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Individuals with Fontan circulation (FC) often have diminished exercise capacity and are at risk for psychological problems. The current study examines associations between exercise capacity and psychological functioning in children and adolescents with FC. A multidisciplinary team evaluated participants in a clinic for pediatric patients with FC. Participants completed cardiopulmonary exercise testing (CPET). Parent and child were administered a psychological questionnaire (BASC-3) to measure child depression, anxiety, and inattention symptoms. Individuals who completed CPET with adequate effort and a psychological measure were eligible for inclusion. Clinical sample (n = 51) was 55% male with a mean age of 13.6 years (SD = 2.5). A majority had hypoplastic left heart syndrome (51%). Parent-report of inattention was negatively correlated with peak VO2 (R =  - .307, 95% CI - .549/ - .018, P = 0.038). Self-report of anxiety was positively correlated with HR recovery at 3 (R = .438, 95% CI .155/.655, P = 0.004) and 8 (R = .432, 95% CI .147/.651, P = 0.004) minutes post exercise. Depression was positively correlated with HR recovery at 3 min for parent-report (R = .294, 95% CI .004/.538, P = 0.047) and 8 min for self-report (R = .410, 95% CI .122/.635, P = 0.007). Greater inattention may have negatively impacted CPET engagement, reflected in lower peak VO2. The more rapid decline from max HR to recovery for those with greater depression and anxiety symptoms was unexpected, perhaps explained by a reduction in anxiety state after exercise or possibly an age effect, as a blunted HR decline has been found in adult cardiac patients with depression/anxiety., (© 2024. The Author(s).)

The Fontan operation is the current standard of care for single-ventricle congenital heart disease. Individuals with a Fontan circulation (FC) exhibit central venous hypertension and face life-threatening complications of hepatic fibrosis, known as Fontan-associated liver disease (FALD). The fundamental biology and mechanisms of FALD are little understood. Here, we generated a transcriptomic and epigenomic atlas of human FALD at single-cell resolution using multiomic snRNA-ATAC-seq. We found profound cell type-specific transcriptomic and epigenomic changes in FC livers. Central hepatocytes (cHep) exhibited the most substantial changes, featuring profound metabolic reprogramming. These cHep changes preceded substantial activation of hepatic stellate cells and liver fibrosis, suggesting cHep as a potential first "responder" in the pathogenesis of FALD. We also identified a network of ligand-receptor pairs that transmit signals from cHep to hepatic stellate cells, which may promote their activation and liver fibrosis. We further experimentally demonstrated that activins A and B promote fibrotic activation in vitro and identified mechanisms of activin A's transcriptional activation in FALD. Together, our single-cell transcriptomic and epigenomic atlas revealed mechanistic insights into the pathogenesis of FALD and may aid identification of potential therapeutic targets.

Today, it is anticipated most individuals diagnosed with single-ventricle malformation will survive surgical reconstruction through a successful Fontan operation. As greater numbers of patients survive, so has the recognition that individuals with Fontan circulation face a variety of challenges. The goal of a normal quality and duration of life will not be reached by all. The hurdles fall into a variety of domains. From a cardiovascular perspective, the Fontan circulation is fundamentally flawed by its inherent nature of creating a state of chronically elevated venous pressure and congestion, accompanied by a relatively low cardiac output. Ventricular dysfunction, atrioventricular valve regurgitation, and arrhythmia may directly impact cardiac performance and can progress with time. Problems are not limited to the cardiovascular system. Fontan circulatory physiology impacts a multitude of biological processes and health parameters outside the heart. The lymphatic circulation is under strain manifesting as variable degrees of protein-rich lymph loss and immune system dysregulation. Organ system dysfunction develops through altered perfusion profiles. Liver fibrosis is ubiquitous, and a process of systemic fibrogenesis in response to circulatory stressors may affect other organs as well. Somatic growth and development can be delayed. Behavioral and mental health problems are common, presenting as clinically important levels of anxiety and depression. Most striking is the high variability in prevalence and magnitude of these complications within the population, indicating the likelihood of additional factors enhancing or mitigating their emergence. We propose that optimal care for the individual with single ventricle and a Fontan circulation is ideally offered in a comprehensive multidisciplinary manner, with attention to elements that are beyond cardiac management alone. In this report, we share the concepts, our experiences, and perspectives on development of a clinic model-the "Fontan rehabilitation, wellness and resilience development" or FORWARD program. We provide insights into the mechanics of our multidisciplinary model of care and the benefits offered serving our growing population of individuals with a Fontan circulation and their families., (© 2022. The Author(s).)

Objective: To evaluate growth in a population of patients with Fontan circulation., Study Design: We performed a cross-sectional evaluation of patients followed in our multidisciplinary Fontan clinic from January 2011 through August 2015. We reviewed the historical data, anthropometry, clinical, and laboratory studies and performed bivariate and multivariate analysis of factors associated with height z score., Results: Patients (n = 210) were included in the study at median age 11.07 years (8.3, 14.73 years) (43% female); 138 (65%) had a dominant right systemic ventricle and 92 (44%) hypoplastic left heart syndrome. Median age at completion of Fontan circulation was 31 months (7.6, 135.8 months). Median height z score was -0.58 (-1.75, 0.26). Twenty-five (12%) had current or past history of protein-losing enteropathy (PLE). Median height z score for those with current or past history of PLE was -2.1 (-2.46, 1.24). Multivariate analysis revealed positive associations between height z score and body mass index z score, time since Fontan, mid-parental height, dominant systemic ventricle type, and serum alkaline phosphatase. Height correlated negatively with known genetic syndrome, PLE, use of stimulant or oral steroid medication., Conclusions: Children with Fontan circulation have mild deficits in height, with greater deficits in those with PLE. Height z score improves with time postsurgery. Improving weight, leading to improved body mass index, may be a modifiable factor that improves growth in those who are underweight. Biochemical markers may be helpful screening tests for high-risk groups in whom to intensify interventions., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background The physiologic hallmarks of the Fontan circulation-chronically elevated central venous pressures and low cardiac output-have significant effects not only on cardiovascular status but also impact other organ systems. Exercise capacity is limited in many and declines with age, accelerating in adolescence, but with wide variability. We explore the relationship between exercise performance and end-organ function in outpatient subjects with a Fontan circulation. Methods and Results This is a cross-sectional analysis of subject end-organ characterization from our outpatient Fontan circulation clinic with peak oxygen consumption (peak Vo 2 ) at cardiopulmonary exercise testing as the primary outcome. We perform linear regression to assess associations between clinical characteristics and peak Vo 2 as well as the magnitude of the association of clinical characteristics with peak Vo 2 . Of 265 subjects age 12.8 (9.5-16.4) years, there is a negative correlation between age and peak Vo 2 (-0.49, P <0.001). Of those undergoing ramp cycle exercise testing, 34% perform above 80% predicted peak Vo 2 . Variables positively associated with peak Vo 2 and their effect size include vitamin D sufficiency (+3.00, P =0.020) and absolute lymphocyte count (+0.23, P =0.005). Status as overweight/obese (-3.91, P =0.003) and hemoglobin (-0.77, P =0.003) are negatively associated. Neither ventricular morphology, timing of Fontan palliation, nor Fontan circulation type affect peak Vo 2 . Conclusions Higher peak Vo 2 in those with a Fontan circulation is associated with younger age, vitamin D sufficiency, absence of overweight/obese, lower hemoglobin, and a healthier hepatic profile. Whether exercise training or other initiatives can modify organ characteristics in those with a Fontan circulation is worthy of exploration.

Fontan-associated protein losing enteropathy is a challenge to treat and is a major contributor to morbidity and mortality in patients with palliated single ventricle. Numerous strategies for management have been proposed, with confusion as to how best to stratify and implement care among the many treatments available. Medical management can be helpful in some, while novel lymphatic interventions hold potential for remission with good results. We review our institutional approach to protein losing enteropathy after Fontan operation and provide a suggested algorithm and pathway for effective care.

Objective: The Fontan operation is a palliative procedure for congenital single ventricle heart disease. Long-term kidney function in this cohort is not well-known. Our aim was to evaluate renal function in long-term survivors post-Fontan palliation, and we hypothesize that this cohort will have a higher prevalence of chronic kidney disease (CKD) compared to controls., Design: We performed a retrospective cohort study of 68 subjects evaluated through the Single Ventricle Survivorship Program at the Children's Hospital of Philadelphia between July 2010 and December 2014 compared to 70 healthy children similar in age and sex. Primary outcome was CKD, defined as estimated glomerular filtration rate (eGFR) <90 mL/min/1.73 m 2 using creatinine and cystatin C-based estimating equations. Secondary outcomes included proteinuria and elevated intact parathyroid hormone., Results: The Fontan cohort included 68 subjects with median age 13 years (IQR 9.0, 17.3) who were median 11.1 years (IQR 6.5, 15.7) post-Fontan palliation. This cohort was compared to 70 healthy individuals (median age 15.5 years (IQR 12.5, 18.3). Although median eGFRs were comparable: 102.6 vs. 101.9 mL/min/1.73 m 2 (P = .89) in Fontan vs. healthy subjects <18 years of age (Full CKiD equation), and 128.5 vs. 129.7 mL/min/1.73 m 2 (P = .56) in Fontan vs. healthy subjects ≥18 years of age (CKD-EPI creatinine and cystatin formula); 10% of Fontan subjects had an eGFR<90 mL/min/1.73 m 2 . Median intact parathyroid hormone level was higher at 59.4 pg/mL (IQR 43.0, 83.1) in the Fontan group compared to 23.4 pg/mL (IQR 16.7, 30.0) in controls (P ≤ .001). Proteinuria was present in 10% of the Fontan group compared to 4.7% in controls (P = .27)., Conclusion: Ten percent of long-term survivors post-Fontan palliation had eGFR <90 ml/min/1.73 m 2 , and higher median parathyroid hormone levels compared to controls. Taken together, these measures may indicate early kidney disease. Future studies will focus on longitudinal assessment of kidney function and evaluation of risk factors for CKD post-Fontan palliation., (© 2016 Wiley Periodicals, Inc.)

The medical records of all patients born between 1 September, 2000, and 31 August, 2002, and undergoing the first stage of Norwood reconstruction, were retrospectively reviewed for details of the perioperative course. We found 99 consecutive patients who met the criterions for inclusion. Hospital mortality for the entire cohort was 15.2%, but was 7.3%, with 4 of 55 dying, in the setting of a "standard" risk profile, as opposed to 25.0% for those with a "high" risk profile, 11 of 44 patients dying in this group. Extracorporeal membrane oxygenation was utilized in 7 patients, with 6 deaths. Median postoperative length of stay in the hospital was 14 days, with a range from 2 to 85 days, and stay in the cardiac intensive care unit was 11 days, with a range from 2 to 85 days. Delayed sternal closure was performed in 18.2%, with a median of 1 day until closure, with a range from zero to 5 days. Excluding isolated delayed sternal closure, and cannulation and decannulation for extracorporeal support, 24 patients underwent 33 cardiothoracic reoperations, including exploration for bleeding in 12, diaphragmatic plication in 4; shunt revision in 4, and other procedures in 13. The median duration of total mechanical ventilation was 4.0 days, with a range from 0.7 to 80.5 days. Excluding those who died, the median total duration of mechanical ventilation was 3.8 days, with a range from 0.9 to 46.3 days. Reintubation for cardiorespiratory failure or upper airway obstruction was performed in 31 patients. Postoperative electroencephalographic and/or clinical seizures occurred in 13 patients, with 7 discharged on anti-convulsant medications. Postoperative renal failure, defined as a level of creatinine greater than 1.5 mg/dl, was present in 13 patients. Eleven had significant thrombocytopenia, with fewer than 20,000 platelets per microl, and injury to the vocal cords was identified in eight patients. Risk factors for longer length of stay included lower Apgar scores, preoperative intubation, early reoperations, reintubation and sepsis, but not weight at birth, genetic syndromes, the specific surgeon, or the duration of surgery. Although mortality rates after the first stage of reconstruction continue to fall, the course in the intensive care unit is remarkable for significant morbidity, especially involving the cardiac, pulmonary and central nervous systems. These patients utilize significant resources during the first hospitalization. Further studies are necessary to stratify the risks faced by patients with hypoplasia of the left heart in whom the first stage of Norwood reconstruction is planned, to determine methods to reduce perioperative morbidity, and to determine the long-term implications of short-term complications, such as diaphragmatic paresis, injury to the vocal cords, prolonged mechanical ventilation, and postoperative seizures.

An increasingly complex group of children is now being followed as outpatients after surgery for congenital heart disease. A variety of complications and physiologic perturbations, both expected and unexpected, may present during follow-up, and should be anticipated by the practitioner and discussed with the patient and family. The purpose of this position article is to provide a framework for outpatient follow-up of complex congenital heart disease, based on a review of current literature and the experience of the authors.

Discharging neonates to home after cardiac surgery takes time, effective communication, and a commitment to continuity of care. The efforts of all members of a multidisciplinary team are necessary and valuable to ensure success. The discharge process involves many steps beginning at the time of admission and continuing past the actual discharge date. Discharge planning is an evolving process rather than a single event.

Background: Prostate-specific antigen (PSA) is secreted exclusively by prostatic epithelial cells, and its serum concentration is increased in men with prostatic disease, including cancer. We evaluated its usefulness in the detection and staging of prostate cancer., Methods: We measured serum PSA concentrations in 1653 healthy men 50 or more years old. Those with PSA values greater than or equal to 4.0 micrograms per liter then underwent rectal examination and prostatic ultrasonography. Ultrasound-directed prostatic needle biopsies were performed in the men with abnormal findings on rectal examination, ultrasonography, or both. The results were compared with those in 300 consecutively studied men 50 or more years old who underwent ultrasound-directed biopsy because of symptoms or abnormal findings on rectal examination., Results: Serum PSA levels ranged from 4.0 to 9.9 micrograms per liter in 6.5 percent of the 1653 men (107). Nineteen of the 85 men in this group (22 percent) who had prostatic biopsies had prostate cancer. Serum PSA levels were 10.0 micrograms per liter or higher in 1.8 percent of the 1653 men (30). Eighteen of the 27 men in this group (67 percent) who had prostatic biopsies had cancer. If rectal examination alone had been used to screen the men who had biopsies, 12 of the 37 cancers (32 percent) would have been missed. If ultrasonography alone had been used to screen these men, 16 of the 37 cancers (43 percent) would have been missed. Serum PSA measurement had the lowest error rate of the tests, and PSA measurement plus rectal examination had the lowest error rate of the two-test combinations., Conclusions: The combination of measurement of the serum PSA concentration and rectal examination, with ultrasonography performed in patients with abnormal findings, provides a better method of detecting prostate cancer than rectal examination alone.