Lars C Huber

University of Zurich, Zürich, Zurich, Switzerland

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Publications (56)339.28 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Pulmonary hypertension (PH) due to COPD has dismal prognosis. We reviewed the long-term effect of PH-target therapy in severe PH-COPD.
    Beiträge zur Klinik der Tuberkulose 10/2014; · 2.06 Impact Factor
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    ABSTRACT: Pulmonary hypertension is an "umbrella term" used for a spectrum of entities resulting in an elevation of the pulmonary arterial pressure. Clinical symptoms include dyspnea and fatigue which in the absence of adequate therapeutic intervention may lead to progressive right heart failure and death. The pathogenesis of pulmonary hypertension is characterized by three major processes including vasoconstriction, vascular remodeling and microthrombotic events. In addition accumulating evidence point to a cytokine driven inflammatory process as a major contributor to the development of pulmonary hypertension.This review summarizes the latest clinical and experimental developments in inflammation associated with pulmonary hypertension with special focus on Interleukin-6, and its role in vascular remodeling in pulmonary hypertension.
    Respiratory research 04/2014; 15(1):47. · 3.64 Impact Factor
  • Mattia Arrigo, Lars C Huber
    Chest 02/2014; 145(2):413. · 7.13 Impact Factor
  • Matthias Brock, Silvia Ulrich, Lars Christian Huber
    European Respiratory Journal 01/2014; 43(1):313-4. · 6.36 Impact Factor
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    ABSTRACT: Sleep-disturbed breathing (SDB) is common in pre-capillary pulmonary hypertension (PH) and impairs daytime performance. In lack of proven effective treatments, we tested whether nocturnal oxygen therapy (NOT) or acetazolamide improve exercise performance and quality of life in patients with pre-capillary PH and SDB. This was a randomized, placebo-controlled, double-blind, three period cross-over trial. Participants received NOT (3 L/min), acetazolamide tablets (2 × 250 mg), and sham-NOT/placebo tablets each during 1 week with 1-week washout between treatment periods. Twenty-three patients, 16 with pulmonary arterial PH, 7 with chronic thromboembolic PH, and with SDB defined as mean nocturnal oxygen saturation <90% or oxygen saturation dips >10 h(-1) with daytime PaO2 ≥7.3 kPa participated. Assessments at the end of the treatment periods included a 6 min walk distance (MWD), SF-36 quality of life, polysomnography, and echocardiography. Medians (quartiles) of the 6 MWD after NOT, acetazolamide, and placebo were 480 m (390;528), 440 m (368;468), and 454 m (367;510), respectively, mean differences: NOT vs. placebo +25 m (95% CI 3-46, P= 0.027), acetazolamide vs. placebo -9 m (-34-17, P = 0.223), and NOT vs. acetazolamide +33 (12-45, P < 0.001). SF-36 quality of life was similar with all treatments. Nocturnal oxygen saturation significantly improved with both NOT and acetazolamide. Right ventricular fractional area change was greater on NOT compared with placebo (P = 0.042) and acetazolamide (P = 0.027). In patients with pre-capillary PH and SDB on optimized pharmacological therapy, NOT improved the 6 MWD compared with placebo already after 1 week along with improvements in SDB and haemodynamics. NTC01427192.
    European Heart Journal 12/2013; · 14.72 Impact Factor
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    ABSTRACT: Introduction Despite new treatment options targeted at its three main pathogenic pathways, prognosis of idiopathic pulmonary arterial hypertension has remained dismal, with 3-year survival rates around 70 %. Antiproliferative agents have emerged as a new therapeutic concept. However, they may exert their effects only after a prolonged period of time. Case description Herein we present a patient who, despite being on a triple targeted drug therapy including high-dose intravenous prostanoids, still had severe pulmonary hypertension. After 4 years treatment with the tyrosine kinase inhibitor imatinib, the patient could be weaned from intravenous prostanoids and attained a persistent hemodynamic normalization. Conclusions Antiproliferative agents might be a promising new class of drugs in pulmonary arterial hypertension. However, the occurrence of unexpected side effects like the increased incidence of subdural hematomas, has led to the recommendation that at present such an off-label use is strongly discouraged, and that further studies elucidating the risk/benefit ratio of tyrosine kinase inhibitors are clearly needed.
    International journal of clinical pharmacy. 11/2013;
  • Simon A Müggler, Lars C Huber
    The Lancet Infectious Diseases 10/2013; 13(10):833. · 19.97 Impact Factor
  • Mattia Arrigo, Lars C Huber
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    ABSTRACT: Heart rate, blood pressure, and vascular tone, as well as ventilator drive, respiratory rate, and breathing pattern, are, at least in part, under the control of specific reflexes. These reflexes are mediated by a complex network of baroreceptors and chemoreceptors in the arterial system of the carotids, aorta, and left heart, including receptors in the left atrium, the ventricle, and the coronary arteries; irritants in the upper airways and stretch receptors in the lower airways; juxtacapillary-located nonmyelinated fibers in the alveoli and in the bronchial arterial system; and muscle spindles that evoke changes in the membrane potential upon alteration of sarcolemmal tension. Some of these reflexes, usually named after the first individual to describe them, have spread as eponyms into propaedeutic education and clinical work. Because these euphonic eponyms are enigmatic to most clinicians today, this article is intended to provide a short overview of these reflexes, including the historical context of their describers. As evidenced by their clinical implications, the eponyms discussed are revealed to be more than curiosities taught during undergraduate medical education.
    The American journal of cardiology 08/2013; 112(3):449-53. · 3.58 Impact Factor
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    ABSTRACT: Objective To elucidate whether the microRNA (miRNA) cluster miR-17–92 contributes to the activated phenotype of rheumatoid arthritis synovial fibroblasts (RASFs). MethodsRASFs were stimulated with tumor necrosis factor α (TNFα), and the expression and regulation of the miR-17–92 cluster were studied using real-time quantitative PCR (PCR) and promoter activity assays. RASFs were transfected with single precursor molecules of miRNAs from miR-17–92 and the expression of matrix-degrading enzymes and cytokines was measured by quantitative PCR and enzyme-linked immunosorbent assay. Potential miRNA targets were identified by computational prediction and were validated using reporter gene assays and Western blotting. The activity of NF-κB signaling was determined by reporter gene assays. ResultsWe found that TNFα induces the expression of miR-17–92 in RASFs in an NF-κB–dependent manner. Transfection of RASFs with precursor molecules of single members of miR-17–92 revealed significantly increased expression levels of matrix-degrading enzymes, proinflammatory cytokines, and chemokines in precursor miR-18a (pre-miR-18a)–transfected RASFs. Using reporter gene assays, we identified the NF-κB pathway inhibitor TNFα-induced protein 3 as a new target of miR-18a. In addition, pre-miR-18a–transfected RASFs showed stronger activation of NF-κB signaling, both constitutively and in response to TNFα stimulation. Conclusion Our data suggest that the miR-17–92–derived miR-18a contributes to cartilage destruction and chronic inflammation in the joint through a positive feedback loop in NF-κB signaling, with concomitant up-regulation of matrix-degrading enzymes and mediators of inflammation in RASFs.
    Arthritis & Rheumatology 04/2013; 65(4). · 7.48 Impact Factor
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    ABSTRACT: Objective: To elucidate whether the microRNA (miRNA) cluster miR-17-92 contributes to the activated phenotype of rheumatoid arthritis synovial fibroblasts (RASF). Methods: RASF were stimulated with tumor necrosis factor alpha (TNFα? and expression and regulation of the miR-17-92 cluster were studied using quantitative real-time PCR (qPCR) and promoter activity assays. RASF were transfected with single precursor molecules of miRNAs from miR-17-92 and the expression of matrix-degrading enzymes and cytokines was measured by qPCR and enzyme-linked immunosorbent assay. Potential miRNA targets were identified by computational prediction and validated using reporter gene assays and Western blot. The activity of NF-κB signaling was determined by reporter gene assay. Results: We found that TNFα induces the expression of miR-17-92 in RASF in a nuclear factor kappa B (NF-κB)-dependent manner. Transfection of RASF with precursor molecules of single members of miR-17-92 revealed significantly increased expression levels of matrix-degrading enzymes, proinflammatory cytokines and chemokines in pre-miR-18a-transfected RASF. Using reporter gene assays we identified the NF-κB pathway inhibitor TNFα-induced protein 3 (TNFAIP3) as a new target of miR-18a. In consequence, pre-miR-18a-transfected RASF showed stronger activation of NF-κB signaling, both constitutively and in response to TNFα-stimulation. Conclusion: Our data suggest that the miR-17-92-derived miR-18a contributes to cartilage destruction and chronic inflammation in the joint through a positive feedback loop in NF-κB signaling with concomitant upregulation of matrix-degrading enzymes and inflammatory mediators in RASF. © 2012 American College of Rheumatology.
    Arthritis & Rheumatology 12/2012; · 7.48 Impact Factor
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    ABSTRACT: BACKGROUND: Individuals with precapillary pulmonary hypertension (PH) experience severely impaired quality of life. A disease-specific outcome measure for PH, the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) was developed and validated in the UK and subsequently adapted for use in additional countries. The aim of this study was to translate and assess the reliability and validity of the CAMPHOR for German-speaking populations. METHODS: Three main adaptation stages involved; translation (employing bilingual and lay panels), cognitive debriefing interviews with patients and validation (assessment of the adaptation's psychometric properties). The psychometric evaluation included 107 patients with precapillary PH (60 females; age mean (standard deviation) 60 (15) years) from 3 centres in Austria, Germany and Switzerland. RESULTS: No major problems were found with the translation process with most items easily rendered into acceptable German. Participants in the cognitive debriefing interviews found the questionnaires relevant, comprehensive and easy to complete. Psychometric analyses showed that the adaptation was successful. The three CAMPHOR scales (symptoms, activity limitations and quality of life) had excellent test-retest reliability correlations (Symptoms = 0.91; Activity limitations = 0.91; QoL = 0.90) and internal consistency (Symptoms = 0.94; Activity limitations = 0.93; QoL = 0.94). Predicted correlations with the Nottingham Health Profile provided evidence of the construct validity of the CAMPHOR scales. The CAMPHOR adaptation also showed known group validity in its ability to distinguish between participants based on perceived general health, perceived disease severity, oxygen use and NYHA classification. CONCLUSIONS: The CAMPHOR has been shown to be valid and reliable in the German population and is recommend for use in clinical practice.
    Health and Quality of Life Outcomes 09/2012; 10(1):110. · 2.27 Impact Factor
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    ABSTRACT: BACKGROUND: A low resting heart rate (HR) is prognostically favourable in healthy individuals and in patients with left heart disease. In this study we investigated the impact of HR at diagnosis on long-term outcome in patients with differently classified precapillary pulmonary hypertension (pPH). METHODS: pPH patients diagnosed as pulmonary arterial (PAH) or inoperable chronic thromboembolic pulmonary hypertension (CTEPH) were registered and regularly followed at our centre Baseline characteristics and events defined as either death or lung transplantation were noted. The prognostic value of HR was analysed using Kaplan Meier estimates, live tables and Cox regression. RESULTS: 206 patients with PAH (148) and inoperable CTEPH (58) were included. The median HR was 82 bpm. pPH with a HR below 82 bpm had a significantly longer overall event-free survival (2409 vs.1332 days, p = .000). This advantage was similarly found if PAH and CTEPH were analysed separately. Although a lower HR was associated with a better hemodynamic and functional class, HR was a strong and independent prognostic marker for transplant free survival even if corrected for age, sex, hemodynamics and functional status. CONCLUSION: We show that resting HR at diagnosis is a strong and independent long-term prognostic marker in PAH and CTEPH. Whether reducing HR by pharmacological agents would improve outcome in pPH has to be assessed by future trials with high attention to safety.
    Respiratory research 09/2012; 13(1):76. · 3.64 Impact Factor
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    ABSTRACT: Martorell hypertensive ischemic leg ulcer (Martorell ulcer) is characterized by distinct alterations in the arteriolar wall of subcutaneous vessels, leading to progressive narrowing of the vascular lumen and increase of vascular resistance. These changes are similar to the alterations observed in pulmonary arterioles in patients with chronic pulmonary hypertension (PH). This study was aimed to assess an association between the two disorders. In this case-control study, 14 patients with Martorell ulcer were clinically assessed for the presence of pulmonary hypertension using transthoracic Doppler echocardiography. Data from patients were compared to 28 matched hypertensive controls. Systolic pulmonary arterial pressure (sPAP) in patients with Martorell ulcer was significantly higher than in the control group (33.8 ± 16.9 vs 25.3 ± 6.5 mmHg, p = 0.023); the prevalence of pulmonary hypertension was 31% (5/14) in patients and 7% (2/28) in controls (p = 0.031). No differences were seen in left heart size and function between patients and controls. This study provides first evidence that subcutaneous arteriolosclerosis, the hallmark of Martorell ulcer, is associated with PH. These findings suggest that patients with Martorell leg ulcer might be at significant risk to develop elevated pulmonary arterial pressure. Patients with leg ulcers who present with dyspnea should be evaluated by echocardiography for the presence of pulmonary hypertension.
    Respiratory research 06/2012; 13:45. · 3.64 Impact Factor
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    ABSTRACT: We report the case of a 76-year-old female patient presenting with deep venous thrombosis and upper cervical lymphadenopathy. A computed tomography (CT) scan showed multiple hepatic lesions with a high suspicion of metastatic disease from an unknown primary tumor. The differential diagnosis of lymphadenopathy and hepatic lesions includes malignant tumors and various infectious diseases. The diagnostic process, however, revealed lymph node tuberculosis with multiple hepatic granulomas despite a repeatedly negative interferon-γ release assay. A combined antituberculosis therapy led to complete clinical remission.
    Der Internist 04/2012; 53(6):756-9. · 0.33 Impact Factor
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    ABSTRACT: AimsDysregulation of the bone morphogenetic protein receptor type 2 (BMPR2) is a hallmark feature that has been described in several forms of pulmonary hypertension. We recently identified the microRNA miR-20a within a highly conserved pathway as a regulator of the expression of BMPR2. To address the pathophysiological relevance of this pathway in vivo, we employed antagomiR-20a and investigated whether specific inhibition of miR-20a could restore functional levels of BMPR2 and, in turn, might prevent pulmonary arterial vascular remodelling.Methods and resultsFor specific inhibition of miR-20a, cholesterol-modified RNA oligonucleotides (antagomiR-20a) were synthesized. The experiments in mice were performed by using the hypoxia-induced mouse model for pulmonary hypertension and animal tissues were analysed for right ventricular hypertrophy and pulmonary arterial vascular remodelling. Treatment with antagomiR-20a enhanced the expression levels of BMPR2 in lung tissues; moreover, antagomiR-20a significantly reduced wall thickness and luminal occlusion of small pulmonary arteries and reduced right ventricular hypertrophy. To assess BMPR2 signalling and proliferation, we performed in vitro experiments with human pulmonary arterial smooth muscle cells (HPASMCs). Transfection of HPASMCs with antagomiR-20a resulted in activation of downstream targets of BMPR2 showing increased activation of Id-1 and Id-2. Proliferation of HPASMCs was found to be reduced upon transfection with antagomiR-20a.ConclusionThis is the first report showing that miR-20a can be specifically targeted in an in vivo model for pulmonary hypertension. Our data emphasize that treatment with antagomiR-20a restores functional levels of BMPR2 in pulmonary arteries and prevents the development of vascular remodelling.
    European Heart Journal 03/2012; · 14.72 Impact Factor
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    ABSTRACT: The acute-phase response is an inflammatory process triggered mainly by the cytokine IL-6. Signaling of IL-6 is transduced by activation of STAT3 (signal transducer and activator of transcription 3), which rapidly induces the production of acute-phase proteins such as haptoglobin and fibrinogen. Another target of the IL-6/STAT3 signal transduction pathway is the microRNA cluster miR-17/92. Here, we investigated the interplay of miR-17/92 and STAT3 signaling and its impact on the acute-phase response in primary human hepatocytes and hepatoma (HepG2) cells. Employing a reporter gene system consisting of STAT3-sensitive promoter sequences, we show that the miR-17/92 cluster member miR-18a enhanced the transcriptional activity of STAT3. IL-6 stimulation experiments in miR-18a-overexpressing hepatocytes and HepG2 cells revealed an augmented acute-phase response indicated by increased expression and secretion of haptoglobin and fibrinogen. This effect was due, at least in part, to repression of PIAS3 (protein inhibitor of activated STAT, 3), a repressor of STAT3 activity, which we identified as a novel direct target of miR-18a. Finally, we demonstrate that the expression of miR-17/92 in primary hepatocytes and HepG2 cells is modulated by IL-6. Our data reveal, for the first time, a microRNA-mediated positive feedback loop of IL-6 signal transduction leading to an enhanced acute-phase response in human hepatocytes.
    Journal of Biological Chemistry 09/2011; 286(46):40142-50. · 4.65 Impact Factor
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    ABSTRACT: To study the expression, regulation and function of the histone methyltransferase enhancer of zeste homologue 2 (EZH2) in synovial fibroblasts (SF) from patients with rheumatoid arthritis (RA) and osteoarthritis (OA). SF were obtained from RA and OA patients undergoing joint surgery. Expression levels were assessed by quantitative real-time PCR and western blot. Kinase inhibitors and reporter gene assays were employed to study signalling pathways. Functional analyses included EZH2 overexpression by plasmid transfection and gene silencing by small interfering RNA. Chromatin immunoprecipitation assay was used to analyse histone methylation within distinct promoter regions. By studying the expression and function of EZH2 in SF the authors found that EZH2 is overexpressed in rheumatoid arthritis synovial fibroblasts (RASF) and further induced by tumour necrosis factor alpha through the nuclear factor kappa B and Jun kinase pathways. As a target gene of EZH2 the authors identified secreted frizzled-related protein 1 (SFRP1), an inhibitor of Wnt signalling, which is associated with the activation of RASF, and show that SFRP1 expression correlates with the occupation of its promoter with activating and silencing histone marks. These data strongly suggest that the chronic inflammatory environment of the RA joint induces EZH2 and thus might cause changes in the epigenetic programmes of SF.
    Annals of the rheumatic diseases 05/2011; 70(8):1482-8. · 8.11 Impact Factor
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    ABSTRACT: The serotonin system has repeatedly been associated with the pathogenesis of pulmonary hypertension (PH). Objective: To comparatively analyze plasmatic and intrathrombocytic serotonin levels in arterial and mixed venous blood of patients with PH and unaffected controls to elucidate pulmonary serotonin metabolisms. Catheters were placed in the radial and pulmonary artery in patients with PH (n = 13) for diagnosis and in age-matched controls (n = 6) undergoing percutaneous closure of the patent foramen ovale. Arterial and mixed venous blood samples were immediately centrifuged to obtain plasma and platelets and thereafter frozen at -20°C. After careful thawing, plasmatic and platelet serotonin levels were determined by ELISA. PH was classified as arterial in 4 and chronic thromboembolic in 9 patients with a mean pulmonary artery pressure of 37 (interquartile range: 32-43) mm Hg. Platelet serotonin content was significantly lower in the PH patients than in the controls. The mean transpulmonary gradient (arterial-mixed venous) was negative in the PH group and positive in the controls. An inverse correlation was found between the arterial blood platelet serotonin content and pulmonary hemodynamics. Plasmatic serotonin levels did not differ between the PH and control groups. The lower platelet serotonin concentration in PH patients compared with unaffected controls is an unprecedented finding. The negative transpulmonary platelet serotonin gradient and the strong negative correlation of arterial blood platelet serotonin with pulmonary hemodynamics might indicate increased serotonin uptake in the lungs of PH patients.
    Respiration 01/2011; 81(3):211-6. · 2.92 Impact Factor
  • Lars C Huber, Véronique Müller
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    ABSTRACT: To the Editor: In their review article, Agnelli and Becattini (July 15 issue)(1) discuss many important topics in acute pulmonary embolism. We would like to highlight the importance of the use of pulmonary magnetic resonance imaging (MRI) in the diagnosis of this condition, since substantial technical developments have been introduced in recent years.(2),(3) Continued improvements include the use of parallel imaging, angiography technique, and pulmonary perfusion,(2)-(4) with the latter showing the most promise for the diagnosis of pulmonary embolism.(3) However, even in protocols without pulmonary perfusion, large studies have shown good results with the use of MRI.(5) Overall, . . .
    New England Journal of Medicine 11/2010; 363(20):1973-4; author reply 1974-5. · 54.42 Impact Factor
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    ABSTRACT: Smoking is a well-known risk factor for cardiovascular, lung, and many other diseases. Smoking can induce pulmonary arterial hypertension (PAH) in animal models; PAH is common in smokers with COPD and thereby not correlated with the degree of airway obstruction. The impact of tobacco smoke exposure on the development of PAH in humans is not known. In a case-control study we assessed smoking and secondhand smoke exposure in all patients with PAH and chronic thromboembolic pulmonary hypertension (CTEPH) seen at our pulmonary hypertension clinic from 2002 until July 2008. Data from patients with PAH were compared with CTEPH and healthy control subjects from the Swiss Health Survey 2007. Ninety-one patients with PAH were compared with 64 patients with CTEPH and 18,747 control subjects (women 58, 36, 10,331, respectively). Tobacco smoking was significantly more common in PAH compared with CTEPH and control subjects. This difference could be attributed to men. Patients with PAH also smoked longer and more heavily compared with patients with CTEPH. In addition, secondhand smoke exposure was significantly longer in nonsmokers with PAH compared with control subjects. Our data indicate that tobacco smoke exposure may be a risk factor for men with PAH. Considering smoking as a risk factor for PAH will have implications in counseling patients and especially their hitherto unaffected relatives. Further research on the pathogenetic role of smoking in PAH is warranted.
    Chest 11/2010; 138(5):1086-92. · 7.13 Impact Factor

Publication Stats

1k Citations
339.28 Total Impact Points

Institutions

  • 2004–2013
    • University of Zurich
      • • Internal Medicine Unit
      • • Center for Integrative Human Physiology
      Zürich, Zurich, Switzerland
  • 2007–2008
    • Johannes Gutenberg-Universität Mainz
      • Orthopädische Klinik und Poliklinik
      Mainz, Rhineland-Palatinate, Germany
  • 2005–2007
    • Friedrich-Alexander Universität Erlangen-Nürnberg
      • Rheumatology and Immunology Clinic
      Erlangen, Bavaria, Germany
  • 2006
    • Semmelweis University
      • Department of Genetics, Cell and Immunobiology
      Budapest, Budapest fovaros, Hungary