Publications by authors named "Rajan Saggar"

88 Publications

Brain Structural Changes in Patients with Pulmonary Arterial Hypertension.

J Neuroimaging 2021 Feb 9. Epub 2021 Feb 9.

Department of Anesthesiology, University of California Los Angeles, Los Angeles, CA.

Background And Purpose: Patients with pulmonary arterial hypertension (PAH) frequently present with anxiety, depression, autonomic, and cognitive deterioration, which may indicate brain changes in regions that control these functions. However, the precise regional brain-injury in sites that regulate cognitive, autonomic, and mood functions in PAH remains unclear. We examined the shifts in regional gray matter (GM) volume, using high-resolution T1-weighted images, and brain tissue alterations, using T2-relaxometry procedures, in PAH compared to healthy subjects.

Methods: We collected two high-resolution T1-weighted series, and proton-density and T2-weighted images using a 3.0-Tesla magnetic resonance imaging scanner from 9 PAH and 19 healthy subjects. Both high-resolution T1-weighted images were realigned and averaged, partitioned to GM tissue type, normalized to a common space, and smoothed. Using proton-density and T2-weighted images, T2-relaxation maps were calculated, normalized to a common space, and smoothed. Whole-brain GM volume and T2-relaxation maps were compared between PAH and controls using analysis of covariance (covariates, age, sex, and total-brain-volume; false discover rate corrections).

Results: Significantly decreased GM volumes, indicating tissue injury, emerged in multiple brain regions, including the hippocampus, insula, cerebellum, parahippocampus, temporal, frontal, and occipital gyri, cingulate, amygdala, and thalamus. Higher T2-relaxation values, suggesting tissue damage, appeared in the cerebellum, hippocampus, parahippocampus, frontal, lingual, and temporal and occipital gyri, and cingulate areas in PAH compared to healthy subjects.

Conclusions: PAH patients showed significant GM injury and brain tissue changes in sites that regulate cognition, autonomic, and mood functions. These findings indicate a brain structural basis for functional deficits in PAH patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jon.12840DOI Listing
February 2021

Long-Term Outcomes in Patients With Connective Tissue Disease-Associated Pulmonary Arterial Hypertension in the Modern Treatment Era: Meta-Analyses of Randomized, Controlled Trials and Observational Registries.

Arthritis Rheumatol 2021 Feb 3. Epub 2021 Feb 3.

University of Michigan, Ann Arbor.

Objective: Data on the magnitude of benefit of modern therapies for pulmonary arterial hypertension (PAH) in connective tissue disease (CTD)-associated PAH are limited. In this study, we performed meta-analyses of randomized, controlled trials (RCTs) and registries to quantify the benefit of these modern therapies in patients with CTD-PAH.

Methods: The PubMed and Embase databases were searched for articles reporting data from RCTs or registries published between January 1, 2000 and November 25, 2019. Eligibility criteria included multicenter studies with ≥30 CTD-PAH patients. For an RCT to be included, the trial had to evaluate an approved PAH therapy, and long-term risks of clinical morbidity and mortality or 6-minute walk distance had to be reported. For a registry to be included, survival rates had to be reported. Random-effects models were used to pool the data.

Results: Eleven RCTs (total of 4,329 patients; 1,267 with CTD-PAH) and 19 registries (total of 9,739 patients; 4,008 with CTD-PAH) were included. Investigational therapy resulted in a 36% reduction in the risk of clinical morbidity/mortality events both in the overall PAH population (hazard ratio [HR] 0.64, 95% confidence interval [95% CI] 0.54, 0.75; P < 0.001) and in CTD-PAH patients (HR 0.64, 95% CI 0.51, 0.81; P < 0.001) as compared to control subjects. The survival rate was lower in CTD-PAH patients compared to all PAH patients (survival rate 62%, 95% CI 57, 67% versus 72%, 95% CI 69, 75% at 3 years). The survival rate in CTD-PAH patients treated primarily after 2010 was higher than that in CTD-PAH patients treated before 2010 (survival rate 73%, 95% CI 62, 81% versus 65%, 95% CI 59, 71% at 3 years).

Conclusion: Modern therapy provides a similar reduction in morbidity/mortality risk in patients with CTD-PAH when compared to the PAH population overall. Risk of death is higher in CTD-PAH patients than in those with PAH overall, but survival has improved in the last 10 years, which may be related to increased screening and/or new treatment approaches. Early detection of PAH in patients with CTD and up-front intensive treatment are warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/art.41669DOI Listing
February 2021

A multicentric quality-control study of exercise Doppler echocardiography of the right heart and the pulmonary circulation. The RIGHT Heart International NETwork (RIGHT-NET).

Cardiovasc Ultrasound 2021 Jan 20;19(1). Epub 2021 Jan 20.

Cardiology Division, A Cardarelli Hospital, Naples, Italy.

Purpose: This study was a quality-control study of resting and exercise Doppler echocardiography (EDE) variables measured by 19 echocardiography laboratories with proven experience participating in the RIGHT Heart International NETwork.

Methods: All participating investigators reported the requested variables from ten randomly selected exercise stress tests. Intraclass correlation coefficients (ICC) were calculated to evaluate the inter-observer agreement with the core laboratory. Inter-observer variability of resting and peak exercise tricuspid regurgitation velocity (TRV), right ventricular outflow tract acceleration time (RVOT Act), tricuspid annular plane systolic excursion (TAPSE), tissue Doppler tricuspid lateral annular systolic velocity (S'), right ventricular fractional area change (RV FAC), left ventricular outflow tract velocity time integral (LVOT VTI), mitral inflow pulsed wave Doppler velocity (E), diastolic mitral annular velocity by TDI (e') and left ventricular ejection fraction (LVEF) were measured.

Results: The accuracy of 19 investigators for all variables ranged from 99.7 to 100%. ICC was > 0.90 for all observers. Inter-observer variability for resting and exercise variables was for TRV = 3.8 to 2.4%, E = 5.7 to 8.3%, e' = 6 to 6.5%, RVOT Act = 9.7 to 12, LVOT VTI = 7.4 to 9.6%, S' = 2.9 to 2.9% and TAPSE = 5.3 to 8%. Moderate inter-observer variability was found for resting and peak exercise RV FAC (15 to 16%). LVEF revealed lower resting and peak exercise variability of 7.6 and 9%.

Conclusions: When performed in expert centers EDE is a reproducible tool for the assessment of the right heart and the pulmonary circulation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12947-021-00238-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819251PMC
January 2021

Left main coronary artery compression in pulmonary hypertension.

Catheter Cardiovasc Interv 2020 Nov 25. Epub 2020 Nov 25.

Division of Cardiology, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, California, USA.

Extrinsic compression of the left main coronary artery (LMCA) by a dilated pulmonary artery (PA) in the setting of pulmonary arterial hypertension (PAH) is an increasingly recognized disease entity. LMCA compression has been associated with angina, arrhythmia, heart failure, and sudden cardiac death in patients with PAH. Recent studies suggest that at least 6% of patients with PAH have significant LMCA compression. Screening for LMCA compression can be achieved with computed coronary tomography angiography, with a particular emphasis on assessment of PA size and any associated downward displacement and reduced takeoff angle of the LMCA. Indeed, evidence of a dilated PA (>40 mm), a reduced LMCA takeoff angle (<60°), and/or LMCA stenosis on CCTA imaging should prompt further diagnostic evaluation. Coronary angiography in conjunction with intravascular imaging has proven effective in diagnosing LMCA compression and guiding subsequent treatment. While optimal medical therapy and surgical correction remain in the clinician's arsenal, percutaneous coronary intervention has emerged as an effective treatment for LMCA compression. Given the prevalence of LMCA compression, its associated morbidity, and mortality, and the wide array of successful treatment strategies, maintaining a high degree of suspicion for this condition, and understanding the potential treatment strategies is critical.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ccd.29401DOI Listing
November 2020

Occult Colonic Perforation in a Patient With Coronavirus Disease 2019 After Interleukin-6 Receptor Antagonist Therapy.

Open Forum Infect Dis 2020 Nov 12;7(11):ofaa424. Epub 2020 Sep 12.

Division of Pulmonary and Critical Care, Department of Medicine at University of California, Los Angeles, California, USA.

Background: Interleukin-6 blockade (IL-6) has become a focus of therapeutic investigation for the coronavirus disease 2019 (COVID-19).

Methods: We report a case of a 34-year-old with COVID-19 pneumonia receiving an IL-6 receptor antagonist (IL-6Ra) who developed spontaneous colonic perforation. This perforation occurred despite a benign abdominal exam and in the absence of other known risk factors associated with colonic perforation.

Results: Examination of the colon by electron microscopy revealed numerous intact severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virions abutting the microvilli of the colonic mucosa. Multiplex immunofluorescent staining revealed the presence of the SARS-CoV-2 spike protein on the brush borders of colonic enterocytes that expressed angiotensin-converting enzyme 2. However, no viral particles were observed within the enterocytes to suggest direct viral injury as the cause of colonic perforation.

Conclusions: These data and absence of known risk factors for spontaneous colonic perforation implicate IL-6Ra therapy as the potential mediator of colonic injury in this case. Furthermore, this report provides the first in situ visual evidence of the virus in the colon of a patient presenting with colonic perforation adding to growing evidence that intact infectious virus can be present in the stool.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ofid/ofaa424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543619PMC
November 2020

Single-cell Study of Two Rat Models of Pulmonary Arterial Hypertension Reveals Connections to Human Pathobiology and Drug Repositioning.

Am J Respir Crit Care Med 2020 Oct 6. Epub 2020 Oct 6.

UCLA, 8783, Los Angeles, California, United States.

Rationale: The cellular and molecular landscape and translational value of commonly used models of pulmonary arterial hypertension (PAH) are poorly understood. Single-cell transcriptomics can enhance molecular understanding of preclinical models and facilitate their rational use and interpretation.

Objectives: We aim to determine and prioritize dysregulated genes, pathways, and cell types in lungs of PAH rat models to assess relevance to human PAH and identify drug repositioning candidates.

Methods: Single-cell RNA-seq was performed on the lungs of monocrotaline, Sugen-hypoxia, and control rats to identify altered genes and cell types, followed by validation using flow-sorted cells, RNA in situ hybridization, and immunofluorescence. Relevance to human PAH was assessed by histology of lungs from patients and via integration with human PAH genetic loci and known disease genes. Candidate drugs were predicted using Connectivity Map.

Measurements And Main Results: Distinct changes in genes and pathways in numerous cell types were identified in Sugen-hypoxia and monocrotaline lungs. Widespread upregulation of NF-κB signaling and downregulation of interferon signaling was observed across cell types. Sugen-hypoxia non-classical monocytes and monocrotaline conventional dendritic cells showed particularly strong NF-κB pathway activation. Genes altered in Sugen-hypoxia non-classical monocytes were significantly enriched for PAH-associated genes and genetic variants, and candidate drugs predicted to reverse the changes were identified. An open-access online platform was developed to share single-cell data and drug candidates (http://mergeomics.

Research: idre.ucla.edu/PVDSingleCell/).

Conclusions: Our study revealed the distinct and shared dysregulation of genes and pathways in two commonly used PAH models for the first time at single-cell resolution and demonstrated their relevance to human PAH and utility for drug repositioning.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1164/rccm.202006-2169OCDOI Listing
October 2020

Weight loss for critical care patient to improve lung transplantation candidacy: A case report.

Respir Med Case Rep 2020 18;31:101193. Epub 2020 Aug 18.

Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.

A 47-year-old male with morbid obesity and progressive pulmonary fibrosis was admitted to the intensive care unit (ICU) with worsening hypoxia and nocturnal ventilator dependence. Due to a significant oxygen requirement, the patient could only safely remain in an acute care setting. Unfortunately, he was not eligible for lung transplantation due to having obesity, a relative contraindication to lung transplantation due to potential for post transplantation complications and increased mortality. Therefore, we treated the patient with a modified very low calorie diet (MVLCD) to achieve weight loss. He had successful, sustained weight loss over a period of seven weeks and reached a target weight that made him eligible for transplantation. He subsequently underwent successful bilateral lung transplantation. The patient had improved metabolic parameters and no side effects attributable to the reduced calorie diet. This report shows that in patients with end stage lung disease and a poor prognosis without transplantation, inpatient weight loss is safe and may allow for potentially lifesaving lung transplantation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.rmcr.2020.101193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7451811PMC
August 2020

Radiographic and Histopathologic Features in Sarcoidosis: A Pictorial Display.

Semin Respir Crit Care Med 2020 Oct 10;41(5):758-784. Epub 2020 Aug 10.

Division of Pulmonary, Critical Care Medicine, Allergy, and Clinical Immunology, David Geffen School of Medicine at UCLA, Los Angeles, California.

Sarcoidosis is a multisystemic granulomatous disorder that can affect virtually any organ. However, pulmonary and thoracic lymph node involvement predominates; abnormalities on chest radiographs are present in 80 to 90% of patients with sarcoidosis. High-resolution computed tomographic (HRCT) scans are superior to chest X-rays in assessing extent of disease, and some CT features may discriminate an active inflammatory component (which may be amenable to therapy) from fibrosis (for which therapy is not indicated). Typical findings on HRCT include micronodules, perilymphatic and bronchocentric distribution, perihilar opacities, and varying degrees of fibrosis. Less common findings on CT include mass-like or alveolar opacities, miliary opacities, mosaic attenuation, honeycomb cysts, and cavitation. With progressive disease, fibrosis, architectural distortion, upper lobe volume loss with hilar retraction, coarse linear bands, cysts, and bullae may be observed. We discuss the salient CT findings in patients with sarcoidosis (with a major focus on pulmonary features) and present classical radiographic and histopathological images of a few extrapulmonary sites.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0040-1712534DOI Listing
October 2020

Rebuttal From Drs Channick and Saggar.

Chest 2019 12;156(6):1047-1048

David Geffen School of Medicine at UCLA, Los Angeles, CA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.chest.2019.07.006DOI Listing
December 2019

COUNTERPOINT: Should Initial Combination Therapy Be the Standard of Care in Pulmonary Arterial Hypertension? No.

Chest 2019 12;156(6):1043-1045

David Geffen School of Medicine at UCLA, Los Angeles, CA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.chest.2019.07.004DOI Listing
December 2019

Capillary Proliferation in Systemic-Sclerosis-Related Pulmonary Fibrosis: Association with Pulmonary Hypertension.

ACR Open Rheumatol 2019 Mar 15;1(1):26-36. Epub 2019 Mar 15.

University of California Los Angeles.

Objective: We sought to determine if any histopathologic component of the pulmonary microcirculation can distinguish systemic sclerosis (SSc)-related pulmonary fibrosis (PF) with and without pulmonary hypertension (PH).

Methods: Two pulmonary pathologists blindly evaluated 360 histologic slides from lungs of 31 SSc-PF explants or autopsies with (n = 22) and without (n = 9) PH. The presence of abnormal small arteries, veins, and capillaries (pulmonary microcirculation) was semiquantitatively assessed in areas of preserved lung architecture. Capillary proliferation (CP) within the alveolar walls was measured by its distribution, extent (CP % involvement), and maximum number of layers (maximum CP). These measures were then evaluated to determine the strength of their association with right heart catheterization-proven PH.

Results: Using consensus measures, all measures of CP were significantly associated with PH. Maximum CP had the strongest association with PH ( = 0.013; C statistic 0.869). Maximum CP 2 or more layers and CP % involvement 10% or greater were the optimal thresholds that predicted PH, both with a sensitivity of 56% and specificity of 91%. The CP was typically multifocal rather than focal or diffuse and was associated with a background pattern of usual interstitial pneumonia. There was a significant but weaker relationship between the presence of abnormal small arteries and veins and PH.

Conclusion: In the setting of advanced SSc-PF, the histopathologic feature of the pulmonary microcirculation best associated with PH was capillary proliferation in architecturally preserved lung areas.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/acr2.1003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858021PMC
March 2019

Endotype-phenotyping may predict a treatment response in progressive fibrosing interstitial lung disease.

EBioMedicine 2019 Dec 12;50:379-386. Epub 2019 Nov 12.

Department of Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Los Angeles, CA 90095, USA. Electronic address:

Background: Some interstitial lung disease (ILD) patients develop a progressive fibrosing-ILD phenotype (PF-ILD), with similar persistent lung function decline suggesting common molecular pathways involved. Nintedanib, a tyrosine kinase inhibitor targeting the PDGF, FGF, VEGF and M-CSF pathways, has shown comparable efficacy in idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-associated ILD (SSc-ILD). We hypothesize that Nintedanib targeted molecular pathways will be augmented to a similar degree across PF-ILD regardless of aetiology.

Methods: We collected explanted lung tissue at the time of lung transplantation from 130 PF-ILD patients (99 (76%) IPF, 14 (11%) SSc-ILD, 17 (13%) other PF-ILD), and wedge biopsies from 200 donor lungs and measured PDGF, FGF, VEGF and M-CSF concentrations by Luminex.

Findings: The concentrations of PDGF-AA, PDGF-BB, FGF-2, VEGF and M-CSF were significantly increased in PF-ILD lungs compared to donor lungs (PDGF-AA 93·0 pg/ml [±97·2] vs. 37·5 pg/ml [±35·4], p < 0·001; PDGF-BB 102·5 pg/ml [±78·8] vs. 61·9 pg/ml [±47·0], p < 0·001; FGF-2 1442·4 pg/ml [±426·6] vs. 1201·7 pg/ml [±535·2], p = 0·009; VEGF 40·6 pg/ml [±20·1] vs. 24·9 pg/ml [±29·5], p < 0·001; and M-CSF 25526 pg/ml [±24,799] vs. 6120 pg/ml [±7245], p < 0·001). There were no significant differences in these growth factor/angiogenic molecules/cytokine concentrations when segregated by IPF, SSc-ILD and other PF-ILDs.

Interpretation: Nintedanib specific targeted molecular pathways are augmented to a similar magnitude in all PF-ILD lung tissue as compared to controls, suggesting that Nintedanib treatment may be efficacious in PF-ILD regardless of aetiology. We speculate that clinical trials using Nintedanib for PF-ILD with or without IPF or SSc-ILD should show a similar relative reduction in FVC decline as seen in IPF and SSc-ILD (∼45-50%).

Funding: Health Grant P01-HL108793 (JAB), South-Eastern Norway Regional Health Authority Grant 2018072 (AMHV).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ebiom.2019.10.050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6921223PMC
December 2019

Mitochondrial DNA Stimulates TLR9-Dependent Neutrophil Extracellular Trap Formation in Primary Graft Dysfunction.

Am J Respir Cell Mol Biol 2020 03;62(3):364-372

Department of Medicine.

The immune system is designed to robustly respond to pathogenic stimuli but to be tolerant to endogenous ligands to not trigger autoimmunity. Here, we studied an endogenous damage-associated molecular pattern, mitochondrial DNA (mtDNA), during primary graft dysfunction (PGD) after lung transplantation. We hypothesized that cell-free mtDNA released during lung ischemia-reperfusion triggers neutrophil extracellular trap (NET) formation via TLR9 signaling. We found that mtDNA increases in the BAL fluid of experimental PGD (prolonged cold ischemia followed by orthotopic lung transplantation) and not in control transplants with minimal warm ischemia. The adoptive transfer of mtDNA into the minimal warm ischemia graft immediately before lung anastomosis induces NET formation and lung injury. TLR9 deficiency in neutrophils prevents mtDNA-induced NETs, and TLR9 deficiency in either the lung donor or recipient decreases NET formation and lung injury in the PGD model. Compared with human lung transplant recipients without PGD, severe PGD was associated with high levels of BAL mtDNA and NETs, with evidence of relative deficiency in DNaseI. We conclude that mtDNA released during lung ischemia-reperfusion triggers TLR9-dependent NET formation and drives lung injury. In PGD, DNaseI therapy has a potential dual benefit of neutralizing a major NET trigger (mtDNA) in addition to dismantling pathogenic NETs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1165/rcmb.2019-0140OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055700PMC
March 2020

Histological hallmarks and role of Slug/PIP axis in pulmonary hypertension secondary to pulmonary fibrosis.

EMBO Mol Med 2019 09 29;11(9):e10061. Epub 2019 Aug 29.

Division of Molecular Medicine, Department of Anesthesiology & Perioperative Medicine, UCLA, Los Angeles, CA, USA.

Pulmonary hypertension secondary to pulmonary fibrosis (PF-PH) is one of the most common causes of PH, and there is no approved therapy. The molecular signature of PF-PH and underlying mechanism of why pulmonary hypertension (PH) develops in PF patients remains understudied and poorly understood. We observed significantly increased vascular wall thickness in both fibrotic and non-fibrotic areas of PF-PH patient lungs compared to PF patients. The increased vascular wall thickness in PF-PH patients is concomitant with a significantly increased expression of the transcription factor Slug within the macrophages and its target prolactin-induced protein (PIP), an extracellular matrix protein that induces pulmonary arterial smooth muscle cell proliferation. We developed a novel translational rat model of combined PF-PH that is reproducible and shares similar histological features (fibrosis, pulmonary vascular remodeling) and molecular features (Slug and PIP upregulation) with human PF-PH. We found Slug inhibition decreases PH severity in our animal model of PF-PH. Our study highlights the role of Slug/PIP axis in PF-PH.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.15252/emmm.201810061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6728601PMC
September 2019

Pulmonary tumor thrombotic microangiopathy: a systematic review.

Pulm Circ 2019 Apr-Jun;9(2):2045894019851000

3 Division of Pulmonary and Critical Care Medicine, Olive View - UCLA Medical Center, Los Angeles, CA, USA.

Pulmonary tumor thrombotic microangiopathy (PTTM) is a fatal disease process in which pulmonary hypertension (PH) develops in the setting of malignancy. The purpose of this study is to present a detailed analysis of cases of PTTM reported in literature in the hopes of achieving more ante-mortem diagnoses. We conducted a systematic review of currently published and available cases of PTTM by searching the term "pulmonary tumor thrombotic microangiopathy" on the Pubmed.gov database. Seventy-nine publications were included consisting of 160 unique cases of PTTM. The most commonly reported malignancy was gastric adenocarcinoma (94 cases, 59%). Cough and dyspnea were reported in 61 (85%) and 102 (94%) cases, respectively. Hypoxemia was reported in 96 cases (95%). Elevation in D-dimer was noted in 36 cases (95%), presence of anemia in 32 cases (84%), and thrombocytopenia in 30 cases (77%). Common findings on chest computed tomography (CT) included ground-glass opacities (GGO) in 28 cases (82%) and nodules in 24 cases (86%). PH on echocardiography was noted in 59 cases (89%) with an average right ventricular systolic pressure of 71 mmHg. Common features of PTTM that are reported across the published literature include presence of dyspnea and cough, hypoxemia, with abnormal CT findings of GGO, nodules, and mediastinal/hilar lymphadenopathy, and PH. PTTM is a universally fatal disease process and this analysis provides a detailed examination of all the available published data that may help clinicians establish an earlier diagnosis of PTTM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/2045894019851000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6540517PMC
April 2019

Critical Care of Patients After Pulmonary Thromboendarterectomy.

J Cardiothorac Vasc Anesth 2019 Nov 8;33(11):3110-3126. Epub 2019 Mar 8.

Department of Internal Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA.

Pulmonary thromboendarterectomy (PTE) remains the only curative surgery for patients with chronic thromboembolic pulmonary hypertension (CTEPH). Postoperative intensive care unit care challenges providers with unique disease physiology, operative sequelae, and the potential for detrimental complications. Central concerns in patients with CTEPH immediately after PTE relate to neurologic, pulmonary, hemodynamic, and hematologic aspects. Institutional experience in critical care for the CTEPH population, a multidisciplinary team approach, patient risk assessment, and integration of current concepts in critical care determine outcomes after PTE surgery. In this review, the authors will focus on specific aspects unique to this population, with integration of current available evidence and future directions. The goal of this review is to provide the cardiac anesthesiologist and intensivist with a comprehensive understanding of postoperative physiology, potential complications, and contemporary intensive care unit management immediately after pulmonary endarterectomy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.jvca.2019.03.005DOI Listing
November 2019

BOLA (BolA Family Member 3) Deficiency Controls Endothelial Metabolism and Glycine Homeostasis in Pulmonary Hypertension.

Circulation 2019 05;139(19):2238-2255

Center for Pulmonary Vascular Biology and Medicine, Center for Metabolism and Mitochondrial Medicine, Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology and Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, PA (Q.Y., Y.-Y.T., Y.T., J.Z., V.N., M.K.C., J.P., W.S., J.S., M.R., M.S., N.K., T.S., M.Z., N.F., S.S., S.Y.C.).

Background: Deficiencies of iron-sulfur (Fe-S) clusters, metal complexes that control redox state and mitochondrial metabolism, have been linked to pulmonary hypertension (PH), a deadly vascular disease with poorly defined molecular origins. BOLA3 (BolA Family Member 3) regulates Fe-S biogenesis, and mutations in BOLA3 result in multiple mitochondrial dysfunction syndrome, a fatal disorder associated with PH. The mechanistic role of BOLA3 in PH remains undefined.

Methods: In vitro assessment of BOLA3 regulation and gain- and loss-of-function assays were performed in human pulmonary artery endothelial cells using siRNA and lentiviral vectors expressing the mitochondrial isoform of BOLA3. Polymeric nanoparticle 7C1 was used for lung endothelium-specific delivery of BOLA3 siRNA oligonucleotides in mice. Overexpression of pulmonary vascular BOLA3 was performed by orotracheal transgene delivery of adeno-associated virus in mouse models of PH.

Results: In cultured hypoxic pulmonary artery endothelial cells, lung from human patients with Group 1 and 3 PH, and multiple rodent models of PH, endothelial BOLA3 expression was downregulated, which involved hypoxia inducible factor-2α-dependent transcriptional repression via histone deacetylase 1-mediated histone deacetylation. In vitro gain- and loss-of-function studies demonstrated that BOLA3 regulated Fe-S integrity, thus modulating lipoate-containing 2-oxoacid dehydrogenases with consequent control over glycolysis and mitochondrial respiration. In contexts of siRNA knockdown and naturally occurring human genetic mutation, cellular BOLA3 deficiency downregulated the glycine cleavage system protein H, thus bolstering intracellular glycine content. In the setting of these alterations of oxidative metabolism and glycine levels, BOLA3 deficiency increased endothelial proliferation, survival, and vasoconstriction while decreasing angiogenic potential. In vivo, pharmacological knockdown of endothelial BOLA3 and targeted overexpression of BOLA3 in mice demonstrated that BOLA3 deficiency promotes histological and hemodynamic manifestations of PH. Notably, the therapeutic effects of BOLA3 expression were reversed by exogenous glycine supplementation.

Conclusions: BOLA3 acts as a crucial lynchpin connecting Fe-S-dependent oxidative respiration and glycine homeostasis with endothelial metabolic reprogramming critical to PH pathogenesis. These results provide a molecular explanation for the clinical associations linking PH with hyperglycinemic syndromes and mitochondrial disorders. These findings also identify novel metabolic targets, including those involved in epigenetics, Fe-S biogenesis, and glycine biology, for diagnostic and therapeutic development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCULATIONAHA.118.035889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6519484PMC
May 2019

Right Ventricular Functional Reserve in Early-Stage Idiopathic Pulmonary Fibrosis: An Exercise Two-Dimensional Speckle Tracking Doppler Echocardiography Study.

Chest 2019 02 10;155(2):297-306. Epub 2018 Dec 10.

Division of Cardiology, Heart Department, 'Cava de' Tirreni and Amalfi Coast' Hospital, University Hospital, Salerno, Italy.

Background: The most important determinant of long-term survival in patients with idiopathic pulmonary fibrosis is the right ventricular (RV) adaptation to the increased pulmonary vascular resistance. Our aim was to explore RV contractile reserve during stress echocardiography in early-stage IPF.

Methods: Fifty early-stage patients with IPF and 50 healthy control patients underwent rest and stress echocardiography, including RV two-dimensional speckle tracking echocardiography. At peak exertion, blood gas analysis and spirometry were also assessed.

Results: At rest, RV diameters were mildly increased in IPF; however, although RV conventional systolic function indexes were similar between the IPF and control groups, RV global longitudinal strain and RV lateral wall longitudinal strain (LWLS) were significantly reduced in the IPF cohort. During physical exercise, patients with IPF showed a reduced exercise tolerance with lower maximal workload (P < .01), level of oxygen saturation (P < .001), and peak heart rate (P < .01). Systolic and diastolic BP values were similar in both groups. Systolic pulmonary artery pressure (PAPs) increase (ΔPAPs) during exertion was higher in IPF vs healthy subjects (P < .0001); RV LWLS increase (ΔRV LWLS) during exercise was lower in patients with IPF vs control patients (P < .00001). By multivariable analysis, RV LWLS at rest and ΔRV LWLS were directly related to peak exertion capacity, PAPs, and blood oxygen saturation level (Spo; P < .0001). Δ RV LWLS was directly related to diffusion lung carbon monoxide (P < .0001).

Conclusions: RV myocardial dysfunction is already present at rest in early-stage IPF and worsens during exertion as detected by two-dimensional speckle-tracking echocardiography. The RV altered contractile reserve appears to be related to reduced exercise tolerability and impaired pulmonary hemodynamic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.chest.2018.11.015DOI Listing
February 2019

Augmented concentrations of CX3CL1 are associated with interstitial lung disease in systemic sclerosis.

PLoS One 2018 20;13(11):e0206545. Epub 2018 Nov 20.

Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.

Background: Dysregulation of Fractalkine (CX3CL1) and its receptor CX3CR1 has been linked to the pathobiology of chronic inflammatory conditions. We explored CX3CL1 in systemic sclerosis (SSc) related progressive interstitial lung disease (ILD) and pulmonary hypertension (PH) in two different but complementary sources of biomaterial.

Methods: We collected lung tissue at the time of lung transplantation at UCLA from SSc-ILD patients (n = 12) and healthy donors (n = 12); and serum samples from the prospective Oslo University Hospital SSc cohort (n = 292) and healthy donors (n = 100). CX3CL1 was measured by ELISA. Cellular sources of CX3CL1/CX3CR1 in lung tissues were determined by immunohistochemistry and immunofluorescence. ILD progression and new onset PH endpoints were analysed.

Results: CX3CL1 concentrations were increased in SSc in lung tissue as well as in sera. In the UCLA cohort, CX3CL1 was highly correlated with DLCO. In the SSc-ILD lungs, CX3CL1 was identified in reactive type II pneumocytes and airway epithelial cells. CX3CR1 stained infiltrating interstitial mononuclear cells, especially plasma cells. In the Oslo cohort, CX3CL1 correlated with anti-Topoisomerase-I-antibody and lung fibrosis. CX3CL1 was associated with ILD progression in multivariable regression analysis but not PH.

Conclusion: CX3CL1 is associated with progressive SSc-ILD but not SSc-PH. The CX3CR1/CX3CL1-biological axis may be involved in recruiting antibody secreting plasma cells to SSc lungs, thereby contributing to the immune-mediated pathobiology of SSc-ILD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0206545PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6245508PMC
April 2019

The Right Heart International Network (RIGHT-NET): Rationale, Objectives, Methodology, and Clinical Implications.

Heart Fail Clin 2018 Jul;14(3):443-465

Cardiology Division, Heart Department, "Cava de' Tirreni and Amalfi Coast" Hospital, University of Salerno, Salerno, Italy. Electronic address:

The Right Heart International Network is a multicenter international study aiming to prospectively collect exercise Doppler echocardiography tests of the right heart pulmonary circulation unit (RHPCU) in large cohorts of healthy subjects, elite athletes, and individuals at risk of or with overt pulmonary hypertension. It is going to provide standardization of exercise stress echocardiography of RHPCU and explore the full physiopathologic response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.hfc.2018.03.010DOI Listing
July 2018

Pulmonary Hypertension Related to Chronic Obstructive Pulmonary Disease and Diffuse Parenchymal Lung Disease: A Focus on Right Ventricular (Dys)Function.

Heart Fail Clin 2018 Jul;14(3):403-411

Pulmonary and Critical Care Medicine, University of California, Los Angeles, David Geffen School of Medicine, 10833 Le Conte Avenue, Room 37-131 CHS, Box 951690, Los Angeles, CA 90095, USA. Electronic address:

Diffuse pulmonary lung disease and chronic obstructive pulmonary disease is a heterogeneous population that can manifest pulmonary hypertension. These subgroups are classified as primarily World Health Organization group 3. Available data suggest that the impact of pulmonary hypertension targeted therapy in diffuse pulmonary lung disease and chronic obstructive pulmonary disease is limited and survival is poor despite attempted treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.hfc.2018.03.006DOI Listing
July 2018

Pulmonary Hypertension: The Role of Lung Transplantation.

Heart Fail Clin 2018 Jul;14(3):327-331

Lung Institute, University of Arizona, Banner University Medical Center, 755 E. McDowell Road, 3rd Floor, Phoenix, AZ 85006, USA. Electronic address:

Despite advances in targeted medical therapy, pulmonary arterial hypertension (PAH) remains a fatal disease because of progressive right ventricular dysfunction. For patients who are refractory to medical therapy, heart-lung and lung transplantation are important treatment options. Because of longer waiting time, surgical interventions including extracorporeal lung support and atrial septostomy can be used in PAH patients bridging to transplantation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.hfc.2018.02.007DOI Listing
July 2018

pDCs in lung and skin fibrosis in a bleomycin-induced model and patients with systemic sclerosis.

JCI Insight 2018 05 3;3(9). Epub 2018 May 3.

Autoimmunity and Tolerance Laboratory.

Fibrosis is the end result of most inflammatory conditions, but its pathogenesis remains unclear. We demonstrate that, in animals and humans with systemic fibrosis, plasmacytoid DCs (pDCs) are unaffected or are reduced systemically (spleen/peripheral blood), but they increase in the affected organs (lungs/skin/bronchoalveolar lavage). A pivotal role of pDCs was shown by depleting them in vivo, which ameliorated skin and/or lung fibrosis, reduced immune cell infiltration in the affected organs but not in spleen, and reduced the expression of genes and proteins implicated in chemotaxis, inflammation, and fibrosis in the affected organs of animals with bleomycin-induced fibrosis. As with animal findings, the frequency of pDCs in the lungs of patients with systemic sclerosis correlated with the severity of lung disease and with the frequency of CD4+ and IL-4+ T cells in the lung. Finally, treatment with imatinib that has been reported to reduce and/or prevent deterioration of skin and lung fibrosis profoundly reduced pDCs in lungs but not in peripheral blood of patients with systemic sclerosis. These observations suggest a role for pDCs in the pathogenesis of systemic fibrosis and identify the increased trafficking of pDCs to the affected organs as a potential therapeutic target in fibrotic diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/jci.insight.98380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6012518PMC
May 2018

Stressing the Cardiopulmonary Vascular System: The Role of Echocardiography.

J Am Soc Echocardiogr 2018 05 21;31(5):527-550.e11. Epub 2018 Mar 21.

Heart Department, University Hospital, Salerno, Italy. Electronic address:

The cardiopulmonary vascular system represents a key determinant of prognosis in several cardiorespiratory diseases. Although right heart catheterization is considered the gold standard for assessing pulmonary hemodynamics, a comprehensive noninvasive evaluation including left and right ventricular reserve and function and cardiopulmonary interactions remains highly attractive. Stress echocardiography is crucial in the evaluation of many cardiac conditions, typically coronary artery disease but also heart failure and valvular heart disease. In stress echocardiographic applications beyond coronary artery disease, the assessment of the cardiopulmonary vascular system is a cornerstone. The possibility of coupling the left and right ventricles with the pulmonary circuit during stress can provide significant insight into cardiopulmonary physiology in healthy and diseased subjects, can support the diagnosis of the etiology of pulmonary hypertension and other conditions, and can offer valuable prognostic information. In this state-of-the-art document, the topic of stress echocardiography applied to the cardiopulmonary vascular system is thoroughly addressed, from pathophysiology to different stress modalities and echocardiographic parameters, from clinical applications to limitations and future directions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.echo.2018.01.002DOI Listing
May 2018

Pulmonary Allograft Versus Host Disease.

Transplant Direct 2017 Dec 20;3(12):e333. Epub 2017 Nov 20.

Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/TXD.0000000000000749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5828692PMC
December 2017

Exercise-Induced Pulmonary Hypertension: Translating Pathophysiological Concepts Into Clinical Practice.

Chest 2018 07 31;154(1):10-15. Epub 2018 Jan 31.

'Cava de' Tirreni and Amalfi Coast' Hospital, Division of Cardiology, Heart Department, University Hospital, Salerno, Italy. Electronic address:

Exercise stress testing of the pulmonary circulation for the diagnosis of latent or early-stage pulmonary hypertension (PH) is gaining acceptance. There is emerging consensus to define exercise-induced PH by a mean pulmonary artery pressure > 30 mm Hg at a cardiac output < 10 L/min and a total pulmonary vascular resistance> 3 Wood units at maximum exercise, in the absence of PH at rest. Exercise-induced PH has been reported in association with a bone morphogenetic receptor-2 gene mutation, in systemic sclerosis, in left heart conditions, in chronic lung diseases, and in chronic pulmonary thromboembolism. Exercise-induced PH is a cause of decreased exercise capacity, may precede the development of manifest PH in a proportion of patients, and is associated with a decreased life expectancy. Exercise stress testing of the pulmonary circulation has to be dynamic and rely on measurements of the components of the pulmonary vascular equation during, not after exercise. Noninvasive imaging measurements may be sufficiently accurate in experienced hands, but suffer from lack of precision, so that invasive measurements are required for individual decision-making. Exercise-induced PH is caused either by pulmonary vasoconstriction, pulmonary vascular remodeling, or by increased upstream transmission of pulmonary venous pressure. This differential diagnosis is clinical. Left heart disease as a cause of exercise-induced PH can be further ascertained by a pulmonary artery wedge pressure above or below 20 mm Hg at a cardiac output < 10 L/min or a pulmonary artery wedge pressure-flow relationship above or below 2 mm Hg/L/min during exercise.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.chest.2018.01.022DOI Listing
July 2018

The Impact of Allograft CXCL9 during Respiratory Infection on the Risk of Chronic Lung Allograft Dysfunction.

OBM Transplant 2018 30;2(4). Epub 2018 Nov 30.

Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1690, USA.

Background: The long term clinical significance of respiratory infections after lung transplantation remains uncertain.

Methods: In this retrospective single-center cohort study of 441 lung transplant recipients, we formally evaluate the association between respiratory infection and chronic lung allograft dysfunction (CLAD). We furthermore hypothesized that bronchoalveolar lavage fluid (BALF) CXCL9 concentrations are augmented during respiratory infections, and that episodes of infection with elevated BALF CXCL9 are associated with greater CLAD risk.

Results: In univariable and multivariable models adjusted for other histopathologic injury patterns, respiratory infection, regardless of the causative organism, was a strong predictor of CLAD development (adjusted HR 1.8 95% CI 1.3-2.6). Elevated BALF CXCL9 concentrations during respiratory infections markedly increased CLAD risk in a dose-response manner. An episode of respiratory infection with CXCL9 concentrations greater than the 25, 50, and 75 percentile had adjusted HRs for CLAD of 1.8 (95% CI 1.1-2.8), 2.4 (95% CI 1.4-4.0) and 4.4 (95% CI 2.4-8.0), respectively.

Conclusions: Thus, we demonstrate that respiratory infections, regardless of the causative organism, are strong predictors of CLAD development. We furthermore demonstrate for the first time, the prognostic importance of BALF CXCL9 concentrations during respiratory infections on the risk of subsequent CLAD development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21926/obm.transplant.1804029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693350PMC
November 2018

Gene Expression Profiling of Bronchoalveolar Lavage Cells During Aspergillus Colonization of the Lung Allograft.

Transplantation 2018 06;102(6):986-993

Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA.

Background: Aspergillus colonization after lung transplant is associated with an increased risk of chronic lung allograft dysfunction (CLAD). We hypothesized that gene expression during Aspergillus colonization could provide clues to CLAD pathogenesis.

Methods: We examined transcriptional profiles in 3- or 6-month surveillance bronchoalveolar lavage fluid cell pellets from recipients with Aspergillus fumigatus colonization (n = 12) and without colonization (n = 10). Among the Aspergillus colonized, we also explored profiles in those who developed CLAD (n = 6) or remained CLAD-free (n = 6). Transcription profiles were assayed with the HG-U133 Plus 2.0 microarray (Affymetrix). Differential gene expression was based on an absolute fold difference of 2.0 or greater and unadjusted P value less than 0.05. We used NIH Database for Annotation, Visualization and Integrated Discovery for functional analyses, with false discovery rates less than 5% considered significant.

Results: Aspergillus colonization was associated with differential expression of 489 probe sets, representing 404 unique genes. "Defense response" genes and genes in the "cytokine-cytokine receptor" Kyoto Encyclopedia of Genes and Genomes pathway were notably enriched in this list. Among Aspergillus colonized patients, CLAD development was associated with differential expression of 69 probe sets, representing 64 unique genes. This list was enriched for genes involved in "immune response" and "response to wounding", among others. Notably, both chitinase 3-like-1 and chitotriosidase were associated with progression to CLAD.

Conclusions: Aspergillus colonization is associated with gene expression profiles related to defense responses including cytokine signaling. Epithelial wounding, as well as the innate immune response to chitin that is present in the fungal cell wall, may be key in the link between Aspergillus colonization and CLAD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/TP.0000000000002058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5962368PMC
June 2018

The authors reply.

Crit Care Med 2017 12;45(12):e1306

Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA;Division of Pulmonary and Critical Care Medicine, Department of Medicine, Weill Cornell Medical College, New York, NY;Division of Pulmonary Critical Care and Sleep Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, PA;Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/CCM.0000000000002742DOI Listing
December 2017

Pulmonary Hypertension Complicating Connective Tissue Disease.

Semin Respir Crit Care Med 2017 10 15;38(5):619-635. Epub 2017 Oct 15.

Division of Pulmonary, Critical Care Medicine, Clinical Immunology, and Allergy, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0037-1606203DOI Listing
October 2017