Integrated Clinical and Magnetic Resonance Imaging Assessments Late After Fontan Operation.

BACKGROUND: Several clinical and cardiac magnetic resonance (CMR)-derived parameters have been shown to be associated with death or heart transplant late after the Fontan operation. OBJECTIVES: The objective of this study was to identify the relative importance and interactions of clinical and CMR-based parameters for risk stratification after the Fontan operation. METHODS: Fontan patients were retrospectively reviewed. Clinical and CMR parameters were analyzed using univariable Cox regression. The primary endpoint was time to death or (listing for) heart transplant. To identify the patients at highest risk for the endpoint, classification and regression tree survival analysis was performed, including all significant variables from Cox regression. RESULTS: The cohort consisted of 416 patients (62% male) with a median age of 16 years (25th, 75th percentiles: 11, 23 years). Over a median follow-up of 5.4 years (25th, 75th percentiles: 2.4, 10.0 years) after CMR, 57 patients (14%) reached the endpoint (46 deaths, 7 heart transplants, 4 heart transplant listings). Lower total indexed end-diastolic volume (EDVi) was the strongest predictor of transplant-free survival. Among patients with dilated ventricles (EDVi ≥156 ml/BSA1.3), worse global circumferential strain (GCS) was the next most important predictor (73% vs. 44%). In patients with smaller ventricles (EDVi <156 ml/BSA1.3), New York Heart Association functional class ≥II was the next most important predictor (30% vs. 4%). CONCLUSIONS: In this cohort of patients late after Fontan operation, increased ventricular dilation was the strongest independent predictor of death or transplant (listing). Patients with both ventricular dilation and worse GCS were at highest risk. These data highlight the value of integrating CMR and clinical parameters for risk stratification in this population.

GDF-15 (Growth Differentiation Factor 15) Is Associated With Hospitalization and Mortality in Patients With a Fontan Circulation.

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 É£GT (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.

Serial cardiovascular magnetic resonance feature tracking indicates early worsening of cardiac function in Fontan patients.

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/m2) 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 < 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.

Pulmonary artery size is associated with functional clinical status in the Fontan circulation.

OBJECTIVE: In 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. METHODS: This 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). RESULTS: Age 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 (ß=0.359, p=0.007) for pVO2 (adjusted R2=0.442, with maximum heart rate and oxygen pulse at peak exercise). CONCLUSIONS: Pulmonary 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.

CMR feature tracking left ventricular strain-rate predicts ventricular tachyarrhythmia, but not deterioration of ventricular function in patients with repaired tetralogy of Fallot.

BACKGROUND: Myocardial strain has been shown to predict outcome in various cardiovascular diseases, including congenital heart diseases. The aim of this study was to evaluate the predictive value of cardiac magnetic resonance (CMR) feature-tracking derived strain parameters in repaired tetralogy of Fallot (rTOF) patients for developing ventricular tachycardia (VT) and deterioration of ventricular function. METHODS: Patients with rTOF who underwent CMR investigation were included. Strain and strain-rate of both ventricles were assessed using CMR feature tracking. The primary outcome was a composite of the occurrence of sustained VT or non-sustained VT requiring invasive therapy. The secondary outcome was analyzed in patients that underwent a second CMR after 1.5 to 3.5 years. Deterioration was defined as reduction (≥10%) in right ventricular (RV) ejection fraction, reduction (≥10%) in left ventricular (LV) ejection fraction or increase (≥30 mL/m2) in indexed RV end-diastolic volume compared to baseline. RESULTS: 172 patients (median age 24.3 years, 54 patients <18 years) were included. Throughout a median follow-up of 7.4 years, 9 patients (4.5%) experienced the primary endpoint of VT. Multivariate Cox-regression analysis showed that LV systolic circumferential strain-rate was independently predictive of primary outcome (p = 0.023). 70 patients underwent a serial CMR, of whom 14 patients (20%) showed ventricular deterioration. Logistic regression showed no predictive value of strain and strain-rate parameters. CONCLUSIONS: In patients with rTOF, LV systolic circumferential strain-rate is an independent predictor for the development of VT. Ventricular strain parameters did not predict deterioration of ventricular function in the studied population.

Natural History of Double Inlet Left Ventricle and Pulmonary Hypertension in an Adult Patient.

Almost 80% of univentricular cardiac malformations with left morphology consist of a double inlet left ventricle (DILV). We report on the natural history of a 28-year-old male patient with DILV and ventriculoarterial discordance, patent ductus arteriosus, pulmonary hypertension and juxtaductal aortic coarctation. (Level of Difficulty: Intermediate.).

Intracardiac anatomical relationships and potential for streaming in double inlet left ventricles.

The aim of this study was to gain better understanding of the variable anatomical features of double inlet left ventricle hearts without cavopulmonary connection that would potentially facilitate favorable streaming. Thirty-nine post-mortem specimens of double inlet left ventricle without cavopulmonary connection were investigated. The focus was on anatomical characteristics that could influence the flow and separation of deoxygenated and oxygenated blood in the ventricles. Elements of interest were the ventriculoarterial connection, the spatial relationship of the ventricles, the position and size of the great arteries, the ventricular septal defect, the presence of relative outflow tract stenosis and the relationship of the inflow and outflow tracts. The most common anatomy was a discordant ventriculoarterial connection with an anatomically left-sided morphologically right ventricle (n = 12, 31%). When looking at the pulmonary trunk/aorta ratio, 21 (72%) hearts showed no pulmonary stenosis relative to the aorta. The ventricular septal defect created a relative subpulmonary or subaortic stenosis in 13 (41%) cases. Sixteen (41%) hearts had a parallel relationship of the inflow and outflow tracts, facilitating separation of deoxygenated and oxygenated blood streams. On the other end of the spectrum were 10 (25%) hearts with a perpendicular relationship, which might lead to maximum mixing of the blood streams. The relationship of the inflow and outflow tracts as well as the presence of (sub-) pulmonary stenosis might play a crucial role in the distribution of blood in double inlet left ventricle hearts. Additional in vivo studies will be necessary to confirm this postulation.

Both Exocrine Pancreatic Insufficiency and Signs of Pancreatic Inflammation Are Prevalent in Children with Complicated Severe Acute Malnutrition: An Observational Study.

OBJECTIVES: To assess whether pancreatic function is impaired in children with severe acute malnutrition, is different between edematous vs nonedematous malnutrition, and improves by nutritional rehabilitation. STUDY DESIGN: We followed 89 children with severe acute malnutrition admitted to Queen Elizabeth Central Hospital in Blantyre, Malawi. Stool and blood samples were taken on admission and 3 days after initial stabilization to determine exocrine pancreatic function via fecal elastase-1 (FE-1) and serum trypsinogen and amylase levels. RESULTS: A total of 33 children (37.1%) had nonedematous severe acute malnutrition, whereas 56 (62.9%) had edematous severe acute malnutrition. On admission, 92% of patients showed evidence of pancreatic insufficiency as measured by FE-1 <200 µg/g of stool. Patients with edematous severe acute malnutrition were more likely to have low FE-1 (98% vs 82.8%, P = .026). FE-1 levels remained low in these individuals throughout the assessment period. Serum trypsinogen was elevated (>57 ng/mL) in 28% and amylase in 21% (>110 U/L) of children, suggesting pancreatic inflammation. CONCLUSION: Exocrine pancreatic insufficiency is prevalent in children with severe acute malnutrition and especially in children with edematous severe acute malnutrition. In addition, biochemical signs suggestive of pancreatitis are common in children with severe acute malnutrition. These results have implications for standard rehabilitation treatment of children with severe acute malnutrition who may benefit from pancreatic enzyme replacement therapy. TRIAL REGISTRATION: ISRCTN.com: 13916953.

End-ischemic machine perfusion reduces bile duct injury in donation after circulatory death rat donor livers independent of the machine perfusion temperature.

A short period of oxygenated machine perfusion (MP) after static cold storage (SCS) may reduce biliary injury in donation after cardiac death (DCD) donor livers. However, the ideal perfusion temperature for protection of the bile ducts is unknown. In this study, the optimal perfusion temperature for protection of the bile ducts was assessed. DCD rat livers were preserved by SCS for 6 hours. Thereafter, 1 hour of oxygenated MP was performed using either hypothermic machine perfusion, subnormothermic machine perfusion, or with controlled oxygenated rewarming (COR) conditions. Subsequently, graft and bile duct viability were assessed during 2 hours of normothermic ex situ reperfusion. In the MP study groups, lower levels of transaminases, lactate dehydrogenase (LDH), and thiobarbituric acid reactive substances were measured compared to SCS. In parallel, mitochondrial oxygen consumption and adenosine triphosphate (ATP) production were significantly higher in the MP groups. Biomarkers of biliary function, including bile production, biliary bicarbonate concentration, and pH, were significantly higher in the MP groups, whereas biomarkers of biliary epithelial injury (biliary gamma-glutamyltransferase [GGT] and LDH), were significantly lower in MP preserved livers. Histological analysis revealed less injury of large bile duct epithelium in the MP groups compared to SCS. In conclusion, compared to SCS, end-ischemic oxygenated MP of DCD livers provides better preservation of biliary epithelial function and morphology, independent of the temperature at which MP is performed. End-ischemic oxygenated MP could reduce biliary injury after DCD liver transplantation.