Seiko Kuwata

Cardiac biomarkers in children with congenital heart disease.

BackgroundMost congenital heart diseases (CHDs) have specific hemodynamics, including volume and pressure overload, as well as cyanosis and pulmonary hypertension, associated with anatomical abnormalities. Such hemodynamic abnormalities can cause activation of neurohormones, inflammatory cytokines, fibroblasts, and vascular endothelial cells, which in turn contribute to the development of pathologic conditions such as cardiac hypertrophy, fibrosis, and cardiac cell damages and death. Measuring biomarker levels facilitates the prediction of these pathological changes, and provides information about the stress placed on the myocardial cells, the severity of the damage, the responses of neurohumoral factors, and the remodeling of the ventricle. Compared to the ample information on cardiac biomarkers in adult heart diseases, data from children with CHD are still limited.Data sourcesWe reviewed cardiac biomarkers-specifically focusing on troponin as a biomarker of myocardial damage, amino-terminal procollagen type III peptide (PIIIP) as a biomarker of myocardial fibrosis and stromal remodeling, and B-type natriuretic peptide (BNP)/N-terminal proBNP as biomarkers of cardiac load and heart failure, by introducing relevant publications, including our own, on pediatric CHD patients as well as adults.ResultsLevels of highly sensitive troponin I are elevated in patients with atrial septal defects (ASDs) and ventricular septal defects (VSDs). PIIIP levels are also elevated in patients with ASD, VSD, pulmonary stenosis, and Tetralogy of Fallot. Measurement of BNP and N-terminal proBNP levels shows good correlation with heart failure score in children.ConclusionsIn the treatment of children with CHD requiring delicate care, it is vital to know the specific degree of myocardial damage and severity of heart failure. Cardiac biomarkers are useful tools for ascertaining the condition of CHDs with ease and are likely to be useful in determining the appropriate care of pediatric cardiology patients.

Arterial stiffness in patients after Kawasaki disease without coronary artery involvement: Assessment by performing brachial ankle pulse wave velocity and cardio-ankle vascular index

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±121cm/s vs. 886±135cm/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.

Assessment of ventricular relaxation and stiffness using early diastolic mitral annular and inflow velocities in pediatric patients with heart disease

This study was undertaken to test the hypothesis that noninvasive echocardiographic indexes obtained using early diastolic mitral annular and inflow velocities reflect diastolic function in children. We included in this study 61 consecutive pediatric patients (age 0.4–13 years) who underwent cardiac catheterization for various heart diseases with biventricular circulation. Left ventricular (LV) pressure was measured using a high-fidelity manometer to obtain the time constant of relaxation (τ) and LV chamber stiffness (K). Echocardiography was simultaneously performed during catheterization. Data acquisition was repeated after the administration of dobutamine. The peak early mitral annular velocity (e′) and τ showed a significant inverse correlation (r = −0.42). Receiver-operating characteristic (ROC) analysis to determine the 90th percentile of τ yielded an area under the curve (AUC) of 0.86 for a septal e′ < 6.2 cm/s, with sensitivity and specificity of 0.83. The dobutamine-induced changes in e′ closely correlated with those in τ (r = −0.69). The deceleration time (DT) showed a significant but weak negative correlation with K (r = −0.35), and ROC analysis to determine the 90th percentile of Κ yielded an AUC of 0.82 for a DT <100 ms, with sensitivity of 0.80 and specificity of 0.77. The ratio of peak early mitral inflow velocity (E) to e′ (E/e′) significantly correlated with LV end-diastolic pressure (EDP; r = 0.48, P < 0.0005), and ROC analysis to determine the 90th percentile of EDP (>12.96 mmHg) yielded an AUC of 0.81 for an E/e′ > 16.4, with sensitivity of 0.71 and specificity of 0.93. The e′, DT, and E/e′ values in our study reflect the diastolic function in our pediatric population. However, the weak correlations between these indexes and invasive measures of diastolic function suggest that these indexes are useful in detecting diastolic dysfunction but not in determining the absolute values of diastolic dysfunction. Therefore, a future study is warranted to develop an efficient algorithm for systematic noninvasive evaluation of LV diastolic function in children.

Novel mechanisms for cerebral blood flow regulation in patients with congenital heart disease.

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.

Vulnerability of Coronary Circulation After Norwood Operation

BACKGROUND We hypothesized that the myocardial oxygen supply-demand balance is impaired in patients after a Norwood procedure and that an abnormal oxygen supply-demand balance is associated with pronounced activation of the renin-angiotensin-aldosterone system and worse clinical outcome after this procedure. METHODS To investigate the myocardial oxygen supply-demand balance, the subendocardial viability ratio (SEVR) was measured in 29 hypoplastic left heart syndrome patients after the Norwood procedure, in 27 patients with pulmonary atresia whose pulmonary blood flow was supplied from the aortopulmonary (AP) shunt, and in 30 control patients who were considered to have normal biventricular circulation. The SEVR in Norwood (0.57 ± 0.18) and AP shunt (0.66 ± 0.10) patients was significantly reduced compared with that in controls (0.94 ± 0.25, p < 0.001 vs Norwood and AP shunt). RESULTS After controlling for heart rate, the SEVR was significantly lower in Norwood than in AP shunt patients (p < 0.001). Importantly, the SEVR was significantly lower in Norwood patients with poor clinical outcomes (cardiac arrest before second-stage operation, progressive tricuspid regurgitation, or reduction of ejection fraction <0.35) than in the remaining Norwood patients (0.51 ± 0.12 vs 0.69 ± 0.22, p < 0.01). An SEVR of less than 0.52 had a more than 76% probability of having a poor outcome (p < 0.05). Furthermore, a lower SEVR was significantly correlated with more pronounced renin-angiotensin-aldosterone system activation and elevated natriuretic peptides in serum. Multiple regression analysis revealed that increased aortic stiffness and a smaller neoaorta relative to the native descending aorta were independent determinants of reduced SEVR. CONCLUSIONS Myocardial oxygen supply-demand imbalance is intrinsic to Norwood circulation but may be improved by technical refinement of aortic reconstruction or afterload-reducing medication with renin-angiotensin-aldosterone system blockade.

Non-invasive assessment of liver fibrosis by magnetic resonance elastography in patients with congenital heart disease undergoing the Fontan procedure and intracardiac repair

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.

Report from the Japanese Society of Pediatric Cardiology and Cardiac Surgery Research Committee on Cardio‐Vascular Function in Adult Patients with Congenital Heart Disease: Mechanism of Aortic Root Dilation and Cardio‐Vascular Function in Patients with Tetralogy of Fallot

The aortic root dilation in tetralogy of Fallot (TOF) is a long‐term clinical problem, because a severely dilated aorta can lead to aortic regurgitation, dissection, or rupture, which can be fatal, necessitating surgical intervention. The details of the mechanism of aortic root dilation, however, are unclear. We have shown that aortic stiffness is increased in patients with repaired TOF, and may mirror the histological abnormality of elastic fiber disruption and matrix expansion. This aortic stiffness is related closely to the aortic dilation, indicating that aortic stiffness may be a predictor of outcome of aortic dilation. Furthermore, the aortic volume overload is a very important determinant of aortic diameter in TOF patients before corrective surgery. In addition, a chromosomal abnormality and the transforming growth factor‐β signaling pathway, a major contributor to aortic dilation in Marfan syndrome, also affect this mechanism. In this way, aortic dilation in TOF patients is suggested to be a multifactorial disorder. The aim of this review was therefore to clarify the mechanism of aortic dilation in TOF, focusing on recent research findings. Studies linking histopathology, mechanical properties, molecular/cellular physiology, and clinical manifestations of aortic dilation facilitate appropriate treatment intervention and improvement of long‐term prognosis of TOF.

Cystatin C and body surface area are major determinants of the ratio of N-terminal pro-brain natriuretic peptide to brain natriuretic peptide levels in children

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 logNT/BNP was affected by PCWP (r=-0.12) and logCysC (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 logBSA, but PCWP (β=-0.10), logCysC (β=0.22), and logBSA (β=-0.66) were independent factors of logNT/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.

A case of acute encephalopathy with biphasic seizures and late reduced diffusion associated with Streptococcus pneumoniae meningoencephalitis

Acute encephalopathy with biphasic seizures and reduced diffusion (AESD) encompasses a group of encephalopathy characterized by biphasic seizures and disturbance of consciousness in the acute stage followed in the subacute stage by reduced diffusion in the subcortical white matter on magnetic resonance imaging. The etiology of AESD is viral infection and associated pathological changes. Here we report the first case of AESD caused by bacterial infection (Streptococcus pneumoniae meningitis) in a 1-year-old boy.

Influence of Left Ventricular Stiffness on Hemodynamics in Patients With Untreated Atrial Septal Defects

BACKGROUND Although left ventricular (LV) stiffening with age is believed to increase left-to-right shunting in patients with atrial septal defects (ASD), clinical data have not confirmed this. We sought determinants of the pulmonary-to-systemic flow ratio (Qp/Qs) in patients with untreated ASD. METHODS AND RESULTS We retrospectively studied 180 patients with ASD who underwent percutaneous ASD closure between 2007 and 2011. Qp/Qs and LV stiffness were measured before ASD closure.The median age of the subjects was 18 years, and 117 (65.0%) were female. The mean ASD size adjusted for square root of body surface area (BSA) was 14.4±4.2 mm/m, and the Qp/Qs was 2.28±0.74. Adjusted ASD size most strongly related to Qp/Qs (r=0.74, P<0.0001). Multivariate analysis revealed that LV stiffness was a significant predictor of Qp/Qs, independently of adjusted ASD size and vascular resistance (P=0.0015). Based on the multivariate model that accounts for the effects of LV stiffness and vascular resistance, the minimal adjusted diameter that can cause a Qp/Qs of 2.0 was predicted to be 7.3 mm/m. CONCLUSIONS Qp/Qs in ASD can change significantly depending on LV stiffness, suggesting that it would increase with age. An ASD >7.3 mm/m in diameter has the potential to cause significant left-to-right shunting, and may require closure regardless of hemodynamic status at the time of assessment.