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Background Pulmonary arterial hypertension (PAH) is a progressive disease with limited survival. Iron deficiency (ID) correlates with disease severity and mortality. While oral iron supplementation was shown to be insufficient in such patients, the potential impact of parenteral iron on clinical measures warrants further investigation. Methods We retrospectively analysed the long‐term effects of intravenous ferric carboxymaltose (FCM) on iron status and clinical measures in patients with PAH and ID [ferritin

Background Pulmonary hypertension (PH) in COPD is a poorly investigated clinical condition. Research Question Which factors determine the outcome of PH in COPD? Study Design and Methods We analyzed the characteristics and outcome of patients enrolled in the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) with moderate or severe PH in COPD as defined during the 6th PH World Symposium who received medical therapy for PH and compared them with patients with idiopathic pulmonary arterial hypertension (IPAH). Results The population included incident patients with moderate PH in COPD (n = 68), with severe PH in COPD (n = 307), and with IPAH (n = 489). Patients with PH in COPD were older, predominantly male, and treated mainly with phosphodiesterase-5 inhibitors. Despite similar hemodynamic impairment, patients with PH in COPD achieved a worse 6-min walking distance (6MWD) and showed a more advanced World Health Organization functional class (WHO FC). Transplant-free survival rates at 1, 3, and 5 years were higher in the IPAH group than in the PH in COPD group (IPAH: 94%, 75%, and 55% vs PH in COPD: 86%, 55%, and 38%; P = .004). Risk factors for poor outcomes in PH in COPD were male sex, low 6MWD, and high pulmonary vascular resistance (PVR). In patients with severe PH in COPD, improvements in 6MWD by ≥ 30 m or improvements in WHO FC after initiation of medical therapy were associated with better outcomes. Interpretation Patients with PH in COPD were functionally more impaired and had a poorer outcome than patients with IPAH. Predictors of death in the PH in COPD group were sex, 6MWD, and PVR. Our data raise the hypothesis that some patients with severe PH in COPD may benefit from PH treatment. Randomized controlled studies are necessary to explore this hypothesis further. Trial Registry ClinicalTrials.gov; No.: NCT01347216 ; URL: www.clinicaltrials.gov

Background Respiratory dyssynchrony (RD) is a phenomenon that may be reflected by reduced breathing efficiency (CO2 output relative to minute ventilation, V E/ V CO2 slope) or by Exercise oscillatory ventilation (EOV). Low breathing efficiency and EOV indicate a worse prognosis in chronic heart failure patients with reduced ejection fraction (HFrEF). However, only little is known about their role in other forms of structural myocardial diseases. In this study, we assessed the prognostic impact of RD in hypertrophic non-obstructive cardiomyopathy (HNCM) as a subgroup of patients with heart failure and preserved ejection fraction (HFpEF). Methods and results We selected n = 132 HNCM patients (pts) who underwent cardiopulmonary exercise testing (CPET) during baseline assessment. The average follow-up was 4.3 ± 3.6 years. The primary endpoint was a composite of death, heart transplantation (HTX), and implantation of a ventricular assist device (VAD). Respiratory dyssynchrony, as measured by EOV, was recorded in 18 pts. (14%), and as measured by a V E/ V CO2 relationship of higher than 34 in 34 pts. (26%). In total, 22 (16.7%) pts. met the endpoint. Multivariate COX regression Analysis were made for EOV, V E/ V CO2 and the combination of EOV and V E/ V CO2. All parameters correlated significantly with the endpoint: EOV (hazard ratio [HR]: 3.7; p = 0.006), V E/ V CO2 > 34 (HR: 5.6; p = 0.001) and EOV and V E/ V CO2: (HR: 6.1; p ≤ 0.001). Conclusion This is the first study to demonstrate the prognostic impact of RD on pts. with HNCM, and to investigate EOV as a novel factor to aid risk stratification in HNCM.

BACKGROUND: The prognostic value of improvement endpoints that have been used in clinical trials of treatments for pulmonary arterial hypertension (PAH) needs to be further investigated. METHODS: Using the COMPERA database, we evaluated the prognostic value of improvements in functional class (FC) and absolute or relative improvements in 6-min walking distance (6MWD) and N-terminal fragment of pro-brain natriuretic peptide (NT-proBNP). In addition, we investigated multicomponent endpoints based on prespecified improvements in FC, 6MWD and NT-proBNP that have been used in recent PAH trials. Finally, we assessed the predictive value of improvements determined by risk stratification tools. The effects of changes from baseline to first follow-up (3-12 months after initiation of PAH therapy) on consecutive survival were determined by Kaplan-Meier analysis with Log-Rank testing and Cox proportional hazard analyses. RESULTS: All analyses were based on 596 patients with newly diagnosed PAH for whom complete data were available at baseline and first follow-up. Improvements in FC were associated with improved survival, whereas absolute or relative improvements in 6MWD had no predictive value. For NT-proBNP, absolute declines conferred no prognostic information while relative declines by ≥35% were associated with better survival. Improvements in multicomponent endpoints were associated with improved survival and the same was found for risk stratification tools. CONCLUSION: While sole improvements in 6MWD and NT-proBNP had minor prognostic relevance, improvements in multicomponent endpoints and risk stratification tools based on FC, 6MWD, and NT-proBNP were associated with improved survival. These tools should be further explored as outcome measures in PAH trials. ispartof: JOURNAL OF HEART AND LUNG TRANSPLANTATION vol:41 issue:7 pages:971-981 ispartof: location:United States status: published

BackgroundRisk stratification plays an essential role in the management of patients with pulmonary arterial hypertension (PAH). The current European guidelines propose a three-stratum model to categorise risk as low, intermediate or high, based on the expected 1-year mortality. However, with this model, most patients are categorised as intermediate risk. We investigated a modified approach based on four risk categories, with intermediate risk subdivided into intermediate-low and intermediate-high risk.MethodsWe analysed data from the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA), a European pulmonary hypertension registry, and calculated risk at diagnosis and first follow-up based on World Health Organization functional class, 6-min walk distance (6MWD) and serum levels of brain natriuretic peptide (BNP) or N-terminal pro-BNP (NT-proBNP), using refined cut-off values. Survival was assessed using Kaplan–Meier analyses, log-rank testing and Cox proportional hazards models.ResultsData from 1655 patients with PAH were analysed. Using the three-stratum model, most patients were classified as intermediate risk (76.0% at baseline and 63.9% at first follow-up). The refined four-stratum risk model yielded a more nuanced separation and predicted long-term survival, especially at follow-up assessment. Changes in risk from baseline to follow-up were observed in 31.1% of the patients with the three-stratum model and in 49.2% with the four-stratum model. These changes, including those between the intermediate-low and intermediate-high strata, were associated with changes in long-term mortality risk.ConclusionsModified risk stratification using a four-stratum model based on refined cut-off levels for functional class, 6MWD and BNP/NT-proBNP was more sensitive to prognostically relevant changes in risk than the original three-stratum model.

Aims Timely referrals for transplantation and left ventricular assist device (LVAD) play a key role in favourable outcomes in patients with advanced heart failure (HF). The purpose of the Catheter Ablation for atrial fibrillation in patientS with end‐sTage heart faiLure and Eligibility for Heart Transplantation (CASTLE‐HTx) trial is to test the hypothesis that atrial fibrillation (AF) ablation has beneficial effects on mortality and morbidity during ‘waiting time’ for heart transplantation (HTx) or to prolong the time span until LVAD implantation. Methods and Results CASTLE‐HTx is a randomized evaluation of ablative treatment of AF in patients with severe left ventricular dysfunction who are candidates and eligible for HTx. The primary endpoint is the composite of all‐cause mortality, worsening of HF requiring a high urgent transplantation, or LVAD implantation. The secondary study endpoints are all‐cause mortality, cardiovascular mortality, cerebrovascular accidents, worsening of HF requiring unplanned hospitalization, AF burden reduction, unplanned hospitalization due to cardiovascular reason, all‐cause hospitalization, quality of life, number of delivered implantable cardioverter defibrillator therapies, time to first implantable cardioverter defibrillator therapy, number of device‐detected ventricular tachycardia/ventricular fibrillation episodes, left ventricular function, exercise tolerance, and percentage of right ventricular pacing. Ventricular myocardial tissue will be obtained from patients who will undergo LVAD implantation or HTx to assess the effect of catheter ablation on human HF myocardium. CASTLE‐HTx will randomize 194 patients over a minimum time period of 2 years. Conclusions CASTLE‐HTx will determine if AF ablation has beneficial effects on mortality in patients with end‐stage HF who are eligible for HTx.

BackgroundCardiopulmonary exercise testing (CPET) may provide prognostically valuable information during follow-up after pulmonary embolism (PE).ObjectiveTo investigate the association of patterns and degree of exercise limitation, as assessed by CPET, with clinical, echocardiographic, laboratory abnormalities and quality of life (QoL) after PE.MethodsIn a prospective cohort study of unselected consecutive all-comers with PE, survivors of the index acute event underwent 3-month and 12-month follow-up, including CPET. We defined cardiopulmonary limitation as ventilatory inefficiency or insufficient cardiocirculatory reserve. Deconditioning was defined as peak VO2ResultsOverall, 396 patients were included. At 3 months, prevalence of cardiopulmonary limitation and deconditioning was 50.1% (34.7% mild/moderate; 15.4% severe) and 12.1%, respectively; at 12 months, it was 44.8% (29.1% mild/moderate 15.7% severe) and 14.9%. Cardiopulmonary limitation and its severity were associated with age (OR per decade 2.05; 95% CI 1.65–2.55), history of chronic lung disease (OR 2.72; 95% CI 1.06–6.97), smoking (OR 5.87; 2.44–14.15), and intermediate- or high-risk acute PE (OR 4.36; 95% CI 1.92–9.94). Severe cardiopulmonary limitation at 3 months was associated with the prospectively defined, combined clinical-haemodynamic endpoint of “post-PE impairment” (OR 6.40, 95% CI 2.35–18.45) and with poor disease-specific and generic health-related QoL.ConclusionAbnormal exercise capacity of cardiopulmonary origin is frequent after PE, being associated with clinical and hemodynamic impairment as well as long-term QoL reduction. CPET can be considered for selected patients with persisting symptoms after acute PE to identify candidates for closer follow-up and possible therapeutic interventions.

BackgroundSince 2015, the European pulmonary hypertension guidelines recommend the use of combination therapy in most patients with pulmonary arterial hypertension (PAH). However, it is unclear to what extent this treatment strategy is adopted in clinical practice and if it is associated with improved long-term survival.MethodsWe analysed data from COMPERA, a large European pulmonary hypertension registry, to assess temporal trends in the use of combination therapy and survival of patients with newly diagnosed PAH between 2010 and 2019. For survival analyses, we looked at annualised data and at cumulated data comparing the periods 2010–2014 and 2015–2019.ResultsA total of 2531 patients were included. The use of early combination therapy (within 3 months after diagnosis) increased from 10.0% in patients diagnosed with PAH in 2010 to 25.0% in patients diagnosed with PAH in 2019. The proportion of patients receiving combination therapy 1 year after diagnosis increased from 27.7% to 46.3%. When comparing the 2010–2014 and 2015–2019 periods, 1-year survival estimates were similar (89.0% (95% CI 87.2–90.9%) and 90.8% (95% CI 89.3–92.4%), respectively), whereas there was a slight but nonsignificant improvement in 3-year survival estimates (67.8% (95% CI 65.0–70.8%) and 70.5% (95% CI 67.8–73.4%), respectively).ConclusionsThe use of combination therapy increased from 2010 to 2019, but most patients still received monotherapy. Survival rates at 1 year after diagnosis did not change over time. Future studies need to determine if the observed trend suggesting improved 3-year survival rates can be confirmed.

BACKGROUND: Among patients meeting diagnostic criteria for idiopathic pulmonary arterial hypertension (IPAH), there is an emerging lung phenotype characterised by a low diffusion capacity for carbon monoxide (DLCO) and a smoking history. The present study aimed at a detailed characterisation of these patients. METHODS: We analysed data from two European pulmonary hypertension registries, COMPERA (launched in 2007) and ASPIRE (from 2001 onwards), to identify patients diagnosed with IPAH and a lung phenotype defined by a DLCO of less than 45% predicted and a smoking history. We compared patient characteristics, response to therapy, and survival of these patients to patients with classical IPAH (defined by the absence of cardiopulmonary comorbidities and a DLCO of 45% or more predicted) and patients with pulmonary hypertension due to lung disease (group 3 pulmonary hypertension). FINDINGS: The analysis included 128 (COMPERA) and 185 (ASPIRE) patients with classical IPAH, 268 (COMPERA) and 139 (ASPIRE) patients with IPAH and a lung phenotype, and 910 (COMPERA) and 375 (ASPIRE) patients with pulmonary hypertension due to lung disease. Most patients with IPAH and a lung phenotype had normal or near normal spirometry, a severe reduction in DLCO, with the majority having no or a mild degree of parenchymal lung involvement on chest computed tomography. Patients with IPAH and a lung phenotype (median age, 72 years [IQR 65-78] in COMPERA and 71 years [65-76] in ASPIRE) and patients with group 3 pulmonary hypertension (median age 71 years [65-77] in COMPERA and 69 years [63-74] in ASPIRE) were older than those with classical IPAH (median age, 45 years [32-60] in COMPERA and 52 years [38-64] in ASPIRE; p

We sought to unravel pathomechanisms of the transition of maladaptive right ventricular (RV) remodeling to right heart failure (RHF) upon pressure overload. Exposure of C57BL/6J and C57BL/6N mice to pulmonary artery banding disclosed a tight relation of structural remodeling with afterload, but a dissociation from RV systolic function. Reduced release of mitochondrial reactive oxygen species in C57BL/6J mice prevented the development of RHF. In patients with left heart failure, increased oxidative damage in RV sections was associated with severely impaired RV function. In conclusion, reactive oxygen species are involved in the transition of maladaptive RV remodeling to RHF.

Funding Acknowledgements Type of funding sources: None. Introduction Left ventricular assist device (LVAD) is an expanding therapy in end-stage heart failure today. Although LVAD therapy bears the potential to normalize cardiac output, a majority of patients show a severely impaired physical condition at the time of LVAD implantation. To date, no validated standardized training protocol is available, and established practices to effectively improve LVAD patients’ exercise tolerance is lacking. This study sought to investigate exercise capacity quantified by cardiopulmonary exercise testing (CPX) and a standardized six-minute walk test (6MWT) in patients after LVAD implantation. Methods We enrolled 30 end-stage heart failure patients who had received an LVAD implantation 20.7 ± 7.6 days prior to examination, mean age 54.9 ± 7.8 years, 26 males (87 %). Exercise tolerance was assessed using cardiopulmonary exercise testing (CPX) for maximal and submaximal exercise capacity, followed by a standardized (6MWT). Results Patients showed peak oxygen uptake values of 8.3 ± 2.4 ml/min/kg at a mean workload of 46.7 ± 11.3 watts and a mean anaerobic threshold of 6.7 ± 1.7 ml/min/kg at a workload of 32.6 ± 6.9 watts. Mean standardized 6-minute walking distance was at 183.8 ± 71.4 meters. There were no adverse events during exercise testing. Conclusions Cardiopulmonary exercise testing (CPX) and standardized 6MWT show severely impaired cardiopulmonary exercise capacity in patients after LVAD implantation, warranting further studies for dedicated training protocols, specifically focusing on LVAD patients to improve exercise tolerance at an acceptable safety profile.

In the present practice review, we will explain how to perform and interpret a cardiopulmonary exercise test (CPET) in heart failure patients. Specifically, we will explain why cycle ergometer should be preferred to treadmill, the type of protocol needed, and the ideal exercise duration. Thereafter, we will discuss how to interpret CPET findings and determine the parameters that should be included. We will focus specifically on: peak VO2 (absolute value and a percentage of its predicted value), exercise duration, respiratory exchange ratio, peak work rate, heart rate, O2 pulse, end-tidal carbon dioxide pressure (PetCO2), PetO2, and -if blood gas samples are obtained-dead space to tidal volume ratio. Moreover, we will discuss the physiological and clinical value of anaerobic threshold, respiratory compensation point, ventilation vs. VCO2 and VO2 vs. work relationships. Finally, attention will be dedicated to exercise-induced periodic breathing. We will also discuss when and why CPET should be integrated with other measurements in the so-called complex CPET. Specifically: a) when and how to use a complex non-invasive CPET, which integrates CPET measurements with non-invasive cardiac output determination, working muscle near-infrared spectroscopy, transthoracic echocardiography, thoracic ultrasound, and lung diffusion analysis; b) when and how to use a complex minimally invasive CPET, in which CPET is combined with esophageal balloon recordings or with serial arterial blood sampling for blood gas analysis; c) when and how to use a complex invasive CPET, which usually implies the presence of a Swan Ganz catheter in the pulmonary artery and an arterial line.

ZusammenfassungDie Ende 2015 veröffentlichten ESC/ERS-Leitlinien und andere internationale Empfehlungen definierten die pulmonale Hypertonie (PH) bisher durch einen invasiv gemessenen mittleren pulmonal arteriellen Druck (mPAP) ≥ 25 mmHg in Ruhe. Auf dem 6th World Symposium on Pulmonary Hypertension in Nizza wurde eine Modifikation dieser hämodynamischen Definition im Sinne einer Senkung des Schwellenwertes auf > 20 mmHg vorgeschlagen. Für die präkapilläre PH wird zusätzlich ein pulmonaler Gefäßwiderstand (PVR) ≥ 3 Wood-Einheiten (WE) gefordert. Diese Änderung muss im Hinblick auf die zugrunde liegende Rationale und mögliche Konsequenzen kritisch hinterfragt werden; es bedarf daher einer eingehenden Erläuterung. Insbesondere muss klargestellt werden, dass diese Änderung aktuell keinen Einfluss auf die evidenzbasierte und zulassungskonforme Verschreibung von Medikamenten zur gezielten Therapie der pulmonal arteriellen Hypertonie (PAH) hat.

Pulmonary arterial hypertension (PAH) is a chronic disease that is associated with a significant and progressive limitation of exercise tolerance. The pathophysiological mechanisms of exercise intolerance during exercise are complex, multifactorial, and in fact not limited to the pulmonary circulation and the right ventricle. Disturbance of autonomic nervous function leads to an enhanced chemosensitivity, as well as respiratory and peripheral muscle weakness, and systemic endothelial dysfunction, which together play important roles in PAH pathophysiology and symptomatology. This article is focused on the different pathophysiological mechanisms of exercise intolerance in PAH, their interactions, and their relevance for clinical practice.

To evaluate the value of spectral-detector CT (SDCT) in the diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH), its differentiation against other etiologies of pulmonary hypertension (PH) and in the prediction of disease severity.60 patients with suspected PH underwent SDCT. Additional diagnostic tests in accordance with the ESC guidelines including right heart catherization and VQ-SPECT were performed. After full diagnostic work-up patients were classified as: 21 precapillary PH, 5 postcapillary PH, 6 combined pre- and postcapillary PH, 19 CTEPH, 9 no PH. SDCT examinations were analyzed by two blinded readers deciding on the diagnosis of CTEPH and scoring the extent of perfusion abnormalities on iodine density images. An additional reading was performed using conventional CTPA images only.With access to SDCT data, both readers reached a sensitivity of 100% for the diagnosis of CTEPH with a specificity of 95.1% and 87.8%. On analysis of conventional CTPA images alone, specificity and diagnostic confidence decreased for both readers (Specificity 90.2 and 85.3%) while sensitivity dropped for the less experienced reader only (Sensitivity 78.9%). Patients with PH showed significantly more perfusion abnormalities than patients without PH (16.6 ± 8.4 vs. 9.5 ± 8.9 p 0.001) and the extent of perfusion abnormalities correlated with the mean pulmonary artery pressure (r = 0.37 p = 0.008).SDCT offers confident identification of patients with CTEPH and enables a comprehensive analysis of pulmonary vasculature, pulmonary perfusion and the lung parenchyma in a single examination for patients with suspected PH.

Heart failure with preserved ejection fraction (HFpEF) is frequently associated with pulmonary hypertension (PH), which substantially impacts survival. Based on pulmonary vascular resistance (PVR) and the diastolic pressure gradient (DPG), current guidelines distinguish between isolated post-capillary PH (IpcPH) and combined post- and pre-capillary PH (CpcPH). However, the therapeutic consequences of this sub-classification remain entirely unclear. We specifically investigated the efficacy and safety of PDE5i in patients with HFpEF and CpcPH.In 40 hemodynamically precisely characterized patients with HFpEF and Cpc-PH who were treated with a PDE5i for at least 12 months, the therapeutic effect on 6-minute walk distance (6MWD), WHO functional class (FC), NTproBNP levels, right ventricular function, and hospitalization rates was evaluated.Patients' mean age was 73 ± 9 years, and comorbidities were frequent (78% hypertension, 58% atrial fibrillation, 35% diabetes). Initially, 38 patients (95%) were in WHO-FC III and 2 patients (5%) in WHO-FC II. Prior to PDE5i initiation, mean PAPm was 46.2 ± 10.3 mmHg, PAWP 21.2 ± 4.7 mmHg, DPG 5.5 ± 7.2 mmHg, and PVR 6.2 ± 3.0 WU. After 12 months of PDE5i therapy, the 6MWD increased from initially 277 ± 17 to 340 ± 18 m (p 0.001), and the proportion of patients in WHO-FC I/II increased from 5% to 37.5%. NTproBNP levels decreased by 33% (p = 0.004), and TAPSE improved from 16.8 ± 0.7 mm at baseline to 18.2 ± 0.6 mm (p = 0.01). The rate of HF-associated hospitalizations was substantially lower in the 12 months post PDE5i initiation compared to the prior 12 months. The DPG had no impact on the response to therapy. No deaths occurred, and typical side effects of PDE5i were observed.These data indicate that at least a subset of precisely characterized patients with HFpEF and CpcPH who tolerate PDE5i may benefit from targeted therapy. A randomized study in this particular sub-population is warranted.

Atrial septal defect (ASD) is one of the most frequent congenital heart diseases (CHD). Up to 10% of adults with an ASD develop pulmonary arterial hypertension (PAH, PAH-CHD) in their lifetime. Despite improved therapy options, gravidity remains a substantial risk for both maternal and neonatal mortality in PAH-CHD patients. In our patient, gravidity remained uncomplicated until week 32, under specific monotherapy with tadalafil, before onset of dyspnea and markedly increase of systolic pulmonary arterial pressure (PAP) was observed in echocardiography. Urgent Caesarian delivery was performed without any complications and a healthy baby was born. However, immediately afterwards, the patient desaturated (SpO2 65%, PaO 2 37 mmHg) due to a shunt inversion with now right-to-left shunt through the residual ASD. She was admitted to our intensive care unit and specific PH therapy was escalated to a triple combination of tadalafil, ambrisentan, and iloprost. Hereafter, in a slow process of approximately three weeks, the patient's condition improved to baseline. This rare case of a young woman with high-risk pregnancy in PAH-CHD highlights the hemodynamic changes and treatment options during pregnancy in these patients and emphasizes the urgency of a close monitoring at specialized GUCH/PAH centers with experience in managing PAH under these circumstances.