Robert Naeije

University Hospital Brussels, Bruxelles, Brussels Capital Region, Belgium

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Publications (452)2218.26 Total impact

  • Robert Naeije, Stefano Ghio
    European Respiratory Journal 01/2015; 45(1):33-5. · 7.13 Impact Factor
  • Robert Naeije, Michele D'Alto, Paul R Forfia
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    ABSTRACT: There has been a lot of progress in measurement techniques of the pulmonary circulation in recent years, and this has required updating of basic physiological knowledge. Pulmonary artery pressures (PAP) are normally low and dependent on left atrial pressure (LAP) and cardiac output (CO). Therefore, defining the functional state of the pulmonary circulation for the detection of pulmonary vascular disease or evaluation of disease progression requires measurements of PAP, Pla and CO. Invasive measurements have lately improved by a better definition of zero leveling and of the effects of intrathoracic pressure changes, and understanding of the inherent limitations of fluid-filled thermodilution catheters. The effects of LAP and pulmonary flow on PAP in health and disease are now integrated in the hemodynamic diagnosis of pulmonary hypertension. Development of alternative noninvasive approaches is critically dependent on their potential to quantify pulmonary vascular pressures and CO. Doppler echocardiography and magnetic resonance imaging are coming close. Both approaches are performant for flow measurements, but pressures remain indirectly assessed from flow velocities and/or structural changes. Doppler echocardiography or magnetic resonance imaging have been shown to be accurate, allowing for valid population studies, but with insufficient precision for single number-derived clinical decision making. Copyright © 2014. Published by Elsevier Inc.
    Progress in Cardiovascular Diseases 12/2014; · 2.44 Impact Factor
  • Robert Naeije, Marco Guazzi
    The Journal of Heart and Lung Transplantation. 12/2014;
  • Gabor Kovacs, Robert Naeije, Horst Olschewski
    American Journal of Respiratory and Critical Care Medicine 11/2014; 190(10):1198-9. · 11.99 Impact Factor
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    ABSTRACT: Pulmonary hypertension (PH) secondary to left heart disease (LHD) is a largely underappreciated therapeutic target. Except for a specific focus on PH consequences in patients with advanced heart failure (HF) receiving a left ventricular assist device or candidates for heart transplant, prevention and treatment of initial subclinical forms of PH are not considered a priority in the management of this chronic disease population. Nonetheless, there is recent growing evidence supporting a clinical and prognostic role of PH in the elderly populations and in HF with preserved ejection fraction (pEF). Although the prevalence of PH in these populations still remains largely unknown, there is a large potential for effective pharmacological approaches that might impact the natural history of HFpEF by targeting earlier stages. However, pharmacological studies performed to date with traditional pulmonary vasodilators (i.e. prostanoids and endothelin receptor blockers) in cohorts with HF and left-sided PH have not been positive, primarily because of concomitant systemic hypotension and hepatic toxicity. The encouraging prelimiray data with more selective well-tolerated pulmonary vasodilators, such as phosphodiesterase type 5 inhibitors and guanylate cyclase stimulators/activators, however, suggest the need for new targets of pulmonary microvascular dysfunction and for treating PH-LHD at both early and later stages of the disease process.
    Progress in Cardiovascular Diseases 11/2014; · 2.44 Impact Factor
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    ABSTRACT: Right ventricular contractile response to pharmacological stress in pulmonary arterial hypertension (PAH) has not been characterised. We evaluated right ventricular contractile reserve in adults with PAH using dobutamine stress echocardiography. 16 PAH patients and 18 age-matched controls underwent low-dose dobutamine stress echocardiography. Contractile reserve was assessed by the change (Δ; peak stress minus rest value) in tricuspid annular plane systolic excursion (TAPSE) and tricuspid annular systolic velocity (S'). A subgroup of 13 PAH patients underwent treadmill cardiopulmonary exercise testing for peak oxygen uptake (V'O2peak). At rest, TAPSE and S' were reduced in the PAH group compared with controls (1.7±0.4 versus 2.4±0.2 cm and 9.7±2.6 cm·s(-1) versus 12.5±1.2 cm·s(-1), respectively; p<0.05). Contractile reserve was markedly attenuated in PAH compared to controls (ΔTAPSE 0.1±0.2 versus 0.6±0.3 cm and ΔS' 4.6±2.8 versus 11.2±3.6 cm·s(-1); p<0.0001). In the sub-group of PAH patients with preserved right ventricular systolic function at rest, contractile reserve remained depressed compared to controls. V'O2peak was significantly correlated with ΔS' (r = 0.87, p = 0.0003) and change in stroke volume (r = 0.59, p = 0.03). Dobutamine stress can reveal sub-clinical reduction in right ventricular contractile reserve in patients with PAH. A correlation with exercise capacity suggests potential clinical value beyond resting measurements.
    European Respiratory Journal 10/2014; · 7.13 Impact Factor
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    ABSTRACT: The differential diagnosis between pre- and postcapillary pulmonary hypertension (PH) is of major therapeutic relevance and thus requires optimal clinical probability assessment with echocardiography. We prospectively analyzed 152 consecutive patients referred to a PH center over a 1-year period undergoing quasi-simultaneous (within 1 hour) echocardiography and right heart catheterization. Echocardiography was performed as usually recommended for the assessment of PH and left heart conditions. PH was defined as a mean pulmonary artery pressure ≥ 25 mm Hg. Postcapillary PH was diagnosed on the basis of a pulmonary capillary wedge pressure >15 mm Hg. Ten of 152 patients (7%) had no PH, 81 of 152 (53%) had precapillary PH, and 61 of 152 (40%) had postcapillary PH. The following five echocardiographic variables were found to predict precapillary PH: right heart chamber larger than the left (P = .0018), left ventricular eccentricity index > 1.2 (P = .0039), dilated inferior vena cava without inspiratory collapse (P = .0076), E/e' ratio ≤10 (P = .00001), and the right ventricle forming the heart apex (P = .0144). Beta coefficients from multiple logistic regression were significant for dilated inferior vena cava without inspiratory collapse (P = .0464) and E/e' ratio ≤ 10 (P = .0002). The score based on β coefficients, ranging from 3 to 34 points, resulted in optimal discrimination at >5, with a positive predictive value of 67.9% and a negative predictive value of 77.5% for precapillary PH. Echocardiography enables a clinically satisfactory differential diagnosis between pre- and postcapillary PH. Copyright © 2014 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.
    Journal of the American Society of Echocardiography: official publication of the American Society of Echocardiography 10/2014; · 2.98 Impact Factor
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    ABSTRACT: Endothelin receptor antagonists improve pulmonary arterial hypertension (PAH). Mutations in the bone morphogenetic protein (BMP) type 2 receptor (BMPR2) predispose to PAH. Here, we sought to determine whether there might exist interactions between these 2 signaling pathways and their effect on the acquisition of the altered phenotype of pulmonary artery smooth muscle cells (PA-SMCs) observed in PAH. Expression of BMPR2, of the BMP agonist BMP4, and of the BMP antagonists gremlin1 and gremlin2 was evaluated in lungs and in PA-SMCs from 6 PAH patients and 14 controls treated with endothelin-1. Endothelin-1 pre-treated PA-SMCs were assessed for proliferation, apoptosis, and downstream signaling activation of Smad1/5/8 and p38 mitogen-activated protein kinase (p38(MAPK)) after BMP2 treatment. In PA-SMCs from PAH patients, expression of BMPR2 and BMP4 decreased, whereas expression of gremlin1 and gremlin2 increased compared with controls. Treatment of control PA-SMCs with endothelin-1 induced a dose-dependent increase in gremlin1 and gremlin2, whereas BMPR2 and BMP4 expression decreased, reaching similar levels as those observed in PAH cells. In control PA-SMCs, endothelin-1 pre-treatment reduced inhibitor of DNA binding 1 (Id1) expression and Smad1/5/8 activation induced by BMP2, whereas it enhanced p38(MAPK) activation. Moreover, BMP2 decreased serum-induced proliferation and increased the pro-apoptotic Bax/Bcl-2 ratio. These effects were attenuated by endothelin-1 pre-treatment. Endothelin-1 did not alter BMPR2 signaling in PA-SMCs from PAH patients. Endothelin-1 downregulates canonical BMPR2 signaling. This is related to decreased BMPR2 and increased anti-BMP gremlin expression associated with increased activation of p38(MAPK) and results in PA-SMC proliferation. Copyright © 2014 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.
    The Journal of Heart and Lung Transplantation 09/2014; · 5.61 Impact Factor
  • Laurence Dewachter, Robert Naeije
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    ABSTRACT: Introduction: Parenteral prostacyclins are considered the gold standard treatment of severe pulmonary arterial hypertension (PAH). However, the technical and clinical burden of their continuous parenteral administration has led to the development of long-acting oral analogs.Areas covered: Following suggestive uncontrolled studies, an initial 3-month randomized placebo-controlled trial of the oral prostacyclin analog beraprost sodium (BPS) was completed, demonstrating significant improvement in the primary endpoint, which was the six-minute walk test. However, a subgroup analysis revealed that only idiopathic PAH patients benefited from the drug, secondary end points were negative and dosing was limited by side effects. A second 1-year randomized trial with a primary end point combining clinical stability and exercise capacity was negative. A secondary analysis revealed significant improvement after BPS intake at 6 months. Recent open-label studies with a modified release BPS formulation (BPS-MR) suggested long-term improvement in exercise capacity and clinical state in PAH patients. Randomized controlled trials with BPS-MR are underway but have been slowed by regulatory requirements of single optical isomer reformulation of BPS-MR (BPS-414d-MR).Expert opinion: BPS is efficacious in PAH but has failed until now in randomized controlled trials mainly because of side effects limiting dosing. Successive reformulations will hopefully produce better tolerated, purer and longer-acting preparations.
    Expert Opinion on Orphan Drugs. 09/2014;
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    ABSTRACT: Prognosis in pulmonary hypertension (PH) is largely determined by RV function. However, uncertainty remains about what metrics of RV function might be most clinically relevant. The purpose of this study was to assess the clinical relevance of metrics of RV functional adaptation to increased afterload.
    Heart (British Cardiac Society) 09/2014; · 6.02 Impact Factor
  • Echocardiography 09/2014; · 1.26 Impact Factor
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    ABSTRACT: The right ventricle (RV) can be described in terms of 3 components: the inlet, the apex, and the infundibulum. In the normal adult, the RV shows an arrangement suited for pumping blood against low resistance, with a mass about one sixth that of left ventricle (LV) mass, and a larger volume than the LV. The RV is able to manage a progressive increase in the afterload by increasing contractility and remodeling. The gold standard measurement of contractility is maximal elastance (Emax), or the ratio between end-systolic pressure (ESP) and end-systolic volume (ESV), and the best measurement of afterload is arterial elastance (Ea), or the ratio between ESP and stroke volume (SV). The ratio Emax/Ea defines RV-arterial coupling. The optimal energy transfer from the RV to the pulmonary circulation is measured at Emax/Ea ratios of 1.5–2. In the presence of pulmonary hypertension, the SV/ESV ratio may be an acceptable surrogate of Emax/Ea. The right atrium (RA) has 3 anatomical components: the appendage, the venous part, and the vestibule. It is a dynamic structure having different functions: reservoir, conduit, and booster pump function. In case of increased afterload, the RA is enlarged, denoting high RA pressure, as a consequence of elevated RV diastolic pressure. RA area is a strong predictor of adverse clinical outcome in pulmonary arterial hypertension. In patients with severe pulmonary hypertension, in several congenital heart diseases, and in Eisenmenger syndrome, symptoms and prognosis are greatly dependent on RV function and its ability to adapt to a chronic increase in afterload.
    Echocardiography 09/2014; · 1.26 Impact Factor
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    ABSTRACT: Echocardiography is a key screening tool in the diagnostic algorithm of pulmonary arterial hypertension (PAH). It provides an estimate of right ventricular function and pulmonary artery pressure, either at rest or during exercise, and is useful in ruling out secondary causes of pulmonary hypertension (PH) such as left heart disease or congenital heart disease. Several studies have showed that echocardiography is insufficiently precise as single tool for the ultimate diagnosis of PH respect to the right heart catheterization, considered the gold standard technique. Echocardiography is valuable in assessing prognosis and treatment options, monitoring the efficacy of specific therapeutic interventions, and detecting the preclinical stages of disease. The ideal imaging modality for accurate noninvasive assessment of the right heart should be accurate and precise, not influenced by loading conditions, routinely practicable and easily repeatable. For all such reasons and considering that PAH is a rare and severe condition, a complete noninvasive assessment of right heart function requires a deep knowledge of the disease and a multimodality approach.
    Echocardiography 09/2014; · 1.26 Impact Factor
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    Robert Naeije, Michele D'Alto
    European Respiratory Journal 08/2014; 44(2):553-4. · 7.13 Impact Factor
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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 06/2014; 9(6):e100310. · 3.53 Impact Factor
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    ABSTRACT: If a competition between the oxygen demands of limb and respiratory muscles happens, hypoxia may favour redistribution of blood flow from peripheral to respiratory muscles during heavy exercise. This hypothesis was tested in eighteen lowlanders and 27 highlanders at 4,350 m altitude. During an incremental exercise, the regional tissue oxygen saturation (rSO2) and tissue hemoglobin concentration ([Hbt]) of the intercostal muscles and vastus medialis were monitored simultaneously by NIRS. The intercostal and vastus medialis rSO2 values were lower at altitude than at sea level (–10%, p < 0.001) and decreased similarly during incremental exercise (p < 0.001) while [Hbt] values increased. At maximal exercise, the intercostal rSO2 was lower than the vastus medialis rSO2 in lowlanders (-7%, p < 0.001). In highlanders the time patterns were similar but intercostal rSO2 was less decreased at exercise (p < 0.05). Maximal exercise performed in hypoxia did not alter the kinetics of rSO2 and [Hbt] in peripheral muscles. These findings do not favour the hypothesis of blood flow redistribution.
    Respiratory Physiology & Neurobiology 06/2014; · 1.97 Impact Factor
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    ABSTRACT: The accuracy of pulmonary vascular pressure measurements is of great diagnostic and prognostic relevance. However, there is variability of zero leveling procedures, and the current recommendation of end-expiratory reading may not always be adequate. A review of physiological and anatomical data, comforted by recent imaging, leads to the practical recommendation of zero leveling at the cross-section of three trans-thoracic planes which are respectively mid-chest frontal, transverse through the fourth intercostal space, and mid-sagittal. As for the inevitable respiratory pressure swings, end-expiratory reading at functional residual capacity allows for minimal influence of elastic lung recoil on pulmonary pressure reading. However, hyperventilation is associated with changes in end-expiratory lung volume and increased intra-thoracic pressure, eventually exacerbated by expiratory muscle contraction and dynamic hyperinflation, all increasing pulmonary vascular pressures. This problem is amplified in patients with obstructed airways. With the exception of dynamic hyper-inflation states, it is reasonable to assume that negative inspiratory and positive expiratory intrathoracic pressures cancel each other out, so averaging pulmonary vascular pressures over several respiratory cycles is most often preferable. This recommendation may be generalized, for the purpose of consistency, and makes sense as pulmonary blood flow measurements are not corrected either for phasic inspiratory and expiratory changes in clinical practice.
    American Journal of Respiratory and Critical Care Medicine 05/2014; · 11.04 Impact Factor
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    ABSTRACT: Background Elevated serum uric acid is detected in pulmonary arterial hypertension (PAH) and is associated with poor patient outcomes. High serum uric acid is an independent risk factor for cardiovascular disease and renal impairment. We analyzed the effects of endothelin receptor antagonism on serum uric acid in PAH patients participating in the Sitaxentan to Relieve Impaired Exercise (STRIDE)-2/2X trial, and the impact of uric acid on 6-minute walk distance (6MWD), time to clinical worsening (TtCW), and survival. Methods In the 18-week, double-blind, placebo-controlled STRIDE-2 trial, 246 PAH patients were randomized and received matched placebo, sitaxentan 50 or 100 mg orally once daily, or open-label bosentan 125 mg twice daily. STRIDE-2X was a 1-year, open-label extension of STRIDE-2. Results Baseline serum uric acid was similar between groups. Increased serum uric acid was a significant risk factor for 1-year mortality and TtCW. Compared with placebo, sitaxentan 50 and 100 mg, and bosentan all reduced serum uric acid (p<0.05). Reduced serum uric acid correlated with increased 6MWD (p=0.0037). Conclusions Endothelin receptor antagonism reduces serum uric acid in PAH patients, and this reduction is associated with improved survival and longer TtCW. Further prospective studies are needed to investigate the pathogenic role of serum uric acid in PAH and its prognostic potential.
    The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 05/2014; · 5.61 Impact Factor
  • Robert Naeije, Marion Delcroix
    European Respiratory Journal 05/2014; 43(5):1541-1542. · 7.13 Impact Factor
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    ABSTRACT: The 6 minutes walk test (6MWT) is often shown to be the best predictor of mortality in pulmonary hypertension (PH) probably because it challenges the failing heart to deliver adequate cardiac output. We hypothesised that the 6MWT elicits maximal cardiac output as measured during a maximal cardiopulmonary exercise testing (CPET). 18 patients with chronic thromboembolic pulmonary hypertension (n = 12) or pulmonary arterial hypertension (n = 6) and 10 healthy subjects performed a 6MWT and CPET with measurements of cardiac output (non invasive rebreathing device) before and directly after exercise. Heart rate was measured during 6MWT with a cardiofrequence meter. Cardiac output and heart rate measured at the end of the 6MWT were linearly related to 6MW distance (mean±SD: 490±87 m). Patients with a high NT-pro-BNP achieve a maximum cardiac output during the 6MWT, while in normal subjects and in patients with a low-normal NT-proBNP, cardiac output at the end of a 6MWT was lower than achieved at maximum exercise during a CPET. In both cases, heart rate is the major determinant of exercise-induced increase in cardiac output. However, stroke volume increased during CPET in healthy subjects, not in PH patients. Maximal cardiac output is elicited by 6MWT in PH patients with failing right ventricle. Cardiac output increase is dependent on chronotropic response in patients with PH.
    PLoS ONE 03/2014; 9(3):e92324. · 3.53 Impact Factor

Publication Stats

9k Citations
2,218.26 Total Impact Points


  • 1976–2014
    • University Hospital Brussels
      Bruxelles, Brussels Capital Region, Belgium
  • 1975–2014
    • Vrije Universiteit Brussel
      • • Department of Cardiology
      • • Physiology (FYSP)
      • • Department of Intensive Care Medicine
      • • Department of Internal Medicine
      Bruxelles, Brussels Capital Region, Belgium
  • 2013
    • Monaldi Hospital
      Napoli, Campania, Italy
    • Papworth Hospital NHS Foundation Trust
      Papworth, England, United Kingdom
  • 2002–2013
    • Université Libre de Bruxelles
      • • Faculty of Medicine
      • • Laboratory of Physiology and Physiopathology (PHYSIO)
      • • Department of Pathology
      • • Intensive Care Unit
      Bruxelles, Brussels Capital Region, Belgium
    • Hôpital Antoine-Béclère – Hôpitaux universitaires Paris-Sud
      Clamart, Île-de-France, France
  • 2012
    • The University of Western Ontario
      London, Ontario, Canada
    • Université de Poitiers
      Poitiers, Poitou-Charentes, France
    • University of Cambridge
      Cambridge, England, United Kingdom
  • 2009–2012
    • Second University of Naples
      • Faculty of Medicine and Surgery
      Caserta, Campania, Italy
    • University of Wisconsin, Madison
      • Department of Biomedical Engineering
      Madison, MS, United States
  • 2008–2012
    • VU University Medical Center
      • Institute for Cardiovascular Research (ICaR-VU)
      Amsterdamo, North Holland, Netherlands
    • Vienna General Hospital
      Wien, Vienna, Austria
    • University of Alabama at Birmingham
      Birmingham, Alabama, United States
    • Medical University of Bialystok
      Belostok, Podlasie, Poland
  • 1998–2012
    • Universitair Ziekenhuis Leuven
      • Department of Cardiology
      Louvain, Flanders, Belgium
  • 2006
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
    • University-Hospital Brugmann UVC
      Bruxelles, Brussels Capital Region, Belgium
  • 2005–2006
    • Erasmushogeschool Brussel
      Bruxelles, Brussels Capital Region, Belgium
  • 2000
    • University Hospital of Lausanne
      • Service de médecine interne
      Lausanne, VD, Switzerland
  • 1979–1989
    • Centre Hospitalier Universitaire Saint-Pierre
      Bruxelles, Brussels Capital Region, Belgium