Shuenn-Nan Chiu

Reversal of Cardiac Dysfunction after Enzyme Replacement in Patients with Infantile-Onset Pompe Disease

OBJECTIVE To compare the effects of enzyme replacement therapy (ERT) on cardiac performance in symptomatic and symptom-free infants with Pompe disease. STUDY DESIGN Patients diagnosed between 1983 and 2008 were identified. Before the initiation of ERT, systolic dysfunction appeared only in patients > or = 5 months; thus we used this cut-point in age to divide clinically symptomatic patients into early and late treatment groups (Clin-E and Clin-L). Newborn screening (NBS) identified symptom-free patients. RESULTS Among a total of 40 patients, 14 received ERT: 5 in the Clin-L, 4 in the Clin-E, and 5 in the NBS groups. All patients showed cardiomegaly, hypertrophic myocardium, and elevated B-type natriuretic peptide (measured in the Clin-E and NBS groups). ERT improved the survival and outcomes. Regressed myocardial hypertrophy and lowered B-type natriuretic peptide level occurred after 1 to 6 months of ERT. Nonetheless, there were 2 deaths and 2 survivors requiring ventilator support in the Clin-L group. Despite the regressed QRS voltage and shortened QT dispersion, life-threatening arrhythmias were still observed in 3, but none in the NBS group. CONCLUSION ERT may restore the cardiac function in both symptomatic and symptom-free patients, but the beneficial effect may be unpredictable if given after the age of 5 months.

Clinical Implication of the C Allele of the ITPKC Gene SNP rs28493229 in Kawasaki Disease: Association With Disease Susceptibility and BCG Scar Reactivation.

Background: A functional single nucleotide polymorphism (SNP) (rs28493229) in the inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) gene has been linked to the susceptibility to Kawasaki disease (KD). The implication remains unclear. Subjects and Methods: Genotyping for the ITPKC polymorphism was conducted on 280 unrelated Taiwanese children with KD and 492 healthy ethnically and gender-matched controls. The clinical manifestations and laboratory data were systemically collected. Results: The GC and CC genotypes of ITPKC gene SNP rs28493229 were overrepresented in KD patients (GG:GC:CC was 236:43:1, C allele frequency: 8.04%) than those in the controls (GG:GC:CC was 454:37:1, C allele frequency: 3.96%; OR: 2.23, P = 0.001). In KD patients, those with GC or CC genotypes of SNP rs28493229 (19/44) were more likely to have reactivation at the Bacille Calmette-Guérin (BCG) inoculation site than those with GG genotypes (66/236; OR: 1.96, P = 0.044). Such association was particularly strong in patients aged <20 months (OR: 3.26, P = 0.017). The other clinical manifestations were not related to this SNP. There were 160 (57.1%) patients with coronary arterial lesions. The development and the severity of coronary arterial lesion were also not associated with this SNP. Comparison between patients with and without BCG reactivation revealed only one difference: patients with reactivation were younger. Conclusion: In a cohort from a population with the worlds third highest incidence of KD, we demonstrated that the C-allele of ITPKC SNP rs28493229 is associated with KD susceptibility and BCG scar reactivation during the acute phase, although its frequency is lower than that in the Japanese cohort (22.6%), suggesting this SNP contributes to KD susceptibility through induced hyperimmune function reflected in the BCG reactivation.

Transcatheter closure of atrial septal defect without balloon sizing.

Objective: To evaluate the safety and feasibility of transcatheter closure of atrial septal defect (ASD) without balloon sizing. Methods: A total of 243 patients (group I), aged 2.1–76 years (median 22 years), underwent transcatheter closure of ASD without balloon sizing. The maximal diameter of the defect was measured on transesophageal echocardiographic (TEE) images. The size of device selected was generally 4–6 mm and 5–8 mm larger than the maximal diameter, if the defect was <14 mm and ≥14 mm, respectively. The results of ASD closure in group I were compared with those of 271 patients (group II, median age 11 years) who underwent ASD closure with balloon sizing prior to the study period. Results: Of the 243 patients in group I, the maximal defect diameter ranged from 5.2 to 37 mm (mean 17.5 ± 6.6 mm, median 17 mm). A total of 247 Amplatzer septal occluders were deployed in 240 patients. Two patients were found to develop distal embolization of a device the next day. Therefore, failure occurred in five patients. Comparing the results between group I and group II, there was no significant difference in success rate (238/243 vs. 263/271), incidence of embolization (2/243 vs. 2/271) and complete closure rate at 3‐month follow‐up (94.1% vs. 95.8%). There is significant difference in mean age (26.6 ± 20.2 vs. 19.1 ± 17.6), maximal defect diameter (17.5 ± 6.6 vs. 14.1 ± 5.9 mm) and Qp/Qs ratio (2.77 ± 1.11 vs. 2.48 ± 0.97) between group I and II. The mean diameter of device used was significantly larger in group I than in group II (23.1 ± 8.1 vs. 19.6 ± 7 mm, P < 0.001). Conclusions: Balloon sizing may not be necessary in transcatheter closure of ASD.

Long-Term Survival and Unnatural Deaths of Patients With Repaired Tetralogy of Fallot in an Asian Cohort

Background— Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease in Taiwan. This study investigates the long-term survival and risks of TOF in an Asian cohort. Methods and Results— This study enrolled 819 consecutive patients with TOF (61.1% male), who received total correction between 1970 and 2002, as participants. Patient medical records were reviewed, and the survival status of those out of contact was confirmed by death records retrieved from the National Health database. The mean (±SD) patient age at cardiac repair was 6.5±7.6 years, and a prior shunt operation was performed in 119 (14.5%) of the patients. At cardiac repair, a transannular patch for right ventricle outlet reconstruction was required in 444 (54.2%) of the patients. After 13 808 patient-years of follow-up, the 30-year survival rate was 90.5%. The annual mortality rate increased from 0.123% in the initial 15 years after repair to 0.395% thereafter (P<0.05). The presence of major aortopulmonary collateral arteries, older operative age, and previous shunt operation are independent risks of late cardiac deaths. Secondary to cardiac mortality, unnatural deaths (accident and suicide) accounted for 27.6% of late deaths, significantly higher compared with that of the general population (odds ratio, 2.18; P=0.028). Conclusions— In this Asian TOF cohort, except for a late decrease after 15 years, long-term survival after cardiac repair was satisfactory. Although cardiac death was the most common cause of late death, accidents or suicide may also be associated with late mortality, suggesting a potential role for psychosocial support.

Blood Pressure after Surgery among Obese and Nonobese Children with Obstructive Sleep Apnea

Objectives Treating obstructive sleep apnea in children is found to be associated with blood pressure decreases. However, exactly how adenotonsillectomy (T&A) affects blood pressure in obese and nonobese children remains unclear. This study assesses how obesity affects blood pressure in children with sleep apnea after T&A. Study Design Case series with chart review. Setting A tertiary referral center. Subjects and Methods From 2010 to 2012, a total of 78 children were included. Based on propensity score methods (age, sex, and preoperative apnea-hypopnea index matched), children were assigned to either the obese group (n = 39) or the nonobese group (n = 39). All children received adenotonsillectomy. We recorded clinical symptoms, preoperative overnight polysomnography (PSG), and subsequent PSG within 3 months after T&A. We measured blood pressure 3 times before PSG (nocturnal blood pressure) and after PSG (morning blood pressure) in a sleep laboratory. Results Following surgery, the nonobese group had a significantly decreased nocturnal diastolic blood pressure (DBP) index (–12.0 to −18.8, P = .018), morning systolic blood pressure (SBP; 111.1 to 105.8 mm Hg, P = .014), SBP index (–5.4 to −10.9, P = .008), and DBP (–12.0 to −18.7, P = .023). Nevertheless, all blood pressure parameters in the obese group were not significantly changed postoperatively. The nonobese group improved more than obese group in nocturnal and morning DBP and DBP index by 2-way analysis of variance. Conclusion Among the children receiving T&A as treatment for OSA, nonobese children improved more than obese children did in terms of blood pressure, allowing us to infer that obese children with OSA may benefit less from T&A in cardiovascular morbidities.

Analysis of 24-Hour Ambulatory Blood Pressure Monitoring in Children With Obstructive Sleep Apnea: A Hospital-Based Study.

AbstractIn the present study, we aimed to verify associations between ambulatory blood pressure (ABP) and pediatric obstructive sleep apnea (OSA) in a hospital-based population.This was a cross-sectional observational study on children aged 4 to 16 years with OSA-related symptoms from a tertiary referral medical center. All children received overnight polysomnography and 24-hour recording of ABP. Severity of the disease was classified as primary snoring (apnea-hypopnea index, AHI <1), mild OSA (AHI 1–5), and moderate-to-severe OSA (AHI >5).For 195 children enrolled in this study (mean age, 7.8 ± 3.4 years; 69% boy), ABP increased as severity of OSA increased. During daytime, children with moderate-to-severe OSA had significantly higher systolic blood pressure (BP) (117.0 ± 12.7 vs 110.5 ± 9.3 mmHg), mean arterial pressure (MAP) (85.6 ± 8.1 vs 81.6 ± 6.8 mmHg), and diastolic BP load (12.0 ± 9.6 vs 8.4 ± 10.9 mmHg) compared with children with primary snoring. During nighttime, children with moderate-to-severe OSA had significantly higher systolic BP (108.6 ± 15.0 vs 100.0 ± 9.4 mmHg), MAP (75.9 ± 9.6 vs 71.1 ± 7.0 mmHg), systolic BP load (44.0 ± 32.6 vs 26.8 ± 24.5 mmHg), systolic BP index (0.5 ± 13.1 vs −6.8 ± 8.5 mmHg), and higher prevalence of systolic hypertension (47.6% vs 14.7 %) compared with children with primary snoring. Multiple linear regression analyses revealed an independent association between AHI and nighttime systolic BP and MAP after adjusting for adiposity variables.This large hospital-based study showed that children with moderate-to-severe OSA had a higher ABP compared with children who were primary snorers. As elevated BP in childhood predicts future cardiovascular risks, children with severe OSA should be treated properly to prevent further adverse cardiovascular outcomes.

Severe Bacterial Infection in Patients with Heterotaxy Syndrome

OBJECTIVE To determine the incidence of sepsis in patients with heterotaxy syndrome. STUDY DESIGN From our institutional database, we identified patients with heterotaxy syndrome and other complex congenital heart disease (CHD) born between 2001 and 2011. Severe bacterial infection was defined as sepsis with positive culture result or infection with abscess formation. RESULTS We enrolled 95 patients with heterotaxy syndrome (88 with right atrial isomerism and 7 with left atrial isomerism) and 142 patients with complex CHD. With 1026 person-years follow-up, the 5-year survival was 52% and 65.7% in heterotaxy and complex CHD groups, respectively (P = .239). Community-acquired severe bacterial infection occurred only in heterotaxy syndrome (13 episodes in 10 patients, 3 of whom had spleen noted at imaging study) with 2- and 5 years cumulative severe bacterial infection rate of 9.6% and 14.5%, respectively. The overall mortality rate of those with community-acquired severe bacterial infection was 31%. Pneumococcus and Citrobacter freundii were the most common pathogens. Nosocomial severe bacterial infection occurred in 33.3% of all patients and 12.5% of all procedures. The rates (0.59 and 0.52/100 hospitalization days in heterotaxy and complex CHD group) and the pathogens of nosocomial severe bacterial infection were similar between heterotaxy and complex CHD groups. CONCLUSIONS Patients with heterotaxy syndrome are at high risk for community-acquired severe bacterial infection and also have high mortality rate whether the spleen is present or not. The risk of nosocomial severe bacterial infection seems similar to that of patients with other complex CHD.

Implication of early-onset biliary atresia and extrahepatic congenital anomalies.

Background:  The aim of the present study was to determine the rate of early‐onset biliary atresia (BA) and its implications, for embryonic‐type BA in Taiwan, a high‐prevalence area for BA. The relationship between the timing of disease onset and congenital extrahepatic anomalies was also identified.

Genetic Syndromes and Outcome After Surgical Repair of Pulmonary Atresia and Ventricular Septal Defect

BACKGROUND Genetic syndromes, especially 22q11 deletion (del22q11) syndrome, are common in patients with pulmonary atresia and ventricular septal defect (PA-VSD), but their association with long-term outcomes varies. The purpose of this study was to evaluate the long-term outcome after complete repair of PA-VSD and to determine the impact of genetic syndromes. METHODS We reviewed our experience of 125 patients with PA-VSD who received primary or staged repair between 1978 and 2010. Evaluations for genetic syndromes included clinical features, cytogenetic analysis, and fluorescence in situ hybridization or multiplex ligation-dependent probe amplification. RESULTS Genetic syndromes were documented in 26 patients (20.8%), including del22q11 in 16 patients, trisomy 21 in 2 patients, and other syndromes in 8 patients. The prevalence of hypoplastic pulmonary arteries was not significantly different between the syndromic and nonsyndromic groups. After 1,069 patient-years of follow-up, 20-year survival was 90% ± 6% in patients without syndromes and 14% ± 23% in patients with syndromes (p < 0.01). Multivariate analysis identified the presence of a genetic syndrome as an important risk factor for hospital and late mortality. Subgroup analysis showed that genetic syndromes other than del22q11 were associated with worse outcome. The rate of 10-year freedom from cardiac reintervention after repair was 53% ± 11%, with hypoplastic pulmonary arteries before repair as a major risk factor (p = 0.02). CONCLUSIONS Genetic syndromes significantly affect survival after repair of PA-VSD, whereas genetic syndromes do not represent additional risk for reintervention. Repair is feasible in patients with syndromes, but suboptimal long-term outcome should be addressed when counseling parents.

Abnormal Matrix Remodeling in Adolescents and Young Adults with Kawasaki Disease Late after Onset

BACKGROUND Patients with a history of Kawasaki disease (KD), have been found to have pericoronary and myocardial fibrosis. Serum biomarkers of fibrosis may be sensitive indices for detection of these late cardiac complications in KD patients. METHODS We studied a cohort of 60 adolescents and young adults comprising 10 KD patients with persistent coronary artery lesions (CAL) occurring at a mean (SD) time of 14.5 (4.4) years after disease onset, 25 KD patients with no CAL after disease onset, and 25 healthy age-matched volunteers. We compared laboratory data from the patients and volunteers, including lipid profile, liver function, amino-terminal propeptide of type III procollagen (PIIINP), matrix metalloproteinase 9 (MMP-9), tissue inhibitor of metalloproteinase 1 (TIMP-1), and MMP-9:TIMP-1 ratios. Severity of CAL was determined on the basis of computed tomography determinations of the frequency of aneurysms and the extent of coronary stenosis/occlusion, thrombosis, and calcification. RESULTS Increased PIIINP and decreased MMP-9 and TIMP-1 concentrations and decreased MMP-9:TIMP-1 ratios were found not only in KD patients with persistent CAL but also in KD patients without CAL, although to a lesser extent in the latter group. In KD patients, the concentrations of PIIINP were positively associated with the severity of coronary stenosis/occlusion (r = 0.72, P = 0.011) and with the extent of coronary thrombus (r = 0.64, P = 0.014). The concentrations of high-sensitivity C-reactive protein, however, did not differ across groups. CONCLUSIONS Our results demonstrate alterations in extracellular matrix biomarkers in KD patients, suggesting enhanced collagen synthesis and ameliorated degradation in adolescents and young adults late after the onset of KD. We also observed an association between the concentrations of PIIINP and the extent of coronary stenosis/occlusion or thrombosis in KD patients, a finding that needs confirmation in further studies.