Prenatal Vitamin D Supplementation and Child Respiratory Health: A Randomised Controlled Trial

PMCID: PMC3691177This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Riata lead failure in pediatric and congenital heart disease patients

BackgroundImplantable cardioverter defibrillator (ICD) lead failures occur at higher rates in pediatric and congenital heart disease (CHD) patients.ObjectiveTo determine the rate and timing of Riata lead failure in pediatric and CHD patients.MethodsThis was a retrospective, multicenter cohort study of pediatric patients and adults with CHD with implantation of a Riata or Riata ST lead between 2002 and 2009. The prevalence and timing of electrical failure and conductor coil externalization (CCE) were determined.ResultsFiftyâ eight patients and 63 leads from seven centers were included. Median (interquartile range [IQR]) age at implant was 14.4 (11.5â 18.7) years and median followâ up was 8.7 (7.3â 11.1) years. The underlying diagnosis was a primary arrhythmia disorder in 45%, cardiomyopathy in 31%, and CHD in 28% of patients. Electrical failure occurred in 43% and CCE in 16% of leads at median lead ages of 4.7 (3.4â 7.5) and 4.3 (3.9â 7.0) years, respectively. Median lead survival free from electrical failure or CCE was 7.9 (95% confidence interval, 5.8â 10.0) years. Fortyâ one percent of leads were functional at the end of the followâ up period, and 33% were extracted with a complication rate of 5%.ConclusionsThe rate of Riata lead electrical failure was high in children and patients with CHD, while the rate of CCE was comparable with published data. Counseling on lead management should factor in the high rate of electrical failure with considerations for elective replacement.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/148409/1/jce13812_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148409/2/jce13812.pd

Efficacy of Ryr2 Inhibitor EL20 in Induced Pluripotent Stem Cell-Derived Cardiomyocytes from a Patient with Catecholaminergic Polymorphic Ventricular Tachycardia.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited cardiac arrhythmia syndrome that often leads to sudden cardiac death. The most common form of CPVT is caused by autosomal-dominant variants in the cardiac ryanodine receptor type-2 (RYR2) gene. Mutations in RYR2 promote calcium (Ca ) leak from the sarcoplasmic reticulum (SR), triggering lethal arrhythmias. Recently, it was demonstrated that tetracaine derivative EL20 specifically inhibits mutant RyR2, normalizes Ca handling and suppresses arrhythmias in a CPVT mouse model. The objective of this study was to determine whether EL20 normalizes SR Ca handling and arrhythmic events in induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from a CPVT patient. Blood samples from a child carrying RyR2 variant RyR2 variant Arg-176-Glu (R176Q) and a mutation-negative relative were reprogrammed into iPSCs using a Sendai virus system. iPSC-CMs were derived using the Stemdiff kit. Confocal Ca imaging was used to quantify RyR2 activity in the absence and presence of EL20. iPSC-CMs harbouring the R176Q variant demonstrated spontaneous SR Ca release events, whereas administration of EL20 diminished these abnormal events at low nanomolar concentrations (IC = 82 nM). Importantly, treatment with EL20 did not have any adverse effects on systolic Ca handling in control iPSC-CMs. Our results show for the first time that tetracaine derivative EL20 normalized SR Ca handling and suppresses arrhythmogenic activity in iPSC-CMs derived from a CPVT patient. Hence, this study confirms that this RyR2-inhibitor represents a promising therapeutic candidate for treatment of CPVT

In silico prediction of drug therapy in catecholaminergic polymorphic ventricular tachycardia.

Key pointsThe mechanism of therapeutic efficacy of flecainide for catecholaminergic polymorphic ventricular tachycardia (CPVT) is unclear. Model predictions suggest that Na(+) channel effects are insufficient to explain flecainide efficacy in CPVT. This study represents a first step toward predicting therapeutic mechanisms of drug efficacy in the setting of CPVT and then using these mechanisms to guide modelling and simulation to predict alternative drug therapies. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by fatal ventricular arrhythmias in structurally normal hearts during β-adrenergic stimulation. Current treatment strategies include β-blockade, flecainide and ICD implementation--none of which is fully effective and each comes with associated risk. Recently, flecainide has gained considerable interest in CPVT treatment, but its mechanism of action for therapeutic efficacy is unclear. In this study, we performed in silico mutagenesis to construct a CPVT model and then used a computational modelling and simulation approach to make predictions of drug mechanisms and efficacy in the setting of CPVT. Experiments were carried out to validate model results. Our simulations revealed that Na(+) channel effects are insufficient to explain flecainide efficacy in CPVT. The pure Na(+) channel blocker lidocaine and the antianginal ranolazine were additionally tested and also found to be ineffective. When we tested lower dose combination therapy with flecainide, β-blockade and CaMKII inhibition, our model predicted superior therapeutic efficacy than with flecainide monotherapy. Simulations indicate a polytherapeutic approach may mitigate side-effects and proarrhythmic potential plaguing CPVT pharmacological management today. Importantly, our prediction of a novel polytherapy for CPVT was confirmed experimentally. Our simulations suggest that flecainide therapeutic efficacy in CPVT is unlikely to derive from primary interactions with the Na(+) channel, and benefit may be gained from an alternative multi-drug regimen

Risk of cardiac disease and observations on lack of potential predictors by clinical history among children presenting for cardiac evaluation of mid-exertional syncope

This study aimed to evaluate the incidence of cardiac disorders among children with mid-exertional syncope evaluated by a paediatric cardiologist, determine how often a diagnosis was not established, and define potential predictors to differentiate cardiac from non-cardiac causes. Study design We carried out a single-centre, retrospective review of children who presented for cardiac evaluation due to a history of exertional syncope between 1999 and 2012. Inclusion criteria included the following: (1) age ⩽18 years; (2) mid-exertional syncope; (3) electrocardiogram, echocardiogram and an exercise stress test, electrophysiology study, or tilt test, with exception of long QT, which did not require additional testing; and (4) evaluation by a paediatric cardiologist. Mid-exertional syncope was defined as loss of consciousness in the midst of active physical activity. Patients with peri-exertional syncope immediately surrounding but not during active physical exertion were excluded. A total of 60 patients met the criteria for mid-exertional syncope; 32 (53%) were diagnosed with cardiac syncope and 28 with non-cardiac syncope. A majority of cardiac patients were diagnosed with an electrical myopathy, the most common being Long QT syndrome. In nearly half of the patients, a diagnosis could not be established or syncope was felt to be vasovagal in nature. Neither the type of exertional activity nor the symptoms or lack of symptoms occurring before, immediately preceding, and after the syncopal event differentiated those with or without a cardiac diagnosis. Children with mid-exertional syncope are at risk for cardiac disease and warrant evaluation. Reported symptoms may not differentiate benign causes from life-threatening disease

In-hospital arrhythmia development and outcomes in pediatric patients with acute myocarditis

Cardiac arrhythmias are a complication of myocarditis. There are no large studies of in-hospital arrhythmia development and outcomes in pediatric patients with acute myocarditis. This was a retrospective 2-center review of patients ≤21 years hospitalized with acute myocarditis from 1996 to 2012. Fulminant myocarditis was defined as the need for inotropic support within 24 hours of presentation. Acute arrhythmias occurred at presentation and subacute after admission. Eighty-five patients (59% men) presented at a median age of 10 years (1 day to 18 years). Arrhythmias occurred in 38 patients (45%): 16 acute, 12 subacute, and 9 acute and subacute (1 onset unknown). Arrhythmias were associated with low voltages on the electrocardiogram (14 of 34, 41% vs 6 of 47, 13%; odds ratio [OR] 4.78, 95% confidence interval [CI] 1.60 to 14.31) and worse outcome (mechanical support, orthotopic heart transplant, or death; OR 7.59, 95% CI 2.61 to 22.07) but were not statistically significantly associated with a fulminant course, ST changes, initial myocardial function, lactate, creatinine level, C-reactive protein and/or erythrocyte sedimentation rate, or troponin I level, after adjusting for multiple comparisons. Subacute arrhythmias were associated with preceding ST changes (10 of 15, 67% vs 15 of 59, 25%, OR 5.87, 95% CI 1.73 to 19.93). All patients surviving to discharge had arrhythmia resolution or control before discharge (10 on antiarrhythmic), with 1 exception (patient with complete heart block requiring a pacemaker). At 1-year follow-up, there were 3 recurrences of ventricular arrhythmias, but no arrhythmia-related mortality. In conclusion, arrhythmias are common in pediatric patients with myocarditis, occurring in nearly 1/2 of all hospitalized children and are associated with a worse outcome. Early identification of subacute arrhythmias using electrocardiographic changes may help management. A majority of patients do not require continued postdischarge arrhythmia treatment

Distinct Cellular Basis for Early Cardiac Arrhythmias, the Cardinal Manifestation of Arrhythmogenic Cardiomyopathy, and the Skin Phenotype of Cardiocutaneous Syndromes

Arrhythmogenic cardiomyopathy is caused primarily by mutations in genes encoding desmosome proteins. Ventricular arrhythmias are the cardinal and typically early manifestations, whereas myocardial fibroadiposis is the pathological hallmark. HomozygousDSP(desmoplakin) andJUP(junction protein plakoglobin) mutations are responsible for a subset of patients with arrhythmogenic cardiomyopathy who exhibit cardiac arrhythmias and dysfunction, palmoplanter keratosis, and hair abnormalities (cardiocutaneous syndromes)