Exercise Hemodynamics Predict Pulmonary Arterial Hypertension in BMPR2 Mutation Carriers.

BACKGROUND: Exercise hemodynamics are recommended for early detection of pulmonary arterial hypertension (PAH) and have been suggested to be predictive of future development of PAH in high-risk populations such as BMPR2 mutation carriers. However, the optimal exercise hemodynamic screening parameter remains to be determined. Recent data suggest that pulmonary vascular distensibility coefficient (α) may serve as a useful parameter for early detection of PAH. RESEARCH QUESTION: What is the value of exercise hemodynamics, including α, for predicting the occurrence of PAH during long-term follow-up in BMPR2 mutation carriers? STUDY DESIGN AND METHODS: Fifty-two asymptomatic BMPR2 mutation carriers who underwent symptom-limited exercise hemodynamic assessment were followed up for a median of 10 years. The impact of hemodynamics at rest and exercise, presence of exercise pulmonary hypertension, and α on occurrence of PAH during long-term follow-up were assessed. RESULTS: During long-term follow-up, five patients demonstrated PAH. Patients who demonstrated PAH showed a significantly lower α (0.8 ± 0.4%/mm Hg) than patients without PAH (1.8 ± 0.8%/mm Hg; P = .008). The only hemodynamic parameter that predicted the occurrence of PAH during long-term follow-up at regression analysis was α. Receiver operating characteristic analysis showed that α ≤ 1.5%/mm Hg predicted PAH occurrence with a specificity of 75% and sensitivity of 100%. INTERPRETATION: Before development of PAH in BMPR2 mutation carriers, α is reduced markedly and may serve as a useful parameter in the setting of early disease detection. Given the low event rate, caution is warranted in interpreting these results, highlighting the need for validation studies.

Sleep-related disorders in patients with precapillary pulmonary hypertension.

Precapillary pulmonary hypertension (PcPH) is associated with the development of sleep-related disorders and impairment of sleep quality. With growing recognition of the clinical relevance of sleep-related conditions in PcPH, this narrative review seeks to discuss the spectrum of disorders encountered in clinical practice, pathophysiological mechanisms linking PcPH with sleep-related disorders, and potential therapeutic considerations. Current evidence demonstrates a higher prevalence of impaired sleep quality, sleep-disordered breathing, sleep-related hypoxia, and restless leg syndrome in patients with PcPH. These sleep-related disorders could further lead to impairment of quality of life in a patient population with already a high symptom burden. Recent data suggest that sleep-related hypoxia is strongly linked to worse right ventricular function and higher risk of transplantation or death. However, limited studies have investigated the role of oxygen therapy or positive airway pressure therapy improving symptoms or outcomes. Abnormal iron homeostasis is highly prevalent in PcPH and may contribute to the development of restless legs syndrome/periodic limb movement of sleep. To improve sleep management in PcPH, we highlight future research agenda and advocate close collaboration between pulmonary hypertension specialists and sleep physicians.

Impact of Left Heart Disease Risk Factors on Outcomes in Pulmonary Arterial Hypertension Therapy.

BACKGROUND: Current guidelines recommend initial monotherapy for pulmonary arterial hypertension (PAH) with cardiopulmonary comorbidities, despite limited available evidence to guide management. RESEARCH QUESTION: Do left heart disease (LHD) risk factors have an impact on treatment response and influence applicability of risk assessment in a real-world cohort of patients with PAH? STUDY DESIGN AND METHODS: The Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) trial criteria was used to define the phenotype of patients with PAH with risk factors for LHD. Treatment strategy, functional outcome, long-term survival, and risk discrimination were compared with a reference PAH cohort using the Pulmonary Hypertension Society of Australia and New Zealand Registry. RESULTS: A total of 487 incident patients with PAH diagnosed between 2011 and 2020 were included. Of these, 103 (21.1%) fulfilled the definition of PAH with LHD risk factors, with 384 (78.9%) remaining as the reference group. Patients in the PAH with LHD risk factors group were older (66 ± 13 vs 58 ± 19 years; P < .001), had lower pulmonary vascular resistance (393 ± 266 vs 708 ± 391 dyn.s/cm5; P = .031), and had worse 6-min walk distance (286 ± 130 vs 327 ± 136 m; P = .005) at diagnosis. The PAH with LHD risk factors group was less likely to receive initial combination therapy (27% vs 44%; P = .02). Changes in 6-min walk distance at 12 months were similar in both groups (43 ± 77 m in the PAH with LHD risk factors group and 50 ± 90 m in the reference group; P = .50), including when stratified by initial treatment strategy (PAH with LHD risk factors group vs reference PAH group: monotherapy: 40 ± 81 vs 38 ± 95 m, P = .87; combination therapy: 53 ± 78 vs 64 ± 106 m, P = .511). Functional class improvements were also similar in both groups. REVEAL Registry 2.0 risk score effectively discriminated risk in both populations (C statistic = 0.756 for the PAH with LHD risk factors group and C statistic = 0.750 for the reference PAH group). There was no difference in survival between the two groups (log-rank test, P = .29). INTERPRETATION: In a real-world cohort, patients with PAH with LHD risk factors were less likely to be exposed to initial combination therapy. Nevertheless, selected patients with PAH with LHD risk factors who were treated with initial combination therapy derived similar functional response compared with the reference group. Further studies are needed to phenotype patients with PAH with cardiopulmonary comorbidities who may benefit from initial combination therapy.

Real-world evidence to advance knowledge in pulmonary hypertension: Status, challenges, and opportunities. A consensus statement from the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative's Real-world Evidence Working Group.

This manuscript on real-world evidence (RWE) in pulmonary hypertension (PH) incorporates the broad experience of members of the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative Real-World Evidence Working Group. We aim to strengthen the research community's understanding of RWE in PH to facilitate clinical research advances and ultimately improve patient care. Herein, we review real-world data (RWD) sources, discuss challenges and opportunities when using RWD sources to study PH populations, and identify resources needed to support the generation of meaningful RWE for the global PH community.

Impact of cystic fibrosis multidisciplinary virtual clinics on patient experience, time commitments and costs.

BACKGROUND AND AIMS: The experience of outpatient care may differ for select patient groups. This prospective study evaluates the adult patient experience of multidisciplinary outpatient cystic fibrosis (CF) care with videoconferencing through telehealth compared with face-to-face care the year prior. METHODS: People with CF without a lung transplant were recruited. Patient-reported outcomes were obtained at commencement and 12 months into the study, reflecting both their face-to-face and telehealth through videoconferencing experience, respectively. Three patient cohorts were analysed: (i) participants with a regional residence, (ii) participants with a nonregional including metropolitan residence and (iii) participants with colonised multiresistant microbiota. RESULTS: Seventy-four patients were enrolled in the study (mean age, 37 ± 11 years; 50% male; mean forced expiratory volume in the first second of expiration, 60% [standard deviation, 23]) between February 2020 and May 2021. No differences between models were observed in the participants' rating of the health care team, general and mental health rating, and their confidence in handling treatment plans at home. No between-group differences in the Cystic Fibrosis Questionnaire - Revised (CFQ-R) were observed. Travel duration and the cost of attending a clinic was significantly reduced, particularly for the regional group (4 h, AU$108 per clinic; P < 0.05). A total of 93% respondents preferred to continue with a hybrid approach. CONCLUSION: In this pilot study, participants' experience of care and quality of life were no different with face-to-face and virtual care between the groups. Time and cost-savings, particularly for patients living in regional areas, were observed. Most participants preferred to continue with a hybrid model for outpatient care.

Acute Vasoreactivity Testing and Outcomes in Pulmonary Arterial Hypertension: A Call for Increased Testing.

BACKGROUND: Pulmonary arterial hypertension (PAH) has a progressive, unremitting clinical course. Vasoreactivity testing (VdT) during right heart catheterisation (RHC) identifies a subgroup with excellent long-term response to calcium channel blockade (CCB). Reporting on these patients is limited. Established in 2011, the Pulmonary Hypertension Society of Australia and New Zealand (PHSANZ) registry offers the opportunity to assess the frequency of VdT during RHC, treatment and follow up of PAH patients. METHODS: Registry data from 3,972 PAH patients with index RHC revealed 1,194 VdT appropriate patients. Data was analysed in three groups: 1) VdT+CCB+: VdT positive, CCB treated; 2) VdT+CCB-: VdT positive, no CCB prescribed, 3) VdT-/noVdT: VdT negative, or VdT not tested. Data was reviewed for adherence to guidelines, clinical response (World Health Organization functional class [WHO FC], 6-minute-walk-distance [6MWD], RHC), and outcomes (survival or lung transplantation). RESULTS: Patients included had idiopathic (IPAH=1,087), heritable (HPAH=67) and drug or toxin-induced PAH (DPAH=40). A VdT was performed in 22% (268/1,194), with incomplete data in 26% (70/268); 28% (55/198) were VdT+. Analysis group allocation was: VdT+CCB+ (33/55), VdT+CCB- (22/55), VdT- (143)/noVdT (996). From patients with 1-year data VdT+CCB+ and VdT-/noVdT patients improved WHO FC, 6MWD and cardiac index (CI); VdT+CCB- data remained similar. Within the VdT+CCB+ group, 30% (10/33) were long-term CCB responders with a 100% 5-year survival; non-responders had a 61% survival at 5.4 years. Long-term responders were younger at diagnosis (40 yrs vs 54 yrs). CONCLUSION: Use of VdT testing and documentation is poor in this contemporary patient cohort. Nonetheless, survival in VdT+CCB+ patients from the PHSANZ registry is excellent, supporting guidelines promoting VdT testing. Strategies to promote the use of VdT are warranted.

Quality of home spirometry performance amongst adults with cystic fibrosis.

Spirometry is usually performed under the supervision of a trained respiratory scientist to ensure acceptability and repeatability of results. To evaluate the quality of spirometry performance by adult cystic fibrosis (CF) patients with and without observation by a trained respiratory scientist, an observational, single centre study was conducted between February to December 2020. 74 adults were recruited and instructed to perform spirometry without supervision within 24 h of their remote CF clinic consultation. Spirometry was repeated at their consultation, supervised by a respiratory scientist using video conferencing. The majority of patients achieved grade A (excellent) or B (very good) spirometry quality with (95%) and without supervision (93%) independent of lung function severity. Similarly, forced expiratory volume in 1 second demonstrated no significant differences with paired spirometry performed within a 24 hour period. For a large proportion of adult CF patients, unsupervised portable spirometry produces acceptable and repeatable results.

Pulmonary Hypertension Definition, Classification, and Epidemiology in Asia.

Pulmonary hypertension (PH) is caused by a range of conditions and is important to recognize as it is associated with increased mortality. Pulmonary arterial hypertension refers to a group of PH subtypes affecting the distal pulmonary arteries for which effective treatment is available. The hemodynamic definition of pulmonary arterial hypertension has recently changed which may lead to greater case recognition and earlier treatment. The prevalence of specific PH etiologies may differ depending on geographic region. PH caused by left heart disease is the most common cause of PH worldwide. In Asia, there is greater proportion of congenital heart disease- and connective tissue disease- (especially systemic lupus erythematosus) related PH relative to the West. This review summarizes the definition, classification, and epidemiology of PH as it pertains to Asia.

Diagnosis of myositis-associated interstitial lung disease: Utility of the myositis autoantibody line immunoassay.

OBJECTIVES: The detection of myositis autoantibodies (MA) in patients with interstitial lung disease (ILD) has major implications for diagnosis and management, especially amyopathic and forme frustes of idiopathic inflammatory myositis-associated ILD (IIM-ILD). Use of the MA line immunoblot assay (MA-LIA) in non-rheumatological cohorts remains unvalidated. We assessed the diagnostic performance of the MA-LIA and explored combined models with clinical variables to improve identification of patients with IIM-ILD. METHODS: Consecutive patients referred to a specialist ILD clinic, with ILD-diagnosis confirmed at multidisciplinary meeting, and MA-LIA performed within six months of baseline were included. Pre-specified MA-LIA thresholds were evaluated for IIM-ILD diagnosis. RESULTS: A total 247 ILD patients were included (IIM-ILD n = 12, non-IIM connective tissue disease-associated ILD [CTD-ILD] n = 52, idiopathic interstitial pneumonia [IIP] n = 115, other-ILD n = 68). Mean age was 64.8 years, with 45.3% female, mean FVC 75.5% and DLCO 59.2% predicted. MA were present in 13.8% overall and 83.3% of IIM-ILD patients. The most common MA in IIM-ILD and non-IIM ILD patients were anti-Jo-1 (prevalence 40%) and anti-PMScl (29.2%) autoantibodies respectively. The pre-specified low-positive threshold (>10 signal intensity) had the highest discriminative capacity for IIM-ILD (AUC 0.86). Combining MA-LIA with age, gender, clinical CTD-manifestations and an overlap non-specific interstitial pneumonia/organising pneumonia pattern on HRCT improved discrimination for IIM-ILD (AUC 0.96). CONCLUSION: The MA-LIA is useful to support a diagnosis of IIM-ILD as a complement to multi-disciplinary ILD assessment. Clinical interpretation is optimised by consideration of the strength of the MA-LIA result together with clinical and radiological features of IIM-ILD.

Waitlist and post-transplant outcomes for eisenmenger syndrome: A comparison of transplant strategies.

BACKGROUND: End-stage Eisenmenger syndrome (ES) due to unrepaired atrial septal defect (ASD) or ventricular septal defect (VSD) is an indication for lung transplantation (LTx) or heart-lung transplantation (HLTx). Limited evidence exists as to the optimal transplant strategy for this unique population. AIM: To describe waitlist characteristics and post-transplant outcomes in patients with ES-ASD or ES-VSD. METHODS: Using the ISHLT Registry, data were extracted for all ES-ASD or ES-VSD patients who underwent transplantation between 1987 and 2018. Additional data were sought for patients listed for LTx or HLTx in the OPTN Registry during the same period. Early era was defined as 1987-2004, and current era was defined as 2005-2018. RESULTS: In the current era, patients with ES-ASD or ES-VSD represented a lessening proportion of all LTx and HLTx. Compared to LTx for other indications, the odds of transplantation were significantly less for both ES-ASD 0.18 [0.07-0.50] and ES-VSD 0.03 [0.004-0.22]. In the early era, an equivalent survival was observed for ES-ASD who underwent HLTx versus LTx (p = 0.47), and superior survival for ES-VSD (p = 0.015). In contrast, ES-ASD patients who underwent LTx from the current era displayed better survival compared with HLTx, 10-year survival 52% vs 30% p = 0.036. Similar survival were observed for ES-VSD for both transplant strategies (p = 0.68). CONCLUSION: LTx shows superior survival outcomes in the current era for ES ASD patients, and equivalent outcomes for ES-VSD. In the current era, ES-ASD or ES-VSD patients were less likely to be transplanted than other candidates for LTx.

The isobaric pulmonary arterial compliance in pulmonary hypertension.

Pulmonary hypertension is associated with stiffening of pulmonary arteries which increases right ventricular pulsatile loading. High pulmonary artery wedge pressure (PAWP) in postcapillary pulmonary hypertension (Pc-PH) further decreases pulmonary arterial compliance (PAC) at a given pulmonary vascular resistance (PVR) compared with precapillary pulmonary hypertension, thus responsible for a higher total arterial load. In all other vascular beds, arterial compliance is considered as mainly determined by the distending pressure, due to non-linear stress-strain behaviour of arteries. We tested the applicability, advantages and drawbacks of two comparison methods of PAC depending on the level of mean pulmonary arterial pressure (mPAP; isobaric PAC) or PVR. Right heart catheterisation data including PAC (stroke volume/pulse pressure) were obtained in 112 Pc-PH (of whom 61 had combined postcapillary and precapillary pulmonary hypertension) and 719 idiopathic pulmonary arterial hypertension (iPAH). PAC could be compared over the same mPAP range (25-66 mmHg) in 792 (95.3%) out of 831 patients and over the same PVR range (3-10.7 WU) in only 520 (62.6%) out of 831 patients. The main assumption underlying comparisons at a given PVR was not verified as the PVR×PAC product (RC-time) was not constant but on the contrary more variable than mPAP. In the 788/831 (94.8%) patients studied over the same PAC range (0.62-6.5 mL·mmHg-1), PVR and thus total arterial load tended to be higher in iPAH. Our study favours comparing PAC at fixed mPAP level (isobaric PAC) rather than at fixed PVR. A reappraisal of the effects of PAWP on the pulsatile and total arterial load put on the right heart is needed, and this point deserves further studies.

Baseline Characteristics and Survival of an Australian Interstitial Pneumonia with Autoimmune Features Cohort.

BACKGROUND AND OBJECTIVE: The research term "interstitial pneumonia with autoimmune features" (IPAF) encompasses interstitial lung disease (ILD) patients with autoimmune features not meeting diagnostic criteria for a defined connective tissue disease (CTD). It remains unclear if IPAF is a distinct disease entity with implications for management and prognosis. We describe an Australian IPAF population and compare their baseline characteristics and outcomes with distinct cohorts of idiopathic interstitial pneumonia (IIP), CTD-ILD, and unclassifiable ILD. METHODS: Review of 291 consecutive patients attending a specialist ILD clinic was performed. Patients with a diagnosis of IIP, CTD-ILD, and unclassifiable ILD by ILD-multidisciplinary meeting (ILD-MDM) were included. Patients meeting the IPAF criteria were identified. Baseline clinical data, survival, and progression were compared between ILD groups. RESULTS: 226 patients were included, 36 meeting the IPAF criteria. IPAF patients demonstrated a high prevalence of autoantibodies to tRNA synthetase (35.3%), Ro52 (27.8%), and neutrophilic cytoplasmic antigens (ANCA; 20.0%). IPAF and CTD-ILD patients demonstrated similar clinical characteristics (mean age 66.6 and 63.7 years, respectively, female predominant, frequent CTD-manifestations). Lung function did not differ between ILD groups. Disease severity, pulmonary hypertension (PH), and ILD-MDM diagnosis were strong predictors of worse transplant-free survival (TFS). Meeting the IPAF criteria was not associated with TFS. CONCLUSIONS: We identified IPAF as a heterogeneous phenotype that overlaps considerably with CTD-ILD. Disease severity, PH, and ILD-MDM diagnosis were more powerful predictors of survival outcomes than meeting the IPAF criteria.

Pulmonary Vascular Disease as a Systemic and Multisystem Disease.

Pulmonary arterial hypertension (PAH) is a disease of progressive pulmonary vascular remodeling due to abnormal proliferation of pulmonary vascular endothelial and smooth muscle cells and endothelial dysfunction. PAH is a multisystem disease with systemic manifestations and complications. This article covers the chronic heart failure syndrome, including the systemic consequences of right ventricle-pulmonary artery uncoupling and neurohormonal activation, skeletal and respiratory muscle effects, systemic endothelial dysfunction and coronary artery disease, systemic inflammation and infection, endocrine and metabolic changes, the liver and gut axis, sleep, neurologic complications, and skin and iron metabolic changes.

Inspiratory Muscle Training Improves Inspiratory Muscle Strength and Functional Exercise Capacity in Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension: A Pilot Randomised Controlled Study.

BACKGROUND: Exercise intolerance is present even in the early stages of pulmonary arterial hypertension (PAH) and is associated with poorer prognosis. Respiratory muscle dysfunction is common and may contribute to exercise limitation. We sought to investigate the effects of inspiratory muscle training (IMT) to improve exercise capacity in PAH. METHODS: Adults with PAH were prospectively recruited and randomly assigned to either IMT or a control group. At baseline and after 8 weeks, assessment of respiratory muscle function, pulmonary function, neurohormonal activation, 6-minute walk distance and cardiopulmonary exercise testing variables were conducted. Inspiratory muscle strength was assessed by maximal static inspiratory pressure (PImax). The IMT group performed two cycles of 30 breaths at 30-40% of their PImax 5 days a week for 8 weeks. RESULTS: Twelve (12) PAH patients (60±14 years, 10 females) were recruited and randomised (six in the IMT group and six in the control group). After 8 weeks, the IMT group improved PImax by 31 cmH2O compared with 10 cmH2O in controls, p=0.02. Following IMT, 6-minute walk distance improved by 24.5 m in the IMT group and declined by 12 m in the controls (mean difference 36.5 m, 95% CI 3.5-69.5, p=0.03). There was no difference in peak oxygen uptake between-groups (mean difference 0.4 mL/kg/min, 95% CI -2.6 to 3.4, p=0.77). There was no difference in the mean change between-groups in neurohormonal activation or pulmonary function. CONCLUSION: In this pilot randomised controlled study, IMT improved PImax and 6-minute walk distance in PAH patients.

Priorities and expectations of patients attending a multidisciplinary interstitial lung disease clinic.

BACKGROUND AND OBJECTIVE: The significant and progressive morbidity associated with ILD mean that patients often struggle with the impact of this disease on their QOL and independence. To date, no studies have investigated the importance of multidisciplinary care on patient experience in ILD. We aimed to determine the expectations and priorities of patients attending a tertiary referral centre multidisciplinary ILD clinic. In particular, we sought to learn how important the multidisciplinary element of the clinic was to patients and which aspects of the clinic were most valued. METHODS: An 18-item patient questionnaire was developed in conjunction with expert physicians and specialist nurses involved in the ILD clinic and sent to all patients on the centre's ILD registry at the time of the study (n = 240). Patients rated the importance of different aspects of their experience of attending the clinic. Data collected were analysed using descriptive statistics. Comparisons across disease severity were made using two-sided Z-tests for independent proportions. RESULTS: A total of 100 respondents comprised the study group. Almost all respondents valued the multidisciplinary aspect of the clinic. Obtaining an accurate diagnosis and improving their disease understanding was most important to respondents. The importance of the ILD specialist nurse for both education and support increased with worsening disease severity. CONCLUSION: Our results suggest that a multidisciplinary approach to the management of ILD with additional focus on patient education, as well as tailoring care to disease severity, is a plausible pathway to improving the patient experience with ILD.

Screening for pulmonary arterial hypertension in adults carrying a BMPR2 mutation.

BACKGROUND: Heritable pulmonary arterial hypertension (PAH) is most commonly due to heterozygous mutations of the BMPR2 gene. Based on expert consensus, guidelines recommend annual screening echocardiography in asymptomatic BMPR2 mutation carriers. The main objectives of this study were to evaluate the characteristics of asymptomatic BMPR2 mutation carriers, assess their risk of occurrence of PAH and detect PAH at an early stage in this high-risk population. METHODS: Asymptomatic BMPR2 mutation carriers underwent screening at baseline and annually for a minimum of 2 years (DELPHI-2 study; ClinicalTrials.gov: NCT01600898). Annual screening included clinical assessment, ECG, pulmonary function tests, 6-min walk distance, cardiopulmonary exercise testing, chest radiography, echocardiography and brain natriuretic peptide (BNP) or N-terminal (NT)-proBNP level. Right heart catheterisation (RHC) was performed based on predefined criteria. An optional RHC at rest and exercise was proposed at baseline. RESULTS: 55 subjects (26 males; median age 37 years) were included. At baseline, no PAH was suspected based on echocardiography and NT-proBNP levels. All subjects accepted RHC at inclusion, which identified two mild PAH cases (3.6%) and 12 subjects with exercise pulmonary hypertension (21.8%). At long-term follow-up (118.8 patient-years of follow-up), three additional cases were diagnosed, yielding a PAH incidence of 2.3% per year (0.99% per year in males and 3.5% per year in females). All PAH cases remained at low-risk status on oral therapy at last follow-up. CONCLUSIONS: Asymptomatic BMPR2 mutation carriers have a significant risk of developing incident PAH. International multicentre studies are needed to confirm that refined multimodal screening programmes with regular follow-up allow early detection of PAH.