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1
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Lui JK, Cozzolino M, Winburn M, Trojanowski MA, Wiener RS, LaValley MP, Bujor AM, Gopal DM, Klings ES. Role of Left Ventricular Dysfunction in Systemic Sclerosis-Related Pulmonary Hypertension. Chest 2024; 165:1505-1517. [PMID: 38128607 PMCID: PMC11177103 DOI: 10.1016/j.chest.2023.12.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Revised: 11/11/2023] [Accepted: 12/13/2023] [Indexed: 12/23/2023] Open
Abstract
BACKGROUND In systemic sclerosis (SSc), pulmonary hypertension remains a significant cause of morbidity and mortality. Although conventionally classified as group 1 pulmonary arterial hypertension, systemic sclerosis-related pulmonary hypertension (SSc-PH) is a heterogeneous disease. The contribution of left-sided cardiac disease in SSc-PH remains poorly understood. RESEARCH QUESTION How often does left ventricular (LV) dysfunction occur in SSc among patients undergoing right heart catheterization and how does coexistent LV dysfunction with SSc-PH affect all-cause mortality in this patient population? STUDY DESIGN AND METHODS We conducted a retrospective, observational study of 165 patients with SSc who underwent both echocardiography and right heart catheterization. LV dysfunction was identified using LV global longitudinal strain (GLS) on speckle-tracking echocardiography based on a defined threshold of > -18%. SSc-PH was defined by a mean pulmonary artery pressure > 20 mmHg. RESULTS Among patients with SSc who have undergone right heart catheterization, LV dysfunction occurred in 74.2% with SSc-PH and 51.2% without SSc-PH. The median survival of patients with SSc-PH and LV dysfunction was 67.9 (95% CI, 38.3-102.0) months, with a hazard ratio of 12.64 (95% CI, 1.73-92.60) for all-cause mortality when adjusted for age, sex, SSc disease duration, and FVC compared with patients with SSc without pulmonary hypertension with normal LV function. INTERPRETATION LV dysfunction is common in SSc-PH. Patients with SSc-PH and LV dysfunction by LV GLS have increased all-cause mortality. This suggests that LV GLS may be helpful in identifying underlying LV dysfunction and in risk assessment of patients with SSc-PH.
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Affiliation(s)
- Justin K Lui
- Pulmonary Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA.
| | - Matthew Cozzolino
- Section of Cardiovascular Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA
| | - Morgan Winburn
- Section of Cardiovascular Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA
| | - Marcin A Trojanowski
- Section of Rheumatology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA
| | - Renda Soylemez Wiener
- Pulmonary Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA; Center for Healthcare Organization & Implementation Research, VA Boston Healthcare System, Boston, MA
| | - Michael P LaValley
- Section of Rheumatology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA; Department of Biostatistics, Boston University School of Public Health, Boston, MA
| | - Andreea M Bujor
- Section of Rheumatology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA
| | - Deepa M Gopal
- Section of Cardiovascular Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA
| | - Elizabeth S Klings
- Pulmonary Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA
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Zhang N, Liu S, Zhang Z, Liu Y, Mi L, Xu K. Lung Transplantation: A Viable Option for Connective Tissue Disease? Arthritis Care Res (Hoboken) 2023; 75:2389-2398. [PMID: 37052523 DOI: 10.1002/acr.25133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 03/24/2023] [Accepted: 04/11/2023] [Indexed: 04/14/2023]
Abstract
Interstitial lung disease (ILD) and pulmonary hypertension (PH) caused by connective tissue disease (CTD) are one of the main causes of morbidity and death in patients. Although the International Society for Heart & Lung Transplant suggested that ILD and PH related to CTD are rare indications for lung transplantation in 2006, many lung transplantation centers are concerned that the multisystem involvement of CTD will affect survival outcomes after lung transplantation, and CTD is regarded as a relative contraindication for lung transplantation. However, long-term and short-term survival after lung transplantation in CTD patients is similar compared with survival in common indications for lung transplantation such as idiopathic pulmonary fibrosis (IPF), and no higher incidence of complications after transplantation in many lung transplant centers. This suggests that lung transplantation may be beneficial in CTD patients with disease that progresses to end-stage lung disease, and CTD should not be considered a contraindication for lung transplantation. In the future, more prospective studies are needed to analyze the risk factors of lung transplantation in CTD patients to improve survival rates and reduce the risk of complications. This narrative review summarizes the selection and evaluation of candidates for CTD before lung transplantation and describes the clinical outcomes in CTD after lung transplantation in large-capacity lung transplantation center. The purpose of this review is to help rheumatologists decide when to refer patients with CTD-related lung involvement to a lung transplantation center and the conditions to consider before transplantation and to provide confidence to lung transplant experts.
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Affiliation(s)
- Na Zhang
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China and Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shizhou Liu
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China and Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhaoliang Zhang
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences Tongji Shanxi Hospital, Taiyuan, China
| | - Ying Liu
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China and Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Liangyu Mi
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences Tongji Shanxi Hospital, Taiyuan, China
| | - Ke Xu
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China and Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Tuhy T, Hassoun PM. Clinical features of pulmonary arterial hypertension associated with systemic sclerosis. Front Med (Lausanne) 2023; 10:1264906. [PMID: 37828949 PMCID: PMC10565655 DOI: 10.3389/fmed.2023.1264906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 09/11/2023] [Indexed: 10/14/2023] Open
Abstract
Systemic sclerosis is an autoimmune disorder of the connective tissue characterized by disordered inflammation and fibrosis leading to skin thickening and visceral organ complications. Pulmonary involvement, in the form of pulmonary arterial hypertension and/or interstitial lung disease, is the leading cause of morbidity and mortality among individuals with scleroderma. There are no disease-specific therapies for pulmonary involvement of scleroderma, and pulmonary arterial hypertension in this cohort has typically been associated with worse outcomes and less clinical response to modern therapy compared to other forms of Group I pulmonary hypertension in the classification from the World Symposium on Pulmonary Hypertension. Ongoing research aims to delineate how pathologic microvascular remodeling and fibrosis contribute to this poor response and offer a window into future therapeutic targets.
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Affiliation(s)
| | - Paul M. Hassoun
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
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Abstract
Pulmonary hypertension (PH) describes heterogeneous population of patients with a mean pulmonary arterial pressure >20 mm Hg. Rarely, PH presents as a primary disorder but is more commonly part of a complex phenotype associated with comorbidities. Regardless of the cause, PH reduces life expectancy and impacts quality of life. The current clinical classification divides PH into 1 of 5 diagnostic groups to assign treatment. There are currently no pharmacological cures for any form of PH. Animal models are essential to help decipher the molecular mechanisms underlying the disease, to assign genotype-phenotype relationships to help identify new therapeutic targets, and for clinical translation to assess the mechanism of action and putative efficacy of new therapies. However, limitations inherent of all animal models of disease limit the ability of any single model to fully recapitulate complex human disease. Within the PH community, we are often critical of animal models due to the perceived low success upon clinical translation of new drugs. In this review, we describe the characteristics, advantages, and disadvantages of existing animal models developed to gain insight into the molecular and pathological mechanisms and test new therapeutics, focusing on adult forms of PH from groups 1 to 3. We also discuss areas of improvement for animal models with approaches combining several hits to better reflect the clinical situation and elevate their translational value.
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Affiliation(s)
- Olivier Boucherat
- Pulmonary Hypertension Research Group, Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, QC, Canada
- Department of Medicine, Université Laval, Québec, QC, Canada
| | - Vineet Agrawal
- Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Allan Lawrie
- Dept of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK & Insigneo institute for in silico medicine, Sheffield, UK
| | - Sebastien Bonnet
- Pulmonary Hypertension Research Group, Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, QC, Canada
- Department of Medicine, Université Laval, Québec, QC, Canada
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Parajuli N, Kosanovic D. Editorial: Oxidative Stress in Cardiovascular Diseases and Pulmonary Hypertension. Front Cardiovasc Med 2022; 9:868988. [PMID: 35402568 PMCID: PMC8983953 DOI: 10.3389/fcvm.2022.868988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Accepted: 02/28/2022] [Indexed: 11/13/2022] Open
Affiliation(s)
- Nirmal Parajuli
- Immunology Research Program, Henry Ford Health System, Detroit, MI, United States
- *Correspondence: Nirmal Parajuli
| | - Djuro Kosanovic
- Department of Pulmonology, I. M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
- Djuro Kosanovic
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Rallidis LS, Papangelopoulou K, Makavos G, Varounis C, Anthi A, Orfanos SE. Low-Dose Dobutamine Stress Echocardiography for the Early Detection of Pulmonary Arterial Hypertension in Selected Patients with Systemic Sclerosis Whose Resting Echocardiography Is Non-Diagnostic for Pulmonary Hypertension. J Clin Med 2021; 10:jcm10173972. [PMID: 34501420 PMCID: PMC8432002 DOI: 10.3390/jcm10173972] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 08/21/2021] [Accepted: 08/25/2021] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Dobutamine stress echocardiography (DSE) has limited application in systemic sclerosis (SSc). We examined DSE usefulness in revealing pulmonary arterial hypertension (PAH) in selected SSc patients whose resting echocardiography for pulmonary hypertension (PH) was non-diagnostic. METHODS Forty SSc patients underwent right heart catheterization (RHC) and, simultaneously, low-dose DSE (incremental doses up to 20 μg/kg/min). Inclusion criteria were: preserved left and right ventricular (RV) function (tricuspid annulus plane systolic excursion [TAPSE] ≥ 16 mm and tissue Doppler imaging-derived systolic velocity of tricuspid annulus [RVS'] > 10 cm/s), normal pulmonary function tests, and baseline maximal tricuspid regurgitation (TR) velocity of 2.7-3.2 m/s. RESULTS Of 36 patients who completed DSE, resting RHC diagnosed PAH in 12 patients (33.3%). At 20 μg/kg/min, patients with PAH had higher TR velocity, higher pulmonary arterial pressure measured by RHC, and lower RV inotropic response compared with patients without PAH. A cut-off value of maximal TR velocity >3.1 m/s had a sensitivity of 80%, a specificity of 84.2%, and an accuracy of 82.4% for the detection of PAH. CONCLUSIONS Low-dose DSE has a satisfactory diagnostic accuracy for the early detection of PAH in highly selected SSc patients whose baseline echocardiographic measurements for PH lie in the gray zone.
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Affiliation(s)
- Loukianos S. Rallidis
- Second Department of Cardiology and Pulmonary Hypertension Clinic, Attikon Hospital, School of Medicine, National & Kapodistrian University of Athens, 16462 Athens, Greece; (K.P.); (G.M.); (C.V.)
- Correspondence: ; Tel.: +30-210-992-9106
| | - Konstantina Papangelopoulou
- Second Department of Cardiology and Pulmonary Hypertension Clinic, Attikon Hospital, School of Medicine, National & Kapodistrian University of Athens, 16462 Athens, Greece; (K.P.); (G.M.); (C.V.)
| | - Georgios Makavos
- Second Department of Cardiology and Pulmonary Hypertension Clinic, Attikon Hospital, School of Medicine, National & Kapodistrian University of Athens, 16462 Athens, Greece; (K.P.); (G.M.); (C.V.)
| | - Christos Varounis
- Second Department of Cardiology and Pulmonary Hypertension Clinic, Attikon Hospital, School of Medicine, National & Kapodistrian University of Athens, 16462 Athens, Greece; (K.P.); (G.M.); (C.V.)
| | - Anastasia Anthi
- Second Department of Critical Care and Pulmonary Hypertension Clinic, Attikon Hospital, School of Medicine, National & Kapodistrian University of Athens, 16462 Athens, Greece;
| | - Stylianos E. Orfanos
- First Department of Critical Care and Pulmonary Hypertension Center, Evangelismos General Hospital, Medical School, National & Kapodistrian University of Athens, 10676 Athens, Greece;
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The Role of Exercise Doppler Echocardiography to Unmask Pulmonary Arterial Hypertension in Selected Patients with Systemic Sclerosis and Equivocal Baseline Echocardiographic Values for Pulmonary Hypertension. Diagnostics (Basel) 2021; 11:diagnostics11071200. [PMID: 34359284 PMCID: PMC8307336 DOI: 10.3390/diagnostics11071200] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Revised: 06/23/2021] [Accepted: 06/29/2021] [Indexed: 02/06/2023] Open
Abstract
Recently, a lower mean pulmonary arterial pressure (PAP) cutoff of >20 mmHg for pulmonary hypertension (PH) definition has been proposed. We examined whether exercise Doppler echocardiography (EDE) can unmask PA hypertension (PAH) in systemic sclerosis (SSc) patients whose baseline echocardiography for PH is equivocal. We enrolled 49 patients with SSc who underwent treadmill EDE. Tricuspid regurgitation (TR) velocity was recorded immediately after EDE. Inotropic reserve of right ventricle (RV) was assessed by the change (post-prior to exercise) of tissue Doppler imaging-derived peak systolic velocity (S) of tricuspid annulus. Inclusion criteria comprised preserved left and RV function, and baseline TR velocity between 2.7 and 3.2 m/s. All patients had right-heart catheterization (RHC) within 48 h after EDE. From 46 patients with good quality of post-exercise TR velocity, RHC confirmed PAH in 21 (45.6%). Post-exercise TR velocity >3.4 m/s had a sensitivity of 90.5%, a specificity of 80% and an accuracy of 84.8% in detecting PAH. Inotropic reserve of RV was positively correlated with maximum achieved workload in METs (r = 0.571, p < 0.001). EDE has a good diagnostic accuracy for the identification of PAH in selected SSc patients whose baseline echocardiographic measurements for PH lie in the gray zone, and it is also potentially useful in assessing RV contractile reserve.
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Semalulu T, Rudski L, Huynh T, Langleben D, Wang M, Fritzler MJ, Pope J, Baron M, Hudson M. An evidence-based strategy to screen for pulmonary arterial hypertension in systemic sclerosis. Semin Arthritis Rheum 2020; 50:1421-1427. [PMID: 32245697 DOI: 10.1016/j.semarthrit.2020.02.013] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 02/20/2020] [Accepted: 02/25/2020] [Indexed: 11/29/2022]
Abstract
BACKGROUND Clinical practice guidelines recommend screening all systemic sclerosis (SSc) patients for pulmonary arterial hypertension (PAH) with yearly echocardiograms. There is a paucity of evidence to support these guidelines. RESEARCH QUESTION Can a prediction model identify SSc patients with a very low probability of PAH and therefore not requiring annual screening echocardiogram? STUDY DESIGN AND METHODS We performed a case-control study of 925 unselected SSc subjects nested in a multi-centered, longitudinal cohort. The probability of PAH for each subject was calculated using the results of multivariate logistic regression models. A cut-off was identified for the estimated probability of PAH below which no subject developed PAH (100% sensitivity). RESULTS Study subjects were predominantly female (87.5%), with mean (SD) age 58.6 (11.7) years and disease duration of 18.2 (12.2) years. Thirty-seven subjects developed PAH during 5407.97 person-years of observation (incidence rate 0.68 per 100 person-years). Shortness of breath (SOB), diffusing capacity for carbon monoxide (DLCO) and NT-proBNP were independent predictors of PAH. All SSc-PAH cases had a probability of PAH of >1.1%. Subjects below this cut-off, none of whom had PAH, accounted for 46.2% of the study population. INTERPRETATION A simple prediction model identified subjects at very low probability of PAH who could potentially forego annual screening echocardiogram. This represents almost half of SSc subjects in a general SSc population. This study, which is the first evidence-based study for the rational use of follow-up echocardiograms in an unselected SSc cohort, requires validation. The scoring system is freely available online at http://pahtool.ladydavis.ca.
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Affiliation(s)
- T Semalulu
- Department of Medicine, McMaster University, Canada
| | - L Rudski
- Department of Medicine, McGill University, Montreal, Canada; Division of Cardiology, Jewish General Hospital, Montreal, Canada
| | - T Huynh
- Department of Medicine, McGill University, Montreal, Canada; Division of Cardiology, McGill University Health Centre, Montreal, Canada
| | - D Langleben
- Department of Medicine, McGill University, Montreal, Canada; Division of Cardiology, Jewish General Hospital, Montreal, Canada; Lady Davis Institute for Medical Research, Montreal, Canada
| | - M Wang
- Lady Davis Institute for Medical Research, Montreal, Canada
| | | | - M J Fritzler
- Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - J Pope
- St. Joseph's Healthcare, London, Canada
| | - M Baron
- Department of Medicine, McGill University, Montreal, Canada; Division of Rheumatology, Jewish General Hospital, Room A-725, 3755 Côte Sainte-Catherine Road, Montreal, Quebec H3T 1E2, Canada
| | - M Hudson
- Department of Medicine, McGill University, Montreal, Canada; Lady Davis Institute for Medical Research, Montreal, Canada; Division of Rheumatology, Jewish General Hospital, Room A-725, 3755 Côte Sainte-Catherine Road, Montreal, Quebec H3T 1E2, Canada.
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9
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Xanthouli P, Jordan S, Milde N, Marra A, Blank N, Egenlauf B, Gorenflo M, Harutyunova S, Lorenz HM, Nagel C, Theobald V, Lichtblau M, Berlier C, Ulrich S, Grünig E, Benjamin N, Distler O. Haemodynamic phenotypes and survival in patients with systemic sclerosis: the impact of the new definition of pulmonary arterial hypertension. Ann Rheum Dis 2020; 79:370-378. [PMID: 31818805 DOI: 10.1136/annrheumdis-2019-216476] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 11/25/2019] [Accepted: 11/25/2019] [Indexed: 12/20/2022]
Abstract
BACKGROUND In this study, we investigated the impact of the new haemodynamic definition of pulmonary arterial hypertension (PAH) as proposed by the 6th PH World Symposium on phenotypes and survival in patients with systemic sclerosis (SSc). METHODS In SSc patients who were prospectively and consecutively screened for PAH including right heart catheterisation in Heidelberg or Zurich, haemodynamic and clinical variables have been reassessed according to the new PAH definition. Patients have been followed for 3.7±3.7 (median 3.4) years; Kaplan-Meier survival analysis was performed. Patients with significant lung or left heart disease were excluded from comparative analyses. RESULTS The final dataset included 284 SSc patients, 146 patients (49.2%) had mean pulmonary arterial pressure (mPAP) ≤20 mm Hg, 19.3% had mPAP 21-24 mm Hg and 29.4% had mPAP ≥25 mm Hg. In the group of mildly elevated mPAP, only four patients (1.4% of the whole SSc cohort) had pulmonary vascular resistance (PVR) values ≥3 Wood Units (WU) and could be reclassified as manifest SSc-APAH. Twenty-eight (9.8%) patients with mPAP of 21-24 mm Hg and PVR ≥2 WU already presented with early pulmonary vascular disease with decreased 6 min walking distance (6MWD) (p<0.001), TAPSE (p=0.004) and pulmonary arterial compliance (p<0.001). A PVR ≥2 WU was associated with reduced long-term survival (p=0.002). PVR and 6MWD were independent prognostic predictors in multivariate analysis. CONCLUSION The data of this study show that a PVR threshold ≥3 WU is too high to enable an early diagnosis of PAH. A PVR threshold ≥2 WU was already associated with pulmonary vascular disease, significantly reduced survival and would be more appropriate in SSc patients with mild PAH.
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Affiliation(s)
- Panagiota Xanthouli
- Centre for Pulmonary Hypertension, Thoraxklinik Heidelberg gGmbH at Heidelberg University Hospital, Heidelberg, Germany
- Translational Lung Research Center Heidelberg (TLRC), Member of the German Center for Lung Research (DZL), Heidelberg, Germany
| | - Suzana Jordan
- Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland
| | - Nicklas Milde
- Centre for Pulmonary Hypertension, Thoraxklinik Heidelberg gGmbH at Heidelberg University Hospital, Heidelberg, Germany
- Translational Lung Research Center Heidelberg (TLRC), Member of the German Center for Lung Research (DZL), Heidelberg, Germany
| | | | - Norbert Blank
- Department of Internal Medicine V: Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg, Germany
| | - Benjamin Egenlauf
- Centre for Pulmonary Hypertension, Thoraxklinik Heidelberg gGmbH at Heidelberg University Hospital, Heidelberg, Germany
- Translational Lung Research Center Heidelberg (TLRC), Member of the German Center for Lung Research (DZL), Heidelberg, Germany
| | - Matthias Gorenflo
- Department of Pediatric Cardiology, University Hospital Heidelberg, Heidelberg, Germany
| | - Satenik Harutyunova
- Centre for Pulmonary Hypertension, Thoraxklinik Heidelberg gGmbH at Heidelberg University Hospital, Heidelberg, Germany
- Translational Lung Research Center Heidelberg (TLRC), Member of the German Center for Lung Research (DZL), Heidelberg, Germany
| | - Hanns-Martin Lorenz
- Department of Internal Medicine V: Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg, Germany
| | - Christian Nagel
- Centre for Pulmonary Hypertension, Thoraxklinik Heidelberg gGmbH at Heidelberg University Hospital, Heidelberg, Germany
- Translational Lung Research Center Heidelberg (TLRC), Member of the German Center for Lung Research (DZL), Heidelberg, Germany
- Lung centre, Klinikum Mittelbaden gGmbH, Baden-Baden Balg, Germany
| | - Vivienne Theobald
- Centre for Pulmonary Hypertension, Thoraxklinik Heidelberg gGmbH at Heidelberg University Hospital, Heidelberg, Germany
- Translational Lung Research Center Heidelberg (TLRC), Member of the German Center for Lung Research (DZL), Heidelberg, Germany
| | - Mona Lichtblau
- Department of Pulmonology, University Hospital Zurich, Zurich, Switzerland
| | - Charlotte Berlier
- Department of Pulmonology, University Hospital Zurich, Zurich, Switzerland
| | - Silvia Ulrich
- Department of Pulmonology, University Hospital Zurich, Zurich, Switzerland
| | - Ekkehard Grünig
- Centre for Pulmonary Hypertension, Thoraxklinik Heidelberg gGmbH at Heidelberg University Hospital, Heidelberg, Germany
- Translational Lung Research Center Heidelberg (TLRC), Member of the German Center for Lung Research (DZL), Heidelberg, Germany
| | - Nicola Benjamin
- Centre for Pulmonary Hypertension, Thoraxklinik Heidelberg gGmbH at Heidelberg University Hospital, Heidelberg, Germany
- Translational Lung Research Center Heidelberg (TLRC), Member of the German Center for Lung Research (DZL), Heidelberg, Germany
| | - Oliver Distler
- Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland
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10
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Allanore Y, Gharibdoost F, Jamshidi AR, Javinani A, Avouac J, Rastkar E, Hooshmandi S, Kavosi H. Comparison of the clinical phenotype of systemic sclerosis patients in Iran and France in two university centers. JOURNAL OF SCLERODERMA AND RELATED DISORDERS 2019; 4:149-159. [PMID: 35382390 PMCID: PMC8922647 DOI: 10.1177/2397198318809224] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Accepted: 09/30/2018] [Indexed: 06/29/2024]
Abstract
OBJECTIVES Systemic sclerosis is a severe and rare chronic auto-immune multisystem disorder characterized by vasculopathy and skin stiffness. Ethnic and geographical origin can influence the outcomes. In this study, we compared the phenotypic characteristics of Iranian and French patients. METHODS This cross-sectional study was performed on 200 Iranian and 268 French systemic sclerosis patients. Iranian patients collected from the Iranian systemic sclerosis cohort of the Rheumatology Research Center, Shariati hospital, Tehran University of Medical Sciences. The French population was monocentric, and it was constituted by the patients included locally in the EUSTAR database in December 2016. RESULTS The mean age at onset was significantly lower in Iranian patients (35.58 ± 11.68 vs 47.06 ± 13.54, p-value < 0.001). The female-to-male ratio was approximately 5.2:1 and was not different in the two populations. The prevalence of diffuse cutaneous systemic sclerosis was significantly higher in Iranian patients (60.2% vs 42.85%, p-value < 0.001). Calcinosis cutis and joint synovitis were more prevalent in French patients (p-value = 0.013, <0.001). The positivity of anti-topoisomerase antibody was higher in Iranian patients, whereas the anti-centromere antibody predominated in French cases (p-value < 0.001). Restrictive pattern of pulmonary function test was more common in Iranian patients (p-value < 0.001), while estimated pulmonary arterial pressure by echocardiography was higher in French patients (p-value < 0.001). CONCLUSION It seems that systemic sclerosis occurred in younger ages among Iranian female with the predominance of diffuse cutaneous subtype. In addition, lung interstitial disease appeared to be more prevalent and severe in Iranians than French patients.
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Affiliation(s)
- Yannick Allanore
- Department of Rheumatology, Cochin Hospital, Paris Descartes University, Paris, France
| | - Farhad Gharibdoost
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Ahmad Reza Jamshidi
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Javinani
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Jérôme Avouac
- Department of Rheumatology, Cochin Hospital, Paris Descartes University, Paris, France
| | - Elnaz Rastkar
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Sadid Hooshmandi
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Hoda Kavosi
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran
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11
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Rieth AJ, Richter MJ, Berkowitsch A, Frerix M, Tarner IH, Mitrovic V, Hamm CW. Intravenous sildenafil acutely improves hemodynamic response to exercise in patients with connective tissue disease. PLoS One 2018; 13:e0203947. [PMID: 30235235 PMCID: PMC6147445 DOI: 10.1371/journal.pone.0203947] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2018] [Accepted: 08/29/2018] [Indexed: 11/18/2022] Open
Abstract
Background Hemodynamic assessment during exercise may unmask an impaired functional reserve of the right ventricle and the pulmonary vasculature in patients with connective tissue disease. We assessed the effect of intravenous sildenafil on the hemodynamic response to exercise in patients with connective tissue disease. Methods In this proof-of-concept study, patients with connective tissue disease and mean pulmonary arterial pressure (mPAP) >20 mm Hg were subjected to a supine exercise hemodynamic evaluation before and after administration of intravenous sildenafil 10 mg. Results Ten patients (four with moderately elevated mPAP 21–24 mm Hg; six with mPAP >25 mm Hg) underwent hemodynamic assessment. All of them showed markedly abnormal exercise hemodynamics. Intravenous sildenafil was well tolerated and had significant hemodynamic effects at rest and during exercise, although without pulmonary selectivity. Sildenafil reduced median total pulmonary resistance during exercise from 6.22 (IQR 4.61–8.54) to 5.24 (3.95–6.96) mm Hg·min·L-1 (p = 0.005) and increased median pulmonary arterial capacitance during exercise from 1.59 (0.93–2.28) to 1.74 (1.12–2.69) mL/mm Hg (p = 0.005). Conclusions In patients with connective tissue disease who have an abnormal hemodynamic response to exercise, intravenous sildenafil improved adaption of the right ventricular-pulmonary vascular unit to exercise independent of resting mPAP. The impact of acute pharmacological interventions on exercise hemodynamics in patients with pulmonary vascular disease warrants further investigation. Trial registration Clinicaltrials.gov NCT01889966.
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Affiliation(s)
- Andreas J. Rieth
- Department of Cardiology, Kerckhoff-Klinik GmbH, Bad Nauheim, Germany
- * E-mail:
| | - Manuel J. Richter
- Department of Pneumology, Kerckhoff-Klinik GmbH, Bad Nauheim, Germany
- Department of Internal Medicine, Justus Liebig University Giessen, Universities of Giessen and Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), Giessen, Germany
| | | | - Marc Frerix
- Department of Rheumatology and Clinical Immunology, Kerckhoff-Klinik GmbH, Bad Nauheim, Germany
| | - Ingo H. Tarner
- Department of Rheumatology and Clinical Immunology, Kerckhoff-Klinik GmbH, Bad Nauheim, Germany
| | - Veselin Mitrovic
- Department of Cardiology, Kerckhoff-Klinik GmbH, Bad Nauheim, Germany
| | - Christian W. Hamm
- Department of Cardiology, Kerckhoff-Klinik GmbH, Bad Nauheim, Germany
- Department of Cardiology, Justus Liebig University Giessen, Universities of Giessen and Marburg, Giessen, Germany
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12
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Johnson ZI, Jones JD, Mukherjee A, Ren D, Feghali-Bostwick C, Conley YP, Yates CC. Novel classification for global gene signature model for predicting severity of systemic sclerosis. PLoS One 2018; 13:e0199314. [PMID: 29924864 PMCID: PMC6010260 DOI: 10.1371/journal.pone.0199314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Accepted: 06/05/2018] [Indexed: 11/25/2022] Open
Abstract
Progression of systemic scleroderma (SSc), a chronic connective tissue disease that causes a fibrotic phenotype, is highly heterogeneous amongst patients and difficult to accurately diagnose. To meet this clinical need, we developed a novel three-layer classification model, which analyses gene expression profiles from SSc skin biopsies to diagnose SSc severity. Two SSc skin biopsy microarray datasets were obtained from Gene Expression Omnibus. The skin scores obtained from the original papers were used to further categorize the data into subgroups of low (<18) and high (≥18) severity. Data was pre-processed for normalization, background correction, centering and scaling. A two-layered cross-validation scheme was employed to objectively evaluate the performance of classification models of unobserved data. Three classification models were used: support vector machine, random forest, and naive Bayes in combination with feature selection methods to improve performance accuracy. For both input datasets, random forest classifier combined with correlation-based feature selection (CFS) method and naive Bayes combined with CFS or support vector machine based recursive feature elimination method yielded the best results. Additionally, we performed a principal component analysis to show that low and high severity groups are readily separable by gene expression signatures. Ultimately, we found that our novel classification prediction model produced global gene signatures that significantly correlated with skin scores. This study represents the first report comparing the performance of various classification prediction models for gene signatures from SSc patients, using current clinical diagnostic factors. In summary, our three-classification model system is a powerful tool for elucidating gene signatures from SSc skin biopsies and can also be used to develop a prognostic gene signature for SSc and other fibrotic disorders.
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Affiliation(s)
- Zariel I. Johnson
- Department of Health Promotions and Development, University of Pittsburgh School of Nursing, Pittsburgh, PA, United States of America
| | - Jacqueline D. Jones
- Department of Biological & Environmental Sciences, Troy University, Troy, AL, United States of America
| | - Angana Mukherjee
- Department of Biological & Environmental Sciences, Troy University, Troy, AL, United States of America
| | - Dianxu Ren
- Health and Community Systems, University of Pittsburgh School of Nursing, Pittsburgh, PA, United States of America
| | - Carol Feghali-Bostwick
- Department of Rheumatology & Immunology, University of South Carolina, Charleston, SC, United States of America
| | - Yvette P. Conley
- Department of Health Promotions and Development, University of Pittsburgh School of Nursing, Pittsburgh, PA, United States of America
- Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Cecelia C. Yates
- Department of Health Promotions and Development, University of Pittsburgh School of Nursing, Pittsburgh, PA, United States of America
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America
- * E-mail:
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13
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Karampitsakos T, Tzouvelekis A, Chrysikos S, Bouros D, Tsangaris I, Fares WH. Pulmonary hypertension in patients with interstitial lung disease. Pulm Pharmacol Ther 2018; 50:38-46. [PMID: 29605286 DOI: 10.1016/j.pupt.2018.03.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2017] [Revised: 03/12/2018] [Accepted: 03/28/2018] [Indexed: 01/20/2023]
Abstract
Interstitial lung diseases (ILDs) comprise a broad and heterogeneous group of more than two hundred diseases with common functional characteristics. Their diagnosis and management require a multidisciplinary approach. This multidisciplinary approach involves the assessment of comorbid conditions including pulmonary hypertension (PH) that exerts a dramatic impact on survival. The current World Health Organization (WHO) classification of PH encompasses many of the interstitial lung diseases into WHO Group 3, while sarcoidosis, Pulmonary Langerhans Cell Histiocytosis and lymphangioleiomyomatosis are placed into WHO Group 5 as diseases with unclear or multifactorial mechanisms. Connective tissue diseases could span any of the 5 WHO groups based on the primary phenotype into which they manifest. Interestingly, several challenging phenotypes present with features that overlap between two or more WHO PH groups. Currently, PH-specific treatment is recommended only for patients classified into WHO Group 1 PH. The lack of specific treatment for other groups, including PH in the setting of ILD, reflects the poor outcomes of these patients. Thus, identification of the optimal strategy for ILD patients with PH remains an amenable need. This review article provides a brief overview of biomarkers indicative of vascular remodeling in interstitial lung disease, summarizes the current state of knowledge regarding patients with PH and ILD and highlights future perspectives that remain to be addressed.
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Affiliation(s)
| | - Argyrios Tzouvelekis
- First Academic Department of Pneumonology, Hospital for Thoracic Diseases, "Sotiria", Medical School, National and Kapodistrian University of Athens, Athens, Greece; Division of Immunology, Biomedical Sciences Research Center "Alexander Fleming", Athens, Greece
| | - Serafeim Chrysikos
- 5(th) Department of Pneumonology, Hospital for Thoracic Diseases, "Sotiria", Athens, Greece
| | - Demosthenes Bouros
- First Academic Department of Pneumonology, Hospital for Thoracic Diseases, "Sotiria", Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Iraklis Tsangaris
- Second Critical Care Department, Attikon Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Wassim H Fares
- Section of Pulmonary, Critical Care & Sleep Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
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14
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Lung Manifestations in the Rheumatic Diseases. Chest 2017; 152:1283-1295. [PMID: 28552544 DOI: 10.1016/j.chest.2017.05.015] [Citation(s) in RCA: 72] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Revised: 05/15/2017] [Accepted: 05/16/2017] [Indexed: 12/21/2022] Open
Abstract
Lung ailments in rheumatic diseases present unique challenges for diagnosis and management and are a source of significant morbidity and mortality for patients. Unlike the idiopathic interstitial pneumonias, patients with rheumatic diseases experience lung disease in the context of a systemic disease that may make it more difficult to recognize and that may present greater risks with treatment. Despite recent advances in our awareness of these diseases, there is still a significant lack of understanding of natural history to elucidate which patients will have disease that is progressive and thus warrants treatment. What we do know is that a subset of patients with rheumatic disease experience parenchymal lung disease that can prognostically resemble idiopathic pulmonary fibrosis, such as in rheumatoid arthritis, and that others can have aggressive inflammatory lung disease in the context of autoimmune myositis, systemic sclerosis, or an undifferentiated autoimmune process. As we enter into a paradigm shift where we view lung health as a cornerstone of our care of patients with rheumatic diseases, we hopefully will improve our ability to identify those patients at highest risk for pulmonary disease and progression, and offer emerging treatments which will result in better outcomes and a better quality of life.
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15
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Meprin metalloproteases: Molecular regulation and function in inflammation and fibrosis. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2017; 1864:2096-2104. [PMID: 28502593 DOI: 10.1016/j.bbamcr.2017.05.011] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/18/2017] [Revised: 05/05/2017] [Accepted: 05/09/2017] [Indexed: 01/03/2023]
Abstract
The zinc-endopeptidases meprin α and meprin β are extracellular proteases involved in connective tissue homeostasis, intestinal barrier function and immunological processes. Meprins are unique among other extracellular proteases with regard to cleavage specificity and structure. Meprin α and meprin β have a strong preference for negatively charged amino acids around the scissile bond, reflected by cleavage sites identified in procollagen I, the amyloid precursor protein (APP) and the interleukin-6 receptor (IL-6R). In this review we report on recent findings that summarize the complex molecular regulation of meprins, particular folding, activation and shedding. Dysregulation of meprin α and meprin β is often associated with pathological conditions such as neurodegeneration, inflammatory bowel disease and fibrosis. Based on mouse models and patient data we suggest meprins as possible key regulators in the onset and progression of fibrotic disorders, leading to severe diseases such as pulmonary hypertension. This article is part of a Special Issue entitled: Proteolysis as a Regulatory Event in Pathophysiology edited by Stefan Rose-John.
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Pros and Cons of Echocardiography in the Screening, Diagnosis and Follow-up of Patients with Systemic Sclerosis Pulmonary Arterial Hypertension – a Rheumatologist's Perspective. JOURNAL OF SCLERODERMA AND RELATED DISORDERS 2017. [DOI: 10.5301/jsrd.5000229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Purpose Our objective was to review the evidence regarding echocardiography in patients with systemic sclerosis (SSc) and possible pulmonary hypertension (PH). Methods The literature was reviewed. In addition, a survey was conducted of 315 rheumatologists/internists with a self-declared interest in SSc, to determine their preferred use of echocardiograms. Results The most relevant literature findings come from two studies, the DETECT study and one from the Australian Scleroderma Interest Group. In both these studies, it appears that the use of non-echocardiographic variables such as pulmonary function tests (PFTs) and values of serum N-terminal pro-brain natriuretic peptide (NT-proBNP), are adequate on their own in suggesting which patients are at high risk of PH. Echocardiograms added very little information and in fact may confuse the picture by appearing to be normal when in fact underlying PH is present. With regard to the survey, 157 physicians (49.8%) responded. Of those, 67% felt that an echocardiogram should be ordered on every patient with SSc every year. Ninety-five percent (95%) said the reason was to screen for the development of significant PH, 65% said the reason was to screen for the development of significant intrinsic cardiac disease and 38% said that the reason was to adhere to accepted international recommendations. Conclusions Despite popular belief and current recommendations, in the opinion of the author, echocardiograms are not necessary in every SSc patient every year. Cheaper tests such as PFTs and NT-proBNP are adequate in most cases to suggest when a right heart catheterization should be performed.
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17
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Yoo SJ, Park JH, Park Y, Lee JH, Sun BJ, Kim J, Yoo IS, Shim SC, Kang SW. Prevalence of Pulmonary Arterial Hypertension in Korean Adult Patients with Systemic Sclerosis: Result of a Pilot Echocardiographic Screening Study. J Cardiovasc Ultrasound 2016; 24:312-316. [PMID: 28090259 PMCID: PMC5234342 DOI: 10.4250/jcu.2016.24.4.312] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Revised: 11/29/2016] [Accepted: 11/30/2016] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND Pulmonary arterial hypertension (PAH) is a major cause of morbidity and mortality among patients with systemic sclerosis (SSc). Early detection and prompt treatment of PAH associated with SSc (SSc-PAH) result in better prognosis. We conducted echocardiographic study to presume the prevalence of PAH in Korean adult SSc patients and to diagnose SSc-PAH in their early stages with right heart catheterization (RHC). METHODS We performed free of charge echocardiographic study including 37 adult SSc patients at the Chungnam National University Hospital. The possibility of PAH is determined by the estimation of pulmonary arterial pressure by peak tricuspid regurgitation velocity of > 3.0 m/s. Patients with possible PAH were recommended to undergo RHC to confirm the diagnosis. RESULTS In 37 patients, 8 patients were suspected with PAH. Among them, 6 patients agreed to be examined with RHC, and 4 were confirmed with PAH. The prevalence of possible PAH was 21.6% (8 of 37 patients), and that of confirmed PAH was 10.8% (4 of 37 patients). Four patients who were confirmed with SSc-PAH through RHC have been treated with specific pulmonary vasodilators and maintained stable. CONCLUSION Eight patients (21.6%) were possible PAH and 4 (10.8%) were diagnosed as SSc-PAH by RHC after the echocardiographic screening study of 37 adult SSc patients.
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Affiliation(s)
- Su-Jin Yoo
- Division of Rheumatology, Department of Internal Medicine, School of Medicine, Chungnam National University, Chungnam National University Hospital, Daejeon, Korea
| | - Jae-Hyeong Park
- Division of Cardiology, Department of Internal Medicine, School of Medicine, Chungnam National University, Chungnam National University Hospital, Daejeon, Korea
| | - Yunseon Park
- Division of Cardiology, Department of Internal Medicine, School of Medicine, Chungnam National University, Chungnam National University Hospital, Daejeon, Korea
| | - Jae-Hwan Lee
- Division of Cardiology, Department of Internal Medicine, School of Medicine, Chungnam National University, Chungnam National University Hospital, Daejeon, Korea
| | - Byung-Joo Sun
- Division of Cardiology, Department of Internal Medicine, School of Medicine, Chungnam National University, Chungnam National University Hospital, Daejeon, Korea
| | - Jinhyun Kim
- Division of Rheumatology, Department of Internal Medicine, School of Medicine, Chungnam National University, Chungnam National University Hospital, Daejeon, Korea
| | - In Seol Yoo
- Division of Rheumatology, Department of Internal Medicine, School of Medicine, Chungnam National University, Chungnam National University Hospital, Daejeon, Korea
| | - Seung Cheol Shim
- Division of Rheumatology, Department of Internal Medicine, School of Medicine, Chungnam National University, Chungnam National University Hospital, Daejeon, Korea
| | - Seong Wook Kang
- Division of Rheumatology, Department of Internal Medicine, School of Medicine, Chungnam National University, Chungnam National University Hospital, Daejeon, Korea
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Marini C, Formichi B, Bauleo C, Michelassi C, Airò E, Rossi G, Giuntini C. Survival protection by bodyweight in isolated scleroderma-related pulmonary artery hypertension. Intern Emerg Med 2016; 11:941-52. [PMID: 27052360 DOI: 10.1007/s11739-016-1446-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2015] [Accepted: 03/22/2016] [Indexed: 10/22/2022]
Abstract
In chronic heart failure (CHF) due to systemic cardiovascular disease, obese patients have better survival. Bodyweight versus survival was analyzed post hoc in subjects with limited scleroderma (SSc) and isolated pulmonary artery hypertension (PAH), i.e. with CHF due to pulmonary vascular disease. Rheumatologists referred scleroderma subjects for evaluation, and PAH was ascertained by right heart catheterization (RHC). Forty-nine SSc-PAH subjects were stratified by body mass index (BMI): obese 7 (14.3 %), overweight 11 (22.4 %), normal weight 21 (42.9 %), and underweight 10 (20.4 %) for 24-month follow-up and pooled together for long-term 72-month follow-up. Survival was analyzed by Kaplan-Meier method. Multivariate Cox proportional hazards modeling helped to assess variables associated to survival. At 24 months (17 events), survival increases with BMI across four groups (logrank for trend P = 0.031). By Cox multivariate mortality, best model included: BMI (P = 0.043), low lung diffusion (DLco, P = 0.007), and reduced stroke volume index (SVI, P = 0.017). At 72 month (37 events), higher BMI values were associated with better survival but not significantly (P = 0.076). By multivariate modeling BMI did not enter any model, whereas low DLco entered all (P < 0.001). Also low SVI (P = 0.02) and low mixed venous saturation (SvO2, P = 0.009) were associated with the prognosis. From PAH diagnosis to final event, BMI had small (5.4 %), but significant decline (P < 0.001). This is ascribed to CHF progression, and may explain BMI predictive power weakening. The results suggest BMI decline should be contrasted, DLco is useful for screening and with SVI and SvO2 for assessing prognosis and treatment.
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Affiliation(s)
- Carlo Marini
- Fondazione Regione Toscana "G. Monasterio", Via G. Moruzzi 1, Ghezzano, 56124, Pisa, Italy.
- Dipartimento Cardio-Toracico, e Vascolare, Università degli Studi, Via Paradisa 2, Pisa, Italy.
| | - Bruno Formichi
- Fondazione Regione Toscana "G. Monasterio", Via G. Moruzzi 1, Ghezzano, 56124, Pisa, Italy
- Istituto di Fisiologia Clinica del CNR, Via Moruzzi 1, Ghezzano, 56124, Pisa, Italy
| | - Carolina Bauleo
- Fondazione Regione Toscana "G. Monasterio", Via G. Moruzzi 1, Ghezzano, 56124, Pisa, Italy
| | - Claudio Michelassi
- Istituto di Fisiologia Clinica del CNR, Via Moruzzi 1, Ghezzano, 56124, Pisa, Italy
| | - Edoardo Airò
- Fondazione Regione Toscana "G. Monasterio", Via G. Moruzzi 1, Ghezzano, 56124, Pisa, Italy
| | - Giuseppe Rossi
- Unit of Epidemiology and Biostatistics, Istituto di Fisiologia Clinica del CNR, Via G. Moruzzi 1, Ghezzano, 56124, Pisa, Italy
| | - Carlo Giuntini
- Dipartimento Cardio-Toracico, e Vascolare, Università degli Studi, Via Paradisa 2, Pisa, Italy
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Gao L, Emond MJ, Louie T, Cheadle C, Berger AE, Rafaels N, Vergara C, Kim Y, Taub MA, Ruczinski I, Mathai SC, Rich SS, Nickerson DA, Hummers LK, Bamshad MJ, Hassoun PM, Mathias RA, Barnes KC. Identification of Rare Variants in ATP8B4 as a Risk Factor for Systemic Sclerosis by Whole-Exome Sequencing. Arthritis Rheumatol 2016; 68:191-200. [PMID: 26473621 DOI: 10.1002/art.39449] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2014] [Accepted: 09/24/2015] [Indexed: 01/02/2023]
Abstract
OBJECTIVE To determine the contribution of rare variants as genetic modifiers of the expressivity, penetrance, and severity of systemic sclerosis (SSc). METHODS We performed whole-exome sequencing of 78 European American patients with SSc, including 35 patients without pulmonary arterial hypertension (PAH) and 43 patients with PAH. Association testing of case-control probability for rare variants was performed using the unified sequence kernel association test with optimal kernel weighting and small sample adjustment by comparing all SSc patients with a reference population of 3,179 controls from the Exome Sequencing Project 5,500 exome data set. Replication genotyping was performed in an independent sample of 3,263 patients (415 patients with SSc and 2,848 controls). We conducted expression profiling of messenger RNA from 61 SSc patients (19 without PAH and 42 with PAH) and 41 corresponding controls. RESULTS The ATP8B4 gene was associated with a significant increase in the risk of SSc (P = 2.77 × 10(-7)). Among the 64 ATP8B4 variants tested, a single missense variant, c.1308C>G (F436L, rs55687265), provided the most compelling evidence of association (P = 9.35 × 10(-10), odds ratio [OR] 6.11), which was confirmed in the replication cohort (P = 0.012, OR 1.86) and meta-analysis (P = 1.92 × 10(-7), OR 2.5). Genes involved in E3 ubiquitin-protein ligase complex (ASB10) and cyclic nucleotide gated channelopathies (CNGB3) as well as HLA-DRB5 and HSPB2 (heat-shock protein 27) provided additional evidence of association (P < 10(-5)). Differential ATP8B4 expression was observed among the SSc patients compared to the controls (P = 0.0005). CONCLUSION ATP8B4 may represent a putative genetic risk factor for SSc and pulmonary vascular complications.
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Affiliation(s)
- Li Gao
- Johns Hopkins University, Baltimore, Maryland
| | | | | | | | | | | | | | - Yoonhee Kim
- National Human Genome Research Institute, NIH, Baltimore, Maryland
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Minai OA, Nguyen Q, Mummadi S, Walker E, McCarthy K, Dweik RA. Heart rate recovery is an important predictor of outcomes in patients with connective tissue disease-associated pulmonary hypertension. Pulm Circ 2015; 5:565-76. [PMID: 26401258 DOI: 10.1086/682432] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2014] [Accepted: 05/05/2015] [Indexed: 11/03/2022] Open
Abstract
Reduced heart rate recovery (HRR) after exercise is associated with increased mortality in cardiac and pulmonary diseases. We sought to evaluate the association between HRR after the 6-minute walk test (6MWT) and outcomes in patients with connective tissue disease-associated pulmonary hypertension (CTD-PH). Data were obtained by review of the medical records. HRR was defined as the difference in heart rate at the end of the 6MWT and after 1 minute (HRR1), 2 minutes (HRR2), and 3 minutes (HRR3) of rest. All patients with pulmonary hypertension and a diagnosis of systemic sclerosis, systemic lupus erythematosus, or mixed connective tissue disease who underwent the 6MWT between August 1, 2009, and October 30, 2011, were included (n = 66). By Kaplan-Meier analysis, HRR1, HRR2, and HRR3 at different cutoff points were all good predictors, with HRR1 of <16 being the best predictor of time to clinical worsening (log-rank P < 0.0001), hospitalization (log-rank P = 0.0001), and survival (log-rank P < 0.003). By proportional hazards regression, patients with HRR1 of <16 were at increased risk of clinical worsening (hazard ratio [HR]: 6.4 [95% confidence interval (CI): 2.6-19.2]; P < 0.0001], hospitalization (HR: 6.6 [95% CI: 2.4-23]; P < 0.0001), and death (HR: 4.5 [95% CI: 1.6-15.7]; P = 0.003). Patients in the highest tercile (HRR1 of ≥19) were unlikely to have a clinical worsening event (HR: 0.1 [95% CI: 0.04-0.5]; P = 0.001], to be hospitalized (HR: 0.1 [95% CI: 0.02-0.5]; P = 0.001), or to die (HR: 0.3 [95% CI: 0.07-0.9]; P = 0.04]. In conclusion, in patients with CTD-PH, abnormal HRR1 (defined as HRR1 of <16) after the 6MWT is a strong predictor of clinical worsening, time to clinical worsening, survival, and hospitalization.
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Affiliation(s)
- Omar A Minai
- Department of Pulmonary, Allergy, and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Quyen Nguyen
- Department of Medicine, Medicine Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Srinivas Mummadi
- Department of Pulmonary Medicine, Oregon Health and Science University, Portland, Oregon, USA
| | - Esteban Walker
- Department of Qualitative Health Sciences, Cleveland Clinic, Cleveland, Ohio, USA
| | - Kevin McCarthy
- Department of Pulmonary, Allergy, and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Raed A Dweik
- Department of Pulmonary, Allergy, and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, Cleveland, Ohio, USA
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Miao CG, Xiong YY, Yu H, Zhang XL, Qin MS, Song TW, Du CL. Critical roles of microRNAs in the pathogenesis of systemic sclerosis: New advances, challenges and potential directions. Int Immunopharmacol 2015; 28:626-33. [DOI: 10.1016/j.intimp.2015.07.042] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2015] [Revised: 07/12/2015] [Accepted: 07/29/2015] [Indexed: 02/06/2023]
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Bossone E, Dellegrottaglie S, Patel S, Grunig E, D'Andrea A, Ferrara F, Gargiulo P, D'Alto M, Soricelli A, Cittadini A, Sanz J, Perrone-Filardi P, Rubenfire M. Multimodality Imaging in Pulmonary Hypertension. Can J Cardiol 2015; 31:440-59. [DOI: 10.1016/j.cjca.2015.02.012] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2014] [Revised: 02/16/2015] [Accepted: 02/16/2015] [Indexed: 01/25/2023] Open
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Mathai SC, Hassoun PM, Puhan MA, Zhou Y, Wise RA. Sex differences in response to tadalafil in pulmonary arterial hypertension. Chest 2015; 147:188-197. [PMID: 25122150 DOI: 10.1378/chest.14-0263] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022] Open
Abstract
BACKGROUND Pulmonary arterial hypertension (PAH) is a progressive disease with high rates of morbidity and mortality. Current therapies improve symptoms, functional capacity, and, in select cases, survival. Little is known about patient factors that may predict the likelihood of patient-important, clinically relevant responses to therapy such as the 6-min walk distance (6MWD) and health-related quality of life (HRQoL). METHODS Data from the randomized clinical trial of tadalafil in PAH were used. Adjusted logistic regression models were created to examine the relationship between baseline characteristics and odds of achieving the minimal important difference (MID) in three parameters, defined as either a > 33-m increase in 6MWD, a > 5-unit increase in physical component summary score of the Medical Outcomes Study Short Form-36 (SF-36), or a > 5-unit increase in mental component summary score of the SF-36. RESULTS The study included 405 subjects. Younger age, male sex, lower baseline 6MWD, and disease etiology were associated with greater odds of achieving the MID for the 6-min walk test. Active treatment, younger age, and male sex were associated with greater odds of achieving the MID for the physical component summary score. Male sex was associated with greater odds of achieving the MID for the mental component summary score. CONCLUSIONS Age, sex, baseline functional capacity, and disease etiology are variably associated with the likelihood of achieving clinically relevant responses in patient-important outcomes to PAH-specific therapy such as 6MWD and HRQoL. The increased likelihood of response in men compared with women is a novel finding and may reflect pathophysiologic differences between sexes.
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Affiliation(s)
- Stephen C Mathai
- Division of Pulmonary and Critical Care Medicine (Drs Mathai, Hassoun, and Wise), Johns Hopkins University School of Medicine, Baltimore, MD
| | - Paul M Hassoun
- Division of Pulmonary and Critical Care Medicine (Drs Mathai, Hassoun, and Wise), Johns Hopkins University School of Medicine, Baltimore, MD.
| | - Milo A Puhan
- Division of Pulmonary and Critical Care Medicine (Drs Mathai, Hassoun, and Wise), Johns Hopkins University School of Medicine, Baltimore, MD
| | - Yi Zhou
- United Therapeutics Corporation, Research Triangle Park, NC
| | - Robert A Wise
- Institute of Social and Preventive Medicine, University of Zurich, Zurich, Switzerland; and United Therapeutics Corporation, Research Triangle Park, NC
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Blanco I, Mathai S, Shafiq M, Boyce D, M Kolb T, Chami H, K Hummers L, Housten T, Chaisson N, L Zaiman A, M Wigley F, J Tedford R, A Kass D, Damico R, E Girgis R, M Hassoun P. Severity of systemic sclerosis-associated pulmonary arterial hypertension in African Americans. Medicine (Baltimore) 2014; 93:177-185. [PMID: 25181310 PMCID: PMC4602454 DOI: 10.1097/md.0000000000000032] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
Abstract
African Americans (AA) with systemic sclerosis (SSc) have a worse prognosis compared to Americans of European descent (EA). We conducted the current study to test the hypothesis that AA patients with SSc have more severe disease and poorer outcomes compared to EA patients when afflicted with pulmonary arterial hypertension (PAH). We studied 160 consecutive SSc patients with PAH diagnosed by right heart catheterization, comparing demographics, hemodynamics, and outcomes between AA and EA patients. The cohort included 29 AA and 131 EA patients with similar baseline characteristics except for increased prevalence of diffuse SSc in AA. AA patients had worse functional class (FC) (80% FC III-IV vs 53%; p = 0.02), higher brain natriuretic peptide (NT-pro-BNP) (5729 ± 9730 pg/mL vs 1892 ± 2417 pg/mL; p = 0.02), more depressed right ventricular function, a trend toward lower 6-minute walk distance (263 ± 111 m vs 333 ± 110 m; p = 0.07), and worse hemodynamics (cardiac index 1.95 ± 0.58 L/min/m vs 2.62 ± 0.80 L/min/m; pulmonary vascular resistance 10.3 ± 6.2 WU vs 7.6 ± 5.0 WU; p < 0.05) compared with EA patients. Kaplan-Meier survival estimates for AA and EA patients, respectively, were 62% vs 73% at 2 years and 26% vs 44% at 5 years (p > 0.05). In conclusion, AA patients with SSc-PAH are more likely to have diffuse SSc and to present with significantly more severe PAH compared with EA patients. AA patients also appear to have poorer survival, though larger studies are needed to investigate this association definitively.
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MESH Headings
- Adult
- Black or African American
- Autoantibodies/blood
- Cardiac Catheterization/methods
- Echocardiography/methods
- Exercise Test/methods
- Familial Primary Pulmonary Hypertension
- Female
- Humans
- Hypertension, Pulmonary/blood
- Hypertension, Pulmonary/diagnosis
- Hypertension, Pulmonary/ethnology
- Hypertension, Pulmonary/etiology
- Hypertension, Pulmonary/physiopathology
- Kaplan-Meier Estimate
- Male
- Middle Aged
- Natriuretic Peptide, Brain/blood
- Outcome Assessment, Health Care
- Peptide Fragments/blood
- Prevalence
- Prognosis
- Scleroderma, Systemic/blood
- Scleroderma, Systemic/complications
- Scleroderma, Systemic/diagnosis
- Scleroderma, Systemic/ethnology
- Scleroderma, Systemic/physiopathology
- Severity of Illness Index
- United States/epidemiology
- Ventricular Dysfunction, Right/etiology
- Ventricular Dysfunction, Right/physiopathology
- White People
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Affiliation(s)
- Isabel Blanco
- Divisions of Pulmonary and Critical Care Medicine (IB, SCM, DB, TMK, HC, TH, NC, ALZ, RD, REG, PMH), General Internal Medicine (MS, FMW), Rheumatology (LKH), and Cardiology (RJT, DAK), Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) (IB), Barcelona, Spain; and Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES) (IB), Spain
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25
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Chaisson NF, Hassoun PM. Systemic sclerosis-associated pulmonary arterial hypertension. Chest 2014; 144:1346-1356. [PMID: 24081346 DOI: 10.1378/chest.12-2396] [Citation(s) in RCA: 112] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
Pulmonary arterial hypertension (PAH) is the leading cause of death in systemic sclerosis (SSc) and affects up to 12% of all patients with SSc, with a 50% mortality rate within 3 years of PAH diagnosis. Compared with the idiopathic form of PAH (IPAH), patients with SSc-associated PAH (SSc-PAH) have a threefold increased risk of death and may receive a diagnosis late in the course of disease because of insidious onset and the high prevalence of cardiac, musculoskeletal, and pulmonary parenchymal comorbidities. Treatment with conventional forms of PAH therapy often yield poor results compared with IPAH cohorts; unfortunately, the exact reasons behind this remain poorly understood but likely include variations in the pathologic mechanisms, differences in cardiovascular response to increasing afterload, and inadequate strategies to detect and treat SSc-PAH early in its course. Current methods for screening and longitudinal evaluation of SSc-PAH, such as the 6-min walk test, transthoracic echocardiography, and MRI, each have notable advantages and disadvantages. We provide an up-to-date, focused review of SSc-PAH and how it differs from IPAH, including pathogenesis, appropriate screening for disease onset, and new approaches to treatment and longitudinal assessment of this disease.
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Affiliation(s)
- Neal F Chaisson
- Division of Pulmonary and Critical Care, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Paul M Hassoun
- Division of Pulmonary and Critical Care, Johns Hopkins University School of Medicine, Baltimore, MD.
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26
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Mathew R. Pathogenesis of pulmonary hypertension: a case for caveolin-1 and cell membrane integrity. Am J Physiol Heart Circ Physiol 2013; 306:H15-25. [PMID: 24163076 DOI: 10.1152/ajpheart.00266.2013] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Pulmonary hypertension (PH) is a progressive disease with a high morbidity and mortality rate. Despite important advances in the field, the precise mechanisms leading to PH are not yet understood. Main features of PH are loss of vasodilatory response, the activation of proliferative and antiapoptotic pathways leading to pulmonary vascular remodeling and obstruction, elevated pressure and right ventricular hypertrophy, resulting in right ventricular failure and death. Experimental studies suggest that endothelial dysfunction may be the key underlying feature in PH. Caveolin-1, a major protein constituent of caveolae, interacts with several signaling molecules including the ones implicated in PH and modulates them. Disruption and progressive loss of endothelial caveolin-1 with reciprocal activation of proliferative pathways occur before the onset of PH, and the rescue of caveolin-1 inhibits proliferative pathways and attenuates PH. Extensive endothelial damage/loss occurs during the progression of the disease with subsequent enhanced expression of caveolin-1 in smooth muscle cells. This caveolin-1 in smooth muscle cells switches from being an antiproliferative factor to a proproliferative one and participates in cell proliferation and cell migration, possibly leading to irreversible PH. In contrast, the disruption of endothelial caveolin-1 is not observed in the hypoxia-induced PH, a reversible form of PH. However, proliferative pathways are activated in this model, indicating caveolin-1 dysfunction. Thus disruption or dysfunction of endothelial caveolin-1 leads to PH, and the status of caveolin-1 may determine the reversibility versus irreversibility of PH. This article reviews the role of caveolin-1 and cell membrane integrity in the pathogenesis and progression of PH.
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Affiliation(s)
- Rajamma Mathew
- Section of Pediatric Cardiology and Department of Physiology, Maria Fareri Children's Hospital/New York Medical College, Valhalla, New York
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27
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Vera-Lastra O, Porres-Aguilar M. Pulmonary arterial hypertension associated with systemic sclerosis: Current diagnostic approach and therapeutic strategies. World J Rheumatol 2012; 2:12-20. [DOI: 10.5499/wjr.v2.i2.12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Pulmonary arterial hypertension (PAH) represents a devastating vascular complication of systemic sclerosis (SSc) and is found in 10%-15% of cases carrying a severe prognosis. PAH has a dramatic impact on the clinical course and overall survival, being the single most common cause of death in patients with this entity. The clinical course and aggressive progression of PAH has led clinicians to perform annual screening for it, since early detection and diagnosis are the cornerstone of a prompt therapeutic intervention. The diagnosis of PAH can be challenging to clinicians, particularly in its early stages, since in the context of SSc, the multiple causes of dyspnea need to be assessed. Doppler echocardiography represents the best initial screening tool, however, right heart catheterization remains the gold standard and definitive diagnostic means. Remarkable advances have been achieved in elucidating the pathogenesis of PAH in the past two decades, leading to the development of disease-specific targeted therapies: prostacyclin analogues, endothelin receptor antagonists and inhibitors of five phosphodiesterase pathways. However, the clinical response to these therapies in SSc-associated PAH has not been as great as the one seen with idiopathic PAH. This review also focuses on the diagnosis and novel therapies that are currently available for PAH, as well as potential future therapeutic developments based on newly acquired knowledge of diverse pathogenic mechanisms.
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28
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29
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Robbins IM, Moore TM, Blaisdell CJ, Abman SH. National Heart, Lung, and Blood Institute Workshop: improving outcomes for pulmonary vascular disease. Circulation 2012; 125:2165-70. [PMID: 22388326 DOI: 10.1161/circulationaha.112.092924] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Ivan M Robbins
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
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30
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Robbins IM, Moore TM, Blaisdell CJ, Abman SH. Improving outcomes for pulmonary vascular disease. Am J Respir Crit Care Med 2012; 185:1015-20. [PMID: 22335936 DOI: 10.1164/rccm.201201-0049ws] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Recognizing the importance of improving lung health through lung disease research, the National Heart, Lung, and Blood Institute (NHLBI) convened a workshop of multidisciplinary experts for the following purpose: (1) to review the current scientific knowledge underlying the basis for treatment of adults and children with pulmonary vascular diseases (PVDs); (2) to identify gaps, barriers, and emerging scientific opportunities in translational PVD research and the means to capitalize on these opportunities; (3) to prioritize new research directions that would be expected to affect the clinical course of PVDs; and (4) to make recommendations to the NHLBI on how to fill identified gaps in adult and pediatric PVD clinical research. Workshop participants reviewed experiences from previous PVD clinical trials and ongoing clinical research networks with other lung disorders, including acute respiratory distress syndrome, chronic obstructive lung disease, and idiopathic pulmonary fibrosis, as well. Bioinformatics experts discussed strategies for applying cutting-edge health information technology to clinical studies. Participants in the workshop considered approaches in the following broad concept areas: (1) improved phenotyping to identify potential subjects for appropriate PVD clinical studies; (2) identification of potential new end points for assessing key outcomes and developing better-designed PVD clinical trials; and (3) the establishment of priorities for specific clinical research needed to advance care of patients with various subsets of PVDs from childhood through adulthood. This report provides a summary of the objectives and recommendations to the NHLBI concentrating on clinical research efforts that are needed to better diagnose and treat PVDs.
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Affiliation(s)
- Ivan M Robbins
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
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31
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Gomez-Arroyo J, Saleem SJ, Mizuno S, Syed AA, Bogaard HJ, Abbate A, Taraseviciene-Stewart L, Sung Y, Kraskauskas D, Farkas D, Conrad DH, Nicolls MR, Voelkel NF. A brief overview of mouse models of pulmonary arterial hypertension: problems and prospects. Am J Physiol Lung Cell Mol Physiol 2012; 302:L977-91. [PMID: 22307907 DOI: 10.1152/ajplung.00362.2011] [Citation(s) in RCA: 149] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Many chronic pulmonary diseases are associated with pulmonary hypertension (PH) and pulmonary vascular remodeling, which is a term that continues to be used to describe a wide spectrum of vascular abnormalities. Pulmonary vascular structural changes frequently increase pulmonary vascular resistance, causing PH and right heart failure. Although rat models had been standard models of PH research, in more recent years the availability of genetically engineered mice has made this species attractive for many investigators. Here we review a large amount of data derived from experimental PH reports published since 1996. These studies using wild-type and genetically designed mice illustrate the challenges and opportunities provided by these models. Hemodynamic measurements are difficult to obtain in mice, and right heart failure has not been investigated in mice. Anatomical, cellular, and genetic differences distinguish mice and rats, and pharmacogenomics may explain the degree of PH and the particular mode of pulmonary vascular adaptation and also the response of the right ventricle.
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Affiliation(s)
- Jose Gomez-Arroyo
- Victoria Johnson Center for Obstructive Lung Disease Research, Virginia Commonwealth University, 1220 E. Broad St., Richmond, VA 23298, USA
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32
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Affiliation(s)
- Yusuke Fukuda
- Department of Cardiology, Fukuoka University School of Medicine, Japan.
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Cantisani C, Mattozzi C, Giancristoforo S, D'Epiro S, Richetta AG. Bosentan treatment of digital ulcers related to autoimmune disorders. Drug Dev Res 2011. [DOI: 10.1002/ddr.20483] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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35
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Rubin LJ, Morrell NW. New frontiers in pulmonary hypertension. Expert Rev Respir Med 2011; 5:139-40. [DOI: 10.1586/ers.11.22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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