension.

Rationale: Sex hormones play a role in pulmonary arterial hypertension (PAH), but the menstrual cycle has never been studied.Objectives: We conducted a prospective observational study of eight women with stable PAH and 20 healthy controls over one cycle.Methods: Participants completed four study visits 1 week apart starting on the first day of menstruation. Relationships between sex hormones, hormone metabolites, and extracellular vesicle microRNA (miRNA) expression and clinical markers were compared with generalized linear mixed modeling.Results: Women with PAH had higher but less variable estradiol (E2) levels (P < 0.001) that tracked with 6-minute walk distance (P < 0.001), N-terminal prohormone of brain natriuretic peptide (P = 0.03) levels, and tricuspid annular plane systolic excursion (P < 0.01); the direction of these associations depended on menstrual phase. Dehydroepiandrosterone sulfate (DHEA-S) levels were lower in women with PAH (all visits, P < 0.001). In PAH, each 100-µg/dl increase in DHEA-S was associated with a 127-m increase in 6-minute walk distance (P < 0.001) and was moderated by the cardioprotective E2 metabolite 2-methoxyestrone (P < 0.001). As DHEA-S increased, N-terminal prohormone of brain natriuretic peptide levels decreased (P = 0.001). Expression of extracellular vesicle miRNAs-21, -29c, and -376a was higher in PAH, moderated by E2 and DHEA-S levels, and tracked with hormone-associated changes in clinical measures.Conclusions: Women with PAH have fluctuations in cardiopulmonary function during menstruation driven by E2 and DHEA-S. These hormones in turn influence transcription of extracellular vesicle miRNAs implicated in the pathobiology of pulmonary vascular disease and cancer.

Culture of pulmonary artery endothelial cells from pulmonary artery catheter balloon tips: considerations for use in pulmonary vascular disease.

Endothelial dysfunction is a hallmark of pulmonary arterial hypertension (PAH) but there are no established methods to study pulmonary artery endothelial cells (PAECs) from living patients. We sought to culture PAECs from pulmonary artery catheter (PAC) balloons used during right-heart catheterisation (RHC) to characterise successful culture attempts and to describe PAEC behaviour.PAECs were grown in primary culture to confluence and endothelial cell phenotype was confirmed. Standard assays for apoptosis, migration and tube formation were performed between passages three to eight. We collected 49 PAC tips from 45 subjects with successful PAEC culture from 19 balloons (39%).There were no differences in subject demographic details or RHC procedural details in successful versus unsuccessful attempts. However, for subjects who met haemodynamic criteria for PAH, there was a higher but nonsignificant (p=0.10) proportion amongst successful attempts (10 out of 19, 53%) versus unsuccessful attempts (nine out of 30, 30%). A successful culture was more likely in subjects with a lower cardiac index (p=0.03) and higher pulmonary vascular resistance (p=0.04). PAECs from a subject with idiopathic PAH were apoptosis resistant compared to commercial PAECs (p=0.04) and had reduced migration compared to PAECs from a subject with portopulmonary hypertension with high cardiac output (p=0.01). PAECs from a subject with HIV-associated PAH formed fewer (p=0.01) and shorter (p=0.02) vessel networks compared to commercial PAECs.Sustained culture and characterisation of PAECs from RHC balloons is feasible, especially in PAH with high haemodynamic burden. This technique may provide insight into endothelial dysfunction during PAH pathogenesis.

High-Risk Pulmonary Embolism: Current Evidence-Based Practices.

Acute pulmonary embolism (PE) causes significant morbidity and mortality, particularly for patients with subsequent right ventricular (RV) dysfunction. Once diagnosed, risk stratification is imperative for therapeutic decision making and centers on evaluation of RV function. Treatment includes supportive care, systemic anticoagulation, and consideration of reperfusion therapy. In addition to systemic anticoagulation, patients with high-risk PE should receive reperfusion therapy, typically with systemic thrombolysis. The role of reperfusion therapies, which include catheter-based interventions, systemic thrombolysis, and surgical embolectomy, are controversial in the management of intermediate risk PE. Catheter directed thrombolysis (CDT) can be considered in certain intermediate risk patients although prospective, comparative data for its use are lacking. Surgical or catheter embolectomy are viable treatment options for high-risk patients in whom reperfusion therapy is warranted but who have absolute contraindications to thrombolysis. Further research is needed to better elucidate which patients with PE would most benefit from advanced reperfusion therapies.

Validation of the REVEAL Prognostic Equation and Risk Score Calculator in Incident Systemic Sclerosis-Associated Pulmonary Arterial Hypertension.

OBJECTIVE: A prognostic equation and risk score calculator derived from the Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL) are being used to predict 1-year survival in patients with pulmonary arterial hypertension (PAH), but little is known about the performance of these REVEAL survival prediction tools in systemic sclerosis (SSc)-associated PAH (SSc-PAH). METHODS: Prospectively gathered data from the Johns Hopkins Pulmonary Hypertension Program and Pulmonary Hypertension Assessment and Recognition of Outcome in Scleroderma Registries were used to evaluate the predictive accuracy of the REVEAL models for predicting the probability of 1-year survival in patients with SSc-PAH. Model discrimination was assessed by comparison of the Harrell's C-index, model fit was assessed using multivariable regression techniques, and model calibration was assessed by comparing predicted to observed survival estimates. RESULTS: The validation cohort consisted of 292 SSc-PAH patients with a 1-year survival rate of 87.4%. The C-index for predictive accuracy of the REVEAL prognostic equation (0.734, 95% confidence interval [95% CI] 0.652-0.816) and for the risk score (0.743, 95% CI 0.663-0.823) demonstrated good discrimination, comparable to that in the model development cohort. The calibration slope was 0.707 (95% CI 0.400-1.014), indicating that the overall model fit was marginal (P = 0.06). The magnitude of risk assigned to low distance on the 6-minute walk test (6MWD) and elevated serum levels of brain natriuretic peptide (BNP) was lower in the validation cohort than was originally seen in the REVEAL derivation cohort. Model calibration was poor, particularly for the highest risk groups. CONCLUSION: In predicting 1-year survival in patients newly diagnosed as having SSc-PAH, the REVEAL prognostic equation and risk score provide very good discrimination but poor calibration. REVEAL prediction scores should be interpreted with caution in newly diagnosed SSc-PAH patients, particularly those with higher predicted risk of poor 1-year survival resulting from a low 6MWD or a high BNP serum level.

Chronic Thromboembolic Pulmonary Hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a distinct type of pulmonary hypertensive disease, characterized by incomplete or abnormal resolution of acute pulmonary embolism such that residual emboli become organized and fibrotic. CTEPH can occur in patients without a prior history of venous thromboembolism, and is diagnosed based on precapillary pulmonary hypertension on right heart catheterization with evidence of chronic emboli on ventilation/perfusion scan, chest imaging, or pulmonary angiogram. Pulmonary endarterectomy (PEA) is often curative, and results in improved survival. In patients for whom PEA is not feasible, medical therapy has been effective in improving hemodynamics and functional capacity.

Lower DHEA-S levels predict disease and worse outcomes in post-menopausal women with idiopathic, connective tissue disease- and congenital heart disease-associated pulmonary arterial hypertension.

High oestradiol (E2) and low dehydroepiandrosterone-sulfate (DHEA-S) levels are risk factors for pulmonary arterial hypertension (PAH) in men, but whether sex hormones are related to PAH in women is unknown.Post-menopausal women aged ≥55 years with PAH were matched by age and body mass index to women without cardiovascular disease. Plasma sex hormone levels were measured by immunoassay.Lower levels of DHEA-S (p<0.001) and higher levels of E2 (p=0.02) were associated with PAH. In PAH cases (n=112), lower DHEA-S levels were associated with worse haemodynamics (all p<0.01) and more right ventricular dilatation and dysfunction (both p=0.001). Lower DHEA-S levels were associated with shorter 6-min walking distance (6MWD) (p=0.01) and worse functional class (p=0.004). Each Ln(1 µg·dL-1) decrease in DHEA-S was associated with a doubling in the risk of death (hazard ratio 2.0, 95% CI 1.5-2.7; p<0.001). Higher levels of E2 were associated with shorter 6MWD (p=0.03) and worse functional class (p=0.01).High E2 and low DHEA-S levels are associated with the risk and severity of PAH in post-menopausal women. Hormonal modulation should be studied as a treatment strategy in PAH.