Investigating Fontan Failure Using Mathematical Modeling

Babies born with a single functioning heart ventricle instead of two require a series of surgeries during the first few years of life to redirect their blood flow, resulting in a Fontan circulation. Patients with Fontan circulations have excellent early survival; however, over time, their circulations begin to fail, ultimately resulting in their death. Currently, the only treatment for failing Fontan circulation is a heart transplant; however, many Fontan patients do not survive long enough to receive a donor heart. One of the reasons for this is a lack of understanding of the Fontan failure cascade. Often patients are identified as failing when they do not have enough time left to receive a heart transplant. The objective of this problem is to develop mathematical models of healthy and failing Fontan circulations to i) improve our understanding of Fontan failure from a hemodynamic perspective, and ii) identify physiologically-relevant ranges of parameters.

Lumped parameter models for two-ventricle and healthy and failing extracardiac Fontan circulations

Fontan circulations are surgical strategies to treat infants born with single ventricle physiology. Clinical and mathematical definitions of Fontan failure are lacking, and understanding is needed of parameters indicative of declining physiologies. Our objective is to develop lumped parameter models of two-ventricle and single-ventricle circulations. These models, their mathematical formulations and a proof of existence of periodic solutions are presented. Sensitivity analyses are performed to identify key parameters. Systemic venous and systolic left ventricular compliances and systemic capillary and pulmonary venous resistances are identified as key parameters. Our models serve as a framework to study the differences between two-ventricle and single-ventricle physiologies and healthy and failing Fontan circulations.

Yếu tố tiên lượng của thất bại với tuần hoàn fontan giai đoạn sớm: kết quả sau 8 năm triển khai phẫu thuật fontan

Mục tiêu: nghiên cứu đươc tiến hành nhằm đánh giá kết quả sau phẫu thuật Fontan ở nhóm bệnh nhân tim sinh lý 1 thất, xác định tỉ lệ thất bại với tuần hoàn Fontan ở giai đoạn sớm (early Fontan failure- EFF) và sơ bộ khảo sát các yếu tố nguy cơ trên nhóm bệnh nhân này. Đối tượng và phương pháp: tổng số 145 bệnh nhân đã được tiến hành phẫu thuật Fontan tại Trung tâm tim mạch- Bệnh viện E trong giai đoạn từ tháng 8/2012 đến 12/2019. Kết quả sau mổ được tập trung nghiên cứu và phân tích là tình trạng thất bại với tuần hoàn Fontan ở giai đoạn sớm (EFF). Kết quả: tỷ lệ gặp EFF trong nghiên cứu là 9,66% (14 trường hợp, trong đó có 13 trường hợp tử vong và 1 trường hợp chấm dứt tuần hoàn Fontan). Phân tích đơn biến với các biến số trước mổ chỉ ra một số yếu tố nguy cơ liên quan với EFF bao gồm: thể bệnh giải phẫu thông sàn nhĩ thất thể không cân xứng, bất thường đảo ngược phủ tạng, tình trạng hở van nhĩ thất từ trước mổ, tuần hoàn bàng hệ chủ- phổi lớn phát hiện trên siêu âm, tình trạng tăng áp lực động mạch phổi và tăng sức cản hệ mạch máu phổi trước mổ. Phân tích đơn biến với các yếu tố trong quá trình phẫu thuật có liên quan với EFF bao gồm: tiến hành tạo hình động mạch phổi hoặc sửa van nhĩ thất cùng thời điểm phẫu thuật Fontan, tăng áp lực động mạch phổi, và tình trạng chảy máu trong mổ. Dấu hiệu phù ngay sau mổ cũng có liên quan chặt chẽ với EFF. Tổng số 22 yếu tố nguy cơ được tiến hành khảo sát và phân tích đa biến, xác định được 3 yếu tố độc lập thực sự làm gia tăng nguy cơ EFF sau mổ: tăng áp lực động mạch phổi trước mổ (OR: 1.84, 95%CI: 1.12 – 3.00, p=0.016), tiến hành sửa van nhĩ thất cùng thời điểm phẫu thuật Fontan (OR: 65.85, 95%CI: 1.95–2228.14, p=0.020), và tình trạng tăng áp lực động mạch phổi ngay sau mổ (OR: 1.66, 95%CI: 1.19–2.33, p=0.004). Kết luận: trong nghiên cứu này, tỉ lệ EFF sau phẫu thuật Fontan còn tương đối cao, và là nguyên nhân chính của tỉ lệ tử vong sau mổ. Tình trạng tăng áp lực động mạch phổi trước và ngay sau mổ, cùng với tiến hành sửa van nhĩ thất cùng thời điểm phẫu thuật Fontan là các yếu tố nguy cơ độc lập liên quan đến EFF sau mổ. 1

Path ahead for ‘low risk’ adolescents living with a Fontan circulation

ObjectiveA high risk of morbidity and mortality is well documented in adults with a Fontan circulation. The difference in outcomes between those with and without significant morbidity at the time of transition to adult care has not been well characterised.MethodsWe analysed clinical outcomes in patients enrolled in the Australian and New Zealand Fontan Registry ≥16 years of age. Low risk (LR) Fontan patients were defined as those without history of sustained arrhythmia, thromboembolic event, transplantation, Fontan conversion, protein-losing enteropathy, plastic bronchitis, New York Heart Association class III/IV and/or moderate/severe atrioventricular valve regurgitation or ventricular dysfunction. Increased risk (IR) patients had one or more risk factor.ResultsInclusion criteria were met in 822 patients; mean age 26±8 years, median follow-up from age 16 was 9 years, 203 had atriopulmonary connection (APC) and 619 had total cavopulmonary connection (TCPC). Survival at 30 years was higher in the LR versus IR; 94% versus 82% (p=0.005), 89% versus 77% (p=0.07) for APC and 96% versus 89% (p=0.05) for TCPC. LR patients experienced less Fontan failure (HR 0.34, 95% CI 0.23 to 0.49, p<0.001) and ventricular dysfunction (HR 0.46, 95% CI 0.29 to 0.71, p=0.001) compared with IR patients. For LR TCPC patients, modelled survival projections at 60 years were 49%–67%.ConclusionsClinical outcomes for adolescents LR at transition to adult care are markedly superior to those who have established risk factors for Fontan failure, which is an important consideration when formulating individualised long-term risk estimates and counselling patients.

Abstract 16744: MR Lymphatic Burden in Fontan Correlates With Outcomes

Introduction: The importance of the lymphatic circulation in Fontan physiology is incompletely understood and may have implications in Fontan ‘failure’. Non-invasive imaging of the lymphatic system with heavily T2-weighted MRI sequences could be a useful tool for patient surveillance and prognostication. We sought to quantify lymphatic burden in Fontan patients and correlate with clinical status. Methods: Consecutive pediatric Fontan patients, <18 years-old with clinical cardiac MRI that had routine acquisition of lymphatic 3D T2 FSE imaging performed from May 2017 to Oct 2019 were included. ‘Lymphatic burden’ was quantified by thresholding-based segmentation of the 3D T2 FSE maximum intensity projection image (fig), generating a surrogate measurement of lymphatic volume, and was performed by 2 independent readers blinded to patient status. Spearman correlation and Mann-Whitney tests were used. Results: There were 48 patients (27 males) with median age at MRI of 12.9 (9.4-14.7) years, age at Fontan of 3.3 (2.9-3.8) years, and time from Fontan at MRI of 9.2 (5.9-10.4) years. Inter-rater agreement for lymphatic burden was excellent (ICC 0.96 [0.94-0.98]). Greater lymphatic burden correlated with hospital length of stay and duration of chest tube drainage post-Fontan (r =0.423, p=0.003 and r=0.419, p=0.003). Median lymphatic burden was greater in patients that had chylous effusions post-Fontan (286 (157-492) ml vs 123 (60-271) ml, p=0.011) and in patients with composite adverse outcome (n=12) defined by heart failure (n=3), transplant assessment (n=2), recurrent effusions (n=8), Fontan thrombus (n=2), and/or PLE (n=6) post-Fontan; (458 (266-2016) ml vs 130 (272-256) ml, p=0.005). Pre-Fontan mean PA pressure and time from Fontan did not correlate with lymphatic burden (r=0.062, p=0.676 and r=0.139, p= 0.343). Conclusion: Quantification of MR lymphatic burden is a reliable tool to assess lymphatic status post-Fontan and is associated with clinical outcomes.

Abstract 13382: Increased Adiposity is Associated With Risk of Adverse Clinical Events in Fontan Patients

Introduction: Increased adiposity and reduced lean mass are prevalent in Fontan patients and could be impactful because of the reliance on the peripheral muscle pump and the importance of favourable pulmonary physiology in univentricular physiology. The current study aimed to determine the impact of body fat and lean mass on the risk of adverse outcomes in Fontan patients. Methods: Patients with dual-energy X-ray absorptiometry (DXA) scans from the Australian and New Zealand Fontan Registry were included; they had been consecutively recruited for 2 previous cohort studies. Regression analysis was used to characterize the association between body composition and the composite endpoint of Fontan failure (which included death, transplantation, New York Heart Association (NYHA) functional class III/IV, protein-losing enteropathy, and plastic bronchitis) and development of moderate or worse ventricular dysfunction. Results: 131 DXA scans were analyzed, with mean follow-up of 2.5 (SD 2.2) years after DXA. Mean body fat percentage (%BF) was 29% (SD 10) with 48% having increased adiposity compared with local reference data. Mean appendicular lean mass index (ALMI) z-score was -1.5 (SD 1.1); one third of patients had skeletal muscle deficiency (defined as ALMI z-score between -1 and -2) and another third had Fontan-associated myopenia (defined as ALMI z-score &lt -2). Nine patients reached the composite endpoint during the follow-up period. Age and %BF were predictors of the endpoint in univariable regression (age: HR 1.09 per year, 95% CI 1.02-1.17, p = 0.01; %BF: HR 1.08, 95% CI 1.01-1.17, p = 0.03). On multivariable regression, %BF remained a significant predictor with every 1% increase conferring an 9% increased risk (HR 1.09, 95% CI 1.00-1.19; p = 0.045). ALMI was not a predictor of the endpoint (HR 1.40, 95% CI 0.71-2.76, p = 0.33). However, all patients who experienced a Fontan failure event (n=4) concurrently had increased adiposity and skeletal muscle deficiency. Conclusions: Increased adiposity is associated with increased risk for adverse clinical outcomes. Appropriate lifestyle interventions to optimise body composition should be an important aspect of routine care in this population.

Evaluation of Fontan failure by classifying the severity of Fontan-associated liver disease: a single-centre cross-sectional study

OBJECTIVES Fontan-associated liver disease (FALD) is a hallmark of the failing Fontan circulation, but no general classification of FALD severity exists. In this study, we propose a scoring system to grade the severity of FALD and analyse its applicability for evaluation of Fontan failure. METHODS From 2017 to 2019, a total of 129 successive Fontan patients received a comprehensive hepatic assessment. The FALD score was based on results from laboratory testing, hepatic ultrasound and transient elastography by assigning scoring points for each abnormality detected. FALD severity was graded mild, moderate and severe. Haemodynamic assessment was performed using echocardiography, cardiopulmonary exercise testing and catheterization. RESULTS FALD was graded absent/ mild, moderate and severe in 53, 26 and 50 patients, respectively. Cardiopulmonary capacity was significantly impaired in patients with severe FALD compared to patients with absent/mild FALD (P = 0.001). The FALD score significantly correlated with pulmonary artery pressure (P = 0.001), end-diastolic ventricular pressure (P &lt; 0.001), hepatic venous pressure (P = 0.004) and wedged hepatic venous pressure (P = 0.009). Fontan failure was present in 21 patients. FALD was graded moderate in 2 and severe in 19 of these patients. The FALD score accurately discriminated patients with and without Fontan failure (sensitivity 90.5%, specificity 71.3%). CONCLUSIONS The FALD score significantly correlates with impaired Fontan haemodynamics. A cut-off value ≥6.0 has a high diagnostic accuracy in detecting Fontan failure. Clinical trial registry DRKS (GCTR, German clinical trial registry) Clinical trial registration number DRKS00015039