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Abstract Portopulmonary hypertension (PoPH) is a type of pulmonary vascular disease due to portal hypertension that exhibits high morbidity and mortality. The mechanisms driving disease are unknown, and transcriptional characteristics unique to the PoPH liver remain unexplored. Here, we apply single nuclear RNA sequencing to compare cirrhotic livers from patients with and without PoPH. We identify characteristics unique to PoPH in cells surrounding the central hepatic vein, including increased growth differentiation factor signaling, enrichment of the arginine biosynthesis pathway, and differential expression of the bone morphogenic protein type II receptor and estrogen receptor type I genes. These results provide insight into the transcriptomic characteristics of the PoPH liver and mechanisms by which PoPH cellular dysfunction might contribute to pulmonary vascular remodeling.

Abstract Knowledge of what outcomes are most meaningful to pulmonary arterial hypertension (PAH) stakeholders is limited. In this qualitative study, patients and clinicians endorsed personalized physical activity, symptoms, and psychosocial well‐being as key outcomes to assess PAH treatment response, yet few are routinely measured in PAH clinical trials.

Abstract Women with pulmonary arterial hypertension (PAH) experience multiple symptoms, including dyspnea, fatigue, and sleep disturbance, that impair their health‐related quality of life (HRQOL). However, we know little about phenotypic subgroups of patients with PAH with similar, concurrent, multiple symptoms. The objectives of this study were to define the “symptome” by symptom cluster phenotypes and compare characteristics such as biomarkers, cardiac structure and function (echocardiography), functional capacity (6‐min walk distance), and HRQOL between the groups. This cross‐sectional study included 60 women with PAH. Subjects completed an assessment battery: Pulmonary Arterial Hypertension Symptom Scale, Pittsburgh Sleep Quality Index, Multidimensional Dyspnea Profile, Patient‐Reported Outcomes Measurement Information System (PROMIS®) Physical Function, PROMIS® Sleep‐Related Impairment, and the emPHasis‐10. Subjects also underwent transthoracic echocardiography, phlebotomy, 6‐min walk distance, and actigraphy. The three symptoms of dyspnea, fatigue, and sleep disturbance were used to define the symptom clusters. Other PAH symptoms, plasma and serum biomarkers, cardiac structure and function (echocardiography), exercise capacity (6‐min walk distance), sleep (actigraphy), and HRQOL were compared across phenotypes. The mean age was 50 ± 18 years, 51% were non‐Hispanic white, 32% were non‐Hispanic Black and 40% had idiopathic PAH. Cluster analysis identified Mild (n = 28, 47%), Moderate (n = 20, 33%), and Severe Symptom Cluster Phenotypes (n = 12, 20%). There were no differences for age, race, or PAH etiology between the phenotypes. WHO functional class (p

BACKGROUND Children with single ventricle heart disease have significant morbidity and mortality. The maternal–fetal environment (MFE) may adversely impact outcomes after neonatal cardiac surgery. We hypothesized that impaired MFE would be associated with an increased risk of death after stage 1 Norwood reconstruction. METHODS AND RESULTS We performed a retrospective cohort study of children with hypoplastic left heart syndrome (and anatomic variants) who underwent stage 1 Norwood reconstruction between 2008 and 2018. Impaired MFE was defined as maternal gestational hypertension, preeclampsia, gestational diabetes, and/or smoking during pregnancy. Cox proportional hazards regression models were used to investigate the association between impaired MFE and death while adjusting for confounders. Hospital length of stay was assessed with the competing risk of in‐hospital death. In 273 children, the median age at stage 1 Norwood reconstruction was 4 days (interquartile range [IQR], 3–6 days). A total of 72 children (26%) were exposed to an impaired MFE; they had more preterm births (18% versus 7%) and a greater percentage with low birth weights

Abstract 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

Background: Pulmonary hypertension is a complication of chronic lung diseases (PH-CLD) associated with significant morbidity and mortality. Management guidelines for PH-CLD emphasize the treatment of the underlying lung disease, but the role of PH-targeted therapy remains controversial. We hypothesized that treatment approaches for PH-CLD would be variable across physicians depending on the type of CLD and the severity of PH.Methods and Results: Between May and July 2020, we conducted an online survey of PH experts asking for their preferred treatment approach in seven hypothetical cases of PH-CLD of varying severity. We assessed agreement amongst clinicians for initial therapy choice using Fleiss' kappa calculations. Over 90% of respondents agreed that they would treat cases of severe PH in the context of mild lung disease with some form of PH-targeted therapy. For cases of severe PH in the context of severe lung disease, over 70% of respondents agreed to use PH-targeted therapy. For mild PH and mild lung disease cases,

Introduction: Tetralogy of Fallot (TOF) repair is associated with excellent operative survival. However, a subset of patients experiences post-operative complications, which can significantly alter the early and late post-operative course. We utilized a machine learning approach to identify risk factors for post-operative complications after TOF repair.Methods: We conducted a single-center prospective cohort study of children

Background Low cardiorespiratory fitness (CRF) and obesity are risk factors for heart failure but their associations with right ventricular (RV) systolic function and pulmonary artery systolic pressure (PASP) are not well understood. Methods and Results Participants in the CARDIA (Coronary Artery Risk Development in Young Adults) study who underwent maximal treadmill testing at baseline and had a follow‐up echocardiographic examination at year 25 were included. A subset of participants had repeat CRF and body mass index (BMI) assessment at year 20. The associations of baseline and changes in CRF and BMI on follow‐up (baseline to year 20) with RV systolic function parameters (tricuspid annular plane systolic excursion, RV Doppler systolic velocity of the lateral tricuspid annulus), and PASP were assessed using multivariable‐adjusted linear regression models. The study included 3433 participants. In adjusted analysis, higher baseline BMI but not CRF was significantly associated with higher PASP. Among RV systolic function parameters, higher baseline CRF and BMI were significantly associated with higher tricuspid annular plane systolic excursion and RV systolic velocity of the lateral tricuspid annulus. In the subgroup of participants with follow‐up assessment of CRF or BMI at year 20, less decline in CRF was associated with higher RV systolic velocity of the lateral tricuspid annulus and lower PASP, while greater increase in BMI was significantly associated with higher PASP in middle age. Conclusions Higher CRF in young adulthood and less decline in CRF over time are each significantly associated with better RV systolic function. Higher baseline BMI and greater age‐related increases in BMI are each significantly associated with higher PASP in middle age. These findings provide insights into possible mechanisms through which low fitness and obesity may contribute toward risk of heart failure.

Readmissions for pulmonary hypertension are poorly understood and understudied. We sought to determine national estimates and risk factors for 30-day readmission after pulmonary hypertension-related hospitalizations. We utilized the Healthcare Cost and Utilization Project Nationwide Readmission Database, which has weighted estimates of roughly 35 million discharges in the US. Adult patients with primary International Classification of Disease, Ninth Revision, Clinical Modification diagnosis codes of 416.0 and 416.8 for primary and secondary pulmonary hypertension with an index admission between 2012 and 2014 and any readmission within 30 days of the index event were identified. Predictors of 30-day readmission were identified using multivariable logistic regression with adjustment for covariates. Results showed that the national estimate for Primary Pulmonary Hypertension vs Secondary Pulmonary Hypertension-related index events between 2012 and 2014 with 30-day readmission was 247 vs 2550 corresponding to a national readmission risk estimate of 17% vs 18.3%, respectively. The presence of fluid and electrolyte disorders, renal failure, and alcohol abuse were associated with increased risk of readmission in Primary Pulmonary Hypertension, while factors associated with Secondary Pulmonary Hypertension readmissions included anemia, congestive heart failure, lung disease, fluid and electrolyte disorders, renal failure, diabetes, and liver disease. The median cost of Primary Pulmonary Hypertension admissions and readmissions were $46,132 (IQR: $25,384–$85,647) and $41,604.50 (IQR: $22,481.50–$84,420.50), respectively. The median costs of Secondary Pulmonary Hypertension admissions and readmissions were $34,893 (IQR: $19,670–$66,143) and $36,279 (IQR: $19,059–$74,679), respectively. In conclusion, approximately 19% of Primary Pulmonary Hypertension and Secondary Pulmonary Hypertension hospitalizations result in 30-day readmission, with significant costs accrued during the index hospitalization and readmission. With evolving clinical terminology and diagnostic codes, future study will need to better clarify underlying factors associated with readmissions amongst pulmonary hypertension sub-types, and identify methods and procedures to minimize readmission risk.

High-attenuation areas (HAA) are a computed tomography-based quantitative measure of subclinical interstitial lung disease (ILD). We aimed to validate HAA in lung regions that are less subject to artefacts, such as extravascular lung water or dependent atelectasis. We examined the associations of HAA within six lung regions (basilar, non-basilar, peel, core, basilar peel, basilar core) with serum biomarkers of lung remodelling, forced vital capacity (FVC), visually-assessed interstitial lung abnormalities (ILA), and all-cause and ILD-specific mortality. We performed cross-sectional and longitudinal analyses of participants in the Multi-Ethnic Study of Atherosclerosis, a prospective cohort of 6814 adults aged 45–84 years without known cardiovascular disease who underwent cardiac computed tomography. Median regional HAA ranged from 3.8% in the peel to 4.8% in the basilar core. Doubling of regional HAA was associated with greater serum matrix metalloproteinase-7 (range 3.8% to 10.3%; p≤0.01), higher odds of ILA (OR 1.42 to 2.20; p≤0.03), and a higher risk of all-cause mortality (hazard ratio 1.20 to 1.47; p≤0.001). Doubling of regional HAA was associated with greater serum interleukin-6 (4.9% to 10.3%; p≤0.005) and higher risk of ILD-specific mortality (hazard ratio 3.30 to 3.98; p

Background Risk‐adjusted adverse event (AE) rates have been used to measure the quality of pediatric and congenital cardiac catheterization laboratories. In other settings, failure to rescue (FTR) has demonstrated utility as a quality metric. Methods and Results A multicenter retrospective cohort study was performed using data from the IMPACT (Improving Adult and Congenital Treatment) Registry between January 2010 and December 2016. A modified FTR metric was developed for pediatric and congenital cardiac catheterization laboratories and then compared with pooled AEs. The associations between patient‐ and hospital‐level factors and outcomes were evaluated using hierarchical logistic regression models. Hospital risk standardized ratios were then calculated. Rankings of risk standardized ratios for each outcome were compared to determine whether AEs and FTR identified the same high‐ and low‐performing centers. During the study period, 77 580 catheterizations were performed at 91 hospitals. Higher annual hospital catheterization volume was associated with lower odds of FTR (odds ratio: 0.68 per 300 cases; P=0.0003). No association was seen between catheterization volume and odds of AEs. Odds of AEs were instead associated with patient‐ and procedure‐level factors. There was no correlation between risk standardized ratio ranks for FTR and pooled AEs (P=0.46). Hospital ranks by catheterization volume and FTR were associated (r=−0.28, P=0.01) with the largest volume hospitals having the lowest risk of FTR. Conclusions In contrast to AEs, FTR was not strongly associated with patient‐ and procedure‐level factors and was significantly associated with pediatric and congenital cardiac catheterization laboratory volume. Hospital rankings based on FTR and AEs were not significantly correlated. We conclude that FTR is a complementary measure of catheterization laboratory quality and should be included in future research and quality‐improvement projects.

Abstract Background We conducted a genome-wide association study (GWAS) of subclinical interstitial lung disease (ILD), defined as high attenuation areas (HAA) on CT, in the population-based Multi-Ethnic Study of Atherosclerosis Study. Methods We measured the percentage of high attenuation areas (HAA) in the lung fields on cardiac CT scan defined as voxels with CT attenuation values between -600 and -250 HU. Genetic analyses were performed in MESA combined across race/ethnic groups: non-Hispanic White (n = 2,434), African American (n = 2,470), Hispanic (n = 2,065) and Chinese (n = 702), as well as stratified by race/ethnicity. Results Among 7,671 participants, regions at genome-wide significance were identified for basilar peel-core ratio of HAA in FLJ35282 downstream of ANRIL (rs7852363, P = 2.1x10−9) and within introns of SNAI3-AS1 (rs140142658, P = 9.6x10−9) and D21S2088E (rs3079677, P = 2.3x10−8). Within race/ethnic groups, 18 additional loci were identified at genome-wide significance, including genes related to development (FOXP4), cell adhesion (ALCAM) and glycosylation (GNPDA2, GYPC, GFPT1 and FUT10). Among these loci, SNP rs6844387 near GNPDA2 demonstrated nominal evidence of replication in analysis of n = 1,959 participants from the Framingham Heart Study (P = 0.029). FOXP4 region SNP rs2894439 demonstrated evidence of validation in analysis of n = 228 White ILD cases from the Columbia ILD Study compared to race/ethnicity-matched controls from MESA (one-sided P = 0.007). In lung tissue from 15 adults with idiopathic pulmonary fibrosis compared to 15 adults without lung disease. ANRIL (P = 0.001), ALCAM (P = 0.03) and FOXP4 (P = 0.046) were differentially expressed. Conclusions Our results suggest novel roles for protein glycosylation and cell cycle disinhibition by long non-coding RNA in the pathogenesis of ILD.

Pulmonary hypertension (PH) is highly heterogeneous and despite treatment advances it remains a life-shortening condition. There have been significant advances in imaging technologies, but despite evidence of their potential clinical utility, practice remains variable, dependent in part on imaging availability and expertise. This statement summarizes current and emerging imaging modalities and their potential role in the diagnosis and assessment of suspected PH. It also includes a review of commonly encountered clinical and radiological scenarios, and imaging and modeling-based biomarkers. An expert panel was formed including clinicians, radiologists, imaging scientists, and computational modelers. Section editors generated a series of summary statements based on a review of the literature and professional experience and, following consensus review, a diagnostic algorithm and 55 statements were agreed. The diagnostic algorithm and summary statements emphasize the key role and added value of imaging in the diagnosis and assessment of PH and highlight areas requiring further research.

Background. The role of liver transplantation (LT) in the management of portopulmonary hypertension (POPH) is poorly understood. The aim of this study was to better understand provider attitudes and practice patterns regarding the management of patients with POPH and to assess the concordance between clinical practice and current guidelines. Methods. We performed a multicenter survey study of hepatologists and pulmonary hypertension (PH) physicians at US LT centers that performed >50 transplants per year. Survey responses are summarized as number (%). Associations were assessed using a Wilcoxon-rank sum, chi-square, or Fisher exact test, as appropriate. Results. Seventy-four providers from 35 centers were included. There was marked variability regarding screening practices, management, and attitudes. Forty-two percent responded that POPH nearly always or often improves with LT, and 15.5% reported that POPH rarely or never improves. In contrast to current guidelines, 50.7% agreed that treated POPH should be an indication for LT in patients with compensated cirrhosis. Hepatologists were more likely than PH physicians to agree that POPH should be an indication for LT (P = 0.02). Forty-nine percent of respondents thought that the current POPH Model for End-stage Liver Disease exception criteria should be modified, and management of patients with an elevated mean pulmonary arterial pressure and normal pulmonary vascular resistance differed from current policies. Conclusions. There is marked variability in provider attitudes and practice patterns regarding the management of POPH. This study highlights the need for prospective studies to inform practice and for improved implementation of practice guidelines in order to standardize care.

Pulmonary arterial compliance (PAC), invasively assessed by the ratio of stroke volume to pulmonary arterial (PA) pulse pressure, is a sensitive marker of right ventricular (RV)-PA coupling that differs across the spectrum of pulmonary hypertension (PH) and is predictive of outcomes. We assessed whether the echocardiographically derived ratio of RV outflow tract velocity time integral to PA systolic pressure (RVOT-VTI/PASP) (a) correlates with invasive PAC, (b) discriminates heart failure with preserved ejection-associated PH (HFpEF-PH) from pulmonary arterial hypertension (PAH), and (c) is associated with functional capacity. We performed a retrospective cohort study of patients with PAH (n = 70) and HFpEF-PH (n = 86), which was further dichotomized by diastolic pressure gradient (DPG) into isolated post-capillary PH (DPG

Background Cardiac catheterization is an important but costly component of health care for young patients with cardiac disease. Measurement of variation in their cost between hospitals and identification of the reasons for this variation may help reduce cost without compromising quality. Methods and Results Using data from Pediatric Health Information Systems Database from January 2007 to December 2015, the costs of 9 procedures were measured. Mixed‐effects multivariable models were used to generate case‐mix–adjusted estimates of each hospital's cost for each procedure and measure interhospital variation. Procedures (n=35 637) from 43 hospitals were studied. Median costs varied from $8249 (diagnostic catheterization after orthotopic heart transplantation) to $38 909 (transcatheter pulmonary valve replacement). There was marked variation in the cost of procedures between hospitals with 3.5‐ to 8.9‐fold differences in the case‐mix–adjusted cost between the most and least expensive hospitals. No significant correlation was found between hospitals’ procedure‐specific mortality rates and costs. Higher procedure volume was not associated with lower cost except for diagnostic procedures in heart transplant patients and pulmonary artery angioplasty. At the hospital level, the proportion of cases that were outliers (>95th percentile) was significantly associated with rank in terms of cost (Spearman's ρ ranging from 0.37 to 0.89, P

BackgroundWe sought to identify patient and surgical factors associated with time to hospital discharge in patients undergoing complete repair for tetralogy of Fallot. Methods and ResultsWe performed a prospective cohort study of patients with tetralogy of Fallot admitted for complete repair between May 1, 2012 and June 2, 2017 at Children's Hospital of Philadelphia with detailed demographic, clinical, and operative characteristics. The primary outcome was time to hospital discharge. Cox proportional hazards models were used to identify patient and operative predictors of time to hospital discharge. We enrolled 151 subjects, 62.8% male, 65.6% non‐Hispanic white, and 9.9% non‐Hispanic black. The median time to hospital discharge was 7 days (interquartile range 4, 12). Five patients died in the hospital, all of whom underwent tetralogy of Fallot repair beyond the neonatal period. Greater birth weight was associated with higher rate of hospital discharge (hazard ratio [HR]=1.35, 95% confidence interval (CI) =1.11, 1.64), while absent pulmonary valve versus pulmonary stenosis (HR=0.27, 95% CI=0.08, 0.91), pulmonary valve atresia versus pulmonary stenosis (HR=0.57, 95% CI=0.33, 0.97), presence of aortopulmonary collaterals (HR=0.44, 95% CI=0.24, 0.84), complete repair performed in the neonatal period (

Pulmonary hypertension (PH) causes significant morbidity and mortality in children due to right ventricular (RV) failure. We sought to determine the effect of prostacyclin analogues on RV function assessed by echocardiography in children with PH. We conducted a retrospective cohort study of children with PH treated with a prostacyclin analogue (epoprostenol or treprostinil) between January 2001 and August 2015 at our center. Data were collected before initiation of treatment (baseline) and at 1–3 and 6–12 months after. Protocolized echocardiogram measurements including tricuspid annular plane systolic excursion (TAPSE) and RV global longitudinal strain were made with blinding to clinical information. Forty-nine individuals (65% female), aged 0–29 years at the time of prostacyclin initiation were included. Disease types included pulmonary arterial hypertension (idiopathic [35%], heritable [2%], and congenital heart disease-associated [18%]), developmental lung disease (43%), and chronic thromboembolic PH (2%). Participants received intravenous (IV) epoprostenol (14%) and IV/subcutaneous (SQ) (67%) or inhaled (18%) treprostinil. Over the study period, prostacyclin analogues were associated with improvement in TAPSE ( P = 0.007), RV strain ( P

This study explores the racial and ethnic differences in presentation, severity, and treatment of patients with pulmonary arterial hypertension (PAH) in a large multicenter registry. African American and Hispanic patients are more likely to present with associated PAH compared to non-Hispanic whites. Hispanic patients with PAH were less likely to be treated with PAH-specific medications compared to non-Hispanic whites.

BackgroundSystemic arterial stiffness is recognized as a major contributor to development of left ventricular dysfunction and failure; however, the relationship of systemic arterial properties and the right ventricle (RV) is unknown. Methods and ResultsThe associations between systemic arterial measures (total arterial compliance [TAC], systemic vascular resistance [SVR], and aortic augmentation index [AI]) and RV morphology (mass, end‐systolic [RVESV] and end‐diastolic volume [RVEDV], and ejection fraction [RVEF]) were examined using data from the Multi‐Ethnic Study of Atherosclerosis. All analyses were adjusted for anthropometric, demographic, and clinical variables and the corresponding left ventricular parameter. A total of 3842 subjects without clinical cardiovascular disease were included with a mean age of 61 years, 48% male, 39% non‐Hispanic white, 25% Chinese‐American, 23% Hispanic, and 13% black. RV measures were within normal range for age and sex. A 1‐mL/mm Hg decrease in TAC was associated with 3.9‐mL smaller RVESV, 7.6‐mL smaller RVEDV, and 2.4‐g lower RV mass. A 5‐Wood‐unit increase in SVR was associated with 0.6‐mL decrease in RVESV, 1.7‐mL decrease in RVEDV, and 0.4‐g decrease in RV mass. A 1% increase in AI was associated with 0.2‐mL decrease in RVEDV. We found significant effect modification by age, sex, and race for some of these relationships, with males, whites, and younger individuals having greater decreases in RV volumes and mass. ConclusionsMarkers of increased systemic arterial load were associated with smaller RV volumes and lower RV mass in a population of adults without clinical cardiovascular disease.