Elie Fadel

Université Paris-Sud 11, Orsay, Île-de-France, France

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Publications (185)682.84 Total impact

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    ABSTRACT: Chronic thromboembolic pulmonary hypertension is a rare but underdiagnosed disease. The development of imaging played a crucial role for the screening and the decision of operability over the past few years. Indeed, chronic thromboembolic pulmonary hypertension is the only type of pulmonary hypertension with a potential curative treatment: pulmonary endarterectomy. It is a complexe surgical procedure performed under cardiopulmonary bypass with deep hypothermia and circulatory arrest. The aim of the procedure is to completely remove the scar tissue inside the pulmonary arteries down to the segmental and sub-segmental levels. Compared to lung transplantation, which carries a postoperative mortality of 15-20% and a 5-year survival of 50%, pulmonary endarterectomy is a curative treatment with a postoperative mortality of less than 3%. However, lung transplantation remains an option for young patients with inoperable distal disease or after pulmonary endarterectomy failure. Considering that medical history of deep venous thrombosis or pulmonary embolism is lacking in 25 to 50%, the diagnosis of chronic thromboembolic pulmonary hypertension remains challenging. The lung V/Q scan is useful for the diagnosis showing ventilation and perfusion mismatches. Lesions located at the level of the pulmonary artery, the lobar or segmental arteries may be accessible to surgical removal. The pulmonary angiogram with the lateral view and the pulmonary CT scan help to determine the level of the intravascular lesions. If there is a correlation between the vascular obstruction assessed by imaging and the pulmonary resistance, pulmonary endarterectomy carries a postoperative mortality of less than 3% and has a high rate of success. If the surgery is performed at a later stage of the disease, pulmonary arteriolitis developed mainly in unobstructed territories and participated in the elevated vascular resistance. At this stage, postoperative risk is higher.
    Presse medicale (Paris, France : 1983). 08/2014;
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    ABSTRACT: Limited numbers of operated patients with chronic thromboembolic pulmonary hypertension (CTEPH) are refractory to pulmonary endarterectomy (PEA) and experience persistent pulmonary hypertension (PH). We retrospectively assessed lung histology available from nine patients with persistent PH (ineffective PEA (inPEA) group) and from eight patients transplanted for distal CTEPH inaccessible by PEA (noPEA group). Microscopically observed peculiarities were compared with the histology of a recently developed CTEPH model in piglets. Pre-interventional clinical/haemodynamic data and medical history of patients from the inPEA and noPEA groups were collected and analysed. Conspicuous remodelling of small pulmonary arteries/arterioles, septal veins and pre-septal venules, including focal capillary haemangiomatosis, as well as pronounced hypertrophy and enlargement of bronchial systemic vessels, were the predominant pattern in histology from both groups. Most findings were reproduced in our porcine CTEPH model. Ink injection experiments unmasked abundant venular involvement in so-called small vessel or microvascular disease, as well as post-capillary bronchopulmonary shunting in human and experimental CTEPH. Microvascular disease is partly due to post-capillary remodelling in human and experimental CTEPH and appears to be related to bronchial-to-pulmonary venous shunting. Further studies are needed to clinically assess the functional importance of this finding.
    European Respiratory Journal 08/2014; · 6.36 Impact Factor
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    ABSTRACT: To conduct a systematic literature review and pooled data analysis focusing on outcome after en bloc resection of pulmonary sulcus non-small cell lung cancer (NSCLC) invading the spine.
    Annals of surgery. 07/2014;
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    ABSTRACT: After lung transplantation, increased left ventricular (LV) filling can lead to LV failure, increasing the risk of post-operative complications and mortality. LV dysfunction in pulmonary arterial hypertension (PAH) is characterized by a reduced LV ejection fraction and impaired diastolic function.
    Journal of the American College of Cardiology 07/2014; 64(1):28-37. · 14.09 Impact Factor
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    ABSTRACT: Locally advanced thymoma can often involve the phrenic nerve (PN) due to its location on the mediastinal pleura. However, en bloc resection including the PN may cause severe postoperative complications, especially in myasthenia gravis patients. The aim of the study was to determine whether a PN involved could be spared during thymoma resection. A retrospective study was conducted on patients who underwent resection of Masaoka Stage III and IV thymomas adherent, on digital palpation, to at least one PN in our institution between 1998 and 2012. An en bloc resection of the tumour with the invaded PN was performed unless patients with no preoperative PN paralysis had: both PN involved, compromised preoperative lung function, severe myasthenia gravis, severe comorbidities or minimal PN involvement (PN adherent to the edge of the tumour). All patients received postoperative radiation therapy. There were 114 patients with a mean age of 57 years (range, 28-84). PN was spared in 73 patients (64%) and removed in 41 (36%). Sixty-five patients had Masaoka Stage III (57%) and 49 had Stage IV (43%); these were similar between both groups. On permanent histology, 6 (15%) of the resected PN were not involved, whereas a permanent postoperative PN palsy was found in 4 (5.4%) patients where the PN was spared. Postoperative mortality and morbidity were 0 and 15% in the spared group and 2.4 and 9.7% in the resected group, respectively (P = 0.56). Recurrence rate was significantly higher in the spared group (39.5 vs 19.5%; P = 0.02) but the 5-year disease-free survival rates (53.6 vs 66.8%, P = 0.14) and overall 5-year survival (85 vs 88%, P = 0.6) were not significantly different between the spared- and resected-PN groups, respectively. Sparing the PN during thymoma resection achieved good long-term and disease-free survivals in high-risk patients comparable with en bloc PN resection. However, it carried a higher risk of recurrence despite adjuvant radiation therapy.
    European journal of cardio-thoracic surgery: official journal of the European Association for Cardio-thoracic Surgery 02/2014; · 2.40 Impact Factor
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    ABSTRACT: Pericytes and their crosstalk with endothelial cells (ECs) 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 (FGF)-2 and interleukin (IL)-6 signaling, leads to abnormal microvascular pericyte coverage causing pulmonary arterial medial thickening. In human lung tissues, numbers of pericytes are substantially increased (up to 2-fold) in distal PAH pulmonary arteries as compared to controls. Interestingly, human pulmonary pericytes exhibit, in vitro, an accentuated proliferative and migratory response to conditioned media from human idiopathic PAH (iPAH) ECs as compared to conditioned media from control cells. Importantly, by using an anti-FGF-2 neutralizing antibody, we attenuated these proliferative and migratory responses, whereas by using an anti-IL-6 neutralizing antibody, we decreased the migratory response without affecting the proliferative response. Furthermore, in our murine retinal angiogenesis model, both FGF-2 and IL-6 administration increased pericyte coverage. Finally, using iPAH 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 (TGF)-β, in contrast to FGF-2 and IL-6, promotes human pulmonary pericyte differentiation into contractile smooth muscle-like cells. This is the first report of excessive pericyte coverage in distal pulmonary arteries in human PAH. We are also showing that this phenomenon is directly linked with pulmonary endothelial dysfunction.
    Circulation 01/2014; · 15.20 Impact Factor
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    ABSTRACT: Lung injury (LI) due to gastric-acid aspiration is associated with poor posttransplantation outcomes. We investigated the effects of ex vivo lung perfusion (EVLP) reconditioning and surfactant administration on LI due to gastric-acid aspiration. Thirty piglets were allocated at random to five groups: the lungs were studied 24 hr after gastric juice-induced LI of the left lower lobe (LLL), LI followed by EVLP (4 hr), or LI followed by LLL surfactant lavage immediately before EVLP; sham animals were studied 24 hr after saline infusion alone or followed by EVLP. Gross anatomy, hemodynamics, and aerodynamics were evaluated; neutrophil and bacterial counts were determined in bronchoalveolar lavage (BAL) fluid and blood. LLLs were evaluated based on a semi-quantitative histologic score, apoptotic cell death (TUNEL), and inflammatory cytokine levels. The sham and sham-EVLP groups were not significantly different. Compared with sham, LI animals had irreversible atelectasis, higher lung infection rates (P<0.0001) and BAL neutrophil percentages (P<0.0001), lower PaO2 (P=0.0006), higher IL-1 (P=0.022) and IL-8 (P=0.006), higher apoptotic cell percentages (P=0.007), and worse histologic severity scores (P<0.0001). EVLP alone did not improve these findings. Adding surfactant before EVLP returned PaO2, pulmonary vascular resistance, and apoptotic-cell percentage to sham-EVLP values but only partially improved the histologic severity score. Local surfactant infusion immediately before EVLP improved the function of donor lungs injured by gastric juice aspiration. This strategy may hold promise for decreasing the shortage of donor lungs.
    Transplantation 01/2014; · 3.78 Impact Factor
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    ABSTRACT: Myasthenia gravis (MG) is an autoimmune disease mainly mediated by anti-acetylcholine receptor (AChR) antibodies. In the late onset, a thymoma, tumor of the thymus, is quite frequent. However, the events leading to thymoma and MG are not understood. As thymoma-associated MG (MG-T) patients also display anti-interferon type I (IFN-I) neutralizing antibodies, we investigated if MG-T could be associated with an anti-viral signature. RT-PCR analyses demonstrated huge increases of IFN-I subtypes, IFN-α2, -α8, -ω and -β, in thymoma-associated MG but not in thymomas without MG or in control thymuses. Next, we investigated if dsRNA signaling pathway involvement could be observed in MG-T, as recently observed in early-onset MG. We observed an abnormal regulation of dsRNA-sensing molecules with an increase of toll-like receptor 3 (TLR3), and a decrease of protein kinase R (PKR) and dsRNA helicases (RIG-I and MDA5) in thymoma from MG patients. We also detected a decreased expression of p53, the tumor suppressor that is known to be down-regulated by dsRNA. Altogether, these results strongly suggest that MG-T could be linked to a viral infection. As p16 (CDKN2A), a marker of HPV infections, was up-regulated in MG-T, we thus screened DNA from thymomas for human papillomavirus (HPV) by real-time PCR using HPV consensus SPF10 primers. RT-PCR results were negative for all samples tested. We confirmed the absence of HPV DNA detection by end point PCR using FAP primers to amplify a larger panel of HPV genotypes. Our data clearly demonstrate INF-I overexpression together with the activation of innate immunity pathways in thymoma-associated MG suggesting that MG might develop after a pathogen infection. We were not able to relate thymoma to HPV infections and the implication of other pathogens is discussed.
    Journal of Autoimmunity 01/2014; · 8.15 Impact Factor
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    ABSTRACT: Myasthenia gravis (MG) is an autoimmune disease in which the thymus frequently presents follicular hyperplasia and signs of inflammation and T cells display a defect in suppressive regulation. Defects in a suppressive assay can indicate either the defective function of Treg cells or the resistance of Tconv cells to suppression by Treg cells. The aim of this study was to determine which cells were responsible for this defect and to address the mechanisms involved. We first performed cross-experiment studies using purified thymic Treg cells and Tconv cells from controls (CTRL) and MG patients. We confirmed that MG Treg cells were defective in suppressing CTRL Tconv proliferation, and we demonstrated for the first time that MG Tconv cells were resistant to Treg cell suppression. The activation of MG Tconv cells triggered a lower upregulation of FoxP3 and a higher upregulation of CD4 and CD25 than CTRL cells. To investigate the factors that could explain these differences, we analyzed the transcriptomes of purified thymic Treg and Tconv cells from MG patients in comparison to CTRL cells. Many of the pathways revealed by this analysis are involved in other autoimmune diseases, and T cells from MG patients exhibit a Th1/Th17/Tfh signature. An increase in IL-17-related genes was only observed in Treg cells, while increases in IFN-γ, IL-21, and TNF-α were observed in both Treg and Tconv cells. These results were confirmed by PCR studies. In addition, the role of TNF-α in the defect in Tconv cells from MG patients was further confirmed by functional studies. Altogether, our results indicate that the immunoregulatory defects observed in MG patients are caused by both Treg cell and Tconv cell impairment and involve several pro-inflammatory cytokines, with TNF-α playing a key role in this process. The chronic inflammation present in the thymus of MG patients could provide an explanation for the escape of thymic T cells from regulation in the MG thymus.
    Journal of Autoimmunity 01/2014; · 8.15 Impact Factor
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    ABSTRACT: The thymus plays a primary role in early-onset Myasthenia Gravis (MG) mediated by anti-acetylcholine receptor (AChR) antibodies. As we recently showed an inflammatory and anti-viral signature in MG thymuses, we investigated in detail the contribution of interferon (IFN)-I and IFN-III subtypes in thymic changes associated with MG. We showed that IFN-I and IFN-III subtypes, but especially IFN-β, induced specifically α-AChR expression in thymic epithelial cells (TECs). We also demonstrated that IFN-β increased TEC death and the uptake of TEC proteins by dendritic cells. In parallel, we showed that IFN-β increased the expression of the chemokines CXCL13 and CCL21 by TECs and lymphatic endothelial cells, respectively. These two chemokines are involved in germinal center (GC) development and overexpressed in MG thymus with follicular hyperplasia. We also demonstrated that the B-cell activating factor (BAFF), which favors autoreactive B-cells, was overexpressed by TECs in MG thymus and was also induced by IFN-β in TEC cultures. Some of IFN-β effects were down-regulated when cell cultures were treated with glucocorticoids, a treatment widely used in MG patients that decreases the number of thymic GCs. Similar changes were observed in vivo. The injections of Poly(I:C) to C57BL/6 mice triggered a thymic overexpression of IFN-β and IFN-α2 associated with increased expressions of CXCL13, CCL21, BAFF, and favored the recruitment of B cells. These changes were not observed in the thymus of IFN-I receptor KO mice injected with Poly(I:C), even if IFN-β and IFN-α2 were overexpressed. Altogether, these results demonstrate that IFN-β could play a central role in thymic events leading to MG by triggering the overexpression of α-AChR probably leading to thymic DC autosensitization, the abnormal recruitment of peripheral cells and GC formation.
    Journal of Autoimmunity 01/2014; · 8.15 Impact Factor
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    ABSTRACT: Little is known about the resolution of symptoms of nosocomial pneumonia (NosoP) after lung and heart-lung transplantation. The aim of this study was to describe the clinical response to antimicrobial therapy in (ICU) patients with NosoP after lung or heart-lung transplantation. Between January 2008 and August 2010, 79 lung or heart-lung transplantations patients were prospectively studied. NosoPwas confirmed by quantitative cultures of bronchoalveolar lavage or endotracheal aspirates. Clinical variables, sequential organ failure assessment (SOFA) score, and radiologic score were recorded from start of therapy until day 9. Thirty-five patients (44%) experienced 64 episodes of NosoP in ICU. Fourteen patients (40%) had NosoP recurrence. Most frequently isolated organisms were Enterobacteriaceae (30%), Pseudomonas aeruginosa (25%), and Staphylococcus aureus (20%). Sequential organ failure assessment (SOFA) score improved significantly at day 6 and C-reactive protein level at day 9. SOFA and radiologic scores differed significantly between patients with and without NosoP recurrence at day 3 and 9. The ICU mortality rate did not differ between patients with and without NosoP recurrence, and free of NosoP (14.3%, 9.5%, 11.4%, respectively) (p = 0.91). Severities of illness and lung injury were the two major risk factors for NosoP recurrence. Occurrence of NosoP has no impact on ICU mortality.
    Clinical Transplantation 01/2014; 28(1):27-36. · 1.63 Impact Factor
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    ABSTRACT: Background Cardiac allograft vasculopathy (CAV) is a major factor limiting long-term survival after heart transplantation (HTx). Specific determinants of CAV and long-term outcome after CAV occurrence have been poorly investigated after heart-lung transplantation (HLTx). Methods Between January 1996 and December 2006, 79 patients underwent HLTx (36.3±12.2 y-o; 47% men) and 141 patients underwent HTx (49.2±12.3 y-o; 77% men) in two different institutions. CAV grading was reviewed in both groups according to the 2010 standardised nomenclature of the International Society for Heart and Lung Transplantation. The mean post-transplant follow-up was 94 months [1-181]. Results Overall 10-year survival rate was 58% after HTx and 43% after HLTx (P=0.11). CAV (grade1 or more)-freedom survival rate was 95% at 4 years and 69% at 10 years after HLTx, and respectively 77% and 39% after HTx (P<0.01). Mean cyclosporine blood levels were similar between groups at 3, 6, 12, 24 and 36 months. The main causes of mortality beyond 5 years after HTx and HLTx were malignancies and bronchiolitis obliterans respectively. By multivariate analysis, recipients who developed more than 3 acute myocardial rejections during the first year post-transplant were exposed to a higher risk of CAV ([1.065-2.33]95%CI, P=0.02). Episodes of acute pulmonary rejection and bronchiolitis obliterans were not associated with an increased risk of CAV (P=0.52 and P=0.30). Conclusion HLTx recipients appeared protected from CAV compared to HTx patients in this retrospective study. Repeated acute cardiac rejections were independent predictors of CAV. Unlike bronchiolitis obliterans, CAV had a very low impact on long-term survival after HLTx.
    The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 01/2014; · 3.54 Impact Factor
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    ABSTRACT: Rationale Pulmonary microvascular disease (PMD) develops in both occluded and nonoccluded territories in patients with chronic thromboembolic pulmonary hypertension (CTEPH) and may cause persistent pulmonary hypertension after pulmonary endarterectomy. Endothelin (ET)-1 and interleukin (IL)-6 are potential PMD-severity biomarkers but whether they are related to occluded or nonoccluded territories remains unknown.We assessed PMD and ET-1/IL-6 gene expression profiles in occluded and nonoccluded territories with and without chronic lung reperfusion in an animal CTEPH model. Methods Chronic PH was induced in 10 piglets by left pulmonary artery (PA) ligation followed by weekly embolization of right lower-lobe arteries with enbucrilate tissue adhesive for 5 weeks. At week 6, 5/10 animals underwent left PA reperfusion. At week 12, animals with and without reperfusion were compared to sham animals (n=5). Hemodynamics, lung morphometry, and ET-1/IL-6 gene expression profiles were assessed in the left lung (LL,occluded territories) and right upper lobe (RUL, nonoccluded territories). Results At week 12, mean PA pressure (mmHg) remained elevated without reperfusion (29.0±2.8 vs. 27.0±1.1, P=0.502) but decreased after reperfusion (30.0±1.5 vs. 20.5±1.7, P=0.013). Distal media thickness in the LL and RUL pulmonary arteries and systemic vasculature to the LL were significantly lower in the reperfused and sham groups compared to the nonreperfused group. PMD progression was related to ET-1 and IL-6 gene expression in the RUL and to the ETA/ETB gene expression ratio in the LL. Conclusions PMD regressed in occluded and nonoccluded territories after lung reperfusion. Changes in ET-1 and IL-6 gene expression were associated with PMD in nonoccluded territories.
    The Journal of Heart and Lung Transplantation. 01/2014;
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    ABSTRACT: Mutations affecting transforming growth factor-beta (TGF-β) superfamily receptors, activin receptor-like kinase (ALK)-1, and endoglin (ENG) occur in patients with pulmonary arterial hypertension (PAH). To determine whether the TGF-β/ALK1/ENG pathway was involved in PAH, we investigated pulmonary TGF-β, ALK1, ALK5, and ENG expressions in human lung tissue and cultured pulmonary-artery smooth-muscle-cells (PA-SMCs) and pulmonary endothelial cells (PECs) from 14 patients with idiopathic PAH (iPAH) and 15 controls. Seeing that ENG was highly expressed in PEC, we assessed the effects of TGF-β on Smad1/5/8 and Smad2/3 activation and on growth factor production by the cells. Finally, we studied the consequence of ENG deficiency on the chronic hypoxic-PH development by measuring right ventricular (RV) systolic pressure (RVSP), RV hypertrophy, and pulmonary arteriolar remodeling in ENG-deficient (Eng+/-) and wild-type (Eng+/+) mice. We also evaluated the pulmonary blood vessel density, macrophage infiltration, and cytokine expression in the lungs of the animals. Compared to controls, iPAH patients had higher serum and pulmonary TGF-β levels and increased ALK1 and ENG expressions in lung tissue, predominantly in PECs. Incubation of the cells with TGF-β led to Smad1/5/8 phosphorylation and to a production of FGF2, PDGFb and endothelin-inducing PA-SMC growth. Endoglin deficiency protected mice from hypoxic PH. As compared to wild-type, Eng+/- mice had a lower pulmonary vessel density, and no change in macrophage infiltration after exposure to chronic hypoxia despite the higher pulmonary expressions of interleukin-6 and monocyte chemoattractant protein-1. The TGF-β/ALK1/ENG signaling pathway plays a key role in iPAH and experimental hypoxic PH via a direct effect on PECs leading to production of growth factors and inflammatory cytokines involved in the pathogenesis of PAH.
    PLoS ONE 01/2014; 9(6):e100310. · 3.53 Impact Factor
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    ABSTRACT: Chronic thromboembolic pulmonary hypertension is a rare but underdiagnosed disease. The development of imaging played a crucial role for the screening and the decision of operability over the past few years. Indeed, chronic thromboembolic pulmonary hypertension is the only type of pulmonary hypertension with a potential curative treatment: pulmonary endarterectomy. It is a complexe surgical procedure performed under cardiopulmonary bypass with deep hypothermia and circulatory arrest. The aim of the procedure is to completely remove the scar tissue inside the pulmonary arteries down to the segmental and sub-segmental levels. Compared to lung transplantation, which carries a postoperative mortality of 15–20% and a 5-year survival of 50%, pulmonary endarterectomy is a curative treatment with a postoperative mortality of less than 3%. However, lung transplantation remains an option for young patients with inoperable distal disease or after pulmonary endarterectomy failure. Considering that medical history of deep venous thrombosis or pulmonary embolism is lacking in 25 to 50%, the diagnosis of chronic thromboembolic pulmonary hypertension remains challenging. The lung V/Q scan is useful for the diagnosis showing ventilation and perfusion mismatches. Lesions located at the level of the pulmonary artery, the lobar or segmental arteries may be accessible to surgical removal. The pulmonary angiogram with the lateral view and the pulmonary CT scan help to determine the level of the intravascular lesions. If there is a correlation between the vascular obstruction assessed by imaging and the pulmonary resistance, pulmonary endarterectomy carries a postoperative mortality of less than 3% and has a high rate of success. If the surgery is performed at a later stage of the disease, pulmonary arteriolitis developed mainly in unobstructed territories and participated in the elevated vascular resistance. At this stage, postoperative risk is higher.
    La Presse Médicale. 01/2014;
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    ABSTRACT: Systemic sclerosis per se should not be considered as an a priori contraindication for a pre-transplantation assessment in patients with advanced interstitial lung disease and/or pulmonary hypertension. For lung or heart-lung transplantation, a multidisciplinary approach, adapting the pre-transplant assessment to systemic sclerosis and optimizing systemic sclerosis patient management before, during and after surgery should improved the short- and long-term prognosis. Indications and contraindications for transplantation have to be adapted to the specificities of systemic sclerosis. A special focus on the digestive tract involvement and its thorough evaluation are mandatory before transplantation in systemic sclerosis. As the esophagus is almost always involved, isolated gastro-oesophageal reflux disease, pH metry and/or manometry abnormalities should not be a systematic per se contraindication for pre-transplantation assessment. Corticosteroids may be harmful in systemic sclerosis as they are associated with acute renal crisis. A low dose corticosteroids protocol for immunosuppression is therefore advisable in systemic sclerosis.
    La Presse Médicale. 01/2014;
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    ABSTRACT: The objective of this study was to determine the factors independently associated with septal curvature in patients with pulmonary arterial hypertension (PAH). Eighty-five consecutive patients with PAH who had an echocardiogram and a right heart catheterization within 24 hours of each others were included in the study. Septal curvature was assessed at the mid-papillary level using the eccentricity index (EI). Marked early systolic septal anterior motion was defined as a change in EI > 0.2 between end-diastole and early systole. Inter-ventricular mechanical delay was calculated as the percent time difference between right ventricular (RV) to left ventricular (LV) end-ejection time normalized for the RR interval. Average age was 45 ± 11 years and the majority of patients were women (75%). Mean right atrial pressure was 11 ± 7 mmHg, mean PAP was 52 ± 13 mmHg, relative RV area 1.8 ± 0.9, and RV fractional area change 24 ± 8%. End-diastolic EI was 1.6 ± 0.4 and systolic EI was 2.5 ± 0.8. On multivariate analysis relative pulmonary pressure, relative RV area, and inter-ventricular mechanical delay were independently associated with systolic EI (R(2) = 0.72, P < 0.001). Independent determinants of diastolic EI included relative RV area and mean PAP (R(2) = 0.69, P < 0.001). A systolic EI >1.08 differentiated patients with PAH from healthy controls with an AUC = 0.99. Patients with early systolic septal anterior motion (44% of subjects) had lower exercise capacity, more extensive ventricular remodeling, and worst ventricular function. Septal curvature is a useful marker of structural, hemodynamic, and electromechanical ventricular interdependence in PAH.
    Echocardiography 12/2013; · 1.26 Impact Factor
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    ABSTRACT: Evidence is increasing of a link between interferon (IFN) and pulmonary arterial hypertension (PAH). Conditions with chronically elevated endogenous IFNs such as systemic sclerosis (SSc) are strongly associated with PAH. Furthermore, therapeutic use of type I IFN is associated with PAH. This was recognised at the 2013 World Symposium on Pulmonary Hypertension where the urgent need for research into this was highlighted. To explore the role of type I IFN in PAH. Cells were cultured using standard approaches. Cytokines were measured by ELISA. Gene and protein expression were measured using RT-PCR, Western blotting and immunohistochemistry. The role of type I IFN in PAH in vivo was determined using type I IFN receptor knock out (IFNAR1(-/-)) mice. Human lung cells responded to types I and II but not III IFN correlating with relevant receptor expression. Type I, II and III IFN levels were elevated in serum of SSc-PAH patients. Serum IP10 and ET-1 were raised and strongly correlated together. IP10 correlated positively with pulmonary haemodynamics and serum brain natriuretic peptide and negatively with 6-minute walk test and cardiac index. Endothelial cells grown out of the blood of PAH patients were more sensitive to the effects of type I IFN than cells from healthy donors. PAH lung demonstrated increased IFNAR1 protein levels. IFNAR1(-/-) mice were protected from the effects of hypoxia on the right heart, vascular remodelling and raised serum ET-1 levels. These data indicate that type I IFN, via an action of IFNAR1, mediates PAH.
    Circulation Research 12/2013; · 11.86 Impact Factor
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    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.
    Nature Genetics 12/2013; · 35.21 Impact Factor
  • Chest 12/2013; 144(6):1953-8. · 7.13 Impact Factor

Publication Stats

2k Citations
682.84 Total Impact Points

Institutions

  • 2000–2014
    • Université Paris-Sud 11
      • Service de Pneumologie
      Orsay, Île-de-France, France
    • Centre Hospitalier Universitaire de Caen
      Caen, Lower Normandy, France
  • 1998–2014
    • Centre Chirurgical Marie Lannelongue
      Plessis-Robinson, Île-de-France, France
  • 2012
    • VU University Medical Center
      Amsterdamo, North Holland, Netherlands
  • 2009
    • Université Libre de Bruxelles
      Bruxelles, Brussels Capital Region, Belgium
  • 2008
    • Armed Forces Biomedical Research Institute, France
      Bretigny, Île-de-France, France
  • 2007
    • Marmara University
      İstanbul, Istanbul, Turkey
  • 2006
    • University of Toronto
      Toronto, Ontario, Canada
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 2005
    • Hôpital Antoine-Béclère – Hôpitaux universitaires Paris-Sud
      Clamart, Île-de-France, France