Hsin Hui Chiu

Losartan Added to β-Blockade Therapy for Aortic Root Dilation in Marfan Syndrome: A Randomized, Open-Label Pilot Study

OBJECTIVE To assess the tolerability and efficacy of the investigational use of the angiotensin II receptor blocker losartan added to β-blockade (BB) to prevent progressive aortic root dilation in patients with Marfan syndrome (MFS). PATIENTS AND METHODS Between May 1, 2007, and September 31, 2011, 28 patients with MFS (11 males [39%]; mean ± SD age, 13.1±6.3 years) with recognized aortic root dilation (z score >2.0) and receiving BB (atenolol or propranolol) treatment were enrolled. They were randomized to receive BB (BB: 13 patients) or β-blockade and losartan (BB-L: 15 patients) for 35 months. RESULTS In the BB-L group, aortic root dilation was reduced with treatment, and the annual dilation rate of the aortic root was significantly lower than that of the BB group (0.10 mm/yr vs 0.89 mm/yr; P=.02). The absolute aortic diameters at the sinus of Valsalva, annulus, and sinotubular junction showed similar trends, with a reduced rate of dilation in the BB-L group (P=.02, P=.03, and P=.03, respectively). Five patients (33%) treated with BB-L were noted to have a reduced aortic root diameter. However, the differences between the groups regarding changes in aortic stiffness and cross-sectional compliance were not statistically significant. CONCLUSION This randomized, open-label, active controlled trial mostly based on a pediatric population demonstrated for the first time that losartan add-on BB therapy is safe and provides more effective protection to slow the progression of aortic root dilation than does BB treatment alone in patients with MFS. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00651235.

Quality of life in adults with congenital heart disease: biopsychosocial determinants and sex-related differences

Objectives To assess the quality of life (QoL) in adults with congenital heart disease (ACHD) and to explore the sex-related differences and biopsychosocial determinants in an Asian cohort. Design Prospective cross-sectional clinical study. Setting One tertiary medical centre in Taiwan. Patients and methods The QoL of ACHD (≥20 years) was investigated using the Taiwanese version of the QoL questionnaire designed by the WHO, which assesses four domains of QoL (physical, psychological, social and environmental). Personality, psychological distress and family support were assessed using the Maudsley Personality Inventory, Brief Symptom Rating Scale, and the Family APGAR score, respectively. Results A total of 289 patients (age 33.2±10.6 years; 36% men) were studied. ACHD women had significantly lower QoL scores in the physical and psychological domains compared to the age-matched general population, whereas no differences were observed between ACHD men and the general population. Multivariate analysis showed that female gender was associated with poorer physical QoL; the sex difference in the psychological QoL was mediated by psychological distress. Interaction analysis showed that the effect of family support on the psychological domain of QoL may be different by sex. The determinants of QoL varied between different domains. Extroversion personality trait, psychological distress and family support were common determinants of most domains of QoL. Conclusions In ACHD, female gender was associated with poor physical and psychological QoL. The common denominators for QoL were primarily personality trait, psychological distress and family support, but not disease severity.

Epidemiological Profile of Marfan Syndrome in a General Population: A National Database Study

OBJECTIVE To explore the current epidemiological profile of Marfan syndrome in a general population. PATIENTS AND METHODS Patients who had received a diagnosis of Marfan syndrome were identified from the Taiwan National Health Insurance database records from January 1, 2000, through December 31, 2012 (average population size, 22,765,535). Cardiovascular events and interventions were identified by using the respective International Classification of Diseases codes. RESULTS We identified 2329 patients (58% men) with Marfan syndrome. The overall prevalence was 10.2 (95% CI, 9.8-10.7) per 100,000 individuals, with peaks at the age of 15 to 19, 10 to 14, and 20 to 24 years. The minimal birth incidence of 23.3 (95% CI, 21.7-23.3) per 100,000 individuals was estimated in those aged 20 to 29 years. The average annual mortality was 0.23% (69 deaths), mostly owing to cardiac causes (including dissection and sudden death in 40 patients, 58%). Aortic dissection occurred in 226 patients (10%; 61% men) at a mean age of 36.6±10.7 years. The probability of freedom from dissection was 99%, 80%, and 66% at the age of 20, 40, and 50 years, respectively. Of the 69 deaths and 226 dissections during the follow-up period, more than half of the cases occurred before the age of 40 years. Cardiovascular intervention was performed in 360 patients, with early mortality being higher in the emergent operation group (8%) than in the elective group (0%). CONCLUSION From this national cohort study, the minimal birth incidence was 23.3 per 100,000 individuals, that is, possibly 1 patient with Marfan syndrome per 4286 people. Despite medical advances, aortic dissection still occurs in about one-tenth of the patients and carries a high mortality risk. Early diagnosis and timely medical interventions are warranted.

Population-based study of pediatric sudden death in Taiwan

OBJECTIVES We sought to estimate the incidence of pediatric sudden death (SD) in Taiwan. STUDY DESIGN Cases of SD were identified from National Health Insurance databases, 2000 to 2006. RESULTS In the Taiwan pediatric population (age, 0 to 18 years; 5.44 million), the neonatal, infant, postneonatal infant, and under-5 years mortality rates were 3, 6, 2.81, and 8.02 per 1000 live births, and the 1 to 18 years mortality rate was 33 per 100 000 person-years. There were 1528 SDs (59% boys). In the population 1 to 18 years, annual incidence of SD was 2.7 (95% confidence interval, 2.6 to 2.9), ranging from 0.7 (11 to 12 years) to 6.1 (1 to 2 years) per 100 000. Male predominance was noted (3.2 vs 2.2 per 100 000), particularly in groups ages 16, 17, and 18 years. The proportionate mortality ratio by SD ranged from 1.8% to 12.0% (8.9 +/- 2.2%), being lowest in the group ages 11 to 12 years. In infants, the incidence of SD was 0.36 per 1000 live births, and the proportionate mortality ratio by SD was 1.0% and 11.7% in the neonates and postneonatal infants. CONCLUSIONS The incidence of pediatric SD in Taiwan, an Asian country with a child health care index comparable with that in the United States, was within the range from Western reports and indicated male predominance and a nadir around 11 to 12 years.

Comparison of 3 risk estimation methods for predicting cardiac outcomes in pregnant women with congenital heart disease

BACKGROUND Three risk estimation methods for predicting the cardiac outcomes of pregnancy in women with heart disease have been proposed. This study was designed to compare their prediction performance in an Asian cohort with congenital heart disease (CHD). METHODS AND RESULTS This study enrolled pregnant women with CHD who delivered their babies after the 20th gestational week between 1985 and 2011. Of 268 pregnancies in 190 women with CHD, 18 (6.7%) had cardiac complications. The incidence of maternal cardiac events among women with a CARPREG index of 0, 1 or 2 was 3.4%, 27.3% and 100%. The incidence was 2.7%, 8.6%, 11.1%, 40% and 17.6% for those with a ZAHARA score 0-0.5, 0.51-1.5, 1.51-2.5, 2.51-3.5 and >3.5. Among patients with a modified World Health Organization (WHO) classification I, II, III and IV, the incidence of maternal cardiac events was 0%, 4.0%, 12.2% and 25.7%. The c-statistic was 0.732 (95% confidence interval (CI): 0.589, 0.876; P<0.001) for the CARPREG score, 0.737 (95% CI: 0.611, 0.864; P=0.001) for the ZAHARA score and 0.827 (95% CI: 0.745, 0.909; P<0.001) for the WHO classification. CONCLUSIONS All 3 risk estimation methods had good performance in predicting maternal cardiac outcomes; however, the modified WHO classification demonstrated superior discrimination and calibration.

Mutation spectrum of the fibrillin‐1 (FBN1) gene in Taiwanese patients with Marfan syndrome

The aim of this study was to establish a national database of mutations in the fibrillin‐1 (FBN1) gene that cause Marfan syndrome (MFS) in the Taiwanese population. In this study, we screened 294 patients from 157 families for the presence of FBN1 mutations using polymerase chain reaction/ denaturing high performance liquid chromatography (PCR/DHPLC). We identified 56 mutations in 62 of the 157 (40%) families including 49 single‐base substitutions (36 missense mutations, seven nonsense mutations, and six splicing sites), one small insertion, four small deletions, one small indel (insertion and deletion), and one exonic deletion (Exon 36). When family history was taken into consideration, the mutation detection rate rose to 91% (29 of 32). We further investigated the phenotypic data and found that one third (47 of 157) of the families fit the Ghent criteria for MFS. Based on that data, the mutation rate was 98% (46/47). That finding implies that family history and the Ghent criteria play a more important role than clinical manifestations in establishing a clinical diagnosis of Marfan syndrome. Among the 56 mutations found in this study, 40 (71%) have not been registered in the Human Gene Mutation Database (HGMD) or in the Universal Mutation Database (UMD). This is the first study of the mutation spectrum of MFS in a cohort of patients in Taiwan. The database is expected to considerably improve genetic counseling for and medical care of MFS families.

Left ventricular geometry, global function, and dyssynchrony in infants and children with pompe cardiomyopathy undergoing enzyme replacement therapy.

BACKGROUND Enzyme replacement therapy (ERT) for infantile-onset Pompe disease effectively reduces the left ventricular (LV) mass. This study sought to explore detailed process of LV reverse remodeling after ERT with the use of tissue Doppler and stain rate imaging. METHODS AND RESULTS Nine infants and children with Pompe cardiomyopathy undergoing ERT for ≥1 year, as well as 36 healthy control subjects, were studied. Global systolic and diastolic function was evaluated by peak systolic and early-diastolic velocity at mitral annulus. Temporal systolic and diastolic dyssynchrony was evaluated by the coefficient of variation of the time from the QRS complex to peak systolic and early-diastolic strain rate among 12 LV segments. All pre-ERT patients had impaired global systolic and diastolic function as well as increased regional dyssynchrony (P < .001 for each of all). During the regression of LV hypertrophy, all of these functional indices improved (P for trend <.001), with temporal diastolic dyssynchrony being a significant factor linking to LV mass index in multivariate analysis (P < .001). CONCLUSIONS ERT improved global LV function and dyssynchrony in Pompe patients. The relationship between LV mass and temporal diastolic dyssynchrony during reverse remodeling suggested a pathophysiologic role of dyssynchrony in Pompe cardiomyopathy.

Increased microvolt T-wave alternans in patients with repaired tetralogy of Fallot

BACKGROUND Microvolt T wave alternans (MTWA) is an indicator of repolarization heterogeneity and a predictor of ventricular arrhythmia in adults with ischemic or dilated cardiomyopathy. Its implication in patients with repaired tetralogy of Fallot (TOF) is still unclear. This study sought to define the changes and the clinical implication of MTWA in these patients. METHODS Treadmill examination with modified moving average beat analysis (MMA) for MTWA was performed in 101 repaired TOF patients (60.4% male). Data from 103 age- and sex-matched subjects with normal hearts served as controls. RESULTS The age at latest follow-up was 20.0 ± 10.6 years. Total repair (60.4% received a transannular right ventricular outflow patch) was performed at a mean age of 4.8(± 5.8) years. After excluding 11 patients with indeterminate data, the MTWA data in 90 TOF patients revealed higher values than those in the control (25.1 ± 14.0 vs. 17.6 ± 9.2 μV, p<0.001). The values were best correlated to the presence of severe pulmonary regurgitation (p=0.006). Ten (9.9%) patients experienced late ventricular arrhythmic events. They tended to have higher MTWA values than those without (34.0 ± 16.5 vs. 24.2 ± 13.5 and p=0.053). Although the MTWA per se would not predict the late arrhythmia events better than QRS duration alone, the positive and negative predictive values increased slightly after adding the MTWA to QRS duration. CONCLUSIONS MTWA, as measured by MMA, increased in repaired TOF patients particularly in those with severe pulmonary regurgitation and late arrhythmia events. To predict late ventricular arrhythmia, MTWA however was not superior to QRS duration alone.

Identification of fibrillin-1 gene mutations in Marfan syndrome by high-resolution melting analysis

Marfan syndrome has been associated with approximately 562 mutations in the fibrillin-1 (FBN1) gene. Mutation scanning of the FBN1 gene with DNA direct sequencing is time-consuming and expensive because of its large size. This study analyzed the diagnostic value of high-resolution melting analysis as an alternative method for scanning of the FBN1 gene. A total of 75 polymerase chain reaction (PCR) amplicons (179-301bp, average 256bp) that covered the complete coding regions and splicing sites were evaluated on the 96-well LightCycler system. Melting curves were analyzed as fluorescence derivative plots (-dF/dT vs. temperature). To determine the sensitivity of this method, a total of 82 samples from patients with Marfan syndrome and 50 unaffected individuals were analyzed. All mutations reported in this study had been confirmed previously by direct sequencing analysis. Melting analysis identified 48 heterozygous variants. The variant c.3093 G>T (exon 25) was incorrectly identified by melting curve analysis. The sensitivity of the technique in this sample was 98.78% (81/82). This study demonstrated that high-resolution melting analysis is a reliable gene scanning method with greater speed than DNA sequencing. Our results support the use of this technology as an alternative method for the diagnosis of Marfan syndrome as well as its suitability for high-throughput mutation scanning of other large genes.

The EXIT (Ex Utero Intrapartum Treatment) procedure

Fetuses with upper airway obstruction have a high mortality rate if proper airway management is not immediately administered after delivery. The EXIT (ex utero intrapartum treatment) procedure is a new technique that establishes the fetal airway while uteroplacental circulation is still maintained. The prognosis of such neonates has much improved after the introduction of this procedure. We report two neonates with prenatal diagnosis of upper airway obstruction; they were born smoothly via the EXIT procedure. The first was a case of epignathus, a rare type of nasopharyngeal or oropharyngeal teratoma derived from all three germ cell layers with variable maturity. The second was a case of giant lymphangioma that resulted from localized malformations in the development of the lymphatic system. Furthermore, compared with routine cesarean section, the short-term maternal outcomes were not different with regard to infection rate, estimated blood loss, wound complication, and postpartum hospital stay.