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1.  Comparison of Treatment Response in Idiopathic and Connective Tissue Disease–associated Pulmonary Arterial Hypertension 
Rationale: Studies suggest that patients with connective tissue disease–associated pulmonary arterial hypertension (CTD-PAH) have a poorer treatment response to therapies for PAH compared with patients with idiopathic PAH (IPAH), but individual randomized controlled trials (RCTs) have been underpowered to examine differences within these subgroups.
Objectives: To compare the effect of therapy for PAH in CTD-PAH versus IPAH.
Methods: We obtained individual participant data from phase III placebo-controlled RCTs of therapies for PAH submitted to the U.S. Food and Drug Administration for drug approval. A treatment-by-diagnosis interaction term evaluated differences in treatment response between CTD-PAH and IPAH. Outcomes included change in 6-minute-walk distance (∆6MWD) from baseline to 12 weeks, clinical worsening, and all-cause mortality.
Measurements and Main Results: The study sample included 827 participants with CTD-PAH and 1,935 with IPAH from 11 RCTs. Patients with CTD-PAH had less improvement in 6MWD when assigned to active treatment versus placebo compared with patients with IPAH (difference in treatment effect on ∆6MWD in CTD-PAH vs. IPAH, −17.3 m; 90% confidence interval, −31.3 to −3.3; P for interaction = 0.043). Treatment was less effective in reducing the occurrence of clinical worsening in CTD-PAH versus IPAH (P for interaction = 0.012), but there was no difference in the placebo-adjusted effect of treatment on mortality (P for interaction = 0.65).
Conclusions: Treatment for PAH was less effective in CTD-PAH compared with IPAH in terms of increasing 6MWD and preventing clinical worsening. The heterogeneity of treatment response supports the need for identifying therapies that are more effective for CTD-PAH.
doi:10.1164/rccm.201507-1456OC
PMCID: PMC4642205  PMID: 26291092
pulmonary hypertension; clinical trial; meta-analysis
2.  Pulmonary Microvascular Blood Flow in Mild Chronic Obstructive Pulmonary Disease and Emphysema. The MESA COPD Study 
Rationale: Smoking-related microvascular loss causes end-organ damage in the kidneys, heart, and brain. Basic research suggests a similar process in the lungs, but no large studies have assessed pulmonary microvascular blood flow (PMBF) in early chronic lung disease.
Objectives: To investigate whether PMBF is reduced in mild as well as more severe chronic obstructive pulmonary disease (COPD) and emphysema.
Methods: PMBF was measured using gadolinium-enhanced magnetic resonance imaging (MRI) among smokers with COPD and control subjects age 50 to 79 years without clinical cardiovascular disease. COPD severity was defined by standard criteria. Emphysema on computed tomography (CT) was defined by the percentage of lung regions below −950 Hounsfield units (−950 HU) and by radiologists using a standard protocol. We adjusted for potential confounders, including smoking, oxygenation, and left ventricular cardiac output.
Measurements and Main Results: Among 144 participants, PMBF was reduced by 30% in mild COPD, by 29% in moderate COPD, and by 52% in severe COPD (all P < 0.01 vs. control subjects). PMBF was reduced with greater percentage emphysema−950HU and radiologist-defined emphysema, particularly panlobular and centrilobular emphysema (all P ≤ 0.01). Registration of MRI and CT images revealed that PMBF was reduced in mild COPD in both nonemphysematous and emphysematous lung regions. Associations for PMBF were independent of measures of small airways disease on CT and gas trapping largely because emphysema and small airways disease occurred in different smokers.
Conclusions: PMBF was reduced in mild COPD, including in regions of lung without frank emphysema, and may represent a distinct pathological process from small airways disease. PMBF may provide an imaging biomarker for therapeutic strategies targeting the pulmonary microvasculature.
doi:10.1164/rccm.201411-2120OC
PMCID: PMC4595687  PMID: 26067761
pulmonary microvascular blood flow (PMBF); gadolinium-enhanced MRI; chronic obstructive pulmonary disease (COPD); lung emphysema; small airway disease
4.  Particulate Matter Exposure and Cardiopulmonary Differences in the Multi-Ethnic Study of Atherosclerosis 
Environmental Health Perspectives  2016;124(8):1166-1173.
Background:
Particulate matter (PM) exposure may directly affect the pulmonary vasculature. Although the pulmonary vasculature is not easily measurable, differential associations for right ventricular (RV) and left ventricular (LV) mass may provide an indirect assessment of pulmonary vascular damage.
Objectives:
We tested whether long-term exposure to PM < 2.5 μm (PM2.5) is associated with greater RV mass and RV mass/end-diastolic volume ratio relative to the LV.
Methods:
The Multi-Ethnic Study of Atherosclerosis performed cardiac magnetic resonance (CMR) imaging among participants 45–84 years old without clinical cardiovascular disease in 2000–2002 in six U.S. cities. A fine-scale spatiotemporal model estimated ambient PM2.5 exposure in the year before CMR; individually weighted estimates accounted for indoor exposure to ambient PM2.5. Linear regression models were adjusted for demographics, anthropometrics, smoking status, cardiac risk factors, and LV parameters, with additional adjustment for city.
Results:
The 4,041 included participants had a mean age of 61.5 years, and 47% were never smokers. The mean ambient PM2.5 was 16.4 μg/m3 and individually weighted PM2.5 was 11.0 μg/m3. PM2.5 exposure was associated with greater RV mass [ambient: 0.11 g per 5 μg/m3 (95% CI: –0.05, 0.27); individually weighted: 0.20 g per 5 μg/m3 (95% CI: 0.04, 0.36)] and a greater RV mass/end-diastolic volume ratio conditional on LV parameters. City-adjusted results for RV mass were of greater magnitude and were statistically significant for both measures of PM2.5, whereas those for RV mass/end-diastolic volume ratio were attenuated.
Conclusions:
Long-term PM2.5 exposures were associated with greater RV mass and RV mass/end-diastolic volume ratio conditional on the LV; however, additional adjustment for city attenuated the RV mass/end-diastolic volume findings. These findings suggest that PM2.5 exposure may be associated with subclinical cardiopulmonary differences in this general population sample.
Citation:
Aaron CP, Chervona Y, Kawut SM, Diez Roux AV, Shen M, Bluemke DA, Van Hee VC, Kaufman JD, Barr RG. 2016. Particulate matter exposure and cardiopulmonary differences in the Multi-Ethnic Study of Atherosclerosis. Environ Health Perspect 124:1166–1173; http://dx.doi.org/10.1289/ehp.1409451
doi:10.1289/ehp.1409451
PMCID: PMC4977039  PMID: 26859533
5.  Determinants of 6-minute walk distance in patients with idiopathic pulmonary fibrosis undergoing lung transplant evaluation 
Pulmonary Circulation  2016;6(1):30-36.
Little is known about the physiologic determinants of 6-minute walk distance in idiopathic pulmonary fibrosis. We investigated the demographic, pulmonary function, echocardiographic, and hemodynamic determinants of 6-minute walk distance in patients with idiopathic pulmonary fibrosis evaluated for lung transplantation. We performed a cross-sectional analysis of 130 patients with idiopathic pulmonary fibrosis who completed a lung transplantation evaluation at the Hospital of the University of Pennsylvania between 2005 and 2010. Multivariable linear regression analysis was used to generate an explanatory model for 6-minute walk distance. After adjustment for age, sex, race, height, and weight, the presence of right ventricular dilation was associated with a decrease of 50.9 m (95% confidence interval [CI], 8.4–93.3) in 6-minute walk distance (P=0.02). For each 200-mL reduction in forced vital capacity, the walk distance decreased by 15.0 m (95% CI, 9.0–21.1; P<0.001). For every increase of 1 Wood unit in pulmonary vascular resistance, the walk distance decreased by 17.3 m (95% CI, 5.1–29.5; P=0.006). Six-minute walk distance in idiopathic pulmonary fibrosis depends in part on circulatory impairment and the degree of restrictive lung disease. Future trials that target right ventricular morphology, pulmonary vascular resistance, and forced vital capacity may potentially improve exercise capacity in patients with idiopathic pulmonary fibrosis.
doi:10.1086/685022
PMCID: PMC4809664  PMID: 27076905
exercise capacity; interstitial lung disease; right ventricular dilation
6.  Adverse Events in Connective Tissue Disease–Associated Pulmonary Arterial Hypertension 
Objective
Patients with connective tissue disease (CTD)–associated pulmonary arterial hypertension (PAH) have a poorer prognosis compared to those with idiopathic PAH, but little is known about the differences in treatment-related adverse events (AEs) and serious adverse events (SAEs) between these groups. This study was undertaken to characterize these differences.
Methods
Individual patient-level data from 10 randomized controlled trials of therapies for PAH were obtained from the US Food and Drug Administration. Patients diagnosed as having either CTD-associated PAH or idiopathic PAH were included. A treatment-by-diagnosis interaction term was used to examine whether the effect of treatment on occurrence of AEs differed between patients with CTD-associated PAH and those with idiopathic PAH. Studies were pooled using fixed-effect models.
Results
The study sample included 2,370 participants: 716 with CTD-associated PAH and 1,654 with idiopathic PAH. In the active treatment group compared to the placebo group, the risk of AEs was higher among patients with CTD-associated PAH than among those with idiopathic PAH (odds ratio [OR] 1.57, 95% confidence interval [95% CI] 1.00–2.47 versus OR 0.94, 95% CI 0.69–1.26; P for interaction = 0.061), but there was no difference in the risk of SAEs in analyses adjusted for age, race, sex, hemodynamic findings, and laboratory values. Despite the higher occurrence of AEs in patients with CTD-associated PAH assigned to active therapy compared to those receiving placebo, the risk of drug discontinuation due to an AE was similar to that in patients with idiopathic PAH assigned to active therapy (P for interaction = 0.27).
Conclusion
Patients with CTD-associated PAH experienced more treatment-related AEs compared to those with idiopathic PAH in therapeutic clinical trials. These findings suggest that the overall benefit of advanced therapies for PAH may be attenuated by the greater frequency of AEs.
doi:10.1002/art.39220
PMCID: PMC4949955  PMID: 26016953
7.  Pericardial Fat and Right Ventricular Morphology: The Multi-Ethnic Study of Atherosclerosis- Right Ventricle Study (MESA-RV) 
PLoS ONE  2016;11(6):e0157654.
Background
Pericardial fat has been implicated in the pathogenesis of obesity-related cardiovascular disease. Proposed mechanisms may be relevant in right heart failure, but relationships between pericardial fat and right ventricular (RV) morphology have not been explored.
Methods
The Multi-Ethnic Study of Atherosclerosis is a prospective cohort that enrolled participants without clinical cardiovascular disease. Pericardial fat was measured using computed tomography and RV parameters using cardiac MRI. Linear regression estimated associations of pericardial fat with RV mass, RV end diastolic volume (RV-EDV), RV end systolic volume (RV-ESV), RV stroke volume (RV-SV), and RV ejection fraction (RV-EF). Limited models adjusted for age, gender, race, height, and study site with and without weight. Fully adjusted models also accounted for socioeconomic parameters and health behaviors. Adjustment for left ventricular morphology, metabolic syndrome, and systemic inflammation was also performed.
Results
The study sample included 3988 participants with complete assessment of RV morphology, pericardial fat and all covariates. Greater pericardial fat volume was associated with reduced RV mass (-0.3g per 40 cm3 increase in pericardial fat, p<0.001), smaller RV-EDV (-3.7ml per 40 cm3 increase in pericardial fat, p<0.001), smaller RV-ESV (-1.0ml per 40cm3 increase in pericardial fat, p<0.001), and smaller RV-SV (-2.7mL per 40 cm3 increase in pericardial fat, p<0.001) in participants after adjustment for weight. Associations were unchanged when accounting for health behaviors, markers of systemic inflammation, and the metabolic syndrome.
Conclusions
Greater pericardial fat was associated with reduced RV mass, smaller RV-EDV, smaller RV-ESV, and smaller RV-SV in participants after adjustment for weight. Relationships between pericardial fat and RV morphology could be relevant to diseases of right heart failure.
doi:10.1371/journal.pone.0157654
PMCID: PMC4911142  PMID: 27311062
8.  Sildenafil for Chronic Obstructive Pulmonary Disease: A Randomized Crossover Trial 
COPD  2012;9(3):268-275.
Rationale
Pulmonary hypertension with exercise is common in chronic obstructive pulmonary disease (COPD) and may contribute to exercise limitation in this disease. We aimed to determine the effects of treatment with sildenafil on exercise capacity in patients with COPD and emphysema.
Methods
We performed a randomized, double-blind, placebo-controlled 2-period crossover trial of sildenafil thrice daily in ten adults with COPD and emphysema on CT scan without pulmonary hypertension. We randomized study participants to 4 weeks of sildenafil (or placebo) followed by a 1-week washout and then 4 weeks of placebo (or sildenafil). The 2 primary outcomes were the 6-minute walk distance and oxygen consumption at peak exercise.
Results
Sildenafil had no effect on 6-minute walk distance (placebo-corrected difference = −7.8 m, 95% confidence interval, −23.2 to 7.5 m, p = 0.35) or oxygen consumption at peak exercise (placebo-corrected difference = −0.1 ml/kg/min, 95% confidence interval −2.1 to 1.8 ml/kg/min, p = 0.89). Sildenafil increased the alveolar-arterial oxygen gradient (p = 0.02), worsened symptoms (p = 0.04), and decreased quality-of-life (p = 0.03). Adverse events were more frequent while receiving sildenafil (p = 0.005).
Conclusions
Routine sildenafil administration did not have a beneficial effect on exercise capacity in patients with COPD and emphysema without pulmonary hypertension. Sildenafil significantly worsened gas exchange at rest and quality of life. (clinicaltrials.gov NCT00104637).
doi:10.3109/15412555.2011.651180
PMCID: PMC4904720  PMID: 22360383
Sildenafil; Emphysema; Clinical Trial; COPD; Pulmonary hypertension
9.  Oestradiol metabolism and androgen receptor genotypes are associated with right ventricular function 
The European respiratory journal  2015;47(2):553-563.
Sex hormones are linked to right ventricular (RV) function, but the relationship between genetic variation in these pathways and RV function is unknown.
We performed a cross-sectional study of 2761 genotyped adults without cardiovascular disease. The relationships between RV measures and single nucleotide polymorphisms (SNPs) in 10 candidate genes were assessed. Urinary oestradiol (E2) metabolites produced by cytochrome P4501B1 (CYP1B1) and serum testosterone were measured in women and men respectively. In African-American (AA) women, the CYP1B1 SNP rs162561 was associated with RV ejection fraction (RVEF), such that each copy of the A allele was associated with a 2.0% increase in RVEF. Haplotype analysis revealed associations with RVEF in AA (global p<7.2×10−6) and white (global p=0.05) women. In white subjects, higher E2 metabolite levels were associated with significantly higher RVEF. In men, androgen receptors SNPs (rs1337080; rs5918764) were significantly associated with all RV measures and modified the relationship between testosterone and RVEF.
Genetic variation in E2 metabolism and androgen signalling was associated with RV morphology in a sex-specific manner. The CYP1B1 SNP identified is in tight linkage disequilibrium with SNPs associated with pulmonary hypertension and oncogenesis, suggesting these pathways may underpin sexual dimorphism in RV failure.
doi:10.1183/13993003.01083-2015
PMCID: PMC4831135  PMID: 26647441
10.  Are Hemodynamics Surrogate Endpoints in Pulmonary Arterial Hypertension? 
Circulation  2014;130(9):768-775.
Background
While frequently assessed in trials and clinical practice, hemodynamic response to therapy has never been validated as a surrogate endpoint for clinical events in pulmonary arterial hypertension (PAH).
Methods and Results
We performed a patient-level pooled analysis of four randomized placebo-controlled trials to determine if treatment-induced changes in hemodynamic values at 12 weeks accounted for the relationship between treatment assignment and the probability of early clinical events (death, lung transplantation, atrial septostomy, PAH hospitalization, withdrawal for clinical worsening, escalation in PAH therapy). We included 1119 subjects with PAH. The median (interquartile range) age was 48 (37 – 59), and 23% were men. 656 (59%) received active therapy (101 [15%] iloprost, 118 [18%] sitaxsentan, 204 [31%] sildenafil, and 233 [36%] subcutaneous treprostinil). Active treatment significantly lowered right atrial pressure (RAP), mean pulmonary artery pressure (mPAP), and pulmonary vascular resistance and increased cardiac output and index (p < 0.01 for all). Changes in hemodynamic values (except for RAP and mPAP) were significantly associated with the risk of a clinical event (p ≤ 0.01 for all). While active treatment approximately halved the odds of a clinical event compared to placebo (p < 0.001), changes in hemodynamics accounted for only 1.2 – 13.9% of the overall treatment effect.
Conclusions
Treatment-induced changes in hemodynamics at 12 weeks only partially explain the impact of therapy on the probability of early clinical events in PAH. These findings suggest that resting hemodynamics are not valid surrogate endpoints for short-term events in PAH clinical trials.
doi:10.1161/CIRCULATIONAHA.114.009690
PMCID: PMC4146736  PMID: 24951771
hemodynamics; pulmonary heart disease; trials
12.  Protein quantitative trait loci analysis identifies genetic variation in the innate immune regulator TOLLIP in post lung transplant primary graft dysfunction risk 
Summary
We previously identified plasma plasminogen activator inhibitor-1 (PAI-1) level as a quantitative lung injury biomarker in PGD. We hypothesized plasma levels of PAI-1 used as a quantitative trait could facilitate discovery of genetic loci important in PGD pathogenesis.
A 2-stage cohort study was performed. In stage 1, we tested associations of loci with PAI-1 plasma level using linear modeling. Genotyping was performed using the Illumina CVD Bead Chip v2. Loci meeting a p<5×10−4 cutoff were carried forward and tested in Stage 2 for association with PGD.
297 enrollees were evaluated in Stage 1. 6 loci, associated with PAI-1, were carried forward to Stage 2 and evaluated in 728 patients. rs3168046 (Toll interacting protein, TOLLIP) was significantly associated with PGD (p=0.006). The increased risk of PGD for carrying at least one copy of this variant was 11.7% [95% CI: 4.9%, 18.5%]. The false positive rate for individuals with this genotype who did not have PGD was 6.1%.
Variants in the TOLLIP gene are associated with higher circulating PAI-1 plasma levels and validate for association with clinical PGD. A protein quantitative trait analysis for PGD risk prioritizes genetic variations in TOLLIP, and supports a role for toll-like receptors in PGD pathogenesis.
doi:10.1111/ajt.13525
PMCID: PMC4767612  PMID: 26663441
Primary Graft Dysfunction; Lung transplantation; Genes; quantitative trait; innate immunity
13.  Interleukin-6 and Tumor Necrosis Factor-α Are Associated with Quality of Life–Related Symptoms in Pulmonary Arterial Hypertension 
Rationale: Inflammation is associated with symptoms in many chronic illnesses; however, this link has not been established in pulmonary arterial hypertension.
Objectives: The objective of this study was to investigate the association between inflammatory markers and quality of life–related symptoms in patients with pulmonary arterial hypertension. We hypothesized that higher circulating IL-6 and tumor necrosis factor-α levels would be associated with worse quality of life–related symptoms.
Methods: We performed a secondary analysis using baseline and 3-month assessments of 62 subjects in a clinical trial of aspirin and simvastatin to determine the association between plasma IL-6 and tumor necrosis factor-α levels and the Medical Outcomes Study Short Form-36 subscales (pain, vitality, mental health).
Measurements and Main Results: The mean age was 49.7 ± 13.4 years; 87% were female. Higher IL-6 levels were significantly associated with lower Medical Outcomes Study Short Form-36 subscale scores, indicating worse bodily pain, vitality, and mental health (all P < 0.01). Higher tumor necrosis factor-α levels were significantly associated with increased bodily pain, but better mental health scores.
Conclusions: IL-6 and tumor necrosis factor-α levels are associated with certain quality of life domains in patients with pulmonary arterial hypertension.
Clinical trial registered with www.clinicaltrials.gov (NCT00384865).
doi:10.1513/AnnalsATS.201410-463OC
PMCID: PMC4418312  PMID: 25615959
pulmonary arterial hypertension; interleukin-6; tumor necrosis factor-α; fatigue; pain
14.  Noninvasive Tests for the Diagnostic Evaluation of Dyspnea Among Outpatients: the Multi-Ethnic Study of Atherosclerosis Lung Study 
The American journal of medicine  2014;128(2):171-180.e5.
Background
Dyspnea on exertion is a common and debilitating complaint, yet evidence for the relative value of cardiac and pulmonary tests for the evaluation of chronic dyspnea among adults without known cardiac or pulmonary disease is limited.
Methods
The Multi-Ethnic Study of Atherosclerosis (MESA) enrolled participants ages 45-84 years who were free of clinical cardiovascular disease from six communities; participants with clinical pulmonary disease were excluded from this report. Dyspnea on exertion was assessed via structured interview. Tests included electrocardiograms, cardiac computed tomography (CT) for coronary artery calcium, cardiac magnetic resonance imaging, spirometry, percent emphysema (percent of lung regions < -950 Hounsfield Units) on CT, inflammatory biomarkers and N-terminal pro-Brain Natriuretic Peptide (NT-proBNP). Logistic regression was used to identify independent correlates of dyspnea after adjustment for age, sex, body mass index, physical activity, anxiety, and leg pain.
Results
Among 1,969 participants without known cardiopulmonary disease, 9% had dyspnea. The forced expiratory volume in one second (FEV1) (p <0.001), NT-proBNP (p=0.004), and percent emphysema on CT (p=0.004) provided independent information on the probability of self-reported dyspnea. Associations with the FEV1 were stronger among smokers and participants with other recent respiratory symptoms or seasonal allergies; associations with NT-proBNP were present only among participants with coexisting symptoms of lower extremity edema. Only the FEV1 provided a significant improvement in the receiver operating curve.
Conclusions
Among adults without known cardiac or pulmonary disease reporting dyspnea on exertion, spirometry, NT-proBNP, and CT imaging for pulmonary parenchymal disease were the most informative tests.
doi:10.1016/j.amjmed.2014.09.023
PMCID: PMC4346168  PMID: 25447621
dyspnea; spirometry; COPD; emphysema; heart failure; atherosclerosis; diagnostic tests
15.  Objective estimates improve risk stratification for primary graft dysfunction after lung transplantation 
Primary graft dysfunction (PGD) is a major cause of early mortality after lung transplant. We aimed to define objective estimates of PGD risk based on readily available clinical variables, using a prospective study of 11 centers in Lung Transplant Outcomes Group (LTOG). Derivation included 1255 subjects from 2002–2010; with separate validation in 382 subjects accrued from 2011–2012. We used logistic regression to identify predictors of grade 3 PGD at 48/72 hours, and decision curve methods to assess impact on clinical decisions. 211/1255 subjects in the derivation and 56/382 subjects in the validation developed PGD. We developed 3 prediction models, where low-risk recipients had a normal BMI (18.5–25 kg/m2), COPD/CF, and absent or mild PH (mPAP< 40mmHg). All others were considered higher-risk. Low-risk recipients had a predicted PGD risk of 4–7%, and high-risk a predicted PGD risk of 15–18%. Adding a donor-smoking lung to a higher-risk recipient significantly increased PGD risk, although risk did not change in low-risk recipients. Validation demonstrated that probability estimates were generally accurate and that models worked best at baseline PGD incidences between 5–25%. We conclude that valid estimates of PGD risk can be produced using readily-available clinical variables.
doi:10.1111/ajt.13262
PMCID: PMC4721238  PMID: 25877792
Primary Graft Dysfunction; Prediction; Lung transplantation; Acute Lung Injury
16.  Pulmonary arteriole gene expression signature in idiopathic pulmonary fibrosis 
The European respiratory journal  2013;41(6):1324-1330.
A third of patients with idiopathic pulmonary fibrosis (IPF) develop pulmonary hypertension (PH-IPF), which is associated with increased mortality. Whether an altered gene expression profile in the pulmonary vasculature precedes the clinical onset of PH-IPF is unknown. We compared gene expression in the pulmonary vasculature of IPF patients with and without PH with controls.
Pulmonary arterioles were isolated using laser capture microdissection from 16 IPF patients: eight with PH (PH-IPF) and eight with no PH (NPH-IPF), and seven controls. Probe was prepared from extracted RNA, and hybridised to Affymetrix Hu133 2.0 Plus genechips. Biometric Research Branch array tools and Ingenuity Pathway Analysis software were used for analysis of the microarray data.
Univariate analysis revealed 255 genes that distinguished IPF arterioles from controls (p<0.001). Mediators of vascular smooth muscle and endothelial cell proliferation, Wnt signalling and apoptosis were differentially expressed in IPF arterioles. Unsupervised and supervised clustering analyses revealed similar gene expression in PH-IPF and NPH-IPF arterioles.
The pulmonary arteriolar gene expression profile is similar in IPF patients with and without coexistent PH. Pathways involved in vascular proliferation and aberrant apoptosis, which may contribute to pulmonary vascular remodelling, are activated in IPF patients.
doi:10.1183/09031936.00084112
PMCID: PMC4720265  PMID: 23728404
DNA microarray; laser capture microdissection; pulmonary arterial hypertension; usual interstitial pneumonia
17.  The Impact of Left Ventricular Hypertrophy on Survival in Candidates for Liver Transplantation 
Left ventricular hypertrophy (LVH) occurs in 12% to 30% of patients with cirrhosis; however, its prognostic significance is not well studied. We assessed the association of LVH with survival in patients undergoing a liver transplantation (LT) evaluation. We performed a multicenter cohort study of patients undergoing an evaluation for LT. LVH was defined with transthoracic echocardiography. The outcome of interest was all-cause mortality. LVH was present in 138 of 485 patients (28%). Patients with LVH were older, more likely to be male and African American, and were more likely to have hypertension. Three hundred forty-five patients did not undergo transplantation (212 declined, and 133 were waiting): 36 of 110 patients with LVH (33%) died, whereas 57 of 235 patients without LVH (24%) died (P = 0.23). After LT, 8 of 28 patients with LVH (29%) died over the course of 3 years, whereas 9 of 112 patients without LVH (8%) died (P = 0.007). This finding was independent of conventional risk factors for LVH, and all deaths for patients with LVH occurred within 9 months of LT. No clinical or demographic characteristics were associated with mortality among LVH patients. In conclusion, the presence of LVH is associated with an early increase in mortality after LT, and this is independent of conventional risk factors for LVH. Further studies are needed to confirm these findings and identify factors associated with mortality after transplantation to improve outcomes.
doi:10.1002/lt.23875
PMCID: PMC4342997  PMID: 24659368
18.  Validity of the Surface Electrocardiogram Criteria for Right Ventricular Hypertrophy: The MESA - Right Ventricle Study 
Objectives
We aimed to assess the diagnostic properties of ECG criteria for RVH measured by cardiac magnetic resonance imaging (cMRI) in adults without clinical cardiovascular disease.
Background
Current electrocardiographic (ECG) criteria for right ventricular hypertrophy (RVH) were based on cadaveric dissection in small studies.
Methods
The Multi-Ethnic Study of Atherosclerosis performed cMRIs with complete right ventricle (RV) interpretation on 4,062 participants without clinical cardiovascular disease. Endocardial margins of the RV were manually contoured on diastolic and systolic images. The ECG screening criteria for RVH from the 2009 AHA Recommendations for Standardization and Interpretation of the ECG were examined in participants with and without left ventricular hypertrophy or reduced ejection fraction. RVH was defined using sex-specific normative equations based on age, height, and weight.
Results
The study sample with normal left ventricular morphology and function (n = 3,719) was 61.3 ± 10.0 years old, 53.5% female, 39.6% Caucasian, 25.5% African-American, 21.9% Hispanic, and 13.0% Asian. The mean BMI was 27.9 ± 5.0 kg/m2. Six percent had RVH which was generally mild. Traditional ECG criteria were specific (many > 95%) but had low sensitivity for RVH by cMRI. The positive predictive values were not sufficiently high as to be clinically useful (maximum 12%). The results did not differ based on age, sex, race, smoking status, or with including participants with abnormal LV mass or function. Classification and regression tree analysis revealed that no combination of ECG variables was better than the criteria used singly.
Conclusions
The recommended ECG screening criteria for RVH are not sufficiently sensitive or specific for screening for mild RVH in adults without clinical cardiovascular disease.
doi:10.1016/j.jacc.2013.08.1633
PMCID: PMC3944058  PMID: 24080107
Right Ventricular Hypertrophy; Magnetic Resonance Imaging; Electrocardiogram
19.  Profiling the role of mammalian target of rapamycin in the vascular smooth muscle metabolome in pulmonary arterial hypertension 
Pulmonary Circulation  2015;5(4):667-680.
Increased proliferation and resistance to apoptosis of pulmonary arterial vascular smooth muscle cells (PAVSMCs), coupled with metabolic reprogramming, are key components of pulmonary vascular remodeling, a major and currently irreversible pathophysiological feature of pulmonary arterial hypertension (PAH). We recently reported that activation of mammalian target of rapamycin (mTOR) plays a key role in increased energy generation and maintenance of the proliferative, apoptosis-resistant PAVSMC phenotype in human PAH, but the downstream effects of mTOR activation on PAH PAVSMC metabolism are not clear. Using liquid and gas chromatography–based mass spectrometry, we performed pilot metabolomic profiling of human microvascular PAVSMCs from idiopathic-PAH subjects before and after treatment with the selective adenosine triphosphate–competitive mTOR inhibitor PP242 and from nondiseased lungs. We have shown that PAH PAVSMCs have a distinct metabolomic signature of altered metabolites—components of fatty acid synthesis, deficiency of sugars, amino sugars, and nucleotide sugars—intermediates of protein and lipid glycosylation, and downregulation of key biochemicals involved in glutathione and nicotinamide adenine dinucleotide (NAD) metabolism. We also report that mTOR inhibition attenuated or reversed the majority of the PAH-specific abnormalities in lipogenesis, glycosylation, glutathione, and NAD metabolism without affecting altered polyunsaturated fatty acid metabolism. Collectively, our data demonstrate a critical role of mTOR in major PAH PAVSMC metabolic abnormalities and suggest the existence of de novo lipid synthesis in PAVSMCs in human PAH that may represent a new, important component of disease pathogenesis worthy of future investigation.
doi:10.1086/683810
PMCID: PMC4671741  PMID: 26697174
mammalian target of rapamycin; pulmonary arterial hypertension; pulmonary arterial vascular smooth muscle cell metabolome
20.  H2 Receptor Antagonists and Right Ventricular Morphology: The MESA Right Ventricle Study 
Rationale: H2 receptor antagonist (H2RA) use is common and may act directly on the heart through myocardial H2 receptors or indirectly through changes in pulmonary vascular resistance.
Objectives: To determine the relationship between histamine H2RA use and right ventricular (RV) morphology.
Methods: We studied 4,122 participants in the Multi-Ethnic Study of Atherosclerosis without clinical cardiovascular disease who had magnetic resonance imaging assessment of RV morphology and ascertainment of medication use. Multivariable linear regression estimated cross-sectional associations between H2RA use and RV morphology after adjusting for demographics, anthropometrics, smoking status, diabetes mellitus, and hypertension. Further adjustments for co-medication use, left ventricular parameters, lung structure and function, renal function, or inflammatory markers were considered in separate models. Analyses in a subcohort restricted to H2RA or proton pump inhibitor users accounted for confounding by the indication of gastroesophageal reflux disease.
Measurements and Main Results: H2RA use was associated with lower RV mass (–0.7 g; 95% confidence interval, –1.2 to –0.2 g; P = 0.004) and smaller RV end-diastolic volume (–4.2 ml; 95% confidence interval, –7.2 to –1.2 ml; P = 0.006). This relationship was unchanged with adjustment for co-medication use, lung structure and function, renal function, and inflammation. The relationship with RV mass was independent of left ventricular mass. Results were similar in the smaller cohort restricted to proton pump inhibitor and H2RA users.
Conclusions: H2RA use was associated with lower RV mass and smaller RV end-diastolic volume. Additional study of histamine and H2 receptors in cardiopulmonary diseases affecting the RV may have direct clinical relevance.
doi:10.1513/AnnalsATS.201407-344OC
PMCID: PMC4298988  PMID: 25295642
histamine; histamine H2 receptors; heart ventricles; pulmonary hypertension
21.  Relationship of CRP, IL-6, and Fibrinogen with Right Ventricular Structure and Function: The MESA-Right Ventricle Study 
International journal of cardiology  2013;168(4):3818-3824.
Background/objectives
Inflammation contributes to the pathogenesis of disease associated with the left ventricle (LV); yet, our understanding of the effect of inflammation on the right ventricle (RV) is quite limited.
Methods and results
The relationships of C-reactive protein (CRP), interleukin-6 (IL-6) and fibrinogen with RV morphology and function (from cardiac MRI) were examined in participants free of clinical cardiovascular disease (n=4,009) from the Multi-Ethnic Study of Atherosclerosis (MESA)-RV study. Multivariable regressions (linear, quantile [25th and 75th] and generalized additive models [GAM]) were used to examine the independent association of CRP, IL-6 and fibrinogen with RV mass, RV end-diastolic volume (RVEDV), RV end-systolic volume (RVESV), RV stroke volume (RVSV) and RV ejection fraction (RVEF). Unadjusted and adjusted analyses revealed strong inverse associations between both CRP and IL-6 with RV mass, RVEDV, RVESV and RVSV (all p<0.01); there were no associations with RVEF. These relationships remained significant after adjustment for the respective LV parameters and lung function. However, GAM models suggested that extreme values of CRP and IL-6 might have positive associations with RV parameters. Fibrinogen showed significant associations in unadjusted models, but no associations after adjustment or in sensitivity analyses.
Conclusion
Levels of CRP and IL-6 are independently associated with RV morphology even after adjustment for the respective LV measure in this multi-ethnic population free of cardiovascular disease. Systemic inflammation may contribute to RV structural changes independent of effects on the LV.
doi:10.1016/j.ijcard.2013.06.028
PMCID: PMC3805818  PMID: 23932860
Systemic inflammation; right ventricle; heart failure; Multi-Ethnic Study of Atherosclerosis
22.  Adipokines and the Right Ventricle: The MESA-RV Study 
PLoS ONE  2015;10(9):e0136818.
Objective
Obesity is associated with changes in both right (RV) and left (LV) ventricular morphology, but the biological basis of this finding is not well established. We examined whether adipokine levels were associated with RV morphology and function in a population-based multiethnic sample free of clinical cardiovascular disease.
Methods
We examined relationships of leptin, resistin, TNF-α, and adiponectin with RV morphology and function (from cardiac MRI) in participants (n = 1,267) free of clinical cardiovascular disease from the Multi-Ethnic Study of Atherosclerosis (MESA)-RV study. Multivariable regressions (linear, quantile [25th and 75th] and generalized additive models [GAM]) were used to examine the independent association of each adipokine with RV mass, RV end-diastolic volume (RVEDV), RV end-systolic volume (RVESV), RV stroke volume (RVSV) and RV ejection fraction (RVEF).
Results
Higher leptin levels were associated with significantly lower levels of RV mass, RVEDV, RVESV and stroke volume, but not RVEF, after adjustment for age, gender, race, height and weight. These associations were somewhat attenuated but still significant after adjustment for traditional risk factors and covariates, and were completely attenuated when correcting for the respective LV measures. There were no significant interactions of age, gender, or race/ethnicity on the relationship between the four adipokines and RV structure or function.
Conclusions
Leptin levels are associated with favorable RV morphology in a multi-ethnic population free of cardiovascular disease, however these associations may be explained by a yet to be understood bi-ventricular process as this association was no longer present after adjustment for LV values. These findings complement the associations previously shown between adipokines and LV structure and function in both healthy and diseased patients. The mechanisms linking adipokines to healthy cardiovascular function require further investigation.
doi:10.1371/journal.pone.0136818
PMCID: PMC4562601  PMID: 26348768
23.  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.
doi:10.1086/675988
PMCID: PMC4070771  PMID: 25006444
pulmonary hypertension; heart failure; inflammation; right ventricle; Mendelian randomization
24.  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.
doi:10.1164/rccm.201209-1583CI
PMCID: PMC3570657  PMID: 23155142
hepatopulmonary syndrome; hypertension; pulmonary; liver cirrhosis; pulmonary circulation
25.  Association of emphysema-like lung on cardiac computed tomography and mortality in persons without airflow obstruction: the Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study 
Annals of internal medicine  2014;161(12):863-873.
Background
Whereas low lung function is known to predict mortality in the general population, the prognostic significance of emphysema on computed tomography (CT) in persons without chronic obstructive pulmonary disease (COPD) remains uncertain.
Objective
To determine whether greater emphysema-like lung on CT is associated with all-cause mortality among persons without airflow obstruction or COPD in the general population.
Design
Prospective cohort study.
Setting
Population-based, multiethnic sample from 6 US communities.
Participants
2965 participants ages 45-84 years without airflow obstruction on spirometry.
Measurements
Emphysema-like lung was defined on cardiac CT as the number of lung voxels less than -950 Hounsfield Units, and was adjusted for the number of total imaged lung voxels.
Results
Among 2965 participants, 50.9% of whom never smoked, there were 186 deaths over a median of 6.2 years. Greater emphysema-like lung was independently associated with increased mortality (adjusted hazard ratio [HR]1.14 per one-half of the interquartile range, 95% CI 1.04-1.24, P=0.004), adjusting for potential confounders including cardiovascular risk factors and the forced expiratory volume in one second. Generalized additive models supported a linear association between emphysema-like lung and mortality without evidence for a threshold. The association was of greatest magnitude among smokers, although multiplicative interaction terms did not support effect modification by smoking status.
Limitations
Cardiac CT scans did not include lung apices. The number of deaths was limited among subgroup analyses.
Conclusions
Emphysema-like lung on CT was associated with all-cause mortality among persons without airflow obstruction or COPD in a general population sample, particularly among smokers. Recognition of the independent prognostic significance of emphysema on CT among patients without COPD on spirometry is warranted.
Primary Funding Source
NIH/NHLBI.
doi:10.7326/M13-2570
PMCID: PMC4347817  PMID: 25506855

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