[Show abstract][Hide abstract] ABSTRACT: Introduction: Epoprostenol was the first targeted therapy available for the treatment of pulmonary arterial hypertension (PAH). Since then great advances in our knowledge of the disease have been made and the spectrum of therapeutic options for PAH has expanded. After an overview of current available treatments, this article describes the new pharmacotherapy options and their place in the management of PAH.Areas covered: This paper is based on a literature search and the review of studies published on PAH pharmacotherapy using the MEDLINE database.Expert opinion: The last decade has been particularly important in PAH management with the emergence of six new molecules, the development of novel routes of administration and improvement of pharmacokinetics. Moreover, pediatric formulations have been developed. However, further research is required to inform clinicians regarding optimal choices of combination therapies (progressive add-on therapy or upfront combination therapy, selection of associated molecules regarding the patient’s profile...), to continue to improve the quality of life of patients with new drugs and to reach the ultimate goal of curing the disease.
Expert Opinion on Pharmacotherapy 08/2015; DOI:10.1517/14656566.2015.1074177 · 3.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background.
Cardiac output (CO) is a major diagnostic and prognostic factor in pre-capillary pulmonary hypertension (PH). Reference methods for CO determination, like thermodilution (TD), require invasive procedures and allow only steady-state measurements. The Modelflow® (MF) method is an appealing technique for this purpose as it allows non-invasive and beat-by-beat determination of CO.
We aimed to compare CO values obtained simultaneously from non-invasive pulse wave analysis by MF (COMF) and by TD (COTD) to determine its precision and accuracy in pre-capillary PH. The study was performed on 50 patients with pulmonary arterial hypertension (PAH) or chronic thrombo-embolic PH (CTEPH). CO was determined at rest in all patients (n=50) and during nitric oxide vasoreactivity test, fluid challenge or exercise (n=48).
Baseline COMF and COTD were 6.18 ± 1.95 and 5.46 ± 1.95 L•min-1, respectively. Accuracy and precision were 0.72 and 1.04 L•min-1, respectively. Limits of agreement (LoA) ranged from -1.32 to 2.76 L•min-1. Percentage error (PE) was ±35.7%. Overall sensitivity and specificity of COMF for directional change were 95.2% and 82.4%, (n=48) and 93.3% and 100% for directional changes during exercise (n=16), respectively. After application of a correction factor (1.17 ± 0.25), neither proportional nor fixed bias was found for subsequent CO determination (n=48). Accuracy was -0.03 L•min−1 and precision 0.61 L•min−1. LoA ranged from -1.23 to 1.17 L•min−1 and PE was ±19.8%.
After correction against a reference method, MF is precise and accurate enough to determine absolute values and beat-by-beat relative changes of CO in pre-capillary PH.
PLoS ONE 07/2015; 10(7). DOI:10.1371/journal.pone.0134221 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Until recently, three classes of medical therapy were available for the treatment of pulmonary arterial hypertension (PAH)-prostanoids, endothelin receptor antagonists and phosphodiesterase type 5 (PDE5) inhibitors. With the approval of the soluble guanylate cyclase stimulator riociguat, an additional drug class has become available targeting a distinct molecular target in the same pathway as PDE5 inhibitors. Treatment recommendations currently include the use of all four drug classes to treat PAH, but there is a lack of comparative data for these therapies. Therefore, an understanding of the mechanistic differences between these agents is critical when making treatment decisions. Combination therapy is often used to treat PAH and it is therefore important that physicians understand how the modes of action of these drugs may interact to work as complementary partners, or potentially with unwanted consequences. Furthermore, different patient phenotypes mean that patients respond differently to treatment; while a certain monotherapy may be adequate for some patients, for others it will be important to consider alternating or combining compounds with different molecular targets. This review describes how the four currently approved drug classes target the complex pathobiology of PAH and will consider the distinct target molecules of each drug class, their modes of action, and review the pivotal clinical trial data supporting their use. It will also discuss the rationale for combining drugs (or not) from the different classes, and review the clinical data from studies on combination therapy.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
[Show abstract][Hide abstract] ABSTRACT: Inflammation and endothelial dysfunction are considered two primary instigators of pulmonary arterial hypertension (PAH). CD74 is a receptor for the pro-inflammatory cytokine macrophage migration-inhibitory factor (MIF). This ligand/receptor complex initiates survival pathways and cell proliferation, triggers the synthesis/secretion of major pro-inflammatory factors and cell adhesion molecules.
We hypothesized that MIF/CD74 signaling pathway is over-expressed in idiopathic PAH (iPAH) and contributes to a pro-inflammatory endothelial cell (EC) phenotype.
In human lung tissues, ICAM-1, VCAM-1, and E-selectin expressions are markedly up-regulated in endothelium of distal iPAH pulmonary arteries. Circulating MIF levels are increased in serum of PAH patients as compared to controls and T-cell lymphocytes represent a source of this overabundance. In addition, CD74 is highly expressed in the endothelium of muscularized pulmonary arterioles and in cultured pulmonary ECs from iPAH, contributing to an exaggerated recruitment of peripheral blood mononuclear cells (PBMCs) to pulmonary iPAH ECs. Finally, we found that curative treatments with the MIF antagonist ISO-1 or anti-CD74 neutralizing antibodies partially reverse development of pulmonary hypertension in rats and substantially reduced inflammatory cell infiltration.
We report here that CD74 and MIF are markedly increased and activated in iPAH patients, contributing to the abnormal pro-inflammatory phenotype of pulmonary ECs in iPAH.
American Journal of Respiratory and Critical Care Medicine 07/2015; DOI:10.1164/rccm.201402-0322OC · 11.99 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Exercise can distend the normally compliant, thin-walled pulmonary vessels. Loss of distensibility has been suggested as an early marker of pulmonary vascular remodeling. We hypothesized that in mild pulmonary vascular disease (PVD), a reduction in vascular distensibility during exercise occurs prior to the development of overt resting pulmonary hypertension (PH).
Distensibility α during exercise (% change in vessel diameter per mmHg increase in transmural pressure) was estimated in 90 subjects using a model of the pulmonary circulation and invasive hemodynamic data. Distensible properties in mild PVD without resting PH (PVD-noPH) (n=33) were compared to controls (n=26) and PVD with overt resting PH (PVD-PH) (n=31).
Resting mean pulmonary artery pressure (mPpa) was 14±4, 20±3 and 34±10 mmHg with corresponding exercise mPpa-cardiac output slopes of 1.5±0.6, 3.5±0.9 and 5.7±3.2 for controls, PVD-noPH and PVD-PH groups, respectively. The distensible model produced high accuracy and precision with no mean bias and 95% limits of agreement of -4.5 to 4.5 mmHg between calculated and measured mPpa. Distensibility α was lowest in PVD-PH, intermediate in PVD-noPH, and highest in controls (0.25±0.14 vs. 0.45±0.24 vs. 1.40±0.45%/mmHg, p<0.0001). Distensibility α discriminated PVD-noPH from controls with sensitivity of 88% and specificity of 100%. The discriminatory performance of α was similar for the subgroup of PVD-noPH with strictly normal resting mean Ppa ≤20 mmHg.
Loss of pulmonary vascular distensibility during exercise occurs prior to resting PH in PVD. The utility of α as a novel vascular index for the early detection of PVD warrants further validation.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: -Pulmonary veno-occlusive disease (PVOD) is an uncommon form of pulmonary hypertension (PH) characterized by obstruction of small pulmonary veins and a dismal prognosis. PVOD may be sporadic or heritable because of biallelic mutations of the EIF2AK4 gene coding for GCN2. Isolated case reports suggest that chemotherapy may be a risk factor for PVOD.
METHODS AND RESULTS: -We reported on the clinical, functional, and hemodynamic characteristics and outcomes of seven cases of PVOD induced by mitomycin-C (MMC) therapy, from the French PH Registry. All patients displayed squamous anal cancer and were treated with MMC alone or MMC plus 5-fluoruracil. The estimated annual incidence of PVOD in the French population that have anal cancer is 3.9/1000 patients, which is much higher than the incidence of PVOD in the general population (0.5/million/year). In rats, intraperitoneal administration of MMC induced PVOD, as demonstrated by PH at right-heart catheterization at days 21-35 and major remodeling of small pulmonary veins associated with foci of intense microvascular endothelial-cell proliferation of the capillary bed. In rats, MMC administration was associated with dose-dependent depletion of pulmonary GCN2 content and decreased smad1/5/8 signaling. Amifostine prevented development of MMC-induced PVOD in rats.
CONCLUSIONS: -MMC therapy is a potent inducer of PVOD in humans and rats. Amifostine prevents MMC-induced PVOD in rats and should be tested as a preventive therapy for MMC-induced PVOD in humans. MMC-induced PVOD in rats represents a unique model to test novel therapies in this devastating orphan disease.
[Show abstract][Hide abstract] ABSTRACT: Pulmonary hypertension (PH) is characterized by an elevation in mean pulmonary artery pressure leading to right heart failure and ultimately death. Growth factors play a role in PH development and their targeting may open novel therapeutic strategies in this disease.
To evaluate the nerve growth factor NGF as a potential new target in PH.
Expression and/or activation of NGF and its receptors were evaluated in rat experimental PH induced by chronic hypoxia (CH) or monocrotaline (MCT) and in human PH (idiopathic or associated to chronic obstructive pulmonary disease). Effects of exogenous NGF were evaluated ex vivo on pulmonary arterial inflammation and contraction, and in vitro on pulmonary vascular cell proliferation and migration. Effects of NGF inhibition were evaluated in vivo with anti-NGF blocking antibodies administered both in rat CH- and MCT-induced PH.
Our results show increased expression of NGF and/or increased expression/activation of its receptors in experimental and human PH. Ex vivo/in vitro studies showed NGF ability to induce pulmonary vascular cell proliferation and migration, pulmonary arterial hyperreactivity and increased secretion of pro-inflammatory cytokines. In vivo, anti-NGF blocking antibodies not only prevented but also reversed PH in rats, through significant reduction of pulmonary arterial hyperreactivity, remodeling and inflammation, all pathological PH key features.
Our study provide evidence for critical roles of NGF in PH. Owing the recent development of anti-NGF blocking antibodies as a possible new pain treatment, such therapeutic strategy of NGF inhibition may be of interest in PH.
American Journal of Respiratory and Critical Care Medicine 06/2015; DOI:10.1164/rccm.201410-1851OC · 11.99 Impact Factor