Quantification of ventricular stress in univentricular hearts during early childhood using age-independent zlog-NT-proBNP.

BACKGROUND: Children with univentricular hearts (UVH) undergo up to three palliative surgical procedures to achieve complete circulatory separation (Fontan circulation). As a marker of cardiac wall stress, NT-proBNP is a promising tool to assess systemic ventricular load in these patients. However, different reference intervals (RI) apply to each stage, as NT-proBNP is highly age-dependent. METHODS: Children undergoing systemic-to-pulmonary (SP) shunt placement (stage 1), bidirectional cavopulmonary shunt (BCPS, stage 2) or total cavopulmonary connection (TCPC, stage 3) between 2011 and 2021 with NT-proBNP measurement within 7 days before surgery were included. Furthermore, outpatients after TCPC with NT-proBNP measurement were enrolled. Biomarker levels were evaluated using its age-adjusted z-score ("zlog-NT-proBNP"; age-independent RI, -1.96 to +1.96), allowing comparison between different stages and revealing changes in systemic ventricular load independent of the marked physiological decline in RI with age. RESULTS: Overall, 289 children (227 before, 62 after TCPC) met the eligibility criteria. Median time between blood sampling and surgery (SP shunt/BCPS/TCPC) was 2 [1-3] days and 3.2 [2.0-4.5] years after TCPC. Age-adjusted zlog-NT-proBNP levels were 3.47 [2.79-3.93] in children with native UVH (before SP shunt), 3.10 [1.89-3.58] at stage 1 (before BCPS), 1.08 [0.51-1.88] at stage 2 (before TCPC), and 1.09 [0.72-1.75] at stage 3 (after TCPC/Fontan completion). Consequently, BCPS revealed the strongest decrease (median - 2.02 logarithmized standard deviations, p < 0.001). CONCLUSIONS: In children with UVH undergoing staged Fontan palliation, zlog-NT-proBNP is a highly promising tool for course assessment of systemic ventricular load, independent of the age-related decline in physiological NT-proBNP concentration.

Increased Circulating Endothelin 1 Is Associated With Postoperative Hypoxemia in Infants With Single-Ventricle Heart Disease Undergoing Superior Cavopulmonary Anastomosis.

Background Inadequate pulmonary vascular growth results in morbidity for many children with single-ventricle heart disease (SVHD). Endothelin 1 (ET1) is a potent vasoconstrictor and stimulator of pulmonary artery smooth muscle proliferation. Circulating ET1 levels and their association with outcomes have not been studied during early SVHD palliation. We aimed to define circulating levels of ET1 in patients with SVHD undergoing stage 2 palliation and evaluate their relationship to postoperative hypoxemia. We hypothesized that patients with SVHD with higher ET1 concentration would have a greater post-stage 2 hypoxemia. Methods and Results Prospective cohort study of 55 subjects with SVHD undergoing stage 2 palliation and 50 controls. Samples for ET1 analysis were collected at preoperation (systemic and pulmonary vein) and 2, 24, and 48 hours postoperation for cases and a single time point for controls. The primary outcome was percentage of first 48 postoperative hours with clinically significant hypoxemia (saturation, <70%). ET1 concentration was lower in preoperative cases than controls (2.2 versus 2.7 pg/mL; P=0.0015) and in the pulmonary vein than systemic vein (1.7 versus 2.2 pg/mL; P<0.001). ET1 level increased by 2 hours postoperation and trended back to baseline by 48 hours. Higher preoperative pulmonary vein ET1 and 2 hours postoperative ET1 were associated with larger hypoxemia burden (10.6% versus 2.7% [P=0.0081]; and 7.6% versus 3.2% [P=0.01], respectively). Multivariable testing demonstrated ET1 concentration and cardiopulmonary bypass time were associated with hypoxemia, whereas catheterization measurements and clinical variables were not. Conclusions Infants with SVHD with higher perioperative ET1 concentration experience more post-stage 2 hypoxemia. ET1 activity may be a modifiable risk factor of pulmonary vascular inadequacy for stage 2 palliation.

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.

Micro-RNA 150-5p predicts overt heart failure in patients with univentricular hearts.

BACKGROUND: In patients with left heart failure, micro-RNAs (miRNAs) have been shown to be of diagnostic and prognostic value. The present study aims to identify those miRNAs in patients with univentricular heart (UVH) disease that may be associated with overt heart failure. METHODS: A large panel of human miRNA arrays were used to determine miRNA expression profiles in the blood of 48 UVH patients and 32 healthy controls. For further selection, the most abundantly expressed miRNA arrays were related to clinical measures of heart failure and selected miRNAs validated by polymerase chain reaction were used for the prediction of overt heart failure and all-cause mortality. RESULTS: According to microarray analysis, 50 miRNAs were found to be significantly abundant in UVH patients of which miR-150-5p was best related to heart failure parameters. According to ROC analysis, NT-proBNP levels (AUC 0.940, 95% CI 0.873-1.000; p = 0.001), miR-150-5p (AUC 0.905, 95% CI 0.779-1.000; p = 0.001) and a higher NYHA class ≥ III (AUC 0.893, 95% CI 0.713-1.000; p = 0.002) were the 3 most significant predictors of overt heart failure. Using a combined biomarker model, AUC increased to 0.980 indicating an additive value of miR-150-5p. Moreover, in the multivariate analysis, a higher NYHA class ≥ III (p = 0.005) and miR-150-5p (p = 0.006) turned out to be independent predictors of overt heart failure. CONCLUSION: In patients with UVH, miR-150-5p is an independent predictor of overt heart failure and thus may be used in the risk assessment of these patients.

Outcome of patients with functional single ventricular heart after pacemaker implantation: What makes it poor, and what can we do?

BACKGROUND: Pacemaker implantation in patients with single ventricle is associated with poor outcomes. OBJECTIVE: The purpose of this study was to determine the reasons for the poor outcomes of pacemaker implantation. METHODS: We performed a retrospective chart review of patients with single ventricle who had undergone permanent pacemaker implantation. Patients were categorized into 3 groups based on the site of pacing and the proportion of ventricular pacing (VP) as follows: (1) atrial pacing group with atrial pacing only (n = 11); (2) low VP group with low daily VP proportion (<50%; n = 12); and (3) high VP group with high daily VP proportion (≥50%; n = 15). Pacing leads were placed at the epicardium in all patients. RESULTS: No patients in the atrial pacing or low VP groups died, whereas the survival rate in the high VP group was 58.9% and 39.3% at 10 and 20 years, respectively, after pacemaker implantation. Among the post-Fontan patients, plasma brain natriuretic peptide (BNP) levels significantly increased with the proportion of VP: 11.7, 20.3, and 28.4 pg/mL in the atrial pacing, low VP, and high VP groups, respectively (P = 0.04). In the high VP group, the plasma BNP level was significantly lower in patients with an apical pacing lead than in those with a nonapical pacing lead (27.0 pg/mL vs 82.8 pg/mL, respectively; P = .03). CONCLUSION: A higher proportion of VP was associated with poor outcome and higher plasma BNP levels, probably due to ventricular dyssynchrony. In epicardial ventricular pacing, apical pacing is better to avoid the increase in ventricular stress and plasma BNP level.