Meta-analysis: Incidence of cirrhosis and hepatocellular carcinoma in patients with Fontan palliation.

BACKGROUND AND AIMS: The Fontan palliation is the final stage of surgery for many children born with univentricular physiology. Almost all Fontan patients develop liver fibrosis which may eventually lead to cirrhosis and hepatocellular carcinoma (HCC). These are important causes of morbidity and mortality in these patients. We performed a systematic review and meta-analysis to assess the incidence of cirrhosis and HCC in Fontan patients and stratify it based on time since surgery. METHODS: A literature search of seven databases identified 1158 records. Studies reporting the number of cirrhosis and HCC cases in Fontan patients and time since Fontan surgery were included. In the cirrhosis cohort, we included only those studies where all patients underwent liver biopsy. RESULTS: A total of 23 studies were included: 12 and 13 studies in the cirrhosis and HCC cohorts, respectively, with two studies included in both cohorts. The incidence of cirrhosis was 0.97 per 100 patient-years (95% CI 0.57-1.63), with the incidence and cumulative incidence ≥20 years post Fontan surgery being 1.61 per 100 patient-years (95% CI 1.24-2.08) and 32.2% (95% CI 25.8%-39.4%), respectively. The incidence of HCC was 0.12 per 100 patient-years (95% CI 0.07-0.21), with the incidence and cumulative incidence ≥20 years post Fontan surgery being 0.20 per 100 patient-years (95% CI 0.12-0.35) and 3.9% (95% CI 2.2%-6.8%), respectively. Only about 70% of patients with HCC (20/28) had underlying cirrhosis. CONCLUSION: The incidence of cirrhosis and HCC increases over time, especially at ≥20 years post Fontan surgery. Studies are needed to further identify at-risk patients in order to streamline surveillance for these highly morbid conditions.

Patient Engagement in Research: Considerations in Creating a Registry for Adults with Congenital Heart Disease.

PURPOSE OF REVIEW: Patient engagement is defined as the meaningful involvement and active partnership of patients and key partners throughout the entire research project. This article reviews the importance of developing a patient engagement plan to promote better alignment of research with patients' and clinicians' real-world needs and concerns. RECENT FINDINGS: The Congenital Heart Initiative (CHI) launched in 2020 is an entirely web-based longitudinal registry designed in close coordination with the adult congenital heart disease (ACHD) community it is intended to serve. Successful community engagement has resulted in real-world data being collected in large scale in a rare disease population. Establishing patient engagement plans is critical to conducting patient-centered outcomes research. Continued improvement of community engagement strategies is needed to ensure the entire ACHD population is represented to facilitate future research and improved clinical care.

Are dynamic measurements of central venous pressure in Fontan circulation during exercise or volume loading superior to resting measurements?

BACKGROUND: The main objective measure to assess the health of the Fontan circulation is the pressure measurement of the superior vena cava or pulmonary arteries. We reviewed the literature for benefits of measuring resting pressure in the Fontan circuit and explored whether dynamic measurement by volume loading or exercise has the potential to refine this diagnostic tool. METHODS: PubMed was searched for articles showing a relationship between resting post-operative central venous pressure or pulmonary artery pressure and Fontan failure. Relationships between post-operative central venous pressure or pulmonary artery pressure and volume loading changes, such as during exercise or volume loading during cardiac catheterization, were also queried. RESULTS: A total of 44 articles mentioned relationships between resting central venous pressure or pulmonary artery pressure and Fontan failure. Only 26 included an analysis between the variables and only seven of those articles found pressure to be predictive of Fontan failure. Ten articles examined the relationship between exercise or volume loading and outcomes and demonstrated a large individual variation of pressures under these dynamic conditions. CONCLUSIONS: Based on current literature, there is not a lot of strong evidence to show that elevated resting central venous pressure or pulmonary artery pressure is predictive of Fontan failure. Some individuals experience dramatic increases in central venous pressure or pulmonary artery pressure under increased loading conditions with exercise or bolus fluid infusion, while others experience increases closer to that of a healthy control population. Further studies are needed to examine whether more dynamic and continuous monitoring of systemic venous pressures might better predict outcomes in patients with Fontan circulation.

End-stage heart failure in congenitally corrected transposition of the great arteries: a multicentre study.

BACKGROUND AND AIMS: For patients with congenitally corrected transposition of the great arteries (ccTGA), factors associated with progression to end-stage congestive heart failure (CHF) remain largely unclear. METHODS: This multicentre, retrospective cohort study included adults with ccTGA seen at a congenital heart disease centre. Clinical data from initial and most recent visits were obtained. The composite primary outcome was mechanical circulatory support, heart transplantation, or death. RESULTS: From 558 patients (48% female, age at first visit 36 ± 14.2 years, median follow-up 8.7 years), the event rate of the primary outcome was 15.4 per 1000 person-years (11 mechanical circulatory support implantations, 12 transplantations, and 52 deaths). Patients experiencing the primary outcome were older and more likely to have a history of atrial arrhythmia. The primary outcome was highest in those with both moderate/severe right ventricular (RV) dysfunction and tricuspid regurgitation (n = 110, 31 events) and uncommon in those with mild/less RV dysfunction and tricuspid regurgitation (n = 181, 13 events, P < .001). Outcomes were not different based on anatomic complexity and history of tricuspid valve surgery or of subpulmonic obstruction. New CHF admission or ventricular arrhythmia was associated with the primary outcome. Individuals who underwent childhood surgery had more adverse outcomes than age- and sex-matched controls. Multivariable Cox regression analysis identified older age, prior CHF admission, and severe RV dysfunction as independent predictors for the primary outcome. CONCLUSIONS: Patients with ccTGA have variable deterioration to end-stage heart failure or death over time, commonly between their fifth and sixth decades. Predictors include arrhythmic and CHF events and severe RV dysfunction but not anatomy or need for tricuspid valve surgery.

The Fontan Udenafil Exercise Longitudinal Trial: Subgroup Analysis.

The Pediatric Heart Network's Fontan Udenafil Exercise Longitudinal (FUEL) Trial (Mezzion Pharma Co. Ltd., NCT02741115) demonstrated improvements in some measures of exercise capacity and in the myocardial performance index following 6 months of treatment with udenafil (87.5 mg twice daily). In this post hoc analysis, we evaluate whether subgroups within the population experienced a differential effect on exercise performance in response to treatment. The effect of udenafil on exercise was evaluated within subgroups defined by baseline characteristics, including peak oxygen consumption (VO2), serum brain-type natriuretic peptide level, weight, race, gender, and ventricular morphology. Differences among subgroups were evaluated using ANCOVA modeling with fixed factors for treatment arm and subgroup and the interaction between treatment arm and subgroup. Within-subgroup analyses demonstrated trends toward quantitative improvements in peak VO2, work rate at the ventilatory anaerobic threshold (VAT), VO2 at VAT, and ventilatory efficiency (VE/VCO2) for those randomized to udenafil compared to placebo in nearly all subgroups. There was no identified differential response to udenafil based on baseline peak VO2, baseline BNP level, weight, race and ethnicity, gender, or ventricular morphology, although participants in the lowest tertile of baseline peak VO2 trended toward larger improvements. The absence of a differential response across subgroups in response to treatment with udenafil suggests that the treatment benefit may not be restricted to specific sub-populations. Further work is warranted to confirm the potential benefit of udenafil and to evaluate the long-term tolerability and safety of treatment and to determine the impact of udenafil on the development of other morbidities related to the Fontan circulation.Trial Registration NCT0274115.

COVID-19-Related Thrombotic and Bleeding Events in Adults With Congenital Heart Disease.

Background: Altered coagulation is a striking feature of COVID-19. Adult patients with congenital heart disease (ACHD) are prone to thromboembolic (TE) and bleeding complications. Objectives: The purpose of this study was to investigate the prevalence and risk factors for COVID-19 TE/bleeding complications in ACHD patients. Methods: COVID-19-positive ACHD patients were included between May 2020 and November 2021. TE events included ischemic cerebrovascular accident, systemic and pulmonary embolism, deep venous thrombosis, myocardial infarction, and intracardiac thrombosis. Major bleeding included cases with hemoglobin drop >2 g/dl, involvement of critical sites, or fatal bleeding. Severe infection was defined as need for intensive care unit, endotracheal intubation, renal replacement therapy, extracorporeal membrane oxygenation, or death. Patients with TE/bleeding were compared to those without events. Factors associated with TE/bleeding were determined using logistic regression. Results: Of 1,988 patients (age 32 [IQR: 25-42] years, 47% male, 59 ACHD centers), 30 (1.5%) had significant TE/bleeding: 12 TE events, 12 major bleeds, and 6 with both TE and bleeding. Patients with TE/bleeding had higher in-hospital mortality compared to the remainder cohort (33% vs 1.7%; P < 0.0001) and were in more advanced physiological stage (P = 0.032) and NYHA functional class (P = 0.01), had lower baseline oxygen saturation (P = 0.0001), and more frequently had a history of atrial arrhythmia (P < 0.0001), previous hospitalization for heart failure (P < 0.0007), and were more likely hospitalized for COVID-19 (P < 0.0001). By multivariable logistic regression, prior anticoagulation (OR: 4.92; 95% CI: 2-11.76; P = 0.0003), cardiac injury (OR: 5.34; 95% CI: 1.98-14.76; P = 0.0009), and severe COVID-19 (OR: 17.39; 95% CI: 6.67-45.32; P < 0.0001) were independently associated with increased risk of TE/bleeding complications. Conclusions: ACHD patients with TE/bleeding during COVID-19 infection have a higher in-hospital mortality from the illness. Risk of coagulation disorders is related to severe COVID-19, cardiac injury during infection, and use of anticoagulants.

Long-Term Outcomes After Atrial Switch Operation for Transposition of the Great Arteries.

BACKGROUND: For patients with d-loop transposition of the great arteries (d-TGA) with a systemic right ventricle after an atrial switch operation, there is a need to identify risks for end-stage heart failure outcomes. OBJECTIVES: The authors aimed to determine factors associated with survival in a large cohort of such individuals. METHODS: This multicenter, retrospective cohort study included adults with d-TGA and prior atrial switch surgery seen at a congenital heart center. Clinical data from initial and most recent visits were obtained. The composite primary outcome was death, transplantation, or mechanical circulatory support (MCS). RESULTS: From 1,168 patients (38% female, age at first visit 29 ± 7.2 years) during a median 9.2 years of follow-up, 91 (8.8% per 10 person-years) met the outcome (66 deaths, 19 transplantations, 6 MCS). Patients experiencing sudden/arrhythmic death were younger than those dying of other causes (32.6 ± 6.4 years vs 42.4 ± 6.8 years; P < 0.001). There was a long duration between sentinel clinical events and end-stage heart failure. Age, atrial arrhythmia, pacemaker, biventricular enlargement, systolic dysfunction, and tricuspid regurgitation were all associated with the primary outcome. Independent 5-year predictors of primary outcome were prior ventricular arrhythmia, heart failure admission, complex anatomy, QRS duration >120 ms, and severe right ventricle dysfunction based on echocardiography. CONCLUSIONS: For most adults with d-TGA after atrial switch, progress to end-stage heart failure or death is slow. A simplified prediction score for 5-year adverse outcome is derived to help identify those at greatest risk.

SARS-CoV-2 Infection and Associated Cardiovascular Manifestations and Complications in Children and Young Adults: A Scientific Statement From the American Heart Association.

Coronavirus disease 2019 (COVID-19) resulted in a global pandemic and has overwhelmed health care systems worldwide. In this scientific statement, we describe the epidemiology, pathophysiology, clinical presentations, treatment, and outcomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and multisystem inflammatory syndrome in children and young adults with a focus on cardiovascular manifestations and complications. We review current knowledge about the health consequences of this illness in children and young adults with congenital and acquired heart disease, the public health burden and health disparities of this infection in these populations, and vaccine-associated myocarditis.

Advances in Managing Transition to Adulthood for Adolescents With Congenital Heart Disease: A Practical Approach to Transition Program Design: A Scientific Statement From the American Heart Association.

It is now expected that most individuals with congenital heart disease will survive to adulthood, including those with complex heart conditions. Maintaining lifelong medical care requires those with congenital heart disease to eventually transfer from pediatric to adult-oriented health care systems. Developing health care transition skills and gaining independence in managing one's own health care is imperative to this process and to ongoing medical and psychosocial success. This scientific statement reviews the recent evidence regarding transition and provides resources, components, and suggestions for development of congenital heart disease transition programs with the goals of improving patient knowledge, self-management, and self-efficacy skills to the level they are capable to eventually integrate smoothly into adult-oriented health care. Specifically, the scientific statement updates 3 sections relevant to transition programming. First, there is a review of specific factors to consider, including social determinants of health, psychosocial well-being, and neurocognitive status. The second section reviews costs of inadequate transition including the public health burden and the impairment in individual quality of life. Finally, the last section discusses considerations and suggestions for transition program design including communication platforms, a family-centered approach, and individual models. Although this scientific statement reviews recent literature surrounding transitions of care for individuals with congenital heart disease there remain significant knowledge gaps. As a field, we have yet to determine ideal timing and methods of transition, and barriers to transition and transfer remain, particularly for the underserved populations. The consequences of poor health care transition are great and garnering outcomes and information through organized, multifaceted, collaborative approaches to transition is critical to improving the lifelong care of individuals with congenital heart disease.

Operational and Ethical Considerations for a National Adult Congenital Heart Disease Database.

As more adults survive with congenital heart disease, the need to better understand the long-term complications, and comorbid disease will become increasingly important. Improved care and survival into the early and late adult years for all patients equitably requires accurate, timely, and comprehensive data to support research and quality-based initiatives. National data collection in adult congenital heart disease will require a sound foundation emphasizing core ethical principles that acknowledge patient and clinician perspectives and promote national collaboration. In this document we examine these foundational principles and offer suggestions for developing an ethically responsible and inclusive framework for national ACHD data collection.

Prevention of VAP: Endless evolving evidences-systematic literature review.

INTRODUCTION: Prevention of ventilator associated pneumonia (VAP) is the focus in critical care units. Immunocompromised patients, older adults, and postoperative patients are at greater risk for VAP. With the dynamic changes in the empirical world, updated evidence must be used to guide the standard of practice. This literature review assimilates the recent evidence for VAP prevention. METHOD: The Preferred Reporting Items for Systematic Reviews and Meta-analysis framework guided the selection of the included research articles. Medline, EBSCO host, CINAHL, UpToDate and Google Scholar databases explored, for relevant publications between 2010 and 2020. The quality of evidence for the 14 studies selected were rated using the hierarchy of quantitative research designs. RESULTS: Evidence-based VAP preventive strategies are prevention of aspiration, minimizing ventilator days, reducing the pathogen load, safe endotracheal suction practices, and pharmaceutical preventive measures. The mandates for VAP preventive measures among coronavirus disease 2019 (COVID-19) patients is included. CONCLUSION: Though some of these themes identify with the past, the nuances in their implementation are highlights of this review. The review reiterates the need to revisit ambiguous practices implemented for VAP prevention. Adherence to evidence-based practices, by education, training, and reduction of workload is the key to VAP prevention.

COVID-19 in Adults With Congenital Heart Disease.

BACKGROUND: Adults with congenital heart disease (CHD) have been considered potentially high risk for novel coronavirus disease-19 (COVID-19) mortality or other complications. OBJECTIVES: This study sought to define the impact of COVID-19 in adults with CHD and to identify risk factors associated with adverse outcomes. METHODS: Adults (age 18 years or older) with CHD and with confirmed or clinically suspected COVID-19 were included from CHD centers worldwide. Data collection included anatomic diagnosis and subsequent interventions, comorbidities, medications, echocardiographic findings, presenting symptoms, course of illness, and outcomes. Predictors of death or severe infection were determined. RESULTS: From 58 adult CHD centers, the study included 1,044 infected patients (age: 35.1 ± 13.0 years; range 18 to 86 years; 51% women), 87% of whom had laboratory-confirmed coronavirus infection. The cohort included 118 (11%) patients with single ventricle and/or Fontan physiology, 87 (8%) patients with cyanosis, and 73 (7%) patients with pulmonary hypertension. There were 24 COVID-related deaths (case/fatality: 2.3%; 95% confidence interval: 1.4% to 3.2%). Factors associated with death included male sex, diabetes, cyanosis, pulmonary hypertension, renal insufficiency, and previous hospital admission for heart failure. Worse physiological stage was associated with mortality (p = 0.001), whereas anatomic complexity or defect group were not. CONCLUSIONS: COVID-19 mortality in adults with CHD is commensurate with the general population. The most vulnerable patients are those with worse physiological stage, such as cyanosis and pulmonary hypertension, whereas anatomic complexity does not appear to predict infection severity.

Recurrent sustained atrial arrhythmias and thromboembolism in Fontan patients with total cavopulmonary connection.

BACKGROUND: Total cavopulmonary connection (TCPC) is associated with a lower risk of incident atrial arrhythmias as compared to atriopulmonary Fontan, but the risk of recurrent atrial arrhythmias is unknown in this population. The purpose of this study was to determine the incidence and risk factors for recurrent atrial arrhythmias and thromboembolic complications in patients with TCPC. METHODS: This is a retrospective multicenter study conducted by the Alliance for Adult Research in Congenital Cardiology (AARCC), 2000-2018. The inclusion criteria were TCPC patients (age > 15 years) with prior history of atrial arrhythmia. RESULTS: A total of 103 patients (age 26 ± 7 years; male 58 [56%]) met inclusion criteria. The mean age at initial arrhythmia diagnosis was 13 ± 5 years, and atrial arrhythmias were classified as atrial flutter/tachycardia in 85 (83%) and atrial fibrillation in 18 (17%). The median duration of follow-up from the first episode of atrial arrhythmia was 14.9 (12.1-17.3) years, and during this period 64 (62%) patients had recurrent atrial arrhythmias (atrial flutter/tachycardia 51 [80%] and atrial fibrillation 13 [20%]) with annual incidence of 4.4%. Older age was a risk factor for arrhythmia recurrence while the use of a class III anti-arrhythmic drug was associated with a lower risk of recurrent arrhythmias. The incidence of thromboembolic complication was 0.6% per year, and the cumulative incidence was 4% and 7% at 5 and 10 years respectively from the time of first atrial arrhythmia diagnosis. There were no identifiable risk factors for thromboembolic complications in this cohort. CONCLUSIONS: Although TCPC provides superior flow dynamics and lower risk of incident atrial arrhythmias, there is a significant risk of recurrent arrhythmias among TCPC patients with a prior history of atrial arrhythmias. These patients may require more intensive arrhythmia surveillance as compared to other TCPC patients.

Cardiovascular outcomes of pregnancy in Turner syndrome.

OBJECTIVES: Women with Turner syndrome (TS) are frequently counselled against pregnancy due to lack of data and unclear aortic dissection risk. However, with advances in fertility therapy, more women with TS are contemplating pregnancy. This study compared rates of adverse cardiovascular (CV) outcomes among: (1) pregnant and non-pregnant women with TS and (2) pregnant women with TS with/without structural heart disease. METHODS: Retrospective analysis of pregnant and age-matched non-pregnant controls with TS (2005-2017) across 10 CV centres was done. Data were collected at initial evaluation in pregnancy and outcomes were assessed to 6 months postpartum. Adverse CV events were defined as CV death, aortic dissection/rupture and/or aortic intervention. Non-pregnant age-matched controls were followed over the same time period. RESULTS: Sixty-eight pregnancies were included (60 women, mean age 33 years, 48% primigravid, 49% fertility therapy, 80% structurally normal heart, 25% XO karyotype). Based on American Society of Reproductive Medicine criteria, 10 pregnancies occurred in women stratified to high-risk category. There were no CV events in the pregnant women or in the non-pregnant women with TS. Obstetric events complicated 12 (18%) pregnancies with 9 (13%) attributed to hypertensive disorder of pregnancy. Fetal events included small for gestational age neonates (18%), preterm delivery (15%) and fetal death (3%). CONCLUSIONS: This study helps to refine the approach to pregnancy in women with TS. Among women with TS without structural heart disease, pregnancy does not impose an increased risk of CV outcomes. Among women with TS with structural heart disease, the risk of pregnancy is not as prohibitive as previously described but does require ongoing evaluation.

Development of a Novel Adult Congenital Heart Disease-Specific Patient-Reported Outcome Metric.

Background Patient-reported outcome metrics (PROs) quantify important outcomes in clinical trials and can be sensitive measures of patient experience in clinical practice. Currently, there is no validated disease-specific PRO for adults with congenital heart disease (ACHD). Methods and Results We conducted a preliminary psychometric validation of a novel ACHD PRO. ACHD patients were recruited prospectively from 2 institutions and completed a series of questionnaires, a physician health assessment, and a 6-minute walk test. Participants returned to complete the same questionnaires and assessment 3 months±2 weeks later. We tested the internal consistency and test-retest reliability by comparing responses among clinically stable patients at the 2 study visits. We assessed convergent and divergent validity by comparison of ACHD PRO responses to existing validated questionnaires. We assessed responsiveness by comparison with patient-reported clinical change. One hundred three patients completed 1 study visit and 81 completed both. The ACHD PRO demonstrated good internal consistency in each of its 5 domains (Cronbach's α: 0.87; 0.74; 0.74; 0.90; and 0.89, respectively) and in the overall summary score (0.92). Test-retest reliability was good with an intraclass correlation ≥0.73 for all domains and 0.78 for the Summary Score. The ACHD PRO accurately assessed domain concepts based on comparison with validated standards. Preliminary estimates of responsiveness suggest sensitivity to clinical status. Conclusions These studies provide initial support for the validity and reliability of the ACHD PRO. Further studies are needed to assess its sensitivity to changes in clinical status.

Diagnosis and management of the adult patient with a failing Fontan circulation.

Since the original description, the Fontan operation has been widely used for the palliation of children with single ventricle physiology. Although the Fontan operation revolutionized the survival rates of patients with single ventricle physiology, it carries an inevitable risk for long-term morbidity and mortality that impacts clinical outcomes and quality of life. This review will focus on the evaluation and treatment of the patient with the failing Fontan phenotype, with an emphasis on creating an individualized treatment plan.

Genetic considerations for adults with congenital heart disease.

Congenital heart disease (CHD) remains the most common birth defect, with an estimated incidence of approximately 1% of all births. The population of adults with CHD is growing rapidly with advances in medical care. Overall survival to adulthood in the current era estimated to exceed 90%. Genetic causes of CHD can be classified into several broad categories: (a) chromosomal aneuploidy, (b) large chromosomal deletion or duplication, (c) single gene mutation, and (d) copy number variation. However, only 20-30% of CHD cases have an established etiology characterized by either genetic abnormalities or environmental factors. The role of genetics in the field of adult CHD is only increasing. More adult patients with CHD are seeking genetic counseling to understand the etiology of their underlying CHD and the risks to future offspring. A multidisciplinary approach is essential to provide appropriate counseling to patients regarding indications for genetic testing and interpretations of results. Novel advances with precision medicine may soon enable clinicians to individualize therapies for a comprehensive approach to the care of adult patients with CHD.

Results of the FUEL Trial.

BACKGROUND: The Fontan operation creates a total cavopulmonary connection, a circulation in which the importance of pulmonary vascular resistance is magnified. Over time, this circulation leads to deterioration of cardiovascular efficiency associated with a decline in exercise performance. Rigorous clinical trials aimed at improving physiology and guiding pharmacotherapy are lacking. METHODS: The FUEL trial (Fontan Udenafil Exercise Longitudinal) was a phase III clinical trial conducted at 30 centers. Participants were randomly assigned udenafil, 87.5 mg twice daily, or placebo in a 1:1 ratio. The primary outcome was the between-group difference in change in oxygen consumption at peak exercise. Secondary outcomes included between-group differences in changes in submaximal exercise at the ventilatory anaerobic threshold, the myocardial performance index, the natural log of the reactive hyperemia index, and serum brain-type natriuretic peptide. RESULTS: Between 2017 and 2019, 30 clinical sites in North America and the Republic of Korea randomly assigned 400 participants with Fontan physiology. The mean age at randomization was 15.5±2 years; 60% of participants were male, and 81% were white. All 400 participants were included in the primary analysis with imputation of the 26-week end point for 21 participants with missing data (11 randomly assigned to udenafil and 10 to placebo). Among randomly assigned participants, peak oxygen consumption increased by 44±245 mL/min (2.8%) in the udenafil group and declined by 3.7±228 mL/min (-0.2%) in the placebo group (P=0.071). Analysis at ventilatory anaerobic threshold demonstrated improvements in the udenafil group versus the placebo group in oxygen consumption (+33±185 [3.2%] versus -9±193 [-0.9%] mL/min, P=0.012), ventilatory equivalents of carbon dioxide (-0.8 versus -0.06, P=0.014), and work rate (+3.8 versus +0.34 W, P=0.021). There was no difference in change of myocardial performance index, the natural log of the reactive hyperemia index, or serum brain-type natriuretic peptide level. CONCLUSIONS: In the FUEL trial, treatment with udenafil (87.5 mg twice daily) was not associated with an improvement in oxygen consumption at peak exercise but was associated with improvements in multiple measures of exercise performance at the ventilatory anaerobic threshold. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02741115.

Age- and Lesion-Related Comorbidity Burden Among US Adults With Congenital Heart Disease: A Population-Based Study.

Background As patients with congenital heart disease (CHD) are living longer, understanding the comorbidities they develop as they age is increasingly important. However, there are no published population-based estimates of the comorbidity burden among the US adult patients with CHD. Methods and Results Using the IBM MarketScan commercial claims database from 2010 to 2016, we identified adults aged ≥18 years with CHD and 2 full years of continuous enrollment. These were frequency matched with adults without CHD within categories jointly defined by age, sex, and dates of enrollment in the database. A total of 40 127 patients with CHD met the inclusion criteria (mean [SD] age, 36.8 [14.6] years; and 48.2% were women). Adults with CHD were nearly twice as likely to have any comorbidity than those without CHD (P<0.001). After adjusting for covariates, patients with CHD had a higher prevalence risk ratio for "previously recognized to be common in CHD" (risk ratio, 9.41; 95% CI, 7.99-11.1), "other cardiovascular" (risk ratio, 1.73; 95% CI, 1.66-1.80), and "noncardiovascular" (risk ratio, 1.47; 95% CI, 1.41-1.52) comorbidities. After adjusting for covariates and considering interaction with age, patients with severe CHD had higher risks of previously recognized to be common in CHD and lower risks of other cardiovascular comorbidities than age-stratified patients with nonsevere CHD. For noncardiovascular comorbidities, the risk was higher among patients with severe than nonsevere CHD before, but not after, the age of 40 years. Conclusions Our data underscore the unique clinical needs of adults with CHD compared with their peers. Clinicians caring for CHD may want to use a multidisciplinary approach, including building close collaborations with internists and specialists, to help provide appropriate care for the highly prevalent noncardiovascular comorbidities.