Novel Liver Injury Phenotypes and Outcomes in Clinical Trial Participants with Pulmonary Hypertension.

RATIONALE: Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) cause right ventricular dysfunction which can impact other solid organs. However, the profiles and consequences of hepatic injury due to PAH and CTEPH have not been well-studied. OBJECTIVES: We aimed to identify underlying patterns of liver injury in a cohort of PAH and CTEPH patients enrolled in 15 randomized clinical trials conducted between 1998 and 2014. METHODS: We used unsupervised machine learning to identify liver injury clusters in 13 trials and validated the findings in two additional trials. We then determined whether these liver injury clusters were associated with clinical outcomes or treatment effect heterogeneity. MEASUREMENTS AND MAIN RESULTS: Our training dataset included 4,219 patients and our validation dataset included 1,756 patients with serum total bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, and albumin data. Using k-means clustering, we identified phenotypes with no liver injury, hepatocellular injury, cholestatic injury, and combined injury patterns. Patients in the cholestatic injury liver cluster had the shortest time to clinical worsening and the highest risk of mortality. The cholestatic injury group also experienced the greatest placebo-corrected treatment effect on six-minute walk distance. Randomization to the experimental arm transitioned patients to a healthier liver status. CONCLUSIONS: Liver injury was associated with adverse outcomes in patients with PAH and CTEPH. Randomization to active treatment had beneficial effects on liver health compared to placebo. The role of liver disease (often subclinical) in determining outcomes warrants prospective studies.

Pulmonary Hypertension and Anastrozole (PHANTOM): A Randomized, Double-Blind, Placebo-Controlled Trial.

RATIONALE: Inhibition of aromatase with anastrozole reduces pulmonary hypertension in experimental models. OBJECTIVES: We aimed to determine whether anastrozole improved six-minute walk distance (6MWD) at six months in pulmonary arterial hypertension (PAH). METHODS: We performed a randomized, double-blind, placebo-controlled Phase II clinical trial of anastrozole in subjects with PAH at seven centers. Eighty-four post-menopausal women and men with PAH were randomized in a 1:1 ratio to receive anastrozole 1 mg or placebo by mouth daily, stratified by sex using permuted blocks of variable sizes. All subjects and study staff were masked. The primary outcome was the change from baseline in 6MWD at six months. Using intent-to-treat analysis, we estimated the treatment effect of anastrozole using linear regression models adjusted for sex and baseline 6MWD. Assuming 10% loss to follow-up, we anticipated having 80% power to detect a difference in the change in 6MWD of 22 meters. MEASUREMENTS AND MAIN RESULTS: Forty-one subjects were randomized to placebo and 43 to anastrozole and all received the allocated treatment. Three subjects in the placebo group and two in the anastrozole group discontinued study drug. There was no significant difference in the change in 6MWD at six months (placebo-corrected treatment effect -7.9 m, 95%CI -32.7 - 16.9, p = 0.53). There was no difference in adverse events between the groups. CONCLUSIONS: Anastrozole did not show a significant effect on 6MWD compared to placebo in post-menopausal women and men with PAH. Anastrozole was safe and did not show adverse effects. Clinical trial registration available at www. CLINICALTRIALS: gov, ID: NCT03229499.

Pulmonary arterial hypertension treatment: an individual participant data network meta-analysis.

BACKGROUND AND AIMS: Effective therapies that target three main signalling pathways are approved to treat pulmonary arterial hypertension (PAH). However, there are few large patient-level studies that compare the effectiveness of these pathways. The aim of this analysis was to compare the effectiveness of the treatment pathways in PAH and to assess treatment heterogeneity. METHODS: A network meta-analysis was performed using individual participant data of 6811 PAH patients from 20 Phase III randomized clinical trials of therapy for PAH that were submitted to the US Food and Drug Administration. Individual drugs were grouped by the following treatment pathways: endothelin, nitric oxide, and prostacyclin pathways. RESULTS: The mean (±standard deviation) age of the sample was 49.2 (±15.4) years; 78.4% were female, 59.7% had idiopathic PAH, and 36.5% were on background PAH therapy. After covariate adjustment, targeting the endothelin + nitric oxide pathway {ß: 43.7 m [95% confidence interval (CI): 32.9, 54.4]}, nitric oxide pathway [ß: 29.4 m (95% CI: 22.6, 36.3)], endothelin pathway [ß: 25.3 m (95% CI: 19.8, 30.8)], and prostacyclin pathway [oral/inhaled ß: 19.1 m (95% CI: 14.2, 24.0), intravenous/subcutaneous ß: 24.4 m (95% CI: 15.1, 33.7)] significantly increased 6 min walk distance at 12 or 16 weeks compared with placebo. Treatments also significantly reduced the likelihood of having clinical worsening events. There was significant heterogeneity of treatment effects by age, body mass index, hypertension, diabetes, and coronary artery disease. CONCLUSIONS: Drugs targeting the three traditional treatment pathways significantly improve outcomes in PAH, with significant treatment heterogeneity in patients with some comorbidities. Randomized clinical trials are warranted to identify the most effective treatment strategies in a personalized approach.

Minimal Clinically Important Difference in the 6-minute-walk Distance for Patients with Pulmonary Arterial Hypertension.

Rationale: The 6-minute-walk distance (6MWD) is an important clinical and research metric in pulmonary arterial hypertension (PAH); however, there is no consensus about what minimal change in 6MWD is clinically significant. Objectives: We aimed to determine the minimal clinically important difference in the 6MWD. Methods: We performed a meta-analysis using individual participant data from eight randomized clinical trials of therapy for PAH submitted to the U.S. Food and Drug Administration to derive minimal clinically important differences in the 6MWD. The estimates were externally validated using the Pulmonary Hypertension Association Registry. We anchored the change in 6MWD to the change in the Medical Outcomes Survey Short Form physical component score. Measurements and Main Results: The derivation (clinical trial) and validation (Pulmonary Hypertension Association Registry) samples were comprised of 2,404 and 537 adult patients with PAH, respectively. The mean ± standard deviation age of the derivation sample was 50.5 ± 15.2 years, and 1,849 (77%) were female, similar to the validation sample. The minimal clinically important difference in the derivation sample was 33 meters (95% confidence interval, 27-38), which was almost identical to that in the validation sample (36 m [95% confidence interval, 29-43]). The minimal clinically important difference did not differ by age, sex, race, pulmonary hypertension etiology, body mass index, use of background therapy, or World Health Organization functional class. Conclusions: We estimated a 6MWD minimal clinically important difference of approximately 33 meters for adults with PAH. Our findings can be applied to the design of clinical trials of therapies for PAH.

MUC5B, telomere length and longitudinal quantitative interstitial lung changes: the MESA Lung Study.

BACKGROUND: The MUC5B promoter variant (rs35705950) and telomere length are linked to pulmonary fibrosis and CT-based qualitative assessments of interstitial abnormalities, but their associations with longitudinal quantitative changes of the lung interstitium among community-dwelling adults are unknown. METHODS: We used data from participants in the Multi-Ethnic Study of Atherosclerosis with high-attenuation areas (HAAs, Examinations 1-6 (2000-2018)) and MUC5B genotype (n=4552) and telomere length (n=4488) assessments. HAA was defined as the per cent of imaged lung with attenuation of -600 to -250 Hounsfield units. We used linear mixed-effects models to examine associations of MUC5B risk allele (T) and telomere length with longitudinal changes in HAAs. Joint models were used to examine associations of longitudinal changes in HAAs with death and interstitial lung disease (ILD). RESULTS: The MUC5B risk allele (T) was associated with an absolute change in HAAs of 2.60% (95% CI 0.36% to 4.86%) per 10 years overall. This association was stronger among those with a telomere length below an age-adjusted percentile of 5% (p value for interaction=0.008). A 1% increase in HAAs per year was associated with 7% increase in mortality risk (rate ratio (RR)=1.07, 95% CI 1.02 to 1.12) for overall death and 34% increase in ILD (RR=1.34, 95% CI 1.20 to 1.50). Longer baseline telomere length was cross-sectionally associated with less HAAs from baseline scans, but not with longitudinal changes in HAAs. CONCLUSIONS: Longitudinal increases in HAAs were associated with the MUC5B risk allele and a higher risk of death and ILD.

Heterogeneity of treatment effects by risk in pulmonary arterial hypertension.

BACKGROUND: It is currently unknown if disease severity modifies response to therapy in pulmonary arterial hypertension (PAH). We aimed to explore if disease severity, as defined by established risk-prediction algorithms, modified response to therapy in randomised clinical trials in PAH. METHODS: We performed a meta-analysis using individual participant data from 18 randomised clinical trials of therapy for PAH submitted to the United States Food and Drug Administration to determine if predicted risk of 1-year mortality at randomisation modified the treatment effect on three outcomes: change in 6-min walk distance (6MWD), clinical worsening at 12 weeks and time to clinical worsening. RESULTS: Of 6561 patients with a baseline US Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL 2.0) score, we found that individuals with higher baseline risk had higher probabilities of clinical worsening but no difference in change in 6MWD. We detected a significant interaction of REVEAL 2.0 risk and treatment assignment on change in 6MWD. For every 3-point increase in REVEAL 2.0 score, there was a 12.49 m (95% CI 5.86-19.12 m; p=0.001) greater treatment effect in change in 6MWD. We did not detect a significant risk by treatment interaction on clinical worsening with most of the risk-prediction algorithms. CONCLUSIONS: We found that predicted risk of 1-year mortality in PAH modified treatment effect as measured by 6MWD, but not clinical worsening. Our findings highlight the importance of identifying sources of treatment heterogeneity by predicted risk to tailor studies to patients most likely to have the greatest treatment response.

Cardiac index and hepatopulmonary syndrome in liver transplantation candidates: The pulmonary vascular complications of liver disease study.

BACKGROUND AND AIMS: Hepatopulmonary syndrome (HPS) and a hyperdynamic circulation are common complications of advanced liver disease, but the relationship between HPS and cardiac index (CI) is poorly understood. We sought to compare CI in patients with and without HPS and to assess the relationship between CI and symptoms, quality of life, gas exchange, and exercise capacity among liver transplantation (LT) candidates. We performed a cross-sectional analysis within the Pulmonary Vascular Complications of Liver Disease 2 study, a multicenter prospective cohort study of patients being evaluated for LT. We excluded patients with obstructive or restrictive lung disease, intracardiac shunting, and portopulmonary hypertension. We included 214 patients (81 with HPS and 133 controls without HPS). Compared with controls, patients with HPS had a higher CI (least square mean 3.2 L/min/m 2 , 95% CI 3.1-3.4 vs. 2.8 L/min/m 2 , 95% CI 2.7-3.0, p < 0.001) after adjustment for age, sex, Model for End-stage Liver Disease-Sodium (MELD-Na) score and beta-blocker use, and a lower systemic vascular resistance. Among all LT candidates, CI was correlated with oxygenation (Alveolar-arterial oxygen gradient r =0.27, p < 0.001), intrapulmonary vasodilatation severity ( p < 0.001), and biomarkers of angiogenesis. Higher CI was independently associated with dyspnea and worse functional class and physical quality of life after adjusting for age, sex, MELD-Na, beta-blocker use, and HPS status. HPS was associated with a higher CI among LT candidates. Independent of HPS, higher CI was associated with increased dyspnea and worse functional class, quality of life, and arterial oxygenation.

Six-Minute walk distance predicts outcomes in liver transplant candidates.

A 6-minute walk test is a simple tool for assessing submaximal exercise capacity. We sought to determine whether a 6-minute walk distance (6MWD) predicts outcomes in patients with cirrhosis. The Pulmonary Vascular Complications of Liver Disease 2 study is a multicenter, prospective cohort study that enrolled adults with portal hypertension during liver transplantation evaluation. We excluded subjects with an incident or prevalent portopulmonary hypertension. The 6-minute walk test was performed using standardized methods. Cox proportional hazards modeling and multivariable linear regression analysis were performed to determine the relationship between baseline 6MWD and outcomes. The study sample included 352 subjects. The mean 6MWD was 391±101 m. For each 50-meter decrease in 6MWD, there was a 25% increase in the risk of death (HR 1.25, 95% CI [1.11, 1.41], p < 0.001) after adjustment for age, gender, body mass index, MELD-Na, and liver transplant as a time-varying covariate. In a multistate model, each 50-meter decrease in 6MWD was associated with an increased risk of death before the liver transplant ( p < 0.001) but not after the transplant. 6MWD was similar to MELD-Na in discriminating mortality. Each 50-meter decrease in 6MWD was associated with an increase in all-cause ( p < 0.001) and transplant-free hospitalizations ( p < 0.001) in multivariable models for time-to-recurrent events. Shorter 6MWD was associated with worse Short Form-36 physical ( p < 0.001) and mental component scores ( p = 0.05). In conclusion, shorter 6MWD is associated with an increased risk of death, hospitalizations, and worse quality of life in patients evaluated for liver transplantation. The 6-minute walk distance may be a useful adjunct for risk assessment in patients undergoing liver transplant evaluation.

A Survey of Implementation of ABCDE Protocols.

BACKGROUND: Spontaneous awakening trials (SATs), spontaneous breathing trials (SBTs), delirium assessment/management, early mobility have been termed the ABCDE bundle. The ABCDE bundle has been proven to improve patient outcomes. However, there is often a long gap in dissemination and implementation of evidence-based medicine. OBJECTIVES: To determine the prevalent implementation of and determinants for ABCDE protocol adoption in Pennsylvania. METHODS: We developed a survey of ABCDE bundle protocols. We surveyed factors around implementation including written protocol presence, standardized assessments to guide protocols, timing of creation of protocols, and estimated adherence to protocols. We also collected data on factors that might be determinants for protocol adoption including ICU staffing models, hospital and ICU level factors. We validated the survey tool using the Michigan Health and Hospital Association Keystone ICU collaborative. We then administered the validated survey to a leader of the medical ICU or mixed medical-surgical ICU of all Pennsylvania Hospitals. Multivariable logistic and ordinal regression were used to determine associations between ICU staffing models and hospital and ICU level factors with the presence of ABCDE bundle protocols. RESULTS: In the study cohort of Pennsylvania ICUs (n = 144), we had 100 respondents (69% response). The median number of hospital beds among the respondents was 185 (IQR 111-355) with a median of 14 ICU beds (IQR 10-20). 86% reported spontaneous awakening trial protocols, 60% reported spontaneous breathing trial protocols, 43% reported delirium assessment/management protocols, and 27% reported early mobility protocols. Being a medical ICU compared to a mixed medical-surgical ICU (OR 3.48, 95% CI 1.19-10.21, P = .02) and presence of multidisciplinary rounds (OR 4.97, 95% CI 2.07-11.94, P < .001) were associated with increasing number of ABCDE bundle protocol components. CONCLUSIONS: Variable implementation of ABCDE bundle protocols was present across Pennsylvania. Team communication is important to implementation of these protocols.

Associations of Monocyte Count and Other Immune Cell Types with Interstitial Lung Abnormalities.

Rationale: Higher blood monocyte counts are associated with worse survival in adults with clinically diagnosed pulmonary fibrosis. Their association with the development and progression of interstitial lung abnormalities (ILA) in humans is unknown. Objectives: We evaluated the associations of blood monocyte count, and other immune cell types, with ILA, high-attenuation areas, and FVC in four independent cohorts. Methods: We included participants with measured monocyte counts and computed tomographic (CT) imaging enrolled in MESA (Multi-Ethnic Study of Atherosclerosis, n = 484), AGES-Reykjavik (Age/Gene Environment Susceptibility Study, n = 3,547), COPDGene (Genetic Epidemiology of COPD, n = 2,719), and the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points, n = 646). Measurements and Main Results: After adjustment for covariates, a 1-SD increment in blood monocyte count was associated with ILA in MESA (odds ratio [OR], 1.3; 95% confidence interval [CI], 1.0-1.8), AGES-Reykjavik (OR, 1.2; 95% CI, 1.1-1.3), COPDGene (OR, 1.3; 95% CI, 1.2-1.4), and ECLIPSE (OR, 1.2; 95% CI, 1.0-1.4). A higher monocyte count was associated with ILA progression over 5 years in AGES-Reykjavik (OR, 1.2; 95% CI, 1.0-1.3). Compared with participants without ILA, there was a higher percentage of activated monocytes among those with ILA in MESA. Higher monocyte count was associated with greater high-attenuation areas in MESA and lower FVC in MESA and COPDGene. Associations of other immune cell types were less consistent. Conclusions: Higher blood monocyte counts were associated with the presence and progression of interstitial lung abnormalities and lower FVC.

Impact of hepatopulmonary syndrome in liver transplantation candidates and the role of angiogenesis.

BACKGROUND: Hepatopulmonary syndrome affects 10-30% of patients with cirrhosis and portal hypertension. We evaluated the serum angiogenic profile of hepatopulmonary syndrome and assessed the clinical impact of hepatopulmonary syndrome in patients evaluated for liver transplantation. METHODS: The Pulmonary Vascular Complications of Liver Disease 2 study was a multicentre, prospective cohort study of adults undergoing their first liver transplantation evaluation. Hepatopulmonary syndrome was defined as an alveolar-arterial oxygen gradient ≥15 mmHg (≥20 mmHg if age >64 years), positive contrast-enhanced transthoracic echocardiography and absence of lung disease. RESULTS: We included 85 patients with hepatopulmonary syndrome and 146 patients without hepatopulmonary syndrome. Patients with hepatopulmonary syndrome had more complications of portal hypertension and slightly higher Model for End-Stage Liver Disease-Na score compared to those without hepatopulmonary syndrome (median (interquartile range) 15 (12-19) versus 14 (10-17), p=0.006). Hepatopulmonary syndrome patients had significantly lower 6-min walk distance and worse functional class. Hepatopulmonary syndrome patients had higher circulating angiopoietin 2, Tie2, tenascin C, tyrosine protein kinase Kit (c-Kit), vascular cell adhesion molecule 1 and von Willebrand factor levels, and lower E-selectin levels. Patients with hepatopulmonary syndrome had an increased risk of death (hazard ratio 1.80, 95% CI 1.03-3.16, p=0.04), which persisted despite adjustment for covariates (hazard ratio 1.79, 95% CI 1.02-3.15, p=0.04). This association did not vary based on levels of oxygenation, reflecting the severity of hepatopulmonary syndrome. CONCLUSION: Hepatopulmonary syndrome was associated with a profile of abnormal systemic angiogenesis, worse exercise and functional capacity, and an overall increased risk of death.

Estrogen Signaling and Portopulmonary Hypertension: The Pulmonary Vascular Complications of Liver Disease Study (PVCLD2).

BACKGROUND AND AIMS: Portopulmonary hypertension (POPH) was previously associated with a single-nucleotide polymorphism (SNP) rs7175922 in aromatase (cytochrome P450 family 19 subfamily A member 1 [CYP19A1]). We sought to determine whether genetic variants and metabolites in the estrogen signaling pathway are associated with POPH. APPROACH AND RESULTS: We performed a multicenter case-control study. POPH patients had mean pulmonary artery pressure >25 mm Hg, pulmonary vascular resistance >240 dyn-sec/cm-5 , and pulmonary artery wedge pressure ≤15 mm Hg without another cause of pulmonary hypertension. Controls had advanced liver disease, right ventricular (RV) systolic pressure <40 mm Hg, and normal RV function by echocardiography. We genotyped three SNPs in CYP19A1 and CYP1B1 using TaqMan and imputed SNPs in estrogen receptor 1 using genome-wide markers. Estrogen metabolites were measured in blood and urine samples. There were 37 patients with POPH and 290 controls. Mean age was 57 years, and 36% were female. The risk allele A in rs7175922 (CYP19A1) was significantly associated with higher levels of estradiol (P = 0.02) and an increased risk of POPH (odds ratio [OR], 2.36; 95% confidence interval [CI], 1.12-4.91; P = 0.02) whereas other SNPs were not. Lower urinary 2-hydroxyestrogen/16-α-hydroxyestrone (OR per 1-ln decrease = 2.04; 95% CI, 1.16-3.57; P = 0.01), lower plasma levels of dehydroepiandrosterone-sulfate (OR per 1-ln decrease = 2.38; 95% CI, 1.56-3.85; P < 0.001), and higher plasma levels of 16-α-hydroxyestradiol (OR per 1-ln increase = 2.16; 95% CI, 1.61-2.98; P < 0.001) were associated with POPH. CONCLUSIONS: Genetic variation in aromatase and changes in estrogen metabolites were associated with POPH.

Associations of ω-3 Fatty Acids With Interstitial Lung Disease and Lung Imaging Abnormalities Among Adults.

Docosahexaenoic acid (DHA), an ω-3 polyunsaturated fatty acid, attenuates interstitial lung disease (ILD) in experimental models, but human studies are lacking. We examined associations of circulating levels of DHA and other polyunsaturated fatty acids with hospitalization and death due to ILD over 12 years in the Multi-Ethnic Study of Atherosclerosis (MESA; n = 6,573). We examined cross-sectional associations with CT lung abnormalities in MESA (2000-2012; n = 6,541), the Framingham Heart Study (2005-2011; n = 3,917), and the Age, Gene/Environment Susceptibility-Reykjavik Study (AGES-Reykjavik) (2002-2006; n = 1,106). Polyunsaturated fatty acid levels were determined from fasting blood samples and extracted from plasma phospholipids (MESA and AGES-Reykjavik) or red blood cell membranes (Framingham Heart Study). Higher DHA levels were associated with a lower risk of hospitalization due to ILD (per standard-deviation increment, adjusted rate ratio = 0.69, 95% confidence interval (CI): 0.48, 0.99) and a lower rate of death due to ILD (per standard-deviation increment, adjusted hazard ratio = 0.68, 95% CI: 0.47, 0.98). Higher DHA was associated with fewer interstitial lung abnormalities on computed tomography (per natural log increment, pooled adjusted odds ratio = 0.65, 95% CI: 0.46, 0.91). Higher DHA levels were associated with a lower risk of hospitalization and death due to ILD and fewer lung abnormalities on computed tomography in a meta-analysis of data from population-based cohort studies.

New and Emerging Therapies for Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a pulmonary vasculopathy that causes right ventricular dysfunction and exercise limitation and progresses to death. New findings from translational studies have suggested alternative pathways for treatment. These avenues include sex hormones, genetic abnormalities and DNA damage, elastase inhibition, metabolic dysfunction, cellular therapies, and anti-inflammatory approaches. Both novel and repurposed compounds with rationale from preclinical experimental models and human cells are now in clinical trials in patients with PAH. Findings from these studies will elucidate the pathobiology of PAH and may result in clinically important improvements in outcome.

Associations of Angiopoietins With Heart Failure Incidence and Severity.

BACKGROUND: Angiopoietin-1 and 2 (Ang1, Ang2) are important mediators of angiogenesis. Angiopoietin levels are perturbed in cardiovascular disease, but it is unclear whether angiopoietin signaling is causative, an adaptive response, or merely epiphenomenon of disease activity. METHODS AND RESULTS: In a cohort free of cardiovascular disease at baseline (Multi-Ethnic Study of Atherosclerosis [MESA]), relationships between angiopoietins, cardiac morphology, and subsequent incidence of heart failure or cardiovascular death were evaluated. In cohorts with pulmonary arterial hypertension or left heart disease, associations between angiopoietins, invasive hemodynamics, and adverse clinical outcomes were evaluated. In MESA, Ang2 was associated with a higher incidence of heart failure or cardiovascular death (hazard ratio 1.21 per standard deviation, P < .001). Ang2 was associated with increased right atrial pressure (pulmonary arterial hypertension cohort) and increased wedge pressure and right atrial pressure (left heart disease cohort). Elevated Ang2 was associated with mortality in the pulmonary arterial hypertension cohort. CONCLUSIONS: Ang2 was associated with incident heart failure or death among adults without cardiovascular disease at baseline and with disease severity in individuals with existing heart failure. Our finding that Ang2 is increased before disease onset and that elevations reflect disease severity, suggests Ang2 may contribute to heart failure pathogenesis.

Preoperative echocardiographic parameters predict primary graft dysfunction following pediatric lung transplantation.

The importance of preoperative cardiac function in pediatric lung transplantation is unknown. We hypothesized that worse preoperative right ventricular (RV) systolic and worse left ventricular (LV) diastolic function would be associated with a higher risk of primary graft dysfunction grade 3 (PGD 3) between 48 and 72 hours. We performed a single center, retrospective pilot study of children (<18 years) who had echocardiograms <1 year prior to lung transplantation between 2006 and 2019. Conventional and strain echocardiography parameters were measured, and PGD was graded. Area under the receiver operating characteristic (AUROC) curves and logistic regression were performed. Forty-one patients were included; 14 (34%) developed PGD 3 and were more likely to have pulmonary hypertension (PH) as the indication for transplant (P = .005). PGD 3 patients had worse RV global longitudinal strain (P = .01), RV free wall strain (FWS) (P = .003), RV fractional area change (P = .005), E/e' (P = .01) and lateral e' velocity (P = .004) but not tricuspid annular plane systolic excursion (P = .61). RV FWS (AUROC 0.79, 95% CI 0.62-0.95) and lateral e' velocity (AUROC 0.87, 95% CI 0.68-1.00) best discriminated PGD 3 development and showed the strongest association with PGD 3 (RV FWS OR 3.87 [95% CI 1.59-9.43], P = .003; lateral e' velocity OR 0.10 [95% CI 0.01-0.70], P = .02). These associations remained when separately adjusting for age, weight, primary PH diagnosis, ischemic time, and bypass time. In this pilot study, worse preoperative RV systolic and worse LV diastolic function were associated with PGD 3 and may be modifiable recipient risk factors in pediatric lung transplantation.

Prevalence and Impact of Restrictive Lung Disease in Liver Transplant Candidates.

We investigated the prevalence of spirometric restriction in liver transplantation (LT) candidates and the clinical impacts of restriction. We performed a cross-sectional study within the Pulmonary Vascular Complications of Liver Disease 2 (PVCLD2) study, a multicenter prospective cohort study of patients being evaluated for LT. Patients with obstructive lung disease or missing spirometry or chest imaging were excluded. Patients with and without restriction, defined as a forced vital capacity (FVC) <70% predicted, were compared. Restriction prevalence was 18.4% (63/343). Higher Model for End-Stage Liver Disease-sodium score (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.02-1.11; P = 0.007), the presence of pleural effusions (OR, 3.59; 95% CI, 1.96-6.58; P < 0.001), and a history of ascites (OR, 2.59; 95% CI, 1.26-5.33; P = 0.01) were associated with the presence of restriction, though one-third with restriction had neither pleural effusions nor ascites. In multivariate analysis, restriction was significantly and independently associated with lower 6-minute walk distances (least squares mean, 342.0 [95% CI, 316.6-367.4] m versus 395.7 [95% CI, 381.2-410.2] m; P < 0.001), dyspnea (OR, 2.69; 95% CI, 1.46-4.95; P = 0.002), and lower physical component summary Short Form 36 scores indicating worse quality of life (least squares mean, 34.1 [95% CI, 31.5-36.7] versus 38.2 [95% CI, 36.6-39.7]; P = 0.004). Lower FVC percent predicted was associated with an increased risk of death (hazard ratio, 1.16; 95% CI, 1.04-1.27 per 10-point decrease in FVC percent predicted; P = 0.01). Restriction and abnormal lung function are common in LT candidates; can be present in the absence of an obvious cause, such as pleural effusions or ascites; and is associated with worse exercise capacity, quality of life, and survival.

Pulse Oximetry Is Insensitive for Detection of Hepatopulmonary Syndrome in Patients Evaluated for Liver Transplantation.

Screening for hepatopulmonary syndrome (HPS) using pulse oximetry is recommended in liver transplant (LT) candidates because mortality is increased, independently of the severity of the oxygenation defect. LT exception points may be afforded to those with HPS and severe hypoxemia. We assessed the screening characteristics of pulse oximetry for HPS. The Pulmonary Vascular Complications of Liver Disease 2 study is a multicenter, prospective cohort study of adults undergoing their first LT evaluation. Patients underwent protocolized assessment of oxygen saturation by pulse oximetry (SpO2 ), arterial blood gas, spirometry, and contrast-enhanced echocardiography (CE). HPS was defined as an alveolar-arterial gradient ≥15 mm Hg (≥20 mm Hg if age >64 years), intrapulmonary vascular dilatation on CE, and absence of lung disease. The study sample included 363 patients. Of these, 75 (20.7%; 95% confidence interval [CI], 16.6%-25.2%) met the criteria for HPS. The area under the receiver operating characteristic curve (or c-statistic) for SpO2 in discriminating HPS was 0.59 (95% CI, 0.51-0.66). An SpO2 <96%, recommended by practice guidelines as a threshold to require further testing, had low sensitivity (28%; 95% CI, 18%-28%). The c-statistic of SpO2 in discriminating HPS with a partial pressure of oxygen (PaO2 ) <60 mm Hg (eligible for LT exception points) was 0.76 (95% CI, 0.46-1.00). An SpO2 cutoff of <96% had higher sensitivity for detecting HPS with PaO2 <60 mm Hg (71%; 95% CI, 38%-100%) but was still inadequate. Conclusion: Pulse oximetry is not sufficiently sensitive to screen for HPS in LT candidates. Arterial blood gas and CE are required in LT candidates for diagnosis of HPS.

Association of right atrial structure with incident atrial fibrillation: a longitudinal cohort cardiovascular magnetic resonance study from the Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND: While studies of the left atrium (LA) have demonstrated associations between volumes and emptying fraction with atrial fibrillation (AF), the contribution of right atrial (RA) abnormalities to incident AF remains poorly understood. OBJECTIVES: Assess the association between RA structure and function with incident AF using feature-tracking cardiovascular magnetic resonance (CMR). METHODS: This is a prospective cohort study of all participants in the Multi-Ethnic Study of Atherosclerosis with baseline CMR, sinus rhythm, and free of clinical cardiovascular disease at study initiation. RA volume, strain, and emptying fraction in participants with incident AF (n = 368) were compared against AF-free (n = 2779). Cox proportional-hazards models assessed association between variables. RESULTS: Participants were aged 60 ± 10 yrs., 55% female, and followed an average 11.2 years. Individuals developing AF had higher baseline RA maximum volume index (mean ± standard deviation [SD]: 24 ± 9 vs 22 ± 8 mL/m2, p = 0.002) and minimum volume index (13 ± 7 vs 12 ± 6 mL/m2, p < 0.001), and lower baseline RA emptying fraction (45 ± 15% vs 47 ± 15%, p = 0.02), peak global strain (34 ± 17% vs 36 ± 19%, p < 0.001), and peak free-wall strain (40 ± 23% vs 42 ± 26%, p = 0.049) compared with the AF-free population. After adjusting for traditional cardiovascular risk factors and LA volume and function, we found RA maximum volume index (hazards ratio [HR]: 1.13 per SD, p = 0.041) and minimum volume index (HR: 1.12 per SD, p = 0.037) were independently associated with incident AF. CONCLUSIONS: In a large multiethnic population, higher RA volume indices were independently associated with incident AF after adjustment for conventional cardiovascular risk factors and LA parameters. It is unclear if this predictive value persists when additional adjustment is made for ventricular parameters.

Association between antinuclear antibody seropositivity and telomere length: a nationwide population-based study.

OBJECTIVES: Telomere shortening is a well-established marker of biological aging. Whether telomere erosion coincides with age-related increases in antinuclear antibody (ANA) seropositivity remains unknown. Our study aimed to determine the association between ANA seropositivity and shortened telomeres among 1999-2002 National Health and Nutrition Examination Survey (NHANES) subjects. METHODS: We performed a cross-sectional analysis of 2,188 NHANES study participants with available ANA and telomere length data. ANA testing was performed using indirect immunofluorescence. Telomere lengths were measured via quantitative polymerase chain reaction methods. Applying appropriate sample weighting techniques, we used univariate and multivariate logistic regression methods to assess the association between shortened telomeres (i.e. lowest decile of the cohort) and ANA seropositivity. RESULTS: ANAs were positive in 322 out of 2,188 (14.7%, 95% CI 13.3-16.3%) individuals. Subjects with shortened telomeres were more likely to be older (p<0.001), male (p=0.005), and have a cancer history (p<0.001). A higher proportion of non-Hispanic white participants (61.6% vs. 49.3%) and a lower proportion of non-Hispanic black participants (7.8% vs. 17.9%) had shortened telomeres (p<0.001). Shortened telomeres were not independently associated with ANA seropositivity (OR 1.48, 95% CI 0.87-2.52, p=0.14). However, female sex (OR 1.91, 95% CI 1.23-2.96, p=0.006), age ≥80 years (OR 2.06, 95% CI 1.08-3.92, p=0.03), and African American race (OR 1.58, 95% CI 1.00-2.51, p=0.05) were independent risk factors for ANA seropositivity. Neither sex nor race modified the relationship between ANA seropositivity and telomere length. CONCLUSIONS: Telomere erosion does not appear to be responsible for age-related increases in the prevalence of ANA seropositivity.