Introduction A decreased peripheral oxygen saturation (SpO2) is common in Fontan patients. We aimed to determine whether these patients experience increased nocturnal desaturation (ΔSpO2), and to which extent this may impact sleep quality and exercise performance, compared to healthy controls. Methods 16 adult Fontan patients and 16 healthy, individually matched controls completed questionnaires on quality of life, sleep quality, and daytime sleepiness, performed measurements of lung function and diffusion capacity (DLCO), and cycled in a cardiopulmonary exercise test to volitional exhaustion. Sleep quality was assessed with a wrist-worn actigraph and ΔSpO2 was measured with a pulse oximeter during six nights. Results Fontan patients experienced a larger ΔSpO2 (-3.4±0.8%-points, n=14) compared to their controls (-2.5±0.6%-points, n=14; p=0.001). In patients, ΔSpO2 correlated with baseline SpO2, DLCO, and exercise performance. Fontan patients had a longer sleep onset latency (22.8±9.6 vs. 10.8±6.0 min, p<0.001) and lower self-perceived physical functioning (91±7 vs. 100±0 points; p < 0.001), but similar subjective sleep quality (4.2±1.5 vs. 3.4±1.4 points, p=0.121) and daytime sleepiness (6.1±4.3 vs. 6.3±2.8 points, p=0.884) compared to controls. In patients, daytime sleepiness correlated with the total number of ΔSpO2 events (r=0.74, p=0.003). Conclusion Indices of nocturnal desaturation were related to daytime sleepiness and reduced exercise performance and may therefore be a contributing factor to exercise limitation in adult Fontan patients. Alleviation of nocturnal desaturation may thus be a promising target to improve daytime performance in adult Fontan patients.

Complex congenital heart disease (CHD) is associated with reduced brain volumes, but little is known about the brain developmental trajectory in CHD beyond childhood, which is a critical period for brain maturation. This study reports alterations in brain volumes from a large cross-sectional dataset of patients with CHD and controls, with an age range from childhood to young adulthood. Patients and controls underwent 3 T cerebral MRI and overlapping cognitive assessments. Images were processed using Freesurfer 5.3. The dataset comprised 311 participants, 128 CHD and 183 controls aged between 9 and 32 years (male: 52.1%). Associations between the total brain and grey matter, white matter, and cerebrospinal fluid (CSF) volumes and age, sex, group (CHD vs. controls) and maternal education were analysed using linear mixed models. Global and total grey/white matter volumes were smaller in patients with CHD compared to controls (p < 0.001), whereas CSF volumes did not differ significantly between groups (p = 0.23). No significant interaction between the group, sex and age was found. Larger global brain volume was associated with higher maternal education (p < 0.001) and higher IQ (p < 0.001). Consistent lower brain volume in CHD than in controls throughout childhood and young adulthood suggests that there is no convergence towards healthy peers in CHD brain volumes over time. Functional correlates of smaller brain volumes underscore the importance of longitudinal studies in better understanding the evolution and determinants of impaired brain development in CHD populations.

Background In patients with dextro-transposition of the great arteries, cardiovascular interventions and complications are common after the arterial switch operation (ASO). While complex anatomy—typically defined by ventricular septal defects (VSDs)—is often linked to these outcomes, the independent role of aortic coarctation (CoA) remains unclear. Methods We analysed 502 adults from the EPOCH (European collaboration for Prospective Outcome research in Congenital Heart disease)-ASO multicentre registry (median age 25.5 years). The primary outcome was time to first right ventricular outflow tract (RVOT)-related intervention. Secondary outcomes included left ventricular outflow tract (LVOT)-related interventions and cardiovascular complications. Associations were assessed using adjusted Cox regression and Andersen-Gill models. Results CoA emerged as the strongest independent predictor of RVOT interventions (HR 2.62), LVOT interventions (HR 10.75) and cardiovascular complications (HR 2.16). In contrast, VSD (complex anatomy) showed weaker or no associations. CoA also predicted higher recurrence rates of both RVOT and LVOT interventions. Conclusions Among adults post-ASO, CoA—not VSD—is the dominant anatomical driver of long-term morbidity. These patients require targeted surgical attention and structured, lifelong follow-up to mitigate future complications. Trial registration number NCT04335448 .

Background Adults with congenital heart disease (CHD) experience earlier and higher cardiovascular morbidity and mortality than the general population. Serious illness conversations (SICs) can help align care with patients’ values and preferences but are underused, partly because clinicians lack guidance on when to initiate them. Objectives This study aimed to develop consensus-based clinical criteria that should prompt SICs in adults with CHD, incorporating perspectives from clinical experts, people with lived experience (PWLE), and advocacy group representatives. Methods In a modified Delphi study, an international panel of 39 health care professionals rated 67 potential SIC trigger criteria over 3 rounds. Consensus was predefined as ≥70% agreement. A second panel of 4 PWLEs and 4 advocacy group representatives rated the Round 1 consensus triggers for appropriateness. Triggers deemed sufficient on their own were labeled as “major,” those requiring at least one additional criterion were labeled as “minor.” Results Forty-one clinical experts were invited, of which 39 agreed to participate. Response rates were 94.9% in Rounds 1 and 2, and 92.3% in Round 3. Fifty of 67 criteria (74.6%) reached consensus in Round 1, and all were judged appropriate by PWLE and advocacy group representatives. Eighteen criteria were classified as major, spanning “patient needs,” “CHD-defect characteristics,” “lifetime events,” “preintervention” triggers, “disease progression,” and the surprise question. Conclusions This international consensus identified 18 major trigger criteria to support timely SIC initiation in adults with CHD. These criteria span diverse clinical scenarios and provide a practical framework for integrating SICs into routine care for adults with CHD.

Background/Objectives: Despite advances in transcatheter therapy, surgery remains the gold standard treatment for sinus venosus defect (SVD). However, data on long-term outcomes following surgical repair remain scarce. This multicenter study evaluates the long-term outcomes of surgically treated SVD patients with comparison to surgically and percutaneously treated secundum atrial septal defect (ASD). Methods: Clinical, surgical, imaging and invasive data were retrospectively reviewed from eight centers in Europe. Results: A total of 209 patients were included, of whom 80 were surgically treated SVD, 57 surgically treated secundum ASD and 72 percutaneously treated secundum ASD. Operation for SVD mainly occurred in adulthood, with a median age of 28.5 years (2-68 years). During follow-up, the observed reoperation rate was higher in the SVD cohort than ASD cohorts (p = 0.033), despite shorter follow-up period in the SVD cohort. Reoperations, in the SVD cohort, occurred at a median of 28 years (1-50 years) after index surgery. The need for pacemaker implantation was similar between groups (p = 0.301). The prevalence of late atrial fibrillation did not differ between groups (p = 0.588). Surgically treated SVD tended to have a higher prevalence of atrial flutter and atrial tachycardia, with a significantly higher rate of electrophysiological studies than percutaneously treated secundum ASD (p = 0.013), similar to surgically treated secundum ASD (p = 0.405). Conclusions: Long-term follow-up of surgically treated SVD is essential to monitor for reintervention and arrhythmic complications.

Patients with a systemic right ventricle (sRV)-including those with transposition of the great arteries (TGA) following atrial switch repair (Mustard or Senning procedures) and congenitally corrected TGA-represent one of the greatest challenges in the management of adults with congenital heart disease (ACHD). The right ventricle is not anatomically designed to sustain systemic pressure over a lifetime. As a result, sRV failure is almost inevitable and follows a progressive, multifactorial process that initiates with maladaptive functional and structural changes. In later stages, arrhythmias, conduction delays, and pacing-induced dyssynchrony emerge, accelerating deterioration. Finally, lifestyle and environmental factors such as inactivity, obesity, or pregnancy may trigger clinical decompensation. Recognizing where a patient lies along this continuum and identifying those at highest risk is essential to anticipate deterioration and implement timely interventions. Despite significant advances in the management of ACHD, important gaps in knowledge and research remain regarding the sRV, particularly in understanding its long-term adaptation, predictors of failure, optimal medical therapy, prevention of dyssynchrony, and timing for transplant. We herewith summarize latest evidences on prognostic determinants, multimodality imaging, heart failure therapy, electrical therapy for heart failure, mechanical circulatory systems, and heart transplant in sRV.

Abstract Aims In patients with a systemic right ventricle (sRV), the sRV is faced with an increased afterload compared to a right ventricle in sub-pulmonary position leading to the development of fibrosis followed by ventricular dysfunction. Cardiac magnetic resonance (CMR) T1 mapping (T1), and its derived parameter like the extracellular volume (ECV), allow quantification of interstitial fibrosis. The SERVE study, a multicentric, placebo-controlled trial evaluated the effect of tadalafil in sRV patients. The aim of this sub-analysis of the SERVE trial was to evaluate a) the relationship of T1 mapping parameters to the clinical composite endpoint of hospitalization for heart failure, clinically relevant arrythmias and all-cause mortality and b) its evolution over time, correlation to CMR functional parameters and the impact of study treatment. Methods and results Patients included in the SERVE trial underwent a 1.5T CMR at baseline, one and three-year follow-up. For each CMR exam, native and post-contrast T1, as well as ECV, were calculated. In addition, late gadolinium enhancement (LGE) imaging was performed. CMR were available for sixty patients. Native sRV T1 and ECV above the 75th percentile, but not LGE, were associated with the clinical composite endpoint. There was no significant change and no influence of Tadalafil treatment on sRV T1 and ECV. Conclusion T1 mapping as a non-invasive biomarker of the degree of myocardial fibrosis predicts outcome in patients with sRV and should be incorporated in risk stratification in these patients. PDE-5 inhibitor tadalafil appears to have no impact on the development of interstitial or macroscopic fibrosis.

OBJECTIVE:We aimed to assess the extent of cardiac-related hospitalisations among adult congenital heart disease (ACHD) patients followed at Swiss regional ACHD centres. BACKGROUND:In Switzerland, adult congenital heart disease patients are followed at specialised ACHD centres. According to the Swiss recommendations for standards of adult congenital heart disease care,ACHD centres are categorised as regional and supraregional centres. In contrast to regional centres, supraregional centres require staffing for congenital cardiac surgery and complex congenital cardiac interventions. METHODS:Adult congenital heart disease patients enrolled in the SACHER registry and followed at one of three regional ACHD centres (University Hospital Basel, St Gallen Cantonal Hospital, Lucerne Cantonal Hospital) from May 2014 to March 2022 were included. Data were abstracted by chart review and included demographics, clinical and surgical history, follow-up duration and cardiac-related hospitalisations during follow-up. RESULTS:In total, 1031 patients (accounting for 22% of patients from the entire SACHER cohort) were included (570 at University Hospital Basel, 231 at St Gallen Cantonal Hospital, 230 at Lucerne Cantonal Hospital). During a median (IQR) follow-up of 3 (1-5) years, there were 237 hospitalisations (100 [42%] emergencies) among 136 (13%) patients. The majority of admissions (157, 66%), occurred at the regional centre. Arrhythmias (49 of 64 admissions, 77%) and heart failure hospitalisations (26 of 34, 76%) were mainly managed locally. The main reasons for referral to supraregional ACHD centres were heart surgery (32/56, 57%) and complex structural percutaneous interventions (pulmonary valve replacement [3/3, 100%] and balloon dilation of aortic coarctation [7/7, 100%]). CONCLUSION:In Switzerland, regional ACHD centres provide an important contribution to the management of the growing cohort of adult congenital heart disease patients. Most hospitalisations were managed locally. This was particularly true for emergencies, arrhythmia and heart failure hospitalisations. The main reasons for referral to supraregional ACHD centres were complex percutaneous interventions.

Introduction and objectives: The role of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in the risk prediction of patients with systemic right ventricles (sRV) is not well defined. The aim of this study was to analyze the prognostic value of NT-proBNP in patients with an sRV. Methods: The prognostic value of NT-proBNP was assessed in 98 patients from the SERVE trial. We used an adjusted Cox proportional hazards model, survival analysis, and c-statistics. The composite primary outcome was the occurrence of clinically relevant arrhythmia, heart failure, or death. Correlations between baseline NT-proBNP values and biventricular volumes and function were assessed by adjusted linear regression models. Results: The median age [interquartile range] at baseline was 39 [32-48] years and 32% were women. The median NT-proBNP was 238 [137-429] ng/L. Baseline NT-proBNP concentrations were significantly higher among the 20 (20%) patients developing the combined primary outcome compared with those who did not (816 [194-1094] vs 205 [122-357]; P=.003). In patients with NT-proBNP concentrations> 75th percentile (> 429 ng/L), we found an exponential increase in the sex- and age-adjusted hazard ratio for the primary outcome. The prognostic value of NT-proBNP was comparable to right ventricular ejection fraction and peak oxygen uptake on exercise testing (c-statistic: 0.71, 0.72, and 0.71, respectively). Conclusions: In patients with sRVs, NT-proBNP concentrations correlate with sRV volumes and function and may serve as a simple tool for predicting adverse outcomes. (c) 2024 Sociedad Espanola de Cardiolog & imath;a. Published by Elsevier Espana, S.L.U. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

The Swiss expert group published revised guidelines on the prevention and antibiotic prophylaxis against infective endocarditis in 2021. In this viewpoint article, the group reports on their experiences two years after implementing the new prevention concept, which included information flyers and antimicrobial prophylaxis cards. Challenges included communicating the concept and indications for antimicrobial prophylaxis to both high-risk patients and providers.

AIMS:Data on diuretic use in pregnancy are limited and inconsistent, and consequently it remains unclear whether they can be used safely. Our study aims to evaluate the perinatal outcomes after in-utero diuretic exposure. METHODS AND RESULTS:The Registry Of Pregnancy And Cardiac disease (ROPAC) is a prospective, global registry of pregnancies in women with heart disease. Outcomes were compared between women who used diuretics during pregnancy versus those who did not. Multivariable regression analysis was used to assess the impact of diuretic use on the occurrence of congenital anomalies and foetal growth. Diuretics were used in 382 (6.7%) of the 5739 ROPAC pregnancies, most often furosemide (86%). Age >35 years (odds ratio [OR] 1.5, 95% confidence interval [CI] 1.2-2.0), other cardiac medication use (OR 5.4, 95% CI 4.2-6.9), signs of heart failure (OR 1.7, 95% CI 1.2-2.2), estimated left ventricular ejection fraction <40% (OR 2.9, 95% CI 2.0-4.2), New York Heart Association class >II (OR 3.4, 95% CI 2.3-5.1), valvular heart disease (OR 6.3, 95% CI 4.7-8.3) and cardiomyopathy (OR 3.9, 95% CI 2.6-5.7) were associated with diuretic use during pregnancy. In multivariable analysis, diuretic use during the first trimester was not significantly associated with foetal or neonatal congenital anomalies (OR 1.3, 95% CI 0.7-2.6), and diuretic use during pregnancy was also not significantly associated with small for gestational age (OR 1.4, 95% CI 1.0-1.9). CONCLUSIONS:Our study does not conclusively establish an association between diuretic use during pregnancy and adverse foetal outcomes. Given these findings, it is essential to assess the risk-benefit ratio on an individual basis to guide clinical decisions.

Objective Residual sequelae after surgical repair of tetralogy of Fallot (rTOF) affect clinical outcome. We investigated the prognostic impact of right ventricular (RV) dyssynchrony in adults with rTOF years after the surgical repair.Methods Patients from the Swiss Adult Congenital HEart disease Registry were included. NT-proBNP levels, echocardiography, exercise testing and MRI data were collected. An offline strain analysis to quantify RV-ventricular and interventricular dyssynchrony was performed. The standard deviation of the time-to-peak shortening (TTP) of six RV segments defined the RV Dyssynchrony Index (RVDI). Maximal difference of TTP between RV and left ventricular segments defined the interventricular shortening delay (IVSD). Predictors of a composite adverse event (arrhythmias, hospitalisation for heart failure and death) were identified by multivariate Cox regression analysis. Their median values were used to create a risk score.Results Out of 285 included patients (mean age 34±14 years), 33 patients (12%) experienced an adverse event during a mean follow-up of 48±21 months. No correlation was found between RVDI, IVSD and clinical events. NT-proBNP, right atrial area and peak heart rate were independent predictors of outcomes. After 4 years-follow-up, no adverse events occurred in patients at low risk (score=0 points), while an adverse event occurred in 62% of patients at high risk (score=3 points, p<0.001).Conclusion In our cohort of adults with rTOF, surrogates of RV dyssynchrony did not correlate with outcomes. A multimodality approach was effective in predicting the risk for adverse events.

Atrial arrhythmias are an important cause of morbidity and mortality in adults with congenital heart disease (ACHD). In acquired heart disease, the left atrial (LA) strain has been shown to predict supraventricular tachyarrhythmias (SVT). This study aimed to investigate whether reduced LA strain is associated with SVT in ACHD patients. This retrospective, single-center cohort study collected baseline clinical and echocardiographic data of 206 ACHD patients (157 left heart defect, 49 right heart defect). Patients with sinus rhythm at baseline and a 5-year follow-up (median age 29, IQR 22–41 years) were included. Diagnosis of sustained SVT was determined from clinical reports during the follow-up period. New or recurrent sustained SVT occurred in 16 patients (7.8

Background The determinants and prognostic value of high‐sensitivity cardiac troponin T (hs‐cTnT) among patients with a systemic right ventricle are largely unknown. Methods and Results Ninety‐eight patients from the randomized controlled SERVE (Effect of Phosphodiesterase‐5 Inhibition With Tadalafil on Systemic Right Ventricular Size and Function) trial were included. The correlation between baseline hs‐cTnT concentrations and biventricular volumes and function quantified by cardiac magnetic resonance or cardiac multirow detector computed tomography was assessed by adjusted linear regression models. The prognostic value of hs‐cTnT was assessed by adjusted Cox proportional hazards models, survival analysis, and concordance statistics. The primary outcome was time to the composite of clinically relevant arrhythmia, hospitalization for heart failure, or all‐cause death. Median age was 39 (interquartile range, 32–48) years, and 32% were women. Median hs‐cTnT concentration was 7 (interquartile range, 4–11) ng/L. Coefficients of determination for the relationship between hs‐cTnT concentrations and right ventricular end‐systolic volume index and right ventricular ejection fraction (RVEF) were +0.368 ( P =0.046) and −0.381 ( P =0.018), respectively. The sex‐ and age‐adjusted hazard ratio for the primary outcome of hs‐cTnT at 2 and 4 times the reference level (5 ng/L) were 2.89 (95% CI, 1.14–7.29) and 4.42 (95% CI, 1.21–16.15), respectively. The prognostic performance quantified by the concordance statistics for age‐ and sex‐adjusted models based on hs‐cTnT, right ventricular ejection fraction, and peak oxygen uptake predicted were comparable: 0.71% (95% CI, 0.61–0.82), 0.72% (95% CI, 0.59–0.84), and 0.71% (95% CI, 0.59–0.83), respectively. Conclusions Hs‐cTnT concentration was significantly correlated with right ventricular ejection fraction and right ventricular end‐systolic volume index in patients with a systemic right ventricle. The prognostic accuracy of hs‐cTnT was comparable to that of right ventricular ejection fraction and peak oxygen uptake predicted. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03049540.

Abstract Introduction It is well known, that patients with a systemic (sub-aortic) right ventricle (sRV) for congenitally-corrected transposition of the great arteries (TGA) or with complete TGA after atrial switch operation are more threatened to develop RV dysfunction, relevant supra- and ventricular tachycardia and have a reduced life expectancy. While the randomized, placebo-controlled, double-blinded, multi-centre SERVE trial to investigate the effect of phosphodiesterase-5 inhibitor tadalafil in sRV patients showed negative results on the primary end-point RV endsystolic volume (RVESV), aim of this sub-analysis was to evaluate RV global longitudinal strain (GLS), a more sensitive measure of RV function, by cardiac magnetic resonance (CMR) feature tracking (FT) over time, for treatment effect and to investigate whether RV GLS predicts clinical outcome in sRV patients. Methods CMR volumetric RV and FT parameters were analysed (blinded for patient and assessment time and treatment) at baseline and compared to follow-up (FU) after 3 years, or after 1 year in case of withdrawal of the study drug. FT was performed using appropriate software. Treatment effect was analysed using ANCOVA with baseline values and FU-time as covariates. Values of > 4th quartile of RV GLS were used as cut-off for Kaplan-Meier analysis on the primary outcome, defined as a composite of all-cause death, clinically relevant arrhythmias and hospitalisation for heart failure. Results CMR exams were available for 78 patients at baseline (40±11 years, 33% females) and for 71 patients at FU. No treatment effect of tadalafil compared to the placebo was discovered for RV GLS (p=0.26), RVESVi (p=0.63) and RV ejection fraction (RVEF, p=0.6). Over a 3 years FU-time, RV GLS mildly increased (p=0.0023, figure 1). During FU, 14 patients experienced a clinical outcome: 1 death, 4 hospitalisations for heart failure, and 12 clinically relevant arrhythmic events. An RV GLS > -13.4% was associated with adverse clinical outcome (p=0.003, figure 2). Conclusion In patients with a systemic RV, treatment with Tadalafil had no effect on CMR-derived RV global longitudinal strain compared to placebo. RV GLS changed significantly over the 3 years FU-time. A RV GLS value of > -13.4% is associated with adverse clinical outcome in these patients.Figure 1Figure 2

Introducción y objetivos: El objetivo de este estudio es analizar el valor pronóstico de la fracción aminoterminal del péptido natriurético cerebral (NT-proBNP) en pacientes con ventrículo derecho sistémico (VDs).Métodos: El valor pronóstico de la NT-proBNP se evaluó en 98 pacientes del ensayo clínico SERVE. Se empleó un modelo de riesgos proporcionales de Cox ajustado, análisis de supervivencia y estadístico c. El objetivo primario compuesto fue la ocurrencia de arritmia clínicamente relevante, insuficiencia cardiaca o muerte. Como objetivos secundarios se evaluaron las correlaciones entre los valores basales de NT-proBNP y los volúmenes y la función biventriculares mediante modelos de regresión lineal ajustados.Resultados: La mediana [intervalo intercuartílico] de edad al inicio fue de 39 [32-48] años y el 32% eran mujeres. La mediana de NT-proBNP fue de 238 [137-429] ng/l. Las cifras basales de NT-proBNP fueron significativamente más altas entre los 20 pacientes (20%) que cumplían el objetivo primario combinado (816 [194-1.094] frente a 205 [122-357] ng/l; p = 0,003). En pacientes con valores de NT-proBNP superiores al percentil 75 (> 429 ng/l), se halló un aumento exponencial en la razón de riesgos ajustada por sexo y edad para el resultado primario. El valor pronóstico del NT-proBNP fue comparable al de la fracción de eyección del ventrículo derecho y al del consumo máximo de oxígeno en la prueba de esfuerzo (estadístico c, 0,71, 0,72 y 0,71 respectivamente).Conclusiones: En pacientes con VDs, los valores de NT-proBNP se correlacionan con los volúmenes y la función ventriculares y pueden ser un medio útil para la estratificación del riesgo.

Introduction Congenital heart defects may require surgical intervention such as the Fontan procedure that connects the systemic venous return to the pulmonary arteries. Although this procedure has increased survival, it results in reduced exercise capacity; which is reduced not only due to cardiovascular factors, but respiratory limitations as well. However, there is a lack of evidence outlining ventilatory limitations during constant-load exercise, which better represents exercise in cardiac rehabilitation programs and non-laboratory based exercise. Therefore, the aim of the present study was to compare responses to constant-load exercise in adult Fontan patients with those of healthy well-matched controls. Methods 14 adult Fontan patients (5F, 27 ± 6yrs) were recruited with 14 healthy matched controls. Participants performed forced vital capacity (FVC), as well as maximal inspiratory and and expiratory pressure assessments (MIP and MEP, respectively). Patients performed an incremental cycling test (ICT) to exhaustion to determine peak work rate. Following a period of recovery, patients performed a constant-load cycling test (CLCT) at 70% of peak ICT work rate until exhaustion. Healthy subjects reproduced the exercise of their matched patient. Cardiorespiratory variables and heart rate (HR) were measured using a metabolic cart and a 12-lead electrocardiogram, respectively. Participants were asked to rate their perception of breathlessness and respiratory exertion via a visual analogue scale every 2 min and at peak exercise. Patients without cardiac pacemakers underwent involuntary assessments of respiratory muscle contractility via phrenic (n = 8) nerve magnetic stimulation before and following exercise to quantify respiratory muscle fatigue. Results Patients showed significantly reduced FVC, MIP and MEP compared to controls (all p < 0.025). Patients’ time-to-exhaustion during the CLCT was 7.1 ± 3.3 min. During CLCT vs. the ICT, patients reached maximal HR, respiratory rate (fR), breathlessness, respiratory exertion, and leg exertion. End-exercise V̇O2 during the CLCT did not reach ICT values, with a mean difference of 1.5 ml/kg/min (p = 0.017). Controls did not reach peak ICT responses during the CLCT. During the CLCT, patients displayed significantly elevated minute ventilation (V̇E; mean difference = 21.5 L/min), fR (mean difference = 13.8 breaths-per-minute), breathlessness (mean difference = 3.4 points), and respiratory exertion (mean difference = 2.3 points), along with significantly decreased ventilatory reserve (V̇E/maximal voluntary ventilation; mean difference = 27.5%; all p < 0.002). Following the CLCT, Fontan patients showed a larger decrease in involuntary respiratory muscle contractility (15 ± 12% vs. 2 ± 11%). Finally, a decreased ventilatory reserve was significantly correlated with decreased MIP (r = 0.723, p = 0.003) and MEP (r = 0.623, p = 0.042). Discussion/Conclusion Fontan patients had a lower-than-expected time-to-exhausiton, in part due to their abnormal ventilatory response. First, the increased pulmonary restriction in the Fontan patients likely led to increased V̇E driven by a high fR during exercise. Second, Fontan patients showed decreased ventilatory reserve - which was significantly associated with respiratory muscle weakness. Third, patients showed significantly increased respiratory muscle fatigue following exercise. Collectively, these factors likely contributed to the increased breathlessness and respiratory exertion in patients, leading to increased exercise limitation. Given this, and the fact that patients reached near maximal physiological responses during the CLCT, it’s possible that patients may benefit more from aerobic training at less than 70% of peak word rate, or from interval-training with significant recovery time.