Characteristics and Outcomes of a Single-Centre Cohort of Adult Congenital Heart Disease Patients Referred for Heart Transplant.

BACKGROUND: Adult congenital heart disease (ACHD) services increasingly encounter heart failure (HF) in the ageing ACHD population. Optimal timing of referral for heart transplant (HTx) evaluation in this heterogeneous population is complex and ill-defined. We aim to outline the characteristics and outcomes of ACHD patients referred for HTx from a large Australian ACHD centre. METHOD: Retrospective review of ACHD patients referred for HTx from a primary ACHD centre (1992-2021). Database analysis of patient demographics, characteristics, wait-listing, and transplantation outcomes was performed. RESULTS: A total of 45 patients (mean age 37±9.9 years old; 69% male) were referred for HTx with a mean follow-up of 5.9±6.3 years. Of these, 22 of 45 (49%) were listed and transplanted, including one heart-lung transplant. The commonest diagnosis was dextro-transposition of the great arteries (13/45, 29%). Most patients, 33 of 45 (73.3%) had undergone at least one cardiac surgery in childhood. Indications for HTx referral included HF in 34 of 45 (75%), followed by pulmonary hypertension in 7 of 45 (11%). Median transplant wait-list time was 145 days (interquartile range, 112-256). Of the 23 patients not wait-listed, the reasons included clinical stability in 13 of 45 (29%), psychosocial factors in 2 of 45 (4.4%) and prohibitive surgical risk, including multiorgan dysfunction, in 8 of 45 (17.7%). Transplant was of a single organ in most, 21 of 22 (95.5%). Overall mortality was 5 of 22 (22.7%) in those after HTx, and 14 of 23 (60.9%) in those not listed (p=0.0156). CONCLUSIONS: Increasingly, ACHD patients demonstrate the need for advanced HF treatments. HTx decision-making is complex, and increased mortality is seen in those not wait-listed. Ultimately, the referral of ACHD patients for HTx is underpinned by local decision-making and experience, wait-list times and outcomes.

Impact of Telehealth on Failure to Attend Rates and Patient Re-Engagement in Adult Congenital Heart Disease Clinic.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic paved the way for telehealth consultations. We aimed to determine the impact of telehealth on rates of failure to attend (FTA) in adult congenital heart disease (ACHD) clinics and whether telehealth could re-engage patients with previous FTA face-to-face appointments. METHODS: This was a retrospective audit of a tertiary ACHD clinic over a 12-month pre-telehealth (26 March 2019-17 March 2020) and 12-month post-telehealth implementation period (24 March 2020-16 March 2021). Patients with one or more FTAs during the 24-month study period were included. Our ACHD clinic is run three times per month. Patients with ACHD are offered lifelong follow-up and reviewed annually on average. Re-engagement was defined as two or more consecutive face-to-face FTAs immediately before the telehealth period with subsequent attendance of their telehealth appointment. RESULTS: A total of 359 patients with a total of 623 FTAs were included. Complexity of congenital heart disease was moderate in 56% (202/359) and severe in 19% (69/359) of patients. Overall FTA rate was 18% (623/3,452). FTA rate was significantly lower in the post-telehealth period (15%, 257/1,664) compared with the pre-telehealth period (20%, 366/1,788) (p<0.00001). At study conclusion, 1% of patients had died (5/359). Of the 354 remaining patients, 42% (150/354) were considered lost to follow-up (two or more FTAs including telehealth), 37% (132/354) missed only one clinic appointment, and 20% (72/354) previously considered lost to follow-up had re-engaged in the telehealth period. CONCLUSIONS: Rates of FTA in a tertiary ACHD clinic significantly reduced after the introduction of telehealth consultation. A fifth of patients considered lost to follow-up were re-engaged with telehealth. Additional strategies to further reduce FTA should be explored.

Fontan Hepatopathy-Managing Unknowns.

BACKGROUND AND AIMS: How to best monitor Fontan-associated liver disease (FALD) remains unclear. We describe results from a prospective liver care pathway in adults (n=84) with a Fontan circulation. METHODS: Routine assessment of the liver, by acoustic radiation force frequency and ultrasound was undertaken. Results, including liver biochemistry, systemic ventricular function (echocardiography), functional class, medication use and clinical endpoints (varices, hepatocellular carcinoma, heart transplantation and death) were collated. RESULTS: Most individuals returned a cirrhotic range acoustic radiation force impulse imaging (ARFI) result. ARFI values were greater in the proportion of individuals with hepatic nodularity (p=0.024). Univariate analysis demonstrated moderate correlation with platelet number (Spearmans rho= -0.376, p=0.049). Patients with clinical endpoints had lower platelets (p=0.012) but only a trend to hepatic nodularity (p=0.057). Clinical endpoints were more common in those with ventricular dysfunction (p=0.011). Multivariate analysis revealed that age at Fontan and being on angiotensin converting enzyme inhibitors (ACEI) predicted ARFI score (ß=0.06 [95% CI 0.01-0.09], p=0.007 and ß=0.53 [95% CI 0.17-0.89], p=0.005, respectively). However, these associations were not significant once adjusted for Fontan type, age at ARFI, systemic ventricle morphology, ventricle function, or Model for End-stage Liver Disease (MELD-XI) excluding international normalised ratio (INR) (p>0.05 for all). CONCLUSIONS: Ideal FALD monitoring remains unclear. ARFI has utility as a binary non-invasive indicator of cirrhosis, highlighting individuals who may need more frequent ongoing monitoring for hepatocellular carcinoma. However, no definite advantage to serial ARFI, once cirrhotic range ARFI results are present, has been identified.

Atrioventricular septal defect in Fontan circulation: Right ventricular dominance, not valve surgery, adversely affects survival.

OBJECTIVE: The effect of ventricular dominance and previous atrioventricular valve (AVV) surgery on patient outcomes after Fontan operation remains unclear. We sought to determine the effect of ventricular dominance and previous AVV surgery on transplantation-free survival and long-term AVV competency in patients with atrioventricular septal defect (AVSD) and Fontan circulation. METHODS: We conducted a retrospective study of 1703 patients in the Australia and New Zealand Fontan Registry, who survived Fontan operation between 1987 and 2021. RESULTS: Of 174 patients with AVSD, 60% (105/174) had right ventricular (RV) dominance and 40% (69/174) had left ventricular (LV) dominance. The cumulative incidence of moderate or greater AVV regurgitation at 25 years after Fontan operation in patients with LV dominance was 56% (95% CI, 35%-72%), compared with 54% (95% CI, 40%-67%) in patients with RV dominance (P = .6). Nonetheless, transplantation-free survival at 25 years in patients with LV dominance was 94% (95% CI, 86%-100%), compared with 67% (95% CI, 52%-87%) in patients with RV dominance (hazard ratio, 5.9; 95% CI, 1.4-25.4; P < .01). Of note, transplantation-free survival was not different in patients who underwent AVV surgery before or at Fontan completion compared with those who did not (15 years: 81% [95% CI, 62%-100%] vs 88% [95% CI, 81%-95%]; P = .3). CONCLUSIONS: In patients with AVSD and Fontan circulation the rate of moderate or greater common AVV regurgitation is similar in those with LV and RV dominance. RV dominance, rather than previous AVV surgery, is a risk factor for death or transplantation.

Impact of Aortic Atresia After Fontan Operation in Patients With Hypoplastic Left Heart Syndrome.

BACKGROUND: Patients with aortic atresia have the worst prognosis in the spectrum of hypoplastic left heart syndrome. It remains unknown whether patients with aortic atresia continue to do poorly after Fontan operation. This study aimed to determine the association between aortic atresia and atrioventricular valve (AVV) function and clinical outcomes after Fontan operation in patients with hypoplastic left heart syndrome. METHODS: We performed a retrospective study of 1731 patients who survived the Fontan operation from the Australia and New Zealand Fontan Registry between 1975 and 2020. RESULTS: We identified 188 patients with hypoplastic left heart syndrome, including 99 (53%) with aortic atresia. Overall transplant-free survival and freedom from failure of Fontan circulation at 15 years was 91% (95% CI, 86%-96%) and 79% (95% CI, 71%-88%), respectively. The cumulative incidence of AVV operation at 15 years of age for patients with aortic atresia and aortic stenosis was 28% (95% CI, 19%-38%) and 14% (95% CI, 7%-22%; P = .03), respectively. The cumulative incidence of AVV failure (moderate or greater regurgitation or AVV operation) at 15 years of age for patients with aortic atresia and aortic stenosis was 50% (95% CI, 37%-61%) and 30% (95% CI, 19%-42%; P = .01). Patients with AVV failure were at increased risk of having moderately, or worse, decreased systolic ventricular function (odds ratio 6.7; 95% CI, 1.7-33; P = .01) and failure of Fontan circulation (hazard ratio 3.7; 95% CI, 1.5-9.1; P < .01). CONCLUSIONS: In patients with hypoplastic left heart syndrome, there is no significant difference in transplant-free survival after Fontan operation between patients with aortic atresia and patients with aortic stenosis. However, patients with aortic atresia have a much higher burden of AVV failure than patients with aortic stenosis. Atrioventricular valve failure is associated with failure of Fontan circulation.

Impact of Fontan Fenestration on Long-Term Outcomes: A Propensity Score-Matched Analysis.

Background The long-term impact of fenestration at the time of Fontan operation remains unclear. We aimed to review the early and long-term impact of Fontan fenestration in the Australia and New Zealand cohort. Methods and Results We reviewed 1443 patients (621 fenestrated, 822 nonfenestrated) from the Australia and New Zealand Fontan registry. Data were collected on preoperative demographics, operative details, and follow-up. Propensity-score matching was performed to account for the various preoperative and operative differences and risk factors. Primary outcomes were survival and freedom from failure. Median follow-up was 10.6 years. After propensity-score matching (407 matched pairs), there was no difference in survival (87% versus 90% at 20 years; P=0.16) or freedom from failure (73% versus 80% at 20 years; P=0.10) between patients with and without fenestration, respectively. Although patients with fenestration had longer bypass and cross-clamp times (P<0.001), there was no difference in hospital length of stay or prolonged pleural effusions (P=0.80 and P=0.46, respectively). Freedom from systemic and Fontan circuit thromboembolism was higher in the nonfenestrated group (89%; 95% CI, 88%-95%) than the fenestrated group (84%; 95% CI, 77%-89%; P=0.03). There was no difference in incidence of plastic bronchitis, protein-losing enteropathy, New York Heart Association Class III/IV symptoms, or Fontan takedown. Conclusions In the propensity score-matched analysis we have demonstrated no difference in long-term survival or freedom from Fontan failure in patients with and without fenestration. There was a higher incidence of long-term thromboembolic events in patients with fenestration. Overall, it appears that fenestration in Fontan circulation does not bring long-term benefits.

Natural and Modified History of Atrioventricular Valve Regurgitation in Patients With Fontan Circulation.

BACKGROUND: Atrioventricular valve (AVV) regurgitation is increasingly prevalent in patients with a Fontan circulation. OBJECTIVES: We sought to determine the impact of ventricular dominance and AVV operation on outcomes in patients with a Fontan circulation and ≥moderate AVV regurgitation. METHODS: We conducted a retrospective study, including propensity score matching analysis, of 1,703 patients who survived Fontan operation in Australia and New Zealand from 1987 to 2021. RESULTS: Patients undergoing AVV operation were more likely to have right ventricular (RV) dominance or an atrioventricular septal defect. In the entire cohort, death or transplantation after Fontan operation was significantly higher in patients who underwent AVV operation before or at Fontan completion compared with those who did not (20 years: 18%; 95% CI: 8%-26% vs 13%; 95% CI: 10%-15%; P = 0.03). After propensity score matching, including for RV dominance, there was no significant difference in death or transplantation between the groups (20 years: 18%; 95% CI: 8%-26% vs 16%; 95% CI: 10%-22%; P = 0.41). Only patients with RV dominance who developed ≥moderate AVV regurgitation after Fontan operation were at increased risk of death or transplantation (HR: 2.8; 95% CI: 1.4-5.3; P < 0.01). In patients with left ventricular dominance, there was no significant difference in death or transplantation between patients with ≥moderate AVV regurgitation compared with those with 

Long-term outcomes of the arterial switch operation.

OBJECTIVES: The arterial switch operation (ASO) has excellent early outcomes in the modern era. We sought to determine the long-term outcomes in patients who underwent an ASO at a single institution. METHODS: Patients who underwent an ASO between 1983 and 2015 were identified from the hospital database and retrospectively reviewed using hospital records. RESULTS: From 1983 to 2015, 844 patients with a biventricular circulation underwent an ASO. There were 28 (3.3%, 28/844) early deaths. Follow-up was available for 94% (729/774) of local patients after hospital discharge. Median follow-up was 15 years (interquartile range, 8-20 years). There were 187 (26%, 187/729) patients with more than 20 years of follow-up and 95 (13%, 95/729) patients with more than 25 years of follow-up. Overall survival was 95% (95% confidence interval [CI], 94%-97%) at 10 and 25 years after the ASO. At 25 years after ASO, freedom from overall reintervention was 77% (95% CI, 73%-81%), freedom from reoperation on the neoaortic root or neoaortic valve was 92% (95% CI, 88%-95%), and freedom from coronary reoperation was 99% (95% CI, 98%-99.7%). Left ventricular (LV) systolic function was normal in 595 of 609 (98%) of patients who had LV function quantified at latest follow-up. Of the 95 patients with more than 25 years of follow-up after ASO, 6 (6.3%) had at least moderate neoaortic valve regurgitation (AR) and 8 (8.4%) had undergone replacement of the neoaortic valve. CONCLUSIONS: Overall, survivors of ASO have excellent late survival and normal LV systolic function into adult life. However, AR and reoperation on the neoaortic valve remains an issue for older patients.

The "Super-Fontan" Phenotype: Characterizing Factors Associated With High Physical Performance.

Background: People with a Fontan circulation usually have moderately impaired exercise performance, although a subset have high physical performance ("Super-Fontan"), which may represent a low-risk phenotype. Methods: People with a "Super-Fontan" phenotype were defined as achieving normal exercise performance [≥80% predicted peak oxygen uptake (VO2) and work rate] during cardiopulmonary exercise testing (CPET) and were identified from the Australian and New Zealand Fontan Registry. A Fontan control group that included people with impaired exercise performance (<80% predicted VO2 or work rate) was also identified based on a 1:3 allocation ratio. A subset of participants were prospectively recruited and completed a series of physical activity, exercise self-efficacy, and health-related quality of life questionnaires. Results: Sixty CPETs ("Super-Fontan", n = 15; control, n = 45) were included. A subset ("Super-Fontan", n = 10; control, n = 13) completed a series of questionnaires. Average age was 29 ± 8 years; 48% were males. Exercise capacity reflected by percent predicted VO2 was 67 ± 17% in the entire cohort. Compared to the "Super-Fontan" phenotype, age at Fontan completion was higher in controls (4.0 ± 2.9 vs. 7.2 ± 5.3 years, p = 0.002). Only one (7%) person in the "Super-Fontan" group had a dominant right ventricle compared to 15 (33%) controls (p = 0.043). None of those in the "Super-Fontan" group were obese, while almost a quarter (22%) of controls were obese based on body mass index (p = 0.046). Lung function abnormalities were less prevalent in the "Super-Fontan" group (20 vs. 70%, p = 0.006). Exercise self-efficacy was greater in the "Super-Fontan" group (34.2 ± 3.6 vs. 27.9 ± 7.2, p = 0.02). Self-reported sports participation and physical activity levels during childhood and early adulthood were higher in the "Super-Fontan" group (p < 0.05). The total average time spent participating in structured sports and physical activity was 4.3 ± 2.6 h/wk in the "Super-Fontan" group compared to 2.0 ± 3.0 h/wk in controls, p = 0.003. There were no differences in self-reported current total physical activity score or health-related quality of life between groups (p ≥ 0.05). Conclusions: The "Super-Fontan" phenotype is associated with a healthy weight, lower age at Fontan completion, better exercise self-efficacy, and higher overall levels of sport and physical activity participation during physical development.

Pre- and Post-operative determinants of transplantation-free survival after Fontan. The Australia and New Zealand experience.

BACKGROUND: This review identifies the predictors of late mortality and heart transplantation that remain relevant in the contemporary population of patients with a Fontan circulation, focusing on the potential impact of post-Fontan morbidities on the late outlook of these patients. METHODS AND RESULTS: A total of 1561 patients who had survived the Fontan operation in Australia or New Zealand from 1975 to 2018 were included in this review. Over a median duration of 11.4 years, there was a total of 117 deaths (7%) and 32 heart transplantations (2%). Freedom from death and heart transplantation at 10, 20 and 35 years post Fontan surgery were 94% (95% CI 93-95%), 87% (95 %CI 85-90%) and 66% (95 %CI 57-78%) respectively. Being male, having an atriopulmonary Fontan, pre-Fontan atrioventricular valve intervention, or prolonged pleural effusions post Fontan were predictive of late death or heart transplantation. However, time-dependent variables such as the development of atrial arrhythmia, protein/losing enteropathy or late ventricular dysfunction were stronger predictors of the same outcome. Patients who developed a time-dependent risk factor had a freedom from death and heart transplantation rate of 54% (95 %CI 43-66) at 15 years and 44% (95 %CI 33-57) at 25 years post Fontan. However, 95% (95 %CI 91-99) of patients without any of the identified risk factors were free from death or heart transplantation rate at 25 years post Fontan. CONCLUSION: In conclusion, the occurrence of post-operative complications such as PLE, arrhythmia and ventricular dysfunction will likely precede the late demise of these patients.

Threat of COVID-19 impacting on a quaternary healthcare service: a retrospective cohort study of administrative data.

OBJECTIVES: The threat of a pandemic, over and above the disease itself, may have significant and broad effects on a healthcare system. We aimed to describe the impact of the SARS-CoV-2 pandemic (during a relatively low transmission period) and associated societal restrictions on presentations, admissions and outpatient visits. DESIGN: We compared hospital activity in 2020 with the preceding 5 years, 2015-2019, using a retrospective cohort study design. SETTING: Quaternary hospital in Melbourne, Australia. PARTICIPANTS: Emergency department presentations, hospital admissions and outpatient visits from 1 January 2015 to 30 June 2020, n=896 934 episodes of care. INTERVENTION: In Australia, the initial peak COVID-19 phase was March-April. PRIMARY AND SECONDARY OUTCOME MEASURES: Separate linear regression models were fitted to estimate the impact of the pandemic on the number, type and severity of emergency presentations, hospital admissions and outpatient visits. RESULTS: During the peak COVID-19 phase (March and April 2020), there were marked reductions in emergency presentations (10 389 observed vs 14 678 expected; 29% reduction; p<0.05) and hospital admissions (5972 observed vs 8368 expected; 28% reduction; p<0.05). Stroke (114 observed vs 177 expected; 35% reduction; p<0.05) and trauma (1336 observed vs 1764 expected; 24% reduction; p<0.05) presentations decreased; acute myocardial infarctions were unchanged. There was an increase in the proportion of hospital admissions requiring intensive care (7.0% observed vs 6.0% expected; p<0.05) or resulting in death (2.2% observed vs 1.5% expected; p<0.05). Outpatient attendances remained similar (30 267 observed vs 31 980 expected; 5% reduction; not significant) but telephone/telehealth consultations increased from 2.5% to 45% (p<0.05) of total consultations. CONCLUSIONS: Although case numbers of COVID-19 were relatively low in Australia during the first 6 months of 2020, the impact on hospital activity was profound.

Left bundle branch area pacing in congenitally corrected transposition of great arteries - The obvious choice?

Patients with congenitally corrected transposition of the great arteries (CCTGA) are susceptible to acquired atrioventricular conduction disease in early life. Emerging studies propose that conduction system pacing either by His bundle pacing or bundle branch pacing is advantageous in this population. The anatomical abnormality of CCTGA conveniently positions the left bundle branches on the easily accessible right ventricular septal side. We present a case of a young female CCTGA patient with exercise-induced heart block who received left bundle branch area pacing with the ventricular lead implanted at the conventional right ventricular septal approach without the need for 3-dimensional electroanatomical mapping.

Long-term outcomes of right ventricle-to-pulmonary artery conduit insertion in adults with congenital heart disease: survival analysis by National Death Index.

OBJECTIVES: The aim of this study was to investigate the long-term outcomes following right ventricle-to-pulmonary artery (RV-to-PA) conduit insertion of Medtronic Freestyle® porcine valve (MFV) or pulmonary allograft valve (PAV) in adult patients with congenital heart disease. METHODS: Retrospective medical record review of consecutive RV-to-PA conduit insertion, using either PAV or MFV from 1991 to 2017. Perioperative data and clinic reports were collected. Cause and date of death were obtained from the Australian National Death Index to obtain survival function. RESULTS: In total, 232 patients (median age 31.5 years, interquartile range 25-41 years) underwent RV-to-PA conduit insertion (PAV = 84 and MFV = 148) and were eligible for inclusion [63.8% tetralogy of Fallot (TOF); 11.6% congenital pulmonary stenosis (PS); 24.6% other diagnoses]. The overall median follow-up time was 9.1 years (interquartile range 5.3-12.6 years). The mean gradient was 11.8 ± 7.1 mmHg in PAV and 16.6 ± 9.6 mmHg in MFV patients. Congenital PS patients had 100% survival at 20 years, TOF patients at 5, 10, 15 and 20 years had 99%, 97%, 96% and 96% survival, respectively. Patients with other primary diagnoses at 5, 10, 15 and 20 years had 93%, 91%, 87% and 87% respectively. Freedom from reintervention did not differ significantly at 5 and 10 years between pulmonary allograft (98.6%, 98.6%) and Freestyle® porcine bioprosthesis (97.5%, 93%). CONCLUSIONS: Both valves perform equally well with regard to patients' freedom from reoperation, although transvalvular gradient was higher for Freestyle® patients. Congenital PS and TOF patients had better survival than patients with other primary diagnoses.

Remote Device Interrogation Kiosks (ReDInK) - Pharmacy Kiosk Remote Testing of Pacemakers and Implantable Cardioverter-Defibrillators for Rural Victorians. A Novel Strategy to Tackle COVID-19.

BACKGROUND: In the era of COVID-19, travel restrictions and social distancing measures have changed the landscape for device interrogations of pacemakers and defibrillators for rural Victorians. Previously, device checks were performed infrequently in large volume, face-to-face rural clinics by visiting cardiologists and technicians. Access to remote areas and social distancing restrictions have made these clinics unfeasible to operate. The Cardiac Society of Australia and New Zealand (CSANZ) and Heart Rhythm Society (HRS) COVID-19 consensus statements have suggested the utilisation of remote monitoring to minimise the potential spread of COVID-19 infections between clinicians and high-risk patients. A novel solution to this challenge was the implementation of a remote device interrogation (RI) service located in two kiosks at two rural pharmacies. This service was termed Remote Device Interrogation Kiosks (ReDInK). AIM: This cross-sectional observational study aimed to describe the set-up process, safety and efficacy of RI and customer satisfaction of the ReDInK program. METHODS: Two-hundred-and-ninety-two (292) rurally located patients with implantable cardiac devices were identified via the cardiology department database. Of these, 101 (44%) were enrolled into the ReDInK program across two rurally located pharmacies between April and July 2020. RI was performed and download outcomes were reviewed. A customer satisfaction survey assessed attitudes towards the program and explored options of ongoing service application. RESULTS: Of 101 patients enrolled into ReDInK, 96 (95%) resulted in satisfactory device checks. Four (4) individuals failed-to-attend and one individual experienced technical download issues. Of the 96 satisfactory device checks, three required in-person follow-up for reasons including battery replacement, lead repositioning and in-person programming. No adverse events were reported. A satisfaction telephone survey was conducted with 81 (83%) participants enrolled in ReDInK. Seventy-one (71) individuals (88%) of those surveyed expressed satisfaction and 73 (90%) labelled the process as efficiently conducted. Sixty-nine (69) (85%) participants felt reassured that this service was established during the pandemic. However 47 (58%) participants reported they would still feel comfortable to undergo in-person reviews despite social distancing recommendations. CONCLUSIONS: With the COVID-19 pandemic posing restrictions to social distancing and reducing unnecessary in-person interaction, the ReDInK program emerges as an efficacious and safe solution for patients in rural Victoria. The program's widely positive reception and successful conduction in rural Victoria invites further opportunity for a wider application of similar programs, expanding its role to metropolitan areas.

Exercise Intolerance, Benefits, and Prescription for People Living With a Fontan Circulation: The Fontan Fitness Intervention Trial (F-FIT)-Rationale and Design.

Background: Despite developments in surgical techniques and medical care, people with a Fontan circulation still experience long-term complications; non-invasive therapies to optimize the circulation have not been established. Exercise intolerance affects the majority of the population and is associated with worse prognosis. Historically, people living with a Fontan circulation were advised to avoid physical activity, but a small number of heterogenous, predominantly uncontrolled studies have shown that exercise training is safe-and for unique reasons, may even be of heightened importance in the setting of Fontan physiology. The mechanisms underlying improvements in aerobic exercise capacity and the effects of exercise training on circulatory and end-organ function remain incompletely understood. Furthermore, the optimal methods of exercise prescription are poorly characterized. This highlights the need for large, well-designed, multi-center, randomized, controlled trials. Aims and Methods: The Fontan Fitness Intervention Trial (F-FIT)-a phase III clinical trial-aims to optimize exercise prescription and delivery in people with a Fontan circulation. In this multi-center, randomized, controlled study, eligible Fontan participants will be randomized to either a 4-month supervised aerobic and resistance exercise training program of moderate-to-vigorous intensity followed by an 8-month maintenance phase; or usual care (control group). Adolescent and adult (≥16 years) Fontan participants will be randomized to either traditional face-to-face exercise training, telehealth exercise training, or usual care in a three-arm trial with an allocation of 2:2:1 (traditional:telehealth:control). Children (<16 years) will be randomized to either a physical activity and exercise program of moderate-to-vigorous intensity or usual care in a two-arm trial with a 1:1 allocation. The primary outcome is a change in aerobic exercise capacity (peak oxygen uptake) at 4-months. Secondary outcomes include safety, and changes in cardiopulmonary exercise testing measures, peripheral venous pressure, respiratory muscle and lung function, body composition, liver stiffness, neuropsychological and neurocognitive function, physical activity levels, dietary and nutritional status, vascular function, neurohormonal activation, metabolites, cardiac function, quality of life, musculoskeletal fitness, and health care utilization. Outcome measures will be assessed at baseline, 4-months, and 12-months. This manuscript will describe the pathophysiology of exercise intolerance in the Fontan circulation and the rationale and protocol for the F-FIT.