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.

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.

Chronic thromboembolic pulmonary hypertension in Australia and New Zealand: An analysis of the PHSANZ registry.

BACKGROUND AND OBJECTIVE: Chronic thromboembolic pulmonary hypertension (CTEPH) is a serious condition occurring in 2%-4% of patients after acute pulmonary embolism. Pulmonary endarterectomy (PEA) is a potential cure for technically operable disease. The epidemiology and long-term outcomes of CTEPH have not been previously described in Australia and New Zealand. METHODS: Data were extracted from the Pulmonary Hypertension Society of Australia and New Zealand (PHSANZ) registry for patients diagnosed with CTEPH between January 2004 and March 2020. Baseline characteristics, treatment strategies, outcome data and long-term survival are reported. RESULTS: A total of 386 patients were included with 146 (37.8%) undergoing PEA and 240 (62.2%) in the non-PEA group. PEA patients were younger (55 ± 16 vs. 62 ± 16 years, p < 0.001) with higher baseline 6-min walk distance (6MWD; 405 ± 122 vs. 323 ± 146 m, p = 0.021), whilst both groups had similar baseline pulmonary haemodynamics. Pulmonary hypertension-specific therapy was used in 54% of patients post-PEA and 88% in the non-PEA group. The 1-, 3- and 5-year survival rates were 93%, 87% and 84% for the PEA group compared to 86%, 73% and 62%, respectively, for the non-PEA group (p < 0.001). Multivariate survival analysis showed baseline 6MWD was an independent predictor of survival in both operated and medically managed patients. CONCLUSION: In this first multicentre report of CTEPH in Australia and New Zealand, long-term survival is comparable to that in other contemporary CTEPH registries. However, PEA was only performed in a minority of CTEPH patients (37.8%) and significantly less than overseas reports. Greater awareness of PEA and improved patient access to experienced CTEPH centres are important priorities.

ISHLT consensus document on lung transplantation in patients with connective tissue disease: Part I: Epidemiology, assessment of extrapulmonary conditions, candidate evaluation, selection criteria, and pathology statements.

Patients with connective tissue disease (CTD) and advanced lung disease are often considered suboptimal candidates for lung transplantation (LTx) due to their underlying medical complexity and potential surgical risk. There is substantial variability across LTx centers regarding the evaluation and listing of these patients. The International Society for Heart and Lung Transplantation-supported consensus document on lung transplantation in patients with CTD standardization aims to clarify definitions of each disease state included under the term CTD, to describe the extrapulmonary manifestations of each disease requiring consideration before transplantation, and to outline the absolute contraindications to transplantation allowing risk stratification during the evaluation and selection of candidates for LTx.

Lung transplant graft salvage using aortic homograft for bronchial dehiscence.

The use of aortic homograft in infective pathology is well described. Its use in the repair of post-transplant airway complications has been seldom reported. Herein, we report our experience with the successful use of aortic homograft in the management of post-transplant large airway complications in two patients.

Diagnostic delay in pulmonary arterial hypertension: Insights from the Australian and New Zealand pulmonary hypertension registry.

BACKGROUND AND OBJECTIVE: Early diagnosis of PAH is clinically challenging. Patterns of diagnostic delay in Australian and New Zealand PAH populations have not been explored in large-scale studies. We aimed to evaluate the magnitude, risk factors and survival impact of diagnostic delay in Australian and New Zealand PAH patients. METHODS: A cohort study of PAH patients from the PHSANZ Registry diagnosed from 2004 to 2017 was performed. Diagnostic interval was the time from symptom onset to diagnostic right heart catheterization as recorded in the registry. Factors associated with diagnostic delay were analysed in a multivariate logistic regression model. Survival rates were compared across patients based on the time to diagnosis using Kaplan-Meier method and Cox regression. RESULTS: A total of 2044 patients were included in analysis. At diagnosis, median age was 58 years (IQR: 43-69), female-to-male ratio was 2.8:1 and majority of patients were in NYHA FC III-IV (82%). Median diagnostic interval was 1.2 years (IQR: 0.6-2.7). Age, CHD-PAH, obstructive sleep apnoea and peripheral vascular disease were independently associated with diagnostic interval of ≥1 year. No improvement in diagnostic interval was seen during the study period. Longer diagnostic interval was associated with decreased 5-year survival. CONCLUSION: PAH patients experience significant diagnostic interval, which has not improved despite increased community awareness. Age, cardiovascular and respiratory comorbidities are significantly associated with longer time to diagnosis. Mortality rates appear higher in patients who experience longer diagnostic interval.

Retrospective Validation of the REVEAL 2.0 Risk Score With the Australian and New Zealand Pulmonary Hypertension Registry Cohort.

BACKGROUND: Pulmonary arterial hypertension (PAH) prognosis has improved with targeted therapies; however, the long-term outlook remains poor. Objective multiparametric risk assessment is recommended to identify patients at risk of early morbidity and mortality, and for optimization of treatment. The US Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) 2.0 risk score is a new model proposed for the follow-up of patients with PAH but has not been externally validated. METHODS: The REVEAL 2.0 risk score was applied to a mixed prevalent and incident cohort of patients with PAH (n = 1,011) from the Pulmonary Hypertension Society of Australia and New Zealand (PHSANZ) Registry. Kaplan-Meier survival was estimated for each REVEAL 2.0 risk score strata and for a simplified three-category (low, intermediate, and high risk) model. Sensitivity analysis was performed on an incident-only cohort. RESULTS: The REVEAL 2.0 model effectively discriminated risk in the large external PHSANZ Registry cohort, with a C statistic of 0.74 (both for full eight-tier and three-category models). When applied to incident cases only, the C statistic was 0.73. The three-category REVEAL 2.0 model demonstrated robust separation of 12- and 60-month survival estimates (all risk category comparisons P < .001). Although the full eight-tier REVEAL 2.0 model separated patients at low, intermediate, and high risk, survival estimates overlapped within some of the intermediate- and high-risk strata. CONCLUSIONS: The REVEAL 2.0 risk score was validated in a large external cohort from the PHSANZ Registry. The REVEAL 2.0 model can be applied for risk assessment of patients with PAH at follow-up. The simplified three-category model may be preferred for clinical use and for future comparison with other prognostic models.

Safe and effective exercise training for patients with pulmonary arterial hypertension: putting current evidence into clinical practice.

INTRODUCTION: While there have been significant advances in the medical treatment of pulmonary arterial hypertension (PAH), life expectancy, and quality of life remain reduced in this disease. Strenuous exercise may be hazardous for PAH patients; however, several relatively small trials have confirmed that exercise training programs can be used safely and effectively as adjunctive treatment for selected patients. The use of exercise training is now recommended in consensus international PAH treatment algorithms; however, there is no published guideline detailing how this intervention should be carried out. Areas covered: This review describes the evidence available and evaluates its applicability to 'real life' clinical practice. The limitations of current evidence are acknowledged, and we discuss how the existing data can be applied to management of PAH patients in Australia, New Zealand, and countries with similar healthcare systems. Recommendations for PAH exercise training are proposed including patient selection, program structure and duration, training modalities, training intensity, supervision, monitoring, safety precautions, and outcome assessments. Expert commentary: It is recognized that knowledge gaps remain and further research is required into physiological mechanisms associated with improved exercise capacity, optimal outpatient exercise regimen, durability of benefit, and whether there is any disease-modifying effect or impact on long-term prognosis.

Socioeconomic deprivation is not associated with reduced survival of lung transplant recipients.

BACKGROUND: Important risk factors for long-term survival of lung transplant (LT) recipients are infection, acute graft rejection (AR) and chronic lung allograft dysfunction (CLAD). Socioeconomic deprivation (SED) is associated with increased graft failure rate after heart and kidney transplantation, but has not been investigated in LT recipients. The aim of this study was to evaluate an association between LT recipients' SED status and development of AR, CLAD, and long-term survival. METHODS: This was a retrospective cohort study. Over a 23 y period, 233 patients were identified from the Auckland City Hospital Lung Transplant Registry, Auckland, New Zealand. All patients were divided into two groups according to the 2013 New Zealand Deprivation Index Score. RESULTS: The incidence of AR in the higher SED group was 34.0/100 person-y (95% confidence interval [CI]: 24.7-46.7/100 person-y) and in the lower SED group 40.2/100 person-y (95% CI: 33.5-48.3/100 person-y) (P = 0.373). The incidence of CLAD in the higher SED group was 10.7/100 person-y (95% CI: 6.2-18.4/100 person-y) and 9.3 (6.9-12.5/100 person-y) in the lower SED group (P = 0.645). Mortality in the higher SED group was 12.9/100 person-y (95% CI: 9.2-17.9/100 person-y) and 12.4/100 person-y (95% CI: 10.0-15.3/100 person-y) in the lower SED group (P = 0.834). CONCLUSIONS: SED status of LT recipients in New Zealand has no negative effect on development of AR, CLAD, and patients' survival.

Surveillance bronchoscopy in lung transplant recipients: risk versus benefit.

BACKGROUND: Long-term survival of lung transplant (LT) recipients is limited by the development of the bronchiolitis obliterans syndrome (BOS). A number of risk factors for BOS have been identified, which can be detected using bronchoscopy with transbronchial biopsy (TBB). Many LT units perform routine surveillance bronchoscopy (SB) to detect problems such as: acute rejection (AR); infection, particularly with cytomegalovirus (CMV); and lymphocytic bronchiolitis. This study aimed to assess the safety and efficacy of surveillance bronchoscopy in lung transplant recipients (LTRs), including TBB and bronchoalveolar lavage (BAL). METHODS: All bronchoscopy procedures, including SB and clinically indicated (CB) procedures performed on LTRs in one calendar year, were audited prospectively. Complications and clinical utility were recorded to determine the clinical utility both early (3 months and 3 to 12 months) and late (>12 months) post-LT. RESULTS: In one calendar year, 353 procedures (232 SBs and 121 CBs) were performed on 124 LTRs, with 246 performed <1 year post-LT. The complication rates were similar to those reported previously, except for an increased rate of sedation-related complications, particularly up to 3 months post-LT. SBs showed high rates of acute rejection, particularly in the first year post-LT (p = 0.01). The rate of asymptomatic infection diagnosed on BAL remained high regardless of time post-transplant. CONCLUSIONS: This study confirms that SB can frequently detect clinically significant infection and rejection with very low complication rates. The data support SB with TBB up to 12 months post-LT, and ongoing use of SB with BAL (only) to detect clinically silent infection beyond 1 year post-LT.

Airway vascular changes after lung transplant: potential contribution to the pathophysiology of bronchiolitis obliterans syndrome.

BACKGROUND: Bronchiolitis obliterans syndrome (BOS) remains the primary factor limiting successful lung transplantation. In asthma and lung transplantation BOS-increased sub-mucosal vascularity has been shown to contribute to airflow limitation. Vascularity has 2 components: sprouting angiogenesis (more vessels) and microvascular enlargement (larger vessels). We hypothesized that the lack of a reanastomosed bronchial arterial blood supply at the time of transplant might stimulate angiogenesis and be a risk factor for subsequent BOS. METHODS: Twenty-seven initially stable lung transplant recipients (BOS 0) were recruited at 148 +/- 80 days post-transplant and underwent clinical and bronchoscopic longitudinal follow-up for at least 3 years. Eight remained stable and BOS developed in 19. Nine normal controls were also recruited. Airway vasculature was examined immunohistochemically in endobronchial biopsy (EBB) specimens with collagen IV antibody, quantified by computer image analysis, and expressed as average vessel size, vessel number, and overall vascularity. The effects of demographic, clinical, bronchoalveolar lavage (BAL), and EBB variables on airway vasculature were analyzed in a multivariate model. RESULTS: No significant differences in airway vascularity were found between stable and BOS lung transplant recipients cross-sectionally or longitudinally. However, both lung transplant groups at baseline showed significantly greater airway vascularity compared with normal controls (p < .05). Multivariate analysis suggested that the percentage of BAL CD3+ cells and acute rejection are the most influential variables on airway vasculature. CONCLUSIONS: This study suggests early and persistent airway vasculature changes occur in lung transplant recipients, mainly manifested as microvascular enlargement. Potentially this baseline change contributes to airway obstruction and also puts all lung transplant recipients at risk for further exponential loss of airway caliber with any subsequent airway inflammatory insult.

Interstitial pneumonitis associated with sirolimus: a dilemma for lung transplantation.

Rapamycin/sirolimus (SR), trade named Rapammune (Wyeth-Ayerst, Sydney, Australia), is a potent immunosuppressive drug associated with myelosuppression, hypertension, hyperlipidemia, and infection. Rapamycin/sirolimus-induced pneumonitis has been described previously in renal transplant recipients, and this report describes a stable heart-lung transplant recipient who developed a pulmonary infiltrate that reversed after ceasing SR therapy. We believe that immunosuppression-induced pneumonitis in a lung allograft is a serious dilemma for lung transplant physicians