Matthieu Canuet

Pulmonary Arterial Hypertension in Patients Treated by Dasatinib

Background— The French pulmonary hypertension (PH) registry allows the survey of epidemiological trends. Isolated cases of precapillary PH have been reported in patients who have chronic myelogenous leukemia treated with the tyrosine kinase inhibitor dasatinib. Methods and Results— This study was designed to describe incident cases of dasatinib-associated PH reported in the French PH registry. From the approval of dasatinib (November 2006) to September 30, 2010, 9 incident cases treated by dasatinib at the time of PH diagnosis were identified. At diagnosis, patients had moderate to severe precapillary PH with functional and hemodynamic impairment. No other incident PH cases were exposed to other tyrosine kinase inhibitors at the time of PH diagnosis. Clinical, functional, or hemodynamic improvements were observed within 4 months of dasatinib discontinuation in all but 1 patient. Three patients required PH treatment with endothelin receptor antagonist (n=2) or calcium channel blocker (n=1). After a median follow-up of 9 months (min-max 3–36), the majority of patients did not demonstrate complete clinical and hemodynamic recovery, and no patients reached a normal value of mean pulmonary artery pressure (⩽20 mm Hg). Two patients (22%) died at follow-up (1 of unexplained sudden death and 1 of cardiac failure in the context of septicemia, respectively, 8 and 12 months after dasatinib withdrawal). The lowest estimate of incident PH occurring in patients exposed to dasatinib in France was 0.45%. Conclusions— Dasatinib may induce severe precapillary PH fulfilling the criteria of pulmonary arterial hypertension, thus suggesting a direct and specific effect of dasatinib on pulmonary vessels. Improvement is usually observed after withdrawal of dasatinib.

Role for Interleukin-6 in COPD-Related Pulmonary Hypertension

BACKGROUND Pulmonary artery remodeling triggered by alveolar hypoxia is considered the main mechanism of pulmonary hypertension (PH) in COPD patients. We hypothesized that the risk for PH in COPD is increased by an elevation in the proinflammatory cytokines interleukin (IL)-6, monocyte chemoattractant protein-1 (MCP-1), and IL-1beta, as well as by specific genetic polymorphisms of these cytokines. METHODS We assessed cytokine plasma levels and the polymorphisms G(-174)C IL-6, C(-511)T IL-1beta, and A(-2518)G MCP-1 in 148 COPD patients (recruited at two centers) with right heart catheterization data and 180 control subjects including smokers and nonsmokers. Human pulmonary artery smooth muscle cells (PA-SMCs) were cultured for IL-6 messenger RNA assays under normoxic and hypoxic conditions. RESULTS Patients with PH (mean pulmonary artery pressure [PAP], >or= 25 mm Hg) had lower Pao(2) and higher plasma IL-6 values than those without PH; there were no differences in terms of pulmonary function test results or CT scan emphysema scores. Plasma IL-6 correlated with mean PAP (r = 0.39; p < 0.001) and was included in a multiple stepwise regression analysis, with mean PAP as the dependent variable. In patients with the IL-6 GG genotype, the mean PAP value was significantly higher and PH was more common than in CG or CC patients (adjusted odds ratio, 4.32; 95% confidence interval, 1.96 to 9.54). Exposure to 4 h of hypoxia led to an about twofold increase in IL-6 messenger RNA in cultured human PA-SMCs. CONCLUSIONS Inflammation, most likely involving IL-6, may contribute substantially to PH complicating COPD.

Pulmonary hypertension in antisynthetase syndrome: prevalence, aetiology and survival.

Antisynthetase syndrome is characterised by the association of interstitial lung disease and myositis with different anti-tRNA-synthetase antibodies. The occurrence, aetiology and prognosis of pulmonary hypertension have not yet been evaluated. Among 203 consecutive patients, transthoracic echocardiogram and right heart catheterisation results were retrospectively analysed in the light of clinico-biological, morphological and functional parameters. Definitions of pulmonary hypertension were based on the European Society of Cardiology/European Respiratory Society 2009 guidelines, with severe pulmonary hypertension being defined by a mean pulmonary arterial pressure >35 mmHg. Pulmonary hypertension was suspected by transthoracic echocardiogram in 47 (23.2%) cases, corresponding to pulmonary hypertension “possible” (n=27, 13.3%) or “likely” (n=20, 9.9%). Right heart catheterisation was performed in 21 patients, excluding pulmonary hypertension in five and confirming pre-capillary pulmonary hypertension in 16 (7.9%). Although related to interstitial lung disease in all cases, pre-capillary pulmonary hypertension was severe in 13 (81.3%) patients (mean±sd pulmonary arterial pressure 46±9 mmHg), frequently associated with low cardiac index (mean±sd 2.3±0.8 L·min−1·m−2) and high forced vital capacity/diffusing capacity of the lung for carbon monoxide ratio (2.5±0.6). Pulmonary hypertension was significantly associated with a lower survival rate (p<0.001), with a 3-year survival rate of 58%. The occurrence of pulmonary hypertension in antisynthetase syndrome is significant and dramatically worsens the prognosis. Although systematically associated with interstitial lung disease, pulmonary hypertension was usually severe, suggesting a specific pulmonary vascular involvement. PH in antisynthetase syndrome significantly worsens the prognosis, suggesting a specific pulmonary vascular involvement http://ow.ly/okXyG

Correlation between high-resolution computed tomography findings and lung function in pulmonary langerhans cell histiocytosis

Background: Pulmonary Langerhans cell histiocytosis (PLCH) is an uncommon interstitial lung disease which can lead to serious respiratory failure. The correlation between high-resolution computed tomography (HRCT) findings and lung function have not been studied in depth. Objectives: To assess the relationship between HRCT findings and lung function in PLCH. Methods: Since HRCT abnormalities in PLCH consist mainly of nodular opacities and cystic abnormalities, we determined semiquantitative scores of nodular profusion and cystic extent. We therefore assessed the relationship between HRCT abnormalities on one hand and lung function and gas exchange parameters on the other, in patients with PLCH. Results: In our series of 26 consecutive patients, we found no significant correlation between the score of nodular profusion and lung function or gas exchange parameters. The score of cystic extent showed a quite strong and significant correlation with FEV1/FVC (r = –0.62; p = 0.01), but also with PaO2 (r = –0.69; p = 0.001) and carbon monoxide diffusing capacity (r = –0.60; p < 0.01). Furthermore, the patients with a predominant cystic pattern (n = 7) had the highest grade of dyspnea on exertion (p = 0.004), the lowest FEV1/FVC ratio (p = 0.02) and the lowest PaO2 (p = 0.02) compared to patients with a predominant nodular (n = 12) or a mixed pattern (n = 7). Conclusions: We conclude that in PLCH, the cystic extent on HRCT, but not the nodular profusion, correlates significantly with lung function abnormalities and impairment of gas exchange.

Deterioration of pulmonary hypertension and pleural effusion with bosutinib following dasatinib lung toxicity

Tyrosine kinase inhibitors (TKIs) targeting BCR/ABL such as imatinib, nilotinib, dasatinib, bosutinib and ponatinib have revolutionised the management of patients with chronic myeloid leukaemia (CML) [1]. Pleural effusions and pulmonary arterial hypertension (PAH) have been reported in patients treated with these agents [2–4]. These side-effects are more frequently observed with dasatinib use, with partial or complete reversibility after drug withdrawal [3]. Bosutinib is a second-generation TKI prescribed in case of intolerance or resistance to imatinib, nilotinib or dasatinib. In the present report, we describe two cases of worsening of dasatinib-induced PAH and two cases of severe pleural effusions, suggesting overlapping pulmonary toxicity of bosutinib and dasatinib. Pulmonary complications of bosutinib therapy and potential cross-intolerance with dasatinib http://ow.ly/UKWu303KGhx

Current epoprostenol use in patients with severe idiopathic, heritable or anorexigen-associated pulmonary arterial hypertension: Data from the French pulmonary hypertension registry

OBJECTIVES The current use of intravenous epoprostenol in patients with severe idiopathic, heritable or anorexigen-use associated pulmonary arterial hypertension (IHA-PAH) was investigated. METHODS This observational study evaluated newly diagnosed (≤1 year) patients with IHA-PAH, enrolled in the French pulmonary hypertension (PH) registry between 2006 and 2010 and treated with epoprostenol. Among 209 consecutive patients receiving epoprostenol for the treatment of severe PH, 78 had IHA-PAH, including 43 patients naïve of previous PAH-specific treatment. RESULTS After 4 months of epoprostenol therapy, improvement was observed for treatment naïve patients (n=43) and for patients who had received previous PAH-specific therapy (n=35): NYHA functional class improved in 79% and 44% of these patients, respectively, 6-minute walk distance increased by 146 (p<0.0001) and 41 m (p=0.03), cardiac index increased by 1.2 (p<0.0001) and 0.5 L·min(-1)·m(-2) (p=0.006), and pulmonary vascular resistance decreased by 700 (p<0.0001) and 299 dyn·s·cm(-5) (p=0.009). In the treatment-naïve patient group, upfront combination of epoprostenol and oral PAH therapy tended to be more beneficial compared with epoprostenol monotherapy and was associated with improvement in cardiac index (p=0.03). The observed 1- and 3-year survival estimates from epoprostenol initiation were 84% and 69%, respectively. The highest survival rates were observed for treatment-naïve patients receiving upfront combination of epoprostenol and oral PAH therapy (92% and 88% at 1 and 3 years, respectively). CONCLUSIONS First-line therapy with epoprostenol, especially when combined with oral PAH treatment, was associated with a substantial improvement in clinical and hemodynamic status and favorable survival estimates in patients with severe IHA-PAH.

Long-term outcomes of dasatinib-induced pulmonary arterial hypertension: a population-based study

This study aimed to describe the long-term outcomes of pulmonary arterial hypertension (PAH) induced by dasatinib. 21 incident, right heart catheterisation-confirmed cases of dasatinib-induced PAH were identified from the French Pulmonary Hypertension Registry. Clinical and haemodynamic variables were compared from baseline to last follow-up (median (range) 24 (1–81) months). Median age was 52 years and 15 patients were female (71%). 19 patients received dasatinib for chronic myelogenous leukaemia for a median (range) duration of 42 (8–74) months before PAH diagnosis. No bone morphogenic protein receptor-2 (BMPR2) mutations were found in the 10 patients tested. Dasatinib was uniformly discontinued and 11 patients received PAH medications. Four patients died during follow-up. New York Heart Association functional class improved from 76% in class III/IV to 90% in class I/II (p<0.01). Median (range) 6-min walk distance improved from 306 (0–660) to 430 (165–635) m (p<0.01). Median (range) mean pulmonary arterial pressure improved from 45 (30–70) to 26 (17–50) mmHg (p<0.01) and pulmonary vascular resistance from 6.1 (3.2–27.3) to 2.6 (1.2–5.9) Wood units (p<0.01). Patients treated with PAH medications had worse baseline haemodynamics but similar long-term outcomes to untreated patients. PAH persisted in 37% of patients. Dasatinib-induced PAH frequently improves after discontinuation but persisted in over one-third of patients, therefore systematic follow-up is essential. Dasatinib-induced pulmonary arterial hypertension persists in over one-third of patients despite stopping dasatinib http://ow.ly/xRPt30csyk9

A prospective study of the 6 min walk test as a surrogate marker for haemodynamics in two independent cohorts of treatment-naïve systemic sclerosis-associated pulmonary arterial hypertension.

Objectives Despite the wide use of the 6 min walk distance (6MWD), no study has ever assessed its validity as a surrogate marker for haemodynamics and predictor of outcome in isolated pulmonary arterial hypertension associated with systemic sclerosis (SSc-PAH). We designed this work to address this issue. Methods Treatment-naïve patients with SSc-PAH were prospectively included from two sources: the French PAH Network (a prospective epidemiological cohort) (n=83) and randomised clinical trials submitted for drug approval (Food and Drug Administration) (n=332). Correlations between absolute values of the 6MWD and haemodynamics at baseline, as well as between variations of 6MWD and haemodynamics during follow-up, were studied in both populations. Results In the French cohort, baseline cardiac output (CO) (R2=0.19, p=0.001) and New York Heart Association class (R2=0.10, p<0.001) were significantly and independently correlated with baseline 6MWD in multivariate analysis. A significant, independent, but weaker, correlation with CO was also found in the Food and Drug Administration sample (R2=0.04, p<0.001). During follow-up, there was no association between the changes in 6MWD and haemodynamic parameters in patients under PAH-specific treatments. Conclusions In SSc-PAH, CO independently correlates with 6MWD at baseline, but accounts for a small amount of the variance of 6MWD in both study samples. This suggests that other non-haemodynamic factors could have an impact on the walk distance. Moreover, variations of 6MWD do not reflect changes in haemodynamics among treated patients. Our results suggest that 6MWD is not an accurate surrogate marker for haemodynamic severity, nor an appropriate outcome measure to assess changes in haemodynamics during follow-up in treated SSc-PAH.

Pulmonary Arterial Hypertension-Specific Drug Therapy in COPD Patients with Severe Pulmonary Hypertension and Mild-to-Moderate Airflow Limitation.

Background: Patients with severe pulmonary hypertension (PH) associated with chronic obstructive pulmonary disease (COPD) present a poor outcome. Specific PH treatment could improve the clinical and hemodynamic status of these patients but may worsen arterial blood gases. Objectives: Our study retrospectively included 28 patients with severe precapillary PH (mean pulmonary arterial pressure >35 mm Hg) associated with mild-to-moderate COPD [forced expiratory volume in 1 s (FEV1) >50% predicted]. All patients underwent specific pulmonary arterial hypertension (PAH) treatment as mono-, bi- or triple therapy. Methods: Our single-center study was conducted based on retrospective data of 537 right heart catheterizations (RHCs) performed on patients with COPD from January 2004 to June 2014. An echocardiography, comprehensive blood tests, pulmonary function tests, and a high-resolution computed tomography were performed before the RHCs. All patients underwent RHC with a Swan-Ganz catheter. Results: Compared to baseline, patients treated with specific PAH drugs showed a significant increase in cardiac index at long term (2.5 ± 0.7 liters/min/m2 at baseline vs. 3.2 ± 0.6 liters/min/m2 at 6/12 months; p = 0.003) as well as a decrease in pulmonary vascular resistance in the long term (8.4 ± 4.2 Wood units at baseline vs. 5 ± 1.7 Wood units at 6/12 months; p = 0.008). There was a slight decrease in arterial oxygen tension (PaO2) after 3 months of treatment (-2.4 ± 7.21 mm Hg; p = 0.066). During a median follow-up of 3 years, 12 patients (42.8%) died (including all causes of death). Conclusions: This preliminary report suggests that the use of specific PH therapy in severe PH associated with mild-to-moderate COPD can improve pulmonary hemodynamic parameters, with worsening of PaO2, which had no clinical significance and did not lead to specific PAH therapy withdrawal in any patient.

Right Heart Hemodynamics in Pulmonary Hypertension – An Echocardiography and Catheterization Study –

BACKGROUND Echocardiography (ECHO) plays a key role in both the diagnosis and prognosis of pulmonary hypertension (PH). Many equations have been published to assess right heart hemodynamics using ECHO. The objective of this study was to test the accuracy and precision of different echocardiographic equations in comparison with the right heart catheterization. METHODSANDRESULTS Complete right heart hemodynamic assessments were prospectively obtained from 115 individuals (mean age 66±1 years; 57 males) who had known or suspected PH. Several equations were tested for the estimation of right atrial pressure, mean and systolic pulmonary artery pressure (MPAP), cardiac output, pulmonary capillary wedge pressure (PCWP), and pulmonary vascular resistance (PVR). The accuracy of ECHO was good, with a mean difference <2 mmHg for all of the pressure calculations and ±0.6 L/min for cardiac output. However, the PVR estimation was weak using any one of the formulae. For all the parameters, the precision of ECHO was moderate. The MPAP calculation detected PH with a sensibility of 97% and specificity of 83%. However, ECHO underdiagnosed post-capillary PH. CONCLUSIONS ECHO is a good method for the diagnosis of PH, with an adequate calculation of right pressures, but cannot accurately calculate PCWP and PVR. (Circ J 2016; 80: 2019-2025).