All Publications

  • ANATOMIC, GENETIC AND FUNCTIONAL PROPERTIES OF THE RETINAL CIRCULATION IN PULMONARY HYPERTENSION Pulmonary Circulation Nickel, N. P., Shamskhou, E. A., Razeen, M., Condon, D., Messentier, L., Dubra, A., Liao, Y., Zamanian, R. T., Yuan, K., de Jesus Perez, V. A. 2020

    View details for DOI 10.1177/2045894020905508

  • Low-grade albuminuria in pulmonary arterial hypertension PULMONARY CIRCULATION Nickel, N. P., Perez, V., Zamanian, R. T., Fessel, J. P., Cogan, J. D., Hamid, R., West, J. D., de Caestecker, M. P., Yang, H., Austin, E. D. 2019; 9 (2)
  • PPARgamma Interaction with UBR5/ATMIN Promotes DNA Repair to Maintain Endothelial Homeostasis. Cell reports Li, C. G., Mahon, C., Sweeney, N. M., Verschueren, E., Kantamani, V., Li, D., Hennigs, J. K., Marciano, D. P., Diebold, I., Abu-Halawa, O., Elliott, M., Sa, S., Guo, F., Wang, L., Cao, A., Guignabert, C., Sollier, J., Nickel, N. P., Kaschwich, M., Cimprich, K. A., Rabinovitch, M. 2019; 26 (5): 1333


    Using proteomic approaches, we uncovered a DNA damage response (DDR) function for peroxisome proliferator activated receptor gamma (PPARgamma) through its interaction with the DNA damage sensor MRE11-RAD50-NBS1 (MRN) and the E3 ubiquitin ligase UBR5. We show that PPARgamma promotes ATM signaling and is essential for UBR5 activity targeting ATM interactor (ATMIN). PPARgamma depletion increases ATMIN protein independent of transcription and suppresses DDR-induced ATM signaling. Blocking ATMIN in this context restores ATM activation and DNA repair. We illustrate the physiological relevance of PPARgamma DDR functions by using pulmonary arterial hypertension (PAH) as a model that has impaired PPARgamma signaling related to endothelial cell (EC) dysfunction and unresolved DNA damage. In pulmonary arterial ECs (PAECs) from PAH patients, we observed disrupted PPARgamma-UBR5 interaction, heightened ATMIN expression, and DNA lesions. Blocking ATMIN in PAH PAEC restores ATM activation. Thus, impaired PPARgamma DDR functions may explain the genomic instability and loss of endothelial homeostasis in PAH.

    View details for DOI 10.1016/j.celrep.2019.01.013

    View details for PubMedID 30699358

  • EXPRESS: Low-Grade Albuminuria in Pulmonary Arterial Hypertension. Pulmonary circulation Nickel, N., Perez, V. i., Fessel, J. P., Cogan, J., Hamid, R., West, J. D., de Caestecker, M., Yang, H., Zamanian, R. T., Austin, E. 2019: 2045894018824564

    View details for PubMedID 30632900

  • The 6th World Symposium on Pulmonary Hypertension: what's old is new. F1000Research Condon, D. F., Nickel, N. P., Anderson, R., Mirza, S., de Jesus Perez, V. A. 2019; 8


    In February 2018, the 6th World Symposium on Pulmonary Hypertension (WSPH) brought together experts from various disciplines to review the most relevant clinical and scientific advances in the field of PH over the last 5 years. Based on careful review and discussions by members of the different task forces, major revisions were made on the hemodynamic definition for various forms of PH and new genes were added to the list of genetic markers associated with pulmonary arterial hypertension (PAH) and pulmonary veno-occlusive disease. In addition, the use of risk stratification tools was encouraged as a strategy to reduce one-year mortality risk in PAH patients through early implementation of PAH therapies. While members of the medical community are still debating some of the proposed changes, the new WSPH guidelines advocate early diagnosis and initiation of combination therapy to reduce mortality and improve quality of life in patients with PH.

    View details for DOI 10.12688/f1000research.18811.1

    View details for PubMedID 31249672

    View details for PubMedCentralID PMC6584967

  • BEYOND THE LUNGS: SYSTEMIC MANIFESTATIONS OF PULMONARY ARTERIAL HYPERTENSION. American journal of respiratory and critical care medicine Nickel, N. P., Yuan, K., Dorfmuller, P., Provencher, S., Lai, Y. C., Bonnet, S., Austin, E. D., Koch, C. D., Morris, A., Perros, F., Montani, D., Zamanian, R. T., de Jesus Perez, V. A. 2019


    Pulmonary arterial hypertension (PAH) is a disease characterized by progressive loss and remodeling of the pulmonary arteries resulting in right heart failure and death. Until recently, PAH was seen as a disease restricted to the pulmonary circulation. However, there is growing evidence that PAH patients also exhibit systemic vascular dysfunction, as evidenced by impaired brachial artery flow-mediated dilation, abnormal cerebral blood flow, skeletal myopathy, and intrinsic kidney disease. While some of these anomalies are partially due to right ventricular insufficiency, recent data support a mechanistic link to the genetic and molecular events behind PAH pathogenesis. This review will serve as an introduction to the major systemic findings in PAH and the evidence that supports a common mechanistic link with PAH pathophysiology. In addition, we will discuss recent studies describing morphological changes in systemic vessels and the possible role of bronchopulmonary anastomoses in the development of plexogenic arteriopathy. Based on available evidence, we propose a paradigm in which metabolic abnormalities, genetic injury and systemic vascular dysfunction contribute to systemic manifestations in PAH. This concept not only opens exciting research possibilities, but also encourages clinicians to consider extrapulmonary manifestations in their management of PAH patients.

    View details for DOI 10.1164/rccm.201903-0656CI

    View details for PubMedID 31513751

  • Kidney dysfunction in patients with pulmonary arterial hypertension PULMONARY CIRCULATION Nickel, N. P., O'Leary, J. M., Brittain, E. L., Fessel, J. P., Zamanian, R. T., West, J. D., Austin, E. D. 2017; 7 (1): 38-54


    Pulmonary arterial hypertension (PH) and chronic kidney disease (CKD) both profoundly impact patient outcomes, whether as primary disease states or as co-morbid conditions. PH is a common co-morbidity in CKD and vice versa. A growing body of literature describes the epidemiology of PH secondary to chronic kidney disease and end-stage renal disease (ESRD) (WHO group 5 PH). But, there are only limited data on the epidemiology of kidney disease in group 1 PH (pulmonary arterial hypertension [PAH]). The purpose of this review is to summarize the current data on epidemiology and discuss potential disease mechanisms and management implications of kidney dysfunction in PAH. Kidney dysfunction, determined by serum creatinine or estimated glomerular filtration rate, is a frequent co-morbidity in PAH and impaired kidney function is a strong and independent predictor of mortality. Potential mechanisms of PAH affecting the kidneys are increased venous congestion, decreased cardiac output, and neurohormonal activation. On a molecular level, increased TGF-β signaling and increased levels of circulating cytokines could have the potential to worsen kidney function. Nephrotoxicity does not seem to be a common side effect of PAH-targeted therapy. Treatment implications for kidney disease in PAH include glycemic control, lifestyle modification, and potentially Renin-Angiotensin-Aldosterone System (RAAS) blockade.

    View details for DOI 10.1086/690018

    View details for Web of Science ID 000399052900004

    View details for PubMedCentralID PMC5448543

  • RNA Sequencing Analysis Detection of a Novel Pathway of Endothelial Dysfunction in Pulmonary Arterial Hypertension AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Rhodes, C. J., Im, H., Cao, A., Hennigs, J. K., Wang, L., Sa, S., Chen, P., Nickel, N. P., Miyagawa, K., Hopper, R. K., Tojais, N. F., Li, C. G., Gu, M., Spiekerkoetter, E., Xian, Z., Chen, R., Zhao, M., Kaschwich, M., del Rosario, P. A., Bernstein, D., Zamanian, R. T., Wu, J. C., Snyder, M. P., Rabinovitch, M. 2015; 192 (3): 356-366


    Pulmonary arterial hypertension is characterized by endothelial dysregulation, but global changes in gene expression have not been related to perturbations in function.RNA sequencing was utilized to discriminate changes in transcriptomes of endothelial cells cultured from lungs of patients with idiopathic pulmonary arterial hypertension vs. controls and to assess the functional significance of major differentially expressed transcripts.The endothelial transcriptomes from seven control and six idiopathic pulmonary arterial hypertension patients' lungs were analyzed. Differentially expressed genes were related to BMPR2 signaling. Those downregulated were assessed for function in cultured cells, and in a transgenic mouse.Fold-differences in ten genes were significant (p<0.05), four increased and six decreased in patients vs.No patient was mutant for BMPR2. However, knockdown of BMPR2 by siRNA in control pulmonary arterial endothelial cells recapitulated six/ten patient-related gene changes, including decreased collagen IV (COL4A1, COL4A2) and ephrinA1 (EFNA1). Reduction of BMPR2 regulated transcripts was related to decreased β-catenin. Reducing COL4A1, COL4A2 and EFNA1 by siRNA inhibited pulmonary endothelial adhesion, migration and tube formation. In mice null for the EFNA1 receptor, EphA2, vs. controls, VEGF receptor blockade and hypoxia caused more severe pulmonary hypertension, judged by elevated right ventricular systolic pressure, right ventricular hypertrophy and loss of small arteries.The novel relationship between BMPR2 dysfunction and reduced expression of endothelial COL4 and EFNA1 may underlie vulnerability to injury in pulmonary arterial hypertension.

    View details for DOI 10.1164/rccm.201408-1528OC

    View details for PubMedID 26030479

  • Elafin Reverses Pulmonary Hypertension via Caveolin-1-Dependent Bone Morphogenetic Protein Signaling AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Nickel, N. P., Spiekerkoetter, E., Gu, M., Li, C. G., Li, H., Kaschwich, M., Diebold, I., Hennigs, J. K., Kim, K., Miyagawa, K., Wang, L., Cao, A., Sa, S., Jiang, X., Stockstill, R. W., Nicolls, M. R., Zamanian, R. T., Bland, R. D., Rabinovitch, M. 2015; 191 (11): 1273-1286


    Pulmonary arterial hypertension is characterized by endothelial cell dysfunction, impaired BMPR2 signaling, and increased elastase activity. Synthetic elastase inhibitors reverse experimental pulmonary hypertension but cause hepatotoxicity in clinical studies. The endogenous elastase inhibitor elafin attenuates the development of hypoxic pulmonary hypertension in mice, but its potential to improve endothelial cell function and BMPR2 signaling, and to reverse severe experimental pulmonary hypertension or vascular pathology in the human disease was unknown.To assess elafin-mediated regression of pulmonary vascular pathology in rats with pulmonary hypertension induced by VEGF receptor blockade and hypoxia (Sugen/Hypoxia), and in lung explants from pulmonary hypertension patients. To determine if elafin amplifies BMPR2 signaling in pulmonary artery endothelial cells from controls and patients, and to elucidate the underlying mechanism. Methods, Measurements and Main Results: In Sugen/Hypoxia rats, elafin reduced elastase activity and reversed pulmonary hypertension, judged by regression of right ventricular systolic pressure and hypertrophy and pulmonary artery occlusive changes. Elafin improved endothelial function by increasing apelin, a product of BMPR2 signaling. Elafin induced apoptosis in human pulmonary arterial smooth muscle cells and in lung organ culture elafin decreased neointimal lesions. In normal and patient pulmonary artery endothelial cells, elafin enhanced survival and promoted angiogenesis by increasing pSMAD dependent and independent BMPR2 signaling. This was linked mechanistically to augmented interaction of BMPR2 with caveolin-1 via elafin-mediated stabilization of caveolin-1 on endothelial surfaces.Elafin reverses obliterative changes in rat and human pulmonary arteries via elastase inhibition and caveolin-1 dependent amplification of BMPR2 signaling.

    View details for DOI 10.1164/rccm.201412-2291OC

    View details for Web of Science ID 000356105000014

    View details for PubMedID 25853696

  • BMPR2 Preserves Mitochondrial Function and DNA during Reoxygenation to Promote Endothelial Cell Survival and Reverse Pulmonary Hypertension CELL METABOLISM Diebold, I., Hennigs, J. K., Miyagawa, K., Li, C. G., Nickel, N. P., Kaschwich, M., Cao, A., Wang, L., Reddy, S., Chen, P., Nakahira, K., Alcazar, M. A., Hopper, R. K., Ji, L., Feldman, B. J., Rabinovitch, M. 2015; 21 (4): 596-608


    Mitochondrial dysfunction, inflammation, and mutant bone morphogenetic protein receptor 2 (BMPR2) are associated with pulmonary arterial hypertension (PAH), an incurable disease characterized by pulmonary arterial (PA) endothelial cell (EC) apoptosis, decreased microvessels, and occlusive vascular remodeling. We hypothesized that reduced BMPR2 induces PAEC mitochondrial dysfunction, promoting a pro-inflammatory or pro-apoptotic state. Mice with EC deletion of BMPR2 develop hypoxia-induced pulmonary hypertension that, in contrast to non-transgenic littermates, does not reverse upon reoxygenation and is associated with reduced PA microvessels and lung EC p53, PGC1α and TFAM, regulators of mitochondrial biogenesis, and mitochondrial DNA. Decreasing PAEC BMPR2 by siRNA during reoxygenation represses p53, PGC1α, NRF2, TFAM, mitochondrial membrane potential, and ATP and induces mitochondrial DNA deletion and apoptosis. Reducing PAEC BMPR2 in normoxia increases p53, PGC1α, TFAM, mitochondrial membrane potential, ATP production, and glycolysis, and induces mitochondrial fission and a pro-inflammatory state. These features are recapitulated in PAECs from PAH patients with mutant BMPR2.

    View details for DOI 10.1016/j.cmet.2015.03.010

    View details for Web of Science ID 000352500800014

    View details for PubMedID 25863249

  • Vascular Receptor Autoantibodies in Pulmonary Arterial Hypertension Associated with Systemic Sclerosis AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Becker, M. O., Kill, A., Kutsche, M., Guenther, J., Rose, A., Tabeling, C., Witzenrath, M., Kuehl, A. A., Heidecke, H., Ghofrani, H. A., Tiede, H., Schermuly, R. T., Nickel, N., Hoeper, M. M., Lukitsch, I., Gollasch, M., Kuebler, W. M., Bock, S., Burmester, G. R., Dragun, D., Riemekasten, G. 2014; 190 (7): 808–17


    Systemic sclerosis (SSc)-associated pulmonary arterial hypertension (PAH) portends worse outcome than other forms of PAH. Vasoconstrictive and vascular remodeling actions of endothelin (ET) 1 and angiotensin (Ang) II via endothelin receptor type A (ETAR) and Ang receptor type-1 (AT1R) activation are implicated in PAH pathogenesis.We hypothesized that stimulating autoantibodies (Abs) targeting and activating AT1R and ETAR may contribute to SSc-PAH pathogenesis, and tested their functional and biomarker relevance.Anti-AT1R and -ETAR Abs were detected by ELISA in different cohorts of patients and tested in vitro and in an animal model for their pathophysiological effects.The Abs were significantly higher and more prevalent in patients with SSc-PAH (n = 81) and connective tissue disease-associated PAH (n = 110) compared with other forms of PAH/pulmonary hypertension (n = 106). High anti-AT1R and anti-ETAR Abs predicted development of SSc-PAH and SSc-PAH-related mortality in a prospective analysis. Both Abs increased endothelial cytosolic Ca(2+) concentrations in isolated perfused rat lungs, which could be blocked by respective specific receptor antagonists. Ab-mediated stimulation of intralobar pulmonary rat artery ring segments increased vasoconstrictive responses to Ang II and ET-1, and implicated cross-talk between both pathways demonstrated by reciprocal blockade with respective antagonists. Transfer of SSc-IgG containing both autoantibodies into healthy C57BL/6J mice led to more abundant vascular and airway α-smooth muscle actin expression and inflammatory pulmonary vasculopathy.Anti-AT1R and -ETAR Abs are more frequent in SSc-PAH/connective tissue disease-PAH compared with other forms of pulmonary hypertension, and serve as predictive and prognostic biomarkers in SSc-PAH. Both antibodies may contribute to SSc-PAH via increased vascular endothelial reactivity and induction of pulmonary vasculopathy.

    View details for DOI 10.1164/rccm.201403-0442OC

    View details for Web of Science ID 000343022700015

    View details for PubMedID 25181620

  • Reduced BMPR2 expression induces GM-CSF translation and macrophage recruitment in humans and mice to exacerbate pulmonary hypertension. journal of experimental medicine Sawada, H., Saito, T., Nickel, N. P., Alastalo, T., Glotzbach, J. P., Chan, R., Haghighat, L., Fuchs, G., Januszyk, M., Cao, A., Lai, Y., Perez, V. d., Kim, Y., Wang, L., Chen, P., Spiekerkoetter, E., Mitani, Y., Gurtner, G. C., Sarnow, P., Rabinovitch, M. 2014; 211 (2): 263-280


    Idiopathic pulmonary arterial hypertension (PAH [IPAH]) is an insidious and potentially fatal disease linked to a mutation or reduced expression of bone morphogenetic protein receptor 2 (BMPR2). Because intravascular inflammatory cells are recruited in IPAH pathogenesis, we hypothesized that reduced BMPR2 enhances production of the potent chemokine granulocyte macrophage colony-stimulating factor (GM-CSF) in response to an inflammatory perturbation. When human pulmonary artery (PA) endothelial cells deficient in BMPR2 were stimulated with tumor necrosis factor (TNF), a twofold increase in GM-CSF was observed and related to enhanced messenger RNA (mRNA) translation. The mechanism was associated with disruption of stress granule formation. Specifically, loss of BMPR2 induced prolonged phospho-p38 mitogen-activated protein kinase (MAPK) in response to TNF, and this increased GADD34-PP1 phosphatase activity, dephosphorylating eukaryotic translation initiation factor (eIF2α), and derepressing GM-CSF mRNA translation. Lungs from IPAH patients versus unused donor controls revealed heightened PA expression of GM-CSF co-distributing with increased TNF and expanded populations of hematopoietic and endothelial GM-CSF receptor α (GM-CSFRα)-positive cells. Moreover, a 3-wk infusion of GM-CSF in mice increased hypoxia-induced PAH, in association with increased perivascular macrophages and muscularized distal arteries, whereas blockade of GM-CSF repressed these features. Thus, reduced BMPR2 can subvert a stress granule response, heighten GM-CSF mRNA translation, increase inflammatory cell recruitment, and exacerbate PAH.

    View details for DOI 10.1084/jem.20111741

    View details for PubMedID 24446489

  • Circulating levels of copeptin predict outcome in patients with pulmonary arterial hypertension RESPIRATORY RESEARCH Nickel, N. P., Lichtinghagen, R., Golpon, H., Olsson, K. M., Brand, K., Welte, T., Hoeper, M. M. 2013; 14: 130


    To determine the levels of circulating copeptin in patients with pulmonary arterial hypertension (PAH), and to evaluate its relation with disease severity, outcome and response to treatment.Vasopressin is a key regulator of body fluid homeostasis. The co-secreted protein copeptin serves as surrogate for plasma vasopressin levels and increases in acute and chronic left ventricular dysfunction. Copeptin has not been studied in PAH.Serum copeptin levels were evaluated in a retrospective cohort of 92 treatment-naïve patients with PAH, 39 patients with normal right ventricular hemodynamics (diseased controls) and 14 apparently healthy individuals (healthy controls). In a second prospective cohort of 15 patients with PAH, serial changes of copeptin levels after initiation of PAH treatment were measured. Copeptin levels were compared with clinical, biochemical and hemodynamic parameters as well as response to treatment and clinical outcome.Circulating copeptin levels were elevated in PAH patients compared to diseased controls (20.1 pmol/l vs. 5.1 pmol/l; p = 0.001). Baseline levels of copeptin correlated with NYHA functional class (r = 0.46; p = 0.01), 6 minute walking distance (r = -0.26; p = 0.04), NT-proBNP (r = 0.49, p = 0.01), creatinine (r = 0.39, p = 0.01) and estimated glomerular filtration rate (r = -0.32, p = 0.01). Copeptin levels did not correlate with hemodynamics but decreased after initiation of PAH therapy (p = 0.001). Elevated copeptin levels were associated with shorter survival (p < 0.001) and independent predictors of mortality in a multiple Cox regression analysis (HR1.4; 95% confidence interval 1.1-2.0; p = 0.02).Patients with PAH had elevated copeptin levels. High circulating levels of copeptin were independent predictors of poor outcome, which makes copeptin a potentially useful biomarker in PAH.

    View details for DOI 10.1186/1465-9921-14-130

    View details for Web of Science ID 000327845600002

    View details for PubMedID 24251953

    View details for PubMedCentralID PMC4176098

  • Atrial flutter and fibrillation in patients with pulmonary hypertension INTERNATIONAL JOURNAL OF CARDIOLOGY Olsson, K. M., Nickel, N. P., Tongers, J., Hoeper, M. M. 2013; 167 (5): 2300–2305


    Atrial flutter and fibrillation are being increasingly reported in patients with pulmonary hypertension but little is known about their clinical implications. We sought to determine the incidence and clinical impact of these arrhythmias in patients with pulmonary hypertension.In a 5-year, prospective study, we assessed the incidence of new-onset atrial flutter and fibrillation as well as risk factors, clinical consequences, management, and impact on survival in patients with pulmonary arterial hypertension (PAH, n=157) or inoperable chronic thromboembolic pulmonary hypertension (CTEPH, n=82).The cumulative 5-year incidence of new-onset atrial flutter and fibrillation was 25.1% (95% confidence interval, 13.8-35.4%). The development of these arrhythmias was frequently accompanied by clinical worsening (80%) and signs of right heart failure (30%). Stable sinus rhythm was successfully re-established in 21/24 (88%) of patients initially presenting with atrial flutter and in 16/24 (67%) of patients initially presenting with atrial fibrillation. New-onset atrial flutter and fibrillation were an independent risk factor of death (p=0.04, simple Cox regression analysis) with a higher mortality in patients with persistent atrial fibrillation when compared to patients in whom sinus rhythm was restored (estimated survival at 1, 2 and 3 years 64%, 55%, and 27% versus 97%, 80%, and 57%, respectively; p=0.01, log rank analysis).Atrial flutter and fibrillation develop in a sizable number of patients with PAH or inoperable CTEPH and often lead to clinical deterioration and right heart failure. Mortality is high when sinus rhythm cannot be restored.

    View details for DOI 10.1016/j.ijcard.2012.06.024

    View details for Web of Science ID 000323569600110

    View details for PubMedID 22727973

  • Loss of adenomatous poliposis coli-a3 integrin interaction promotes endothelial apoptosis in mice and humans. Circulation research de Jesus Perez, V. A., Yuan, K., Orcholski, M. E., Sawada, H., Zhao, M., Li, C. G., Tojais, N. F., Nickel, N., Rajagopalan, V., Spiekerkoetter, E., Wang, L., Dutta, R., Bernstein, D., Rabinovitch, M. 2012; 111 (12): 1551-1564


    Pulmonary hypertension (PH) is characterized by progressive elevation in pulmonary pressure and loss of small pulmonary arteries. As bone morphogenetic proteins promote pulmonary angiogenesis by recruiting the Wnt/β-catenin pathway, we proposed that β-catenin activation could reduce loss and induce regeneration of small pulmonary arteries (PAs) and attenuate PH.This study aims to establish the role of β-catenin in protecting the pulmonary endothelium and stimulating compensatory angiogenesis after injury.To assess the impact of β-catenin activation on chronic hypoxia-induced PH, we used the adenomatous polyposis coli (Apc(Min/+)) mouse, where reduced APC causes constitutive β-catenin elevation. Surprisingly, hypoxic Apc(Min/+) mice displayed greater PH and small PA loss compared with control C57Bl6J littermates. PA endothelial cells isolated from Apc(Min/+) demonstrated reduced survival and angiogenic responses along with a profound reduction in adhesion to laminin. The mechanism involved failure of APC to interact with the cytoplasmic domain of the α3 integrin, to stabilize focal adhesions and activate integrin-linked kinase-1 and phospho Akt. We found that PA endothelial cells from lungs of patients with idiopathic PH have reduced APC expression, decreased adhesion to laminin, and impaired vascular tube formation. These defects were corrected in the cultured cells by transfection of APC.We show that APC is integral to PA endothelial cells adhesion and survival and is reduced in PA endothelial cells from PH patient lungs. The data suggest that decreased APC may be a cause of increased risk or severity of PH in genetically susceptible individuals.

    View details for DOI 10.1161/CIRCRESAHA.112.267849

    View details for PubMedID 23011394

    View details for PubMedCentralID PMC3821702

  • Plexiform vasculopathy of severe pulmonary arterial hypertension and microRNA expression JOURNAL OF HEART AND LUNG TRANSPLANTATION Bockmeyer, C. L., Maegel, L., Janciauskiene, S., Rische, J., Lehmann, U., Maus, U. A., Nickel, N., Haverich, A., Hoeper, M. M., Golpon, H. A., Kreipe, H., Laenger, F., Jonigk, D. 2012; 31 (7): 764–72


    Recent studies have revealed that microRNAs (miRNAs) play a key role in the control of angiogenesis and vascular remodeling. Specific miRNAs in plexiform vasculopathy of severe pulmonary arterial hypertension (PAH) in humans have not yet been investigated.We analyzed expression of miR-143/145 (vascular smooth muscle-specific), miR-126 (endothelial-specific) and related mRNAs in plexiform (PLs) and concentric lesions (CLs), which had been laser-microdissected from specimens of formalin-fixed, paraffin-embedded, explanted lungs of PAH patients (n = 12) and unaffected controls (n = 8). Samples were analyzed by real-time polymerase chain reaction, and protein expression was determined by immunohistochemistry.Expression levels of miR-143/145 and its target proteins (e.g., myocardin, smooth muscle myosin heavy chain) were found to be significantly higher in CLs than in PLs, whereas miR-126 and VEGF-A were significantly up-regulated in PLs when compared with CLs, indicating a more prominent angiogenic phenotype of PL. This correlates with a down-regulation of miR-204 as well as an up-regulation of miR-21 in PLs, which in turn corresponds to enhanced cell proliferation.Our findings show that morphologic changes of plexiform vasculopathy in the end-stage PAH lung are reflected by alterations at the miRNA level.

    View details for DOI 10.1016/j.healun.2012.03.010

    View details for Web of Science ID 000305544700015

    View details for PubMedID 22534459

  • The prognostic impact of follow-up assessments in patients with idiopathic pulmonary arterial hypertension EUROPEAN RESPIRATORY JOURNAL Nickel, N., Golpon, H., Greer, M., Knudsen, L., Olsson, K., Westerkamp, V., Welte, T., Hoeper, M. M. 2012; 39 (3): 589–96


    Current guidelines for the treatment of patients with idiopathic pulmonary arterial hypertension (IPAH) recommend basing therapeutic decision-making on haemodynamic, functional and biochemical variables. Most of these parameters have been evaluated as risk predictors at the time of diagnosis. The aim of the present study was to assess the prognostic impact of changes in these parameters after initiation of targeted therapy. A cohort of 109 patients with IPAH who had undergone haemodynamic, functional and biochemical assessments at baseline and 3-12 months after initiation of pulmonary arterial hypertension (PAH)-targeted therapy, were followed for a median 38 months in order to determine predictors of mortality at baseline and during the course of their disease. Within the observation period, 53 (48.6%) patients died and four (3.7%) underwent lung transplantation. Kaplan-Meier estimates for transplantation-free survival were 92%, 67%, and 51% at 1, 3, and 5 yrs, respectively. Among baseline variables, 6-min walk distance, right atrial pressure, cardiac index, mixed-venous oxygen saturation (S(v,O(2))) and N-terminal-pro brain natriuretic peptide (NT-proBNP) were independent predictors of survival. During follow-up, changes in World Health Organization functional class, cardiac index, S(v,O(2)) and NT-proBNP proved significant predictors of outcome. When assigned to prognostic groups, improvements as well as deteriorations in these parameters after initiation of PAH-targeted therapy had a strong impact on survival. Measurements obtained at follow-up had a higher predictive value than variables obtained at baseline. Changes in established predictors of outcome during the course of the disease provide important prognostic information in patients with IPAH.

    View details for DOI 10.1183/09031936.00092311

    View details for Web of Science ID 000300883800013

    View details for PubMedID 21885392

  • Plexiform Lesions in Pulmonary Arterial Hypertension Composition, Architecture, and Microenvironment AMERICAN JOURNAL OF PATHOLOGY Jonigk, D., Golpon, H., Bockmeyer, C. L., Maegel, L., Hoeper, M. M., Gottlieb, J., Nickel, N., Hussein, K., Maus, U., Lehmann, U., Janciauskiene, S., Welte, T., Haverich, A., Rische, J., Kreipe, H., Laenger, F. 2011; 179 (1): 167–79


    Pulmonary arterial hypertension (PAH) is a debilitating disease with a high mortality rate. A hallmark of PAH is plexiform lesions (PLs), complex vascular formations originating from remodeled pulmonary arteries. The development and significance of these lesions have been debated and are not yet fully understood. Some features of PLs resemble neoplastic disorders, and there is a striking resemblance to glomeruloid-like lesions (GLLs) in glioblastomas. To further elucidate PLs, we used in situ methods, such as (fluorescent) IHC staining, three-dimensional reconstruction, and laser microdissection, followed by mRNA expression analysis. We generated compartment-specific expression patterns in the lungs of 25 patients (11 with PAH associated with systemic shunts, 6 with idiopathic PAH, and 8 controls) and GLLs from 5 glioblastomas. PLs consisted of vascular channels lined by a continuously proliferating endothelium and backed by a uniform myogenic interstitium. They also showed up-regulation of remodeling-associated genes, such as HIF1a, TGF-β1, VEGF-α, VEGFR-1/-2, Ang-1, Tie-2, and THBS1, but also of cKIT and sprouting-associated markers, such as NOTCH and matrix metalloproteinases. The cellular composition and signaling seen in GLLs in neural neoplasms differed significantly from those in PLs. In conclusion, PLs show a distinct cellular composition and microenvironment, which contribute to the plexiform phenotype and set them apart from other processes of vascular remodeling in patients with PAH. Neoplastic models of angiogenesis seem to be of limited use in further study of plexiform vasculopathy.

    View details for DOI 10.1016/j.ajpath.2011.03.040

    View details for Web of Science ID 000298307100018

    View details for PubMedID 21703400

    View details for PubMedCentralID PMC3123793

  • GDF-15 is abundantly expressed in plexiform lesions in patients with pulmonary arterial hypertension and affects proliferation and apoptosis of pulmonary endothelial cells RESPIRATORY RESEARCH Nickel, N., Jonigk, D., Kempf, T., Bockmeyer, C. L., Maegel, L., Rische, J., Laenger, F., Lehmann, U., Sauer, C., Greer, M., Welte, T., Hoeper, M. M., Golpon, H. A. 2011; 12: 62


    Growth-differentiation factor-15 (GDF-15) is a stress-responsive, transforming growth factor-β-related cytokine, which has recently been reported to be elevated in serum of patients with idiopathic pulmonary arterial hypertension (IPAH). The aim of the study was to examine the expression and biological roles of GDF-15 in the lung of patients with pulmonary arterial hypertension (PAH).GDF-15 expression in normal lungs and lung specimens of PAH patients were studied by real-time RT-PCR and immunohistochemistry. Using laser-assisted micro-dissection, GDF-15 expression was further analyzed within vascular compartments of PAH lungs. To elucidate the role of GDF-15 on endothelial cells, human pulmonary microvascular endothelial cells (HPMEC) were exposed to hypoxia and laminar shear stress. The effects of GDF-15 on the proliferation and cell death of HPMEC were studied using recombinant GDF-15 protein.GDF-15 expression was found to be increased in lung specimens from PAH patients, compared to normal lungs. GDF-15 was abundantly expressed in pulmonary vascular endothelial cells with a strong signal in the core of plexiform lesions. HPMEC responded with marked upregulation of GDF-15 to hypoxia and laminar shear stress. Apoptotic cell death of HPMEC was diminished, whereas HPMEC proliferation was either increased or decreased depending of the concentration of recombinant GDF-15 protein.GDF-15 expression is increased in PAH lungs and appears predominantly located in vascular endothelial cells. The expression pattern as well as the observed effects on proliferation and apoptosis of pulmonary endothelial cells suggest a role of GDF-15 in the homeostasis of endothelial cells in PAH patients.

    View details for DOI 10.1186/1465-9921-12-62

    View details for Web of Science ID 000291614300001

    View details for PubMedID 21548946

    View details for PubMedCentralID PMC3113721

  • Osteopontin in Patients With Idiopathic Pulmonary Hypertension CHEST Lorenzen, J. M., Nickel, N., Kraemer, R., Golpon, H., Westerkamp, V., Olsson, K. M., Haller, H., Hoeper, M. M. 2011; 139 (5): 1010–17


    Osteopontin (OPN) is a pleiotropic cytokine that has been postulated to play a role in the pathogenesis of idiopathic pulmonary arterial hypertension (IPAH). OPN plasma levels may be related to disease severity and mortality in patients with PAH.OPN plasma levels obtained during right-sided heart catheterization were assessed by a commercially available enzyme-linked immunosorbent assay and related to hemodynamics, exercise capacity, N-terminal pro-brain natriuretic peptide (NT-pro-BNP) level, uric acid level, C-reactive protein level, and survival in two cohorts of patients with IPAH: a 4-year retrospective cohort (n = 70) and a prospective cohort (n = 25) followed for 3 months after initiation of therapy. Forty apparently healthy individuals served as control subjects.Baseline OPN levels were elevated in patients with IPAH compared with healthy control subjects (50.2 ± 35.9 vs 23.7 ± 2.8 ng/mL, P < .0001). In the retrospective as well as in the prospective cohort, OPN levels correlated with mean right atrial pressure and NT-BNP. In the retrospective cohort, OPN levels also correlated with age (r = 0.3, P = .02), 6-min walking distance (r=-0.4, P = .05), and New York Heart Association class (r = 0.4, P = .001). Multivariate Cox analysis demonstrated that baseline OPN levels were independent predictors of mortality (P = .02). When patients were divided according to their baseline OPN values, being normal or elevated at baseline (below or above 34.5 ng/mL), proportional survival rates were 100% vs 80% after 1 year and 77% vs 51% after 3 years, respectively.Circulating OPN predicts survival in patients with IPAH and is associated with a higher New York Heart Association class. OPN, thus, may be useful as a biomarker in IPAH.

    View details for DOI 10.1378/chest.10-1146

    View details for Web of Science ID 000290554300008

    View details for PubMedID 20947652

  • Circulating Angiopoietins In Idiopathic Pulmonary Arterial Hypertension Nickel, N., Kuempers, P., Olsson, K. M., Westerkamp, V., Golpon, H., Hoeper, M. M. AMER THORACIC SOC. 2011
  • Long-term effects of intravenous iloprost in patients with idiopathic pulmonary arterial hypertension deteriorating on non-parenteral therapy BMC PULMONARY MEDICINE Knudsen, L., Schurawlew, A., Nickel, N., Tiede, H., Ghofrani, H. A., Wilkens, H., Ewert, R., Halank, M., Klose, H., Baezner, C., Behr, J., Hoeper, M. M. 2011; 11: 56


    The majority of patients with idiopathic pulmonary arterial hypertension (IPAH) in functional classes II and III are currently being treated with non-parenteral therapies, including endothelin receptor antagonists (ERA), phosphodiesterase (PDE)-5 inhibitors, inhaled iloprost or combinations of these substances. If these treatments fail, current guidelines recommend the addition of parenteral prostanoid therapy. There is, however, limited evidence for the efficacy of parenteral prostanoids when added to combinations of non-parenteral therapies.In this retrospective, multicentre study we collected data from consecutive IPAH patients receiving intravenous iloprost in addition to optimized non-parenteral therapy between Jan 2002 and Dec 2009. Analyses included 6 min walk distance (6MWD), functional class, need for transplantation, and survival.During the observation period, 50 patients were treated with intravenous iloprost in addition to non-parenteral therapy; 44% of the patients were on dual combination therapy and 52% on triple combination. Three months after initiation of iloprost, functional class had improved in 24% of the patients and the median 6MWD had increased from 289 m to 298 m (n.s.). During the observation period, 22 patients (44%) died and 14 (28%) underwent lung transplantation. The probabilities of LuTx-free survival at 1, 3 and 5 years following iloprost initiation were 38%, 17% and 17%, respectively. A 6MWD < 300 m and persistent functional class IV at 3 months after initiation of intravenous iloprost were predictors of an adverse outcome.In essence, late initiation of intravenous iloprost in IPAH patients who previously failed to respond to non-parenteral therapies appears to be of limited efficacy in the majority patients. Alternative therapeutic options are currently not available, underlying the need for the development of new drugs.

    View details for DOI 10.1186/1471-2466-11-56

    View details for Web of Science ID 000208592800056

    View details for PubMedID 22133492

    View details for PubMedCentralID PMC3247176

  • Long-term outcome with intravenous iloprost in pulmonary arterial hypertension EUROPEAN RESPIRATORY JOURNAL Hoeper, M. M., Gall, H., Seyfarth, H. J., Halank, M., Ghofrani, H. A., Winkler, J., Golpon, H., Olsson, K. M., Nickel, N., Opitz, C., Ewert, R. 2009; 34 (1): 132–37


    There is limited data on the long-term efficacy of intravenous iloprost in patients with pulmonary arterial hypertension (PAH). This retrospective multicentre analysis evaluated the clinical course of patients with PAH treated with i.v. iloprost, in most cases after having received inhaled iloprost as first-line therapy. Between 1997 and 2001, 79 PAH patients were treated with i.v. iloprost and followed until 2007. These patients had advanced and progressive disease as indicated by a mean pulmonary vascular resistance of 1,533 dyn x s x cm(-5) at the time of diagnosis and of 1,858 dyn x s x cm(-5) at the onset of i.v. iloprost therapy. Introduction of i.v. iloprost therapy resulted in initial haemodynamic and clinical improvement. At the end of the observation period, however, 50 (61%) patients had died and 21 (26%) required lung transplantation. Transplantation-free survival rates at 1, 3, and 5 yrs were 86%, 59% and 45%, respectively, after the diagnosis of PAH, and 54%, 31% and 15%, respectively, after the introduction of i.v. iloprost therapy. Predictors of an adverse outcome at baseline were a low 6-min walk distance and a low mixed venous oxygen saturation. In conclusion, despite initial haemodynamic and clinical improvement, overall long-term survival with i.v. iloprost therapy was limited.

    View details for DOI 10.1183/09031936.00130408

    View details for Web of Science ID 000267777000019

    View details for PubMedID 19251782

  • Growth differentiation factor-15 in idiopathic pulmonary arterial hypertension AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Nickel, N., Kempf, T., Tapken, H., Tongers, J., Laenger, F., Lehmann, U., Golpon, H., Olsson, K., Wilkins, M. R., Gibbs, J. R., Hoeper, M. M., Wollert, K. C. 2008; 178 (5): 534–41


    Growth-differentiation factor (GDF)-15 is a stress-responsive, transforming growth factor-beta-related cytokine. Circulating levels of GDF-15 provide independent prognostic information in patients with acute pulmonary embolism and chronic left-sided heart failure.To assess the prognostic value of GDF-15 in idiopathic pulmonary arterial hypertension.GDF-15 levels were determined in 76 treatment-naive patients at the time of baseline right heart catheterization. Patients were monitored for a median (range) of 48 (0-101) months (first cohort). Twenty-two additional patients were studied at baseline and 3 to 6 months after initiation of therapy (second cohort).Fifty-five percent of the patients in the first cohort presented with GDF-15 levels above 1,200 ng/L, the previously defined upper reference limit. The risk of death or transplantation at 3 years was 15 and 44% in patients with GDF-15 levels below or above 1,200 ng/L, respectively (P = 0.006). Elevated levels of GDF-15 were associated with increased mean right atrial and pulmonary capillary wedge pressures, a lower mixed venous oxygen saturation (Sv(O(2))), and higher levels of uric acid and N-terminal pro-brain natriuretic peptide (NT-proBNP). After adjustment for hemodynamic and biochemical variables, GDF-15 remained an independent predictor of adverse outcomes (P = 0.002). GDF-15 provided prognostic information in clinically relevant patient subgroups, and added prognostic information to hemodynamic variables and NT-proBNP. Changes in GDF-15 over time in the second cohort were related to changes in NT-proBNP (P = 0.031) and inversely related to changes in Sv(O(2)) (P < 0.001).GDF-15 is a promising new biomarker in idiopathic pulmonary arterial hypertension.

    View details for DOI 10.1164/rccm.200802-235OC

    View details for Web of Science ID 000258841200017

    View details for PubMedID 18565955