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Inherited cardiomyopathies are a heterogeneous group of heart muscle conditions where disease classification has traditionally been based on clinical characteristics. However, this does not always align with genotype. While there are well described challenges of genetic testing, understanding the role of genotype in patient management is increasingly required. We take a gene-by-gene approach, reviewing current evidence for the role of genetic testing in guiding prognosis and management of individuals with inherited cardiomyopathies. In particular, focusing on confident variants in genes definitively associated with arrhythmogenic cardiomyopathy, dilated cardiomyopathy, and hypertrophic cardiomyopathy. This review identifies genotype-specific disease sub-groups with strong evidence supporting the use of genetics in clinical management and highlights that at present, the spectrum of clinical utility is not reflected in current guidelines. Of 13 guideline or expert consensus statements for management of cardiomyopathies, there are seven gene-specific therapeutic recommendations that have been published from four documents. Understanding how genotype influences phenotype provides evidence for the role of genetic testing for prognostic and therapeutic purposes, moving us closer to precision-medicine based care.
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Cardiac magnetic resonance imaging (CMR) is the gold-standard non-invasive method of assessing cardiac structure and function, including tissue characterisation. In systemic sclerosis (SSc), heart involvement (SHI) is a leading cause of mortality yet remains poorly understood. SHI is underestimated by conventional echocardiography, and CMR provides an important opportunity to better identify and quantify subtle myocardial changes including oedema and fibrosis. This review summarises current CMR techniques, the role of CMR in SSc and SHI, and the opportunities to further our understanding of its pathogenesis and management.
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Background: A cardiac hibernoma is a rare phenomenon, with just a handful of reports in the literature. They are difficult to characterize with conventional imaging including echocardiography, computed tomography (CT), cardiac magnetic resonance (CMR), or positron emission tomography (PET). Their definitive diagnosis relies primarily on histopathology via either endovascular or surgical biopsy. Previous case reports have entailed surgical excision followed by histopathology; however, surgery may be unfavourable in some patients with increased perioperative risk. Case summary: We present the case of a 57-year-old woman who was referred to our cardiology service with an interatrial lipomatous mass found incidentally on chest CT for assessment of rib fractures. She had 6 months of unexplained syncope, which was attributed to superior vena cava (SVC) compression demonstrated by chest CT. The mass had benign characteristics on echocardiography, CT, and CMR but was glucose-avid on PET, which indicated a possible malignancy such as liposarcoma. Her comorbid and very significant airways disease precluded her from surgical excision, so instead, endovascular biopsy was performed. Histopathology showed brown fat which was negative for mouse double minute 2 amplification on fluorescence in situ hybridisation testing; hence, a diagnosis was made of hibernoma, a rare benign tumour of brown fat. Given the benign diagnosis and her surgical risk with severe chronic obstructive pulmonary disease, a multidisciplinary recommendation was made favouring conservative management, with careful ongoing follow-up and the consideration of SVC stenting if symptoms progressed. Discussion: The definitive diagnosis of a cardiac hibernoma is complex and relies heavily on histopathology due to the contradictory findings on chest imaging. Careful consideration of management within a multidisciplinary team setting is essential to achieve a successful outcome.
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OBJECTIVES: To report findings from the High Performance Sport New Zealand cardiac screening programme, including comparisons between sexes and ethnicities. DESIGN: Retrospective cohort study. METHODS: Elite Olympic-sport athletes were screened (2012-2022) with personal/family history, physical examination, resting 12-lead ECG and followed from the date of first screening until July 2022. An audit reviewed screening records, including demographic data, ECGs, follow-up and diagnoses. Flagged/equivocal ECGs were re-reviewed (International Criteria). RESULTS: 2075 ECGs from 1189 athletes (53â¯% female, mean age 21â¯years; 83â¯% European, 9â¯% Maori, 5â¯% Pacific Islander, 3â¯% other) were included. No athletes retired for cardiac reasons; there were no cardiac deaths or major cardiac incidents (mean follow-up from first screening: 6.1â¯years (range: 0.6-10.9â¯years)). Diagnoses included Wolff-Parkinson-White (WPW) syndrome (0.7â¯%) and cardiomyopathies (0.3â¯%). Overall, 3.5â¯% of ECGs were abnormal, with ECGs of females more commonly abnormal (4.4â¯% vs 2.5â¯%, pâ¯=â¯0.02) and with a higher proportion of ECGs with abnormal T-wave inversion (TWI) (3.1â¯% vs 0.9â¯%, pâ¯<â¯0.001) compared to males. Of the abnormal TWI in females (all aged ≥16â¯years), 47â¯% was limited to V1-V3 with no other abnormalities. Abnormality rates were similar between Maori, Pacific Islander and European athlete ECGs. CONCLUSIONS: WPW was the most frequent diagnosis, with very little cardiomyopathy found. The proportion of abnormal ECGs was low overall, but higher in females. This was driven by anterior TWI in V1-V3 which was not associated with diagnoses of conditions associated with sudden cardiac death (SCD). There was no difference in the proportion of abnormal ECGs of Maori or Pacific Island athletes compared to European athletes.
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Atletas , Muerte Súbita Cardíaca , Cardiopatías , Femenino , Humanos , Masculino , Adulto Joven , Muerte Súbita Cardíaca/prevención & control , Electrocardiografía , Cardiopatías/diagnóstico , Nueva Zelanda , Estudios RetrospectivosRESUMEN
The coronary microcirculation plays a cardinal role in regulating coronary blood flow to meet the changing metabolic demands of the myocardium. Coronary microvascular dysfunction (CMD) refers to structural and functional remodeling of the coronary microcirculation. CMD plays a role in the pathogenesis of obstructive and non-obstructive coronary syndromes as well as myocardial diseases, including heart failure with preserved ejection fraction (HFpEF). Despite recent diagnostic advancements, CMD is often under-appreciated in clinical practice, and may allow for the development of novel therapeutic targets. This review explores the diagnosis and pathogenic role of CMD across a range of cardiovascular diseases, its prognostic significance, and the current therapeutic landscape.
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Background: Despite historically being considered a channelopathy, subtle structural changes have been reported in Brugada syndrome (BrS) on histopathology and cardiac magnetic resonance (CMR) imaging. It is not known if these structural changes progress over time. Objective: The study sought to assess if structural changes in BrS evolve over time with serial CMR assessment and to investigate the utility of parametric mapping techniques to identify diffuse fibrosis in BrS. Methods: Patients with a diagnosis of BrS based on international guidelines and normal CMR at least 3 years prior to the study period were invited to undergo repeat CMR. CMR images were analyzed de novo and compared at baseline and follow-up. Results: Eighteen patients with BrS (72% men; mean age at follow-up 47.4 ± 8.9 years) underwent serial CMR with an average of 5.0 ± 1.7 years between scans. No patients had late gadolinium enhancement (LGE) on baseline CMR, but 4 (22%) developed LGE on follow-up, typically localized to the right ventricular (RV) side of the basal septum. RV end-systolic volume increased over time (P = .04) and was associated with a trend toward reduction in RV ejection fraction (P = .07). Four patients showed a reduction in RV ejection fraction >10%. There was no evidence of diffuse myocardial fibrosis observed on parametric mapping. Conclusions: Structural changes may evolve over time with development of focal fibrosis, evidenced by LGE on CMR in a significant proportion of patients with BrS. These findings have implications for our understanding of the pathological substrate in BrS and the longitudinal evaluation of patients with BrS.
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BACKGROUND: Computational fluid dynamics (CFD) is increasingly used for the assessment of blood flow conditions in patients with congenital heart disease (CHD). This requires patient-specific anatomy, typically obtained from segmented 3D cardiovascular magnetic resonance (CMR) images. However, segmentation is time-consuming and requires expert input. This study aims to develop and validate a machine learning (ML) method for segmentation of the aorta and pulmonary arteries for CFD studies. METHODS: 90 CHD patients were retrospectively selected for this study. 3D CMR images were manually segmented to obtain ground-truth (GT) background, aorta and pulmonary artery labels. These were used to train and optimize a U-Net model, using a 70-10-10 train-validation-test split. Segmentation performance was primarily evaluated using Dice score. CFD simulations were set up from GT and ML segmentations using a semi-automatic meshing and simulation pipeline. Mean pressure and velocity fields across 99 planes along the vessel centrelines were extracted, and a mean average percentage error (MAPE) was calculated for each vessel pair (ML vs GT). A second observer (SO) segmented the test dataset for assessment of inter-observer variability. Friedman tests were used to compare ML vs GT, SO vs GT and ML vs SO metrics, and pressure/velocity field errors. RESULTS: The network's Dice score (ML vs GT) was 0.945 (interquartile range: 0.929-0.955) for the aorta and 0.885 (0.851-0.899) for the pulmonary arteries. Differences with the inter-observer Dice score (SO vs GT) and ML vs SO Dice scores were not statistically significant for either aorta or pulmonary arteries (p = 0.741, p = 0.061). The ML vs GT MAPEs for pressure and velocity in the aorta were 10.1% (8.5-15.7%) and 4.1% (3.1-6.9%), respectively, and for the pulmonary arteries 14.6% (11.5-23.2%) and 6.3% (4.3-7.9%), respectively. Inter-observer (SO vs GT) and ML vs SO pressure and velocity MAPEs were of a similar magnitude to ML vs GT (p > 0.2). CONCLUSIONS: ML can successfully segment the great vessels for CFD, with errors similar to inter-observer variability. This fast, automatic method reduces the time and effort needed for CFD analysis, making it more attractive for routine clinical use.
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Hemodinámica , Imagen por Resonancia Magnética , Humanos , Estudios Retrospectivos , Valor Predictivo de las Pruebas , Aorta/diagnóstico por imagenRESUMEN
BACKGROUND: Cardiac screening of elite athletes including a 12lead electrocardiogram (ECG) is recommended by numerous international bodies. Current athlete ECG interpretation guidelines recommend the Bazett method to correct the QT interval (QTc). OBJECTIVE: This study sought to investigate normative QTc changes by age using athlete screening ECGs and different QT correction methods in a population of elite cricketers. METHODS: Initial cardiac screening ECGs from an existing database of elite Australian cricketers aged 14-35 years were examined. Average QT interval, QTcB (corrected QT-Bazett), QTcF (Fridericia), QTcH (Hodges), and heart rate (HR) were analyzed by age and sex. RESULTS: A total of 1310 athletes (66% male, 34% female) were included with mean age 19.1 years and mean heart rate 66.9 bpm (range 38-121 bpm). With increasing age, HR decreased and absolute QT increased. The pattern of QTc change with age differed depending on the method of correction: Bazett correction (QTcB) demonstrated a "dish-shaped" or broad U-shaped appearance; while Fridericia and Hodges corrections showed a linear increase in QTc from young to older age. The Bazett method had a stronger correlation of HR with QTc (R2 = 0.32) than either Fridericia (R2 = 0.0007) or Hodges (R2 = 0.009) methods. CONCLUSIONS: The Bazett method is not the most accurate QT correction in athletes, especially during adolescence. In elite cricketers, QTcB revealed a drop in QTc from adolescence to early adulthood due to mis-correction of the QT interval. The Fridericia method has the smoothest correction of HR and least QT variation by age and may be preferred for athlete screening.
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Electrocardiografía , Cardiopatías , Femenino , Masculino , Humanos , Adulto , Adulto Joven , Frecuencia Cardíaca , AustraliaRESUMEN
The Pfizer COVID-19 vaccine is associated with increased myocarditis incidence. Constantly evolving evidence regarding incidence and case fatality of COVID-19 and myocarditis related to infection or vaccination, creates challenges for risk-benefit analysis of vaccination. Challenges are complicated further by emerging evidence of waning vaccine effectiveness, and variable effectiveness against variants. Here, we build on previous work on the COVID-19 Risk Calculator (CoRiCal) by integrating Australian and international data to inform a Bayesian network that calculates probabilities of outcomes for the delta variant under different scenarios of Pfizer COVID-19 vaccine coverage, age groups (≥12 years), sex, community transmission intensity and vaccine effectiveness. The model estimates that in a population where 5% were unvaccinated, 5% had one dose, 60% had two doses and 30% had three doses, there was a substantially greater probability of developing (239-5847 times) and dying (1430-384,684 times) from COVID-19-related than vaccine-associated myocarditis (depending on age and sex). For one million people with this vaccine coverage, where transmission intensity was equivalent to 10% chance of infection over 2 months, 68,813 symptomatic COVID-19 cases and 981 deaths would be prevented, with 42 and 16 expected cases of vaccine-associated myocarditis in males and females, respectively. These results justify vaccination in all age groups as vaccine-associated myocarditis is generally mild in the young, and there is unequivocal evidence for reduced mortality from COVID-19 in older individuals. The model may be updated to include emerging best evidence, data pertinent to different countries or vaccines and other outcomes such as long COVID.
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AIMS: To identify biomarkers of cardiomyopathy in patients with type 2 diabetes mellitus (T2DM) using cardiovascular magnetic resonance (CMR) and to identify associations between functional status, metabolomic profile and myocardial fibrosis. METHODS: In this prospective case control study, patients (n = 49) with T2DM without significant coronary artery disease, and matched controls (n = 18) underwent CMR, cardiopulmonary exercise testing, and plasma metabolomic analyses. RESULTS: Patients with T2DM (n = 49, median [interquartile range] age 61 [56-63] years, 61% male, diabetes duration 11 [7-20] years), historical HbA1c 7.6% (60 mmol/mol) (6.9-8.6) and matched controls (n = 18) were examined. Study patients had increased myocardial extracellular volume (ECV) (26.9 [23.8-30.0] vs 23.4 [22.4-25.5) %, p < 0.001). Increased ECV was associated with male sex (p = 0.04), time with T2DM (p = 0.02), reduced peak VO2 (R2 = 0.48, p = 0.01), increased circulating choline (p = 0.002) and cysteamine (p = 0.002) both of which were also associated with reduced peak VO2 (p < 0.025 and 0.014 respectively). CONCLUSIONS: Patients with well-controlled T2DM without significant coronary disease exhibit focal and diffuse myocardial fibrosis and diffuse myocardial fibrosis is associated with reduced exercise tolerance and metabolites. Plasma metabolites may provide mechanistic insights into diffuse myocardial fibrosis, and cardiopulmonary fitness.
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Cardiomiopatías , Enfermedad de la Arteria Coronaria , Diabetes Mellitus Tipo 2 , Cardiomiopatías/complicaciones , Cardiomiopatías/diagnóstico por imagen , Estudios de Casos y Controles , Enfermedad de la Arteria Coronaria/complicaciones , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/patología , Femenino , Fibrosis , Humanos , Imagen por Resonancia Cinemagnética , Masculino , Persona de Mediana Edad , Miocardio/patología , Valor Predictivo de las Pruebas , Función Ventricular IzquierdaRESUMEN
The coronavirus pandemic has given everyone in society an education on the harms of spread of respiratory illness. Young healthy athletes are far less likely to suffer severe adverse consequences of viral illnesses than the elderly and frail, but they are not completely immune. Chronic fatigue (overtraining) is an uncommon outcome and myocarditis a rare one, but they both warrant due consideration. It is, therefore, a sensible individual strategy to 'stay home when sick' if only for these risks. Traditionally though, athletes have tended to push through (train and play when ill) because of competing concerns, such as key events/matches and 'not wanting to let teammates down'. Data from both low COVID-19 and high COVID-19 countries show that the number of cardiovascular deaths in a society correlates with the number of respiratory deaths at the same time, further linking respiratory viruses to cardiovascular deaths. We are now more aware of public health obligations to prevent the spread of respiratory illnesses, in particular to protect the more vulnerable members the community. This hopefully will correspond with a change in the culture of sport to one where it is considered 'the right thing to do', to 'stay home when sick'.
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Atherosclerosis, which is a primary cause of cardiovascular disease (CVD) deaths around the world, is a chronic inflammatory disease that is characterised by the accumulation of lipid plaques in the arterial wall, triggering inflammation that is regulated by cytokines/chemokines that mediate innate and adaptive immunity. This review focuses on IL-32, -34 and -37 in the stable vs. unstable plaques from atherosclerotic patients. Dysregulation of the novel cytokines IL-32, -34 and -37 has been discovered in atherosclerotic plaques. IL-32 and -34 are pro-atherogenic and associated with an unstable plaque phenotype; whereas IL-37 is anti-atherogenic and maintains plaque stability. It is speculated that these cytokines may contribute to the explanation for the increased occurrence of atherosclerotic plaque rupture seen in patients with COVID-19 infection. Understanding the roles of these cytokines in atherogenesis may provide future therapeutic perspectives, both in the management of unstable plaque and acute coronary syndrome, and may contribute to our understanding of the COVID-19 cytokine storm.
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BACKGROUND: Post-mortem cardiac magnetic resonance (CMR) is a non-invasive alternative to conventional autopsy. At present, diagnostic guidelines for cardiovascular conditions such as hypertrophic cardiomyopathy have not been established. We correlated post-mortem CMR images to definite conventional autopsy findings and hypothesed that elevated T2-weighted signal intensity and RV to LV area ratios can identify myocardial infarction and pulmonary emboli respectively. METHODS: For this unblinded pilot sub-study, we selected cases from the original blinded study that compared post-mortem imaging to conventional autopsy in patients referred for coronial investigation between October 2014 to November 2016. Three groups of scans were selected based on the cause of death identified by conventional autopsy: non-cardiovascular causes of death with no structural cardiac abnormality i.e., control cases, acute/subacute myocardial infarction and pulmonary emboli. Left ventricular (LV) wall thickness, LV myocardial signal intensity and ventricular cavity areas were measured. RESULTS: Fifty-six scans were selected [39 (69.6%) males]: 37 (66.1%) controls, eight (14.3%) acute/subacute myocardial infarction and eleven (19.6%) pulmonary emboli. The median age was 61 years [Interquartile range (IQR) 50-73] and the median time from death to imaging and autopsy was 2 days (IQR 2-3) and 3 days (IQR 3-4). The septal and lateral walls were thicker {15 mm [13-17] and 15 mm [14-18]} on post-mortem CMR than published ante-mortem measurements. Areas of acute/subacute myocardial infarction had significantly higher T2-weighted signal intensity (normalised to skeletal muscle) compared to normal myocardium in those who died from other causes {2.5 [2.3-3.0.] vs. 1.9 [1.8-2.3]; P<0.001}. In cases with pulmonary emboli, there was definite RV enlargement with a larger indexed RV to LV area ratio compared to those who died from other causes {2.9 [2.5-3.0] vs. 1.8 [1.5-2.0]; P<0.001}. CONCLUSIONS: We present potential post-mortem CMR parameters to identify important cardiovascular abnormalities that may be beneficial when conventional autopsy cannot be performed. In patients without cardiovascular disease, LV wall thickness was found to be unreliable in diagnosing hypertrophic cardiomyopathy without histological and/or genetic testing. Elevated T2 signal intensity and RV to LV area ratios may be useful markers for acute/subacute myocardial infarction and pulmonary emboli. Larger studies will be necessary to define cut-offs.
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Athletes sometimes experience transient arrhythmias during intense exercise, which may be difficult to capture with traditional Holter monitors. New and highly portable technology, such as smartphone electrocardiogram (ECG) devices, may be useful in documenting and contribute to diagnosis of exercise-induced arrhythmias. There are little data available regarding the new Kardia 6 lead device (6L) and no data regarding its use in athletic populations. In this short communication, we present pilot data from 30 healthy athletes who underwent a 12lead ECG and subsequent 6L reading. Our pilot data show relatively high levels of agreement for QTc and PR interval and QRS duration, with the 6L readings slightly but significantly shorter on average.
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Electrocardiografía , Teléfono Inteligente , Arritmias Cardíacas/diagnóstico , Atletas , HumanosRESUMEN
BACKGROUND: Left ventricular non-compaction has been associated with heart failure, arrhythmia, thromboembolism and sudden death. The prevalence of non-compaction in patients with coarctation of the aorta and its clinical significance remains unknown, although obstructive left heart disease is common in patients with non-compaction. We sought to evaluate the prevalence of left ventricular non-compaction in patients with repaired aortic coarctation as well as its effect on left ventricular size and systolic function. METHODS AND RESULTS: In total, 268 patients (Mean age 26 (inter-quartile range 21-37) years, 63% male) undergoing cardiac magnetic resonance imaging for clinical follow-up were included from three tertiary centres for adult congenital heart disease. Clinical data was obtained from medical records and correlated with ventricular volumes and function. Left ventricular non-compaction was defined as a diastolic non-compacted:compacted dimension ratio >2.3 in the worst affected segment on a long-axis view. Left ventricular non-compaction was present in 8.2% of patients with repaired coarctation. Left ventricular end-diastolic volumes and stroke volumes were significantly higher in patients with non-compaction compared to those without. There were no significant differences in ventricular mass or ejection fraction in these two groups. CONCLUSIONS: Left ventricular non-compaction is relatively common in patients with repaired coarctation of the aorta and correlates with increased left ventricular end-diastolic volumes.
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Coartación Aórtica , Cardiopatías Congénitas , Adulto , Coartación Aórtica/complicaciones , Coartación Aórtica/diagnóstico por imagen , Coartación Aórtica/epidemiología , Femenino , Cardiopatías Congénitas/complicaciones , Cardiopatías Congénitas/epidemiología , Humanos , Masculino , Prevalencia , Volumen Sistólico , Función Ventricular Izquierda , Adulto JovenRESUMEN
Conventional autopsy is the gold standard for identifying unexplained death but due to declines in referrals, there is an emerging role for post-mortem imaging. We evaluated whether post-mortem magnetic resonance (PMMR) and computed tomography (PMCT) are inferior to conventional autopsy. Deceased individuals ≥ 2 years old with unexplained death referred for coronial investigation between October 2014 to December 2016 underwent PMCT and PMMR prior to conventional autopsy. Images were reported separately and then compared to the autopsy findings by independent and blinded investigators. Outcomes included the accuracy of imaging modalities to identify an organ system cause of death and other significant abnormalities. Sixty-nine individuals underwent post-mortem scanning and autopsy (50 males; 73%) with a median age of 61 years (IQR 50-73) and median time from death to imaging of 2 days (IQR 2-3). With autopsy, 48 (70%) had an organ system cause of death and were included in assessing primary outcome while the remaining 21 (30%) were only included in assessing secondary outcome; 12 (17%) had a non-structural cause and 9 (13%) had no identifiable cause. PMMR and PMCT identified the cause of death in 58% (28/48) of cases; 50% (24/48) for PMMR and 35% (17/48) for PMCT. The sensitivity and specificity were 57% and 57% for PMMR and 38% and 73% for PMCT. Both PMMR and PMCT identified 61% (57/94) of other significant abnormalities. Post-mortem imaging is inferior to autopsy but when reported by experienced clinicians, PMMR provides important information for cardiac and neurological deaths while PMCT is beneficial for neurological, traumatic and gastrointestinal deaths.
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Autopsia/métodos , Causas de Muerte , Imagen por Resonancia Magnética , Tomografía Computarizada por Rayos X , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Prospectivos , Sensibilidad y EspecificidadRESUMEN
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.