[Show abstract][Hide abstract] ABSTRACT: Pulmonary hypertension (PH), a common complication of left heart diseases (LHD), negatively impacts symptoms, exercise capacity, and outcome. Although the true prevalence of PH-LHD is unknown, a subset of patients might present significant PH that cannot be explained by a passive increase in left-sided filling pressures. The term "out-of-proportion" PH has been used to identify that population without a clear definition, which has been found less than ideal and created confusion. We propose a change in terminology and a new definition of PH due to LHD. We suggest to abandon "out-of-proportion" PH and to distinguish "isolated post-capillary PH" from "post-capillary PH with a pre-capillary component" on the basis of the pressure difference between diastolic pulmonary artery pressure and pulmonary artery wedge pressure. Although there is no validated treatment for PH-LHD, we provide insights into management and discuss completed and randomized trials in this condition. Finally, we provide recommendations for future clinical trials to establish safety and efficacy of novel compounds to target this area of unmet medical need.
Journal of the American College of Cardiology 12/2013; 62(25 Suppl):D100-8. DOI:10.1016/j.jacc.2013.10.033 · 16.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Chronic obstructive lung disease (COPD) and diffuse parenchymal lung diseases (DPLD), including idiopathic pulmonary fibrosis (IPF) and sarcoidosis, are associated with a high incidence of pulmonary hypertension (PH), which is linked with exercise limitation and a worse prognosis. Patients with combined pulmonary fibrosis and emphysema (CPFE) are particularly prone to the development of PH. Echocardiography and right heart catheterization are the principal modalities for the diagnosis of COPD and DPLD. For discrimination between group 1 PH patients with concomitant respiratory abnormalities and group 3 PH patients (PH caused by lung disease), patients should be transferred to a center with expertise in both PH and lung diseases for comprehensive evaluation. The task force encompassing the authors of this article provided criteria for this discrimination and suggested using the following definitions for group 3 patients, as exemplified for COPD, IPF, and CPFE: COPD/IPF/CPFE without PH (mean pulmonary artery pressure [mPAP] <25 mm Hg); COPD/IPF/CPFE with PH (mPAP ≥25 mm Hg); PH-COPD, PH-IPF, and PH-CPFE); COPD/IPF/CPFE with severe PH (mPAP ≥35 mm Hg or mPAP ≥25 mm Hg with low cardiac index [CI <2.0 l/min/m(2)]; severe PH-COPD, severe PH-IPF, and severe PH-CPFE). The "severe PH group" includes only a minority of chronic lung disease patients who are suspected of having strong general vascular abnormalities (remodeling) accompanying the parenchymal disease and with evidence of an exhausted circulatory reserve rather than an exhausted ventilatory reserve underlying the limitation of exercise capacity. Exertional dyspnea disproportionate to pulmonary function tests, low carbon monoxide diffusion capacity, and rapid decline of arterial oxygenation upon exercise are typical clinical features of this subgroup with poor prognosis. Studies evaluating the effect of pulmonary arterial hypertension drugs currently not approved for group 3 PH patients should focus on this severe PH group, and for the time being, these patients should be transferred to expert centers for individualized patient care.
Journal of the American College of Cardiology 12/2013; 62(25 Suppl):D109-16. DOI:10.1016/j.jacc.2013.10.036 · 16.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Assessment of change in exercise capacity using the 6-min walk distance (6MWD) test has been the primary end-point in the majority of pulmonary arterial hypertension (PAH) clinical trials. The 6MWD has some advantages as an end-point in such studies. It is simple and inexpensive to perform, reproducible and validated. In short-term studies with small patient numbers, as is typical in a rare disease like PAH, using change from baseline in 6MWD as the primary outcome measure demonstrated statistically significant differences between placebo and study drugs, leading to their approval. However, there have been increasing calls for clinical trials to employ primary end-points that reflect long-term disease progression and morbidity. While the 6MWD was initially considered to be a potentially reliable surrogate for disease progression in PAH, there is increasing evidence that this is not necessarily the case. Given this, there is a need to re-examine the role of 6MWD in PAH trials, and to evaluate the evidence supporting whether there is a need to move from 6MWD to more robust measures of clinical outcomes, such as morbidity and mortality. However, in the clinic the 6MWD test, alongside symptoms, haemodynamics and biomarkers, remains a useful tool in the assessment and management of PAH patients.
European Respiratory Review 12/2013; 22(130):487-94. DOI:10.1183/09059180.00006213
[Show abstract][Hide abstract] ABSTRACT: Pulmonary veno-occlusive disease (PVOD) is a rare and devastating cause of pulmonary hypertension that is characterized histologically by widespread fibrous intimal proliferation of septal veins and preseptal venules and is frequently associated with pulmonary capillary dilatation and proliferation. PVOD is categorized into a separate pulmonary arterial hypertension-related group in the current classification of pulmonary hypertension. PVOD presents either sporadically or as familial cases with a seemingly recessive mode of transmission. Using whole-exome sequencing, we detected recessive mutations in EIF2AK4 (also called GCN2) that cosegregated with PVOD in all 13 families studied. We also found biallelic EIF2AK4 mutations in 5 of 20 histologically confirmed sporadic cases of PVOD. All mutations, either in a homozygous or compound-heterozygous state, disrupted the function of the gene. These findings point to EIF2AK4 as the major gene that is linked to PVOD development and contribute toward an understanding of the complex genetic architecture of pulmonary hypertension.
[Show abstract][Hide abstract] ABSTRACT: Pulmonary hypertension (PH) is a progressive disorder characterized by an increase in pulmonary artery pressure and structural changes in the pulmonary vasculature. Several observations indicate that growth factors play a key role in PH by modulating pulmonary artery smooth muscle cell (PA-SMC) function. In rats, established monocrotaline-induced PH (MCT-PH) can be reversed by blocking platelet-derived growth factor receptors (PDGF-R), epidermal growth factor receptors (EGF-R), or fibroblast growth factor receptors (FGF-R). All these receptors belong to the receptor tyrosine kinase (RTK) family.
We evaluated whether RTK blockade by the nonspecific growth factor inhibitor, suramin, reversed advanced MCT-PH in rats via its effects on growth-factor signaling pathways. We found that suramin inhibited RTK and ERK1/2 phosphorylation in cultured human PA-SMCs. Suramin inhibited PA-SMC proliferation induced by serum, PDGF, FGF2, or EGF in vitro and ex vivo. Treatment with suramin from day 1 to day 21 after monocrotaline injection attenuated PH development, as shown by lower values for pulmonary artery pressure, right ventricular hypertrophy, and distal vessel muscularization on day 21 compared to control rats. Treatment with suramin from day 21 to day 42 after monocrotaline injection reversed established PH, thereby normalizing the pulmonary artery pressure values and vessel structure. Suramin treatment suppressed PA-SMC proliferation and attenuated both the inflammatory response and the deposition of collagen.
RTK blockade by suramin can prevent MCT-PH and reverse established MCT-PH in rats. This study suggests that an anti-RTK strategy that targets multiple RTKs could be useful in the treatment of pulmonary hypertension.
PLoS ONE 10/2013; 8(10):e77073. DOI:10.1371/journal.pone.0077073 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Pulmonary arterial hypertension (PAH) is a rare disorder characterized by progressive obliteration of small pulmonary arteries that leads to elevated pulmonary arterial pressure and right heart failure. During the last decades, an improved understanding of the pathophysiology of the disease has resulted in the development of effective therapies targeting endothelial dysfunction (epoprostenol and derivatives, endothelin receptor antagonists and phosphodiesterase type 5 inhibitors). These drugs allow clinical, functional and hemodynamic improvement, but to date, no cure exists for PAH and prognosis remains poor. Recently, several additional pathways have been suggested to be involved in the pathogenesis of PAH, and may represent innovative therapies. In this summary, we review conventional therapy, pharmacological agents currently available for the treatment of PAH and the benefit/risk ratio of potential future therapies.
[Show abstract][Hide abstract] ABSTRACT: Pulmonary hypertension is defined as an increase of mean pulmonary arterial pressure ≥25 mmHg at rest as assessed by right heart catheterization. According to different combinations of values of pulmonary wedge pressure, pulmonary vascular resistance and cardiac output, a hemodynamic classification of pulmonary hypertension has been proposed. Of major importance is the pulmonary wedge pressure which allows to distinguish pre-capillary (pulmonary wedge pressure ≤15 mmHg) and post-capillary (pulmonary wedge pressure >15 mmHg) pulmonary hypertension. Pre-capillary pulmonary hypertension includes the clinical groups 1 (pulmonary arterial hypertension), 3 (pulmonary hypertension due to lung diseases and/or hypoxia), 4 (chronic thrombo-embolic pulmonary hypertension) and 5 (pulmonary hypertension with unclear and/or multifactorial mechanisms). Post-capillary pulmonary hypertension corresponds to the clinical group 2 (pulmonary hypertension due to left heart diseases).
Handbook of experimental pharmacology 10/2013; 218:3-29. DOI:10.1007/978-3-642-38664-0_1
[Show abstract][Hide abstract] ABSTRACT: DVT/PE/Pulmonary Hypertension PostersSESSION TYPE: Original InvestigationPRESENTED ON: Wednesday, October 30, 2013 at 01:30 PM - 02:30 PMPURPOSE: In the SERAPHIN trial (NCT00660179), macitentan significantly reduced the risk of morbidity and mortality (primary endpoint) in pulmonary arterial hypertension (PAH) patients. This analysis evaluated the predictive value of N-terminal pro-B natriuretic peptide (NT-pro-BNP), cardiac index (CI) and pulmonary vascular resistance (PVR) on this outcome.METHODS: 742 PAH patients (≥12 years) were randomized to placebo, 3 mg or 10 mg macitentan, once daily. Hazard ratios (HR; 95% confidence intervals) were calculated to measure the association between the risk of morbidity and mortality and interquartile ranges (lowest=Q1 and highest=Q4) of NT-pro-BNP (n=495), CI (n=145) and PVR (n=145) at baseline, absolute values at Month 6, and change from baseline at Month 6. Univariate models and regression models unadjusted or adjusted for significant covariates were used, independently of treatment group. Analyses were performed in patients with available data for NT-pro-BNP, CI and PVR at Month 6, and from Month 6 up to end of treatment for morbidity and mortality.RESULTS: Median baseline and Month 6 values for the placebo, 3 mg and 10 mg macitentan groups for NT-pro-BNP were 716 and 794 fmol/L (n=160), 841 and 759 fmol/L (n=165) and 807 and 707 fmol/L (n=170), respectively; for CI were 2.51 and 2.28 L/min/m2 (n=50), 2.23 and 2.70 L/min/m2 (n=47) and 2.56 and 3.06 L/min/m2 (n=48), respectively; and for PVR were 800 and 907 dyn.sec/cm5 (n=50), 785 and 600 dyn.sec/cm5 (n=47) and 789 and 536 dyn.sec/cm5 (n=48), respectively. The unadjusted HR for baseline NT-pro-BNP Q1 <517 fmol/L vs Q4 >1362 fmol/L was 6.25 (3.58-10.91), for CI Q1 <1.85 L/min/m2 vs Q4 >2.81 L/min/m2 was 2.62 (1.84-3.72) and for PVR Q1 <522 dyn.sec/cm5 vs Q4 >1314 dyn.sec/cm5 was 3.17 (2.14-4.70). Similarly, higher Month 6 absolute values for NT-pro-BNP and PVR, and lower Month 6 absolute values for CI were associated with significant increased risk in morbidity and mortality. Data were similar for both analyses when adjusted for covariates. There was no consistent association between change from baseline to Month 6 and risk of morbidity and mortality.CONCLUSIONS: Higher NT-pro-BNP and PVR, and lower CI values at baseline and at Month 6 were significantly associated with a higher risk of morbidity and mortality, but changes from baseline were not.CLINICAL IMPLICATIONS: Baseline and absolute values at Month 6 for NT-pro-BNP, CI and PVR are valuable cardiac function predictors of long-term outcome in PAH.DISCLOSURE: Richard Channick; grant monies, Actelion. Marion Delcroix; consultant fee, speaker bureau, advisory committee, Actelion, GlaxoSmithKline, Pfizer, United Therapeutics, Bayer, grant monies, Actelion and GlaxoSmithKline. Nazzareno Galie; consultant fee, speaker bureau, advisory committee, grant monies Actelion, Pfizer, GlaxoSmithKline, Eli Lilly, Bayer. Hossein Ghofrani; consultant fee, speaker bureau, advisory committee, grant monies, Gilead, GlaxoSmithKline, Merck, Novartis, Pfizer, Bayer, Ergonex, Actelion. Pavel Jansa; consultant free, speaker bureau, advisory committee, United Therapeutics, AOP Orphan, Actelion, grant monies, Actelion. Franck-Olivier LeBrun: Employee, Actelion. Sanjay Mehta: grant monies, Heart & Stroke Foundation of Ontario/Canada, Canadian Institute of Health Research, Ontario Thoracic Society. Loic Perchenet: Employee, Actelion. Tomas Pulido: consultant fee, speaker bureau, advisory committee, Actelion, Pfizer, Eli Lilly, Bayer, grant monies Bayer, Actelion, United Therapeutics. B Sastry; consultant fee, speaker bureau, advisory committee, GlaxoSmithKline. Olivier Sitbon; consultant fee, speaker bureau, advisory committee, Actelion, GlaxoSmith Kline, Pfizer, Eli Lilly, United Therapeutics, grant monies, Actelion, GlaxoSmithKline, Pfizer, Eli Lilly, Bayer. Rogerio Souza; consultant fee, speaker bureau, advisory committee, Actelion, Eli Lilly, Bayer, GlaxoSmith Kline. Adam Torbicki; consultant fee, speaker bureau, advisory committee, Actelion, Eli Lilly, grant monies, Actelion, United Therapeutics, AOP Orphan Pharmaceutics, Pfizer, Bristol Myers Squibb, Sanofi Aventis. Lewis Rubin, consultant fee, speaker bureau, advisory committee, Actelion, Pfizer, United Therapeutics, Lung LLC, Gilead, Aires, GlaxoSmithKline, Bayer, GeNo. Gerald Simmonneau; consultant fee, speaker bureau, advisory committee, Actelion, GlaxoSmithKline, Eli Lilly, Pfizer, United Therapeutics, grant monies, Movartis, Actlion, GlaxoSmithKline, Eli Lilly, Pfizer.
[Show abstract][Hide abstract] ABSTRACT: Late-Breaking AbstractsSESSION TYPE: Original Investigation SlidePRESENTED ON: Tuesday, October 29, 2013 at 04:30 PM - 05:30 PMPURPOSE: In the 16-week Phase III CHEST-1 study, riociguat, a novel soluble guanylate cyclase stimulator, significantly improved 6-minute walking distance (6MWD) and a range of secondary endpoints in patients with CTEPH. These improvements were maintained for a further 12 weeks in the CHEST-2 long-term extension study. Here we present 1-year data from CHEST-2.METHODS: Patients with inoperable CTEPH or persistent/recurrent pulmonary hypertension (PH) after pulmonary endarterectomy could enter CHEST-2 after successfully completing CHEST-1 without ongoing riociguat-related serious adverse events. During the initial 8-week blinded titration period of CHEST-2, patients in the riociguat arm continued on their optimum dose (up to 2.5 mg tid) while receiving sham titration; patients in the placebo arm were titrated to their optimum dose of riociguat (up to 2.5 mg tid). The primary endpoints were safety and tolerability; secondary endpoints included change in 6MWD and WHO functional class (FC).RESULTS: Of 261 patients enrolled in CHEST-1, 237 (91%) entered CHEST-2. In this interim analysis (cut-off March 2013), 211 (89%) patients were ongoing and 179 (76%) had received ≥1 year of treatment. Riociguat was well tolerated, with 3% of patients withdrawing due to adverse events. At the end of CHEST-1, mean±SD 6MWD had increased by 50±59 m in the riociguat arm and 8±63 m in the placebo arm of the cohort entering CHEST-2. After 1 year of CHEST-2 (overall population; n=172), 6MWD had increased by 51±62 m versus CHEST-1 baseline. At the end of CHEST-1, FC was improved/stable/worsened in 35/62/3% of riociguat patients and 16/81/2% of placebo patients; after 1 year of CHEST-2 (overall population; n=178), the proportions were 46/49/3% (data missing for two patients) versus CHEST-1 baseline. Twenty-two (9%) patients received additional PH medication during CHEST-2 (n=19 due to worsening PH).CONCLUSIONS: Riociguat has a good long-term safety profile and is the first therapy to show sustained benefits in 6MWD and FC in patients with CTEPH.CLINICAL IMPLICATIONS: Riociguat is a promising option for the long-term treatment of patients with inoperable CTEPH.DISCLOSURE: Gérald Simonneau: Grant monies (from industry related sources): Gerald Simonneau has received grant money paid to his institution from Bayer, Consultant fee, speaker bureau, advisory committee, etc.: Gerald Simonneau has received consulting fees, honorarium and/or support for travel to meetings from Bayer, Other: Gerald Simonneau has received fees for participation in review activities from Bayer Andrea D'Armini: Other: Andrea D'Armini received fees for participation in review activities from Bayer Hossein Ghofrani: Grant monies (from industry related sources): Hossein-Ardeschir Ghofrani has received grant money paid to his institution by Bayer HealthCare, Consultant fee, speaker bureau, advisory committee, etc.: Hossein-Ardeschir Ghofrani has received consulting fees, honorarium and/or support for travel to meetings from Bayer HealthCare Friedrich Grimminger: Grant monies (from industry related sources): Friedrich Grimminger has received grant money paid to his institution by Bayer HealthCare, Consultant fee, speaker bureau, advisory committee, etc.: Friedrich Grimminger has received consulting fees, honorarium and/or support for travel to meetings from Bayer HealthCare Marius Hoeper: Grant monies (from industry related sources): Marius M. Hoeper has received grant money paid to his institution by Bayer, Consultant fee, speaker bureau, advisory committee, etc.: Marius M. Hoeper has received consulting fees, honorarium and/or support for travel from Bayer Pavel Jansa: Consultant fee, speaker bureau, advisory committee, etc.: Pavel Jansa has received consulting fees, honorarium and/or support for travel to meetings from Bayer, Other: Pavel Jansa has received fees for participation in review activities from Bayer Nick Kim: Consultant fee, speaker bureau, advisory committee, etc.: Nick H. Kim has received consulting fees, honorarium and/or support for travel to meetings from Bayer Martin Wilkins: Grant monies (from industry related sources): Martin R. Wilkins has received a grant paid to his institution from Bayer HealthCare, Consultant fee, speaker bureau, advisory committee, etc.: Martin R. Wilkins has received consulting fees, honorarium and/or support for travel to meetings from Bayer HealthCare, Other: Martin R. Wilkins has received fees for participation in review activities from Bayer HealthCare Arno Fritsch: Shareholder: Arno Fritsch has received stock/stock options from Bayer HealthCare, Employee: Arno Fritsch is a full-time employee of Bayer HealthCare Neil Davie: Employee: Neil Davie is a full-time employee of Bayer HealthCare Gerrit Weimann: Employee: Gerrit Weimann is a full-time employee of Bayer HealthCare Eckhard Mayer: Consultant fee, speaker bureau, advisory committee, etc.: Eckhard Mayer has received consulting fees, honorarium and/or support for travel to meetings from Bayer, Other: Eckhard Mayer has received fees for participation in review activities from Bayer The following authors have nothing to disclose: Chen WangRiociguat is an investigational new drug currently in process for registration submission to health authorities, after successful finalisation of a RCT in patients with PAH.