Blood carbon dioxide tension and risk in pulmonary arterial hypertension.

BACKGROUND: Low partial pressure of blood carbon dioxide (PaCO2) is common in patients with pulmonary arterial hypertension (PAH) and may inform on clinical outcomes. We investigated whether PaCO2 measurements could provide prognostic information in addition to standard risk assessment in this group of patients. METHODS: We conducted a retrospective observational cohort study on patients with newly diagnosed idiopathic, heritable or drug/toxin-induced PAH recruited from two European centres. Arterialised capillary blood gas analyses at diagnosis and follow-up were incorporated into standard risk assessment strategies and related to outcomes, defined as lung transplant or death. C statistics from receiver-operated characteristics and Cox regression models were used to assess the predictive value of models with and without PaCO2 measurements. Unsupervised clustering was applied to assess the relation of PaCO2 to haemodynamic and pulmonary function variables. RESULTS: Low PaCO2 measured at diagnosis and follow-up was significantly associated with inferior outcomes in 204 patients with PAH. PaCO2 provided prognostic information independent of established non-invasive variables. Integrating PaCO2 in risk strata improved C statistics of non-invasive and mixed invasive/non-invasive models, and revealed more accurate outcome estimates in regression models. Pairwise correlation and unsupervised cluster analyses supported a link between PaCO2 and haemodynamic variables, particularly with cardiac output, in PAH. CONCLUSIONS: Measuring PaCO2 at diagnosis and during follow-up in patients with PAH provided independent prognostic information and has the potential to improve current risk assessment strategies.

Long-term safety and outcome of intravenous treprostinil via an implanted pump in pulmonary hypertension.

BACKGROUND: We examined safety and long-term outcomes of intravenous treprostinil administered via the implantable LENUS Pro pump in patients with severe pulmonary hypertension (PH). METHODS: Patients with PH undergoing pump implantation between December 2009 and October 2016 in German referral centers were retrospectively analyzed (end of follow-up: May 2017). The primary objective was to determine long-term safety of the implantable pump. Secondary end points were 3-year survival and prognostic relevance of pre-implantation hemodynamics. RESULTS: We monitored 129 patients (120 with pulmonary arterial hypertension, 1 with PH due to lung diseases, and 8 with inoperable chronic thromboembolic PH) for 260 patient-years (median follow-up, 19 months; interquartile range, 11-34 months). There were 82 complications/peri-procedural events in 60 patients; of these, 57 were serious adverse events (0.60 per 1,000 treatment-days), including 2 periprocedural deaths due to right heart failure. The incidence of complications related to the pump, catheter, infection, and pump pocket per 1,000 treatment-days was 0.074, 0.264, 0.032 (3 local infections; no bloodstream infections), and 0.380, respectively. Three-year overall and transplant-free survival were 66.5% and 55.7%, respectively (39 patients died; 16 underwent lung transplantation). Baseline cardiac index independently predicted transplant-free survival (multivariate hazard ratio, 1.90; 95% confidence interval, 1.11-3.28; p = 0.019; n = 95). CONCLUSIONS: Our data suggest that intravenous treprostinil via the LENUS Pro pump in advanced PH is associated with a very low risk of bloodstream infections, but other serious adverse events may occur. Therefore, this therapy needs standardization and should be offered in specialized PH centers only. Further technical advances of the pump system and prospective studies are needed.

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.

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 body's 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.

Selexipag for the treatment of pulmonary arterial hypertension.

INTRODUCTION: Targeted pulmonary vasoactive substances are the cornerstone of treatment in pulmonary arterial hypertension (PAH). Approved drugs act on various receptors and molecules within the pulmonary arteries, mainly causing pulmonary vasodilation and potentially reversing remodeling with consequent improvement of right ventricular function. A key role is attributed to the prostacyclin pathway and especially the prostacyclin receptor (IP). Selexipag is a recently developed, non-prostanoid, oral IP receptor agonist for the treatment of PAH which has been approved in countries/regions including the USA and Europe. AREAS COVERED: We review the discovery and development of drugs targeting IP receptors in PAH and describe preclinical and phase I studies of selexipag. Furthermore, we review important phase II and III selexipag studies and place them into the clinical context of previously approved prostanoids. EXPERT OPINION: Oral selexipag offers a promising therapeutic option within the class of available drugs targeting IP receptors. However, its role as first-line therapy based on its efficacy/side-effect profile in current studies is questionable. Most likely, selexipag will be used in combination with other PAH-specific oral drugs. The potential of selexipag to replace or postpone the use of inhaled or parenteral prostanoids needs to be investigated in future trials.

COPD-associated pulmonary hypertension: clinical implications and current methods for treatment.

INTRODUCTION: Chronic obstructive pulmonary disease is the fourth leading cause of death worldwide, one serious complication being pulmonary hypertension, which occurs in up to 30% of patients and increases mortality drastically. Difficulties in diagnosis and the unclear beneficial effects of PH-specific therapy have hitherto resulted in the absence of approved therapies. Consequently, PH and right heart failure in COPD are still currently treated according to symptoms and not underlying cause Areas covered: This review focuses on the current knowledge of its pathogenesis, clinical picture, diagnosis as well as methods for treatment Expert commentary: Since PH-COPD is an orphan disease with grievous consequences, and diagnosis as well as the right choice of possible treatment is crucial, referral to an expert center in cases of suspicion is necessary. Hitherto there is no officially approved treatment available even though several studies have shown notable improvement in selected individuals, making diagnostics, prognostic markers, and the search for therapeutic agents key issues of interest in this field.

Stimulation of soluble guanylate cyclase prevents cigarette smoke-induced pulmonary hypertension and emphysema.

RATIONALE: Chronic obstructive pulmonary disease (COPD) is a major cause of death worldwide. No therapy stopping progress of the disease is available. OBJECTIVES: To investigate the role of the soluble guanylate cyclase (sGC)-cGMP axis in development of lung emphysema and pulmonary hypertension (PH) and to test whether the sGC-cGMP axis is a treatment target for these conditions. METHODS: Investigations were performed in human lung tissue from patients with COPD, healthy donors, mice, and guinea pigs. Mice were exposed to cigarette smoke (CS) for 6 hours per day, 5 days per week for up to 6 months and treated with BAY 63-2521. Guinea pigs were exposed to CS from six cigarettes per day for 3 months, 5 days per week and treated with BAY 41-2272. Both BAY compounds are sGC stimulators. Gene and protein expression analysis were performed by quantitative real-time polymerase chain reaction and Western blotting. Lung compliance, hemodynamics, right ventricular heart mass alterations, and alveolar and vascular morphometry were performed, as well as inflammatory cell infiltrate assessment. In vitro assays of cell adhesion, proliferation, and apoptosis have been done. MEASUREMENTS AND MAIN RESULTS: The functionally essential sGC ß1-subunit was down-regulated in patients with COPD and in CS-exposed mice. sGC stimulators prevented the development of PH and emphysema in the two different CS-exposed animal models. sGC stimulation prevented peroxynitrite-induced apoptosis of alveolar and endothelial cells, reduced CS-induced inflammatory cell infiltrate in lung parenchyma, and inhibited adhesion of CS-stimulated neutrophils. CONCLUSIONS: The sGC-cGMP axis is perturbed by chronic exposure to CS. Treatment of COPD animal models with sGC stimulators can prevent CS-induced PH and emphysema.