Background-Fetal long QT syndrome (LQTS) is associated with complex arrhythmias including torsades de pointes and 2°atrioventricular block. Sinus bradycardia has also been associated with fetal LQTS, but little is known of this rhythm manifestation. Our purpose was to characterize the fetal heart rate (FHR)/gestational age (GA) profile of fetal LQTS. Methods and Results-We ascertained fetal LQTS subjects by family history (Group 1) or fetal arrhythmia referral (Group 2). We compared FHR in LQTS subjects versus normal fetuses. To identify FHR predictors of LQTS, we calculated a bradycardia index as % of LQTS FHR recordings either Յ110 beats per minute (obstetric standard) or Յ3 rd percentile for GA. Among 42 LQTS subjects, 26 were in Group 1 and 16 in Group 2. There were 536 normal fetuses. The bradycardia index was only 15% for FHR Յ110 beats per minute, but 66% for FHR Յ3rd percentile for GA. Ten fetuses with complex arrhythmias also had severe and sustained sinus bradycardia throughout gestation. Identifying a fetal proband in Group 2 resulted in LQTS diagnosis in 9 unsuspected members of 6 families. Conclusions-FHR varies by GA in both normal and LQTS fetuses. Postnatal evaluation of neonates with FHR Յ3rd percentile for GA may improve ascertainment of LQTS in fetuses, neonates, and undiagnosed family members. (Circulation. 2012;126: 2688-2695.) Key Words: arrhythmias, cardiac Ⅲ fetus Ⅲ long-QT syndrome L ong QT syndrome (LQTS) is reported to have an incidence of 1 in 2500 individuals. Although QT interval prolongation may be an incidental finding, LQTS typically presents in adolescence or young adult life with syncope, sudden death, or cardiac arrest. 1,2 Less frequently, LQTS presents in the perinatal (fetal/neonatal) period; in this setting morbidity and mortality are high, and torsades de pointes (TdP) and 2°atrioventricular (AV) block are signature rhythms. [3][4][5][6] Sinus bradycardia is also a manifestation of fetal LQTS and is reported to be more common than TdP and 2°AV block. For example, as many as 44% to 66% of fetuses diagnosed with LQTS presented with sinus bradycardia at 26 to 40 weeks of gestation. 3,6 -8 In most reports, a fetal heart rate (FHR) Յ110 beats per minute (bpm) at any gestational age (GA) raised suspicion of LQTS. Indeed, FHR of Յ110 bpm at any GA is the obstetric definition of sinus bradycardia. 9 However, little is known of the sensitivity of this finding and how it relates to the subsequent diagnosis of LQTS. Clinical Perspective on p 2695It is well known that FHR in the normal fetus decreases during gestation from about 175 bpm at 10 weeks to 138 bpm at 40 weeks. This phenomenon is believed to be attributable to the increasing dominance of the parasympathetic nervous system on heart rate control as gestation progresses. 10,11 Despite the association between fetal bradycardia and LQTS, the FHR/GA profile, or the range of FHRs of subjects with LQTS, has not been defined. We wondered whether there might be a pathological FHR in the setting of 1:1 AV conduction that was below n...
Background Disorders of the Ras/MAPK pathway have an overlapping skeletal phenotype (eg. scoliosis, osteopenia). The Ras proteins regulate cell proliferation and differentiation and NF1 individuals have osteoclast hyperactivity and increased bone resorption as measured by urine pyridinium crosslinks [pyridinoline (Pyd) and deoxypyridinoline (Dpd)]. Pyd and Dpd are hydroxylysine derived cross-links of collagen found in bone and cartilage and excreted in the urine. Dpd is most abundant in bone. The aim of this study was to evaluate if other syndromes of the Ras/MAPK pathway have increased bone resorption, which may impact the skeletal phenotype. Methods and Results Participants: [Noonan syndrome (n=14), Costello syndrome (n=21), and cardiofaciocutaneous (CFC) syndrome (n=14)]. Pyridinium cross-links from two consecutive first morning urines were extracted after acid hydrolysis and analyzed by High Performance Liquid Chromotography. Three separate analyses of covariance (ANCOVA) were performed to compare Pyd, Dpd, and Dpd/Pyd ratio of each group to controls after controlling for age. Data were compared to 99 healthy controls. Conclusions The Dpd and the Dpd/Pyd ratio were elevated (p<0.0001) in all 3 conditions compared to controls suggesting that collagen degradation was predominantly from bone. The data suggest that the Ras/MAPK signal transduction pathway is important in bone homeostasis.
Rationale Genetic testing for Long QT Syndrome (LQTS) is now a standard and integral component of clinical cardiology. A major obstacle to the interpretation of genetic findings is the lack of robust functional assays to determine the pathogenicity of identified gene variants in a high throughput manner. Objective The goal of this study was to design and test a high throughput in vivo cardiac assay to distinguish between disease-causing and benign KCNH2 (hERG1) variants, using the zebrafish as a model organism. Methods and Results We tested the ability of previously characterized LQTS hERG1 mutations and polymorphisms to restore normal repolarization in the kcnh2-knockdown embryonic zebrafish. The cardiac assay correctly identified a benign variant in 9 of 10 cases (negative predictive value 90%) while correctly identifying a disease-causing variant in 39/39 cases (positive predictive value 100%). Conclusion The in vivo zebrafish cardiac assay approaches the accuracy of the current benchmark in vitro assay for the detection of disease-causing mutations and is far superior in terms of throughput rate. Together with emerging algorithms for interpreting a positive LQTS genetic test, the zebrafish cardiac assay provides an additional tool for the final determination of pathogenicity of gene variants identified in LQTS genetic screening.
High-molecular-weight HA supplementation in culture medium had a dose-dependent effect on matrix production and thus chondrogenic differentiation of MSCs cultured on chitosan sponges. The addition of HA in the surrounding fluid during chondrogenesis should improve cartilage production and may be useful for producing engineered cartilage tissues.
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