Reduced Conduction Velocity Research Articles

Reduction of Conduction Velocity in Patients with Atrial Fibrillation.

It is unknown to what extent atrial fibrillation (AF) episodes affect intra-atrial conduction velocity (CV) and whether regional differences in local CV heterogeneities exist during sinus rhythm. This case-control study aims to compare CV assessed throughout both atria between patients with and without AF. Patients (n = 34) underwent intra-operative epicardial mapping of the right atrium (RA), Bachmann’s bundle (BB), left atrium (LA) and pulmonary vein area (PVA). CV vectors were constructed to calculate median CV in addition to total activation times (TAT) and unipolar voltages. Biatrial median CV did not differ between patients with and without AF (90 ± 8 cm/s vs. 92 ± 6 cm/s, p = 0.56); only BB showed a CV reduction in the AF group (79 ± 12 cm/s vs. 88 ± 11 cm/s, p = 0.02). In patients without AF, there was no predilection site for the lowest CV (P5) (RA: 12%; BB: 29%; LA: 29%; PVA: 29%). In patients with AF, lowest CV was most often measured at BB (53%) and ranged between 15 to 22 cm/s (median: 20 cm/s). Lowest CVs were also measured at the LA (18%) and PVA (29%), but not at the RA. AF was associated with a prolonged TAT (p = 0.03) and decreased voltages (P5) at BB (p = 0.02). BB was a predilection site for slowing of conduction in patients with AF. Prolonged TAT and decreased voltages were also found at this site. The next step will be to determine the relevance of a reduced CV at BB in relation to AF development and maintenance.

Assessment of Myoelectric Manifestations of Muscle Fatigue During Repetitive Isometric Voluntary Contraction in Boys Aged 12-14

Aim: To study the peculiarity of electromyography signal characteristics alternation using different sEMG parameters during repetitive voluntary isometric fatiguing contraction in adolescent boys. 
 Materials and methods. 12 subjects with height 148.75 ± 10 cm; Mass 38.9 ± 7.9 kg; age – 12 to 14 years were recruited. The sEMG signal alteration of external oblique, rectus abdominis, erector spinae muscles during a fatiguing plank were analyzed. A separate one-way repeated measures ANOVA was used to test the statistical significance of task time and electromyography parameters of the global core muscle in the pre-, during- and post-fatigue plank test. One-way Friedman ANOVA was applied for Shapiro-Wilk p < 0.05. The Pearson product-moment correlation coefficient with bivariate linear regressions analysis was performed between the pre-pre fatigue and post-post fatigue amplitude mean and standard deviation values. The Spearman correlation coefficient between amplitude and endurance time both in the pre- and post-fatigue state was conducted. 
 Results. The mean value of rectified amplitude increased (p < 0.05) for all muscles, the standard deviation of amplitude and total spectral power increased significantly (p < 0.05) for all muscles except the erector spinae muscle (p > 0.05). The power at normalized low frequency significantly changed (p = 0.05) in the erector spinae muscle. A significant change in normalized low frequency for agonist/synergist (p = 0.02) and agonist/antagonist muscles (p = 0.05) was observed. The average amplitude value had a significant positive and linear relationship with the amplitude variability both in the pre- to post-fatigue state, except the erector spinae muscle. The time to task failure was not correlated (p > 0.05) with the sEMG amplitude. 
 Conclusions. Increased sEMG amplitude resulted mainly from rapid additional motor unit recruitment and rate coding during muscle fatigue. The reduction of conduction velocity might affect the spectral power with a spectral shift towards low-frequency. Increased variability, agonist/antagonist co-activity during fatiguing contraction might extend the holding time. The postural fatiguing task/plank increases multiarticular joint function by involving several joints and muscles, increases variability in the contribution of synergist muscles. This factor provides an intuitive explanation about the absence of a relationship between endurance time and sEMG amplitude changes.

A 3-D human model of complex cardiac arrhythmias

Cardiac arrhythmias impact over 12 million people globally, with an increasing incidence of acquired arrhythmias. Although animal models have shed light onto fundamental arrhythmic mechanisms, species-specific differences and ethical concerns remain. Current human models using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) either lack the higher order tissue organization of the heart or implement unreliable arrhythmia induction techniques. Our goal was to develop a robust model of acquired arrhythmia by disrupting cardiomyocyte cell-cell signaling – one of the hallmarks of complex arrhythmias. Human 3D microtissues were generated by seeding hydrogel-embedded hiPSC-CMs and cardiac fibroblasts into an established microwell system designed to enable active and passive force assessment. Cell-cell signaling was disrupted using methyl-beta cyclodextrin (MBCD), previously shown to disassemble cardiac gap junctions. We demonstrate that arrhythmias were progressive and present in all microtissues within 5 days of treatment. Arrhythmic tissues exhibited reduced conduction velocity, an increased number of distinct action potentials, and reduced action potential cycle length. Arrhythmic tissues also showed significant reduction in contractile force generation, increased beating frequency, and increased passive tension and collagen deposition, in line with fibrosis. A subset of tissues with more complex arrhythmias exhibited 3D spatial differences in action potential propagation. Pharmacological and electrical defibrillation was successful. Transcriptomic data indicated an enrichment of genes consistent with cardiac arrhythmias. MBCD removal reversed the arrhythmic phenotype, resulting in synchronicity despite not resolving fibrosis. This innovative & reliable human-relevant 3D acquired arrhythmia model shows potential for improving our understanding of arrhythmic action potential conduction and furthering therapeutic development. Statement of significanceThis work describes a 3D human model of cardiac arrhythmia-on-a-chip with high reproducibility, fidelity, and extensive functional applicability. To mimic in vivo conditions, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and cardiac fibroblasts from healthy controls were combined in a biocompatible fibrin hydrogel and seeded between two deflectable polymeric rods. Using the innate functional properties of this 3D model as well as advanced optical imaging techniques we demonstrated dramatic changes in contraction rate, synchronicity, and electrophysiological conduction in arrhythmic tissues relative to controls. Taken together, these data demonstrate the distinctive potential of this new model for pathophysiological studies, and for arrhythmia drug testing applications.

Arrhythmogenic Mechanisms in Hypokalaemia: Insights From Pre-clinical Models.

Potassium is the predominant intracellular cation, with its extracellular concentrations maintained between 3. 5 and 5 mM. Among the different potassium disorders, hypokalaemia is a common clinical condition that increases the risk of life-threatening ventricular arrhythmias. This review aims to consolidate pre-clinical findings on the electrophysiological mechanisms underlying hypokalaemia-induced arrhythmogenicity. Both triggers and substrates are required for the induction and maintenance of ventricular arrhythmias. Triggered activity can arise from either early afterdepolarizations (EADs) or delayed afterdepolarizations (DADs). Action potential duration (APD) prolongation can predispose to EADs, whereas intracellular Ca2+ overload can cause both EADs and DADs. Substrates on the other hand can either be static or dynamic. Static substrates include action potential triangulation, non-uniform APD prolongation, abnormal transmural repolarization gradients, reduced conduction velocity (CV), shortened effective refractory period (ERP), reduced excitation wavelength (CV × ERP) and increased critical intervals for re-excitation (APD–ERP). In contrast, dynamic substrates comprise increased amplitude of APD alternans, steeper APD restitution gradients, transient reversal of transmural repolarization gradients and impaired depolarization-repolarization coupling. The following review article will summarize the molecular mechanisms that generate these electrophysiological abnormalities and subsequent arrhythmogenesis.

Effect of honey and insulin treatment on oxidative stress and nerve conduction in an experimental model of diabetic neuropathy Wistar rats.

Diabetic neuropathy is the most common complication affecting more than 50% of patients with longstanding diabetes. Till date, there are no reports to explain the scientific basis of alternative medicine as an adjunct therapy for treating diabetic neuropathy. Hence, we studied the effect of honey and insulin treatment on hyperglycemia, dyslipidemia, oxidant and anti-oxidant status and nerve conduction in experimental diabetic neuropathy Wistar rats. In this experimental study, forty healthy male Wistar albino rats of 10-12 weeks age, weighing between 150 to 200g were obtained from our institute central animal house. After acclimatization, the rats were divided into control (n = 8) and experimental (n = 32) groups randomly. In the experimental group, type 2 diabetic neuropathy was induced with high fat and high sugar diet for 8 weeks followed by streptozotocin at a dose of 35 mg/kg body weight. Three days after streptozotocin injection, blood glucose levels of rats were measured from fasting samples to confirm diabetes. After the development of diabetes, rats were given standard rodent chow and allowed four more weeks to remain diabetic and to develop neuropathy. Every second week, nerve conduction study was done to confirm neuropathy. All the diabetic rats of experimental group developed neuropathy after 4 weeks of developing diabetes, which was confirmed by significant reduction in conduction velocity of sensory and motor nerve when compared to non-diabetic control group. After the development of neuropathy, these rats were randomly divided into diabetic neuropathy with no treatment group (n = 8) and three treatment groups (n = 8, each). The rats of treatment group were administered with either honey or insulin or honey+insulin for six weeks. After six-weeks of intervention, there was significant decrease in blood glucose and lipids in honey, insulin and honey+insulin treated neuropathy rats, when compared with no treatment group. Malondialdehyde was reduced and total anti-oxidant status improved in all the three treatment groups. There was no significant increase in conduction velocity of sciatic tibial motor nerve in treatment groups when compared with no treatment group. However, the sensory nerve conduction velocity improved significantly in honey+insulin treated neuropathy rats. In conclusion, six-week honey treatment helped in reducing dyslipidemia and oxidative stress. Honey given along with insulin for six-weeks improved sensory nerve conduction velocity in experimental diabetic neuropathy Wistar rats.

The bradycardic agent ivabradine decreases conduction velocity in the AV node and in the ventricles in-vivo

Ivabradine blocks hyperpolarisation-activated cyclic nucleotide-gated (HCN) channels, thereby lowering the heart rate, an action that is used clinically for the treatment of heart failure and angina pectoris. We and others have shown previously that ivabradine, in addition to its HCN channel blocking activity, also inhibits voltage-gated Na channels in vitro at concentrations that may be clinically relevant. Such action may reduce conduction velocity in cardiac atria and ventricles.Here, we explore the effect of administration of ivabradine on parameters of ventricular conduction and repolarization in the surface ECG of anesthetized mice. We found that 5 min after i.p. administration of 10 mg/kg ivabradine spontaneous heart rate had declined by ~13%, which is within the range observed in human clinical studies. At the same time a significant increase in QRS duration by ~18% was observed, suggesting a reduction in ventricular conduction velocity. During transesophageal pacing at heart rates between 100 and 220 beats/min there was no obvious rate-dependence of ivabradine–induced QRS prolongation. On the other hand, ivabradine produced substantial rate-dependent slowing of AV nodal conduction. We conclude that ivabradine prolongs conduction in the AV-node and in the ventricles in vivo.

The Neuroprotective Effect of Mesna on Cisplatin-Induced Neurotoxicity: Behavioral, Electrophysiological, and Molecular Studies.

Peripheral neuropathy and cognitive impairments following cisplatin administration may interfere with the clinical usage of the drug. Mesna is a chemoprotective agent with anti-inflammatory and anti-oxidant effects. Our study aimed to investigate the protective effects of mesna against cisplatin-induced neurotoxicity. Neurotoxicity was induced by the administration of 2.5mg/kg cisplatin twice a week for four consecutive weeks in male Wistar rats. The neuroprotective effect of mesna (150mg/kg/day) was evaluated through behavioral, electrophysiological, and molecular studies. Cisplatin treatment caused passive avoidance memory impairment, increased anxiety-like behaviors, altered thermal sensitivity, and decreased muscle strength in a grip strength test. Our electrophysiological studies indicated that administration of cisplatin induced peripheral sensory neuropathy and decreased the amplitudes of the compound action potential of sensory nerves. Cisplatin administration increased MDA and 4-HNE levels and decreased anti-oxidant (SOD and GPx) enzymes. Proinflammatory cytokines (IL-1β and TNF-α) and metalloproteinase-2 and 9 (MMP-2/9) were increased by cisplatin treatment. Morphological alterations were observed in the dorsal root ganglion (DRG) of cisplatin-treated rats. Cognitive impairments, anxiety, muscle strength, and thermal sensitivity changes induced by cisplatin were improved with mesna treatment. The reduced conduction velocity in sensory nerves was recovered in the cisplatin+mesna group. Mesna partially alleviated redox imbalance, reduced the proinflammatory cytokines, and MMP-2/9 levels. Mesna administration also relieved the morphological changes in DRG of cisplatin-treated rats. In conclusion, our results revealed that mesna can alleviate cisplatin-induced central and peripheral nervous system toxicity. These results support the concept that chemotherapy-induced neuropathy can be partially inhibited via mesna.

Right Atrial Collision Time (RACT): a novel marker of propensity for typical atrial flutter

Abstract Background The risk of typical atrial flutter (AFL) is increased by factors that increase right atrial (RA) size or cause scarring to reduce conduction velocity. These characteristics ensure the macro re-entrant wave front does not meet its refractory tail. The time taken to traverse the circuit would take account of both of these characteristics (being equal to distance divided by velocity), and may provide a superior marker of propensity to develop AFL. Purpose To investigate right atrial collision time (RACT) as a marker of typical AFL. Methods This single centre, prospective study recruited consecutive typical AFL ablation cases that were in sinus rhythm. Controls were consecutive cases other than atrial fibrillation and >50 years of age. Exclusion criteria for both groups were a prior ablation in the RA and class I and III antiarrhythmics. While pacing the coronary sinus ostium at 600 ms, a local activation time map was created to locate the latest collision point on the anterolateral wall, excluding the RA appendage (Figure 1). This RACT approximates half a revolution. Results The AFL group's (n=34) mean RACT was 132.5±15.06 vs 98.7±12.23ms in the controls (n=40) (p<0.01). No significant difference was observed for age (mean 65.6 vs 62.6 (p=0.18)), male (68.8% vs 60% (p=0.59)), body surface area (mean 2.1 vs 2.03 m2 (p=0.24)). The RACT also proved to be a superior marker than the echocardiographic measurement of right atrial area in an apical four chamber view (mean 17.8 vs 16.3 cm2 (p=0.21).A ROC curve indicated an AUC of 0.97 (95% CI: 0.93–1.0, p<0.01). A RACT cut-off of 120 ms had a specificity of 99% and a sensitivity of 75%. Conclusion RACT is a novel and promising marker of propensity for typical AFL. The ability to predict AFL would be of significant clinical value given the risk of stroke and frequent need for ablation. Funding Acknowledgement Type of funding source: None

Xanthine oxidase inhibitor allopurinol improves atrial electrical remodeling in diabetic rats by inhibiting CaMKII/NCX signaling

AimsAtrial fibrillation (AF) is a common arrhythmia which is associated with higher risk of stroke, heart failure and all-cause mortality. Abnormal Ca2+ handling in diabetes mellitus (DM) can cause delayed depolarization involved with increased NCX activity. Complicated mechanisms are involved in atrial remodeling, of which CaMKII may be a key node signal. Therefore, we intend to explore whether CaMKII activation induces atrial electrical remodeling by regulating NCX expression in this study. Main methodsAdult male SD rats were used to establish a diabetic rat model, divided into three groups: the control group, DM group and allopurinol group. Hemodynamic and ECG indicators were recorded, after which electrophysiological studies were conducted. The protein expression of CaMKII, p-CaMKII, XO, MnSOD and NCX was measured by Western blot and immunohistochemistry. H&E and Masson staining were applied for observing myocardial fibrosis. HL-1 cells were cultured for the measurement of ROS generation. Key findingsThe arrangement of atrial myocytes was disordered and the collagen volume fraction of the atrium tissue was elevated in the DM group compared with the control group, and improved by allopurinol. Higher incidence of inducible AF, reduced conduction velocity and higher conduction inhomogeneity were observed in diabetic rats. These electrophysiological abnormalities were accompanied by higher oxidative stress and protein expression of p-CaMKII and NCX. Allopurinol prevented the development of these abnormal changes. SignificanceAllopurinol can improve atrial electrical remodeling by inhibiting CaMKII activity and protein expression of NCX. These data indicate xanthine oxidase inhibition can reduce oxidative stress and ameliorate atrial electrical remodeling.

Progressive length-dependent polyneuropathy in xeroderma pigmentosum group A.

In this study, we aimed to investigate the progression of peripheral nervous system involvement in xeroderma pigmentosum group A (XP-A). We performed nerve conduction studies in 17 genetically confirmed XP-A patients and conducted follow-ups. Of these patients we also analyzed gray matter volume (GMV) using brain MRI and assessed the severity score of clinical and skin manifestation. We found significant reduction in the motor and sensory nerve action potential amplitude and mild reduction in conduction velocity. These findings were predominant in sensory nerves and the lower limbs, were observed since early childhood, and gradually deteriorated with age. The electrophysiological characteristics of XP-A patients are consistent with length-dependent axonal polyneuropathy and there is progressive deterioration from early childhood.

Traumatic partial posterior cord brachial plexus injury in a patient with aberrant innervation of the long head of the triceps by the axillary nerve: Implications in nerve transfer surgery

Brachial plexus repair forms an unmet need in terms of posttraumatic rehabilitation, especially the young population, wherein the incidence of accidents is high. This leads to decrease in the number of functionally active years after the accident. We encountered an interesting case of posttraumatic posterior cord injury predominantly affecting the shoulder abduction beyond 15°. An electrodiagnostic study showed a complete lack of conduction within the axillary nerve with reduced conduction velocity in the radial nerve. We took the patient up for the long head of the triceps transfer to the anterior division of the axillary nerve transfer. Intraoperatively, we found that the long head branch was originating from the axillary nerve at the point of division. As it could not be used for neurotization, we transferred the medial head branch of the radial nerve to the axillary nerve. The patient started to show electroclinical improvement after 3 months of the surgery. A few similar cases have been published, as a cadaveric finding. We report this case to highlight the possibility and need for a high clinical suspicion and also to provide a possible treatment option, in such aberrant anatomy.

Arrhythmia susceptibility in a rat model of acute atrial dilation

Atrial fibrillation (AF) is the most common cardiac arrhythmia, associated with an increased risk of stroke and heart failure. Acute AF occurs in response to sudden increases of atrial hemodynamic load, leading to atrial stretch. The mechanisms of stretch-induced AF were investigated in large mammals with controversial results. We optimized an approach to monitor rat atrial electrical activity using a red-shifted voltage sensitive dye (VSD). The methodology includes cauterization of the main ventricular coronary arteries, allowing improved atrial staining by the VSD and appropriate atrial perfusion for long experiments. Next, we developed a rat model of acute biatrial dilation (ABD) through the insertion of latex balloons into both atria, which could be inflated with controlled volumes. A chronic model of atrial dilation (spontaneous hypertensive rats; SHR) was used for comparison. ABD was performed on atria from healthy Wistar-Kyoto (WKY) rats (WKY-ABD). The atria were characterized in terms of arrhythmias susceptibility, action potential duration and conduction velocity. The occurrence of arrhythmias in WKY-ABD was significantly higher compared to non-dilated WKY atria. In WKY-ABD we found a reduction of conduction velocity, similar to that observed in SHR atria, while action potential duration was unchanged. Low-dose caffeine was used to introduce a drop of CV in WKY atria (WKY-caff), quantitatively similar to the one observed after ABD, but no increased arrhythmia susceptibility was observed with caffeine only. In conclusion, CV decrease is not sufficient to promote arrhythmias; enlargement of atrial surface is essential to create a substrate for acute reentry-based arrhythmias.

P5438Cardiac abnormalities after induction of endoplasmic reticulum stress are associated with mitochondrial dysfunction and connexin43 expression

Abstract Background The endoplasmic reticulum (ER) is responsible for protein synthesis and calcium storage. ER stress, reflected by protein unfolding and calcium handling abnormalities, has been studied as a pathogenetic factor in cardiovascular diseases. Purpose The aim of this study is to examine the effects of ER stress on mechanical and electrophysiological functions in the heart and explore the underlying molecular mechanisms. Methods A total of 30 rats were randomly divided into control, ER stress induction (tunicamycin) and ER stress inhibition (4-phenylbutyric acid, 4-PBA) groups. Results ER stress induction led to significantly systolic and diastolic dysfunction as reflected by maximal increasing/decreasing rate of left intraventricular pressure (±dp/dt), LV peak systolic pressure, LV development pressure and LV end-diastolic pressure. Epicardial electrical mapping performed in vivo revealed reduced conduction velocity, increased conduction heterogeneity and spontaneous ventricular tachycardia. Masson's trichrome staining revealed marked fibrosis in the myocardial interstitium and sub-pericardium and thickened epicardium. Western blot analysis revealed increased pro-fibrotic factor TGF-β1, decreased mitochondrial biogenesis protein PGC-1a, decreased mitochondrial fusion protein MFN2. These changes were associated with decreased mitochondrial membrane potential (MMP) and connexin 43 translocation to mitochondria. These abnormalities can be partially prevented by the ER stress inhibitor 4-PBA. Conclusions Our study shows that ER stress induction can produce cardiac electrical and mechanism dysfunction as well as structural remodeling. Mitochondrial function alterations are contributed by CX43 transposition to mitochondria. These abnormalities can be partially prevented by the ER stress inhibitor 4-PBA. Acknowledgement/Funding National Natural Science Foundation of China (No. 81570298 to T.L.)

Atrial fibrillation and its arrhythmogenesis associated with insulin resistance

BackgroundInsulin resistance (IR) is considered as a risk factor for atrial fibrillation (AF) even before diabetes develops. The pathophysiology and underlying mechanism are largely unclear.MethodsWe investigated the corresponding mechanism in two IR models of rats fed 15-week high-fat (HFa) and high-fructose/cholesterol (HFr) diets. AF was evaluated and induced by burst atrial pacing. Isolated atrial myocytes were used for whole-cell patch clamp and calcium assessment. Ex vivo whole heart was used for optical mapping. Western blot and immunofluorescence were used for quantitative protein evaluation.ResultsBoth HFa and HFr rat atria were vulnerable to AF evaluated by burst atrial pacing. Isolated atrial myocytes from HFa and HFr rats revealed significantly increased sarcoplasmic reticulum calcium content and diastolic calcium sparks. Whole-heart mapping showed prolonged calcium transient duration, conduction velocity reduction, and repetitive ectopic focal discharge in HFa and HFr atria. Protein analysis revealed increased TGF-β1 and collagen expression; increased superoxide production; abnormal upregulation of calcium-homeostasis-related proteins, including oxidized CaMKIIδ, phosphorylated-phospholamban, phosphorylated-RyR-2, and sodium-calcium exchanger; and increased Rac1 activity in both HFa and HFr atria. We observed that inhibition of CaMKII suppressed AF in both HF and HFr diet-fed rats. In vitro palmitate-induced IR neonatal cardiomyocytes and atrial fibroblasts expressed significantly more TGF-β1 than did controls, suggesting paracrine and autocrine effects on both myocytes and fibroblasts.ConclusionsIR engenders both atrial structural remodeling and abnormal intracellular calcium homeostasis, contributing to increased AF susceptibility. The inhibition of CaMKII may be a potential therapeutic target for AF in insulin resistance.

Monocarboxylate transporter 1 in Schwann cells contributes to maintenance of sensory nerve myelination during aging

Schwann cell (SC)-specific monocarboxylate transporter 1 (MCT1) knockout mice were generated by mating MCT1 f/f mice with myelin protein zero (P0)-Cre mice. P0-Cre+/- , MCT1 f/f mice have no detectable early developmental defects, but develop hypomyelination and reduced conduction velocity in sensory, but not motor, peripheral nerves during maturation and aging. Furthermore, reduced mechanical sensitivity is evident in aged P0-Cre+/- , MCT1 f/f mice. MCT1 deletion in SCs impairs both their glycolytic and mitochondrial functions, leading to altered lipid metabolism of triacylglycerides, diacylglycerides, and sphingomyelin, decreased expression of myelin-associated glycoprotein, and increased expression of c-Jun and p75-neurotrophin receptor, suggesting a regression of SCs to a less mature developmental state. Taken together, our results define the contribution of SC MCT1 to both SC metabolism and peripheral nerve maturation and aging.

A human in vitro platform for the evaluation of pharmacology strategies in cardiac ischemia.

Cardiac ischemic events increase the risk for arrhythmia, heart attack, heart failure, and death and are the leading mortality condition globally. Reperfusion therapy is the first line of treatment for this condition, and although it significantly reduces mortality, cardiac ischemia remains a significant threat. New therapeutic strategies are under investigation to improve the ischemia survival rate; however, the current preclinical models to validate these fail to predict the human outcome. We report the development of a functional human cardiac in vitro system for the study of conduction velocity under ischemic conditions. The system is a bioMEMs platform formed by human iPSC derived cardiomyocytes patterned on microelectrode arrays and maintained in serum-free conditions. Electrical activity changes of conduction velocity, beat frequency, and QT interval (the QT-interval measures the period from onset of depolarization to the completion of repolarization) or action potential length can be evaluated over time and under the stress of ischemia. The optimized protocol induces >80% reduction in conduction velocity, after a 4 h depletion period, and a partial recovery after 72 h of oxygen and nutrient reintroduction. The sensitivity of the platform for pharmacological interventions was challenged with a gap junction modulator (ZP1609), known to prevent or delay the depression of conduction velocity induced by ischemic metabolic stress. ZP1609 significantly improved the drastic drop in conduction velocity and enabled a greater recovery. This model represents a new preclinical platform for studying cardiac ischemia with human cells, which does not rely on biomarker analysis and has the potential for screening novel cardioprotective drugs with readouts that are closer to the measured clinical parameters.

Altered transient brain dynamics in multiple sclerosis: Treatment or pathology?

Multiple sclerosis (MS) is a demyelinating, neuroinflammatory, and -degenerative disease that affects the brain's neurophysiological functioning through brain atrophy, a reduced conduction velocity and decreased connectivity. Currently, little is known on how MS affects the fast temporal dynamics of activation and deactivation of the different large-scale, ongoing brain networks. In this study, we investigated whether these temporal dynamics are affected in MS patients and whether these changes are induced by the pathology or by the use of benzodiazepines (BZDs), an important symptomatic treatment that aims at reducing insomnia, spasticity and anxiety and reinforces the inhibitory effect of GABA. To this aim, we employed a novel method capable of detecting these fast dynamics in 90 MS patients and 46 healthy controls. We demonstrated a less dynamic frontal default mode network in male MS patients and a reduced activation of the same network in female MS patients, regardless of BZD usage. Additionally, BZDs strongly altered the brain's dynamics by increasing the time spent in the deactivating sensorimotor network and the activating occipital network. Furthermore, BZDs induced a decreased power in the theta band and an increased power in the beta band. The latter was strongly expressed in those states without activation of the sensorimotor network. In summary, we demonstrate gender-dependent changes to the brain dynamics in the frontal DMN and strong effects from BZDs. This study is the first to characterise the effect of multiple sclerosis and BZDs in vivo in a spatially, temporally and spectrally defined way.

30-LB: Diabetes Complications Including Nephropathy, Neuropathy, and Retinopathy Can Now Be Studied in a New Spontaneous Autoimmune Diabetes Transgenic Model

We have developed a spontaneous humanized transgenic mouse model of autoimmune diabetes chronically develops diabetic complications. Our humanized mouse develop diabetic nephropathy. The basal glomerular membrane thickness was doubled in size at 4 months of age as shown by electron microscopy. The manifestation of glomerulopathy subsequently correlates with microalbuminuria. At 6 month, mice show advanced features of diabetic nephropathy like focal segmental/global glomerular sclerosis and focal tubular atrophy. The typical features of Kimmelstiel-Wilson are seen when severe chronic kidney disease develops. Our humanized mice develop diabetic retinopathy. We have noted a significant increase in acellular capillaries of the retina at the age of 6 months. Ocular tomography revealed a significant reduction in total retinal thickening. Fundoscopic retinal images revealed a classic vascular leakage as observed in humans. Our humanized mice also show diabetic neuropathy. We have observed an impaired sciatic and optic nerve conduction. Specifically, optic nerves at 6-months old diabetic mice showed an increased refractory period of the second compound action potential (CAP). This increase in the refractory period of CAP in the diabetic optic nerves is consistent with the reduced conduction velocity. However, a limb vasculopathy has not been observed so far. In our mouse model, the mouse MHC-II was replaced with human DQ8 in all antigen-presenting cells. The mouse also expresses human GAD65 in pancreatic beta cells. The diabetic phenotype of our mouse mimics the human disease progression. Importantly, our mouse model has a genetic background that compromises beta-cell neogenesis and/or regeneration (1). Our humanized mice model has the closest known phenotype to human diabetes and is most suitable for addressing physiopathology and treatment of diabetes complications. (U.S. Provisional Patent #62/713,827). Disclosure S. Imam: None. J.C. Jaume: None. Funding University of Toledo

Personalized Cardiac Computational Models: From Clinical Data to Simulation of Infarct-Related Ventricular Tachycardia.

In the chronic stage of myocardial infarction, a significant number of patients develop life-threatening ventricular tachycardias (VT) due to the arrhythmogenic nature of the remodeled myocardium. Radiofrequency ablation (RFA) is a common procedure to isolate reentry pathways across the infarct scar that are responsible for VT. Unfortunately, this strategy show relatively low success rates; up to 50% of patients experience recurrent VT after the procedure. In the last decade, intensive research in the field of computational cardiac electrophysiology (EP) has demonstrated the ability of three-dimensional (3D) cardiac computational models to perform in-silico EP studies. However, the personalization and modeling of certain key components remain challenging, particularly in the case of the infarct border zone (BZ). In this study, we used a clinical dataset from a patient with a history of infarct-related VT to build an image-based 3D ventricular model aimed at computational simulation of cardiac EP, including detailed patient-specific cardiac anatomy and infarct scar geometry. We modeled the BZ in eight different ways by combining the presence or absence of electrical remodeling with four different levels of image-based patchy fibrosis (0, 10, 20, and 30%). A 3D torso model was also constructed to compute the ECG. Patient-specific sinus activation patterns were simulated and validated against the patient's ECG. Subsequently, the pacing protocol used to induce reentrant VTs in the EP laboratory was reproduced in-silico. The clinical VT was induced with different versions of the model and from different pacing points, thus identifying the slow conducting channel responsible for such VT. Finally, the real patient's ECG recorded during VT episodes was used to validate our simulation results and to assess different strategies to model the BZ. Our study showed that reduced conduction velocities and heterogeneity in action potential duration in the BZ are the main factors in promoting reentrant activity. Either electrical remodeling or fibrosis in a degree of at least 30% in the BZ were required to initiate VT. Moreover, this proof-of-concept study confirms the feasibility of developing 3D computational models for cardiac EP able to reproduce cardiac activation in sinus rhythm and during VT, using exclusively non-invasive clinical data.

OR28-4 Spontaneous Autoimmune Diabetes in Humanized Mice Carrying Human Type 1 Diabetes Susceptibility

An animal model of type 1 diabetes (T1D), in which human beta cell autoantigen(s) are presented to effector cells in the context of human Major Histocompatibility Complex (MHC) diabetes-susceptibility genes, would be highly desirable for studies of molecular mechanisms of disease and development of antigen-specific immune-therapies applicable to man. It would be especially advantageous to develop an animal model of human T1D that also exhibits the chronic complications of diabetes. Our new spontaneous mouse model of T1D wherein mouse MHC-II was replaced by human DQ8 in all antigen-presenting cells (APCs), and pancreatic Beta-cells were made to express human GAD65 autoantigen resembles most human characteristics of the disease. Our humanized transgenics have a genetic background providing for compromised Beta-cell neogenesis and/or regeneration. Immune cells attack Beta-cells, which in turn leads to a chronically progressive disease characterized by the development of anti-GAD65 antibodies. Flow cytometric analysis of pancreas (PN) and peri-pancreatic lymph nodes (PLN) revealed that CD4 and CD8 T cells build up in the PLN while mostly CD8 infiltrate intra-islet locations, which first causes glucose intolerance, and later on diabetes. Animals spontaneously show hyperglycemia of >250 mg/dl at approximately eight weeks of age. Without intervention, animals develop the classic complications observed in human diabetes (i.e., retinopathy, nephropathy, and neuropathy). To date, all complications of diabetes have been observed in our model (1). Our humanized transgenics develop diabetic retinopathy. Diabetic mice develop a significant increase of acellular capillaries in the retina as compared to non-diabetic controls as early as 6 months. Ocular tomography revealed that total retinal thickening was reduced in diabetic mice. Fundoscopic retinal images also revealed vascular leakage only in diabetic mice. Six-month-old diabetic mice also show advanced features of diabetic nephropathy like focal segmental/global glomerular sclerosis and focal tubular atrophy. Basal glomerular membrane doubles in size at three months as shown by electron microscopy as compared to non-diabetic controls. Moreover, our humanized mice also show diabetic neuropathy. Optic nerves of 6-month-old diabetic mice show an increase in the refractory period of the second compound action potential (CAP) as compared to non-diabetic mice (p < 0.05). This increase in the refractory period of CAP in the diabetic optic nerves is consistent with the reduced conduction velocity over non-diabetic controls. Conclusively, our humanized mice model is the closest one to human diabetes and is not just suitable for therapies to halt diabetes and its development but also to address the physiopathology and treatment of diabetes complications. 1) U.S. Provisional Patent #62/713,827 Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.