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Chronic thromboembolic pulmonary disease (CTEPD) is characterized by organized nonresolving thrombi in pulmonary arteries (PA). In CTEPD with pulmonary hypertension (PH), chronic thromboembolic PH (CTEPH), early wave reflection results in abnormalities of pulsatile afterload and augmented PA pressures. We hypothesized that exercise during right heart catheterization (RHC) would elicit more frequent elevations of pulsatile vascular afterload than resistive elevations in patients with CTEPD without PH. The interdependent physiology of pulmonary venous and PA hemodynamics was also evaluated. Consecutive patients with CTEPD without PH (resting mean PA pressure ≤20 mmHg) undergoing an exercise RHC were identified. Latent resistive and pulsatile abnormalities of pulmonary vascular afterload were defined as an exercise mean PA pressure/cardiac output >3 WU, and PA pulse pressure to PA wedge pressure (PA PP/PAWP) ratio >2.5, respectively. Forty‐five patients (29% female, 53 ± 14 years) with CTEPD without PH were analyzed. With exercise, 19 patients had no abnormalities (ExNOR), 26 patients had abnormalities (ExABN) of pulsatile (20), resistive (2), or both (4) elements of pulmonary vascular afterload. Exercise elicited elevations of pulsatile afterload (53%) more commonly than resistive afterload (13%) (p < 0.001). ExABN patients had lower PA compliance and higher pulmonary vascular resistance at rest and exercise and prolonged resistance‐compliance time product at rest. The physiological relationship between changes in PA pressures relative to PAWP was disrupted in the ExABN group. In CTEPD without PH, exercise RHC revealed latent pulmonary vascular afterload elevations in 58% of patients with more frequent augmentation of pulsatile than resistive pulmonary vascular afterload. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) is a rare condition with the potential to progress to right heart failure. Point-of-Care Ultrasonography (POCUS), used and interpreted in real time at the bedside to further the cardiopulmonary assessment, has the potential to improve the longitudinal care of PAH patients in the ambulatory setting. Patients from PAH clinics at two academic medical centers were randomized to either a POCUS assessment cohort or non-POCUS standard care (ClinicalTrials.gov identifier NCT05332847). The POCUS group received blinded heart, lung, and vascular ultrasound assessments. Thirty-six patients were randomized to the study and followed over time. Mean age was 65 in both groups and majority female (76.5% and 88.9% females in POCUS and control, respectively). Median time for POCUS assessment was 11 min (range 8–16). There were significantly more changes in management in the POCUS group than control (73% vs. 27%, p-value < 0.001). Multivariate analysis revealed that management changes were more likely to occur with a POCUS assessment, with an odds ratio (OR) of 12 when POCUS was added to physical exam vs. OR of 4.6 compared to physical examination alone (p < 0.001). POCUS in the PAH clinic is feasible and, when combined with physical examination, increases the number of findings and results in changes in management without significantly prolonging visit encounters. POCUS may help support clinical evaluation and decision making in ambulatory PAH clinics. [ABSTRACT FROM AUTHOR]

Purpose: To perform a systematic review and meta-analysis assessing the safety and efficacy of balloon pulmonary angioplasty (BPA) in the treatment of chronic thromboembolic pulmonary hypertension (CTEPH). Materials and Methods: Systematic literature searches were performed from inception to June 2022 to identify studies assessing BPA for CTEPH. Outcomes of interest included the following functional and hemodynamic measures: (a) six-minute walk distance (6MWD), (b) New York Heart Association (NYHA) status, (c) World Health Organization (WHO)-Functional Class status, (d) cardiac index (CI), (e) mean pulmonary artery pressure (mPAP), (f) mean right atrial pressure (mRAP), and (g) pulmonary vascular resistance (PVR). Subgroup analysis was also performed for BPA in post-pulmonary endarterectomy (PEA) patients. All reported BPA-related complications were also recorded. Forty unique studies with a total of 1763 patients were identified for meta-analysis. Results: All functional and hemodynamic parameters improved significantly following BPA; 6MWD increased 70 m (95% CI 58–82; P < 0.001), NYHA class improved by − 0.9 classes (95% CI − 1.0 to − 0.8; P < 0.001), WHO-FC class improved by − 1 classes ((95% CI − 1.2 to − 0.9; P < 0.001), CI increased 0.26 L/min/m2 (95% CI 0.17–0.35; P < 0.001), mPAP decreased − 13.2 mmHg (95% CI − 14.7 to − 11.8; P < 0.001), mRAP decreased − 2.2 mmHg (95% CI − 2.8 to − 1.6; P < 0.001), and PVR decreased − 311 dyne/cm/s−5 (95% CI − 350 to − 271; P < 0.001). Meta-analysis of patients who underwent BPA for persistent pulmonary hypertension post-PEA demonstrated significant improvements in 6MWD, WHO-FC, PVR and mPAP. Most common complications included lung injury (8.16%), hemoptysis (7.07%) and vessel injury (5.05%). Conclusion: BPA represents a safe and effective treatment option for select individuals with CTEPH with significant improvements in hemodynamic parameters, improved exercise tolerance and a relatively low risk of major complications. [ABSTRACT FROM AUTHOR]

Exercise imposes increased pulmonary vascular afterload based on rises in pulmonary artery (PA) wedge pressure, declines in PA compliance, and resistance‐compliance time. In health, afterload stress stabilizes during steady‐state exercise. Our objective was to examine alterations of these exercise‐associated stresses in states of pre‐ and post‐capillary pulmonary hypertension (PH). PA hemodynamics were evaluated at rest, 2 and 7 min of steady‐state exercise at moderate intensity in patients who exhibited Pre‐capillary (n = 22) and post‐capillary PH (n = 22). Patients with normal exercise hemodynamics (NOR‐HD) (n = 32) were also studied. During exercise in all groups, PA wedge pressure increased at 2 min, with no further change at 7 min. In post‐capillary PH and NOR‐HD, increases in PA diastolic pressure and diastolic pressure gradient remained stable at 2 and 7 min of exercise, while in pre‐capillary PH, both continued to increase at 7 min. The behavior of the diastolic pressure gradient was linearly related to the duration of resistance‐compliance time at rest (r2 = 0.843) and exercise (r2 = 0.760). Exercise resistance‐compliance time was longer in pre‐capillary PH associated with larger increases in diastolic pressure gradient. Conversely, resistance‐compliance time was shortest in post‐capillary PH compared to pre‐capillary PH and NOR‐HD and associated with limited increases in exercise diastolic pressure gradient. During steady‐state, modest‐intensity exercise‐specific patterns of pulmonary vascular afterload responses were observed in pre‐ and post‐capillary PH relative to NOR‐HD. Longer resistance‐compliance time related to greater increases in PA diastolic pressure and diastolic pressure gradients in pre‐capillary PH, while shorter resistance‐compliance time appeared to limit these increases in post‐capillary PH. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Chronic thromboembolic pulmonary hypertension (CTEPH) is a distinct form of precapillary pulmonary hypertension classified as group 4 by the World Symposium on Pulmonary Hypertension (WSPH) and should be excluded during an episode of acute pulmonary embolism (PE). Patients presenting to emergency departments with sudden onset of signs and symptoms of acute PE may already have a pre-existing CTEPH condition decompensated by the new PE episode. Identifying an underlying and undiagnosed CTEPH during acute PE, while challenging, is an important consideration as it will alter the patients' acute and long-term management. Differential diagnosis and evaluation require an interdisciplinary expert team. Analysis of the clinical condition, the CT angiogram, and the hemodynamic situation are important considerations; patients with CTEPH usually have significantly higher sPAP at the time of index PE, which is unusual and unattainable in the context of acute PE and a naïve right ventricle. The imaging may reveal signs of chronic disease such as right ventricle hypertrophy bronchial collaterals and atypical morphology of the thrombus. There is no standard for the management of acute on chronic CTEPH. Herein, we provide a diagnostic and management algorithm informed by several case descriptions and a review of the literature. [ABSTRACT FROM AUTHOR]

The spectrum of patients referred for suspected pulmonary arterial hypertension (PAH) includes a population with clinical features suggestive of pulmonary hypertension due to left heart disease (PH‐LHD). Even after right heart catheterization (RHC) performed at rest, it can be a challenge to identify patients who will clearly benefit from PAH drug therapy. Therefore, the objective of this study was to evaluate the role of exercise RHC to influence decisions regarding prescription of PAH drug therapy in this population. A retrospective cohort study was conducted of older adults with risk factors for PH‐LHD and suspected PH referred for exercise RHC. One year follow‐up was conducted to record clinical outcomes, all changes in PAH drug therapy, and changes in patient‐reported quality of life. The final cohort included 61 patients, mean age of 69 ± 10; 44% and 34% had a history of coronary artery disease and atrial fibrillation respectively. Exercise changed the proportional breakdown of hemodynamic diagnoses from 36% No PH, 44% PAH, and 20% PH‐LHD at rest to 15% No PH, 36% PAH, and 49% PH‐LHD. Although a significant proportion of patients were reclassified as PH‐LHD, there was an overall increase in the proportion of patients receiving PAH drug therapy, particularly for those with PAH confirmed by exercise RHC. A total of 11 PAH drug prescriptions were employed before exercise RHC increasing to 24 after (p = 0.002). Patients receiving PAH therapy demonstrated significant improvement in self‐reported quality of life. Exercise RHC appeared to influence selection of PAH drug therapy. [ABSTRACT FROM AUTHOR]

We examined patterns of avoidance when existential emotional topics were raised during conversations with patients with pulmonary arterial hypertension (PAH), an incurable life-limiting disease. 30 adult outpatients with PAH were recruited for a 20 to 60-minute interview about their illness experience. Qualitative content analysis was used to identify avoidance strategies that patients employed. Participants averaged 58 years in age (SD = 18), 77% were female, and mean length of illness was 6.3 years (SD = 5.3). We found four avoidance strategies: (1) Reversal, when individuals would begin discussing a negative concern and then backtrack to more positive sentiments; (2) Diversion for when patients would sidetrack the conversation to a different and less uncomfortable topic; (3) Diminishment for when a concern is raised and then made to seem unimportant; and (4) Obstruction, when patients refuse to discuss a concern further. Exploration of existential concerns can elicit distress but may be necessary to promote adaptation to progressive illness and to the foreseeable challenges that may affect the sense of life meaning and value. By recognizing when existential concerns may be present but not adequately discussed, clinicians may be better able to assist patients to cope and prepare for the future. [ABSTRACT FROM AUTHOR]

Background and objective: Osteopontin (OPN) is a pleiotropic cytokine involved in the proliferation of pulmonary artery smooth muscle cells (PA‐SMC). OPN is upregulated in the lungs of patients with pulmonary hypertension (PH) associated with pulmonary fibrosis, suggesting that the lung is a source of OPN. We hypothesized that OPN lung expression is elevated in Group I pulmonary arterial hypertension (PAH) and is correlated to haemodynamics. Methods: Microarray analysis (Affymetrix) was performed after RNA was extracted from explanted lungs in 15 patients with Group I PAH who underwent lung transplantation (LTx) and 11 normal controls. PA pressure levels were recorded intraoperatively, immediately before starting LTx. Serum OPN levels were measured in subjects with PAH, Group II PH and normal controls on the day of right heart catheterization. Results: OPN was among the top five upregulated genes in PAH compared to normal controls, which was confirmed by reverse transcription polymerase chain reaction (RT‐PCR). OPN expression was similar and equally elevated in different subtypes of PAH. A strong significant correlation was observed between mean pulmonary arterial pressure and OPN gene expression. Ingenuity pathway analysis showed the involvement of OPN in functions and networks relevant to angiogenesis, cell death and proliferation of PA‐SMC. OPN serum levels did not differ in subjects with Group I PAH and Group II PH. Conclusion: In the lungs of patients with severe PAH, OPN is highly expressed and the level of expression is significantly correlated to disease severity. OPN may play an important role in the vascular remodelling process of PAH. See relatedEditorial Osteopontin (OPN), a pleiotropic cytokine, was identified among the top five upregulated genes in the lung explants from patients with Group I pulmonary arterial hypertension, compared to normal controls. Its expression correlated strongly to haemodynamic severity. Ingenuity pathway analysis showed the involvement of OPN in functions and networks relevant to vascular remodelling. [ABSTRACT FROM AUTHOR]

Objective: This study sought to determine the prevalence, predictors, prognostic relevance and evolution of pulmonary hypertension (PH) (mean pulmonary artery pressure ≥25 mm Hg) in adult patients with a subaortic right ventricle (RV) in a biventricular circulation (2V-RV).Methods: We analysed retrospective data from patients with 2V-RV undergoing cardiac catheterisation in our centre between 2000 and 2018. Echocardiographic assessment of subpulmonary ventricular pressures (left ventricular systolic pressure (LVSP)), age and B-type natriuretic peptide (BNP) were assessed as PH screening tools. Kaplan-Meier curves examined time to a composite outcome of death, transplant or ventricular assist device (VAD). Data from repeat catheterisations were analysed to evaluate PH changes over time, including the effects of therapy.Results: A total of 141 patients (median age 39 (IQR 33-45) years, 68% men) underwent 191 cardiac catheterisations. At baseline, 55% had PH (isolated postcapillary 24%, combined precapillary and postcapillary 26% and precapillary 5%). BNP (area under the curve 0.80; 95% CI 0.72 to 0.88; p<0.0001), but not age at catheterisation or echocardiographic estimates of LVSP were associated with the presence of PH. The absence of PH and BNP <100 pg/mL discriminated a subgroup at very low risk during short-term (2.5 (1.3-3.9) years) follow-up (p<0.0001). Diuretics, milrinone and VAD improved haemodynamics over time.Conclusion: PH is prevalent in patients with 2V-RV even when asymptomatic. It is difficult to identify by echocardiography and most importantly, is strongly associated with adverse outcomes. PH affects prognosis and transplant options for this patient group and yet is often amenable to treatment. Awareness of these results ought to lower the threshold for invasive haemodynamic assessment and may change the management of failing patients with 2V-RV. [ABSTRACT FROM AUTHOR]

Aims The assumption of equivalence between right ventricular (RV) and pulmonary arterial systolic pressure is fundamental to several assessments of RV or pulmonary vascular haemodynamic function. Our aims were to (i) determine whether systolic pressure gradients develop across the RV outflow tract in healthy adults during exercise, (ii) examine the potential correlates of such gradients, and (iii) consider the effect of such gradients on calculated indices of RV function. Methods and results Healthy untrained and endurance-trained adult volunteers were studied using right-heart catheterization at rest and during submaximal cycle ergometry. RV and pulmonary artery (PA) pressures were simultaneously transduced, and the cardiac output was determined by thermodilution. Systolic pressures, peak and mean gradients, and indices of chamber, vascular, and valve function were analysed offline. Summary data are reported as mean ± standard deviation or median (interquartile range). No significant RV outflow tract gradients were observed at rest [mean gradient = 4 (3–5) mmHg], and the calculated effective orifice area was 3.6 ± 1.0 cm2. The increase in right ventricular systolic pressure during exercise was greater than the PA systolic pressure. Accordingly, mean gradients were developed during light exercise [8 (7–9) mmHg] and increased during moderate exercise [12 (9–14) mmHg, P  < 0.001]. The magnitude of the mean gradient was linearly related to the cardiac output (r 2 = 0.70, P  < 0.001). Conclusions In healthy adults without pulmonic stenosis, systolic pressure gradients develop during exercise, and the magnitude is related to the blood flow rate. [ABSTRACT FROM AUTHOR]

Despite an expanded armamentarium of medical therapies, pulmonary arterial hypertension (PAH) remains a progressive disease associated with significant morbidity and premature mortality. Lung transplantation (LT) is the last safety net for patients failing medical therapy, providing excellent overall long-term survival and healthrelated quality-of-life outcomes in line with more common parenchymal lung disease indications. Waitlist mortality remains disproportionally elevated, however, reflecting an inability of the lung allocation score to completely capture PAH disease severity, and a propensity for PAH to deteriorate rapidly without warning, even in patients who appear externally "well." Early referral to a LT center can mitigate these risks and facilitate rapid listing if necessary. Several bridging therapies are available to support severely unwell patients to LT, such as extracorporeal life support (ECLS) and atrial septostomy. Unique perioperative considerations include higher rates of primary graft dysfunction and dynamic right ventricular outflow obstruction which may, at least in part, reflect rapid afterload reduction in the face of a conditioned right ventricle. Extending ECLS into the perioperative period may ameliorate these risks by allowing more gradual adaptation of both ventricles to their new loading conditions. Chronic lung allograft dysfunction, particularly bronchiolitis obliterans syndrome, remains a major cause of long-term morbidity and mortality, and complications from corticosteroid and immunosuppressive therapy are common. Nevertheless, the morbidity, mortality, and burden of disease management after LT continue to improve and compare favorably to that of refractory PAH in carefully selected patients. [ABSTRACT FROM AUTHOR]

Chronic thromboembolic pulmonary hypertension (CTEPH) is an underdiagnosed potential complication of acute or recurrent pulmonary thromboembolic disease. Multiple studies suggest that up to 5% of patients with acute pulmonary thromboembolic disease go on to develop CTEPH. The prognosis of untreated CTEPH is poor, but advances in medical and surgical treatments over the past few decades have improved patient outcomes. The gold standard and curative treatment for CTEPH is pulmonary endarterectomy; however, some patients are inoperable and others who have undergone pulmonary endarterectomy experience persistent or recurrent pulmonary hypertension despite medical therapy. In recent years, balloon pulmonary angioplasty has emerged as a primary and adjunctive treatment for these CTEPH patients at expert or specialized centers. This review outlines an approach to balloon pulmonary angioplasty for CTEPH, including clinical presentation and evaluation; patient selection and indications; treatment planning; equipment and technique; overcoming technical challenges; recognition and management of complications; postprocedural care and clinical follow-up; and expected outcomes. [ABSTRACT FROM AUTHOR]

Rationale: The average age of lung transplant recipients is increasing, and the mix of recipient indications for transplantation is changing. Objectives: To determine whether the health-related quality-of-life (HRQL) benefit of lung transplantation differs by recipient age and diagnosis. Methods: In this prospective cohort study, we obtained serial HRQL measurements in adults with advanced lung disease who subsequently underwent lung transplantation (2004-2012). HRQL assessments included the St. George's Respiratory Questionnaire, 36-Item Short-Form Health Survey (SF-36), EQ-5D, Standard Gamble, and Visual Analog Scale for current health. We used linear mixed effects models for associations between age or diagnosis and changes in HRQL with transplantation. To address potential survivorship bias, we fitted Markov models to the distribution of discrete post-transplant health states (HRQL better than pretransplant, not better, or dead) and estimated quality-adjusted life-years post-transplant. Measurements and Main Results: A total of 430 subjects were listed, 387 were transplanted, and 326 provided both pretransplant and post-transplant data. Transplantation conferred large improvements in all HRQL measures: St. George's change of -47 units (95% confidence interval, -48 to -44), 36-Item Short-Form Health Survey physical component summary score of 17.7 (16.5-18.9), EQ-5D of 0.27 (0.24-0.30), Standard Gamble of 0.48 (0.44-0.51), and Visual Analog of 44 (42-47). Age was not associated with meaningful differences in the HRQL benefits of transplantation. There was less HRQL benefit in interstitial lung disease than in cystic fibrosis. Conclusions: Lung transplantation confers large HRQL benefits, which vary by recipient diagnosis, but do not differ substantially in older recipients. [ABSTRACT FROM AUTHOR]

Background and objective In this study, we evaluated survival in rheumatoid arthritis-associated pulmonary arterial hypertension ( RA-PAH) compared with idiopathic pulmonary arterial hypertension ( IPAH) patients, and evaluate differences in disease severity and treatment. Methods We conducted a retrospective cohort study of RA-PAH and IPAH at the University Health Network Pulmonary Hypertension Programme, Toronto, Canada. The primary outcome was time to all-cause mortality. We evaluated survival using Kaplan- Meier curves. Using a propensity score-matched cohort, we used Cox proportional hazards models to estimate survival. Results Screening 1385 patients identified 18 RA-PAH and 155 IPAH patients. RA-PAH patients had an older median age of onset (64.0 vs 53.7 years) and lower baseline mean pulmonary arterial pressure (m PAP) (41 vs 50 mm Hg, P = 0.02). RA-PAH patients tended to have a higher proportion of females (83% vs 70%, relative risk 0.55, 95% confidence interval ( CI): 0.19-1.57), lower proportion with baseline World Health Organization functional class III/IV (39% vs 52%), lower median baseline brain natriuretic peptide (58.4 vs 95.0 pg/mL) and longer baseline 6-min walk distance (440 vs 397 m). There were 35 deaths, 2/18 (11%) RA-PAH patients and 33/155 (21%) IPAH patients. The unadjusted 1-year survival was 93% for RA-PAH and 94% for IPAH. In the matched cohort, there were seven deaths: 2/18 (11%) RA-PAH and 5/18 (28%) IPAH patients, hazard ratio 1.53 (95% CI: 0.15-2.84). Separation of survival curves did not achieve statistical significance, log-rank 0.56. Conclusions Compared with IPAH patients, RA-PAH patients have an older age of onset and lower baseline m PAP. RA-PAH patients have comparable survival to IPAH patients. [ABSTRACT FROM AUTHOR]

In the face of tremendous advances in our understanding of the pathophysiology and new treatment options, for many patients, pulmonary arterial hypertension (PAH) remains a progressive condition. The often-relentless reduction in the cross-sectional area of the pulmonary vasculature leads to progressive increase in right ventricular (RV) afterload. Although the right ventricle can adapt to an increase in afterload, progression of the pulmonary vasculopathy in PAH causes many patients to develop progressive RV failure.1 Alternately, for those with other forms of pulmonary hypertension, worsening lung disease or cardiac disease may destabilize the RV function. Acute RV decompensation may be triggered by disorders that lead to either an acute increase in cardiac demand (such as sepsis, surgery, or pregnancy), or an increase in ventricular afterload (such as an interruption in medical therapy or pulmonary embolism), or destabilization of a compensated RV (such as arrhythmia or volume overload). The poor reserve of the RV, RV ischemia, and adverse RV influence on left ventricular filling may lead to a global reduction in oxygen delivery and multiorgan failure.² The goals of this article are to provide an approach to right heart failure in the context of an increase in its afterload. This article will focus on pathophysiologic principles on which to build an approach to medical therapies. Mechanical and surgical strategies will be the focus in the accompanying article by Dr de Perrot. [ABSTRACT FROM AUTHOR]

Although multiple, complex molecular studies have been done for understanding the development and progression of pulmonary hypertension (PAH), little is known about the metabolic heterogeneity of PAH. Using a combination of high-throughput liquid-and-gas-chromatography-based mass spectrometry, we found bile acid metabolites, which are normally product derivatives of the liver and gallbladder, were highly increased in the PAH lung. Microarray showed that the gene encoding cytochrome P450 7B1 (CYP7B1), an isozyme for bile acid synthesis, was highly expressed in the PAH lung compared with the control. CYP7B1 protein was found to be primarily localized on pulmonary vascular endothelial cells suggesting de novo bile acid synthesis may be involved in the development of PAH. Here, by profiling the metabolomic heterogeneity of the PAH lung, we reveal a newly discovered pathogenesis mechanism of PAH. [ABSTRACT FROM AUTHOR]

Introduction: Patients with pulmonary hypertension (PH) often present with a variety of physical findings reflecting a volume or pressure overloaded right ventricle (RV). However, there is no consensus regarding the diagnostic utility of the physical examination in PH. Methods: We conducted a systematic review of publications that evaluated the clinical examination and diagnosis of PH using MEDLINE (1946–2013) and EMBASE (1947–2013). We also prospectively evaluated the diagnostic utility of the physical examination findings. Patients who underwent right cardiac catheterization for any reason were recruited. After informed consent, participants were examined by 6 physicians (3 “specialists” and 3 “generalists”) who were unaware of the results of the patient's hemodynamics. Each examiner independently assessed patients for the presence of a RV lift, loud P2, jugular venous distension (JVD), tricuspid insufficiency murmur and right-sided 4th heart sound at rest and during a slow inspiration. A global rating (scale of 1–5) of the likelihood that the patient had pulmonary hypertension was provided by each examiner. Results: 31 articles that assessed the physical examination in PH were included in the final analysis. There was heterogeneity amongst the studies and many did not include control data. The sign most associated with PH in the literature was a loud pulmonic component of the second heart sound (P2). In our prospective study physical examination was performed on 52 subjects (25 met criteria for PH; mPAP ≥25 mmHg). The physical sign with the highest likelihood ratio (LR) was a loud P2 on inspiration with a LR +ve 1.9, 95% CrI [1.2, 3.1] when data from all examiners was analyzed together. Results from the specialist examiners had higher diagnostic utility; a loud P2 on inspiration was associated with a positive LR of 3.2, 95% CrI [1.5, 6.2] and a right sided S4 on inspiration had a LR +ve 4.7, 95% CI [1.0, 15.6]. No aspect of the physical exam, could consistently rule out PH (negative LRs 0.7–1.3). Conclusions: The presence of a loud P2 or audible right-sided 4th heart sound are associated with PH. However the physical examination is unreliable for determining the presence of PH. [ABSTRACT FROM AUTHOR]

Although multiple gene and protein expression have been extensively profiled in human pulmonary arterial hypertension (PAH), the mechanism for the development and progression of pulmonary hypertension remains elusive. Analysis of the global metabolomic heterogeneity within the pulmonary vascular system leads to a better understanding of disease progression. Using a combination of high-throughput liquid-and-gas-chromatography-based mass spectrometry, we showed unbiased metabolomic profiles of disrupted glycolysis, increased TCA cycle, and fatty acid metabolites with altered oxidation pathways in the human PAH lung. The results suggest that PAH has specific metabolic pathways contributing to increased ATP synthesis for the vascular remodeling process in severe pulmonary hypertension. These identified metabolites may serve as potential biomarkers for the diagnosis of PAH. By profiling metabolomic alterations of the PAH lung, we reveal new pathogenic mechanisms of PAH, opening an avenue of exploration for therapeutics that target metabolic pathway alterations in the progression of PAH. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) predominately affects women and is characterised by progressive obliterative pulmonary vascular disease that, even in the face of medical therapies, continues to cause right heart failure and death for many. They compared outcomes in patients who developed PAH during their first pregnancy (n = 108) versus those that developed PAH during their second pregnancy (n = 48). In contrast, an earlier review found that primagravidae suffer a higher risk of death, postulating that patients who had prior successful pregnancies likely had lesser PAH disease and hence lower complication rate with subsequent pregnancies [[1]]. [Extracted from the article]

Despite advances in medical therapies, pulmonary arterial hypertension (PAH), continues to cause significant morbidity and mortality. Although, the right ventricle can adapt to an increase in afterload, progression of the pulmonary vasculopathy that characterizes PAH causes many patients to develop progressive right ventricular (RV) failure. Furthermore, acute RV decompensation may develop fromdisorders that lead to either an acute increase in cardiac demand or an increase in ventricular afterload including interruptions in medical therapy, arrhythmia, or pulmonary embolism. The poor reserve of the right ventricle, RV ischemia, and adverse RV influence on left ventricular filling may lead to a global reduction in oxygen delivery and multiorgan failure. The authors present an approach to patients with advanced PAH focusing on both medical and surgical strategies to improve RV function based upon current evidence and physiological principles. [ABSTRACT FROM AUTHOR]

Patients with congestive heart failure (CHF) due to left ventricular (LV) dysfunction have sympathetic activation specifically directed to the myocardium. Although pulmonary arterial hypertension (PAH) is associated with increased systemic sympathetic activity, its impact on sympathetic drive to ventricular myocardium is unknown. Fifteen patients with PAH (9 women; 54 ± 12 years) were studied: 10 with idiopathic PAH and 5 with a connective tissue disorder. We measured hemodynamics, as well as radiolabeled and endogenous concentrations of arterial and coronary sinus norepinephrine (NE). These measures were repeated after inhaled nitric oxide (NO). Measurement of transcardiac NE concentrations and the cardiac extraction of radiolabeled NE allowed calculation of the corrected transcardiac gradient of NE (CTCG of NE). Comparative data were collected from 15 patients (9 women: 55 ± 12 yr) with normal LV function and 15 patients with CHF (10 women; 53 ± 12 yr). PAH patients had elevated arterial NE concentrations compared with those with normal LV function but were similar to those with CHF. The CTCG of NE was higher in those with PAH than in the normal LV group (3.6 ± 2.2 vs. 1.5 ± 0.9 pmol/ml; P < 0.01) but similar to that seen in those with CHF (3.3 ± 1.4; P = NS). Inhaled NO, which reduced pulmonary artery pressure and increased cardiac output, had no effect on cardiac sympathetic activity. Therefore, cardiac sympathetic activation occurs in PAH. The mechanism of this activation remains uncertain but does not involve elevations in left heart filling pressure. [ABSTRACT FROM AUTHOR]

Objective: To analyze the outcomes of patients with pulmonary arterial hypertension referred for lung transplantation and determine the changes over time. Methods: All patients with pulmonary arterial hypertension referred for lung transplantation in our program from January 1997 to September 2010 were reviewed. Pulmonary arterial hypertension was classified as idiopathic (n = 123) or associated with congenital heart disease (n = 77), connective tissue disease (n = 102), or chronic thromboembolic disease (n = 14). Results: After completing their assessment, 61 patients (19%) were found to be unsuitable for lung transplantation, 38 (12%) refused lung transplantation, 65 (21%) were too early to be listed, and 48 (15%) died before their assessment (n = 34) or being listed (n = 14). Of the 100 patients listed for lung transplantation, 57 underwent bilateral lung transplantation, 22 underwent heart–lung transplantation, 18 died while waiting, and 3 were still waiting. The waiting list mortality was the greatest for patients with connective tissue disease–pulmonary arterial hypertension (34% vs 11% in the remaining patients, P = .005). The number of patients admitted to the hospital to be bridged to lung transplantation increased from 7% in the 1997–2004 cohort to 25% in the 2005–2010 cohort (P = .02). After lung transplantation, the 30-day mortality decreased from 24% in the 1997–2004 group to 6% in the 2005–2010 group (P = .007). The 10-year survival was worse for those with idiopathic pulmonary arterial hypertension (42% vs 70% for the remaining patients, P = .01). The long-term survival reached 69% at 10 years in the patients with connective tissue disease pulmonary arterial hypertension. Conclusions: Lung transplantation is an option for about one third of the patients with pulmonary arterial hypertension referred for lung transplantation. The 30-day mortality after lung transplantation improved significantly over time, but the long-term survival remained similar between the two cohorts. Patients with connective tissue disease–pulmonary arterial hypertension have a high mortality on the waiting list but excellent long-term survival. [ABSTRACT FROM AUTHOR]

The article discusses a study which investigated lung tissue gene expression pattern in patients with pulmonary hypertension (PH) associated with pulmonary fibrosis (PF). Pulmonary arterial pressures (PAPs) were used to determine gene expression signatures. Distinct gene signatures that were observed are described. It has been observed that PF phenotypes can be distinguished by gene expression profiles with and without APH.

The article cites a study on the assessment of persistent pulmonary hypertension after acute pulmonary embolism (PE). It found that after the median of 18 weeks of anticoagulation, 17 of 10 patients showed residual pulmonary artery systolic pressure (PAsP) and eight were determined to be suitable candidates for pulmonary endarterectomy (PEA). It implied that the first group should be evaluated despite the absence of PE and the second group are at risk and must be monitored.

The article examines evidence on the role of vascular thrombosis in the pathophysiology of idiopathic pulmonary arterial hypertension (IPAH). Current evidence shows that chronic vascular thrombosis is present in both IPAH and PAH associated with an underlying condition (APAH). It is also noted that thrombotic arteriopathy may alter the progression and prognosis of IPAH and APAH patients. Thus, the authors emphasize that thrombotic arteriopathy is an important pathophysiologic feature of PAH.

Summary: Overnight extracellular rostral fluid shifts have been shown to be of importance in patients with fluid‐retaining states and are associated with a higher prevalence of sleep apnea. Pulmonary hypertension is frequently associated with right ventricular dysfunction and progressive right ventricular failure, and an increased prevalence of sleep apnea has been described. In light of the importance of fluid shifts in the pathophysiology of sleep apnea, we aimed to explore temporal fluid shifts in patients with pulmonary hypertension with and without sleep apnea. Patients with pulmonary hypertension (WHO Group 1 or 4) had overnight extracellular rostral fluid shift assessment before and a minimum of 3 months after initiation of pulmonary hypertension‐specific therapy. Fluid shift measurements of extracellular leg, abdominal, thoracic and neck fluid volumes were performed simultaneously. Twenty‐nine patients with pulmonary hypertension (age 55 ± 16 years, 69% female) participated. Sleep apnea was diagnosed in 15 subjects (apnea–hypopnea index 14 [8–27] per hr). There were no significant differences in baseline or overnight leg extracellular rostral fluid, abdominal extracellular rostral fluid, thoracic extracellular rostral fluid or neck extracellular rostral fluid between those with and without sleep apnea. There was a significant inverse correlation between the sleep apnea severity and the overnight change in leg extracellular rostral fluid (r = −0.375, p = 0.049). There were no significant differences detected in overnight extracellular rostral fluid shifts from baseline to follow‐up. Treatment‐naïve patients with pulmonary hypertension both with and without sleep apnea demonstrate overnight extracellular rostral fluid shifts from the legs into the thorax and neck. Pulmonary hypertension‐specific treatment, while significantly improving cardiac haemodynamics, had little impact on nocturnal extracellular rostral fluid shifts or the presence of sleep apnea. [ABSTRACT FROM AUTHOR]

Provides information on chronic thromboembolic pulmonary hypertension (CTEPH). Symptoms of CTEPH; Methods used in diagnosing the disease; Treatment of choice for patients with CTEPH.

The impact of sex on long-term outcomes after pulmonary endarterectomy (PEA) for chronic thromboembolic pulmonary hypertension (PH) remains unclear. We therefore examined the early and long-term outcome after PEA to determine whether sex had an impact on the risk of residual PH and need for targeted PH medical therapy. Retrospective study of 401 consecutive patients undergoing PEA at our institution between August 2005 and March 2020 was performed. Primary outcome was the need for targeted PH medical therapy postoperatively. Secondary outcomes included survival and measures of hemodynamic improvement. Females (N = 203, 51%) were more likely to have preoperative home oxygen therapy (29.6% vs 11.6%, p < 0.01), and to present with segmental and subsegmental disease compared to males (49.2% vs 21.2%, p < 0.01). Despite similar preoperative values, females had higher postoperative pulmonary vascular resistance (final total pulmonary vascular resistance after PEA, 437 Dynes∙s∙cm−5 vs 324 Dynes∙s∙cm−5 in males, p < 0.01). Although survival at 10 years was not significantly different between sexes (73% in females vs 84% in males, p = 0.08), freedom from targeted PH medical therapy was lower in females (72.9% vs 89.9% in males at 5 years, p < 0.001). Female sex remained an independent factor affecting the need for targeted PH medical therapy after PEA in multivariate analysis (HR 2.03, 95%CI 1.03–3.98, p = 0.04). Although outcomes are excellent for both sexes, females had greater need for targeted PH medical therapy in the long-term. Early reassessment and long-term follow-up of these patients are important. Further investigations into possible mechanisms to explain the differences are warranted. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Idiopathic pulmonary arterial hypertension (IPAH) is characterized by pulmonary arteriolar narrowing and degeneration associated with in situ thrombosis. We hypothesized that microvascular endothelial injury and apoptosis may be an initiating mechanism in IPAH. Endothelial apoptosis generates endothelial microfragments (EMF), which can activate platelets. Platelets release both VEGF and angiostatin, which depending the balance can inhibit or induce endothelial apoptosis, respectively. Materials and Methods: We measured EMFs from blood of IPAH patients as index of endothelial cell apoptosis/injury and levels of pro- and anti- EC apoptotic factors found in platelets. EMFs and platelets in blood samples from control subjects and patients with IPAH were measured using a 4-color flow cytometry protocol, and platelet levels of VEGF and angiostatin were determined by ELISAs and immunoblotting. Results: Compared to controls, IPAH patients exhibited higher numbers of circulating EMFs and more activated/apoptotic platelets. IPAH patients also exhibited higher levels of platelet angiostatin; however, no significant difference was detected in platelet VEGF levels between the two groups. Conclusions: These results are consistent with an increase in EC dysfunction in patients with IPAH, possibly contributing to the progression of IPAH and its associated thrombosis. [Copyright &y& Elsevier]

ISHLT members have recognized the importance of a consensus statement on the evaluation and management of patients with chronic thromboembolic pulmonary hypertension. The creation of this document required multiple steps, including the engagement of the ISHLT councils, approval by the Standards and Guidelines Committee, identification and selection of experts in the field, and the development of 6 working groups. Each working group provided a separate section based on an extensive literature search. These sections were then coalesced into a single document that was circulated to all members of the working groups. Key points were summarized at the end of each section. Due to the limited number of comparative trials in this field, the document was written as a literature review with expert opinion rather than based on level of evidence. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) is often a progressive and ultimately fatal disease. It is characterized by an elevated mean pulmonary arterial pressure because of disease of the small pulmonary arterioles. PAH leads to a constellation of symptoms, including dyspnea, fatigue, syncope, chest discomfort, and peripheral edema. Disease-targeted therapies for PAH produce symptomatic and functional improvement, but long-term survival remains uncommon without lung transplantation. Palliative care is appropriate to support patients with advanced PAH who typically have a high symptom burden. However, palliative care has historically focused on supporting patients with malignant disease, rather than progressive chronic disease such as PAH. Our aim is to provide palliative care clinicians with a background in the classification, pathophysiology, and modern treatment of PAH. This review describes disease-targeted therapies and their effects on symptoms, physical functioning, and health-related quality of life. We also review the unique physiology of PAH and its implication for palliative interventions. Pharmacological interactions with, and precautions related to commonly used palliative care medications, are discussed. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Bayesian inference has the advantage of formally incorporating prior beliefs about the effect of an intervention into analyses of treatment effect through the use of prior probability distributions or “priors.” Multiple methods to elicit beliefs from experts for inclusion in a Bayesian study have been used; however, the measurement properties of these methods have been infrequently evaluated. The objectives of this study were to evaluate the feasibility, validity, and reliability of a belief elicitation method for Bayesian priors. Study Design and Setting: A single-center, cross-sectional study using a sample of academic specialists who treat pulmonary hypertension patients was conducted to test the feasibility, face and construct validity, and reliability of a belief elicitation method. Using this method, participants expressed the probability of 3-year survival with and without warfarin. Applying adhesive dots or “chips,” each representing 5% probability, in “bins” on a line, participants expressed their uncertainty and weight of belief about the effect of warfarin on 3-year survival. Results: Of the 12 participants, 11 (92%) reported that the belief elicitation method had face validity, 10 (83%) found the questions clear, and 11 (92%) found the response option easy to use. The median time to completion was 10 minutes (5–15 minutes). Internal validity testing found moderate agreement (weighted kappa=0.54–0.57). The intraclass correlation coefficient for test–retest reliability was 0.93. Conclusion: This method of belief elicitation for Bayesian priors is feasible, valid, and reliable. It can be considered for application in Bayesian clinical studies. [Copyright &y& Elsevier]

Abstract: The presence of irreversible pulmonary hypertension in patients with atrial septal defect (ASD) is thought to preclude shunt closure. We report the case of a woman with plexiform pulmonary arteriopathy secondary to an ostium secundum ASD who was able to successfully undergo percutaneous shunt closure following therapy with chronic intravenous prostacyclin (Flolan). One year after closure, the patient was weaned off Flolan over a period of 7 months following the institution of oral Bosentan therapy. Our case illustrates how aggressive vasodilator therapy with prostaglandins may be capable of reducing pulmonary artery pressure and permitting shunt closure in a patient once considered to have “inoperable” pulmonary arteriopathy. [Copyright &y& Elsevier]

The demands on a pulmonary arterial hypertension (PAH) treatment algorithm are multiple and in some ways conflicting. The treatment algorithm usually includes different types of recommendations with varying degrees of scientific evidence. In addition, the algorithm is required to be comprehensive but not too complex, informative yet simple and straightforward. The type of information in the treatment algorithm are heterogeneous including clinical, hemodynamic, medical, interventional, pharmacological and regulatory recommendations. Stakeholders (or users) including physicians from various specialties and with variable expertise in PAH, nurses, patients and patients’ associations, healthcare providers, regulatory agencies and industry are often interested in the PAH treatment algorithm for different reasons. These are the considerable challenges faced when proposing appropriate updates to the current evidence-based treatment algorithm.The current treatment algorithm may be divided into 3 main areas: 1) general measures, supportive therapy, referral strategy, acute vasoreactivity testing and chronic treatment with calcium channel blockers; 2) initial therapy with approved PAH drugs; and 3) clinical response to the initial therapy, combination therapy, balloon atrial septostomy, and lung transplantation. All three sections will be revisited highlighting information newly available in the past 5 years and proposing updates where appropriate. The European Society of Cardiology grades of recommendation and levels of evidence will be adopted to rank the proposed treatments. [ABSTRACT FROM AUTHOR]