V. Ramesh Iyer

Genotype- and mutation site-specific QT adaptation during exercise, recovery, and postural changes in children with long-QT syndrome.

Background— Exercise stress testing has shown diagnostic utility in adult patients with long-QT syndrome (LQTS); however, the QT interval adaptation in response to exercise in pediatric patients with LQTS has received little attention. Methods and Results— One-hundred fifty-eight patients were divided into 3 groups: Those with LQTS type 1 (LQT1) or LQTS type 2 (LQT2) and normal control subjects without cardiovascular disease. Each patient underwent a uniform exercise protocol with a cycle ergometer followed by a 9-minute recovery phase with continuous 12-lead ECG monitoring. Each patient underwent a baseline ECG while resting in the supine position and in a standstill position during continuous ECG recording to determine changes in the QT and RR intervals. Fifty patients were gene-positive for LQTS (n=29 for LQT1 and n=21 for LQT2), and the control group consisted of 108 patients. QT interval adaptation was abnormal in the LQT1 patients compared with LQT2 and control patients (P<0.001). A corrected QT interval (QTc) >460 ms in the late recovery phase at 7 minutes predicted LQT1 or LQT2 versus control subjects with 96% specificity, 86% sensitivity, and a 91% positive predictive value. A recovery &Dgr;QTc(7 min−1 min) >30 ms predicted LQT2 versus LQT1 with 75% sensitivity, 82% specificity, and a 75% positive predictive value. The postural &Dgr;QT was significantly different between LQTS and control groups (P=0.005). Conclusions— Genotype-specific changes in repolarization response to exercise and recovery exist in the pediatric population and are of diagnostic utility in LQTS. An extended recovery phase is preferable to assess the repolarization response after exercise in the pediatric population.

Cardiovascular deaths in children: General overview from the National Center for the Review and Prevention of Child Deaths

BACKGROUND Cardiovascular conditions rank sixth in causes of death in 1- to 19-year-olds. Our study is the first analysis of the cardiovascular death data set from the National Center for the Review and Prevention of Child Deaths, which provides the only systematic collection of cardiovascular deaths in children. METHODS We developed an analytical data set from the National Center for the Review and Prevention of Child Deaths database for cardiovascular deaths in children 0 to 21 years old, reviewing 1,098 cases from 2005 to 2009 in 16 states who agreed to participate. RESULTS Cardiovascular cases were aged 4.8 ± 6.6 years; 55.3%, ≤1 year; 24.6%, ≥10 years; male, 58%; white, 70.5%; black, 22.3%; Hispanic, 19.5%. Prior conditions were present in 48.5%: congenital heart disease, 23%; cardiomyopathies, 4.6%; arrhythmia, 1.7%; and congestive heart failure, 1.6%. Deaths occurred most frequently in urban settings, 49.2%; and in the hospital, 40.4%; home, 26.1%; or at school/work/sports, 4.8%. Emergency medical services were not evenly distributed with differences by age, race, ethnicity, and area. Autopsies (40.4%) occurred more often in those >10 years old (odds ratio [OR] 2.9), blacks (OR 1.6), or in those who died at school/work/sports (OR 3.9). The most common cardiovascular causes of death included congenital heart disease, 40.8%; arrhythmias, 27.1%; cardiomyopathy, 11.8%; myocarditis, 4.6%; congestive heart failure, 3.6%; and coronary artery anomalies, 2.2%. CONCLUSIONS Our study identified differences in causes and frequencies of cardiovascular deaths by age, race, and ethnicity. Prevention of death may be impacted by knowledge of prior conditions, emergency plans, automated external defibrillator programs, bystander cardiopulmonary resuscitation education, and by a registry for all cardiovascular deaths in children.

Increased mitochondrial nanotunneling activity, induced by calcium imbalance, affects intermitochondrial matrix exchanges.

Significance Nanotunnels are long, thin mitochondrial extensions that have been implied in direct long-distance (1 to >5 µm) communication between mitochondria of cardiac myocytes. The engineered RyR2A4860G+/− mutation, resulting in loss of function of the sarcoplasmic reticulum calcium release channel and arrhythmia, induces a striking increase in the frequency of long-distance intermitochondrial communication via nanotunnels without involvement of obvious mitochondrial migration. We use this model for exploring the significance of mitochondrial nanotunneling in myocardium and the contribution of microtubules to the formation of these unusual organelle extensions using EM tomography and live confocal imaging. This study constitutes an approach to arrhythmia investigations that focuses on a new target: the mitochondria. Exchanges of matrix contents are essential to the maintenance of mitochondria. Cardiac mitochondrial exchange matrix content in two ways: by direct contact with neighboring mitochondria and over longer distances. The latter mode is supported by thin tubular protrusions, called nanotunnels, that contact other mitochondria at relatively long distances. Here, we report that cardiac myocytes of heterozygous mice carrying a catecholaminergic polymorphic ventricular tachycardia-linked RyR2 mutation (A4860G) show a unique and unusual mitochondrial response: a significantly increased frequency of nanotunnel extensions. The mutation induces Ca2+ imbalance by depressing RyR2 channel activity during excitation–contraction coupling, resulting in random bursts of Ca2+ release probably due to Ca2+ overload in the sarcoplasmic reticulum. We took advantage of the increased nanotunnel frequency in RyR2A4860G+/− cardiomyocytes to investigate and accurately define the ultrastructure of these mitochondrial extensions and to reconstruct the overall 3D distribution of nanotunnels using electron tomography. Additionally, to define the effects of communication via nanotunnels, we evaluated the intermitochondrial exchanges of matrix-targeted soluble fluorescent proteins, mtDsRed and photoactivable mtPA-GFP, in isolated cardiomyocytes by confocal microscopy. A direct comparison between exchanges occurring at short and long distances directly demonstrates that communication via nanotunnels is slower.

Ultrastructure of cardiac muscle in reptiles and birds: optimizing and/or reducing the probability of transmission between calcium release units

It is known that cardiac myocytes contain three categories of calcium release units (CRUs) all bearing arrays of RyR2: peripheral couplings, constituted of an association of the junctional SR (jSR) with the plasmalemma; dyads, associations between jSR and T tubules; internal extended junctional jSR (EjSR)/corbular jSR that is not associated with plasmalemma/T tubules. The bird hearts, even if fast beating (e.g., in finch and hummingbird) have no T tubules, despite fiber sizes comparable to those of mammalian ventricle, but are rich in EjSR/corbular SR. The heart of small lizard also lacks T tubule, but it has only peripheral couplings and compensates for lack of internal CRUs by the small diameter of its cells. We have extended previous information on chicken heart to finch and lizard by establishing a spatial relationship between RyR2 clusters in jSR of peripheral couplings and clusters of intra-membrane particles identifiable as voltage sensitive calcium channels (CaV1.2) in the adjacent plasmalemma. This provides the structural basis for initiation of the heart beat in all three species. Further we evaluated the distances separating peripheral couplings from each other and between EjSR/corbular SR sites within the bird muscles in all three hearts. The distances suggest that peripheral coupling sites are most likely to act independently of each other and that a calcium wave-front propagation from one internal CRU site to the other across the level of the Z line, may be marginally successful in the chicken, but certainly very effective in the finch.

Development of a data set of national cardiovascular deaths in the young

BACKGROUND The only systematic collection of cardiovascular (CV) deaths in children resides in the database derived from the Case Reporting System of the National Center for the Review and Prevention of Child Deaths (NCRPCD). We describe the process used to develop an analytical data set to inform our understanding of CV deaths in children from this database. METHODS Twenty-five states reporting natural CV deaths during 2005 to 2009 were contacted. Sixteen states agreed to participate. Cases experienced a natural CV death and were 0 to 21 years. Challenges to building a final analytical data set were identified and included reclassification, recategorization, and the development of new variables from existing data, including an algorithm to identify sudden cardiac deaths. RESULTS The final data set included 1,098 cases. Missing data comprised a mean of 41.7% for most key variables. Cardiovascular cases were aged 4.8 ± 6.6 years; 55.3%, ≤1 year, 24.6%, ≥10 years; male, 58%; white, 70.5%; black, 22.3%; and Hispanic, 19.5%. CONCLUSIONS This manuscript provides the first description of the natural CV death data set from the NCRPCD. We identify potential beneficial changes in the NCRPCD Case Reporting System and review process. Analysis of these data will help determine characteristics of CV deaths and allow the assessment of risk factors that can be used to prevent CV death in the young. The rate of CV death can be lowered using knowledge of associations that can be gleaned from this robust database. Best practices for prevention hold promise for a future with fewer deaths that will need to be reviewed.

Managing Arrhythmias before and after Aortic Valve Surgery in Children

The proximity of the coronary arteries and the bundle of His to the aortic valve may contribute to the pathogenesis of arrhythmias in patients with aortic valve disease. Severe aortic valve disease may also adversely alter left ventricular hemodynamics (end-diastolic dimensions and wall stress) and thus create a substrate for ventricular arrhythmias before any intervention is performed. The severity of these arrhythmias depends on the severity of the underlying substrate (or the specific problem, such as aortic stenosis or aortic regurgitation), the age at which the aortic valve intervention was performed, the type of intervention (i.e. transcatheter aortic valve interventions or open aortic valve replacement or repair), and the reversibility of the altered hemodynamics after surgery. Both bradyarrhythmias and tachyarrhythmias are known complications of aortic valve interventions. Although data are scant, this review summarizes the incidence of arrhythmias before and after aortic valve interventions from a pediatric perspective.The proximity of the coronary arteries and the bundle of His to the aortic valve may contribute to the pathogenesis of arrhythmias in patients with aortic valve disease. Severe aortic valve disease may also adversely alter left ventricular hemodynamics (end-diastolic dimensions and wall stress) and thus create a substrate for ventricular arrhythmias before any intervention is performed. The severity of these arrhythmias depends on the severity of the underlying substrate (or the specific problem, such as aortic stenosis or aortic regurgitation), the age at which the aortic valve intervention was performed, the type of intervention (i.e. transcatheter aortic valve interventions or open aortic valve replacement or repair), and the reversibility of the altered hemodynamics after surgery. Both bradyarrhythmias and tachyarrhythmias are known complications of aortic valve interventions. Although data are scant, this review summarizes the incidence of arrhythmias before and after aortic valve interventions from a pediatric perspective.