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1.  Pulmonary Vascular Complications of Liver Disease 
Hepatopulmonary syndrome and portopulmonary hypertension are two pulmonary vascular complications of liver disease. The pathophysiology underlying each disorder is distinct, but patients with either condition may be limited by dyspnea. A careful evaluation of concomitant symptoms, the physical examination, pulmonary function testing and arterial blood gas analysis, and echocardiographic, imaging, and hemodynamic studies is crucial to establishing (and distinguishing) these diagnoses. Our understanding of the pathobiology, natural history, and treatment of these disorders has advanced considerably over the past decade; however, the presence of either still increases the risk of morbidity and mortality in patients with underlying liver disease. There is no effective medical treatment for hepatopulmonary syndrome. Although liver transplantation can resolve hepatopulmonary syndrome, there appears to be worse survival even with transplantation. Liver transplantation poses a very high risk of death in those with significant portopulmonary hypertension, where targeted medical therapies may improve functional status and allow successful transplantation in a small number of select patients.
PMCID: PMC3570657  PMID: 23155142
hepatopulmonary syndrome; hypertension; pulmonary; liver cirrhosis; pulmonary circulation
2.  Erythropoietin upregulation in pulmonary arterial hypertension 
Pulmonary Circulation  2014;4(2):269-279.
The pathophysiologic alterations of patients with pulmonary arterial hypertension (PAH) are diverse. We aimed to determine novel pathogenic pathways from circulating proteins in patients with PAH. Multianalyte profiling (MAP) was used to measure 90 specifically selected antigens in the plasma of 113 PAH patients and 51 control patients. Erythropoietin (EPO) functional activity was assessed via in vitro pulmonary artery endothelial cell networking and smooth muscle cell proliferation assays. Fifty-eight patients had idiopathic PAH, whereas 55 had other forms of PAH; 5 had heritable PAH, 18 had connective tissue disease (15 with scleroderma and 3 with lupus erythematosis), 13 had portopulmonary hypertension, 6 had PAH associated with drugs or toxins, and 5 had congenital heart disease. The plasma-antigen profile of PAH revealed increased levels of several novel biomarkers, including EPO. Immune quantitative and histochemical studies revealed that EPO not only was significantly elevated in the plasma of PAH patients but also promoted pulmonary artery endothelial cell network formation and smooth muscle cell proliferation. MAP is a hypothesis-generating approach to identifying novel pathophysiologic pathways in PAH. EPO is upregulated in the circulation and lungs of patients with PAH and may affect endothelial and smooth muscle cell proliferation.
PMCID: PMC4070770
pulmonary arterial hypertension; plasma proteomics; multianalyte profiling; erythropoietin
3.  Pentraxin-3 and the right ventricle: the Multi-Ethnic Study of Atherosclerosis–Right Ventricle Study 
Pulmonary Circulation  2014;4(2):250-259.
Pentraxin-3 (PTX3) is a protein mediator of innate immunity that is elevated in the setting of left heart disease and pulmonary arterial hypertension. The relationship between PTX3 and right ventricular (RV) structure and function is not known. We included men and women with magnetic resonance imaging assessment of RV structure and function and measurement of PTX3 from the Multi-Ethnic Study of Atherosclerosis, a study of individuals free of clinical cardiovascular disease. Multivariable linear regression estimated associations between PTX3 protein levels and RV measures after adjusting for demographic characteristics, anthropometrics, smoking status, diabetes mellitus, hypertension, and corresponding left ventricular (LV) parameters. Instrumental variable analysis exploiting Mendelian randomization was attempted using two-stage least squares regression. The study sample included 1,779 participants with available PTX3 levels, RV measures, and all covariables. Mean PTX3 level was 2.1 ng/mL. Higher PTX3 was independently associated with greater RV mass and larger RV end-diastolic volume with and without adjustment for the corresponding LV parameters or C-reactive protein (all P < .05). There was no association between PTX3 and RV ejection fraction or stroke volume. Single-nucleotide polymorphisms were not associated with PTX3 protein levels or RV measures after accounting for race. Instrumental variable analysis could not be reliably performed. Higher PTX3 protein levels were associated with greater RV mass and larger RV end-diastolic volume. These associations were independent of common cardiovascular risk factors and LV morphologic changes. Inflammation is associated with differences in the pulmonary circulation-RV axis in adults without clinical cardiovascular disease.
PMCID: PMC4070771
pulmonary hypertension; heart failure; inflammation; right ventricle; Mendelian randomization
4.  Pulmonary Hyperinflation and Left Ventricular Mass 
Circulation  2013;127(14):1503-1511e6.
Left ventricular (LV) mass is an important predictor of heart failure and cardiovascular mortality, yet determinants of LV mass are incompletely understood. Pulmonary hyperinflation in chronic obstructive pulmonary disease (COPD) may contribute to changes in intrathoracic pressure that increase LV wall stress. We therefore hypothesized that residual lung volume in COPD would be associated with greater LV mass.
Methods and results
The Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study recruited smokers aged 50–79 years who were free of clinical cardiovascular disease. LV mass was measured by cardiac magnetic resonance. Pulmonary function testing was performed according to guidelines. Regression models were used to adjust for age, sex, body size, blood pressure and other cardiac risk factors.
Among 119 MESA COPD Study participants, mean age was 69±6 years, 55% were male and 65% had COPD, mostly of mild or moderate severity. Mean LV mass was 128±34 grams. Residual lung volume was independently associated with greater LV mass (7.2 grams per standard deviation increase in residual volume; 95% CI 2.2 to 12; P=0.004), and was similar in magnitude to that of systolic blood pressure (7.6 grams per standard deviation increase in systolic blood pressure, 95% CI 4.3 to 11 grams; p<0.001). Similar results were observed for LV mass to end-diastolic volume ratio (p=0.02) and with hyperinflation measured as residual volume to total lung capacity ratio (P=0.009).
Pulmonary hyperinflation, as measured by residual lung volume or residual lung volume to total lung capacity ratio, is associated with greater LV mass.
PMCID: PMC4018203  PMID: 23493320
Left ventricular mass; hyperinflation; chronic obstructive pulmonary disease
5.  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
6.  Lower Socioeconomic Status Is Associated with Worse Outcomes in Pulmonary Arterial Hypertension 
Rationale: Lower socioeconomic status (SES) confers a heightened risk of common cardiovascular and pulmonary diseases and increased mortality. The association of SES with outcomes in patients with pulmonary arterial hypertension (PAH) is less clear.
Objectives: To determine the association between SES and outcomes in patients with PAH.
Methods: We performed a prospective cohort study at a national referral center for patients with PAH in China. Two hundred sixty-two consecutive incident patients aged 18 to 65 years with a diagnosis of idiopathic PAH were recruited between January 2007 and June 2011 and followed up until November 2011. The primary endpoint was all-cause mortality. An SES score for each patient was derived from their educational level, annual household income, occupation, and medical reimbursement rate.
Measurements and Main Results: Patients with a lower SES had higher unadjusted mortality rates, with 3-year survival estimates of 50.1, 70.8, and 86.0% in increasing tertiles of SES (P for trend < 0.001). After adjustment for clinical features, hemodynamics, and type of PAH treatment, the hazard ratios for death were 2.98 (95% confidence interval, 1.51–5.89) in the lowest tertile of SES and 1.80 (95% confidence interval, 0.89–3.63) in the middle tertile of SES compared with the upper tertile (P for trend = 0.006).
Conclusions: A lower SES is strongly associated with a higher risk of death in idiopathic PAH. This association was independent of clinical characteristics, hemodynamics, and treatment. Addressing the health disparities associated with a lower SES may improve the outcomes of patients with PAH.
PMCID: PMC3603556  PMID: 23220911
pulmonary arterial hypertension; socioeconomic status; survival
7.  Von Willebrand Factor and the Right Ventricle (The MESA-Right Ventricle Study) 
The American journal of cardiology  2012;110(12):1846-1851.
Elevation in plasma activity of von Willebrand Factor (vWF) reflects endothelial dysfunction and predicts death in pulmonary arterial hypertension (PAH). Higher vWF activity is also associated with lower right ventricular (RV) ejection fraction in PAH. Little is known about the relationship between vWF and RV structure and function in adults without cardiovascular disease. In the current investigation, we included 1,976 participants with MRI assessment of RV structure and function and measurement of vWF activity from the Multi-Ethnic Study of Atherosclerosis. Multivariable linear regression was used to estimate the associations between vWF activity and measures of RV structure and function after adjusting for demographics, anthropometrics, smoking, diabetes mellitus, hypertension and the corresponding left ventricular (LV) parameter. The average vWF activity was 140.7 ± 57.2%. Elevated vWF activity was independently associated with lower RV mass, RV end-diastolic volume and RV stroke volume in models with and without adjustment for the corresponding LV parameter (all p < 0.05). There was no association observed between vWF activity and RV ejection fraction. In conclusion, higher vWF activity is associated with lower RV mass, RV end-diastolic volume and RV stroke volume. These associations are independent of common cardiovascular risk factors and LV morphologic changes.
PMCID: PMC3696516  PMID: 22995970
Cardiovascular Imaging; Biomarkers; Pulmonary Hypertension; Right Ventricle
8.  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
9.  Lung Retransplantation 
Clinics in chest medicine  2011;32(2):367-377.
Lung retransplantation comprises a small proportion of lung transplants performed throughout the world, but has become more frequent in recent years. The selection criteria for lung retransplantation are similar to those for initial lung transplant. Survival after lung retransplantation has improved over time, but still lags behind that of initial lung transplantation. These differences in outcome may be attributable to medical comorbidities. Lung retransplantation appears to be ethically justified, however the optimal approach to lung allocation for retransplantation needs to be defined.
PMCID: PMC3081645  PMID: 21511096
lung transplantation; retransplantation
10.  Right Ventricular Structure is Associated with the Risk of Heart Failure and Cardiovascular Death: The MESA-Right Ventricle Study 
Circulation  2012;126(14):1681-1688.
Changes in right ventricular (RV) morphology are associated with morbidity and mortality in heart and lung disease. We examined the association of abnormal RV structure and function with the risk of heart failure (HF) or cardiovascular death in a population-based multiethnic sample free of clinical cardiovascular disease at baseline.
Methods and Results
The Multi-Ethnic Study of Atherosclerosis (MESA) performed cardiac magnetic resonance imaging (MRI) on 5098 participants between 2000–2002 with follow-up for incident heart failure and cardiovascular death (“death”) until January 2008. RV volumes and mass were available for 4204 participants. The study sample (N = 4,144) was 61.4 ± 10.1 years old and 47.6 % male. The presence of RV hypertrophy (increased RV mass) was associated with a more than twice the risk of heart failure or death after adjustment for demographics, body mass index, education, C-reactive protein level, hypertension, and smoking status (HR = 2.52, 95%CI 1.55–4.10, p < 0.001) and a doubling of risk (or more) with left ventricular mass at the mean value or lower (p for interaction = 0.05).
RV hypertrophy was associated with the risk of heart failure or death in a multi-ethnic population free of clinical cardiovascular disease at baseline.
PMCID: PMC3532921  PMID: 22932258
right ventricle; pulmonary heart disease; magnetic resonance imaging; pulmonary hypertension; survival
11.  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
12.  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
13.  Surrogate End Points in Pulmonary Arterial Hypertension: Assessing the Response to Therapy 
Clinics in chest medicine  2007;28(1):75-viii.
Pulmonary arterial hypertension (PAH) is a rare disease which is characterized by increased pulmonary vascular resistance and right heart failure. Recent discoveries in disease pathophysiology have been translated into effective therapies tested in clinical trials. The studies which have led to the regulatory board approval of therapies for PAH have focused on surrogate and intermediate end points, thought to reflect quantity and quality of life, respectively. However, validation of many of these surrogates is incomplete. It is also unknown which indicators of function or long-term survival should be used to formulate decisions regarding addition, discontinuation, or combination of therapies. Identification of suitable end points would therefore not only help investigators design appropriate clinical trials, but also assist clinicians in caring for patients with PAH. Hemodynamic, cardiac imaging, plasma biomarkers, and exercise testing hold some promise as potential surrogate end points for PAH. Functional status and quality of life assessments may also have important roles. Future studies should validate the most promising surrogate markers, so that patients, clinicians, subjects, and investigators may benefit from the advantages they confer on clinical care and on clinical trials.
PMCID: PMC1868503  PMID: 17338929
14.  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
15.  Subclinical Atherosclerosis, Airflow Obstruction and Emphysema: the MESA Lung Study 
Airflow obstruction is independent risk factor for cardiovascular events in the general population. The affected vascular bed and contribution of emphysema to cardiovascular risk are unclear. We examined if an obstructive pattern of spirometry and quantitatively defined emphysema were associated with subclinical atherosclerosis in the carotid, peripheral and coronary circulations.
The Multi-Ethnic Study of Atherosclerosis recruited participants age 45–84 years without clinical cardiovascular disease. Spirometry, carotid intima-media thickness, ankle-brachial index and coronary artery calcium were measured using standard protocols. Percent of emphysema-like lung was measured in the lung windows of cardiac computed tomography scans among 3,642 participants. Multiple linear regression was used to adjust for cardiac risk factors including C-reactive protein.
Decrements in the FEV1 and FEV1/FVC were associated with greater internal carotid intima-media thickness among smokers (P=0.03 and P<0.001, respectively) whereas percent emphysema was associated with reduced ankle-brachial index regardless of smoking history (P=0.004). Coronary artery calcium was associated with neither lung function (prevalence ratio for severe airflow obstruction: 0.99; 95% CI, 0.91 to 1.07) nor percent emphysema.
An obstructive pattern of spirometry and emphysema are associated distinctly and independently with subclinical atherosclerosis in the carotid arteries and peripheral circulation, respectively, and were not independently related to coronary artery calcium.
PMCID: PMC3616898  PMID: 22034646
16.  A multicenter, retrospective study of patients with pulmonary arterial hypertension transitioned from parenteral prostacyclin therapy to inhaled iloprost 
Pulmonary Circulation  2013;3(2):381-388.
Pulmonary arterial hypertension (PAH) is characterized by progressive increases in pulmonary vascular resistance, leading to right heart failure and death. Guidelines recommend customization of treatment, necessitating the development of effective strategies for transitioning patients among treatments. In this study, we characterized our experience with patient transitions from parenteral prostacyclin to inhaled iloprost. We retrospectively assessed records from 11 centers of 37 consecutive patients with PAH aged ≥ 18 years who were treated with intravenous (IV) or subcutaneous (SC) prostacyclin analogues and transitioned to inhaled iloprost. The transition period began on the first day of inhaled iloprost with the intent of discontinuing parenteral prostacyclin and ended on the first day on inhaled iloprost free of parenteral prostacyclin. Persistence was defined as the absence of (1) parenteral prostacyclin while remaining on inhaled iloprost during post-transition Days 1-90 and (2) no reinitiation of parenteral prostacyclin during post-transition Days 90-365. All patients were clinically stable before transitioning to inhaled iloprost. The mean age was 46.5 years, 70.3% were female, 51.4% had idiopathic PAH, and 43.0% were in New York Heart Association Functional Class III. Among patients with an overlapping transition, the mean transition period was 10.5 days. A transition dosing algorithm was used in 10 patients (27.0%). At one year, 78.4% of the patients remained persistent on inhaled iloprost and 81.1% were free of clinical worsening. In selected patients on background oral PAH therapy, transitioning from parenteral prostacyclin to inhaled iloprost appears safe and feasible and is associated with long-term success. Further study is needed to define the optimal patient selection criteria and transition algorithm.
PMCID: PMC3757833  PMID: 24015339
iloprost; persistence; prostacyclin; pulmonary arterial hypertension; transition; treatment strategy
17.  Determinants of Right Ventricular Ejection Fraction in Pulmonary Arterial Hypertension* 
Chest  2008;135(3):752-759.
Right ventricular function is a key determinant of exercise capacity and survival in pulmonary arterial hypertension (PAH). We aimed to study the predictors of right ventricular ejection fraction (RVEF) in patients with newly diagnosed PAH.
We performed a cross-sectional analysis of a retrospective cohort of consecutive patients with idiopathic, familial, or anorexigen-associated PAH who underwent equilibrium radionuclide angiography for measurement of RVEF at baseline.
Of the 84 patients in the cohort, 63 underwent equilibrium radionuclide angiography and right heart catheterization and were included. The mean age was 41 ± 13 years, and 79% of the patients were female. The mean RVEF was 30 ± 8%. RVEF was directly associated with right ventricular stroke volume index and cardiac index, and inversely associated with pulmonary vascular resistance index from right heart catheterization (all p < 0.001). Older age and male sex were associated with lower RVEF (p < 0.05) after adjustment for pulmonary vascular resistance index and left ventricular ejection fraction. Higher plasma von Willebrand factor levels were also independently associated with lower RVEF (p = 0.01) (n = 55). Body size and type of PAH were not associated with RVEF.
Older patients and males with PAH had lower RVEF at baseline than younger patients and females, even after controlling for left ventricular function and hemodynamics. Higher plasma von Willebrand factor levels, a marker of endothelial dysfunction, were also associated with lower RVEF.
PMCID: PMC2834785  PMID: 18849396
hypertension; pulmonary; right ventricle; von Willebrand factor
18.  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
19.  Advancing clinical trial design in pulmonary hypertension 
Pulmonary Circulation  2013;3(1):217-225.
In pulmonary hypertension, as in many other diseases, there is a need for a smarter approach to evaluating new treatments. The traditional randomized controlled trial has served medical science well, but constrains the development of treatments for rare diseases. A workshop was established to consider alternative clinical trial designs in pulmonary hypertension and here discusses their merits, limitations and challenges to implementation of novel approaches.
PMCID: PMC3641733  PMID: 23662200
pulmonary arterial hypertension; clinical trial design; adaptive designs; modeling and simulation; Bayesian modeling; group sequential designs; population enrichment
20.  Six-Minute-Walk Distance Predicts Waiting List Survival in Idiopathic Pulmonary Fibrosis 
Rationale: Functional studies may be useful to predict survival in idiopathic pulmonary fibrosis (IPF). Various cutoffs of 6-min-walk distance (6MWD) have been suggested to identify patients at a high risk of death.
Objectives: To examine the association between 6MWD and survival in patients with IPF listed for lung transplantation, and to identify sensitive and specific cutoffs for predicting death at 6 mo.
Methods: We performed a retrospective cohort study of 454 patients classified as having IPF listed for lung transplantation with the United Network for Organ Sharing between June 30, 2004 and July 22, 2005.
Measurements and Main Results: Lower 6MWD was associated with an increased mortality rate (p value for linear trend < 0.0001). Patients with a walk distance less than 207 m had a more than fourfold greater mortality rate than those with a walk distance of 207 m or more, despite adjustment for demographics, anthropomorphics, FVC % predicted, pulmonary hypertension, and medical comorbidities (adjusted rate ratio, 4.7; 95% confidence interval, 2.5–8.9; p < 0.0001). 6MWD was a significantly better predictor of 6-mo mortality than was FVC % predicted (c-statistic = 0.73 vs. 0.59, respectively; p = 0.02).
Conclusions: Lower 6MWD was strongly and independently associated with an increased mortality rate for wait-listed patients classified as having IPF. 6MWD was a better predictor of death at 6 mo than was FVC % predicted.
PMCID: PMC2648057  PMID: 16778159
cohort; exercise test; lung diseases, interstitial; lung transplantation
21.  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
22.  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
23.  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
24.  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
25.  Percent Emphysema, Airflow Obstruction, and Impaired Left Ventricular Filling 
The New England journal of medicine  2010;362(3):217-227.
Very severe chronic obstructive pulmonary disease causes cor pulmonale with elevated pulmonary vascular resistance and secondary reductions in left ventricular filling, stroke volume, and cardiac output. We hypothesized that emphysema, as detected on computed tomography (CT), and airflow obstruction are inversely related to left ventricular end-diastolic volume, stroke volume, and cardiac output among persons without very severe lung disease.
We measured left ventricular structure and function with the use of magnetic resonance imaging in 2816 persons who were 45 to 84 years of age. The extent of emphysema (expressed as percent emphysema) was defined as the percentage of voxels below −910 Hounsfield units in the lung windows on cardiac computed tomographic scans. Spirometry was performed according to American Thoracic Society guidelines. Generalized additive models were used to test for threshold effects.
Of the study participants, 13% were current smokers, 38% were former smokers, and 49% had never smoked. A 10-point increase in percent emphysema was linearly related to reductions in left ventricular end-diastolic volume (−4.1 ml; 95% confidence interval [CI], −3.3 to −4.9; P<0.001), stroke volume (−2.7 ml; 95% CI, −2.2 to −3.3; P<0.001), and cardiac output (−0.19 liters per minute; 95% CI, −0.14 to −0.23; P<0.001). These associations were of greater magnitude among current smokers than among former smokers and those who had never smoked. The extent of airflow obstruction was similarly associated with left ventricular structure and function, and smoking status had similar modifying effects on these associations. Percent emphysema and airflow obstruction were not associated with the left ventricular ejection fraction.
In a population-based study, a greater extent of emphysema on CT scanning and more severe airflow obstruction were linearly related to impaired left ventricular filling, reduced stroke volume, and lower cardiac output without changes in the ejection fraction.
PMCID: PMC2887729  PMID: 20089972

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