The Canadian Fontan Connection (CANFON): Protocol for a National Lifespan Cohort of People Living With a Fontan Circulation

Abstract

The life expectancy of people living with a Fontan circulation has improved significantly over recent decades. However, this population remains at risk of multiorgan complications and premature mortality with advancing age. Despite growing clinical experience, key knowledge gaps remain in our understanding of Fontan-related morbidity, including the timing, predisposition and progression of complications, their cumulative burden, and their long-term impact on quality of life and functional outcomes. To address these challenges, we establish Canadian Fontan Connection (CANFON), a national, longitudinal cohort of individuals with single ventricle physiology who are either eligible for or living with a Fontan circulation. The design and implementation of CANFON were developed through engagement with Canadian congenital heart disease experts and alignment with international research priorities. Comprehensive clinical data are collected and banked from birth onward, providing an in-depth, lifelong view of each participant’s health. In parallel, participant-reported outcome measures are prospectively collected over a 5-year period. Recruitment occurs in 24 pediatric and adult congenital heart disease centers across Canada. The overarching objectives of CANFON are to (1) establish the health trajectories of Fontan physiology across the lifespan, (2) determine the prevalence and evolution of complications and modifying factors, (3) identify early predictors and risk factors for Fontan failure, and (4) assess the impact of complications on quality of life and functional status through participant-reported outcomes. Beyond its immediate goals, CANFON will serve as a unique, well-phenotyped, pan-Canadian research platform to support nested studies and accelerate progress in understanding and improving outcomes for individuals living with a Fontan circulation nationally and internationally.

The functional univentricular heart is a complex form of congenital heart disease that requires a series of interventions from birth onward to ensure the best possible life expectancy and quality of life. The many forms of a functional univentricular heart have in common the impossibility of performing a cardiac repair that enables a biventricular physiology, in which a second dedicated ventricle pumps blood into the pulmonary circulation.¹ There is, therefore, the need for staged interventions performed in the first years of life to create the Fontan circulation, a configuration in which the single functioning ventricle ensures propulsion of blood to the systemic circulation, while the systemic veins are ultimately connected to the pulmonary arteries, allowing blood to flow passively into the lungs.² In the Fontan circulation, pulmonary impedance disrupts venous return through the pulmonary vascular bed, leading to congestion upstream and restricted flow downstream. Most clinical and physiological complications occurring in those with a Fontan circulation are due to this upstream congestion and downstream restricted flow.³ Despite advances in surgical techniques and medical management, the mechanisms underlying why between 15% and 39% Fontan circulations "fail" so early, whereas others remain stable for decades are not fully understood, suggesting the involvement of a poorly defined complex interplay of cardiovascular and extracardiac factors.4, 5, 6, 7

Rationale

Individuals with a Fontan circulation struggle to live a “normal” life on the background of this life-span condition that requires close surveillance and care by an expert multidisciplinary team. The patient voice, as set out by Reena Clarkson, a person with lived experience, provides the most obvious rationale for our proposed Canadian Fontan Connection (CANFON).

As a child I was always told I had a certain “life expectancy.” After my Fontan procedure, my medical team stopped referring to my “life expectancy” and instead said “let’s see what happens.” While having a looming expiration date motivated me to live life to the fullest within the restrictions of my condition, it meant that I did not plan ahead for adult years. Now as I approach my 40s, I feel like I’m navigating uncharted territory. In addition to the challenges of aging that the general population faces, we Fontan patients have more concerns about keeping all our systems running more smoothly than we did during childhood.

Key to supporting our mental and physical journey into (older) adulthood are the resources, programs and services that our adult congenital heart defect clinics can provide. I am grateful to be living near one of the best clinics in Canada; however, I have heard horror stories from adult patients who are less fortunate. Their inability to access regular care, let alone specialty care, compromises their life experience and puts them right back where their “condition” becomes limiting. A more holistic approach to congenital heart disease (CHD) patient care is needed. That "big picture" and whole body/systems thinking is critical to both mental and physical health and it's so easy to miss or neglect when we have spent our formative years focusing on one system. Through peer support I've learned that many of the health challenges I've faced that are seemingly linked to CHD are very common and similar to what other CHD patients have dealt with. Whether that's an effect of our physiology, sharing that knowledge could save patients years of struggling and frustration.

This testimony highlights the uncertainty faced by many people with a Fontan circulation as they age and the significant need for comprehensive, patient-centered care that extends well beyond childhood. It also underscores the importance of establishing a comprehensive national Fontan network to address medical and psychosocial challenges, ensuring that everyone living with a Fontan circulation, regardless of geographic location, have access to the support and expertise they need.

With an estimated global population of around 70,000 people living with a Fontan circulation—a number expected to double within the next 2 decades because of advances in treatment—and with an estimated number of 2000 to 3000 people living with a single ventricle physiology in Canada, the need to understand and manage Fontan circulation complexities and outcomes is critical.7, 8, 9 The abnormal Fontan circulation is associated with a number of cardiac and noncardiac complications over the long term (Fig. 1). Freedom from death or transplantation among Fontan survivors is 95%, 91%, and 82% at 5, 10, and 20 years, respectively, according to estimates from a 2018 meta-analysis of studies published between 1990 and 2015.^6,10 Freedom from Fontan failure (death, transplantation, or other cardiac complications related to the Fontan circulation) has been reported as 83%, 70%, and 56% at 15, 20, and 25 years, respectively.¹¹ With increasing survival comes new clinical scenarios and long-term complications.⁶ For example, being pregnant with a Fontan circulation is becoming more common, but the associated obstetrical complications and long-term cardiovascular risks for the mother, as well as the perinatal risk for the fetus, remain ill-defined.12, 13, 14, 15, 16, 17 Previously under-recognized extracardiac organ disease, including liver, lymphatic, and kidney issues, are now known to contribute to and/or be the result of Fontan failure trajectory. Substantial work remains to fully characterize these issues, including their predisposing factors, impacts on morbidity and mortality, and interventions to improve outcomes.^18,19

Figure 1.

Life and medical challenges in Fontan circulation. CVD, cardiovascular disease.

Canadian Fontan Connection

The CANFON was established in 2018, with formalization in 2021. CANFON is a national collaboration involving pediatric and adult congenital cardiologists working in partnership with people with lived experience and their families. It leads and facilitates Canadian clinical and translational research with the goal of ultimately improving the lives of those living with a Fontan circulation. CANFON is supported by a dedicated advisory committee composed of individuals with lived experience and family advocates, working in close collaboration with the scientific steering committee. On the advice of the advisory group, the cohort is referred to as the CANFON. This group not only advises on clinical research questions important to those living with a Fontan circulation, but also provides peer-to-peer support and takes the lead in organizing an annual national Fontan education day. The Canadian Fontan website (www.canadianfontan.com) provides another platform to enable patients and health care professionals across Canada to learn and share information and facilitate research across the country.

At the core of CANFON will be a comprehensive, well-characterized lifespan research cohort encompassing all people living with a Fontan circulation and young children with a functionally univentricular heart who will eventually undergo a Fontan operation. In the context of Canada's universal health care system and considering the recommendations for providing the health care of people with complex congenital heart disease in specialized tertiary care centers,²⁰ we are particularly well placed to study this population. This Canadian cohort will serve to address critical questions pertaining to the Fontan population and support Canadian and international research collaborations. This article details the CANFON cohort protocol.

Methods

Objectives

The objectives of CANFON are as follows:

• (1)To provide complete and comprehensive health trajectories of people with a functional univentricular circulation (pre- and post-Fontan) in Canada.
• (2)To better understand the prevalence of complications and complicators over the lifespan of the Fontan circulation.
• (3)To identify early predictors and risk factors for Fontan failure or complications.
• (4)To determine quality of life for people living with a Fontan circulation.
• (5)To assess the impact of the development of complications on the quality of life.
• (6)To enhance research by providing an accessible pan-Canadian well-phenotyped lifespan cohort in which targeted future research projects can be nested.

Population

The study population includes children and adult with a Fontan circulation and those with a univentricular heart who will eventually undergo a Fontan operation. Most people with a functionally univentricular heart are cared for at university tertiary adult or pediatric centers with designated congenital heart disease clinics. The cohort is deliberately inclusive, aiming to capture every individual living with a Fontan circulation in Canada. Those with atypical cardiac anatomies or care trajectories are therefore not excluded but rather identified as such (eg, those with 2 well-developed ventricles who underwent a Fontan operation because of a straddling atrioventricular valve). Inclusion in specific analyses will subsequently be determined on the basis of study-specific research questions and defined study populations. Those with a single ventricle physiology who were never Fontan candidates, such as newborns offered comfort care after birth, are not included.

Study design

This is a pan-Canadian observational cohort with a retrospective and a prospective arm. Eligible participants are identified by local research teams using clinical patient lists, echocardiography data, and research registries where possible. Potentially eligible participants who heard about the study can also reach out to their local care team to be assessed for eligibility. Participants are approached and invited to participate in the study in person at a clinical appointment, or by phone or e-mail. Adults or parents of minor participants are asked to provide consent, and pediatric participants are asked to provide assent when appropriate. For participants who cannot be contacted (loss to follow-up, moved out of the country, etc) and deceased participants, we requested a waiver of consent or a delegated consent for retrospective clinical data collection. This hybrid approach enables broad representation of the population to more accurately characterize the incidence and prevalence of complications, while allowing in-depth assessment of their impact through prospective questionnaires administered to a subset of actively followed and consenting participants (Fig. 2).

Figure 2.

Study flow chart. CANFON, Canadian Fontan Connection; CCPCRN, Canadian Congenital Pediatric Cardiology Research Network.

This work complies with the Canadian Tri-Council Policy Statement on Ethical Conduct for Research Involving Humans. The project will be evaluated by all the relevant jurisdictional research ethics board.

Steering committee

A steering committee composed of experienced investigators in pediatric and congenital cardiology, epidemiology, and methodology is responsible for the scientific orientation of the study and for vetting additional research questions and nested projects. The CANFON cohort benefits from the support of the Canadian Adult Congenital Heart Network, the Canadian Pediatric Cardiology Association, and the Canadian Congenital Pediatric Cardiology Research Network (CCPCRN),²¹ enabling a partnership that integrates and reaches most pediatric and adult congenital cardiology institutions in Canada. These groups provide visibility and access to their networks, help to promote the study, and facilitate knowledge translation. The CCPCRN framework and data banking infrastructure are used to facilitate fair but secure access to research data, as well as smooth data integration and linkage with previous, current, or future research cohorts of participants with Fontan circulation.²¹

Clinical data collection

A summary of the collected data is presented in Table 1. Clinical data are extracted from the participants' medical record. When participants have been seen in multiple cardiology centers, the data are pooled to avoid duplicates. Whenever possible, research data from previous and existing projects and registries are extracted and linked to the CANFON data.^8,22,23 A complete listing of clinical data collection instruments is shown in Supplemental Table S2.

Table 1.

Overview of the collected data

Clinical data

Participant-reported measures and outcomes

Cardiac anatomy  Native cardiac anatomy  Underlying systemic ventricle  Situs and heterotaxy syndrome, etc Complete surgical history  Palliative and pre-Fontan staged operations  Fontan operation details  Post-Fontan reintervention Genetic and vital status  Genetic syndromes  Death (cause)  Transplantation Complications and major events  Endocarditis  Chronic pleural effusions  Protein losing enteropathy  Plastic bronchitis Hospitalization and thromboembolic events  Dates and cause of hospitalization  Thromboembolism events (date, site, and treatment) Arrhythmias and electrophysiology  Arrhythmia events  Electrophysiology testing and interventions  ECG tracings Heart catheterization  Diagnostic catheterization  Interventional catheterization Imaging and functional testing  Echocardiograms  Cardiac MRI and CT  Liver imaging  Exercise testing Outpatient visits  Vitals and blood work  Symptoms and NYHA classification  Medications and comorbidities  Lifestyle Pregnancy  Fertility  Pregnancy and neonatal outcomes

SWLS  Five-item questionnaire designed to assess an individual's overall cognitive evaluation of their satisfaction with life. Responses are rated on a 7-point Likert scale, ranging from "strongly disagree" to "strongly agree." PROMIS  Questionnaire designed to evaluate physical, mental, and social health. Responses are rated on a 5-point Likert scale, tailored to the specific domain being assessed PCQLI  Multi-item questionnaire designed to assess the quality of life in children and adolescents. It evaluates physical, emotional, social, and school functioning, with responses typically rated on a 5-point Likert scale, ranging from "never" to "almost always." Linear analog scale  Single-item measure where participants rate their quality of life by marking a position on a line ranging from “worst quality of life imaginable” (score of 0) to “best quality of life imaginable” (score of 100). Demographics  Self-reported biological sex at birth  Gender  Ethnicity  Employment status  Highest level of education  Household income

CT, computed tomography; ECG, electrocardiogram; EP, electrophysiology; MRI, magnetic resonance imaging; NYHA, New York Heart Association; PCQLI, Pediatric Quality of Life Inventory; PROMIS, Patient-Reported Outcomes Measurement Information System; SWLS, Satisfaction With Life Scale.

Clinical data are collected using a longitudinal structure with repeated data collection instruments for important clinical events. The incidence rate of the following important outcomes will be calculated, when appropriate: survival and transplant-free survival, heart transplantation, other organ transplantation, arrhythmia requiring treatment, or hospitalization, Fontan-associated liver disease, chronic kidney disease, protein-losing enteropathy, cardiovascular hospitalization, all-cause hospitalization, reintervention after Fontan, plastic bronchitis, and stroke.

The definitions of “Fontan failure” and of “Fontan complication” can be multifaceted²⁴ and are expected to be tailored to the various research questions being explored. The clinical data collection forms were designed to mirror the “severity-graded definitions of Fontan-associated complications” recently proposed by the Fontan circulatory failure study investigators.²⁵ We adapted these graded definitions of complications to enable identification of their timing within each participant’s clinical course, thereby allowing calculation of incidence rates for any grade of the listed complications included in the consensus document.

Participant-reported outcome measures

We collect participant-reported measures (PROM) from participants willing to enroll in the prospective arm of the cohort (see also Table 1). The choice of the PROM instruments was based on the proposition of the International Consortium for Health Outcome Measurement.²⁶ For congenital heart defects, the consortium emphasized the use of validated, patient-centered instruments that capture key aspects of their quality of life and overall well-being.²⁷ In addition, we selected instruments that would assess PROM in both children and adults using similar scales and measures to enable a longitudinal appreciation of PROM across the lifespan, without a “break” at 18 years of age. We selected the following participant-reported PROM: the Satisfaction With Life Scale, the Pediatric Cardiac Quality of Life Inventory, and the Patient-Reported Outcomes Measurement Information System.

The Satisfaction With Life Scale measures general satisfaction with life using a 5-item questionnaire.²⁸ The questionnaire has been validated in French and English, with versions adapted for children, adolescents, and adult populations.28, 29, 30, 31

The Pediatric Cardiac Quality of Life Inventory is a disease-specific measure of health-related quality of life developed for children and adolescents with congenital or acquired heart disease.³² It has only been validated in English and for a pediatric population.³³ Minor modifications were made to adapt the adolescent version for adults. The French version was developed by our team through an initial translation of the questionnaire, followed by a forward and backward translation process with the help of a professional interpreter.

The Patient-Reported Outcomes Measurement Information System assesses general physical, mental, and social health,³⁴ using generic measures, rather than disease-specific measures. We use a validated version of the questionnaire in French, English and for adults, children, and adolescents.^35,36

We also use a linear analog scale to evaluate quality of life. This instrument asks participants to position how they self-evaluate their quality of life with the extremes of the scale labeled “worst quality of life imaginable” (score of 0) and “best quality of life imaginable” (score of 100). Its use is recommended to assess overall quality of life.37, 38, 39 Linear analog scales to assess quality of life of participants with heart defects have been used by different groups40, 41, 42, 43 and are part of validated quality of life questionnaires, but the linear scale in isolation outside of these questionnaires has only been validated for adult populations.^40,44, 45, 46

Data collection process and follow-up

Figure 2 illustrates the timeline and data collection process. The overarching intent is to have an ongoing cohort with long-term prospective data collection and outcome updates. Practically, because many institutions and research ethics boards do not allow open-end protocols, the current CANFON protocol includes a 5-year prospective follow-up, with an intent to renew it for as long as there is ongoing scientific value and institutional support.

For participants who consented for prospective data collection, PROM and clinical data are collected at enrollment (year 0), and at year 3 and year 5 (see Fig. 2). The year 0 clinical data collection includes a retrospective component from birth to enrollment. For participants enrolled under a waiver of consent, retrospective clinical data are collected from birth to the time of study inclusion.

The data are entered on the web-based REDCap data capture platform using standardized data reporting instruments. Clinical data are collected by members of the research team. Participants have the opportunity to complete PROM online or on paper, either in clinic or at home. Participants are e-mailed a link or a QR code. All PROM questionnaires can be fully completed online without intervention from the study team. The study team follows up by phone or in clinic for incomplete or missing questionnaires.

Data validation

Participating sites’ research team all receive training and guidance on the implementation and start-up of the study in their site, and on the enrollment and the data collection procedures. Throughout the study, the central coordinating team supports all study sites, monitor progress, and perform data quality check regularly. To further ensure consistency across sites, any recurring or important questions from sites are compiled into a centralized frequently asked questions document accessible to all data extractors.

To further increase data quality, we implemented “on the fly” and post hoc data validation. All data collection instruments include automated alerts for abnormal or extreme values, as well as for missing critical data elements. These alerts inform the data abstractor to review any potential errors or critical missing data. Entered data are then regularly reviewed for data distributions, outliers, errors, and missing elements. Potential errors are flagged, and data queries are created.

Data analysis and data access

CANFON is designed as a data bank that can be used to help answer multiple research questions. The choice of data analysis depends on the research question. Data from the CANFON research are hosted in the CCPCRN Data Center and are banked for future analyses. Research proposals are evaluated by both the CANFON and CCPCRN steering committee. CANFON research data are available to Canadian investigators and can also be linked to other international single ventricle research initiatives. By default, research data remain stored in the CCPCRN Data Center and can be securely accessed remotely to conduct analyses.

Results

As of August 2025, there were 24 sites participating in the CANFON cohort (12 adult sites, 9 pediatric sites, and 3 sites caring for both adult and pediatric patients). These sites are at various stages of study approval and data collection (Fig. 3). There were 583 (185 children and 398 adults) enrolled participants, on an expected number of αpproximately 2000 eligible participants across Canada.

Figure 3.

Site progression. REB, research ethics board.

In addition to the initial study questions and objectives of the CANFON cohort, there are already studies in development that will be nested in the CANFON cohort, leveraging banked data as well as the CANFON data management infrastructure, as outlined in Table 2.

Table 2.

Planned and ongoing ancillary research projects nested in the Canadian Fontan Connection (CANFON) cohort

Prospective deep imaging and hemodynamic phenotyping to correlate how change in connection and pulmonary artery branch diameters, valve function, ventricular size and function, diastolic assessment, longitudinal strain analysis, ultrafast ultrasound for assessment of myocardial stiffness, and invasive hemodynamics correlate with the risk of developing Fontan failure

Assessment of independent predictors of Fontan-associated liver disease on liver biopsy among clinical, novel imaging, laboratory and biological markers, and development of a noninvasive diagnostic prediction model for moderate to severe Fontan-associated liver disease

Assessment of serial changes in digital electrocardiogram parameters by artificial intelligence to predict Fontan failure, Fontan-associated complications, and arrhythmia

Analyses of the genome and metabolome of people with and without Fontan failure to identify genomic and metabolomic predictors of Fontan failure

The results of this cohort, when available, will be presented in peer-reviewed scientific journals, at scientific conferences, and on the CANFON website⁴⁷ and website of the CCPCRN,⁴⁸ a network that connects all the participating hospitals in this study.²¹ Feedback on the results will also be given to the participants.

Discussion

Studies on Fontan circulation and single ventricle physiology are often limited by relatively short follow-up periods. If enrollment proceeds as anticipated, the CANFON cohort, due to its retrospective component and planned large sample size, will document clinical outcomes over a period that may exceed 30 years for some. This approach will provide a comprehensive picture of long-term complications, record a greater number of clinical events, and contribute to a better understanding of the risks and health trajectories.

One of the major strengths of the CANFON cohort lies in the integration of data on PROM, a dimension often poorly documented in people with a univentricular physiology. The important work of the Australia and New Zealand Fontan Registry has contributed to our understanding of quality of life children and adults living with a Fontan circulation,^45,49 but data on PROM remains limited overall. We collect information on PROM at 3 different time points over a 5-year period, and hopefully for many more years to come. This will offer a unique perspective, thus making an important contribution to available knowledge. In addition, by tracking the evolution of PROM over time, we will be able to explore how it varies in response to the complications that have arisen, thus providing valuable elements to better guide patient follow-up and management.

Another strength of this cohort lies in its multicenter nature, bringing together all pediatric and adult cardiology centers across Canada. This national collaboration helps to develop continuous, harmonized follow-up of participants throughout their care, regardless of whether they move from a pediatric to an adult clinic. By integrating both pediatric and adult centers, the CANFON cohort ensures that participants who have reached adulthood and transferred to adult clinics do not have interruption in data collection. This approach is particularly advantageous for a complex population such as that of people living with a Fontan circulation, for whom exhaustive longitudinal follow-up is essential to better understand the evolution of clinical complications at each stage of life. In addition, the national and multicentric nature of this cohort will confer excellent external validity, enhancing their transferability and comparability to Fontan populations elsewhere.

Results from large cohorts of participants with Fontan circulation have been published in recent years.50, 51, 52, 53, 54 Our cohort will help refine and confirm our knowledge of the health trajectories, the complications, and the outcomes of this population. The richness of the CANFON cohort lies in its comprehensive characterization of participants, with data on symptomatology, blood tests, hospitalizations, PROM, imaging, extracardiac organ dysfunction, pregnancies, genetic syndromes, electrophysiological studies, in addition to data on mortality, concomitant diagnoses and details of surgical or catheter interventions, and other common complications. This wealth of detailed data will facilitate Fontan phenotyping and lifespan trajectories.

In addition to the advances that the CANFON cohort will bring to our understanding of the Fontan circulation, we have already shown that it is feasible to bring together most centers caring for people living with a Fontan circulation in Canada and to bridge the gap between pediatric and adult institutions, therefore establishing a truly pan-Canadian cohort spanning all ages.

Limitations

Individuals who consent to participate in the CANFON cohort are enrolled on a voluntary basis, and it is conceivable that they may be different from the overall Fontan population. A small proportion of participants may be lost to follow-up during the prospective phase. Based on the recorded loss to follow-up of approximately 7% in the Australia and New Zealand Fontan registry, we expect a similar proportion in the CANFON cohort.⁵¹ It is possible that more participants will be lost to follow-up in the prospective PROM data collection portion because this portion requires action from the participants. To improve retention, research coordinators remind participants of completing questionnaires, for which an online remote option is available. Also, we will increase participants’ engagement by sharing study progress and results, as well as providing education and resources through the CANFON connection and annual Fontan education day initiative.

It is expected that a subset of people living with a Fontan circulation will be harder to reach (eg, those living remotely, those lost to clinical follow-up, and those with language barriers). Similarly, it is possible that those followed at outreach cardiology clinics will be more difficult to enroll, as the research facilities and resources may be scarcer in these settings. To preserve sample size and representativeness, we asked for a waiver of consent for clinical retrospective data for people who cannot be reached. Clinical outcomes that can be captured in medical charts will thus be available for most patients, which will increase representativeness.

Clinical data are abstracted retrospectively from medical charts, which is subject to information bias. We use a structured electronic form to mitigate this. Studies with similar research settings and abstraction methods have shown that the validity and fidelity of manually collected clinical data in an electronic database are >95%.55, 56, 57 Nevertheless, retrospectively collected data provide less control on potential confounders.

Not all PROM questionnaires have been validated for adults and children in both English and French. Although this absence of formal validation is a limitation, as this may bias scores in subpopulations of this cohort, we elected to use similar instruments in both languages, and we found it important to have questionnaires that assessed the same domains in children adolescents and adults, without a break in the score at 18 years of age.

Conclusions

The CANFON cohort is a Canadian multicenter study designed to investigate the health trajectories and complications of people with single ventricle physiology who are eligible for or already living with a Fontan circulation. By collecting comprehensive data on clinical outcomes and PROM, the CANFON cohort will provide a comprehensive lifespan trajectory from birth to adulthood. The data banking approaches, as well as the Canada-wide collaboration of pediatric and adult cardiology centers enables tackling current and future research questions that should contribute to advancing knowledge on this unique circulation to ultimately optimizing their care and treatment.