Aggressive Afterload Lowering to Improve the Right Ventricle: A New Target for Medical Therapy in Pulmonary Arterial Hypertension?

Despite numerous therapeutic advances in pulmonary arterial hypertension, patients continue to suffer high morbidity and mortality, particularly considering a median age of 50 years. This article explores whether early, robust reduction of right ventricular afterload would facilitate substantial improvement in right ventricular function and thus whether afterload reduction should be a treatment goal for pulmonary arterial hypertension. The earliest clinical studies of prostanoid treatment in pulmonary arterial hypertension demonstrated an important link between lowering mean pulmonary arterial pressure (or pulmonary vascular resistance) and improved survival. Subsequent studies of oral monotherapy or sequential combination therapy demonstrated smaller reductions in mean pulmonary arterial pressure and pulmonary vascular resistance. More recently, retrospective reports of initial aggressive prostanoid treatment or initial combination oral and parenteral therapy have shown marked afterload reduction along with significant improvements in right ventricular function. Some data suggest that reaching threshold levels for pressure or resistance (components of right ventricular afterload) may be key to interrupting the self-perpetuating injury of pulmonary vascular disease in pulmonary arterial hypertension and could translate into improved long-term clinical outcomes. Based on these clues, the authors postulate that improved clinical outcomes might be achieved by targeting significant afterload reduction with initial oral combination therapy and early parenteral prostanoids.

The Operating Room Black Box: Understanding Adherence to Surgical Checklists.

OBJECTIVE: We report for the first time the use of the Operating Room Black Box (ORBB) to track checklist compliance, engagement, and quality. BACKGROUND: Implementation of operative checklists is associated with improved outcomes. Compliance is difficult to monitor. Most studies report either no assessment of checklist compliance or deployed in-person short-term assessment. The ORBB a novel artificially intelligence-driven data analytic platform affords the opportunity to assess checklist compliance without disrupting surgical workflow. METHODS: This was a retrospective review of prospectively collected ORBB data. Operative cases included elective surgery at a quaternary referral center. Cases were analyzed as prepolicy change (first 9 months) or as a postpolicy change (last 9 months). Measures of checklist compliance, engagement, and quality were assessed. RESULTS: There were 3879 cases that were performed and monitored for checklist compliance between August 15, 2020, and February 20, 2022. The overall scores for compliance, engagement, and quality were 81%, 84%, and 67% respectively. When broken down by phase, the scores for time-out were compliance 100%, engagement 98%, and quality 61%. Scores for the debrief phase were 81% for compliance, 98% for engagement, and 66% for quality. After a hospital policy change, the debrief scores improved significantly (85%; P <0.001 for compliance, 88%; P <0.001 for engagement and 71%; P <0.001 for quality). CONCLUSIONS: ORBB provides the unprecedented ability to assess not only compliance with surgical safety checklists but also engagement and quality. Utilization of this technology allows the assessment of compliance in near real time and to accurately address safety threats that may arise from noncompliance.

Estrogen Signaling and Portopulmonary Hypertension: The Pulmonary Vascular Complications of Liver Disease Study (PVCLD2).

BACKGROUND AND AIMS: Portopulmonary hypertension (POPH) was previously associated with a single-nucleotide polymorphism (SNP) rs7175922 in aromatase (cytochrome P450 family 19 subfamily A member 1 [CYP19A1]). We sought to determine whether genetic variants and metabolites in the estrogen signaling pathway are associated with POPH. APPROACH AND RESULTS: We performed a multicenter case-control study. POPH patients had mean pulmonary artery pressure >25 mm Hg, pulmonary vascular resistance >240 dyn-sec/cm-5 , and pulmonary artery wedge pressure ≤15 mm Hg without another cause of pulmonary hypertension. Controls had advanced liver disease, right ventricular (RV) systolic pressure <40 mm Hg, and normal RV function by echocardiography. We genotyped three SNPs in CYP19A1 and CYP1B1 using TaqMan and imputed SNPs in estrogen receptor 1 using genome-wide markers. Estrogen metabolites were measured in blood and urine samples. There were 37 patients with POPH and 290 controls. Mean age was 57 years, and 36% were female. The risk allele A in rs7175922 (CYP19A1) was significantly associated with higher levels of estradiol (P = 0.02) and an increased risk of POPH (odds ratio [OR], 2.36; 95% confidence interval [CI], 1.12-4.91; P = 0.02) whereas other SNPs were not. Lower urinary 2-hydroxyestrogen/16-α-hydroxyestrone (OR per 1-ln decrease = 2.04; 95% CI, 1.16-3.57; P = 0.01), lower plasma levels of dehydroepiandrosterone-sulfate (OR per 1-ln decrease = 2.38; 95% CI, 1.56-3.85; P < 0.001), and higher plasma levels of 16-α-hydroxyestradiol (OR per 1-ln increase = 2.16; 95% CI, 1.61-2.98; P < 0.001) were associated with POPH. CONCLUSIONS: Genetic variation in aromatase and changes in estrogen metabolites were associated with POPH.

Inflammatory bowel diseases, chronic liver diseases and the lung.

This review is devoted to the distinct associations of inflammatory bowel diseases (IBD) and chronic liver disorders with chronic airway diseases, namely chronic obstructive pulmonary disease and bronchial asthma, and other chronic respiratory disorders in the adult population. While there is strong evidence for the association of chronic airway diseases with IBD, the data are much weaker for the interplay between lung and liver multimorbidities. The association of IBD, encompassing Crohn's disease and ulcerative colitis, with pulmonary disorders is underlined by their heterogeneous respiratory manifestations and impact on chronic airway diseases. The potential relationship between the two most prevalent liver-induced pulmonary vascular entities, i.e. portopulmonary hypertension and hepatopulmonary syndrome, and also between liver disease and other chronic respiratory diseases is also approached. Abnormal lung function tests in liver diseases are described and the role of increased serum bilirubin levels on chronic respiratory problems are considered.

Severe pulmonary arterial hypertension: stratification of medical therapies, mechanical support, and lung transplantation.

Severe pulmonary hypertension is recognized by focusing on the clinical signs and tests that demonstrate decompensated right ventricular failure or, in the worst-case scenario, shock. An aggressive treatment regimen including a prostacyclin infusion is required for these patients. Once admitted to the hospital, or the ICU for decompensated right ventricular failure, the short- and long-term outcomes for PAH patients are poor. For those who are candidates, urgent lung transplantation, or extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplantation may be rescue therapy.

Clinical advances in pulmonary arterial hypertension: the year in review.

PURPOSE OF REVIEW: The purpose of this review is to summarize the last year of literature developments in the field of pulmonary arterial hypertension (PAH), with a focus on clinical research. RECENT FINDINGS: Pulmonary vascular research has expanded rapidly over the last decade, resulting in a change in the treatment strategy for PAH. Epidemiologic data from recent registries suggest that patients with PAH are increasing in age and comorbidities. In the modern treatment era, risk stratification for early mortality is increasingly used to guide clinicians in the choice of pulmonary vasodilator therapy. Risk-score calculators have been published and validated for PAH, currently in both the United States and Europe. In addition to increased comorbidities, pulmonary hypertension centers are encountering complicated management situations in these patients, such as pregnancy. Current data suggest that mortality for pregnant pulmonary hypertension patients remains high, although not as high as historical reports. Oral prostacyclin and prostacyclin agonist therapies are currently under investigation to aid in the management of these patients. SUMMARY: Despite treatment advances, mortality remains high for PAH patients. Careful evaluation and risk stratification will help guide the appropriate treatment for PAH patients. Additional therapies are on the horizon for the management of this progressive disease.

Prognosis of pulmonary arterial hypertension patients with pericardial effusion before and after initiation of parenteral prostacyclin therapy.

Few studies have evaluated the effects of pulmonary arterial hypertension therapies on pericardial effusion. We evaluated hemodynamics, echocardiograms, and outcomes for 119 parenteral prostanoid-treated patients. We discovered an increased frequency of pericardial effusions posttreatment, and that a moderate-large pericardial effusion at initiation, but not at 1st follow-up, was significantly associated with mortality.

Palliative care referrals in patients with pulmonary arterial hypertension: The Pulmonary Hypertension Association Registry.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a life limiting disease with substantial symptom burden and healthcare utilization. Palliative care alleviates physical and emotional symptoms for patients with serious illness, and has been underutilized for these patients. OBJECTIVE: To characterize patients with PAH referred to palliative care and identify predictors of referral. METHODS: We conducted an observational study of adult patients enrolled in the Pulmonary Hypertension Association Registry from January 2015 through June 2021, performing descriptive statistics on patient characteristics at baseline for all patients and the subset referred to palliative care. These characteristics were modeled in a backwards elimination Cox regression with time to referral to palliative care as the primary outcome. RESULTS: 92 of 1,578 patients were referred to palliative care (5.8%); 43% were referred at their last visit prior to death. Referrals were associated with increasing age per decade (hazard ratio 1.35 [95% confidence interval 1.16-1.58]), lower body mass index (hazard ratio 0.97 [95% confidence interval 0.94-0.998]), supplemental oxygen use (hazard ratio 2.01 [95% confidence interval 1.28-3.16]), parenteral prostanoid use (hazard ratio 2.88 [95% confidence interval 1.84-4.51]), and worse quality of life, measured via lower physical (hazard ratio 0.97 [95% confidence interval 0.95-0.99]) and mental (hazard ratio 0.98 [95% confidence interval 0.96-0.995]) scores on the 12-item Short Form Health Survey. CONCLUSION: Patients with PAH are infrequently referred to palliative care, even at centers of excellence. Referrals occur in sicker patients with lower quality of life scores, often close to the end of life.

Portopulmonary hypertension: an update.

Portopulmonary hypertension (POPH) is a serious complication of cirrhosis that is associated with mortality beyond that predicted by the Model for End-Stage Liver Disease (MELD) score. Increased pulmonary vascular resistance (PVR) may be initiated by pulmonary vasoconstriction, altered levels of circulating mediators, or shear stress, and can eventually lead to the classic vascular remodeling (plexiform lesion) that characterizes POPH. Portal hypertension is a prerequisite for the diagnosis of POPH, although the severity of pulmonary hypertension is unrelated to the severity of portal hypertension or the nature or severity of liver disease. POPH precludes liver transplantation (LT) unless the mean pulmonary artery pressure (MPAP) can be reduced to a safe level. The concept of an acceptable pressure has changed: we now consider both MPAP and PVR in the diagnosis, and we include the transpulmonary pressure gradient so that we can factor in fluid overload and left ventricular failure. Pulmonary vasodilator therapy includes oral, inhaled, and parenteral agents, and one or more of these agents may significantly lower pulmonary artery pressures to the point that LT becomes possible. The United Network for Organ Sharing recommends MELD exception points for patients with medically controlled POPH, but this varies by region. Patients who undergo LT need specialized intraoperative and postoperative management, which includes the availability of intraoperative transesophageal echocardiography for assessing right ventricular function, and rapidly acting vasodilators (eg, inhaled nitric oxide and/or epoprostenol). Published case series suggest excellent outcomes after LT for patients who respond to medical therapy.

Pulmonary hypertension in parenchymal lung disease.

The pathophysiology of pulmonary hypertension (PH) in parenchymal lung diseases is partially related to hypoxic pulmonary vasoconstriction. PH treatment is controversial for these patients. This article focuses on group III PH, namely PH attributable to lung diseases and/or hypoxia. Group III includes chronic obstructive pulmonary disease and interstitial lung diseases, the most common parenchymal lung diseases associated with PH. It also includes sleep-disordered breathing and hypoventilation from any cause. Other parenchymal lung diseases associated with PH, namely sarcoidosis and systemic vasculitides (group V), are discussed. The data describing PH in specific parenchymal diseases are reviewed.

Transitioning Stable Patients with Pulmonary Arterial Hypertension from Parenteral Prostanoids to Oral Selexipag.

Introduction: Parenteral prostanoids are the most potent therapies for pulmonary arterial hypertension (PAH) but are associated with complications and lifestyle limitations. Carefully selected stable patients may be considered for a transition from parenteral prostanoids to a more convenient oral regimen. We present our experience transitioning patients on parenteral prostanoids to selexipag on an outpatient basis. Methods: This was a retrospective cohort study of all group 1 PAH patients on parenteral prostanoids who transitioned to selexipag using a standardized outpatient-based protocol. Hospitalization and routine prognostic data were recorded. Results: Fourteen patients were followed for a median of 1,240 (1,052-1,528) days; all were functional class (FC) II (n = 9) or III (n = 5). Thirteen patients completed the transition, including 11 who underwent catheterization 376 (321-735) days after discontinuing parenteral therapy. Three patients had unfavorable transitions requiring reinitiation of parenteral treatment. Overall, pulmonary vascular resistance increased (3.3-4.5 WU, p = 0.01), cardiac index fell (4.0-2.8 L/min/m2, p = 0.01), N-terminal pro-hormone of brain natriuretic peptide worsened (111-205 pg/dL, p = 0.03), but PAH-related hospitalizations improved (27-8, p = 0.02). Cardiac imaging, FC, and 6-min walk distance (6MWD) were unchanged. Patients who failed were older (64 vs. 56 years old) with shorter 6MWD (274 vs. 392 m) and higher REVEAL 2.0 scores (11 vs. 3). Conclusions: Transition from parenteral prostanoids to oral selexipag in carefully selected low-risk patients was well-tolerated in many patients, with up to 5 years of follow-up. Overall, the hemodynamic response to transition is unpredictable and close monitoring, particularly in the first year of follow-up, is recommended. Additional evaluation of potential predictors of success is necessary.

Prognostic Value of Echocardiographic Variables Prior to and Following Initiation of Parenteral Prostacyclin Therapy: An Observational Study.

BACKGROUND: Echocardiographic parameters are used as prognostic markers in patients with pulmonary arterial hypertension (PAH) receiving parenteral (IV or subcutaneous [IV/SC]) prostacyclin therapy. However, data on how posttreatment echocardiographic results associate with outcomes are limited. RESEARCH QUESTION: Are echocardiographic parameters pre- and post-parenteral prostacyclin therapy in patients with PAH associated with long-term outcomes? STUDY DESIGN AND METHODS: In this retrospective cohort study, patients with PAH initiated on IV epoprostenol or IV/SC treprostinil therapy between 2007 and 2016 were included and followed up through May 31, 2020. Survival free from transplant was assessed from the time of IV/SC prostacyclin therapy initiation and from first follow-up echocardiogram following at least 90 days of therapy. RESULTS: Patients with PAH initiated on IV/SC prostacyclin therapy (N = 118) were followed up for a median of 7.3 years. Survival was 86%, 79%, and 69% at 1, 2, and 3 years, respectively. Follow-up echocardiogram in 101 patients (median, 178 days; interquartile range, 140-273 days) showed improvement in five echocardiographic measures: right ventricular function, right ventricular systolic pressure, right ventricular diastolic diameter, left ventricular diastolic diameter, and tricuspid regurgitation (TR) severity. TR severity and pericardial effusion were associated with survival from IV/SC therapy initiation, whereas right ventricular diastolic diameter, right atrial (RA) size, TR severity, and inferior vena cava characteristics were associated with survival from first follow-up. In a multivariable analysis incorporating other prognostic measures at first follow-up, walk distance, functional class, N-terminal pro-B-type natriuretic peptide, and RA size resulted in the best fit model for survival. INTERPRETATION: Echocardiographic variables improved following IV/SC therapy, and multiple echocardiographic measures associated significantly with survival, particularly when reassessed after at least 90 days of therapy. RA size in particular may be useful in prognostication in follow-up of patients with PAH on IV/SC therapy.

Erratum: Health disparities and treatment approaches in portopulmonary hypertension and idiopathic pulmonary arterial hypertension: An analysis of the Pulmonary Hypertension Association Registry.

[This corrects the article DOI: 10.1177/20458940211020913.].

ISHLT consensus statement: Perioperative management of patients with pulmonary hypertension and right heart failure undergoing surgery.

Pulmonary hypertension (PH) is a risk factor for morbidity and mortality in patients undergoing surgery and anesthesia. This document represents the first international consensus statement for the perioperative management of patients with pulmonary hypertension and right heart failure. It includes recommendations for managing patients with PH being considered for surgery, including preoperative risk assessment, planning, intra- and postoperative monitoring and management strategies that can improve outcomes in this vulnerable population. This is a comprehensive document that includes common perioperative patient populations and surgical procedures with unique considerations.

Hypoxia-inducible factor-1 α/platelet derived growth factor axis in HIV-associated pulmonary vascular remodeling.

BACKGROUND: Human immunodeficiency virus (HIV) infected patients are at increased risk for the development of pulmonary arterial hypertension (PAH). Recent reports have demonstrated that HIV associated viral proteins induce reactive oxygen species (ROS) with resultant endothelial cell dysfunction and related vascular injury. In this study, we explored the impact of HIV protein induced oxidative stress on production of hypoxia inducible factor (HIF)-1α and platelet-derived growth factor (PDGF), critical mediators implicated in the pathogenesis of HIV-PAH. METHODS: The lungs from 4-5 months old HIV-1 transgenic (Tg) rats were assessed for the presence of pulmonary vascular remodeling and HIF-1α/PDGF-BB expression in comparison with wild type controls. Human primary pulmonary arterial endothelial cells (HPAEC) were treated with HIV-associated proteins in the presence or absence of pretreatment with antioxidants, for 24 hrs followed by estimation of ROS levels and western blot analysis of HIF-1α or PDGF-BB. RESULTS: HIV-Tg rats, a model with marked viral protein induced vascular oxidative stress in the absence of active HIV-1 replication demonstrated significant medial thickening of pulmonary vessels and increased right ventricular mass compared to wild-type controls, with increased expression of HIF-1α and PDGF-BB in HIV-Tg rats. The up-regulation of both HIF-1α and PDGF-B chain mRNA in each HIV-Tg rat was directly correlated with an increase in right ventricular/left ventricular+septum ratio. Supporting our in-vivo findings, HPAECs treated with HIV-proteins: Tat and gp120, demonstrated increased ROS and parallel increase of PDGF-BB expression with the maximum induction observed on treatment with R5 type gp-120CM. Pre-treatment of endothelial cells with antioxidants or transfection of cells with HIF-1α small interfering RNA resulted in abrogation of gp-120CM mediated induction of PDGF-BB, therefore, confirming that ROS generation and activation of HIF-1α plays critical role in gp120 mediated up-regulation of PDGF-BB. CONCLUSION: In summary, these findings indicate that viral protein induced oxidative stress results in HIF-1α dependent up-regulation of PDGF-BB and suggests the possible involvement of this pathway in the development of HIV-PAH.

Parenteral prostanoids for severe Group 3 pulmonary hypertension with right ventricular dysfunction.

BACKGROUND: Group 3 pulmonary hypertension (PH) is a common complication in patients with lung diseases but there are currently no FDA-approved therapies. The data is conflicting, but a few small studies suggest potential benefits in using Group 1 PH therapies in these patients, particularly in severe PH with right ventricular (RV) dysfunction. METHODS: A retrospective cohort study of patients with severe Group 3 PH with RV dysfunction who received parenteral prostanoids from 2007-2018 at our institution was undertaken. Severe PH was defined as mean pulmonary arterial pressure (mPAP) ≥35 mmHg or mPAP 25-34 with cardiac index (CI) <2.4 L/min/m2. Routine prognostic studies including N-terminal prohormone of brain natriuretic peptide (NT-proBNP), 6-minute walk distance (6MWD), WHO Functional Class assessment, oxygen requirement, arterial oxygen saturation, right ventricular systolic pressure (RVSP) and right heart catheterization (RHC) pressures, were obtained before initiation of parenteral therapy and at first clinical follow-up. RESULTS: Nine patients were included. Five were female (55.6%) with a median [interquartile range (IQR)] of 69 [54-71] years. Median CI was 1.8 (1.6-2.4) L/min/m2 and median pulmonary vascular resistance (PVR) was 14.7 (10.7-17.1) Wood units (WU). We found no statistically significant improvement in NT-proBNP levels, exercise capacity, or functional class. Resting oxygen requirement worsened from 4 to 6 L/min (P=0.04) and exertional oxygen saturation nadir worsened from 90% to 83% (P=0.01) despite the increase in FiO2 with exertion. Overall results were heterogenous: several patients demonstrated clinical stabilization, with two undergoing lung transplantation and one showing long-term stability with medical therapy. Symptoms remained severe for most: three patients discontinued prostanoid therapy, choosing to pursue hospice care. CONCLUSIONS: We found no statistically significant improvement in NT-proBNP levels, exercise capacity, or functional class, while oxygen requirement at rest and oxygen saturation during exertion significantly worsened. Our results suggest that parenteral prostanoids should not generally be considered in the treatment of Group 3 PH patients.

Variable Creatinine Levels in Critical Care Patients: A Concerning Knowledge Gap.

An accurate creatinine (Cr) estimate is pivotal for the assessment of renal function. Both patient- and practice-spawned factors palliate the test accuracy of serum creatinine (sCr) and can erratically represent actual kidney function. This study evaluated the caregivers' awareness of enzymatic serum creatinine (E-sCr) assay interfering in dopamine/dobutamine (DD)-infused patient samples and the frequency of such interference in a critical care setting. We conducted an sCr awareness survey among UT Southwestern physicians, nurses, and pharmacists. We then performed a cross-sectional E-sCr comparison against the kinetic Jaffe method using the DD-infused patient samples collected from central venous catheters (CVC), peripherally inserted central catheter (PICC) lines, and the peripheral vein (PV). We retrospectively compared the longitudinal E-sCr results of the CVC/PICC draws with the corresponding blood urea nitrogen (BUN) levels. The survey results show a significant lack of awareness among caregivers about the negative interference of DD infusions on E-sCr. Cross-sectional E-sCr assessment relative to the Jaffe method displayed a negative interference in 12% of CVC/PICC line samples (7/57 DD-infused patients) compared to none in the PV draws. A longitudinal assessment of E-sCr, BUN, and potassium (K) levels from CVC/PICC line samples further confirmed a spurious decrease for E-sCr in about 12/50 (24%) patients who did not show a concurrent BUN or K decrease. The results suggest that a direct PV sampling accompanied by clinical laboratory-directed proactive discussion/activities can foster awareness among caregivers and eschew the false E-sCr estimates in DD-infused patients.

Health disparities and treatment approaches in portopulmonary hypertension and idiopathic pulmonary arterial hypertension: an analysis of the Pulmonary Hypertension Association Registry.

Compared to idiopathic pulmonary arterial hypertension (IPAH), patients with portopulmonary hypertension (POPH) have worse survival. Health disparities may contribute to these differences but have not been studied. We sought to compare socioeconomic factors in patients with POPH and IPAH and to determine whether socioeconomic status and/or POPH diagnosis were associated with treatment and health-care utilization. We performed a cross-sectional study of adults enrolled in the Pulmonary Hypertension Association Registry. Patients with IPAH (n = 344) and POPH (n = 57) were compared. Compared with IPAH, patients with POPH were less likely to be college graduates (19.6% vs. 34.9%, p = 0.02) and more likely to be unemployed (54.7% vs. 30.5%, p < 0.001) and have an annual household income below poverty level (45.7% vs. 19.0%, p < 0.001). Patients with POPH had similar functional class, quality of life, 6-min walk distance, and mean pulmonary arterial pressure with a higher cardiac index. Compared with IPAH, patients with POPH were less likely to receive combination therapy (46.4% vs. 62.2%, p = 0.03) and endothelin receptor antagonists (28.6% vs. 55.1%, p < 0.001) at enrollment with similar treatment at follow-up. Patients with POPH had more emergency department visits (1.7 ± 2.1 vs. 0.9 ± 1.2, p = 0.009) and hospitalizations in the six months preceding enrollment (1.5 ± 2.1 vs. 0.8 ± 1.1, p = 0.02). Both POPH diagnosis and lower education level were independently associated with a higher number of emergency department visits. Compared to IPAH, patients with POPH have lower socioeconomic status, are less likely to receive initial combination therapy and endothelin receptor antagonists but have similar treatment at follow-up, and have increased health-care utilization.