Bidirectional ventricular tachycardia: a hallmark of catecholaminergic polymorphic ventricular tachycardia

Catecholaminergic polymorphic ventricular tachycardia is a familial cardiac arrhythmia that is related to RYR2 or CASQ2 gene mutation. It occurs in patients with structurally normal heart and causes exercise-emotion triggered syncope and sudden cardiac death. We present a 13 year-old girl with recurrent episodes of exercise-related syncope and prior history of sudden death in a first degree relative.     

Identification of a novel idiopathic epilepsy locus in Belgian Shepherd dogs

Epilepsy is the most common neurological disorder in dogs, with an incidence ranging from 0.5% to up to 20% in particular breeds. Canine epilepsy can be etiologically defined as idiopathic or symptomatic. Epileptic seizures may be classified as focal with or without secondary generalization, or as primary generalized. Nine genes have been identified for symptomatic (storage diseases) and one for idiopathic epilepsy in different breeds. However, the genetic background of common canine epilepsies remains unknown. We have studied the clinical and genetic background of epilepsy in Belgian Shepherds. We collected 159 cases and 148 controls and confirmed the presence of epilepsy through epilepsy questionnaires and clinical examinations. The MRI was normal while interictal EEG revealed abnormalities and variable foci in the clinically examined affected dogs. A genome-wide association study using Affymetrix 50K SNP arrays in 40 cases and 44 controls mapped the epilepsy locus on CFA37, which was replicated in an independent cohort (81 cases and 88 controls; combined p = 9.70×10⁻¹⁰, OR = 3.3). Fine mapping study defined a ∼1 Mb region including 12 genes of which none are known epilepsy genes or encode ion channels. Exonic sequencing was performed for two candidate genes, KLF7 and ADAM23. No variation was found in KLF7 but a highly-associated non-synonymous variant, G1203A (R387H) was present in the ADAM23 gene (p = 3.7×10⁻⁸, OR = 3.9 for homozygosity). Homozygosity for a two-SNP haplotype within the ADAM23 gene conferred the highest risk for epilepsy (p = 6.28×10⁻¹¹, OR = 7.4). ADAM23 interacts with known epilepsy proteins LGI1 and LGI2. However, our data suggests that the ADAM23 variant is a polymorphism and we have initiated a targeted re-sequencing study across the locus to identify the causative mutation. It would establish the affected breed as a novel therapeutic model, help to develop a DNA test for breeding purposes and introduce a novel candidate gene for human idiopathic epilepsies.     

Natural history and management of chronic aortic valve disease.

Chronic aortic valve disease involving stenosis, regurgitation or both is insidious and progressive. Severe valvular dysfunction may be present for years without symptoms, but functional deterioration is often rapid once congestive heart failure, angina or syncope with effort is present. As the severity of aortic stenosis may not be easy to assess clinically, the relative usefulness of various tests is considered in this paper. The difficulty with chronic aortic regurgitation lies not in diagnosing the problem but in detecting early left ventricular dysfunction in time to perform the surgery that can prevent further functional deterioration. Patients with significant aortic valve disease should undergo surgery when the important symptoms of dyspnea, angina or syncope with effort first appear. Surgery should also be considered in selected patients with aortic regurgitation in whom left ventricular function has diminished even without symptoms.     

Leadless pacing in a young patient with cardioinhibitory vasovagal syncope

Vasovagal syncope is characterized by vasodilatation and/or bradycardia and thereby a fall in arterial BP and global cerebral perfusion in response to a trigger. Although it is a benign condition, patients with frequent and traumatic episodes need treatment in order to improve quality of life. We describe the case of a 17-years-old boy suffering from cardioinhibitory syncope. At the end of a complete negative cardiac and neurological examination, a loop recorder was implanted. During the subsequent follow-up the ILR documented a 9-s pause. To improve the patient's compliance, and considering cardioinhibitory syncope as a temporary condition, a leadless pacemaker was eventually implanted.     

Late presentation of recurrent syncope after permanent pacemaker implantation due to Lead−Header malapposition

Permanent pacemaker (PPM) malfunction due to electrical connection problems such as a loose set screw or lead-header malapposition is extremely rare. We present a patient with complete heart block (CHB) who had PPM malfunction and recurrent syncope, late (14 months) after initial implantation, which was caused by the ventricular lead pin disengagement from the header resulting in oversensing due to noise, pacing inhibition and recurrent syncope. PPM due to lead-header malapposition this late after device implantation has previously not been reported.     

Syncope: Assessment of risk and an approach to evaluation in the emergency department and urgent care clinic

Syncope is among the most frequent forms of transient loss of consciousness (TLOC), and is characterized by a relatively brief and self-limited loss of consciousness that by definition is triggered by transient cerebral hypoperfusion. Most often, syncope is caused by a temporary drop of systemic arterial pressure below that required to maintain cerebral function, but brief enough not to cause permanent structural brain injury. Currently, approximately one-third of syncope/collapse patients seen in the emergency department (ED) or urgent care clinic are admitted to hospital for evaluation. The primary objective of developing syncope/TLOC risk stratification schemes is to provide guidance regarding the immediate prognostic risk of syncope patients presenting to the ED or clinic; thereafter, based on that risk assessment physicians may be better equipped to determine which patients can be safely evaluated as outpatients, and which require hospital care. In general, the need for hospitalization is determined by several key issues: i) the patient''s immediate (usually considered 1 week to 1 month) mortality risk and risk for physical injury (e.g., falls risk), ii) the patient''s ability to care for him/herself, and iii) whether certain treatments inherently require in-hospital initiation (e.g., pacemaker implantation). However, at present no single risk assessment protocol appears to be satisfactory for universal application, and development of a consensus recommendation is an essential next step.     

Presence and extent of cardiac computed tomography angiography defined coronary artery disease in patients presenting with syncope

Background

In syncope patients, presence of coronary artery disease (CAD) is associated with poor prognosis. However, data concerning CAD prevalence in syncope patients without known cardiovascular disease are lacking. Therefore, the aim of this study was to investigate presence and extent of CAD in syncope patients.

Methods

We included 142 consecutive patients presenting with syncope at the outpatient cardiology clinic who underwent coronary computed tomography (CT) angiography. Syncope type was ascertained by two reviewers, blinded for coronary CT angiography results. Of the patients, 49 had cardiac syncope (arrhythmia or structural cardiopulmonary disease) and 93 had non-cardiac syncope (reflex [neurally-mediated], orthostatic or of unknown cause). Cardiac syncope patients were compared with matched stable chest pain patients regarding age, gender, smoking status, diabetes mellitus type 2 and systolic blood pressure.

Results

Distribution of CAD presence and extent in cardiac and non-cardiac syncope patients was as follows: 72% versus 48% any CAD; 31% versus 26% mild, 8% versus 14% moderate and 33% versus 7% severe CAD.Compared with non-cardiac syncope, patients with cardiac syncope had a significantly higher CAD presence and extent (p = 0.001). Coronary calcium score, segment involvement and stenosis score were also higher in cardiac syncope patients (p-values ≤0.004). Compared to the chest pain control group, patients with cardiac syncope showed a higher, however, non-significant, prevalence of any CAD (72% versus 63%) and severe CAD (33% versus 19%).

Conclusion

Patients with cardiac syncope show a high presence and extent of CAD in contrast to non-cardiac syncope patients. These results suggest that CAD may play an important role in the occurrence of cardiac syncope.

     

Characterization of PTZ-induced seizure susceptibility in a down syndrome mouse model that overexpresses CSTB

Down syndrome (DS) is a complex genetic syndrome characterized by intellectual disability, dysmorphism and variable additional physiological traits. Current research progress has begun to decipher the neural mechanisms underlying cognitive impairment, leading to new therapeutic perspectives. Pentylenetetrazol (PTZ) has recently been found to have positive effects on learning and memory capacities of a DS mouse model and is foreseen to treat DS patients. But PTZ is also known to be a convulsant drug at higher dose and DS persons are more prone to epileptic seizures than the general population. This raises concerns over what long-term effects of treatment might be in the DS population. The cause of increased propensity for epilepsy in the DS population and which Hsa21 gene(s) are implicated remain unknown. Among Hsa21 candidate genes in epilepsy, CSTB, coding for the cystein protease inhibitor cystatin B, is involved in progressive myoclonus epilepsy and ataxia in both mice and human. Thus we aim to evaluate the effect of an increase in Cstb gene dosage on spontaneous epileptic activity and susceptibility to PTZ-induced seizure. To this end we generated a new mouse model trisomic for Cstb by homologous recombination. We verified that increasing copy number of Cstb from Trisomy (Ts) to Tetrasomy (Tt) was driving overexpression of the gene in the brain, we checked transgenic animals for presence of locomotor activity and electroencephalogram (EEG) abnormalities characteristic of myoclonic epilepsy and we tested if those animals were prone to PTZ-induced seizure. Overall, the results of the analysis shows that an increase in Cstb does not induce any spontaneous epileptic activity and neither increase or decrease the propensity of Ts and Tt mice to myoclonic seizures suggesting that Ctsb dosage should not interfere with PTZ-treatment.     

Influence of climate on emergency department visits for syncope: role of air temperature variability

Background

Syncope is a clinical event characterized by a transient loss of consciousness, estimated to affect 6.2/1000 person-years, resulting in remarkable health care and social costs. Human pathophysiology suggests that heat may promote syncope during standing. We tested the hypothesis that the increase of air temperatures from January to July would be accompanied by an increased rate of syncope resulting in a higher frequency of Emergency Department (ED) visits. We also evaluated the role of maximal temperature variability in affecting ED visits for syncope.

Methodology/Principal Findings

We included 770 of 2775 consecutive subjects who were seen for syncope at four EDs between January and July 2004. This period was subdivided into three epochs of similar length: 23 January–31 March, 1 April–31 May and 1 June–31 July. Spectral techniques were used to analyze oscillatory components of day by day maximal temperature and syncope variability and assess their linear relationship.There was no correlation between daily maximum temperatures and number of syncope. ED visits for syncope were lower in June and July when maximal temperature variability declined although the maximal temperatures themselves were higher. Frequency analysis of day by day maximal temperature variability showed a major non-random fluctuation characterized by a ∼23-day period and two minor oscillations with ∼3- and ∼7-day periods. This latter oscillation was correlated with a similar ∼7-day fluctuation in ED visits for syncope.

Conclusions/Significance

We conclude that ED visits for syncope were not predicted by daily maximal temperature but were associated with increased temperature variability. A ∼7-day rhythm characterized both maximal temperatures and ED visits for syncope variability suggesting that climate changes may have a significant effect on the mode of syncope occurrence.     

Effectively desynchronizing deep brain stimulation based on a coordinated delayed feedback stimulation via several sites: a computational study

In detailed simulations we present a coordinated delayed feedback stimulation as a particularly robust and mild technique for desynchronization. We feed back the measured and band-pass filtered local filed potential via several or multiple sites with different delays, respectively. This yields a resounding desynchronization in a naturally demand-controlled way. Our novel approach is superior to previously developed techniques: It is robust against variations of system parameters, e.g., the mean firing rate. It does not require time-consuming calibration. It also prevents intermittent resynchronization typically caused by all methods employing repetitive administration of shocks. We suggest our novel technique to be used for deep brain stimulation in patients suffering from neurological diseases with pathological synchronization, such as Parkinsonian tremor, essential tremor or epilepsy.     

Atomic structure of a single large biomolecule from diffraction patterns of random orientations

The short and intense pulses of the new X-ray free electron lasers, now operational or under construction, may make possible diffraction experiments on single molecule-sized objects with high resolution, before radiation damage destroys the sample. In a single molecule imaging (SMI) experiment thousands of diffraction patterns of single molecules with random orientations are recorded. One of the most challenging problems of SMI is how to assemble these noisy patterns of unknown orientations into a consistent single set of diffraction data. Here we present a new method which can solve the orientation problem of SMI efficiently even for large biological molecules and in the presence of noise. We show on simulated diffraction patterns of a large protein molecule, how the orientations of the patterns can be found and the structure to atomic resolution can be solved. The concept of our algorithm could be also applied to experiments where images of an object are recorded in unknown orientations and/or positions like in cryoEM or tomography.     

Towards a large-scale model of patient-specific epileptic spike-wave discharges

Clinical electroencephalographic (EEG) recordings of the transition into generalised epileptic seizures show a sudden onset of spike-wave dynamics from a low-amplitude irregular background. In addition, non-trivial and variable spatio-temporal dynamics are widely reported in combined EEG/fMRI studies on the scale of the whole cortex. It is unknown whether these characteristics can be accounted for in a large-scale mathematical model with fixed heterogeneous long-range connectivities. Here, we develop a modelling framework with which to investigate such EEG features. We show that a neural field model composed of a few coupled compartments can serve as a low-dimensional prototype for the transition between irregular background dynamics and spike-wave activity. This prototype then serves as a node in a large-scale network with long-range connectivities derived from human diffusion-tensor imaging data. We examine multivariate properties in 42 clinical EEG seizure recordings from 10 patients diagnosed with typical absence epilepsy and 50 simulated seizures from the large-scale model using 10 DTI connectivity sets from humans. The model can reproduce the clinical feature of stereotypy where seizures are more similar within a patient than between patients, essentially creating a patient-specific fingerprint. We propose the approach as a feasible technique for the investigation of patient-specific large-scale epileptic features in space and time.     

Role of potassium lateral diffusion in non-synaptic epilepsy: a computational study

An increase of extracellular potassium ion concentration can result in neuronal hyperexcitability, and thus contribute to non-synaptic epileptiform activity. It has been shown that potassium lateral diffusion alone is sufficient for synchronization in the low-calcium epilepsy in-vitro model. However, it is not yet known whether the lateral diffusion can, by itself, induce seizure activity. We hypothesize that spontaneous sustained neuronal activity can be generated by potassium coupling between neurons. To test this hypothesis, neuronal simulations with 2-cell or 4-cell models were used. Each model neuron was embedded in a bath of K+ and surrounded by interstitial space. Interstitial potassium concentration was regulated by both K+-pump and glial buffer mechanisms. Simulations performed with two coupled neurons with parameter values within physiological range show that, without chemical and electrical synapses, potassium lateral diffusion alone can generate and synchronize zero-Ca2+ non-synaptic epileptiform activity. Simulations performed with a network of four zero-Ca2+ CA1 pyramidal neurons modeled in zero-calcium conditions also show that spontaneous sustained activity can propagate by potassium lateral diffusion alone with a velocity of approximately 0.93 mm/sec. This diffusion model used for the simulations is based on physiological parameters, is robust for various kinetics, and is able to reproduce both the spontaneous triplet bursting of non-synaptic activity and speed of propagation in low-Ca2+ non-synaptic epilepsy experiments. These simulations suggest that potassium lateral diffusion can play an important role in the synchronization and generation on non-synaptic epilepsy.     

Evidence for linkage of adolescent-onset idiopathic generalized epilepsies to chromosome 8-and genetic heterogeneity

Several loci and candidate genes for epilepsies or epileptic syndromes map or have been suggested to map to chromosome 8. We investigated families with adolescent-onset idiopathic generalized epilepsy (IGE), for linkage to markers spanning chromosome 8. The IGEs that we studied included juvenile myoclonic epilepsy (JME), epilepsy with only generalized tonic-clonic seizures occurring either randomly during the day (random grand mal) or on awakening (awakening grand mal), and juvenile absence epilepsy (JAE). We looked for a gene common to all these IGEs, but we also investigated linkage to specific subforms of IGE. We found evidence for linkage to chromosome 8 in adolescent-onset IGE families in which JME was not present. The maximum multipoint LOD score was 3.24 when family members with IGE or generalized spike-and-waves (SW) were considered affected. The LOD score remained very similar (3.18) when clinically normal family members with SW were not considered to be affected. Families with either pure grand mal epilepsy or absence epilepsy contributed equally to the positive LOD score. The area where the LOD score reaches the maximum encompasses the location of the gene for the beta3-subunit of the nicotinic acetylcholine receptor (CHRNB3), thus making this gene a possible candidate for these specific forms of adolescent-onset IGE. The data excluded linkage of JME to this region. These results indicate genetic heterogeneity within IGE and provide no evidence, on chromosome 8, for a gene common to all IGEs.     

Optimizing cardiac material parameters with a genetic algorithm

Determining the unknown material parameters of intact ventricular myocardium can be challenging due to highly nonlinear material behavior. Previous studies combining a gradient-search optimization procedure with finite element analysis (FEA) were limited to two-dimensional (2D) models or simplified three-dimensional (3D) geometries. Here we present a novel scheme to estimate unknown material parameters for ventricular myocardium by combining a genetic algorithm (GA) with nonlinear finite element analysis. This approach systematically explores the domain of the material parameters. The objective function to minimize was the error between simulated strain data and finite element model strains. The proposed scheme was validated for a 2D problem using a realistic material law for ventricular myocardium. Optimized material parameters were generally within 0.5% of the true values. To demonstrate the robustness of the new scheme, unknown material parameters were also determined for a realistic 3D heart model with an exponential hyperelastic material law. When using strains from two material points, the algorithm converged to parameters within 5% of the true values. We conclude that the proposed scheme is robust when estimating myocardial material parameters in 2D and 3D models.     

Physiological phenomenology of neurally-mediated syncope with management implications

Background

Due to lack of efficacy in recent trials, current guidelines for the treatment of neurally-mediated (vasovagal) syncope do not promote cardiac pacemaker implantation. However, the finding of asystole during head-up tilt –induced (pre)syncope may lead to excessive cardioinhibitory syncope diagnosis and treatment with cardiac pacemakers as blood pressure is often discontinuously measured. Furthermore, physicians may be more inclined to implant cardiac pacemakers in older patients. We hypothesized that true cardioinhibitory syncope in which the decrease in heart rate precedes the fall in blood pressure is a very rare finding which might explain the lack of efficacy of pacemakers in neurally-mediated syncope.

Methods

We studied 173 consecutive patients referred for unexplained syncope (114 women, 59 men, 42±1 years, 17±2 syncopal episodes). All had experienced (pre)syncope during head-up tilt testing followed by additional lower body negative suction. We classified hemodynamic responses according to the modified Vasovagal Syncope International Study (VASIS) classification as mixed response (VASIS I), cardioinhibitory without (VASIS IIa) or with asystole (VASIS IIb), and vasodepressor (VASIS III). Then, we defined the exact temporal relationship between hypotension and bradycardia to identify patients with true cardioinhibitory syncope.

Results

Of the (pre)syncopal events during tilt testing, 63% were classified as VASIS I, 6% as VASIS IIb, 2% as VASIS IIa, and 29% as VASIS III. Cardioinhibitory responses (VASIS class II) progressively decreased from the youngest to the oldest age quartile. With more detailed temporal analysis, blood pressure reduction preceded the heart-rate decrease in all but six individuals (97%) overall and in 10 out of 11 patients with asystole (VASIS IIb).

Conclusions

Hypotension precedes bradycardia onset during head-up tilt-induced (pre)syncope in the vast majority of patients, even in those classified as cardioinhibitory syncope according to the modified VASIS classification. Furthermore, cardioinhibitory syncope becomes less frequent with increasing age.     

Validation of a Preclinical Drug Screening Platform for Pharmacoresistant Epilepsy

The successful identification of promising investigational therapies for the treatment of epilepsy can be credited to the use of numerous animal models of seizure and epilepsy for over 80 years. In this time, the maximal electroshock test in mice and rats, the subcutaneous pentylenetetrazol test in mice and rats, and more recently the 6 Hz assay in mice, have been utilized as primary models of electrically or chemically-evoked seizures in neurologically intact rodents. In addition, rodent kindling models, in which chronic network hyperexcitability has developed, have been used to identify new agents. It is clear that this traditional screening approach has greatly expanded the number of marketed drugs available to manage the symptomatic seizures associated with epilepsy. In spite of the numerous antiseizure drugs (ASDs) on the market today, the fact remains that nearly 30% of patients are resistant to these currently available medications. To address this unmet medical need, the National Institute of Neurological Disorders and Stroke (NINDS) Epilepsy Therapy Screening Program (ETSP) revised its approach to the early evaluation of investigational agents for the treatment of epilepsy in 2015 to include a focus on preclinical approaches to model pharmacoresistant seizures. This present report highlights the in vivo and in vitro findings associated with the initial pharmacological validation of this testing approach using a number of mechanistically diverse, commercially available antiseizure drugs, as well as several probe compounds that are of potential mechanistic interest to the clinical management of epilepsy.     

RHEB/mTOR hyperactivity causes cortical malformations and epileptic seizures through increased axonal connectivity

Hyperactivation of the mammalian target of rapamycin (mTOR) pathway can cause malformation of cortical development (MCD) with associated epilepsy and intellectual disability (ID) through a yet unknown mechanism. Here, we made use of the recently identified dominant-active mutation in Ras Homolog Enriched in Brain 1 (RHEB), RHEBp.P37L, to gain insight in the mechanism underlying the epilepsy caused by hyperactivation of the mTOR pathway. Focal expression of RHEBp.P37L in mouse somatosensory cortex (SScx) results in an MCD-like phenotype, with increased mTOR signaling, ectopic localization of neurons, and reliable generalized seizures. We show that in this model, the mTOR-dependent seizures are caused by enhanced axonal connectivity, causing hyperexcitability of distally connected neurons. Indeed, blocking axonal vesicle release from the RHEBp.P37L neurons alone completely stopped the seizures and normalized the hyperexcitability of the distally connected neurons. These results provide new evidence of the extent of anatomical and physiological abnormalities caused by mTOR hyperactivity, beyond local malformations, which can lead to generalized epilepsy.

Hyperactivation of the mTOR pathway can cause cortical malformations and epilepsy. This study reveals that these effects can be uncoupled and that mTOR hyperactivity in a limited set of neurons induces hyperexcitability in non-targeted, healthy neurons, suggesting that it is actually these changes that may underlie mTOR-driven epileptogenesis.