Lars C Huber

University of Zurich, Zürich, Zurich, Switzerland

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Publications (75)373.67 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Vascular remodeling due to excessive proliferation of endothelial and smooth muscle cells is a hallmark feature of pulmonary hypertension. microRNAs (miRNAs) are a class of small, non-coding RNA fragments that have recently been associated with remodeling of pulmonary arteries, in particular by silencing the bone morphogenetic protein receptor type II (BMPR2). Here we identified a novel pathway involving the concerted action of miR-125a, BMPR2 and cyclin-dependent kinase inhibitors (CDKN) that controls a proliferative phenotype of endothelial cells. An in silico approach predicted miR-125a to target BMPR2. Functional inhibition of miR-125a resulted in increased proliferation of these cells, an effect that was found accompanied by upregulation of BMPR2 and reduced expression of the tumor suppressors CDKN1A (p21) and CDKN2A (p16). These data were confirmed in experimental pulmonary hypertension in vivo. Levels of miR-125a were elevated in lung tissue of hypoxic animals that develop pulmonary hypertension. In contrast, circulating levels of miR-125a were found to be lower in mice with pulmonary hypertension as compared to control mice. Similar findings were observed in a small cohort of patients with precapillary pulmonary hypertension. These translational data emphasize the pathogenetic role of miR-125a in pulmonary vascular remodeling. © 2015 by the Society for Experimental Biology and Medicine.
    Experimental Biology and Medicine 04/2015; DOI:10.1177/1535370215579018 · 2.23 Impact Factor
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    ABSTRACT: Levels of microRNAs (miRNAs) are increasingly assessed in biological fluids, for example, in samples obtained by bronchoalveolar lavage (BAL). "Post-collection kinetics" of miRNA expression levels, however, have not been investigated to date. In these experiments, we analyzed the dynamic expression profile of 5 different miRNAs (miR-17, miR-19b, miR-20b, miR-125a, and miR-223-3p) in BAL within the first 24 h following collection by routine bronchoscopy. miRNAs were quantified 0, 1, 4, 8, and 24 h after collection in samples that were kept at 4 °C or at room temperature. The expression of all five miRNAs was found to remain stable between the first 8 h after collection. 24 h after collection miRNAs faced substantial alterations in their expression profile. These data emphasize that BAL samples intended for further miRNA analysis can be handled at room temperature within the first 8 h after bronchoscopy.
    Beiträge zur Klinik der Tuberkulose 03/2015; DOI:10.1007/s00408-015-9719-5 · 2.17 Impact Factor
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    ABSTRACT: We investigated the prevalence of bronchial asthma in patients with Tako-Tsubo Syndrome (TTS). This retrospective case-series study was conducted in a primary care hospital in Zurich, Switzerland. Data of all patients with newly diagnosed TTS (2002 - 2012) were assessed electronically by the use of ICD-10. Asthma prevalence was compared to published epidemiologic data. Bronchial asthma is characterized by airway inflammation and, during attack, release of endogenous catecholamines. Sympathomimetic drugs are the mainstay of treatment for asthma patients. Likewise, catecholamine mediated diffuse microvascular myocardial dysfunction seems to be of critical importance for the development of TTS. 20 cases of TTS were identified. 90% were female, showed a median age of 70±13y [25y - 90y], an apical and/or midventricular ballooning pattern with preserved basal function and a median initial LVEF of 34±9% [25% - 55%]. 65% of patients underwent coronary angiography to rule out significant coronary artery disease. Hypertension was present in 45% of patients, 35% were smokers, none was suffering from diabetes. Prevalence of asthma in patients with TTS was significantly higher compared to the normal population (25% vs. 7%, p=0.012). In 30% of the TTS patients an iatrogenic cause for development of TTS was identified. Prevalence of asthma was significantly higher in patients with TTS compared to epidemiologic data from an age-matched population. Phenotypes of patients developing obstructive ventilatory disease and TTS might share common pathogenic mechanisms beyond the use of bronchodilatators. In addition, we identified other iatrogenic etiologies in patients with TTS.
    The Open Cardiovascular Medicine Journal 02/2015; 9:1-4. DOI:10.2174/1874192401509010001
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    ABSTRACT: Excessive proliferation of human pulmonary artery smooth muscle cells (HPASMC) is one of the major factors that trigger vascular remodeling in hypoxia-induced pulmonary hypertension. Several studies have implicated that hypoxia inhibits the tumour suppressor p21 (CDKN1A). However, the precise mechanism is unknown. The mouse model of hypoxia-induced PH and in vitro experiments were used to assess the impact of microRNAs (miRNAs) on the expression of CDKN1A. In these experiments, the miRNA family miR-130 was identified to regulate the expression of CDKN1A. Transfection of HPASMC with miR-130 decreased the expression of CDKN1A and, in turn, significantly increased smooth muscle proliferation. Conversely, inhibition of miR-130 by anti-miRs and seed blockers increased the expression of CDKN1A. Reporter gene analysis proved a direct miR-130-CDKN1A target interaction. Exposure of HPASMC to hypoxia was found to induce the expression of miR-130 with concomitant decrease of CDKN1A. These findings were confirmed in the mouse model of hypoxia-induced pulmonary hypertension showing that the use of seed blockers against miR-130 restored the expression of CDKN1A. These data suggest that miRNA family miR-130 plays an important role in the repression of CDKN1A by hypoxia. miR-130 enhances hypoxia-induced smooth muscle proliferation and might be involved in the development of right ventricular hypertrophy and vascular remodeling in pulmonary hypertension. Copyright © 2015. Published by Elsevier Ltd.
    The International Journal of Biochemistry & Cell Biology 02/2015; 61. DOI:10.1016/j.biocel.2015.02.002 · 4.24 Impact Factor
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    ABSTRACT: Background: Registries are important for real-life epidemiology on different pulmonary hypertension (PH) groups. Objective: To provide long-term data of the Swiss PH registry of 1998-2012. Methods: PH patients have been classified into 5 groups and registered upon written informed consent at 5 university and 8 associated hospitals since 1998. New York Heart Association (NYHA) class, 6-min walk distance, hemodynamics and therapy were registered at baseline. Patients were regularly followed, and therapy and events (death, transplantation, endarterectomy or loss to follow-up) registered. The data were stratified according to the time of diagnosis into prevalent before 2000 and incident during 2000-2004, 2005-2008 and 2009-2012. Results: From 996 (53% female) PH patients, 549 had pulmonary arterial hypertension (PAH), 36 PH due to left heart disease, 127 due to lung disease, 249 to chronic thromboembolic PH (CTEPH) and 35 to miscellaneous PH. Age and BMI significantly increased over time, whereas hemodynamic severity decreased. Overall, event-free survival was 84, 72, 64 and 58% for the years 1-4 and similar for time periods since 2000, but better during the more recent periods for PAH and CTEPH. Of all PAH cases, 89% had target medical therapy and 43% combination therapy. Of CTEPH patients, 14 and 2% underwent pulmonary endarterectomy or transplantation, respectively; 87% were treated with PAH target therapy. Conclusion: Since 2000, the incident Swiss PH patients registered were older, hemodynamically better and mostly treated with PAH target therapies. Survival has been better for PAH and CTEPH diagnosed since 2008 compared with earlier diagnosis or other classifications. © 2015 S. Karger AG, Basel.
    Respiration 02/2015; DOI:10.1159/000370125 · 2.92 Impact Factor
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    ABSTRACT: Background: An atherosclerotic disease burden sufficient to put lung transplant candidates at risk for end-organ disease after transplantation is considered to be a relative contraindication for lung transplantation. Objectives: The aim of this study was to assess our current practice of cardiac workup by coronary angiography in lung transplant candidates ≥50 years of age. Methods: We retrospectively analyzed 50 consecutive lung transplant candidates ≥50 years of age in which coronary angiography was performed at the University Hospital Zurich (2009-2013). For every patient, the risk of developing an acute coronary event was estimated by using a recalibrated version of the PROCAM study calculator for the Swiss population. Results: The median estimated risk of developing an acute coronary event within 10 years in the study cohort (n = 50) was 4.2% (interquartile range 1.9-7.6), which is considered to be a low risk. Sixteen percent of patients were considered to be at intermediate risk. In 66% of patients, coronary angiography showed no coronary artery disease (CAD). In 28% of patients, CAD without significant stenosis was diagnosed. In 6% of patients, significant coronary stenosis was detected requiring percutaneous coronary intervention. No correlation between the coronary status and the risk score or cardiovascular risk profile was found. Conclusions: The high prevalence of asymptomatic CAD in lung transplant candidates without correlation to a common clinical risk score supports the important role of coronary angiography for the assessment of coronary artery status. This approach might prevent cardiovascular events and improve long-term survival after transplantation. © 2015 S. Karger AG, Basel.
    Respiration 01/2015; DOI:10.1159/000368368 · 2.92 Impact Factor
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    ABSTRACT: Lung transplant recipients require life-long profound immunosuppression, making them prone to respiratory tract infections (RTIs), in particular viral infections, during the winter season. Since RTIs may have severe consequences, of which acute or chronic allograft dysfunction is feared most, early diagnosis and treatment are recommended. Patients monitor lung function daily at home and are instructed to contact the transplant center in case of signs and symptoms suspicious of RTIs. We then obtain nasopharyngeal swabs for viral and bacteriological examination and initiate pre-emptive treatment with antivirals, broadband antibiotics, and sometimes intravenous immunoglobulins. Treatment duration is guided by virology sampling results. As preventive measures, we provide vaccination against seasonal influenza for patients and household contacts and recommend specific daily hygiene measures.
    12/2014; 16(3):144-149. DOI:10.5152/ejp.2014.87597
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    Lars C Huber, Bart Vrugt, Mattia Arrigo
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    ABSTRACT: Pulmonary hypertension is defined as an increase of the mean pulmonary arterial pressure above 25 mm Hg and, as such, the diagnosis requires invasive haemo­ dynamic measurement by right heart catheterisation. More than just a single disease, pulmonary hyperten­ sion is an umbrella term that includes many different disorders and pathophysiological entities. However, most forms of pulmonary hypertension share a final common pathway, in particular the trias of vasocon­ striction, microthrombosis and vascular remodelling. The classification of pulmonary hypertension has been subjected to many changes within the last decade. At the same time, major achievements in our understand­ ing of the complex pathobiology have been made. Here, these developments are discussed in the light of the re­ cently published report from the fifth World Sympo­ sium on pulmonary hypertension.
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    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; DOI:10.1007/s00408-014-9650-1 · 2.17 Impact Factor
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    ABSTRACT: Introduction MicroRNAs (miRs) are involved in the fine tuning of gene expression in cellular processes and can be quantified in plasma. miRs represent a distinct class of easily accessible biomarkers and may play a role in clarifying pathogenic pathways in diseases involving the vascular system, such as obstructive sleep apnea (OSA). Methods miRs were isolated from stored plasma samples of OSA patients who participated in a randomized controlled trial defining the effects of a two-week continuous positive airway pressure (CPAP) therapy withdrawal. The plasma concentrations of 14 miRs selected in a pilot experiment, were measured by qPCR. Results The mean oxygen desaturation index (ODI) change from baseline was 43.0/h (SD 14.5, n=14) in the CPAP withdrawal group and 0.2/h (SD 1.8, n=14) in the CPAP group. Compared to continuing CPAP therapy CPAP withdrawal was associated with a down-regulated plasma concentration of hsa-miR-502-3p by a factor of 2.0 (n=14, p=0.045). In contrast, the plasma concentration of hsa-miR-210, a key regulator in the response to hypoxia, did not change (n=14, p=0.137). Conclusion Short-term CPAP therapy withdrawal in OSA patients resulted in a statistically significant change in the plasma concentration of hsa-miR-502-3p. In vitro studies are necessary to identify possible targets of hsa-miR-502-3p and to substantiate the relevance of our finding in OSA.
    Annual Congress of the European Respiratory Society (ERS) 2014, Munich, Germany; 09/2014
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    ABSTRACT: Bronchiectasis is the term used for irreversibly dilated airways. Exact epidemiological information on the frequency of bronchiectasis is not available, but the morphological findings are increasingly detected and the associated syndrome is more frequently diagnosed due to improved imaging techniques and increased awareness among chest physicians. The workup of these patients includes a wide panel of investigations guided by patient history and clinical presentation. Despite thorough evaluation the aetiology frequently remains unclear. Chronic infection with Pseudomonas aeruginosa is associated with a severe course of the disease and its detection has impacts on the therapeutic management. Chest physiotherapy, mucoactive substances and antibiotics are the mainstay of therapy. In this review the evaluation of bronchiectasis and the recent therapeutic insights for non-cystic fibrosis bronchiectasis are discussed.
    DMW - Deutsche Medizinische Wochenschrift 08/2014; 139(34-35):1714-20. DOI:10.1055/s-0034-1370258 · 0.55 Impact Factor
  • Jahresversammlung der Schweizerischen Gesellschaft für Pneumologie (SGP) 2014, Interlaken, Switzerland; 05/2014
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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. DOI:10.1186/1465-9921-15-47 · 3.38 Impact Factor
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    ABSTRACT: Am Universitätsspital Zürich werden seit mehr als 20 Jahren Lungentrans-plantationen durchgeführt. Die Lungentransplantation stellt eine etablierte Therapieoption im Endstadium nicht-maligner Lungenerkrankungen dar. Verglichen mit den Langzeitverläufen anderer solider Organtransplantationen sind die Ergebnisse nach Lungentransplantation allerdings schlechter: Das mediane Überleben beträgt derzeit etwas mehr als fünf Jahre. Die wichtigste Langzeitkomplikation ist die Entwicklung einer chronischen Allograftdysfunktion (CLAD), meistens in Form eines Bronchiolitis-obliterans-Syndroms (BOS). Dabei kommt es über eine Entzündungsreaktion in den kleinen Luftwegen zu einem zunehmenden Umbau der Lungenstruktur, die sich spirometrisch in einer obstrukti-ven Ventilationsstörung mit progredienter Abnahme der Einsekundenkapzität (FEV 1) manifestiert. Die Ursachen eines BOS und seine Pathogenese sind nicht vollends klar. Trigger für Entzündungsreaktionen (wiederholte akute Abstossungen, respiratorische Infektionen) scheinen aber seine Entwicklung zu begünstigen. Lungentransplantierte Patienten sind anfälliger für Infektionen im Vergleich zu Transplantierten anderer solider Or-gane, ebenso ist die Auswirkung der respiratorischen Infektionen auf den Langzeitverlauf am grössten. Neben der oben erwähnten Komplikationen wie CLAD und BOS sind infektiöse Komplikationen unter ausgebauter Im-munsuppression gefürchtet. Ein Zusammenhang zwischen viralen Infektionen und Abstossungsreaktionen wird seit Jahren vermutet. Bisher konnte aber in keiner Studie eine direkte Kausalität zwischen einem bestimmten re-spiratorischen Virus und einer akuten oder chronischen Abstossung gezeigt werden. Die Entwicklung eines BOS scheint daher eher über (unspezifische) Entzündungsreaktionen als Folge einer respiratorischen Infektion als durch virusspezifische Faktoren bedingt zu sein.
    Praxis 04/2014; 103(8):453-459. DOI:10.1024/1661-8157/a001627
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    ABSTRACT: Whereas pulmonary arterial hypertension is an orphan disease, the term pulmonary hypertension includes several common entities and is of major clinical significance. The pathophysiological triad of vasoconstriction, microthrombosis and vascular remodeling is found in most forms of pulmonary hypertension, independently of the underlying etiology. In this review, novel aspects in the pathogenesis of the remodeling, in particular microRNAs, will be discussed. MicroRNAs are small RNA fragments which bind specifically to the mRNA of a target gene thus decreasing its stability or inhibiting further translation ("gene silencing"). Of major interest is the association between microRNAs and the expression of bone morphogenetic protein receptor type II which has been found to be dysregulated on pulmonary endothelial and vascular smooth muscle cells in several forms of pulmonary hypertension. The specific inhibition of microRNAs by antagomiRs makes microRNAs a potential therapeutic target. Moreover, microRNAs are being validated in serum as biomarkers for diagnosis, severity and prognosis of pulmonary hypertension.
    Pneumologie 04/2014; DOI:10.1055/s-0034-1365456
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    ABSTRACT: Lung transplant recipients have a life-long profound immunosuppression which makes them prone to respiratory tract infections, in particular viral infections during the winter season. Since the respiratory tract infections may have potentially severe consequences, we recommend early diagnosis and treatment. We obtain nasopharyngeal swabs for viral and bacteriological examination and then treat pre-emptively with antivirals, broad-band antibiotics and often also with intravenous immunoglobulins. Treatment duration is often longer than in immunocompetent patients. As preventive measures we provide vaccination against seasonal influenza and recommend specific daily hygiene measures.
    Praxis 04/2014; 103(8):453-9.
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    Mattia Arrigo, Lars C Huber
    Chest 02/2014; 145(2):413. DOI:10.1378/chest.13-1960 · 7.13 Impact Factor
  • Annals of the Rheumatic Diseases 01/2014; 71(Suppl 3):58-58. DOI:10.1136/annrheumdis-2012-eular.1700 · 9.27 Impact Factor
  • Matthias Brock, Silvia Ulrich, Lars Christian Huber
    European Respiratory Journal 01/2014; 43(1):313-4. DOI:10.1183/09031936.00039113 · 7.13 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; DOI:10.1093/eurheartj/eht540 · 14.72 Impact Factor

Publication Stats

2k Citations
373.67 Total Impact Points

Institutions

  • 2004–2015
    • University of Zurich
      • • Center for Integrative Human Physiology
      • • Internal Medicine Unit
      Zürich, Zurich, Switzerland
  • 2009
    • University Hospital Zürich
      Zürich, Zurich, Switzerland
  • 2007
    • Johannes Gutenberg-Universität Mainz
      Mayence, Rheinland-Pfalz, Germany
  • 2006
    • Duke University
      Durham, North Carolina, United States
    • Justus-Liebig-Universität Gießen
      Gieben, Hesse, Germany
  • 2005
    • Duke University Medical Center
      • Division of Rheumatology and Immunology
      Durham, North Carolina, United States