Prognostic Value of Follow-Up Hemodynamic Variables After Initial Management in Pulmonary Arterial Hypertension.

BACKGROUND: Hemodynamic variables such as cardiac index and right atrial pressure have consistently been associated with survival in pulmonary arterial hypertension (PAH) at the time of diagnosis. Recent studies have suggested that pulmonary arterial compliance may also predict prognosis in PAH. The prognostic importance of hemodynamic values achieved after treatment initiation is less well established. METHODS: Our objective was to evaluate the prognostic importance of clinical and hemodynamic variables during follow-up, including pulmonary arterial compliance, after initial management in PAH. We evaluated incident patients with idiopathic, drug- and toxin-induced, or heritable PAH enrolled in the French pulmonary hypertension registry between 2006 and 2016 who had a follow-up right-sided heart catheterization (RHC). The primary outcome was death or lung transplantation. We used stepwise Cox regression and the Kaplan-Meier method to assess variables obtained at baseline and at first follow-up RHC. RESULTS: Of 981 patients, a primary outcome occurred in 331 patients (33.7%) over a median follow-up duration of 2.8 years (interquartile range, 1.1-4.6 years). In a multivariable model considering only baseline variables, no hemodynamic variables independently predicted prognosis. Median time to first follow-up RHC was 4.6 months (interquartile range, 3.7-7.8 months). At first follow-up RHC (n=763), New York Heart Association functional class, 6-minute walk distance, stroke volume index (SVI), and right atrial pressure were independently associated with death or lung transplantation, adjusted for age, sex, and type of PAH. Pulmonary arterial compliance did not independently predict outcomes at baseline or during follow-up. The adjusted hazard ratio for SVI was 1.28 (95% confidence interval, 1.11-1.49; P<0.01) per 10-mL/m2 decrease and for right atrial pressure was 1.05 (95% confidence interval, 1.02-1.09; P<0.01) per 1-mm Hg increase. Among patients who had 2 (n=355) or 3 (n=193) low-risk prognostic features at follow-up, including a cardiac index ≥2.5 L·min-1·m-2, 6-minute walk distance >440 m, and New York Heart Association class I or II functional class, lower SVI was still associated with higher rates of death or lung transplantation (P<0.01). CONCLUSIONS: SVI and right atrial pressure were the hemodynamic variables that were independently associated with death or lung transplantation at first follow-up RHC after initial PAH treatment. These findings suggest that the SVI could be a more appropriate treatment target than cardiac index in PAH.

Ventilatory response to exercise in cardiopulmonary disease: the role of chemosensitivity and dead space.

The lungs and heart are irrevocably linked in their oxygen (O2) and carbon dioxide (CO2) transport functions. Functional impairment of the lungs often affects heart function and vice versa The steepness with which ventilation (V'E) rises with respect to CO2 production (V'CO2 ) (i.e. the V'E/V'CO2 slope) is a measure of ventilatory efficiency and can be used to identify an abnormal ventilatory response to exercise. The V'E/V'CO2 slope is a prognostic marker in several chronic cardiopulmonary diseases independent of other exercise-related variables such as peak O2 uptake (V'O2 ). The V'E/V'CO2 slope is determined by two factors: 1) the arterial CO2 partial pressure (PaCO2 ) during exercise and 2) the fraction of the tidal volume (VT) that goes to dead space (VD) (i.e. the physiological dead space ratio (VD/VT)). An altered PaCO2 set-point and chemosensitivity are present in many cardiopulmonary diseases, which influence V'E/V'CO2 by affecting PaCO2 Increased ventilation-perfusion heterogeneity, causing inefficient gas exchange, also contributes to the abnormal V'E/V'CO2 observed in cardiopulmonary diseases by increasing VD/VT During cardiopulmonary exercise testing, the PaCO2 during exercise is often not measured and VD/VT is only estimated by taking into account the end-tidal CO2 partial pressure (PETCO2 ); however, PaCO2 is not accurately estimated from PETCO2 in patients with cardiopulmonary disease. Measuring arterial gases (PaO2 and PaCO2 ) before and during exercise provides information on the real (and not "estimated") VD/VT coupled with a true measure of gas exchange efficiency such as the difference between alveolar and arterial O2 partial pressure and the difference between arterial and end-tidal CO2 partial pressure during exercise.

Long-term outcome in liver transplantation candidates with portopulmonary hypertension.

Portopulmonary hypertension (PoPH) is diagnosed in 2-6% of liver transplantation (LT) candidates. We studied outcomes of candidates for LT suffering from PoPH. Data were collected retrospectively from a prospective registry. Pulmonary hemodynamic variables were collected at the time of PoPH diagnosis, at last evaluation before LT, and within 6 months and beyond 6 months after LT. Forty-nine patients (35 males, 48 ± 8 years) were analyzed (median Model for End-Stage Liver Disease score 20). At baseline, mean pulmonary artery pressure (mPAP) was 44 ± 10 mm Hg (range 26-73 mm Hg), cardiac index was 3.5 ± 0.9 L/min/m2 , and pulmonary vascular resistance was 5.6 ± 2.8 Wood units. Hemodynamic reassessment performed in 35 patients who were treated with pulmonary arterial hypertension-targeted therapies before LT resulted in significant decreases in both mPAP (36 ± 7 versus 47 ± 10 mm Hg, P < 0.0001) and pulmonary vascular resistance (3.0 ± 1.4 versus 6.1 ± 3.1 Wood units, P < 0.0001). Fourteen patients (29%) died without having had access to LT. Thirty-five patients underwent LT and were followed up for a median of 38 months. Eight patients (23%) died after LT including 5 due to PoPH (after 1 day to 6 months). Among survivors (n = 27), all patients treated with intravenous epoprostenol were weaned off post-LT, and endothelin receptor antagonist or phosphodiesterase type 5 inhibitors were continued in 15/27 patients (55%). At last evaluation, 20/27 patients (74%) had mPAP <35 mm Hg and 8 of them (30%) had mPAP <25 mm Hg. Overall survival estimates after LT were 80%, 77%, and 77% at 6 months, 1 year, and 3 years, respectively. CONCLUSION: Stabilization or reversibility of PoPH seems to be an attainable goal using the combination of pulmonary arterial hypertension-targeted therapies and LT in patients who are transplantation candidates. (Hepatology 2017;65:1683-1692).

Novel targets of omalizumab in asthma.

PURPOSE OF REVIEW: Omalizumab is a recombinant humanized anti-IgE monoclonal antibody approved in the US for moderate to severe persistent allergic asthma (severe persistent asthma in the European Union), uncontrolled despite treatment with inhaled corticosteroids and long-acting beta2 agonists. It reduces asthma exacerbations, symptoms, oral corticosteroid doses, and improves quality of life. RECENT FINDINGS: Omalizumab may have an antiviral effect when used as a preventive therapy for fall exacerbations in children and teenagers. Two proof-of-concept studies have evaluated omalizumab in nonatopic asthma and showed that it is safe and possibly efficacious in some patients. Omalizumab has been successfully studied as add-on to specific immunotherapy in moderate allergic asthma. Its safety in pregnancy has been assessed in the EXPECT registry. Case series also report positive effects in cases of allergic bronchopulmonary aspergillosis, and in nasal disorders frequently associated with asthma. Last, omalizumab may have corticosteroid-sparing effect in a subset of patients with eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome). SUMMARY: Recent studies argue in favor of positive effects of omalizumab beyond its current indications in asthma. Well-designed studies are needed in order to demonstrate the safety and efficacy of omalizumab in these possible novel indications.

Initial dual oral combination therapy in pulmonary arterial hypertension.

Treatment for pulmonary arterial hypertension (PAH) has been underpinned by single-agent therapy to which concomitant drugs are added sequentially when pre-defined treatment goals are not met.This retrospective analysis of real-world clinical data in 97 patients with newly diagnosed PAH (86% in New York Heart Association functional class III-IV) explored initial dual oral combination treatment with bosentan plus sildenafil (n=61), bosentan plus tadalafil (n=17), ambrisentan plus tadalafil (n=11) or ambrisentan plus sildenafil (n=8).All regimens were associated with significant improvements in functional class, exercise capacity, dyspnoea and haemodynamic indices after 4 months of therapy. Over a median follow-up period of 30 months, 75 (82%) patients were still alive, 53 (71%) of whom received only dual oral combination therapy. Overall survival rates were 97%, 94% and 83% at 1, 2 and 3 years, respectively, and 96%, 94% and 84%, respectively, for the patients with idiopathic PAH, heritable PAH and anorexigen-induced PAH. Expected survival rates calculated from the French equation for the latter were 86%, 75% and 66% at 1, 2 and 3 years, respectively.Initial combination of oral PAH-targeted medications may offer clinical benefits, especially in PAH patients with severe haemodynamic impairment.

Increased pericyte coverage mediated by endothelial-derived fibroblast growth factor-2 and interleukin-6 is a source of smooth muscle-like cells in pulmonary hypertension.

BACKGROUND: Pericytes and their crosstalk with endothelial cells are critical for the development of a functional microvasculature and vascular remodeling. It is also known that pulmonary endothelial dysfunction is intertwined with the initiation and progression of pulmonary arterial hypertension (PAH). We hypothesized that pulmonary endothelial dysfunction, characterized by abnormal fibroblast growth factor-2 and interleukin-6 signaling, leads to abnormal microvascular pericyte coverage causing pulmonary arterial medial thickening. METHODS AND RESULTS: In human lung tissues, numbers of pericytes are substantially increased (up to 2-fold) in distal PAH pulmonary arteries compared with controls. Interestingly, human pulmonary pericytes exhibit, in vitro, an accentuated proliferative and migratory response to conditioned media from human idiopathic PAH endothelial cells compared with conditioned media from control cells. Importantly, by using an anti-fibroblast growth factor-2 neutralizing antibody, we attenuated these proliferative and migratory responses, whereas by using an anti-interleukin-6 neutralizing antibody, we decreased the migratory response without affecting the proliferative response. Furthermore, in our murine retinal angiogenesis model, both fibroblast growth factor-2 and interleukin-6 administration increased pericyte coverage. Finally, using idiopathic PAH human and NG2DsRedBAC mouse lung tissues, we demonstrated that this increased pericyte coverage contributes to pulmonary vascular remodeling as a source of smooth muscle-like cells. Furthermore, we found that transforming growth factor-ß, in contrast to fibroblast growth factor-2 and interleukin-6, promotes human pulmonary pericyte differentiation into contractile smooth muscle-like cells. CONCLUSIONS: To the best of our knowledge, this is the first report of excessive pericyte coverage in distal pulmonary arteries in human PAH. We also show that this phenomenon is directly linked with pulmonary endothelial dysfunction.

Pulmonary arterial hypertension in patients treated with interferon.

Isolated cases of pulmonary arterial hypertension (PAH) in patients treated with interferon (IFN) α or ß have been reported in the literature. The aim of this study was to describe all consecutive cases of PAH patients with a history of IFN exposure identified in the French reference centre for severe pulmonary hypertension between 1998 and 2012. A total of 53 patients with PAH and a history of IFN therapy were identified. 48 patients had been treated with IFNα for chronic hepatitis C. Most of them had portal hypertension (85%) and 56% had HIV co-infection. Five additional patients had been treated with IFNß for multiple sclerosis. The diagnosis of PAH was made within 3 years after IFN therapy in 66% of patients. Repeated haemodynamic assessment was available in 13 out of 16 patients exposed to IFN after the diagnosis of PAH. Increased pulmonary vascular resistance >20% was observed in 11 out of 13 cases (median 43% increase; IQR 32-67%). In five of these patients, IFN withdrawal resulted in spontaneous haemodynamic improvement. This retrospective analysis suggests that IFN therapy may trigger PAH. However, most of these patients had other risk factors for PAH. A prospective case-control study is necessary to definitively establish a link between IFN exposure and PAH.

Hypoxemia during sleep and overnight rostral fluid shift in pulmonary arterial hypertension: a pilot study.

Sleep-related breathing disorders, including sleep apnea and hypoxemia during sleep, are common in pulmonary arterial hypertension, but the underlying mechanisms remain unknown. Overnight fluid shift from the legs to the upper airway and to the lungs promotes obstructive and central sleep apnea, respectively, in fluid-retaining states. The main objective was to evaluate if overnight rostral fluid shift from the legs to the upper part of the body is associated with sleep-related breathing disorders in pulmonary arterial hypertension. In a prospective study, a group of stable patients with idiopathic, heritable, related to drugs, toxins, or treated congenital heart disease pulmonary arterial hypertension underwent a polysomnography and overnight fluid shift measurement by bioelectrical impedance in the month preceding or following a one-day hospitalization according to regular pulmonary arterial hypertension follow-up schedule with a right heart catheterization. Results show that among 15 patients with pulmonary arterial hypertension (women: 87%; median (25-75th percentiles); age: 40 (32-61) years; mean pulmonary arterial pressure 56 (46-68) mmHg; pulmonary vascular resistance 8.8 (6.4-10.1) Wood units), two patients had sleep apnea and eight (53%) had hypoxemia during sleep without apnea. The overnight rostral fluid shift was 168 (118-263) mL per leg. Patients with hypoxemia during sleep had a greater fluid shift (221 (141- 361) mL) than those without hypoxemia (118 (44-178) mL, p = 0.045). In conclusion, this pilot study suggests that hypoxemia during sleep is associated with overnight rostral fluid shift in pulmonary arterial hypertension.

Asthma treatment management strategies / Stratégies d'adaptation du traitement de fond de l'asthme

Asthma treatment management strategies. The aim of asthma treatment management strategies is to find the minimum dose of inhaled corticosteroids to achieve disease control, reduce morbidity and mortality, and improve respiratory function in patients with asthma. Assessing asthma control is therefore a key step of the management. The practitioner can use questionnaires such as ACT or ACQ for the evaluation of the patient. Adaptation of drug therapy is achieved by gradually increasing or decreasing the dose of inhaled corticosteroids and by adding or removing any additional therapies (long-acting beta2mimetics, antileukotrienes, tiotropium or theophylline). However, drug therapy is only a part of the global asthma management after confirmation of asthma diagnosis, verification of adherence and inhaled device technique, and investigation for aggravating factors and comorbidities.

Stratégies d'adaptation du traitement de fond de l'asthme. Les stratégies d'adaptation des traitements de l'asthme ont pour objectif la recherche de la dose minimale de corticostéroïdes inhalés permettant d'obtenir le contrôle de la maladie, de diminuer la morbi-mortalité et d'améliorer la fonction respiratoire des patients. L'évaluation du contrôle est donc une étape essentielle de la prise en charge. Le praticien peut s'aider de questionnaires comme l'ACT ou l'ACQ pour l'évaluation du patient. L'adaptation du traitement médicamenteux se fait en augmentant ou en diminuant progressivement la dose de corticostéroïdes inhalés et en ajoutant ou retirant d'éventuels traitements additionnels - bêta-2 mimétiques de longue durée d'action, antileucotriènes, tiotropium, voire théophylline -. Elle ne s'envisage cependant que dans le cadre d'une prise en charge globale du patient, où le diagnostic d'asthme a été confirmé, l'observance et la technique de prise des traitements inhalés vérifiés, et les facteurs aggravants et les comorbidités pris en compte.

Influence of critical closing pressure on systemic vascular resistance and total arterial compliance: A clinical invasive study.

BACKGROUND: Systemic vascular resistance (SVR) and total arterial compliance (TAC) modulate systemic arterial load, and their product is the time constant (Tau) of the Windkessel. Previous studies have assumed that aortic pressure decays towards a pressure asymptote (P∞) close to 0mmHg, as right atrial pressure is considered the outflow pressure. Using these assumptions, aortic Tau values of ∼1.5seconds have been documented. However, a zero P∞ may not be physiological because of the high critical closing pressure previously documented in vivo. AIMS: To calculate precisely the Tau and P∞ of the Windkessel, and to determine the implications for the indices of systemic arterial load. METHODS: Aortic pressure decay was analysed using high-fidelity recordings in 16 subjects. Tau was calculated assuming P∞=0mmHg, and by two methods that make no assumptions regarding P∞ (the derivative and best-fit methods). RESULTS: Assuming P∞=0mmHg, we documented a Tau value of 1372±308ms, with only 29% of Windkessel function manifested by end-diastole. In contrast, Tau values of 306±109 and 353±106ms were found from the derivative and best-fit methods, with P∞ values of 75±12 and 71±12mmHg, and with ∼80% completion of Windkessel function. The "effective" resistance and compliance were ∼70% and ∼40% less than SVR and TAC (area method), respectively. CONCLUSION: We did not challenge the Windkessel model, but rather the estimation technique of model variables (Tau, SVR, TAC) that assumes P∞=0. The study favoured a shorter Tau of the Windkessel and a higher P∞ compared with previous studies. This calls for a reappraisal of the quantification of systemic arterial load.

Dead-space ventilation is linked to exercise capacity and survival in distal chronic thromboembolic pulmonary hypertension.

BACKGROUND: Cardiopulmonary exercise testing (CPET) is frequently used for the evaluation of patients with pulmonary hypertension (PH). Non-operable distal chronic thromboembolic pulmonary hypertension (CTEPH) represents a unique subgroup of PH where microvascular disease resembling pulmonary arterial hypertension (PAH) may predominate and efficacious medical therapy is now available. However, little is known regarding the detailed CPET profile of patients with distal CTEPH, and whether ventilation and gas exchange responses are different from PAH. METHODS: Forty-nine consecutive patients with non-operable distal CTEPH according to multidisciplinary team assessment and 45 PAH patients underwent CPET and right heart catheterization. Patients were followed up for a median of 3.2 years (interquartile range: 1.8 to 4.4). RESULTS: Pulmonary hemodynamics were similar in distal CTEPH and PAH groups, but patients with distal CTEPH achieved a lower percent predicted peak oxygen consumption (59 ± 13% vs 66 ± 14%, p < 0.05). At peak exercise, higher physiologic dead-space fraction (VD/VT) (0.45 ± 0.07 vs 0.35 ± 0.07, p < 0.0001) and higher arterial-to-end-tidal carbon dioxide gradient (9 ± 3 vs 5 ± 3 mm Hg, p < 0.0001) were observed in distal CTEPH compared with PAH. Ventilatory efficiency, expressed as VE/VCO2 slope, was also more impaired in distal CTEPH (52.2 ± 10.1 vs 43.8 ± 8.4 liters/min, p < 0.0001). In the distal CTEPH group only, higher VD/VT was associated with lower peak oxygen consumption (r = -0.46, p = 0.003) and worse survival. CONCLUSIONS: Compared with PAH, a distinct pattern of response to exercise was observed in distal CTEPH, characterized by increased dead-space ventilation that resulted in worse ventilatory efficiency and greater impairment of exercise capacity. In distal CTEPH, dead-space ventilation correlated with exercise capacity and was associated with survival.

[New drugs for severe asthma]. / Les traitements du futur de l'asthme sévère.

Asthma is a very frequent disease with complex and heterogenous immunological and clinical features. Daily inhaled steroids are the cornerstone of the current therapeutics sometimes associated with long-acting ß2-agonist. This controller treatment is effective and allows to control asthma symptoms for the vast majority of the patients. Severe asthma is characterized by a poor level of control of symptoms, with recurrent exacerbations or a chronic airflow limitation despite an optimal management. Severe asthma remains a difficult diagnosis but we have now studies proving the clinical efficacy or promising data about monoclonal antibodies targeting IgE, IL-5, IL-4 or IL-13. Most of these monoclonal antibodies target the Th2 type eosinophilic inflammation without any treatment against non-eosinophilic or Th1 inflammation. Last, it will be essential to assess accurately the cost effectiveness of these expensive treatments, to identify and to qualify the target population for each molecule and to assess its financial impact for the community.

Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is a life-threatening disease that can be induced by dasatinib, a dual Src and BCR-ABL tyrosine kinase inhibitor that is used to treat chronic myelogenous leukemia (CML). Today, key questions remain regarding the mechanisms involved in the long-term development of dasatinib-induced PAH. Here, we demonstrated that chronic dasatinib therapy causes pulmonary endothelial damage in humans and rodents. We found that dasatinib treatment attenuated hypoxic pulmonary vasoconstriction responses and increased susceptibility to experimental pulmonary hypertension (PH) in rats, but these effects were absent in rats treated with imatinib, another BCR-ABL tyrosine kinase inhibitor. Furthermore, dasatinib treatment induced pulmonary endothelial cell apoptosis in a dose-dependent manner, while imatinib did not. Dasatinib treatment mediated endothelial cell dysfunction via increased production of ROS that was independent of Src family kinases. Consistent with these findings, we observed elevations in markers of endothelial dysfunction and vascular damage in the serum of CML patients who were treated with dasatinib, compared with CML patients treated with imatinib. Taken together, our findings indicate that dasatinib causes pulmonary vascular damage, induction of ER stress, and mitochondrial ROS production, which leads to increased susceptibility to PH development.

[Pulmonary hypertension in liver diseases]. / Hypertension pulmonaire et maladies hépatiques.

Portopulmonary hypertension (PoPH) is defined by the combination of portal hypertension and precapillary pulmonary hypertension (mPAP ≥ 25 mmHg, PCWP < 15 mmHg and PVR > 3 Wood units). PoPH is characterised by pathobiological mechanisms that are similar to other forms of pulmonary arterial hypertension. Prevalence of PoPH is estimated at 0.5-5% among patients with portal hypertension with or without cirrhosis. Treatment strategies most commonly employed for PoPH patients are based on recommendations for idiopathic PAH management. Indeed, the choice of specific PAH treatment must take account the severity of the underlying liver disease. Prognosis of PoPH patients is dependent on both the severity of PAH and of the underlying liver disease. PoPH may be a contraindication for orthotopic liver transplantation (OLT) if mean pulmonary arterial pressure is > 35 mmHg associated with severe right ventricular dysfunction or high level of pulmonary vascular resistance (> 3-4 Wood units). Bridge therapy with specific PAH therapies should be considered in those patients in an attempt to improve pulmonary hemodynamic and thereby allow OLT with acceptable risk. Recent data suggest that stabilize, improve or cure PoPH seems to be possible by combining specific PAH therapies and liver transplantation in selected patients. Clinical and experimental evidences suggest that IFN therapy may be a possible risk factor for PAH.

Pathogenesis of pulmonary arterial hypertension: lessons from cancer.

Although the causal pathomechanisms contributing to remodelling of the pulmonary vascular bed in pulmonary arterial hypertension (PAH) are still unclear, several analogous features with carcinogenesis have led to the emergence of the cancer-like concept. The major similarities concern the altered crosstalk between cells from different tissue types, unexplained proliferation and survival of pulmonary smooth muscle and endothelial cells, the metabolic (glycolytic) shifts, and the association with the immune system. However, major differences between PAH and cancer exist, including the absence of invasion and metastasis, as well as the pathogenic genes involved and the degrees of angiogenesis impairment and genetic instability. It is clear that PAH is not a cancer, but this cancer-like concept has opened a new field of investigation and raises the possibility that antiproliferative and/or oncological drugs may exert therapeutic effects not only in cancer, but also in PAH. Such analogies and differences are discussed here.