Manuel J. Richter

Dynamic hyperinflation during exercise in patients with precapillary pulmonary hypertension

BACKGROUND Patients with pulmonary arterial hypertension often present with a mild obstructive lung pattern, however, the functional consequences are not known. METHODS We analysed flow volume loops during exercise in 61 patients with precapillary pulmonary hypertension (PH) (age 55 ± 14 years) in comparison with 21 patients with COPD (60 ± 12 years), 39 patients with pulmonary fibrosis (58 ± 11 years) and 38 healthy controls (HC) (39 ± 15 years). Inspiratory capacity (IC) was measured at rest, and during maximum exercise (max). RESULTS HC exhibited a stable IC of 3.0 ± 0.9 l at rest, and at max. A reduction in IC of 2.6 ± 0.8 l at rest to 2.0 ± 0.7 l at max was observed in patients with COPD. Patients with PH exhibited a significant reduction in IC from 2.3 ± 0.6 l at rest to 2.1 ± 0.6 l at max, while patients with pulmonary fibrosis exhibited a stable IC of 1.8 ± 0.6 at rest and 1.7 ± 0.6 l at max. In patients with PH, a weak negative correlation was drawn between the change in IC (%) and peak VO2 (r = -0.29, p = 0.01), as well as with PVR (r = -0.27, p = 0.02). CONCLUSION Patients with PH demonstrate a characteristic change in IC during exercise, which might contribute to impaired exercise tolerance.

An epidemiological analysis of the burden of chronic thromboembolic pulmonary hypertension in the USA, Europe and Japan

Epidemiological data for chronic thromboembolic pulmonary hypertension (CTEPH) are limited and there are conflicting reports regarding its pathogenesis. A literature review was conducted to identify CTEPH epidemiological data up to June 2014. Data were analysed to provide estimates of the incidence of CTEPH in the USA, Europe and Japan. An epidemiological projection model derived country-specific estimates of future incidence and diagnosis rates of CTEPH. Overall, 25 publications and 14 databases provided quantitative epidemiological data. In the USA and Europe, the crude annual incidence of diagnosed pulmonary embolism and crude annual full (i.e. diagnosed and undiagnosed) incidence of CTEPH were 66–104 and 3–5 cases per 100 000 population, respectively, while in Japan these rates were lower at 6.7 and 1.9 per 100 000 population, respectively. In 2013, 7–29% of CTEPH cases in Europe and the USA were diagnosed, and the majority of patients were in New York Heart Association functional class III/IV at diagnosis. The projection model indicated that incidence of CTEPH will continue to increase over the next decade. These data suggest that CTEPH is underdiagnosed and undertreated, and there is an urgent need to increase awareness of CTEPH. High-quality epidemiological studies are required to increase understanding of CTEPH. Epidemiological data suggest that CTEPH is underdiagnosed and there is an urgent need to improve disease awareness http://ow.ly/J0KC3095U2W

The prognostic significance of inspiratory capacity in pulmonary arterial hypertension.

Background: Patients with pulmonary arterial hypertension (PAH) present with an altered inspiratory capacity (IC) reflecting dynamic hyperinflation (DH) that leads to mechanical constraints and excessive ventilatory demand, particularly during exercise, resulting in exertional dyspnea. Objectives: Assessment of the long-term consequences of altered IC and DH in PAH. Methods: 50 patients with newly diagnosed PAH were prospectively recruited. All patients were assessed by means of right heart catheterization, 6-min walking distance (6MWD) test, lung function and cardiopulmonary exercise testing, including the assessment of IC. Results: 37 patients with idiopathic PAH and 13 patients with conditions associated with PAH (29 female; mean age 51.6 ± 15.1 years; World Health Organization, WHO class, 2.7 ± 0.6) presented with a mean pulmonary arterial pressure of 42.8 ± 15.9 mm Hg and pulmonary vascular resistance (PVR) of 737.2 ± 592.8 dyn*s/cm5. The mean IC at rest was 87.2 ± 17.3% pred. Kaplan-Meier analysis revealed that patients with an IC at rest >89% pred. had a significantly better 5-year survival than those with lower values (94.1 vs. 75.1%; log-rank p = 0.036). Univariate analysis identified IC at rest (% pred.) as a predictor of survival with a hazard ratio (HR) of 5.05 (95% confidence interval, CI, 0.97-26.24, p = 0.054). In multivariate analysis including PVR, WHO class, 6MWD and peak oxygen uptake as covariates, IC at rest remained an independent predictor of survival (HR: 8.06, 95% CI 0.92-70.34; p = 0.059). DH expressed as ΔIC or static hyperinflation expressed as IC/total lung capacity at rest revealed no prognostic significance. Conclusion: In patients with PAH, IC at rest is of prognostic significance at the time of diagnosis.

Procedural safety of a fully implantable intravenous prostanoid pump for pulmonary hypertension

BackgroundIn patients with severe pulmonary arterial hypertension, subcutaneous or catheter-based intravenous application of prostanoids carries a risk of local side effects or systemic infections, which limits their use and acceptance. Recently, a fully implantable pump for continuous application of intravenous treprostinil was approved in Germany. However, surgery is a major risk for patients with severe pulmonary arterial hypertension. The purpose of this study was to investigate the safety of a fully implantable pump inserted under local or general anesthesia in patients with severe pulmonary hypertension.MethodsAll patients with pulmonary hypertension undergoing pump implantation for the continuous application of intravenous treprostinil were included from two German centers. Surgery was performed under local or general anesthesia according to the protocol of the recruiting center. Intra-operative safety and in-hospital complications were analyzed for the two different implantation regimens.ResultsIn total, 51 patients were included. No major intra-operative complications were recorded. During the observation period, two patients died of progressive right heart failure, and two patients required treatment in the intensive care unit for acute right heart decompensation and respiratory failure. In total, major complications occurred in 8 out of 51 patients.ConclusionsOur observational study provides preliminary evidence supporting the procedural safety of a fully implantable pump inserted under local or general anesthesia for patients with severe pulmonary hypertension. The observation of major complications in a subset of patients requires extensive pre- and post-operative assessments. Future trials are required to provide further evidence for the long-term safety and efficacy of the pump using this approach.

The prognostic impact of thyroid function in pulmonary hypertension

BACKGROUND Thyroid disease is common in patients with pulmonary hypertension (PH), but its effect on long-term survival remains unknown. We examined the prognostic significance of thyroid hormone levels of free triiodothyronine (fT3) and free thyroxine and thyroid-stimulating hormone (TSH), and thyroid hormone replacement (THR) therapy in PH. METHODS We conducted a retrospective analysis of 1,756 patients enrolled in the Giessen PH Registry in 1999 to 2013 with baseline thyroid function data; of these, 355, 533, 498, and 370 had pulmonary arterial hypertension (PAH); including 192 with idiopathic PAH (iPAH), PH due to left heart disease, PH due to lung diseases, and chronic thromboembolic PH (CTEPH), respectively. Thyroid function parameters associated with mortality were identified using Cox regression and Kaplan-Meier analyses. RESULTS Transplant-free survival at 1, 3, and 5 years was 86.7%, 65.6%, and 53.0%, respectively. Absence of THR therapy was an independent predictor of death in iPAH (multivariate hazard ratio [HR], 2.50; 95% confidence interval [CI], 1.06-5.75). In patients without THR therapy, TSH levels in the lowest and highest quartiles (compared with the middle 2 quartiles) independently predicted death in iPAH (HR, 1.98; 95% CI, 1.07-3.67), whereas reduced fT3 levels were independently associated with increased death in PAH (HR, 8.30; 95% CI, 2.50-25.00) and CTEPH (HR, 1.79; 95% CI, 1.14-4.20). CONCLUSIONS Thyroid hormone levels and THR therapy are prognostic factors in iPAH, PAH, and CTEPH. Prospective studies are warranted to verify the prognostic significance of thyroid function and the effect of THR therapy in PH.

Acute hemodynamic effects of nebulized iloprost via the I-neb Adaptive Aerosol Delivery system in pulmonary hypertension.

Inhaled iloprost has proven to be an effective therapy in patients with pulmonary hypertension (PH). However, the acute hemodynamic effect of nebulized iloprost delivered via the I-neb Adaptive Aerosol Delivery (AAD) system remains unclear and needs to be assessed. In this study, 126 patients with PH were classified according to current guidelines (59, 34, 29, and 4 patients in groups 1/1′, 3, 4, and 5, respectively; 20 patients had idiopathic pulmonary arterial hypertension [iPAH]), were randomly assigned to inhale iloprost 2.5 μg (n = 67) or 5.0 μg (n = 59) via the I-neb AAD system, and were assessed by right heart catheterization. In seven patients with iPAH, iloprost plasma levels were measured. The two iloprost doses caused decreases from baseline in pulmonary vascular resistance (PVR; 2.5 μg: −14.7%; 5.0 μg: −15.6%) and mean pulmonary arterial pressure (mPAP; 2.5 μg: −11.0%; 5.0 μg: −10.1%) while cardiac index (CI) increased (2.5 μg: +6.5%; 5.0 μg: +6.4%). The subset with iPAH also showed decreases from baseline in PVR and mPAP and an increase in CI. Peak iloprost plasma levels showed no significant difference after inhalation of 2.5 μg or 5.0 μg iloprost (95.5 pg/mL vs. 73.0 pg/mL; P = 0.06). In summary, nebulized iloprost delivered via the I-neb AAD system reduced mPAP and PVR and increased CI from baseline in a heterogeneous group of patients with PH and in the subset with iPAH. In patients with iPAH, inhalation of 2.5 μg or 5.0 μg iloprost resulted in broadly similar peak iloprost plasma levels.

Relevance of angiopoietin-2 and soluble P-selectin levels in patients with pulmonary arterial hypertension receiving combination therapy with oral treprostinil: a FREEDOM-C2 biomarker substudy

Studies have suggested roles for angiopoietin-2 (Ang-2) and soluble P-selectin (sP-selectin) as biomarkers of disease severity and treatment response in pulmonary arterial hypertension (PAH), but additional data are required for validation. We evaluated these biomarkers using data from FREEDOM-C2, in which patients with PAH receiving stable monotherapy or combination therapy were randomized to receive additional treatment with oral treprostinil (up-titrated from 0.25 mg twice daily) or placebo for 16 weeks. Biomarker analysis was optional in FREEDOM-C2. We measured plasma Ang-2 and sP-selectin levels at baseline and at week 16, and we assessed their association with predefined outcomes (6-minute walk distance [6MWD] change from baseline >40 m, 6MWD >380 m, functional class I/II, and/or N-terminal pro-brain natriuretic peptide [NT-proBNP] <1,800 pg/mL at week 16) using Spearman correlation, receiver operating characteristics, and logistic regression. Biomarker data were available for 83 of 157 and 95 of 153 patients in the oral treprostinil and placebo groups, respectively. In the oral treprostinil group, baseline Ang-2 levels correlated with week 16 NT-proBNP levels (P < 0.0001). Baseline Ang-2 ≥12 ng/mL was associated with a reduced likelihood of having NT-proBNP <1,800 pg/mL at week 16 (multivariate odds ratio: 0.08; 95% confidence interval: 0.02–0.32). However, Ang-2 showed no significant association with the other assessed outcomes, and sP-selectin was not associated or correlated with any of the outcomes. These data suggest that Ang-2 and sP-selectin are not associated with response to oral treprostinil in patients already receiving stable PAH therapy. Trial registration: Clinicaltrials.gov identifier NCT00887978.

Effects of exercise training on pulmonary hemodynamics, functional capacity and inflammation in pulmonary hypertension

Pulmonary hypertension (PH) is characterized by severe exercise limitation mainly attributed to the impairment of right ventricular function resulting from a concomitant elevation of pulmonary vascular resistance and pressure. The unquestioned cornerstone in the management of patients with pulmonary arterial hypertension (PAH) is specific vasoactive medical therapy to improve pulmonary hemodynamics and strengthen right ventricular function. Nevertheless, evidence for a beneficial effect of exercise training (ET) on pulmonary hemodynamics and functional capacity in patients with PH has been growing during the past decade. Beneficial effects of ET on regulating factors, inflammation, and metabolism have also been described. Small case-control studies and randomized clinical trials in larger populations of patients with PH demonstrated substantial improvements in functional capacity after ET. These findings were accompanied by several studies that suggested an effect of ET on inflammation, although a direct link between this effect and the therapeutic benefit of ET in PH has not yet been demonstrated. On this background, the aim of the present review is to describe current concepts regarding the effects of exercise on the pulmonary circulation and pathophysiological limitations, as well as the clinical and mechanistic effects of exercise in patients with PH.

Hemodynamic phenotyping based on exercise catheterization predicts outcome in patients with heart failure and reduced ejection fraction

BACKGROUND Exercise right heart catheterization (RHC) unmasks different phenotypes based on hemodynamic response to exertion in patients with heart failure. The prognostic relevance of this approach in patients with heart failure and reduced ejection fraction (HFrEF) is uncertain. METHODS We analyzed 167 patients with HFrEF from the Kerckhoff-Klinik Heart Failure Registry who underwent supine exercise RHC with constant external workload between September 2009 and August 2014. The primary outcome was heart transplant/assist device-free survival. Hemodynamic parameters that significantly predicted outcome were identified by multivariate Cox regression analysis and assessed further by Kaplan-Meier analysis after dichotomization using cutoffs derived from receiver operating characteristic analysis. Hemodynamic phenotypes were defined based on a dichotomized flow response (exercise-induced change in cardiac output [∆CO]) combined with a dichotomized pressure response (exercise-induced change in systolic [∆sPAP] or mean pulmonary arterial pressures). RESULTS ∆CO independently predicted transplant/assist device-free survival (multivariate hazard ratio [HR] 1.67; 95% confidence interval [CI], 1.09-2.58; p = 0.02). Patients with ∆CO ≥1.15 liter/min had significantly better 5-year transplant/assist device-free survival than patients with lower ∆CO (72.9% vs 22.5%; log-rank p < 0.001 [Kaplan-Meier analysis]). The hemodynamic phenotype of ∆CO <1.15 liter/min combined with ∆sPAP <17.5 mm Hg was associated with worse transplant/assist device-free survival than ∆CO ≥1.15 liter/min combined with ∆sPAP ≥17.5 mm Hg (multivariate HR 7.39; 95% CI, 2.27-24.05; p = 0.001). CONCLUSIONS Exercise RHC parameters are important prognostic indices in HFrEF. Hemodynamic phenotyping using ∆CO and ∆sPAP allows enhanced risk stratification.

Thin Air Resulting in High Pressure: Mountain Sickness and Hypoxia-Induced Pulmonary Hypertension

With rising altitude the partial pressure of oxygen falls. This phenomenon leads to hypobaric hypoxia at high altitude. Since more than 140 million people permanently live at heights above 2500 m and more than 35 million travel to these heights each year, understanding the mechanisms resulting in acute or chronic maladaptation of the human body to these circumstances is crucial. This review summarizes current knowledge of the bodys acute response to these circumstances, possible complications and their treatment, and health care issues resulting from long-term exposure to high altitude. It furthermore describes the characteristic mechanisms of adaptation to life in hypobaric hypoxia expressed by the three major ethnic groups permanently dwelling at high altitude. We additionally summarize current knowledge regarding possible treatment options for hypoxia-induced pulmonary hypertension by reviewing in vitro, rodent, and human studies in this area of research.