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1.  Platelet activation in the postoperative period after lung transplantation 
During lung transplantation, cells in the pulmonary parenchyma are subjected to ischemia, hypothermic storage, and reperfusion injury. Platelets, whose granular contents include adhesion receptors, chemokines, and coactivating substances that activate inflammatory and coagulant cascades, likely play a critical role in the lung allograft response to ischemia and reperfusion. The platelet response to the pulmonary allograft, however, has never been studied. Here we report significant platelet activation immediately after lung transplantation.
We performed a prospective cohort study comparing markers of platelet activation in patients undergoing lung transplantation and patients undergoing nontransplant thoracotomy. Plasma levels of soluble P-selectin, soluble CD40 ligand, and platelet–leukocyte conjugates were measured before surgery, after skin closure, and at 6 postoperative hours.
Both soluble P-selectin and soluble CD40 ligand levels increased significantly after lung transplantation but not after thoracotomy. Additionally, platelet–monocyte conjugate fluorescence was significantly higher after lung transplantation than after thoracotomy alone.
These findings suggest that platelet activation is significantly increased after lung transplantation beyond that expected from the postoperative state. The increase in circulating platelet–monocyte conjugates suggests an important interaction between platelets and inflammatory cells. Further research should examine whether platelet activation affects early graft function after lung transplantation.
PMCID: PMC2829430  PMID: 18329493
2.  Clinical Risk Factors for Primary Graft Dysfunction after Lung Transplantation 
Rationale: Primary graft dysfunction (PGD) is the main cause of early morbidity and mortality after lung transplantation. Previous studies have yielded conflicting results for PGD risk factors.
Objectives: We sought to identify donor, recipient, and perioperative risk factors for PGD.
Methods: We performed a 10-center prospective cohort study enrolled between March 2002 and December 2010 (the Lung Transplant Outcomes Group). The primary outcome was International Society for Heart and Lung Transplantation grade 3 PGD at 48 or 72 hours post-transplant. The association of potential risk factors with PGD was analyzed using multivariable conditional logistic regression.
Measurements and Main Results: A total of 1,255 patients from 10 centers were enrolled; 211 subjects (16.8%) developed grade 3 PGD. In multivariable models, independent risk factors for PGD were any history of donor smoking (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.2–2.6; P = 0.002); FiO2 during allograft reperfusion (OR, 1.1 per 10% increase in FiO2; 95% CI, 1.0–1.2; P = 0.01); single lung transplant (OR, 2; 95% CI, 1.2–3.3; P = 0.008); use of cardiopulmonary bypass (OR, 3.4; 95% CI, 2.2–5.3; P < 0.001); overweight (OR, 1.8; 95% CI, 1.2–2.7; P = 0.01) and obese (OR, 2.3; 95% CI, 1.3–3.9; P = 0.004) recipient body mass index; preoperative sarcoidosis (OR, 2.5; 95% CI, 1.1–5.6; P = 0.03) or pulmonary arterial hypertension (OR, 3.5; 95% CI, 1.6–7.7; P = 0.002); and mean pulmonary artery pressure (OR, 1.3 per 10 mm Hg increase; 95% CI, 1.1–1.5; P < 0.001). PGD was significantly associated with 90-day (relative risk, 4.8; absolute risk increase, 18%; P < 0.001) and 1-year (relative risk, 3; absolute risk increase, 23%; P < 0.001) mortality.
Conclusions: We identified grade 3 PGD risk factors, several of which are potentially modifiable and should be prioritized for future research aimed at preventative strategies.
Clinical trial registered with (NCT 00552357).
PMCID: PMC3733407  PMID: 23306540
lung transplantation; clinical risk factors; primary graft dysfunction
3.  Plasma endothelin-1 and vascular endothelial growth factor levels and their relationship to hemodynamics in idiopathic pulmonary fibrosis 
Pulmonary hypertension (PH) is associated with a poor prognosis in idiopathic pulmonary fibrosis (IPF). Endothelin-1 (ET-1) and vascular endothelial growth factor (VEGF) are important in both fibrosis and vascular remodeling.
We sought to determine the relationship between ET-1 and VEGF levels and hemodynamics in patients with IPF. We hypothesized that higher levels of ET-1 and VEGF would be associated with higher pulmonary artery pressures (PAP) and pulmonary vascular resistance (PVR) in patients with IPF.
We performed a cross-sectional analysis of 52 adults with IPF enrolled in a prospective cohort with available clinical data, platelet-free plasma, and hemodynamics. ET-1 and VEGF levels were measured via immunoassay. The associations of ET-1 and VEGF with PAP and PVR were examined using generalized additive models adjusted for age, gender, race/ethnicity, and forced vital capacity (% predicted).
Sixteen of 52 (30.8%) had PH (mean PAP ≥ 25 mmHg). After multivariable adjustment, higher ET-1 levels were significantly associated with higher systolic (p = 0.01), diastolic (p = 0.02), and mean (p = 0.01) PAP and possibly higher PVR (p = 0.09). There were no significant associations between VEGF levels and hemodynamics.
Higher levels of ET-1 were associated with higher PAP and possibly higher PVR in participants with IPF. In a sub-group of patients, ET-1 may be a contributor to pulmonary vascular disease burden in IPF.
PMCID: PMC3495134  PMID: 22869459
idiopathic pulmonary fibrosis; endothelin-1; vascular endothelial growth factor; biomarkers; pulmonary hypertension
4.  Plasma Monocyte Chemotactic Protein-1 (MCP-1) Levels at 24 hours are a Biomarker of Primary Graft Dysfunction Following Lung Transplantation 
MCP-1, also known as CCL2, is a monocyte-attracting chemokine produced in lung epithelial cells. We previously reported an association of increased levels of plasma MCP-1 with primary graft dysfunction (PGD) after lung transplantation in a nested case control study of extreme phenotypes using a multiplex platform. In this study, we sought to evaluate the relationship between plasma MCP-1 levels as a biomarker across the full spectrum of PGD. We performed a prospective cohort study of 108 lung transplant recipients within the Lung Transplant Outcomes Group cohort. Plasma MCP-1 levels were measured pre-transplantation, 6 and 24 hours after transplantation. The primary outcome was development of grade 3 PGD within 72 hours of transplant, with secondary analyses at the 72- hour timepoint. Multivariable logistic regression was used to evaluate confounding. 30 subjects (28%) developed PGD. Median MCP-1 measured at 24 hours post transplant was elevated in subjects with PGD (167.95 vs. 103.5 pg/mL p=0.04). MCP-1 levels at 24 hours were associated with increased odds of grade 3 PGD after lung transplantation (OR for each 100 pg/mL 1.24, 95% CI 1.00, 1.53), and with grade 3 PGD present at the 72-hour timepoint (OR for each 100 pg/mL 1.57, 95% CI 1.18, 2.08), independent of confounding variables in multivariable analyses. MCP-1 levels measured pre-operatively and 6 hours after transplant were not significantly associated with PGD. Persistent elevations in MCP-1 levels at 24 hours are a biomarker of grade 3 PGD post-transplantation. Monocyte chemotaxis may play a role in the pathogenesis of PGD.
PMCID: PMC3500407  PMID: 22989614
Primary Graft Dysfunction; Lung transplantation; Monocyte Chemotactic Protein-1; Acute Lung Injury; Biomarker
5.  An Acute Change in Lung Allocation Score and Survival After Lung Transplantation A Cohort Study 
Annals of internal medicine  2013;158(9):10.7326/0003-4819-158-9-201305070-00004.
Lung transplantation is an effective treatment for patients with advanced lung disease. In the United States, lungs are allocated on the basis of the lung allocation score (LAS), a composite measure of transplantation urgency and utility. Clinical deteriorations result in increases to the LAS; however, whether the trajectory of the LAS has prognostic significance is uncertain.
To determine whether an acute increase in the LAS before lung transplantation is associated with reduced posttransplant survival.
Retrospective cohort study of adult lung transplant recipients listed for at least 30 days between 4 May 2005 (LAS implementation) and 31 December 2010 in the United Network for Organ Sharing registry. An acute increase in the LAS was defined as an LAS change (LASΔ) greater than 5 units between the 30 days before and the time of transplantation. Multivariable Cox proportional hazards models were used to examine the relationship between an LASΔ >5 and posttransplant graft survival.
All U.S. lung transplantation centers.
5749 lung transplant recipients.
Survival time after lung transplantation.
702 (12.2%) patients experienced an LASΔ >5. These patients had significantly worse posttransplant survival (hazard ratio, 1.31 [95% CI, 1.11 to 1.54]; P = 0.001]) after adjustment for the LAS at transplantation and other clinical covariates. The effect of an LASΔ >5 was independent of the LAS at transplantation, underlying diagnosis, center volume, or donor characteristics.
Analysis was based on center-reported data.
An acute increase in LAS before transplantation is associated with posttransplant survival after adjustment for LAS at transplantation. Further emphasis on serial assessment of the LAS could improve prognostication after transplantation.
PMCID: PMC3819715  PMID: 23648947
6.  Variation in PTX3 Is Associated with Primary Graft Dysfunction after Lung Transplantation 
Rationale: Elevated long pentraxin-3 (PTX3) levels are associated with the development of primary graft dysfunction (PGD) after lung transplantation. Abnormalities in innate immunity, mediated by PTX3 release, may play a role in PGD pathogenesis.
Objectives: Our goal was to test whether variants in the gene encoding PTX3 are risk factors for PGD.
Methods: We performed a candidate gene association study in recipients from the multicenter, prospective Lung Transplant Outcomes Group cohort enrolled between July 2002 and July 2009. The primary outcome was International Society for Heart and Lung Transplantation grade 3 PGD within 72 hours of transplantation. Targeted genotyping of 10 haplotype-tagging PTX3 single-nucleotide polymorphisms (SNPs) was performed in lung transplant recipients. The association between PGD and each SNP was evaluated by logistic regression, adjusting for pretransplantation lung disease, cardiopulmonary bypass use, and population stratification. The association between SNPs and plasma PTX3 levels was tested across genotypes in a subset of recipients with idiopathic pulmonary fibrosis.
Measurements and Main Results: Six hundred fifty-four lung transplant recipients were included. The incidence of PGD was 29%. Two linked 5′ region variants, rs2120243 and rs2305619, were associated with PGD (odds ratio, 1.5; 95% confidence interval, 1.1 to 1.9; P = 0.006 and odds ratio, 1.4; 95% confidence interval, 1.1 to 1.9; P = 0.007, respectively). The minor allele of rs2305619 was significantly associated with higher plasma PTX3 levels measured pretransplantation (P = 0.014) and at 24 hours (P = 0.047) after transplantation in patients with idiopathic pulmonary fibrosis.
Conclusions: Genetic variants of PTX3 are associated with PGD after lung transplantation, and are associated with increased PTX3 plasma levels.
PMCID: PMC3480532  PMID: 22822025
primary graft dysfunction; single-nucleotide polymorphism; long pentraxin 3; lung transplantation
7.  A panel of lung injury biomarkers enhances the definition of primary graft dysfunction (PGD) after lung transplantation 
We aimed to identify combinations of biomarkers to enhance the definition of PGD for translational research.
Biomarkers reflecting lung epithelial injury (sRAGE and SP-D), coagulation cascade (PAI-1 and Protein C), and cell adhesion (ICAM-1) were measured in the plasma of 315 subjects derived from the LTOG cohort at 6 and 24 hours after transplantation. We assessed biomarker utility in two ways: first, we tested the discrimination of grade 3 PGD within 72 hours; second, we tested the predictive utility of plasma biomarkers for 90-day mortality.
86/315 subjects (27%) developed PGD. 23 subjects (8%) died within 90 days of transplantation, of which 16 (70%) had PGD. Biomarkers measured at 24 hours had greater discrimination than at 6 hours. Individually, sRAGE (AUC 0.71) and PAI-1 (AUC 0.73) had the best discrimination of PGD. The combinations of sRAGE with PAI-1 (AUC 0.75), PAI-1 with ICAM-1 (AUC 0.75), and PAI-1 with SP-D (AUC 0.76) had the best discrimination. Combinations of greater than 2 biomarkers did not significantly enhance discrimination of PGD. ICAM-1 with PAI-1 (AUC 0.72) and ICAM-1 with sRAGE (AUC of 0.72) had the best prediction for 90-day mortality. The addition of ICAM-1, PAI-1, or sRAGE to the concurrent clinical PGD grade significantly improved prediction of 90-day mortality (p<0.001 each).
Measurement of the combination of a marker of impaired fibrinolysis with an epithelial injury or cell adhesion marker had the best discrimination for PGD and prediction for early mortality, and may provide an alternative outcome useful in future research.
PMCID: PMC3418416  PMID: 22694851
Primary Graft Dysfunction; Lung transplantation; Biomarkers; Acute Lung Injury
8.  Titrated oxygen requirement and prognostication in idiopathic pulmonary fibrosis 
The European Respiratory Journal  2011;39(2):359-365.
The supplemental oxygen flow rate is a common bedside measure of gas exchange impairment. We aimed to determine whether a titrated oxygen requirement predicted mortality in idiopathic pulmonary fibrosis.
We examined 104 adults with idiopathic pulmonary fibrosis enrolled in a prospective cohort study and a validation cohort of 151 adults with a variety of interstitial lung diseases. The titrated oxygen requirement was defined as the lowest oxygen flow rate required to maintain an oxyhemoglobin saturation of 96% while standing. Cox proportional hazards models and time-dependent receiver operating characteristic curves were used to examine survival time.
A higher titrated oxygen requirement was associated with a greater mortality rate independent of forced vital capacity and six-minute walk test results in idiopathic pulmonary fibrosis (adjusted hazard ratio per 1 L/min = 1.10, 95% confidence interval 1.01 to 1.20). The titrated oxygen requirement was at least as accurate as pulmonary function and six-minute walk testing at predicting 1-year mortality. Findings were similar in other interstitial lung diseases.
The titrated oxygen requirement is a simple, inexpensive bedside measurement that aids prognostication in idiopathic pulmonary fibrosis.
PMCID: PMC3236811  PMID: 21885386
Idiopathic pulmonary fibrosis; Interstitial lung diseases; Outcome prediction; Pulmonary fibrosis; Pulmonary gas exchange
9.  Obesity and Primary Graft Dysfunction after Lung Transplantation 
Rationale: Obesity has been linked to acute lung injury and is a risk factor for early mortality after lung transplantation.
Objectives: To examine the associations of obesity and plasma adipokines with the risk of primary graft dysfunction after lung transplantation.
Methods: We performed a prospective cohort study of 512 adult lung transplant recipients with chronic obstructive pulmonary disease or interstitial lung disease enrolled in the Lung Transplant Outcomes Group Study. In a nested case-control study, we measured plasma leptin, adiponectin, and resistin before lung transplantation and 6 and 24 hours after lung transplantation in 40 cases of primary graft dysfunction and 80 control subjects. Generalized linear mixed models and logistic regression were used to estimate risk ratios and odds ratios.
Measurements and Main Results: Grade 3 primary graft dysfunction developed within 72 hours of transplantation in 29% participants. Obesity was associated with a twofold increased risk of primary graft dysfunction (adjusted risk ratio 2.1; 95% confidence interval, 1.7–2.6). The risk of primary graft dysfunction increased by 40% (confidence interval, 30–50%) for each 5 kg/m2 increase in body mass index after accounting for center, diagnosis, cardiopulmonary bypass, and transplant procedure. Higher plasma leptin levels were associated with a greater risk of primary graft dysfunction (sex-adjusted P = 0.02). The associations of both obesity and leptin with primary graft dysfunction tended to be stronger among those who did not undergo cardiopulmonary bypass.
Conclusions: Obesity is an independent risk factor for primary graft dysfunction after lung transplantation.
PMCID: PMC3208644  PMID: 21799077
acute lung injury; leptin; lung transplantation; obesity; primary graft dysfunction
10.  Postoperative estradiol levels associate with the development of primary graft dysfunction in lung transplant patients 
Gender Medicine  2012;9(3):154-165.
Primary graft dysfunction (PGD) frequently complicates lung transplantation in the immediate postoperative period. Both female gender and estradiol modulate the body’s response to injury and may influence the rate of alveolar fluid clearance. We hypothesized that female gender and higher estradiol levels would be associated with a lower risk of PGD after lung transplantation. We measured plasma estradiol levels pre-operatively, 6 hours postoperatively and 24 hours postoperatively in a cohort of 111 lung transplant recipients at two institutions. The mean age was 57 years (+/− 12.5) and 52% were female. The median postoperative estradiol level was 63.9 pg/ml (IQR 28.8–154.3) in men and 65.1 pg/ml (IQR 28.4–217.2) in females. Contrary to our hypothesis, higher estradiol levels at 24 hours were associated with an increased risk of PGD at 72 hours in males (p=0.001). This association was preserved when accounting for other factors known to be associated with PGD. However, there was no relationship between gender and risk of PGD or between estradiol levels and PGD in females. These findings suggest that there may be different biologic effects of estrogens in males and females and highlight the importance of considering gender differences in future studies of PGD.
PMCID: PMC3374892  PMID: 22361838
Lung transplantation; gender; acute lung injury; acute respiratory distress syndrome; estrogen; alveolar fluid clearance
11.  Delayed Access and Survival in Idiopathic Pulmonary Fibrosis 
Rationale: Idiopathic pulmonary fibrosis is often initially misdiagnosed. Delays in accessing subspecialty care could lead to worse outcomes among those with idiopathic pulmonary fibrosis.
Objectives: To examine the association between delayed access to subspecialty care and survival time in idiopathic pulmonary fibrosis.
Methods: We performed a prospective cohort study of 129 adults who met American Thoracic Society criteria for idiopathic pulmonary fibrosis evaluated at a tertiary care center. Delay was defined as the time from the onset of dyspnea to the date of initial evaluation at a tertiary care center. We used competing risk survival methods to examine survival time and time to transplantation.
Measurements and Main Results: The mean age was 63 years and 76% were men. The median delay was 2.2 years (interquartile range 1.0–3.8 yr), and the median follow-up time was 1.1 years. Age and lung function at the time of evaluation did not vary by delay. A longer delay was associated with an increased risk of death independent of age, sex, forced vital capacity, third-party payer, and educational attainment (adjusted hazard ratio per doubling of delay was 1.3, 95% confidence interval 1.03 to 1.6). Longer delay was not associated with a lower likelihood of undergoing lung transplantation.
Conclusions: Delayed access to a tertiary care center is associated with a higher mortality rate in idiopathic pulmonary fibrosis independent of disease severity. Early referral to a specialty center should be considered for those with known or suspected interstitial lung disease.
PMCID: PMC3208648  PMID: 21719755
access to healthcare; healthcare disparities; idiopathic pulmonary fibrosis; interstitial lung disease; survival
12.  Pulmonary Capillary Wedge Pressure Augments Right Ventricular Pulsatile Loading 
Circulation  2011;125(2):289-297.
Right ventricular (RV) failure from increased pulmonary vascular loading is a major cause of morbidity and mortality, yet its modulation by disease remains poorly understood. We tested the hypotheses that, unlike the systemic circulation, pulmonary vascular resistance (RPA) and compliance (CPA) are consistently and inversely related regardless of age, pulmonary hypertension (PH), or interstitial fibrosis, and that this relation may be changed by elevated pulmonary capillary wedge pressure (PCWP), augmenting RV pulsatile load.
Methods and Results
Several large clinical databases with right heart/pulmonary catheterization data were analyzed to determine the RPA-CPA relationship with PH, pulmonary fibrosis, patient age, and varying PCWP. Patients with suspected or documented PH (n=1009) and normal PCWP displayed a consistent RPA-CPA hyperbolic (inverse) dependence; CPA=0.564/(0.047+RPA), with a near constant resistance-compliance product (RC) (0.48±0.17 seconds). In the same patients, the systemic RC was highly variable. Severe pulmonary fibrosis (n=89) did not change the RPA-CPA relation. Increasing patient age led to a very small though statistically significant change in the relation. However, elevation of the PCWP (n=8142) had a larger impact, significantly lowering CPA for any RPA, and negatively correlating RC (p<0.0001).
PH and pulmonary fibrosis do not significantly change the hyperbolic dependence between RPA and CPA, while patient age has only minimal affects. This fixed relationship helps explain the difficulty of reducing total RV afterload by therapies that have modest impact on mean RPA. Higher PCWP appears to enhance net RV afterload by elevating pulsatile, relative to resistive load, and may contribute to RV dysfunction.
PMCID: PMC3264431  PMID: 22131357
ventricular/vascular coupling hemodynamics; heart failure; pulmonary hypertension; pulmonary vascular changes; right ventricle
13.  Elevated Plasma Angiopoietin-2 Levels and Primary Graft Dysfunction after Lung Transplantation 
PLoS ONE  2012;7(12):e51932.
Primary graft dysfunction (PGD) is a significant contributor to early morbidity and mortality after lung transplantation. Increased vascular permeability in the allograft has been identified as a possible mechanism leading to PGD. Angiopoietin-2 serves as a partial antagonist to the Tie-2 receptor and induces increased endothelial permeability. We hypothesized that elevated Ang2 levels would be associated with development of PGD.
We performed a case-control study, nested within the multi-center Lung Transplant Outcomes Group cohort. Plasma angiopoietin-2 levels were measured pre-transplant and 6 and 24 hours post-reperfusion. The primary outcome was development of grade 3 PGD in the first 72 hours. The association of angiopoietin-2 plasma levels and PGD was evaluated using generalized estimating equations (GEE).
There were 40 PGD subjects and 79 non-PGD subjects included for analysis. Twenty-four PGD subjects (40%) and 47 non-PGD subjects (59%) received a transplant for the diagnosis of idiopathic pulmonary fibrosis (IPF). Among all subjects, GEE modeling identified a significant change in angiopoietin-2 level over time in cases compared to controls (p = 0.03). The association between change in angiopoietin-2 level over the perioperative time period was most significant in patients with a pre-operative diagnosis of IPF (p = 0.02); there was no statistically significant correlation between angiopoietin-2 plasma levels and the development of PGD in the subset of patients transplanted for chronic obstructive pulmonary disease (COPD) (p = 0.9).
Angiopoietin-2 levels were significantly associated with the development of PGD after lung transplantation. Further studies examining the regulation of endothelial cell permeability in the pathogenesis of PGD are indicated.
PMCID: PMC3526525  PMID: 23284823
14.  Selecting lung transplant candidates: where do current guidelines fall short? 
In 2010, 1770 lung transplant procedures were performed in the USA, yet 2469 new candidates were added to the waiting list the same year. The shortage of suitable donor lungs requires that transplant professionals select patients for lung transplantation only if they are likely to sustain a survival benefit from the procedure. However, 20% of lung transplant recipients die within the first year of transplantation, suggesting that we are failing to identify those at high risk for severe early complications. In this perspective, we review the current guidelines for the selection of lung transplant candidates, which are based largely on expert opinion and small case series. We also propose the study of new extrapulmonary factors, such as frailty and sarcopenia, that might help improve the prediction of complications and early death after lung transplantation, leading to an improved candidate selection process.
PMCID: PMC3286653  PMID: 22283579
chronic obstructive pulmonary disease; frailty; interstitial lung disease; lung transplantation; obesity; pulmonary arterial hypertension; sarcopenia
15.  Elevated Plasma Long Pentraxin-3 Levels and Primary Graft Dysfunction after Lung Transplantation for Idiopathic Pulmonary Fibrosis 
Primary graft dysfunction (PGD) after lung transplantation may result from ischemia-reperfusion injury (IRI). The innate immune response to IRI may be mediated by Toll-like receptor and IL-1-induced long pentraxin-3 (PTX3) release. We hypothesized that elevated PTX3 levels were associated with PGD. We performed a nested case control study of lung transplant recipients with Idiopathic Pulmonary Fibrosis (IPF) or Chronic Obstructive Pulmonary Disease (COPD) from the Lung Transplant Outcomes Group cohort. PTX3 levels were measured pre-transplant, and 6 and 24 hours post reperfusion. Cases were subjects with grade 3 PGD within 72 of transplantation and controls were those without grade 3 PGD. Generalized estimating equations and multivariable logistic regression was used for analysis. We selected 40 PGD cases and 79 non-PGD controls. Plasma PTX3 level was associated with PGD in IPF but not COPD recipients (p for interaction<0.03). Among patients with IPF, PTX3 levels at 6 and 24 hours were associated with PGD (OR=1.6, p=0.02 at 6hrs; OR=1.4, p=0.008 at 24hrs). Elevated PTX3 levels were associated with the development of PGD after lung transplantation in IPF patients. Future studies evaluating the role of innate immune activation in IPF and PGD are warranted.
PMCID: PMC3206646  PMID: 21883907
Primary Graft Dysfunction; Lung transplantation; Long Pentraxin-3; Idiopathic Pulmonary Fibrosis
16.  A Randomized Clinical Trial of Aspirin and Simvastatin for Pulmonary Arterial Hypertension: ASA-STAT 
Circulation  2011;123(25):2985-2993.
Pulmonary arterial hypertension (PAH) is a progressive disease which causes exercise limitation, heart failure, and death. We aimed to determine the safety and efficacy of aspirin and simvastatin in PAH.
Methods and Results
We performed a randomized, double-blind, placebo-controlled 2 × 2 factorial clinical trial of aspirin and simvastatin in patients with PAH receiving background therapy at four centers. A total of 92 patients with PAH were to be randomized to aspirin 81 mg or matching placebo and simvastatin 40 mg or matching placebo. The primary outcome was six-minute walk distance (6MWD) at six months. Sixty-five subjects were randomized when the trial was terminated by the DSMB after an interim analysis showed futility in reaching the primary end point for simvastatin. After adjustment for baseline 6MWD, there was no significant difference in the 6MWD at six months between aspirin (n = 32) and placebo (n = 33) [placebo-corrected difference = −0.5 m (95%CI, −28.4 – 27.4 m), p = 0.97] or between simvastatin (n = 32) and placebo (n = 33) [placebo-corrected difference = −27.6 m (95%CI, −59.6 – 4.3 m), p = 0.09]. There tended to be more major bleeding episodes with aspirin compared to placebo (4 events vs. 1 event, respectively, p = 0.17).
Neither aspirin nor simvastatin had a significant effect on the 6MWD, although patients randomized to simvastatin tended to have a lower 6MWD at six months. These results do not support the routine treatment of patients with PAH with these medications.
PMCID: PMC3427737  PMID: 21593252
pulmonary hypertension; clinical trial; anti-platelet agents; endothelial dysfunction
17.  The renin-angiotensin system and right ventricular structure and function: The MESA-Right Ventricle Study 
Pulmonary Circulation  2012;2(3):379-386.
The pulmonary vasculature is an important site of renin-angiotensin metabolism. While angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers (collectively AIABs) have a role in left ventricular (LV) disease, the impact of AIABs on right ventricular (RV) function is unknown. AIAB use was determined by medication inventory during the Multi-Ethnic Study of Atherosclerosis baseline examination. RV measures were obtained via cardiac magnetic resonance imaging. The relationship between AIAB use and RV measures was assessed using multivariable linear regression, stratified by race/ethnicity, and adjusted for multiple covariates. AIAB use was associated with lower RV mass (-0.7 g, 95% confidence interval [CI] -1.3 to -0.1, P=0.03) in African Americans (N=1012) after adjustment for multiple covariates including LV mass. Among Caucasians (N=1591), AIAB use was associated with larger RV end-diastolic volume (3.7 mL, 95% CI 0.7-6.8, P=0.02) after adjustment for LV volume. No significant associations were seen between AIAB use and other RV measures or in Hispanic or Chinese American participants. AIAB use was associated with RV morphology in a race-specific and LV-independent manner, suggesting the renin-angiotensin system may play a unique role in RV structure and function. The use of AIABs in those with RV dysfunction warrants further study.
PMCID: PMC3487307  PMID: 23130107
angiotensin-converting enzyme inhibitor; angiotensin II receptor blockers; right ventricle; epidemiology; renin-angiotensin system
18.  Obesity and Underweight Are Associated with an Increased Risk of Death after Lung Transplantation 
Rationale: Obesity is considered a relative contraindication to lung transplantation, based on studies that have not accounted for key confounders. Little is known about the risk of death for underweight candidates after transplantation.
Objectives: To examine the associations of pretransplant obesity and underweight with the risk of death after lung transplantation.
Methods: We examined 5,978 adults with cystic fibrosis, chronic obstructive pulmonary disease, and diffuse parenchymal lung disease who underwent lung transplantation in the United States between 1995 and 2003. We used Cox models and generalized additive models to examine the association between pretransplant body mass index and the risk of death after lung transplantation with adjustment for donor and recipient factors.
Measurements and Main Results: The median follow-up time was 4.2 years. Compared with normal weight recipients, the multivariable-adjusted rates of death were 15% higher for underweight recipients (95% confidence interval, 3 to 28%), 15% higher for overweight recipients (95% confidence interval, 6 to 26%), and 22% higher for obese recipients (95% confidence interval, 8 to 39%). These relationships persisted when stratified by diagnosis. The multivariable-adjusted population attributable fraction was 12% at 1 year and 8% at 5 years.
Conclusions: Both obesity and underweight are independent risk factors for death after lung transplantation, contributing to up to 12% of deaths in the first year after transplantation. Primary care providers and pulmonologists should promote a healthy weight for patients with lung disease long before transplantation is considered.
PMCID: PMC2773915  PMID: 19608717
anthropometry; body mass index; generalized additive models; lung transplantation; obesity
19.  Circulating KL-6, a Biomarker of Lung Injury, in Obstructive Sleep Apnea 
In obstructive sleep apnea (OSA), oxidative stress contributes to endothelial dysfunction in the peripheral circulation. In the lung, oxidative stress can lead to alveolar injury. We hypothesized that patients with obstructive sleep apnea would have biomarker evidence of increased alveolar wall permeability.
We examined sleep characteristics, brachial artery flow-mediated dilation, and plasma KL-6 levels in 11 otherwise healthy patients with OSA and 10 controls at our center.
Plasma KL-6 levels were higher in patients with OSA compared to controls: median 317 U/ml (interquartile range 232 to 506) versus 226 U/ml (interquartile range 179 to 257), respectively. Higher plasma KL-6 levels were associated with greater time spent in sleep with an oxyhemoglobin saturation < 90%, lower nadir saturation, more frequent desaturation of > 4% during sleep, and lower brachial artery flow-mediated dilation. Adjustment for nadir saturation or flow-mediated dilation attenuated the association between plasma KL-6 level and OSA.
Circulating KL-6 levels are elevated in some patients with OSA, possibly reflecting increased alveolar wall permeability.
PMCID: PMC2739049  PMID: 19336590
alveolar wall permeability; biological markers; hypoxia; obstructive sleep apnea
20.  Rationale and design of a Phase II clinical trial of aspirin and simvastatin for the treatment of pulmonary arterial hypertension: ASA-STAT 
Contemporary clinical trials  2010;32(2):280-287.
Pulmonary arterial hypertension (PAH) is a progressive disease which causes exercise limitation, heart failure, and death. Aspirin and simvastatin are highly effective and safe therapies for other cardiovascular diseases characterized by platelet activation and endothelial dysfunction, but have not been formally studied in PAH.
ASA-STAT is a Phase II, randomized, double-blind, placebo-controlled 2 × 2 factorial clinical trial of aspirin and simvastatin in patients with PAH. A total of 92 subjects were to be randomized to aspirin or aspirin placebo and simvastatin or simvastatin placebo. The primary outcome is the distance walked in six minutes at six months after randomization. Secondary measures include brachial artery flow-mediated dilation, circulating biomarkers of platelet and endothelial function, functional class, quality-of-life, and time to clinical end points. The incidence of adverse events will be compared between treatment groups.
Screening and Enrollment
We screened a total of 712 individuals with PAH. Sixty-five subjects were enrolled when the trial was terminated for futility in reaching the primary end point for simvastatin.
This study aims to determine whether aspirin or simvastatin have beneficial biologic or clinical effects in patients with PAH. The safety and side effects of these commonly prescribed cardiovascular drugs will also be assessed.
PMCID: PMC3034822  PMID: 21146637
Pulmonary hypertension; Endothelial dysfunction; platelets; Clinical trial
21.  Elevated Plasma Clara Cell Secretory Protein Concentration is Associated with High-Grade Primary Graft Dysfunction 
Primary graft dysfunction (PGD) is the leading cause of early post-transplant morbidity and mortality after lung transplantation. Clara cell secretory protein (CC16) is produced by the non-ciliated lung epithelium and may serve as a plasma marker of epithelial cell injury. We hypothesized that elevated levels of CC16 would be associated with increased odds of PGD. We performed a prospective cohort study of 104 lung transplant recipients. Median plasma CC16 levels were determined at three time points: pre-transplant and 6 and 24 hours post transplant. The primary outcome was the development of grade 3 PGD within the first 72 hours after transplantation. Multivariable logistic regression was performed to evaluate for confounding by donor and recipient demographics and surgical characteristics. Twenty-nine patients (28%) developed grade 3 PGD within the first 72 hours. The median CC16 level 6 hours after transplant was significantly higher in patients with PGD (13.8 ng/ml (IQR 7.9, 30.4 ng/ml)) than in patients without PGD (8.2 ng/ml (IQR 4.5, 19.1 ng/ml)), p = 0.02. Elevated CC16 levels were associated with increased odds of PGD after lung transplantation. Damage to airway epithelium or altered alveolar permeability as a result of lung ischemia and reperfusion may explain this association.
PMCID: PMC3079443  PMID: 21299834
Primary Graft Dysfunction; Lung transplantation; Clara Cell Secretory Protein
22.  Micromechanics of Alveolar Edema 
The decrease of lung compliance in pulmonary edema underlies ventilator-induced lung injury. However, the cause of the decrease in compliance is unknown. We tested the hypothesis that in pulmonary edema, the mechanical effects of liquid-filled alveoli increase tissue stress in adjacent air-filled alveoli. By micropuncture of isolated, perfused rat lungs, we established a single-alveolus model of pulmonary edema that we imaged using confocal microscopy. In this model, we viewed a liquid-filled alveolus together with its air-filled neighbor at different transpulmonary pressures, both before and after liquid-filling. Instilling liquid in an alveolus caused alveolar shrinkage. As a result, the interalveolar septum was stretched, causing the neighboring air-filled alveolus to bulge. Thus, the air-filled alveolus was overexpanded by virtue of its adjacency to a liquid-filled alveolus. Confocal microscopy at different depths of the liquid-filled alveolus revealed a meniscus. Lung inflation to near-total lung capacity (TLC) demonstrated decreased compliance of the air-filled but not liquid-filled alveolus. However, at near TLC, the air-filled alveolus was larger than it was in the pre-edematous control tissue. In pulmonary edema, liquid-filled alveoli induce mechanical stress on air-filled alveoli, reducing the compliance of air-filled alveoli, and hence overall lung compliance. Because of increased mechanical stress, air-filled alveoli may be susceptible to overdistension injury during mechanical ventilation of the edematous lung.
PMCID: PMC3028256  PMID: 20118224
alveolar edema; compliance; micromechanics; optical sectioning microscopy; fluorescence
23.  Racial Differences in Waiting List Outcomes in Chronic Obstructive Pulmonary Disease 
Rationale: Blacks with chronic illness have poorer outcomes than whites in the United States. The health outcomes of minorities with chronic obstructive pulmonary disease (COPD) on the lung transplant waiting list have not been studied.
Objectives: To compare outcomes of black and white patients with COPD after listing for lung transplantation in the United States.
Methods: Retrospective cohort study of all 280 non-Hispanic black and 5,272 non-Hispanic white adults 40 years and older with COPD listed for lung transplantation in the United States between 1995 and 2004.
Measurements and Main Results: Blacks with COPD were more likely to have pulmonary hypertension, obesity, and diabetes; to lack private health insurance; and to live in poorer neighborhoods than whites. Blacks were less likely to undergo transplantation after listing compared with whites, despite adjustment for age, lung function, pulmonary hypertension, cardiovascular risk factors, insurance coverage, and poverty level (adjusted hazard ratio, 0.83; 95% confidence interval, 0.70–0.98; P = 0.03). This was accompanied by a greater risk of dying or being removed from the list among blacks (unadjusted hazard ratio, 1.31; 95% confidence interval, 1.05–1.63; P = 0.02).
Conclusions: After listing for lung transplantation, black patients with COPD were less likely to undergo transplantation and more likely to die or be removed from the list compared with white patients. Unequal access to care may have contributed to these differences.
PMCID: PMC2258441  PMID: 18006881
racial disparities; lung transplantation; survival; competing risks; black or African American
24.  Vascular Inflammation in Obesity and Sleep Apnea 
Circulation  2010;121(8):1014-1021.
Unrecognized obstructive sleep apnea (OSA) is highly prevalent in obesity. Both obesity and OSA are associated with vascular endothelial inflammation and increased risk for cardiovascular diseases. We investigated directly whether endothelial alterations that are commonly attributed to obesity are in fact related to OSA.
Methods and Results
Seventy-one subjects with body mass index (BMI) ranging from normal to obese underwent attended polysomnography. To assess directly vascular inflammation and oxidative stress, we quantified expression of nuclear factor kappa B (NFκB) and nitrotyrosine by immunofluorescence in freshly harvested venous endothelial cells. To evaluate basal endothelial nitric oxide (NO) production and activity, we quantified expression of endothelial NO synthase (eNOS) and phosphorylated eNOS (P-eNOS). Vascular reactivity was measured by brachial artery flow-mediated dilation (FMD). Expression of eNOS and P-eNOS and FMD were significantly lower whereas expression of nitrotyrosine was significantly greater in OSA patients (n=38) than in OSA-free subjects (n=33) regardless of central adiposity. Expression of NFκB was greater in obese OSA patients than in obese OSA-free subjects (p=0.004). Protein expression and FMD were not significantly affected by increasing BMI or central obesity in OSA patients and in OSA-free subjects. After 4 weeks of continuous positive airway pressure (CPAP) therapy, FMD and expression of eNOS and P-eNOS significantly increased whereas expression of nitrotyrosine and NFκB significantly decreased in OSA patients who adhered with CPAP≥4 hours daily.
Untreated OSA rather than obesity is a major determinant of vascular endothelial dysfunction, inflammation and elevated oxidative stress in obese patients.
PMCID: PMC2864627  PMID: 20159829
obesity; sleep; endothelium; hypoxia
25.  Plasma Levels of Receptor for Advanced Glycation End Products, Blood Transfusion, and Risk of Primary Graft Dysfunction 
Rationale: The receptor for advanced glycation end products (RAGE) is an important marker of lung epithelial injury and may be associated with impaired alveolar fluid clearance. We hypothesized that patients with primary graft dysfunction (PGD) after lung transplantation would have higher RAGE levels in plasma than patients without PGD.
Objectives: To test the association of soluble RAGE (sRAGE) levels with PGD in a prospective, multicenter cohort study.
Methods: We measured plasma levels of sRAGE at 6 and 24 hours after allograft reperfusion in 317 lung transplant recipients at seven centers. The primary outcome was grade 3 PGD (PaO2/FiO2 < 200 with alveolar infiltrates) within the first 72 hours after transplantation.
Measurements and Main Results: Patients who developed PGD had higher levels of sRAGE than patients without PGD at both 6 hours (median 9.3 ng/ml vs. 7.5 ng/ml, respectively; P = 0.028) and at 24 hours post-transplantation (median 4.3 ng/ml vs. 1.9 ng/ml, respectively; P < 0.001). Multivariable logistic regression analyses indicated that the relationship between levels of sRAGE and PGD was attenuated by elevated right heart pressures and by the use of cardiopulmonary bypass. Median sRAGE levels were higher in subjects with cardiopulmonary bypass at both 6 hours (P = 0.003) and 24 hours (P < 0.001). sRAGE levels at 6 hours were significantly associated with intraoperative red cell transfusion (Spearman's ρ = 0.39, P = 0.002 in those with PGD), and in multivariable linear regression analyses this association was independent of confounding variables (P = 0.02).
Conclusions: Elevated plasma levels of sRAGE are associated with PGD after lung transplantation. Furthermore, plasma sRAGE levels are associated with blood product transfusion and use of cardiopulmonary bypass.
PMCID: PMC2778153  PMID: 19661249
primary graft dysfunction; reperfusion injury; lung transplantation; receptor for advanced glycation end products; acute lung injury

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