Suchaya Silvilairat

Use of cardiac markers for monitoring of doxorubixin-induced cardiotoxicity in children with cancer.

The aim of this study was to evaluate N-terminal probrain natriuretic peptides (NT-pro-BNP), cardiac troponin T, and creatinine kinase, MB isoenzyme (CK-MB) in the determination of subclinical left ventricular (LV) dysfunction by echocardiography in patients treated with doxorubicin. We performed a cross-sectional case study of systolic, diastolic function and tissue Doppler imaging by echocardiography in children with cancer who received a certain cumulative dose of doxorubicin. Blood levels for NT-pro-BNP, cardiac troponin T, and CK-MB were analyzed within 6 hours of the cardiac study. Of 30 patients, 5 (16.7%) had LV dysfunction with an abnormally high NT-pro-BNP level of 363±78 pg/mL, whereas patients with normal LV function had an NT-pro-BNP level of 148±173 pg/mL (P=0.012). The NT-pro-BNP level not only inversely correlated with fractional shortening (r=−0.43, P=0.017) and ejection fraction (r=−0.45, P=0.013) but also correlated with mitral deceleration time (r=0.41, P=0.021) and a cumulative dose of doxorubicin (r=0.44, P=0.014). For tissue Doppler imaging, NT-pro-BNP correlated with a peak systolic velocity at the myocardial segment (Sm) (r=−0.40, P=0.027). NT-pro-BNP is a sensitive test and has a moderate relationship with the LV systolic and diastolic function, thus making it a useful cardiac marker for the monitoring of early anthracycline cardiotoxicity.

Heart Rate Variability as an Alternative Indicator for Identifying Cardiac Iron Status in Non-Transfusion Dependent Thalassemia Patients.

Background Iron-overload cardiomyopathy is a major cause of death in thalassemia patients due to the lack of an early detection strategy. Although cardiac magnetic resonance (CMR) T2* is used for early detection of cardiac iron accumulation, its availability is limited. Heart rate variability (HRV) has been used to evaluate cardiac autonomic function and found to be depressed in thalassemia. However, its direct correlation with cardiac iron accumulation has never been investigated. We investigated whether HRV can be used as an alternative indicator for early identification of cardiac iron deposition in thalassemia patients. Methods Ninety-nine non-transfusion dependent thalassemia patients (23.00 (17.00, 32.75) years, 35 male) were enrolled. The correlation between HRV recorded using 24-hour Holter monitoring and non-transferrin bound iron (NTBI), hemoglobin (Hb), serum ferritin, LV ejection fraction (LVEF), and CMR-T2* were determined. Results The median NTBI value was 3.15 (1.11, 6.59) μM. Both time and frequency domains of HRV showed a significant correlation with the NTBI level, supporting HRV as a marker of iron overload. Moreover, the LF/HF ratio showed a significant correlation with CMR-T2* with the receiver operating characteristic (ROC) curve of 0.684±0.063, suggesting that it could represent the cardiac iron deposit in thalassemia patients. HRV was also significantly correlated with serum ferritin and Hb. Conclusions This novel finding regarding the correlation between HRV and CMR-T2* indicates that HRV could be a potential marker in identifying early cardiac iron deposition prior to the development of LV dysfunction, and may be used as an alternative to CMR-T2* for screening cardiac iron status in thalassemia patients.

Delayed diagnosis of Kawasaki disease: risk factors and outcome of treatment

Abstract Background: Kawasaki disease (KD) is associated with a high incidence of coronary artery aneurysms in untreated children. Treatment with intravenous immunoglobulin (IVIG) within the 1st 10 days of illness reduces by approximately fivefold the prevalence of coronary artery abnormalities (CAA). Data regarding delayed diagnosis of KD in Thailand have not been reported in the literature. Aims: To determine the prevalence, risk factors and outcome of delayed diagnosis of KD in Thai patients. Methods: We retrospectively reviewed the medical records of patients at Chiang Mai University Hospital diagnosed as KD during 2000–2008. Patients were classified into two groups: Group I were diagnosed ⩽10 days of fever and Group II were diagnosed >10 days of fever. Results: Of 170 patients, 150 were in Group I [mean (SD) fever 7 (1·45) d] and 20 (11·7%) in Group II [mean (SD) fever 15 (4) d]. There were no statistical differences between the two groups in age, gender, number of KD clinical manifestations or laboratory results, except that Group II were of lower weight (p = 0·01). Group II were younger (p = 0·09) and had more incomplete criteria (p = 0·09) but the differences were not statistically significant. Group II had a higher incidence of CAA (75% vs 19%) (p<0·001), more severe CAA and more resistant cases (31·2% vs 9·5%) (p = 0·04). Conclusion: Patients with delayed diagnosis of KD have a higher risk of developing CAA and of a more severe outcome for coronary artery disease. Education is needed to make healthcare providers and physicians more aware of KD, especially in small children or those with incomplete KD.

Factors Influencing Survival in Patients after Bidirectional Glenn Shunt

Clinical characteristics, echocardiographic values, and catheterization data of 45 patients with a functional univentricular heart who had a bidirectional Glenn shunt instituted between November 1994 and October 2006 were retrospectively reviewed. Median age at operation was 20 months (range, 9 months to 19 years). Median follow-up time after the bidirectional Glenn operation was 4 years (range, 1 day to 11 years). The early mortality rate was 4/45 (8.9%); overall mortality was 24.4%. Actuarial survival after a bidirectional Glenn shunt was 73% ± 8% at 5 years and 55% ± 17% at 10 years. In multivariate Cox proportional hazards analysis, heterotaxy syndrome and systemic right ventricle were independent predictors of mortality after the bidirectional Glenn shunt. Age at operation, oxygen saturation, previous surgery, a pulsatile Glenn shunt, cardiopulmonary bypass, postoperative pulmonary artery pressure, bilateral superior venae cavae, and Nakata index were not predictive of mortality. The presence of heterotaxy syndrome and systemic right ventricle in patients with a functional univentricular heart should lead to aggressive investigation and management strategies.

Cardiac manifestations in HIV-infected Thai children.

Abstract Cardiac complications contribute significantly to morbidity and mortality in HIV-infected children. There have been few reports of cardiac manifestations in HIV-infected children in developing countries. The aims of this study were to evaluate the clinical manifestations and echocardiographic findings in Thai children with HIV infection and determine the clinical predictors of left ventricular dysfunction and pulmonary hypertension. We retrospectively reviewed the medical records of 27 infants infected with HIV perinatally who presented with cardiovascular problems at a tertiary care hospital between 1995 and 2000. The mean age at initial cardiac evaluation was 36 months (range 8-65). Signs and symptoms included dyspnoea in all cases, oedema in 12 (44%), finger clubbing in 11 (41%), cyanosis in 6 (22%) and S3 gallop in 8 (30%). Echocardiographic abnormalities included pericardial effusion in 12 (44 %), right ventricular dilatation in 12 (44%), pulmonary hypertension in 11 (41%), diminished left ventricular fractional shortening in 10 (37%), left ventricular dilatation in 9 (33%) and combined ventricular dilatation in 2 (7%). Left ventricular dysfunction did not correlate with HIV CDC classification, age, nutritional status or clinical signs and symptoms.

Heart Rate Variability for Early Detection of Cardiac Iron Deposition in Patients with Transfusion-Dependent Thalassemia

Background Iron overload cardiomyopathy remains the major cause of death in patients with transfusion-dependent thalassemia. Cardiac T2* magnetic resonance imaging is costly yet effective in detecting cardiac iron accumulation in the heart. Heart rate variability (HRV) has been used to evaluate cardiac autonomic function and is depressed in cases of thalassemia. We evaluated whether HRV could be used as an indicator for early identification of cardiac iron deposition. Methods One hundred and one patients with transfusion-dependent thalassemia were enrolled in this study. The correlation between recorded HRV and hemoglobin, non-transferrin bound iron (NTBI), serum ferritin and cardiac T2* were evaluated. Results The median age was 18 years (range 8–59 years). The patient group with a 5-year mean serum ferritin >5,000 ng/mL included significantly more homozygous β-thalassemia and splenectomized patients, had lower hemoglobin levels, and had more cardiac iron deposit than all other groups. Anemia strongly influenced all domains of HRV. After adjusting for anemia, neither serum ferritin nor NTBI impacted the HRV. However cardiac T2* was an independent predictor of HRV, even after adjusting for anemia. For receiver operative characteristic (ROC) curve analysis of cardiac T2* ≤20 ms, only mean ferritin in the last 12 months and the average of the standard deviation of all R-R intervals for all five-minute segments in the 24-hour recording were predictors for cardiac T2* ≤20 ms, with area under the ROC curve of 0.961 (p<0.0001) and 0.701 (p = 0.05), respectively. Conclusions Hemoglobin and cardiac T2* as significant predictors for HRV indicate that anemia and cardiac iron deposition result in cardiac autonomic imbalance. The mean ferritin in the last 12 months could be useful as the best indicator for further evaluation of cardiac risk. The ability of serum ferritin to predict cardiac risk is stronger than observed in other thalassemia cohorts. HRV might be a stronger predictor of cardiac iron in study populations with lower somatic iron burdens and greater prevalence of cardiac iron deposition.

Pulmonary hypertension in non-transfusion-dependent thalassemia: Correlation with clinical parameters, liver iron concentration, and non-transferrin-bound iron

Abstract Background Pulmonary hypertension is a major cardiac complication in non-transfusion-dependent thalassemia (NTDT). Several clinical and laboratory parameters, including iron overload, have been shown to have a positive correlation with the incidence of pulmonary hypertension. Non-transferrin-bound iron (NTBI) is a form of free-plasma iron that is a good indicator of iron overload. Objectives The aim of this study was to determine the prevalence of pulmonary hypertension in patients with NTDT and to investigate its correlation with the clinical parameters, liver iron concentration (LIC) and NTBI. Methods Patients with NTDT were evaluated using echocardiography, and magnetic resonance imaging for cardiac T2* and LIC. Pulmonary hypertension was defined as peak tricuspid regurgitation velocity ≥2.9 m/s measured using trans-thoracic echocardiography. Clinical parameters and the status of iron overload as determined by LIC, serum ferritin, and NTBI level were evaluated for their association with pulmonary hypertension. Results Of 76 NTDT patients, mean age 23.7 ± 8.5 years, seven patients (9.2%) had pulmonary hypertension. Previous splenectomy (71.4 vs. 24.6%, P-value 0.019), higher cumulative red blood cell (RBC) transfusions (received ≥10 RBC transfusions 85.7 vs. 33.3%, P-value 0.011), higher nucleated RBCs (353 ± 287 vs. 63 ± 160/100 white blood cells, P-value <0.001), and a high NTBI level (5.7 ± 3.0 vs. 3.3 ± 2.8 µmol/l, P-value 0.034) were associated with pulmonary hypertension. There was no significant correlation between LIC or serum ferritin and pulmonary hypertension. Conclusion Pulmonary hypertension in NTDT is common, and is associated with splenectomy and its related factors. NTBI level shows a significant correlation with pulmonary hypertension.

Kawasaki disease in Thai infants compared with older children

Abstract Infants with Kawasaki disease (KD) are at increased risk of having coronary artery abnormalities (CAA). The purpose of this study was to evaluate the clinical features of KD in infants and compare these with findings in older children to determine the risk factors for CAA in infants. All children with KD admitted to a tertiary care hospital between January 1993 and April 2003 were studied retrospectively. Of a total of 51 patients included in the study, 22 (43%) were <1 year of age (mean 8 months, range 2-12 months). All had classical clinical manifestations such as fever, skin rash and mucositis; extremity change occurred in 95%, conjunctivitis in 81% and cervical lymphadenopathy in 27%. Infants had significantly more non-classical symptoms, e.g. diarrhoea (68%), than older children (38%) (p=0.04). The mean number of days before intravenous immunoglobulin (IVIG) treatment was given to infants was 2 days later than in older children. The predictors of CAA in infants were resistance to IVIG treatment (p=0.02) and long duration of fever (p=0.009). Compared with older children, the less typical presentations and delay in diagnosis and treatment in infants might be important factors in CAA in KD.

Clinical spectrum of incomplete Kawasaki disease in Thailand

Abstract Background: Inadequate diagnostic criteria in incomplete Kawasaki disease (KD) patients may lead to misdiagnosis and delayed treatment. However, the risk of coronary artery aneurysm in these patients remains uncertain. Aim: To investigate differences in clinical, laboratory and echocardiographic variables between patients with incomplete KD and classic KD. Method: The medical records of 208 KD patients treated between January 2001 and December 2009 in the Department of Pediatrics, Chiang Mai University Hospital were reviewed retrospectively. Patients with three or fewer major criteria were defined as having incomplete KD. Results: Of the 208 KD patients, 61 (29%) had incomplete KD. In those with incomplete KD, a significantly higher proportion were male (73·8% vs 59·2%, P = 0·03), the diagnosis was made later [mean (SD) day 9·0 (4·2) vs 7·2 (2·5), P = 0·003], there was a higher rate of delayed diagnosis (>10 days, 21% vs 10%, P = 0·02) and the presence of five major criteria was less common. The proportion of associated symptoms (irritability, upper respiratory tract symptoms, diarrhoea, vomiting and reactivation of BCG) and laboratory findings (pyuria, haemoglobin level, white blood count, polymorphonuclear cells, platelet count, erythrocyte sedimentation rate and serum albumin) were comparable in patients with incomplete KD and classic KD. The incomplete KD group tended to have a higher proportion of coronary artery abnormalities but the difference was not statistically significant (38% vs 25%, P = 0·09). However, a significantly greater proportion of the group with incomplete KD had large aneurysms (10% vs 1%, P = 0·009). Conclusions: Incomplete KD and classic KD have the same disease spectrum. Owing to the absence of some major criteria, incomplete KD can be more difficult to diagnose, which can result in delayed diagnosis and a greater risk of large coronary aneurysms.

Loss of function in ROBO1 is associated with tetralogy of Fallot and septal defects

Background Congenital heart disease (CHD) is a common birth defect affecting approximately 1% of newborns. Great progress has been made in elucidating the genetic aetiology of CHD with advances in genomic technology, which we leveraged in recovering a new pathway affecting heart development in humans previously known to affect heart development in an animal model. Methods Four hundred and sixteen individuals from Thailand and the USA diagnosed with CHD and/or congenital diaphragmatic hernia were evaluated with chromosomal microarray and whole exome sequencing. The DECIPHER Consortium and medical literature were searched for additional patients. Murine hearts from ENU-induced mouse mutants and transgenic mice were evaluated using both episcopic confocal histopathology and troponin I stained sections. Results Loss of function ROBO1 variants were identified in three families; each proband had a ventricular septal defect, and one proband had tetralogy of Fallot. Additionally, a microdeletion in an individual with CHD was found in the medical literature. Mouse models showed perturbation of the Slit-Robo signalling pathway, causing septation and outflow tract defects and craniofacial anomalies. Two probands had variable facial features consistent with the mouse model. Conclusion Our findings identify Slit-Robo as a significant pathway in human heart development and CHD.