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Structured Abstract: Introduction: Rates of morbidity and mortality are high in the setting of Fontan physiology and effective medical therapies are not well-established. Clinical trials assessing phosophodiesterase-5-inhibitors, such as sildenafil, have not demonstrated major benefit in patients with a Fontan-type circulation but have only included stable, well-functioning people. Methods: We sought to retrospectively characterize the people followed by the ANZ Fontan Registry prescribed sildenafil >30 days post Fontan-surgery. Results: Of 1867 individuals, 19 (1 %) were prescribed sildenafil and met inclusion criteria; 12 (63 %) were female. Age at commencement was 9 years (IQR 13.5). Reasons for commencement were Fontan failure with elevated Fontan pressure (n = 4), failure without elevated pressure (n = 4), elevated pressure without failure (n = 6), failure symptoms without invasive assessment (n = 3) and pulmonary arterio-venous malformations (n = 2). At baseline hemodynamic study (n = 16) median Fontan pressure was 15.5 mmHg (IQR 3.1) and PVRi was 2.3 WU*m2 (IQR 1.6). Improvement in the clinical indication was noted in 11/19 (58 %). In the subset in whom sildenafil was commenced with PVRi >2 WU*m2 6/7 (86 %) improved clinically. PVRi decreased by 1.8 WU*m2 (IQR 1.0, n = 5, p = 0.03) on treatment in this group, compared with the

Objective: To compare the late outcomes of adults who underwent atrial switch repair for dextro-transposition of the great arteries, based on their risk profile at age 30 years. Methods: We performed a retrospective study of 67 participants who had undergone atrial switch repair. “Low risk” people were defined as those who reached age 30 years or beyond with normal or mildly impaired systemic right ventricular (RV) function with no or mild tricuspid regurgitation (TR). “High risk” people were defined as those who had moderate or severe systemic RV dysfunction, or moderate or severe tricuspid regurgitation by age 30. The primary outcome was transplant-free survival and the secondary outcome was a composite end-point including hospitalisations for heart failure, inotrope requirement, referral for transplantation and transplantation. Results: 52/67 (78%) were classified as “low risk” and 15/67 (22%) were classified as “high risk”. At 45 years, transplant-free survival was 31% for the “high risk” group compared to 87% for “low risk”. All “high risk” people met the composite endpoint at 45 years compared to only 18% of the “low risk” group (hazard ratio 6.3, p = 0.03). Conclusion: Transplant-free survival is markedly reduced in “high risk” atrial switch patients. Risk stratification based on systemic right ventricular function and tricuspid regurgitation at age 30 may predict future health outcomes for atrial switch patients.

People with a Fontan circulation are at risk of neurodevelopmental delay and disability, and cognitive dysfunction, that has significant implications for academic and occupational attainment, psychosocial functioning, and overall quality of life. Interventions for improving these outcomes are lacking. This review article discusses current intervention practices and explores the evidence supporting exercise as a potential intervention for improving cognitive functioning in people living with a Fontan circulation. Proposed pathophysiological mechanisms underpinning these associations are discussed in the context of Fontan physiology and avenues for future research are recommended.

Background Patent foramen ovale (PFO)‐associated platypnea‐orthodeoxia syndrome is characterized by dyspnea and hypoxemia when upright. The pathogenesis is thought to involve an increase in right atrial pressure or change in degree of right to left shunting with upright posture. Methods and Results We sought to characterize patients with platypnea‐orthodeoxia syndrome related to PFO without pulmonary hypertension. We retrospectively reviewed databases at 3 tertiary referral hospitals in New South Wales, Australia from 2000 to 2019. Fourteen patients with a mean age of 69±14 years had a PFO with wide tunnel separation. Mean New York Heart Association Classification was II (±0.9) and 7 inpatients had been confined to bed (from postural symptoms). Baseline oxygen saturations supine were 93%±5% and 84%±6% upright. Two patients had a minor congenital heart defect and 4 had mild parenchymal lung disease with preserved lung function. The mean aortic root diameter was 37±6 mm and distance between aortic root and posterior atrial wall was 16±2 mm. Platypnea‐orthodeoxia syndrome was preceded by surgery in 5 patients and 1 patient had mild pneumonia. Successful closure of the PFO using an Amplatzer device was performed in 11 of 14 patients. Post‐closure, all patients had New York Heart Association Classification I (improvement 1.6±0.9, P

Acute limb ischemia in young adults warrants thorough investigation to determine the underlying cause. Here, we present a case of acute upper limb ischemia in a marathon runner secondary to paradoxical embolism. The patient had associated deep venous thrombosis of the lower limb with multiple pulmonary emboli and patent foramen ovale. This case report emphasizes the under-recognition of intense endurance exercise as a risk factor for venous thromboembolism and highlights the potentially debilitating embolic sequelae of venous thromboembolism in patients with patent foramen ovale. Keywords: Venous thromboembolism, Marathon runner, Paradoxical embolism, Patent foramen ovale

Introduction: It is unknown if the Fontan circulation has an impact on sexual health in men. This study assessed self-reported sexual health and fertility in men with a Fontan circulation.Aims: In this prospective, cross-sectional study, Australian men ≥18 years enrolled in the Fontan Registry of Australia and New Zealand were invited to complete the International Index of Erectile Function (IIEF), alongside questions assessing fertility. These data were compared to historical, age-matched controls.Results: Of 227 eligible men, 54 completed the survey; of those 37 were sexually active and included in the final analysis. Mean age was 28 ± 3 years, age at Fontan was 5 ± 3 years. Fontan type was extra-cardiac conduit in 15 (41%), lateral tunnel in 12 (32%), and atriopulmonary connection (APC) in 10 (27%). Ventricular function was normal in 24 (83%), and all were New York Heart Association Class I (23 patients, 79%) and II (six patients, 21%). Nine participants (24%) had erectile dysfunction (IIEF-EF score ≤25). The severity was mild (IIEF 22–24) in six (16%), mild–moderate (IIEF 17–21) in two (5%), and moderate (IIEF 11–16) in one (3%). Baseline characteristics and current medication usage were similar in those with and without erectile dysfunction. Compared with historical control values, erectile function was not significantly impaired in the Fontan population (p =0.76). Men with a Fontan circulation had decreased levels of sexual desire and overall satisfaction (p < 0.001). There was no correlation between the presence of erectile dysfunction and any assessed parameter. Eleven (30%) of the cohort reported a pregnancy with a prior partner.Conclusion: In our cohort, overall erectile function was comparable between men with a Fontan circulation and historical controls, however sexual desire and overall satisfaction were reduced. There was no correlation between study parameters and the presence of erectile dysfunction. The proportion of the cohort who had a prior pregnancy was congruent with population data.

Background: Patients with cyanotic congenital heart disease (CCHD) may have a low burden of atherosclerosis. Endothelial dysfunction is an early stage of atherosclerosis and endothelial function is previously studied in smaller CCHD groups with different techniques and variable results. We aimed to examine endothelial function and carotid atherosclerosis in a larger group of CCHD patients. Methods: This multicentre study assessed endothelial function in adults with CCHD and controls by measuring the dilatory response of the brachial artery to post-ischemic hyperaemia (endothelium-dependent flow-mediated-vasodilatation (FMD)), and to nitroglycerin (endothelium-independent nitroglycerin-induced dilatation (NID)). Flow was measured at baseline and after ischaemia (reactive hyperaemia). Carotid-intima-media-thickness (CIMT), prevalence of carotid plaque and plaque thickness (cPT-max) were evaluated ultrasonographically. Lipoproteins, inflammatory and vascular markers, including sphingosine-1-phosphate (S1P) were measured. Results: Forty-five patients with CCHD (median age 50 years) and 45 matched controls (median age 52 years) were included. The patients presented with lower reactive hyperaemia (409 ± 114% vs. 611 ± 248%, p

Abstract Background Arterial stiffness is a significant cardiovascular risk factor. Carotid-femoral pulse wave velocity (cfPWV) is the standard for measuring arterial stiffness, but indices such as central augmentation index (cAIx) and carotid artery elasticity (cE[p]) also correlate to arterial stiffness. Early-life determinants of arterial stiffening are not well understood. We assessed the relationship between population-indexed anthropometric and hemodynamic parameters, and arterial stiffness in healthy children. Methods 97 healthy children between 2 to 20 years old were recruited. Z-scores for height, BMI, and brachial systolic (bSBP) and diastolic (bDBP) blood pressure were calculated [1,2]. cfPWV and central arterial waveforms were measured using the Sphygmocor XCEL and CvMS devices (AtCor, Sydney) respectively. Carotid artery maximum and minimum diameters were measured by high-resolution ultrasonography. cfPWV, cE[p], and cAIx were calculated. Results In bivariate analysis, cfPWV was associated with age (b = 0.52, p < 0.01) and bSBP z-score (b = 0.24, p = 0.03). These associations were independent of sex, height z-score, BMI z-score, and bDBP z-score in a multivariable model (R2 = 0.23). cE[p] was significantly associated with age (b = 0.42, p < 0.01), bSBP z-score (b = 0.45, p < 0.01), and height z-score (b = -0.33, p = 0.01), but only bSBP z-score remained statistically significant in the multivariable model (b = 0.45, p < 0.01; R2 = 0.20). cAIx was not associated with anthropometric or hemodynamic z-scores. Conclusion cfPWV is associated with age and bSBP z-score, while cE[p] is associated with bSBP z-score only, suggesting a potentially key association between systolic blood pressure and indices of arterial stiffness independent of age and other parameters of growth during healthy early life.

Background: Central aortic pressure waveforms can be modelled non-invasively in adults using general transfer functions. These techniques have been applied to, but not formally validated in paediatric populations. We recently developed and validated two age-appropriate paediatric transfer functions and sought to determine their effectiveness in children and adolescents. Methods: We recruited 97 healthy children between 2 and 20 years of age in five pre-specified age groups. Central waveforms were estimated by applying two previously developed paediatric transfer functions developed in 8 year and 14 year-old children (8TF, 14TF respectively), and a proprietary adult transfer function (aTF) (Sphygmocor CvMS, AtCor) to radial waveforms measured by tonometry [1]. Estimated central arterial parameters were measured from direct carotid tonometry. Results: 8TF estimates higher cSBP than 14TF, which estimates higher cSBP than aTF across all ages. In contrast, 8TF estimates lower cAIx than 14TF, which estimates lower cAIx than aTF across all ages (Figure 1). 8TF most accurately modelled central arterial waveform features, specifically by cAIx when comparing to carotid tonometry, in early childhood (age groups: 2–6.5 years, 0 ± 14%; 6.6–9.5 years, − 4 ± 19%; 9.6–12.5 years, −6 ± 13%), while 14TF most accurately estimated cAIx in later childhood and adolescence (12.6–15.5 years, −3 ± 11%; 15.6–20 years, 4 ± 13%). Figure 1 Conclusion: Effectiveness of transfer functions for modelling central arterial waveforms in childhood appear to be age-dependent, with evidence of better accuracy when used in populations similar to that in which they were developed. These results support the use of multiple age-appropriate paediatric transfer functions over a generalized paediatric transfer function.

Abstract Background Pulmonary arterial hypertension (PAH) is a leading cause of mortality in systemic sclerosis (SSc). We sought to determine survival, predictors of mortality, and health-related quality of life (HRQoL) related to PAH in a large SSc cohort with PAH. Methods We studied consecutive SSc patients with newly diagnosed (incident) World Health Organization (WHO) Group 1 PAH enrolled in a prospective cohort between 2009 and 2015. Survival methods were used to determine age and sex-adjusted standardised mortality ratio (SMR) and years of life lost (YLL), and to identify predictors of mortality. HRQoL was measured using the Short form 36 (SF-36) instrument. Results Among 132 SSc-PAH patients (112 female (85%); mean age 62 ± 11 years), 60 (45.5%) died, with a median (±IQR) survival time from PAH diagnosis of 4.0 (2.2–6.2) years. Median (±IQR) follow up from study enrolment was 3.8 (1.6–5.8) years. The SMR for patients with SSc-PAH was 5.8 (95% CI 4.3–7.8), with YLL of 15.2 years (95% CI 12.3–18.1). Combination PAH therapy had a survival advantage (p

The Fontan operation is performed as a palliative procedure to improve survival in infants born with a functionally univentricular circulation. The success of the operation is demonstrated by a growing adult Fontan population that exists with this unique physiology. Late follow-up has demonstrated expected and unexpected sequelae, and has shown multisystem effects of this circulation. This review discusses the challenges of managing the late complications in terms of understanding this unique physiology and the innovative therapeutic interventions that are being investigated. The challenge remains to maintain quality of life for adult survivors, as well as extending life expectancy.

Left ventricular non-compaction (LVNC) is a complex clinical condition with no diagnostic gold standard. At present, there is trepidation about the accuracy of the diagnosis, the correlation to clinical outcomes and the long-term medical management. This article reviews the current imaging criteria, the limitations of echocardiography and cardiac magnetic resonance and the consequences of LV hypertrabeculation in athletes.

Objectives: Carotid-femoral pulse wave velocity (cfPWV) is a validated non-invasive measure of aortic stiffness. Risk factors for cfPWV are well described in adulthood, and furthermore cfPWV is associated with incident cardiovascular disease in adults (1). However, risk factors for arterial stiffness in childhood are poorly described (2). Accordingly, we sought to determine the risk factors for cfPWV in childhood and adolescence and hypothesized that cfPWV would be higher amongst those with greater adiposity. Methods: We prospectively recruited 88 healthy children (mean age = 11.0 ± 5.3 years old). Age, weight, height, and blood pressure were measured. cfPWV was assessed using a semi-automated cuff-based device (Sphygmocor XCEL; AtCor Medical, Australia), and body composition using air displacement plethysmography (BOD POD; Cosmed, Italy) (3). Associations with cfPWV were determined by multivariable linear regression, with subsequent mediation analyses to inform likely causal pathways. Results: After adjusting for age and sex, cfPWV was significantly associated with weight, body mass index (BMI), systolic blood pressure, mean blood pressure, heart rate, and lean body mass (LBM), while LBM was significantly associated with height, weight, BMI and fat mass (Table 1). After further adjusting for weight, mean blood pressure and heart rate, LBM remained significantly associated with cfPWV (ß = 0.68; p = 0.007). Mediation analyses indicate that weight mediates the association between age and cfPWV (PM = 76%), and that LBM mediates the relationship between weight and cfPWV (Figure 1). Conclusion: Higher cfPWV in healthy children and adolescents is a function of growth, and this association may be in turn mediated by higher LBM rather than adiposity.

Background: Carotid femoral pulse wave velocity (cfPWV) is directly associated with arterial stiffness in major elastic arteries and predicts future cardiovascular events (1). Little is known of cfPWV as a marker of vascular health in children. Semi-automated cuff-based devices for assessing cfPWV are increasingly popular, although these utilize an algorithm developed and validated in adults (2). Physiological differences between adults and children may thus reduce the accuracy of cuff-based. Methods: We sought to determine the accuracy of a cuff-based cfPWV device in healthy children and determine whether an age-appropriate algorithm increases accuracy. Methods we prospectively recruited 29 healthy children (mean age = 11.5 ± 5.2 years old). cfPWV was measured using a tonometer on the carotid artery and an inflated cuff on the thigh (Sphygmocor XCEL; AtCor Medical, Australia), and using a tonometer on both the carotid artery and femoral artery (SphygmoCor CvMS; AtCor Medical, Australia) as a reference method. We assessed the accuracy of the cuff-based device with its standard algorithm that was developed in adults, and an adjusted algorithm corrected for physiological differences in leg (femoral to thigh cuff) PWV between adult and children (3). Results: Cuff-based device estimates of cfPWV in children had excellent agreement to the reference standard (r = 0.85; Δ = −0.26 ms−1 [SD 0.44]). The adjusted algorithm improved the accuracy of the cuff-based method (r = 0.84; Δ=0.02 ms−1 [SD 0.44]) (Figure 1). Conclusions: Although the cuff-based semi-automatic approach estimates cfPWV with excellent agreement to the reference standard, adjusting the algorithm for known differences in leg PWV improves the accuracy of cuff-based measurement in children.

BackgroundPatients with a Fontan circulation have reduced exercise capacity and respiratory muscle strength. Inspiratory muscle training (IMT) improves exercise capacity and quality of life in adults with heart failure. We assessed whether 6 weeks of a home‐based program of IMT improves inspiratory muscle strength and the ventilatory efficiency of exercise in adolescent patients with a Fontan circulation. Methods and ResultsTwenty‐three adolescent participants (aged 16±2 years) with a Fontan circulation underwent 6 weeks of IMT for 30 minutes daily. Respiratory muscle strength (maximal inspiratory pressure and expiratory pressure), lung function, and exercise capacity (cardiopulmonary exercise testing) were assessed. Fourteen of 23 participants also underwent exercise cardiac magnetic resonance imaging to examine the effects of IMT on cardiac output and systemic and pulmonary blood flow. Six weeks of IMT improved maximal inspiratory pressure by 36±24 cm H2O (61±46%) with no change in maximal expiratory pressure. Ventilatory efficiency of exercise improved after 6 weeks of IMT (from 34.2±7.8 to 32.2±5.6, P=0.04). In those who underwent exercise cardiac magnetic resonance imaging, IMT increased resting cardiac output (from 4.2±1.2 to 4.5±1.0 L/min, P=0.03) and ejection fraction (from 50.1±4.3 to 52.8±6.1%, P=0.03). ConclusionsSix weeks of IMT is associated with improved inspiratory muscle strength, ventilatory efficiency of exercise, and resting cardiac output in young Fontan patients. IMT may be a simple beneficial addition to the current management of Fontan patients, potentially reducing exercise intolerance and long‐term morbidity and mortality.

Sinus venosus atrial septal defects (SV-ASDs) are inter-atrial communications caused by a deficiency of the common wall between the superior or inferior vena cava and the right-sided pulmonary veins. The diagnosis can be challenging, especially in adults with delayed presentation. We present images that illustrate an example of the role of cardiac magnetic resonance imaging (CMRI) in the diagnosis and follow-up of a patient with SV-ASD.

BackgroundData from several previous studies examining heart-rate and cardiovascular risk have hinted at a possible relationship between heart-rate and non-cardiac mortality. We thus systematically examined the predictive value of heart-rate variables on the subsequent risk of death from cancer.MethodsIn the Paris Prospective Study I, 6101 asymptomatic French working men aged 42 to 53 years, free of clinically detectable cardiovascular disease and cancer, underwent a standardized graded exercise test between 1967 and 1972. Resting heart-rate, heart-rate increase during exercise, and decrease during recovery were measured. Change in resting heart-rate over 5 years was also available in 5139 men. Mortality including 758 cancer deaths was assessed over the 25 years of follow-up.FindingsThere were strong, graded and significant relationships between all heart-rate parameters and subsequent cancer deaths. After adjustment for age and tobacco consumption and, compared with the lowest quartile, those with the highest quartile for resting heart-rate had a relative risk of 2.4 for cancer deaths (95% confidence interval: 1.9-2.9, pInterpretationResting and exercise heart rate had consistent, graded and highly significant associations with subsequent cancer mortality in men.