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1.  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.
PMCID: PMC4342997  PMID: 24659368
2.  Validity of the Surface Electrocardiogram Criteria for Right Ventricular Hypertrophy: The MESA - Right Ventricle Study 
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.
Current electrocardiographic (ECG) criteria for right ventricular hypertrophy (RVH) were based on cadaveric dissection in small studies.
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.
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.
The recommended ECG screening criteria for RVH are not sufficiently sensitive or specific for screening for mild RVH in adults without clinical cardiovascular disease.
PMCID: PMC3944058  PMID: 24080107
Right Ventricular Hypertrophy; Magnetic Resonance Imaging; Electrocardiogram
3.  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.
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.
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.
PMCID: PMC3805818  PMID: 23932860
Systemic inflammation; right ventricle; heart failure; Multi-Ethnic Study of Atherosclerosis
4.  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  PMID: 25006444
pulmonary hypertension; heart failure; inflammation; right ventricle; Mendelian randomization
5.  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
6.  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.
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.
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.
Prospective cohort study.
Population-based, multiethnic sample from 6 US communities.
2965 participants ages 45-84 years without airflow obstruction on spirometry.
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.
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.
Cardiac CT scans did not include lung apices. The number of deaths was limited among subgroup analyses.
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
PMCID: PMC4347817  PMID: 25506855
7.  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
8.  Impact of the Hepatopulmonary Syndrome MELD Exception Policy on Outcomes of Patients After Liver Transplantation: An Analysis of the UNOS Database 
Gastroenterology  2014;146(5):1256-1265.e1.
Patients with hepatopulmonary syndrome (HPS) are prioritized for liver transplantation (given exception points) due to their high pre- and post-transplantation mortality. However, few studies have evaluated the outcomes of these patients.
We performed a retrospective cohort study using data submitted to the United Network for Organ Sharing in a study of the effects of room-air oxygenation on pre- and post-transplantation outcomes of patients with HPS. We identified thresholds associated with post-transplantation survival using cubic spline analysis and compared overall survival times of patients with and without HPS.
From 2002 through 2012, nine hundred and seventy-three patients on the liver transplant waitlist received HPS exception points. There was no association between oxygenation and waitlist mortality among patients with HPS exception points. Transplant recipients with more severe hypoxemia had increased risk of death after liver transplantation. Rates of 3-year unadjusted post-transplantation survival were 84% for patients with PaO2 of 44.1–54.0 mm Hg vs 68% for those with PaO2 ≤ 44.0 mm Hg. In multivariable Cox models, transplant recipients with an initial room-air PaO2 ≤ 44.0 mm Hg had significant increases in post-transplantation mortality (hazard ratio = 1.58; 95% confidence interval [CI]: 1.15–2.18) compared with those with a PaO2 of 44.1–54.0 mm Hg. Overall mortality was significantly lower among waitlist candidates with HPS exception points than those without (hazard ratio = 0.82; 95% CI: 0.70–0.96), possibly because patients with HPS have a reduced risk of pre-transplantation mortality and similar rate of post-transplantation survival.
Although there was no association between pre-transplantation oxygenation and waitlist survival in patients with HPS Model for End-Stage Liver Disease exception points, a pre-transplantation room-air PaO2 ≤ 44.0 mm Hg was associated with increased post-transplantation mortality. HPS Model for End-Stage Liver Disease exception patients had lower overall mortality compared with others awaiting liver transplantation, suggesting that the appropriateness of the HPS exception policy should be reassessed.
PMCID: PMC3992191  PMID: 24412528
UNOS; MELD; Allocation; Gas Exchange
9.  Traffic-related Air Pollution and the Right Ventricle. The Multi-ethnic Study of Atherosclerosis 
Rationale: Right heart failure is a cause of morbidity and mortality in common and rare heart and lung diseases. Exposure to traffic-related air pollution is linked to left ventricular hypertrophy, heart failure, and death. Relationships between traffic-related air pollution and right ventricular (RV) structure and function have not been studied.
Objectives: To characterize the relationship between traffic-related air pollutants and RV structure and function.
Methods: We included men and women with magnetic resonance imaging assessment of RV structure and function and estimated residential outdoor nitrogen dioxide (NO2) concentrations from the Multi-ethnic Study of Atherosclerosis, a study of individuals free of clinical cardiovascular disease at baseline. Multivariable linear regression estimated associations between NO2 exposure (averaged over the year prior to magnetic resonance imaging) and measures of RV structure and function after adjusting for demographics, anthropometrics, smoking status, diabetes mellitus, and hypertension. Adjustment for corresponding left ventricular parameters, traffic-related noise, markers of inflammation, and lung disease were considered in separate models. Secondary analyses considered oxides of nitrogen (NOx) as the exposure.
Measurements and Main Results: The study sample included 3,896 participants. In fully adjusted models, higher NO2 was associated with greater RV mass and larger RV end-diastolic volume with or without further adjustment for corresponding left ventricular parameters, traffic-related noise, inflammatory markers, or lung disease (all P < 0.05). There was no association between NO2 and RV ejection fraction. Relationships between NOx and RV morphology were similar.
Conclusions: Higher levels of NO2 exposure were associated with greater RV mass and larger RV end-diastolic volume.
PMCID: PMC4098110  PMID: 24593877
air pollutants; pulmonary circulation; heart ventricles; pulmonary hypertension
10.  Pulmonary Hypertension: NHLBI Workshop on the Primary Prevention of Chronic Lung Diseases 
Annals of the American Thoracic Society  2014;11(Suppl 3):S178-S185.
Pulmonary vascular dysfunction (PVD) precedes the onset of clinical signs and symptoms of pulmonary arterial hypertension (PAH). PAH is defined by the elevation of pulmonary arterial pressure, which often progresses to right ventricular (RV) dysfunction and failure. PAH affects subjects of all ages, and is associated with diverse medical conditions, most of which are rare. Several factors pose immediate challenges to the development of strategies for primary prevention of PAH, including: (1) the idiopathic or primary form of the disease is extremely rare, limiting screening practicality; (2) methods for the detection of preclinical PVD are currently not established; (3) the understanding of determinants of pulmonary vascular growth, structure, and function in normal and PAH states is insufficient; (4) relatively small numbers of “at-risk” subjects are available for long-term studies to accurately assess disease development; and (5) preventative therapies for PVD are lacking. Despite these limitations, leveraging known at-risk patient populations for study, as well as growing progress across multiple disciplines, ranging from systems biology to advanced and more sensitive functional imaging modalities, may facilitate the opportunity to significantly improve primary prevention research and implementation over the next decade.
PMCID: PMC4112504  PMID: 24754827
pulmonary vascular disease; right ventricular failure
12.  “Cor pulmonale parvus” in chronic obstructive pulmonary disease (COPD) and emphysema. The Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study 
The classic cardiovascular complication of chronic obstructive pulmonary disease (COPD) is cor pulmonale, or enlargement of the right ventricle (RV). Most studies of cor pulmonale were conducted decades ago.
We aimed to examine RV changes in contemporary COPD and emphysema using cardiac magnetic resonance imaging (MRI).
We performed a case-control study nested predominantly in two general population studies of 310 participants with COPD and controls ages 50–79 years with ≥ 10 pack-years of smoking and who were free of clinical cardiovascular disease. RV volumes and mass were assessed using MRI. COPD and COPD severity were defined by standard spirometric criteria. Percent emphysema was defined as percent of lung regions <-950 Hounsfield units on full-lung computed tomography; emphysema subtypes were scored by radiologists. Results were adjusted for age, race/ethnicity, sex, height, weight, smoking status, pack-years, systemic hypertension and sleep apnea.
RV end-diastolic volume was reduced in COPD compared to controls (-7.8 mL, 95% CI: -15.0, -0.5 mL; p=0.04). Increasing severity of COPD was associated with smaller RV end-diastolic volume (p=0.004) and lower RV stroke volume (p<0.001). RV mass and ejection fraction were similar between the groups. Greater percent emphysema was also associated with smaller RV end-diastolic volume (p=0.005) and stroke volume (p<0.001), as was the presence of centrilobular and paraseptal emphysema.
RV volumes are lower without significant alterations in RV mass and ejection fraction in contemporary COPD (“cor pulmonale parvus”) and this reduction is related to greater percent emphysema on computed tomography.
PMCID: PMC4347835  PMID: 25440095
right ventricle; chronic obstructive pulmonary disease; pulmonary heart disease; pulmonary hypertension; heart failure
13.  Genetic Variation in the Prostaglandin E2 Pathway Is Associated with Primary Graft Dysfunction 
Rationale: Biologic pathways with significant genetic conservation across human populations have been implicated in the pathogenesis of primary graft dysfunction (PGD). The evaluation of the role of recipient genetic variation in PGD has thus far been limited to single, candidate gene analyses.
Objectives: We sought to identify genetic variants in lung transplant recipients that are responsible for increased risk of PGD using a two-phase large-scale genotyping approach.
Methods: Phase 1 was a large-scale candidate gene association study of the multicenter, prospective Lung Transplant Outcomes Group cohort. Phase 2 included functional evaluation of selected variants and a bioinformatics screening of variants identified in phase 1.
Measurements and Main Results: After genetic data quality control, 680 lung transplant recipients were included in the analysis. In phase 1, a total of 17 variants were significantly associated with PGD, four of which were in the prostaglandin E2 family of genes. Among these were a coding variant in the gene encoding prostaglandin E2 synthase (PTGES2; P = 9.3 × 10−5) resulting in an arginine to histidine substitution at amino acid position 298, and three variants in a block containing the 5′ promoter and first intron of the PTGER4 gene (encoding prostaglandin E2 receptor subtype 4; all P < 5 × 10−5). Functional evaluation in regulatory T cells identified that rs4434423A in the PTGER4 gene was associated with differential suppressive function of regulatory T cells.
Conclusions: Further research aimed at replication and additional functional insight into the role played by genetic variation in prostaglandin E2 synthetic and signaling pathways in PGD is warranted.
PMCID: PMC3977709  PMID: 24467603
lung transplantation; genetics; prostaglandin; regulatory T cells
14.  mTORC2 coordinates pulmonary artery smooth muscle cell metabolism, proliferation and survival in pulmonary arterial hypertension 
Circulation  2013;129(8):864-874.
Enhanced proliferation, resistance to apoptosis and metabolic shift to glycolysis of pulmonary arterial vascular smooth muscle cells (PAVSMC) are key pathophysiological components of pulmonary vascular remodeling in idiopathic pulmonary arterial hypertension (IPAH). The role of distinct mTOR complexes mTORC1 (mTOR-raptor) and mTORC2 (mTOR-rictor) in PAVSMC proliferation and survival in PAH and their therapeutic relevance is unknown.
Methods and Results
Immunohistochemical and immunoblot analyses revealed that mTORC1 and mTORC2 pathways are markedly up-regulated in small remodeled PAs and isolated distal PAVSMC from IPAH subjects that have increased ATP levels, proliferation and survival that depend on glycolytic metabolism. siRNA- and pharmacological-based analysis showed that while both mTORC1 and mTORC2 contributing to proliferation, only mTORC2 is required for ATP generation and survival of IPAH PAVSMC. mTORC2 down-regulated energy sensor AMPK allowing activation of mTORC1-S6 and increased proliferation, and deficiency of pro-apoptotic protein Bim and IPAH PAVSMC survival. Nox4 protein levels were increased in IPAH PAVSMC that was necessary for mTORC2 activation, proliferation and survival. Nox4 levels and mTORC2 signaling were significantly up-regulated in small PAs from hypoxia-exposed rats at days 2-28 of hypoxia. Treatment with the mTOR kinase inhibitor PP242 at days 15-28 suppressed mTORC2, but not Nox4, induced SM-specific apoptosis in small PAs and reversed hypoxia-induced pulmonary vascular remodeling in rats.
These data provide a novel mechanistic link of Nox4-dependent activation of mTORC2 via energy sensor AMPK to increased proliferation and survival of PAVSMC in PAH suggesting a new potential pathway for the therapeutic interventions.
PMCID: PMC3968690  PMID: 24270265
mTORC2; AMPK; IPAH; pulmonary vascular remodeling; energy metabolism; pulmonary vascular changes; proliferation; vascular smooth muscle; signal transduction
15.  Sex and haemodynamics in pulmonary arterial hypertension 
The European respiratory journal  2013;43(2):523-530.
Female sex is a risk factor for pulmonary arterial hypertension (PAH), yet females have better survival than males. We sought to determine if sex was associated with baseline haemodynamics in subjects with PAH, and whether age modified these relationships.
We conducted a pooled analysis from 11 randomised trials submitted to the US Food and Drug Administration. The study sample included 1211 subjects with idiopathic PAH, 25% of whom were males, and 489 subjects with connective tissue disease-associated PAH, 13% of whom were males.
After multivariable adjustment, right atrial pressure was 1.36 mmHg higher (95% CI 0.44–2.27, p=0.004), cardiac index was −0.14 L·min−1·m−2 lower (95% CI −0.23–0.04, p=0.01) and pulmonary vascular resistance was 1.23 Wood units higher (95% CI 0.18–2.27, p=0.02) in males compared with females. Younger males had 5.43 mmHg (95% CI 2.20–8.66, p=0.001) higher mean pulmonary arterial pressures than younger females, but these relationships were attenuated after age 45 years. In the subgroup of connective tissue disease-associated PAH, males may have had higher right atrial pressure.
These findings implicate age as a modifier and provide further evidence of sexual dimorphism in PAH.
PMCID: PMC4338984  PMID: 23949961
16.  Tricuspid Annular Plane Systolic Excursion in the Assessment of Right Ventricular Function in Children and Adolescents after Repair of Tetralogy of Fallot 
Assessing right ventricular (RV) performance is essential for patients with tetralogy of Fallot (TOF). The aim of this study was to investigate the reliability and validity of tricuspid annular plane systolic excursion (TAPSE) against cardiac magnetic resonance imaging measures and cardiopulmonary exercise testing.
A retrospective study was performed in 125 outpatients with repaired TOF with available protocoldriven echocardiography, cardiac magnetic resonance imaging, and exercise stress testing obtained as part of a cross-sectional study. TAPSE was measured on the two-dimensional apical four-chamber view on echocardiography by two readers. Multivariate linear regression was used to examine the association between TAPSE and measures of RV function and exercise capacity.
The mean age was 12.6 ± 3.3 years, 41 patients (33%) were female, and 104 (83%) were white. TAPSE averaged 1.6 ± 0.37 cm, with an interreader intraclass correlation coefficient of 0.78 (n = 18). TAPSE was significantly associated with cardiac magnetic resonance–based RV stroke volume after adjustment for gender and body surface area (β = 13.8; 95% confidence interval, 2.25–25.30; P = .02). TAPSE was not associated with cardiac magnetic resonance–based RV ejection fraction (P = .77). On exercise testing, TAPSE was not associated with peak oxygen consumption, percentage of predicted oxygen consumption, oxygen pulse, or the ventilatory equivalent for carbon dioxide in patients with maximal exercise stress testing (n = 73 [58%]).
TAPSE is reproducibly measured by echocardiography in patients with TOF. It is not associated with RV ejection fraction or exercise performance, and its association with RV stroke volume may be confounded by body size. On the basis of these results, TAPSE is not representative of global RV performance in patients with TOF.
PMCID: PMC4336673  PMID: 23928091
Tricuspid annular plane systolic excursion; Echocardiography; Exercise; Magnetic resonance imaging; Tetralogy of Fallot
17.  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
18.  An Official American Thoracic Society Statement: Pulmonary Hypertension Phenotypes 
Background: Current classification of pulmonary hypertension (PH) is based on a relatively simple combination of patient characteristics and hemodynamics. This limits customization of treatment, and lacks the clarity of a more granular identification based on individual patient phenotypes. Rapid advances in mechanistic understanding of the disease, improved imaging methods, and innovative biomarkers now provide an opportunity to define PH phenotypes on the basis of biomarkers, advanced imaging, and pathobiology. This document organizes our current understanding of PH phenotypes and identifies gaps in our knowledge.
Methods: A multidisciplinary committee with expertise in clinical care (pulmonary, cardiology, pediatrics, and pathology), clinical research, and/or basic science in the areas of PH identified important questions and reviewed and synthesized the literature.
Results: This document describes selected PH phenotypes and serves as an initial platform to define additional relevant phenotypes as new knowledge is generated. The biggest gaps in our knowledge stem from the fact that our present understanding of PH phenotypes has not come from any particularly organized effort to identify such phenotypes, but rather from reinterpreting studies and reports that were designed and performed for other purposes.
Conclusions: Accurate phenotyping of PH can be used in research studies to increase the homogeneity of study cohorts. Once the ability of the phenotypes to predict outcomes has been validated, phenotyping may also be useful for determining prognosis and guiding treatment. This important next step in PH patient care can optimally be addressed through a consortium of study sites with well-defined goals, tasks, and structure. Planning and support for this could include the National Institutes of Health and the U.S. Food and Drug Administration, with industry and foundation partnerships.
PMCID: PMC4291177  PMID: 24484330
biomarkers; consortium; metabolism; pathobiology; pulmonary circulation
19.  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
20.  Sex and Race Differences in Right Ventricular Structure and Function: The MESA-Right Ventricle Study 
Circulation  2011;123(22):2542-2551.
Right ventricular (RV) morphology is an important predictor of outcomes in heart and lung disease, however determinants of RV anatomy have not been well-studied. We examined the demographic factors associated with RV morphology and function in a population-based multiethnic sample free of clinical cardiovascular disease.
Methods and Results
The Multi-Ethnic Study of Atherosclerosis (MESA) performed cardiac magnetic resonance imaging (MRI) on 5098 participants. RV volumes and mass were available for 4204 participants. Normative equations for RV parameters were derived using an allometric approach. The study sample (N = 4123) was 61.5 ± 10.1 years old and 47.5% male. Older age was associated with lower RV mass (~5% lower mass per decade) with larger age-related decrements in men than in women (p for interaction < 0.05). Older age was also associated with higher RV ejection fraction (RVEF), an association which differed between races/ethnicities (p for interaction ≤ 0.01). Overall, men had greater RV mass (~8%) and larger RV volumes than women, but had lower RVEF (4% in absolute terms) (p < 0.001). African Americans had lower RV mass than Caucasians (p ≤ 0.002), whereas Hispanics had higher RV mass (p ≤ 0.02). Using the derived normative equations, 7.3% (95%CI, 6.5–8.1%) met criteria for RV hypertrophy and 5.9% (95%CI, 5.2–6.6%) had RV dysfunction.
In conclusion, age, sex, and race are associated with significant differences in RV mass, RV volumes and RVEF, potentially explaining distinct responses of the RV to cardiopulmonary disease.
PMCID: PMC3111939  PMID: 21646505
right ventricle; pulmonary heart disease; magnetic resonance imaging; pulmonary hypertension
21.  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
22.  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
23.  Sex Hormones Are Associated with Right Ventricular Structure and Function 
Rationale: Sex hormones have effects on the left ventricle, but hormonal influences on the right ventricle (RV) are unknown.
Objectives: We hypothesized that sex hormones would be associated with RV morphology in a large cohort free of cardiovascular disease.
Methods: Sex hormones were measured by immunoassay and RV ejection fraction (RVEF), stroke volume (RVSV), mass, end-diastolic volume, and end-systolic volume (RVESV) were measured by cardiac magnetic resonance imaging in 1,957 men and 1,738 postmenopausal women. The relationship between each hormone and RV parameter was assessed by multivariate linear regression.
Measurements and Main Results: Higher estradiol levels were associated with higher RVEF (β per 1 ln[nmol/L], 0.88; 95% confidence interval [CI], 0.32 to 1.43; P = 0.002) and lower RVESV (β per 1 ln[nmol/L], −0.87; 95% CI, −1.67 to −0.08; P = 0.03) in women using hormone therapy. In men, higher bioavailable testosterone levels were associated with higher RVSV (β per 1 ln[nmol/L], 1.97; 95% CI, 0.20 to 3.73; P = 0.03) and greater RV mass and volumes (P ≤ 0.01). Higher dehydroepiandrosterone levels were associated with higher RVSV (β per 1 ln[nmol/L], 1.37; 95% CI, 0.15 to 2.59; P = 0.03) and greater RV mass (β per 1 ln[nmol/L], 0.25; 95% CI, 0.00 to 0.49; P = 0.05) and volumes (P ≤ 0.001) in women.
Conclusions: Higher estradiol levels were associated with better RV systolic function in women using hormone therapy. Higher levels of androgens were associated with greater RV mass and volumes in both sexes.
PMCID: PMC3081282  PMID: 20889903
sex; sex hormones; right ventricle
24.  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
25.  Physical Activity and Right Ventricular Structure and Function 
Rationale: Intense exercise in elite athletes is associated with increased left ventricular (LV) and right ventricular (RV) mass and volumes. However, the effect of physical activity on the RV in an older community-based population is unknown.
Objectives: We studied the association between levels of physical activity in adults and RV mass and volumes.
Methods: The Multi-Ethnic Study of Atherosclerosis (MESA) performed cardiac magnetic resonance imaging on community-based participants without clinical cardiovascular disease. RV volumes were determined from manually contoured endocardial margins. RV mass was determined from the difference between epicardial and endocardial volumes multiplied by the specific gravity of myocardium. Metabolic equivalent–minutes/day were calculated from the self-reported frequency, duration, and intensity of physical activity.
Measurements and Main Results: The study sample (n = 1,867) was aged 61.8 ± 10 years, 48% male, 44% white, 27% African American, 20% Hispanic, and 9% Chinese. Higher levels of moderate and vigorous physical activity were linearly associated with higher RV mass (P = 0.02) after adjusting for demographics, anthropometrics, smoking, cholesterol, diabetes mellitus, hypertension, and LV mass. Higher levels of intentional exercise (physical activity done for the sole purpose of conditioning or fitness) were nonlinearly associated with RV mass independent of LV mass (P = 0.03). There were similar associations between higher levels of physical activity and larger RV volumes.
Conclusions: Higher levels of physical activity in adults were associated with greater RV mass independent of the associations with LV mass; similar results were found for RV volumes. Exercise-associated RV remodeling may have important clinical implications.
PMCID: PMC3056232  PMID: 20813888
exercise; pulmonary heart disease; pulmonary hypertension; magnetic resonance imaging

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