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Background: In Fontan patients, attrition of ventricular function is well recognized, but early detection of ventricular dysfunction is difficult. The aim of this study is to longitudinally assess ventricular strain in Fontan patients using a new method for cardiac magnetic resonance (CMR) feature tracking, and to investigate the relationship between ventricular strain and cardiac systolic function. Methods and results: In this prospective, standardized follow-up study in 51 Fontan patients, age ≥ 10 years, CMR and concomitant clinical assessment was done at the start of the study and after 2 years. CMR feature tracking was done combining the dominant and hypoplastic ventricles. Global longitudinal strain (GLS) (−17.3% versus −15.9%, P = 0.041) and global circumferential strain (GCS) (−17.7 versus −16.1, P = 0.047) decreased over 2 years' time. Ejection fraction (EF) (57%), cardiac index (CI) (2.7 l/min/m 2) and NYHA functional class (97% in class I/II) were preserved. The strain values of the combined dominant and hypoplastic ventricles were significantly worse compared to those of the dominant ventricle only (GLS −16.8 (−19.5 to −14.0) versus −18.8 (−21.3 to −15.3) respectively, P = 0.001, GCS −18.3 (−22.1 to −14.8) versus −22.5 (−26.3 to −19.4) respectively, P b 0.001). Conclusions: This study showed a decrease in cardiac strain over 2 years in Fontan patients without clinical signs of Fontan failure, where EF, CI and clinical status were still preserved. Cardiac strain might be a sensitive early indicator of systolic ventricular decline. Furthermore, combined strain of the hypoplastic and dominant ventricles seems a more accurate representation of cardiac strain in functionally univentricular hearts.

ObjectiveIn the Fontan circulation, non-pulsatile pulmonary blood flow is suggested to negatively affect pulmonary artery growth. The pulmonary vasculature is regarded a key determinant of outcome after Fontan completion. We hypothesised that in Fontan patients pulmonary artery size correlates with follow-up and functional clinical status.MethodsThis is a single-centre, cross-sectional cohort study. Thirty-nine paediatric and adult Fontan patients with a concomitant cardiac magnetic resonance (CMR) scan and a cardiopulmonary exercise test between 2012 and 2013 were included. CMR-derived left and right pulmonary artery cross-sectional areas were expressed as Nakata index. Functional status was defined as peak oxygen consumption (pVO2) indexed for weight, as percentage of predicted (pred) and as New York Heart Association Functional Class (NYHA-FC).ResultsAge at CMR was 18±7.2 years. Time since Fontan completion was 11.9±7.4 years. Nakata index was lower versus the reference values (238.6±78.5 vs 330±30 mm2/m2, p<0.001). Nakata index correlated negatively with age at CMR (r=−0.393, p=0.013) and time since Fontan completion (r=−0.341, p=0.034). pVO2 was 27.9±8.9 mL/min/kg and pVO2pred was 58.1%±14.1%. Nakata index correlated positively with pVO2 (r=0.468, p=0.003) and pVO2pred (r=0.353, p=0.028). Nakata index correlated negatively with NYHA-FC (r=−0.450, p=0.004). Nakata index was an independent predictor (β=0.359, p=0.007) for pVO2 (adjusted R2=0.442, with maximum heart rate and oxygen pulse at peak exercise).ConclusionsPulmonary artery size expressed as Nakata index is a novel independent predictor for functional clinical status. Nakata index negatively correlated with follow-up duration, suggesting that chronic abnormal non-pulsatile pulmonary blood flow plays a role in lagging pulmonary arterial growth in the Fontan circulation.

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Background We investigated serial serum levels of GDF‐15 (growth differentiation factor 15) in Fontan patients and their relation to outcome. Methods and Results In this single‐center prospective study of consecutive Fontan patients, serial serum GDF ‐15 measurement and clinical assessment was done at baseline (n=81) and after 2 years (n=51). The association between GDF ‐15 and the combined end point of all‐cause mortality, heart transplant listing, and Fontan‐related hospitalization was investigated. Median age at baseline was 21 years (interquartile range: 15–28 years). Median GDF ‐15 serum levels at baseline were 552 pg/mL (interquartile range: 453–729 pg/mL). GDF ‐15 serum levels correlated positively with age, age at Fontan initiation, New York Heart Association class, and serum levels of NT ‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) and ɣGT (γ‐glutamyltransferase) and negatively with exercise capacity. During a median follow‐up of 4.8 years (interquartile range: 3.3–5.5 years), the combined end point occurred in 30 patients (37%). Multivariate Cox regression showed that patients with the highest baseline GDF ‐15 (n=20, defined as the upper quartile) had a higher risk of hospitalization or death than the lowest 3 quartiles (hazard ratio [HR], 2.76; 95% CI , 1.27–6.00; P =0.011). After 2 years of follow‐up, patients in whom serum level of GDF ‐15 increased to >70 pg/mL (n=13) had a higher risk of hospitalization or death than the lowest 3 quartiles (HR, 2.69; 95% CI , 1.03–6.99; P =0.043). Conclusions In Fontan patients, elevated serum levels of GDF ‐15 are associated with worse functional status and predict Fontan‐related events. Furthermore, serial measurements showed that an increase in GDF ‐15 serum level was associated with increased risk for adverse outcome.

With great interest we read the recent article by Wang et al. in Pulmonary Circulation presenting a meta-analysis on the efficacy and safety of pulmonary vasodilator therapy in patients with a Fontan circulation. 1 We commend the authors with this thorough attempt to provide an overview of the available evidence on this important and controversial topic. The authors report that they have performed a metaanalysis of randomized controlled trials (RCTs) and conclude that pulmonary vasodilator therapy, although not reducing mortality, improves peak oxygen consumption (pVO 2), hemodynamics, and 6-min walking distance (6MWD) and reduces NYHA functional class statistically significantly based on nine studies. After thorough assessment of the manuscript and considering the increased interest for the use of pulmonary vasodilator therapy in Fontan patients, we feel the necessity to express our concerns regarding the claims and conclusions drawn by the authors. Meta-analyses can be a valuable tool to assess systematically available information from different studies in order to derive conclusions from the total body of research. However, it cannot provide evidence that is not there. The current meta-analysis includes extremely heterogeneous data from a limited number of studies with significant clinical and methodological diversity. When substantial heterogeneity exists, pooling data from multiple trials and presenting a single summary estimate can be misleading and should be avoided. 2 There are several important points to take into consideration when interpreting this meta-analysis. First, concerning inclusion criteria; two of the included studies are not RCTs (one retrospective design and one prospective design with a historical cohort control group) and thus in fact do not fulfill the authors' inclusion criteria of RCT-only studies. 3,4 Without these two studies there is only one RCT reporting on mean pulmonary artery pressure (mPAP) 5 and only RCT data from one medical center on mortality, 5,6 making a metaanalysis on hemodynamics and mortality a futile attempt.

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