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Protein pool turnover is a critically important cellular homeostatic component, yet it has been little explored in the context of heart failure (HF) pathophysiology. We employed in vivo 2H labeling/ proteome dynamics for non-biased discovery of turnover alterations involving functionally linked cardiac and plasma proteins in canine tachypacing-induced HF, an established preclinical model of dilated cardiomyopathy. Compared to control, dogs with congestive HF displayed bidirectional turnover changes of 28 cardiac proteins, i.e. reduced half-life of several key enzymes involved in glycolysis, homocysteine metabolism and glycogenesis, and increased half-life of proteins involved in proteolysis. Changes in plasma proteins were more modest: only 5 proteins, involved in various functions including proteolysis inhibition, hemoglobin, calcium and ferric-iron binding, displayed increased or decreased turnover rates. In other dogs undergoing cardiac tachypacing, we infused for 2 weeks the myokine Follistatin-like protein 1 (FSTL1), known for its ameliorative effects on HF-induced alterations. Proteome dynamics proved very sensitive in detecting the partial or complete prevention, by FSTL1, of cardiac and plasma protein turnover alterations. In conclusion, our study unveiled, for the first time in a large mammal, numerous HF-related alterations that may serve as the basis for future mechanistic research and/or as conceptually new molecular markers.

Background The incidence of late liver complications such as fibrosis or cirrhosis has increased among patients who have undergone the Fontan procedure. Magnetic resonance elastography (MRE) recently emerged as a technique to clinically evaluate liver fibrosis. However, few reports have described its use in evaluating liver fibrosis in children with congenital heart disease (CHD). Methods and results Fifty-seven children were examined and divided into four groups: 27 with CHD who underwent intracardiac repair (ICR); 16 with CHD who underwent the Fontan procedure (Fontan); 14 in a control group (control); and two with cirrhosis (cirrhosis). Liver stiffness (LS) was measured using MRE. Other assessments included central venous pressure (CVP) as determined by cardiac catheterization. Circulating biomarker levels were also determined. There were no significant differences in biomarker levels among the groups. However, the LS degree was significantly higher in the Fontan group than in the control group. On stepwise multivariate analysis, only the CVP level was a statistically significant independent predictor of LS. There was also a strong correlation between LS and CVP and between LS and time interval since Fontan surgery. Conclusions This study clearly demonstrated that LS was significantly increased after the Fontan procedure and that CVP was a predictor of LS. MRE is a highly sensitive tool that can evaluate liver fibrosis in children who undergo the Fontan procedure and enable earlier detection of LS than biomarkers.

Background The mechanisms that regulate cerebral flow in patients after surgery for congenital heart diseases (CHDs) remain poorly understood. We tested our hypothesis that postoperative patients with CHD have disease- or hemodynamic-specific compensatory mechanisms for maintaining cerebral perfusion. Methods A total of 89 children with specific hemodynamics including Glenn (n = 14), Fontan (n = 19), repaired tetralogy of Fallot (n = 24), and control patients (n = 32) were enrolled. The resistance and blood flow distribution between the brain (Rc and CIc) and lower body (Rs and CIs) were calculated by measuring the hemodynamic changes resulting from inferior vena cava occlusion during cardiac catheterization. Results Despite considerable differences in cardiac index and superior vena cava pressure (SVCp), cerebral blood flow was preserved in all noncontrol groups, with a ratio between the vascular resistances in the cerebral and lower body circulation (Rc/Rs) that was significantly lower than that in controls. Interestingly, the reduced Rc/Rs of Glenn patients was mediated by the reduced Rc, whereas augmented Rs was conducive to the reduced Rc/Rs in the Fontan and tetralogy of Fallot groups. Multivariate analysis revealed that high SVCp was significantly associated with low Rc. Although low cardiac index was significantly associated with increased Rc and Rs, its impact was much greater on Rs than on Rc. Conclusions Compensatory mechanisms for cerebral flow regulation occur according to hemodynamic abnormality type in postoperative patients with CHD. Because such a regulation mechanism implies cerebral circulation fragility, further investigations are needed to address the impacts of cerebral circulation properties on neurodevelopmental outcomes.

Background It remains unclear whether systemic arterial beds other than the coronary arteries are truly healthy in patients without coronary artery lesions (CAL) after Kawasaki disease (KD). We tested the hypothesis that patients with KD without echocardiographic evidence of CAL during the acute phase of the disease have abnormal mechanical properties in systemic arteries later. Methods and results We studied 201 consecutive patients with KD (age 2–23 years, mean 10 ± 4 years; 109 male, 92 female) without CAL during the acute phase. Data were compared with those in 129 control subjects (age 2–25 years, mean 10 ± 4 years; 73 male, 56 female; control group). We examined arterial stiffness by using the brachial–ankle pulse wave velocity (baPWV) and the cardio-ankle vascular index (CAVI). The baPWV in the KD group was significantly higher than that in the control group (913 ± 121 cm/s vs. 886 ± 135 cm/s, p = 0.04). In contrast, there was no significant difference in CAVI (4.0 ± 1.0 vs. 4.2 ± 1.0, p = 0.9) between the two groups. Multivariate analysis indicated a highly significant difference in baPWV (higher baPWV in patients with KD than in controls, p = 0.004), after controlling for age, gender, body height and weight, and systolic and diastolic blood pressure, but no difference in CAVI between the groups. Conclusion Years after KD occurs in patients without apparent CAL during the acute phase, there is a small but significant change in systemic arterial properties, characterized by increased wall stiffness. The clinical importance of these findings must be clarified by performing long-term follow-up studies.

Background Production of N-terminal pro-brain natriuretic peptide (NT) and BNP is equimolar. Although NT clearance occurs only in the kidneys, BNP clearance occurs in the kidneys and other organs. This study tested the hypothesis that NT/BNP ratio in children may be independently related to cystatin C (CysC), a glomerular filtration rate marker, when diastolic function and age/body size are taken into consideration. Methods The study included 430 children (5.3 ± 4.9 years) with heart disease who had undergone cardiac catheterization and simultaneous BNP, NT, and CysC measurements. Pulmonary capillary wedge pressure (PCWP) was used as a ventricular diastolic stretch marker. Variables showing skewed distribution were transformed into a common logarithm. Results Univariate regression revealed that log NT/BNP was affected by PCWP (r = −0.12) and log CysC (r = 0.57). When age and the log of body surface area (BSA) were added to the stepwise regression, age was not adopted because of multicollinearity to log BSA, but PCWP (β = −0.10), log CysC (β = 0.22), and log BSA (β = −0.66) were independent factors of log NT/BNP. Conclusions Renal dysfunction independently increased NT/BNP, whereas high BSA decreased it and is the greatest determinant of NT/BNP. The observation that high PCWP decreased NT/BNP may suggest that worsening heart failure slows BNP clearance from other organs, a compensatory pathway of heart failure. These factors need to be considered when assessing BNP and NT.

Abnormal water metabolism is frequently observed after Fontan surgery. We hypothesized that patients' adrenal hormones show unique responses immediately after Fontan operation and that such a hormonal profile is related to postoperative hemodynamics and water imbalance. Twenty-eight patients who underwent a Fontan operation (n = 16) or a non-Fontan type operation (n = 12; controls) under cardiopulmonary bypass were studied. Postoperative urine cortisol and aldosterone levels were measured daily to minimize the influence of circadian rhythms and temporal hemodynamic variations. Cortisol excretion was markedly elevated on postoperative day (POD) 0 in controls, consistent with a stress-induced cortisol response. Cortisol excretion was not high on POD 0 in Fontan patients and was markedly lower than that in the controls (444 ± 150 vs 34 ± 6 μg/m(2)/day, p0.05), indicating an adrenal insufficiency status. Conversely, aldosterone levels were significantly higher in Fontan patients than in controls immediately after surgery and remained so thereafter. The cortisol-to-aldosterone ratio was significantly lower in Fontan patients on POD 0 (p0.05 vs controls); low cortisol-to-aldosterone ratios were associated with a longer pleural drainage duration and intensive care unit stay. Daily cortisol and aldosterone levels were significantly associated with postoperative hemodynamics; low cortisol levels correlated with low cardiac and urine outputs, whereas high aldosterone levels correlated with low cardiac output and increased blood pressure and central venous pressure. Thus, aldosterone-to-cortisol imbalance occurred specifically after the Fontan operation. This unique hormonal profile significantly affected patients' postoperative water balance and hemodynamics. Modulation of the adrenal hormone could be useful for reducing postoperative complications after the Fontan operation.

Recent studies have shown that bilateral pulmonary artery banding (bil-PAB) for hypoplastic left heart syndrome (HLHS) is not superior to the neonatal Norwood procedure in terms of overall mortality and neurodevelopmental outcome. We tested our hypothesis that bil-PAB is associated with negative hemodynamic effects on cerebral circulation.The acute effects of bil-PAB on cerebral circulation were assessed by serial measurements of cerebral Doppler flow velocities in 9 patients immediately after bil-PAB. To evaluate the chronic effects of bil-PAB on cerebral perfusion, the oxygen demand-supply balance between the lower and upper body, designated as oxygenation balance index (OBI), was calculated in another set of 13 patients using oxymetric data before stage II palliation. Data were compared with those of 13 patients who underwent the Norwood operation.The preoperative cerebral blood flow velocities of the patients were at the lowest levels reported in healthy neonates. Bil-PAB did not increase cerebral blood flow in the first week after the procedure. OBI was significantly lower in patients treated with bil-PAB (p0.005) than in those treated with the Norwood procedure, indicating impaired cerebral perfusion after bil-PAB. Importantly, the OBI in the bil-PAB group, but not in the Norwood group, significantly decreased with time after the procedure. In addition, cerebral perfusion was more vulnerable to the changes in pulmonary and systemic blood flow in the bil-PAB group than in the Norwood group.A hybrid approach followed by comprehensive stage II palliation may not be an optimal strategy for HLHS and should be evaluated further.