Measurement Of Conduction Velocity Research Articles

Visceral fat area is more strongly associated with arterial stiffness than abdominal subcutaneous fat area in Chinese patients with type 2 diabetes

BackgroundFew studies have compared the correlation between visceral fat area (VFA) and abdominal subcutaneous fat area (SFA) with arterial stiffness (AS) in patients with type 2 diabetes (T2D). In addition, there is currently controversy regarding the correlation between VFA and SFA with AS. We aimed to investigate the relationship between VFA and SFA with AS in patients with T2D.MethodsIn this cross-sectional study, 1475 Chinese T2D patients with an average age of 52.32 ± 10.96 years were included. VFA and SFA were determined by a dual bioelectrical impedance analyzer, and AS was determined by measurement of brachial-ankle pulse wave conduction velocity (baPWV). Atherosclerosis was deemed present in study participants with baPWV values higher than 75th percentile (1781 cm/s). Independent correlations of logVFA and logSFA with AS were assessed using multiple linear regression and multivariate logistic regression.ResultsThe baPWV was linked with VFA, waist circumference, and women’s SFA in a general linear correlation study (P < 0.05), but not with body mass index (P = 0.3783) or men’s SFA (P = 0.1899). In both men and women, VFA and SFA were positively correlated with AS, according to the generalized additive model (GAM). After fully adjusting for confounders, multiple linear regression analyses showed that for every 1-unit increase in logVFA, the beta coefficient of baPWV increased by 63.1 cm/s (95% CI: 18.4, 107.8) (P < 0.05). logSFA did not correlate significantly with baPWV (P = 0.125). In the multiple logistic regression analysis, the odds ratio (OR) of elevated baPWV was 1.8 (95% CI: 1.1, 3.1) (P = 0.019) per 1-unit increase in logVFA. logSFA did not correlate significantly with AS (P = 0.091). In the subgroup analysis, the correlation between logVFA and baPWV did not interact across subgroups (P-interaction > 0.05).ConclusionsCompared with SFA, VFA had a stronger independent positive correlation with AS in Chinese T2D patients. Patients with T2D should pay more attention to monitoring VFA and lowering it to minimize cardiovascular events.

Omnipolar conduction velocity mapping for ventricular substrate characterization: Impact of CV estimation method and EGM type on in vivo conduction velocity measurements

BackgroundAreas of abnormal or heterogeneous conduction velocity (CV) are important ablation targets for ventricular tachycardias, yet precise assessment of CV in clinical contact mapping remains challenging. Numerous different CV estimation methods have been proposed. ObjectiveThis study aimed to compare the automated local activation time (LAT)–independent omnipolar-based CV estimation method termed wave speed (WS) with 4 established LAT-based methods to formally establish the quantitative differences between them. MethodsHigh-density contact maps in patients with structurally normal hearts during sinus rhythm (SR) and ventricular ectopy (VE) were retrospectively analyzed. CV was assessed and compared by 5 methods: omnipolar WS, gradient method, planar wavefront fitting, circular wavefront fitting, and radial basis function. CV variations based on electrogram (EGM) type (unipolar, bipolar, and omnipolar), catheter movement, and surrogate markers for catheter contact were analyzed. ResultsThe study included 23 patients (47.8% male; 45.7 ± 17.3 years) with 22 SR maps (11 left ventricle, 11 right ventricle) and 16 VE maps (9 left ventricle, 7 right ventricle). The WS algorithm yielded statistically significant higher CV estimates in SR (mean, 1.41 ± 0.18 m/s) and VE (mean, 1.23 ± 0.18 m/s) maps compared with all LAT-based estimation methods, with absolute differences ranging from 0.1 m/s to 0.81 m/s. Median pointwise differences in SR and VE between WS and LAT-based methods were high, ranging from 0.55 ± 0.15 m/s (WS vs planar wavefront fitting) to 0.67 ± 0.16 m/s (WS vs radial basis function). For LAT-based methods, use of unipolar EGMs yielded significantly higher CV estimates than bipolar or omnipolar EGMs in SR. ConclusionThe CV estimation method has an important, statistically significant impact on ventricular CV measurements. Future work will focus on how these differences affect identification of pathologic conduction slowing in scar-related substrate.

Evaluation of novel open-source software for cardiac optical mapping

KairoSight-3.0 is a recently released Python-based, open-source software for cardiac optical mapping analysis. Addressing challenges in high-resolution electrophysiological data analysis, KairoSight-3.0 facilitates comprehensive studies of cardiac conduction and excitation-contraction coupling. We compared its performance with ElectroMap, focusing on action potential duration and conduction velocity measurements in mouse heart models subjected to ischaemia and flecainide treatment. Our findings reveal that while both software are effective, inherent methodological differences impact measurement outcomes. KairoSight-3.0's robust analysis capabilities make it a valuable tool in cardiac research. Additionally, future directions for KairoSight-3.0 and other mapping analysis tools are explored. Statement of importanceOpen-source methods for analysis of cardiac optical mapping are vital tools in electrophysiological research. Our work directly evaluates the latest version of KarioSight, recently published in JMCC plus, with ElectroMap, an established and widely used tool. Our results show both software are effective in analysis of changes in both conduction and repolarisation. Considering the new features of KairoSight-3.0 and python implementation, our study importantly demonstrates the effectiveness of the software, highlights potential discrepancies between it and ElectroMap, and provides a perspective on future directions for KairoSight-3.0 and other software.

Conduction velocity mapping in atrial fibrillation using omnipolar technology.

Recent studies have shown that atrial slow conduction velocity (CV) is associated with the perpetuation of atrial fibrillation (AF). However, the criteria of CV measurement have not been standardized. The aim of this study was to evaluate the relationship between the slow CV area (SCVA) measured by novel omnipolar technology (OT) and AF recurrence. This study included 90 patients with AF who underwent initial pulmonary vein isolation (PVI). The segmented surface area of the SCVA was measured by left atrial (LA) electrophysiological mapping using OT before the PVI. The proportion of the SCVA at each cutoff value of CV (from<0.6to<0.9m/s) was compared between the patients with and without AF recurrence. During a mean follow-up period of 516±197 days, the recurrence of AF after the initial PVI was observed in 23 (25.5%) patients. In patients with AF recurrence, the proportion of the SCVA in the LA posterior, LA appendage (LAA), and LA anterior were significantly higher than those without AF recurrence. The multivariate analysis indicated that the proportion of the low voltage area and the SCVA in the LA anterior (local CV<0.7m/s) were independent predictors of AF recurrence (hazard ratio [HR], 1.07; 95% confidence interval [CI], 1.01-1.14; p=0.03; HR, 1.40; 95% CI, 1.07-1.83; p=0.01, respectively). By evaluating the local CV using OT, it was indicated that SCVA with CV<0.7m/s in the LA anterior is strongly associated with AF recurrence after PVI.

Association of Sensory Nerve Action Potential Amplitude and Velocity With Type 2 Diabetic Peripheral Neuropathy.

There is ongoing controversy regarding the predominant type of nerve injury in diabetic peripheral neuropathy, whether it is demyelination or axonal degeneration. This study aimed to investigate the association between nerve conduction study parameters, specifically nerve conduction velocity and the amplitude of the action potential, with diabetic peripheral neuropathy and determine their potential as early indicators of the condition. A cross-sectional study was conducted involving diagnosed type 2 diabetes mellitus patients, who were divided into two groups: Group I (n = 111) with symptomatic diabetic peripheral neuropathy and Group II (n = 109) without clinically detectable peripheral neuropathy. Age and sex-matched healthy controls (n = 100) were also included. Nerve conduction velocity measurements were performed on both upper and lower limbs, with motor nerve conduction study focusing on the dominant side using the median and posterior tibial nervesand sensory nerve conduction study using the median and sural nerves. The nerve conduction studies revealed significantly lower sensory nerve action potential amplitudes and compound muscle action potential amplitudes in the median, posterior tibial, and sural nerves of the diabetic groups compared to the control subjects. Furthermore, these changes were more prominent in patients with peripheral neuropathy. Among the 220 diabetic patients analyzed, 135 (61.36%) exhibited nerve conduction abnormalities. The highest rate of abnormality was observed in the sural nerve, followed by the posterior tibial and median nerves. The most common abnormality detected in diabetic patients was a decrease in sensory nerve action potential, followed by a decrease in sensory nerve conduction velocity. The study findings suggest an association between reduced sensory nerve action potential amplitude and diabetic peripheral neuropathy. These results highlight the potential of sensory nerve action potential and velocity as a sensitive indicator of peripheral neuropathy in diabetic patients.

The Effect of Skeletal Fixation on Nerve Healing in a Rat

Objective To investigate the effect of rigid internal skeletal fixation of a rat femoral shaft fracture on the healing of an induced sciatic nerve crush injury as assessed by functional outcomes. Methods Thirty-six male Lewis rats were divided into two groups. A unilateral sciatic nerve crush injury and a same-level transverse femur fracture were created in all animals. Animals in the first group underwent immediate open reduction internal fixation (ORIF) with a stainless steel plate and screws. Animals in the second group were treated non-operatively (NON) without internal or external fixation or bracing. At each of the six-time points relevant to different nerve degeneration and regeneration stages, three animals in each group underwent bilateral limb assessments of electrophysiology, muscle mass, and nerve histomorphometry. Results Outcome measurements of the ORIF group (n=17) and NON group (n=16) showed the ORIF group to have both significantly greater tibialis anterior muscle force generation and sciatic nerve conduction velocity across the zone of injury for the overall groups. Force and conduction velocity measurements were greater for the ORIF group at selective time points in the subgroup analysis. Histologic analysis confirmed a greater cross-sectional area of the sciatic nerve in the ORIF group. Conclusion This study provides information about the influence of the stability of the skeletal and soft tissue environment on the nerve healing process. The significantly greater maximum force generation and conduction velocity and the increased cross-sectional areas with greater axon counts observed in our ORIF group support our hypothesis that rigid internal skeletal fixation of a fracture promotes superior recovery of a concomitant peripheral nerve injury. The findings of this study suggest that superior healing of the peripheral nerve injury may occur with stable skeletal fixation.

Unraveling Impacts of Chamber-Specific Differences in Intercalated Disc Ultrastructure and Molecular Organization on Cardiac Conduction

BackgroundPropagation of action potentials through the heart coordinates the heartbeat. Thus, intercalated discs, specialized cell–cell contact sites that provide electrical and mechanical coupling between cardiomyocytes, are an important target for study. Impaired propagation leads to arrhythmias in many pathologies, where intercalated disc remodeling is a common finding, hence the importance and urgency of understanding propagation dependence on intercalated disc structure. Conventional modeling approaches cannot predict changes in propagation elicited by perturbations that alter intercalated disc ultrastructure or molecular organization, because of lack of quantitative structural data at subcellular through nano scales. ObjectivesThis study sought to quantify intercalated disc structure at these spatial scales in the healthy adult mouse heart and relate them to chamber-specific properties of propagation as a precursor to understanding the effects of pathological intercalated disc remodeling. MethodsUsing super-resolution light microscopy, electron microscopy, and computational image analysis, we provide here the first ever systematic, multiscale quantification of intercalated disc ultrastructure and molecular organization. ResultsBy incorporating these data into a rule-based model of cardiac tissue with realistic intercalated disc structure, and comparing model predictions of electrical propagation with experimental measures of conduction velocity, we reveal that atrial intercalated discs can support faster conduction than their ventricular counterparts, which is normally masked by interchamber differences in myocyte geometry. Further, we identify key ultrastructural and molecular organization features underpinning the ability of atrial intercalated discs to support faster conduction. ConclusionsThese data provide the first stepping stone to elucidating chamber-specific effects of pathological intercalated disc remodeling, as occurs in many arrhythmic diseases.

Right atrial collision time (RACT): A novel marker of propensity for typical atrial flutter.

The risk of typical atrial flutter (AFL) is increased proportionately to right atrial (RA) size or right atrial scarring that results in reduced conduction velocity. These characteristics result in propagation of a flutter wave by ensuring 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 and may provide a novel marker of propensity to develop AFL. Our goal was to investigate right atrial collision time (RACT) as a marker of existing typical AFL. This single-centre, prospective study recruited consecutive typical AFL ablation patients that were in sinus rhythm. Controls were consecutive electrophysiology study patients >18 years of age. While pacing the coronary sinus (CS) ostium at 600 ms, a local activation time map was created to locate the latest collision point on the anterolateral right atrial wall. This RACT is a measure of conduction velocity and distance from CS to a collision point on the lateral right atrial wall. Ninety-eight patients were included in the analysis, 41 with atrial flutter and 57 controls. Patients with atrial flutter were older, 64.7 ± 9.7 versus 52.4 ± 16.8 years (<.001), and more often male (34/41 vs. 31/57 [.003]). The AFL group mean RACT (132.6 ± 17.3 ms) was significantly longer than that of controls (99.1 ± 11.6 ms) (p < .001). A RACT cut-off of 115.5 ms had a sensitivity and specificity of 92.7% and 93.0%, respectively for diagnosis of atrial flutter. A ROC curve indicated an AUC of 0.96 (95% CI: 0.93-1.0, p < .01). RACT is a novel and promising marker of propensity for typical AFL. This data will inform larger prospective studies.

Performance of atrial conduction velocity algorithms: a comparative in-silico study

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): British Heart Foundation Background Atrial conduction velocity is a key determinant of re-entry. Measurement of conduction velocity from electroanatomic mapping data is challenging due to sparsity, distribution, and uncertainty of measurements. Several mathematical methods have been proposed to address these challenges but their relative sensitivity to the typical uncertainty of clinical data is unknown. Furthermore, prior clinical studies utilising these algorithms provide conflicting results. Purpose To assess the performance of conduction velocity methods (triangulation, planar fitting, and radial basis function interpolation) for the calculation of atrial conduction velocity. Method Atrial activation was simulated with known conduction velocity using the monodomain model, Courtemanche cell model and atrial geometry derived from cardiac magnetic resonance imaging with mapped fibre orientations. The model was paced from the pulmonary veins, the mid coronary sinus, and the insertion of Bachmann's bundle. Reconstructed electroanatomic maps were used for conduction velocity calculation in OpenEP[1]. To test the robustness of algorithms to electrogram sampling density, simulated sampling densities were reduced from 16.45 to 8.43 points/cm2 (1950-1000 points/map). To test the robustness to uncertainty in local activation time assignment, random uniform noises with the maximum amplitude of ± 20ms was added to the local activation times from simulations. Mean squared velocity error was calculated using the differences between the ground truth and estimated conduction velocities. Result In electroanatomic maps recreated with high electrogram sampling density (16.45 points/cm2), planar fitting showed a slightly higher error compared to triangulation and the radial basis function methods (0.16 ± 0.03 m/s, 0.11 ± 0.01 m/s and 0.12 ± 0.03 m/s, respectively, P &amp;lt; 0.05). As mapping density was decreased, the relative performance of the planar fitting method increased and in low-density maps (13.5 to 8.43 points/cm2) the planar fitting method resulted in the lowest error. When local activation times were accurately assigned, all methods performed well. However, when uncertainty in local activation time assignment increased, conduction velocities calculated using planar fitting had a significantly lower error compared to those calculated with the triangulation and radial basis function methods (0.19 ± 0.03 m/s, 0.36 ± 0.04 and 0.29 ± 0.04 m/s, respectively, P &amp;lt; 0.05). Conclusion This study highlights the importance of spatial and temporal accuracy for the assessment of conduction velocity. At high electroanatomic mapping sampling densities (&amp;gt;16.9 points/cm2), all methods performed well. Below 13.5 points/cm2 (~1600 points per map), the planar fitting method outperformed the triangulation and radial basis function methods. The differential effects of clinical measurement uncertainty on the accuracy of each method may explain the conflicting results of prior studies.

Small Molecule Positive Modulator of Hepatocyte Growth Factor (HGF)/MET, ATH-1105, Improves Function and Reduces Disease Biomarkers in a TDP-43 Mouse Model of Amyotrophic Lateral Sclerosis (P8-8.007)

<h3>Objective:</h3> Evaluate the preclinical efficacy of the small molecule positive modulator of hepatocyte growth factor (HGF)/MET, ATH-1105, in a mouse model of amyotrophic lateral sclerosis (ALS). <h3>Background:</h3> Activation of the MET receptor by HGF promotes neuroprotective, neurotrophic, and anti-inflammatory mechanisms. Small molecule positive modulators of HGF/MET, including ATH-1105, have been developed to explore the therapeutic potential of this target. ALS is characterized by progressive motor neuron degeneration and demyelination, accompanied by systemic inflammation and pathological aggregation of TAR DNA-binding protein 43 (TDP-43) in 97% of patients. We hypothesized that treatment with ATH-1105 would be beneficial in a TDP-43 mouse model of ALS. <h3>Design/Methods:</h3> ATH-1105 at 10 or 20 mg/kg was orally administered daily to male Prp-TDP43_A315T mice (n=10/group) for two months. At baseline and after one and two months of treatment, we conducted a battery of motor behavior tests, and assessed sciatic nerve health by compound muscle action potential (CMAP) and nerve conduction velocity (NCV) measurements. Plasma biomarkers of inflammation (IL-6, TNF-α) and neurodegeneration (neurofilament light chain [NfL]) were interrogated after one and two months of treatment. Sciatic nerves were stained for quantification of axonal and myelin parameters as well as phospho-TDP-43 aggregation at study termination. <h3>Results:</h3> The deterioration of motor function in TDP-43 animals was significantly mitigated in a dose-dependent manner after treatment with ATH-1105, and significant functional improvement of sciatic nerve conduction was observed. Additionally, plasma levels of all biomarkers assessed were significantly decreased, indicating reduced systemic inflammation and neurodegeneration in treated TDP-43 mice. Sciatic nerve histology revealed a protection of motor axon numbers and myelination, as well as a reduction in axonal phospho-TDP-43 aggregation by ATH-1105. <h3>Conclusions:</h3> ATH-1105 was found to be protective across a multitude of functional and structural measures of ALS disease progression. These findings support the continued development of this small molecule positive modulator of HGF/MET for ALS. <b>Disclosure:</b> Mrs. Kleist has received personal compensation for serving as an employee of Athira Pharma. Mrs. Kleist has received personal compensation for serving as an employee of Alpine Immune Sciences. Mrs. Kleist has stock in Athira Pharma. Mrs. Kleist has stock in Alpine Immune Sciences. Dr. Berthiaume has received personal compensation for serving as an employee of Athira Pharma. Dr. Berthiaume has stock in Athira Pharma. An immediate family member of Dr. Berthiaume has stock in Athira Pharma. Dr. Johnston has received personal compensation for serving as an employee of Athira Pharma, Inc. Dr. Johnston has stock in Athira Pharma, Inc. An immediate family member of Dr. Johnston has stock in Athira Pharma, Inc. Dr. Johnston has received intellectual property interests from a discovery or technology relating to health care. Dr. Reda has received personal compensation for serving as an employee of Athira Pharma, Inc. . Dr. Reda has stock in Athira Pharma, Inc. . Dr. Moebius has received personal compensation in the range of $100,000-$499,999 for serving as an officer or member of the Board of Directors for Athira Pharma, Inc.. Dr. Moebius has stock in Athira Pharma, Inc.. Dr. Church has received personal compensation for serving as an employee of Athira Pharma. Dr. Church has stock in Athira Pharma. Dr. Church has received intellectual property interests from a discovery or technology relating to health care.

Comparative analysis of the cardiomyocyte differentiation potential of induced pluripotent stem cells reprogrammed from human atrial or ventricular fibroblasts.

Background: We had shown that cardiomyocytes (CMs) were more efficiently differentiated from human induced pluripotent stem cells (hiPSCs) when the hiPSCs were reprogrammed from cardiac fibroblasts rather than dermal fibroblasts or blood mononuclear cells. Here, we continued to investigate the relationship between somatic-cell lineage and hiPSC-CM production by comparing the yield and functional properties of CMs differentiated from iPSCs reprogrammed from human atrial or ventricular cardiac fibroblasts (AiPSC or ViPSC, respectively). Methods: Atrial and ventricular heart tissues were obtained from the same patient, reprogrammed into AiPSCs or ViPSCs, and then differentiated into CMs (AiPSC-CMs or ViPSC-CMs, respectively) via established protocols. Results: The time-course of expression for pluripotency genes (OCT4, NANOG, and SOX2), the early mesodermal marker Brachyury, the cardiac mesodermal markers MESP1 and Gata4, and the cardiovascular progenitor-cell transcription factor NKX2.5 were broadly similar in AiPSC-CMs and ViPSC-CMs during the differentiation protocol. Flow-cytometry analyses of cardiac troponin T expression also indicated that purity of the two differentiated hiPSC-CM populations (AiPSC-CMs: 88.23% ± 4.69%, ViPSC-CMs: 90.25% ± 4.99%) was equivalent. While the field-potential durations were significantly longer in ViPSC-CMs than in AiPSC-CMs, measurements of action potential duration, beat period, spike amplitude, conduction velocity, and peak calcium-transient amplitude did not differ significantly between the two hiPSC-CM populations. Yet, our cardiac-origin iPSC-CM showed higher ADP and conduction velocity than previously reported iPSC-CM derived from non-cardiac tissues. Transcriptomic data comparing iPSC and iPSC-CMs showed similar gene expression profiles between AiPSC-CMs and ViPSC-CMs with significant differences when compared to iPSC-CM derived from other tissues. This analysis also pointed to several genes involved in electrophysiology processes responsible for the physiological differences observed between cardiac and non-cardiac-derived cardiomyocytes. Conclusion: AiPSC and ViPSC were differentiated into CMs with equal efficiency. Detected differences in electrophysiological properties, calcium handling activity, and transcription profiles between cardiac and non-cardiac derived cardiomyocytes demonstrated that 1) tissue of origin matters to generate a better-featured iPSC-CMs, 2) the sublocation within the cardiac tissue has marginal effects on the differentiation process.

Role of cardiac mitofusins in cardiac conduction following simulated ischemia–reperfusion

Mitochondrial dysfunction induced by acute cardiac ischemia–reperfusion (IR), may increase susceptibility to arrhythmias by perturbing energetics, oxidative stress production and calcium homeostasis. Although changes in mitochondrial morphology are known to impact on mitochondrial function, their role in cardiac arrhythmogenesis is not known. To assess action potential duration (APD) in cardiomyocytes from the Mitofusins-1/2 (Mfn1/Mfn2)-double-knockout (Mfn-DKO) compared to wild-type (WT) mice, optical-electrophysiology was conducted. To measure conduction velocity (CV) in atrial and ventricular tissue from the Mfn-DKO and WT mice, at both baseline and following simulated acute IR, multi-electrode array (MEA) was employed. Intracellular localization of connexin-43 (Cx43) at baseline was evaluated by immunohistochemistry, while Cx-43 phosphorylation was assessed by Western-blotting. Mfn-DKO cardiomyocytes demonstrated an increased APD. At baseline, CV was significantly lower in the left ventricle of the Mfn-DKO mice. CV decreased with simulated-ischemia and returned to baseline levels during simulated-reperfusion in WT but not in atria of Mfn-DKO mice. Mfn-DKO hearts displayed increased Cx43 lateralization, although phosphorylation of Cx43 at Ser-368 did not differ. In summary, Mfn-DKO mice have increased APD and reduced CV at baseline and impaired alterations in CV following cardiac IR. These findings were associated with increased Cx43 lateralization, suggesting that the mitofusins may impact on post-MI cardiac-arrhythmogenesis.

Abstract 10726: Cardiomyocyte Targeting Peptide to Deliver Amiodarone

Introduction: Amiodarone remains underutilized as an anti-arrhythmic due to significant off-target toxicities with long-term use. We hypothesized that the required dose could be minimized by targeting amiodarone to cardiomyocytes by utilizing a cardiomyocyte targeting peptide (CTP). Methods: CTP (APWHLSSQYSRT) was conjugated to amiodarone via a disulfide bond, HPLC purified, characterized by MALDI/TOF, and stability at 37°C assessed using serial HPLCs over 21 days. Adult, male guinea pigs (GP; n=4/group) were injected intraperitoneally daily with vehicle (7 days), amiodarone (7 days; 80mg/Kg), 1/10 th the molar dose of CTP-amiodarone (5 days), or CTP (5 days), followed by euthanasia, hearts excised, perfused on a Langendorff apparatus with Tyrode’s solution, and placed in a custom-designed chamber blebbistatin (5 μM) to minimize contractions. Bolus injections of voltage (RH237) and Ca 2+ -indicator dye (Rhod-2/AM) were injected to simultaneously map cardiac action potentials (APs) and Ca 2+ transients (CaT), at 610-750nm and 570-595nm, respectively with 2 CMOS cameras, followed by pacing at 250ms to measure conduction velocity (CV), AP and CaT durations (at 90% recovery). Results: CTP-amiodarone produced a single HPLC peak at 16mins that remained stable for 21 days. CTP-amiodarone and amiodarone decreased conduction velocities in myocytes significantly compared to control GPs (0.92±0.05, 0.87±0.08ms, vs. 1.00±0.03m/s respectively, p&lt;0.001). Amiodarone increased AP duration (192±5ms vs. 175±8ms for vehicle, p=0.0025), while CTP-amiodarone decreased it significantly (157±16ms, p=0.0136), similar to CTP alone (155±13, p=0.0039). Both amiodarone and CTP-amiodarone significantly decreased CaTs compared to vehicle treated GPs. CTP-amiodarone and CTP decreased CaTs to an extent greater than amiodarone alone (p&lt;0.001). Conclusions: Our data suggests that amiodarone can be stably covalently linked to CTP, which is able to deliver amiodarone to cardiomyocytes in vivo in GPs, at 1/10 th the dose of amiodarone needed to produce comparable slowing of CVs. The ability of CTP alone to decrease AP durations and CaTs was a surprise finding and merits further study to fully characterize the anti-arrhythmic actions of the CTP-amiodarone conjugate.

Abstract 15591: Acute Dantrolene Treatment Reverses Arrhythmogenic Substrate and Reduces Triggers Induced by Ryanodine Receptor 2 Hyperactivity in Human Hearts

Introduction: Ryanodine receptor 2 (RyR2) hyperactivity is commonly observed in structural heart diseases that are a result of ischemia or heart failure. It results in abnormal calcium handling and calcium leak that can trigger arrhythmias. Dantrolene, a RyR inhibitor, is used to prevent calcium leak from RyR1 in skeletal muscles. Hypothesis: Suppressing RyR2 hyperactivity with acute dantrolene treatment can reduce arrhythmia burden in human hearts. Methods: Human donor hearts that were not used in transplantation were obtained and 1 cm 3 cubes were isolated from the left ventricle. Slices at 400 μm thickness were generated from these cubes, pinned and perfused with Tyrode’s solution in a recording tissue chamber. Pseudo-ECGs were recorded with ECG electrodes and the slices were optically mapped to measure conduction velocity (CV), action potential duration (APD) and calcium transient duration (CaTD). After an initial 30 min equilibration period, baseline optical recordings were obtained. Slices were then treated with 1) Isoproterenol (Iso, 250 nM) to stimulate β-adrenergic receptors, 2) Caffeine (200 μM) for RyR2 receptor activation and 3) Dantrolene (10 μM), sequentially. Dual optical recordings, Vm and Ca, were obtained after each treatment. Results: Substrate: Iso reduced APD (425±36 vs 394±43, p=0.03), as expected, and addition of Caffeine restored APD to baseline. More importantly, addition of Dantrolene prolonged APD even further (460±90, p=0.04). CaTD was also similarly reduced by Iso (445±48 vs 387±25, p=0.04) and restored to baseline by Caffeine+Iso. No significant changes in CV were measured under any condition. Trigger: In slices where PVCs were inducible, Caffeine+Iso increased occurrence of PVCs (20 vs 53 PVCs/min) while addition of Dantrolene reduced PVC incidence (18 PVCs/min). Conclusions: Dantrolene treatment, acutely reversed proarrhythmogenic substrate and reduced triggers and could therefore be a suitable approach for anti-arrhythmic therapy in patients with structural heart disease. Additionally, human LV slice preparation is useful in antiarrhythmic drug studies.

Circle Method for Robust Estimation of Local Conduction Velocity High-Density Maps From Optical Mapping Data: Characterization of Radiofrequency Ablation Sites.

Conduction velocity (CV) slowing is associated with atrial fibrillation (AF) and reentrant ventricular tachycardia (VT). Clinical electroanatomical mapping systems used to localize AF or VT sources as ablation targets remain limited by the number of measuring electrodes and signal processing methods to generate high-density local activation time (LAT) and CV maps of heterogeneous atrial or trabeculated ventricular endocardium. The morphology and amplitude of bipolar electrograms depend on the direction of propagating electrical wavefront, making identification of low-amplitude signal sources commonly associated with fibrotic area difficulty. In comparison, unipolar electrograms are not sensitive to wavefront direction, but measurements are susceptible to distal activity. This study proposes a method for local CV calculation from optical mapping measurements, termed the circle method (CM). The local CV is obtained as a weighted sum of CV values calculated along different chords spanning a circle of predefined radius centered at a CV measurement location. As a distinct maximum in LAT differences is along the chord normal to the propagating wavefront, the method is adaptive to the propagating wavefront direction changes, suitable for electrical conductivity characterization of heterogeneous myocardium. In numerical simulations, CM was validated characterizing modeled ablated areas as zones of distinct CV slowing. Experimentally, CM was used to characterize lesions created by radiofrequency ablation (RFA) on isolated hearts of rats, guinea pig, and explanted human hearts. To infer the depth of RFA-created lesions, excitation light bands of different penetration depths were used, and a beat-to-beat CV difference analysis was performed to identify CV alternans. Despite being limited to laboratory research, studies based on CM with optical mapping may lead to new translational insights into better-guided ablation therapies.

Selenium deficiency is associated with polyneuropathy in primary Sjögren's syndrome.

Selenium plays an important role in the regulation of the immune system. Selenium deficiency is associated with Hashimoto's thyroiditis, a common comorbidity in primary Sjögren's syndrome (pSS). Therefore we aimed to identify whether or not selenium deficiency is also associated with pSS. 107 consecutive female patients with pSS and, as a control, 59 female patients with axial spondyloarthritis were recruited. Later, 11 male pSS patients, 5 of these suffering from polyneuropathy, and 15 male axSpA patients were additionally recruited in order to confirm the results from the female patients. All patients were consulted about their diet and food intolerances and their plasma selenium concentrations were analyzed. Current and previous extraglandular manifestations of pSS were recorded. Patients complaining of misperceptions and tingling paraesthesia underwent measurement of nerve conduction velocity. The proportion of patients and controls with a selenium deficiency was compared using Fisher's exact test. The proportion of female pSS patients with a low selenium concentration <0.63μmol/L (22.4%) was significantly higher than of the controls (1.7%) (p<0.001). Within the group of female patients with pSS, selenium deficiency was significantly associated with the presence of polyneuropathy (45.8% with vs 14.5% without polyneuropathy, p=0.003) and particularly polyneuropathy with motor nerve involvement measured by nerve conduction velocity (41.7% with vs 10.8% without motor neuropathy, p=0.001). The mean selenium concentrations of the 5 male pSS patients with polyneuropathy were significantly lower compared to the 6 pSS patients without polyneuropathy and to the 15 male axSpA controls. PSS and in particular its complication polyneuropathy is associated with selenium deficiency. Measurement of the selenium concentration in blood is advisable in patients with pSS and in particular in the subset of patients with polyneuropathy. Substitution of selenium may be a possible therapy of polyneuropathy associated with pSS.

Efficacy of electroacupuncture with different frequencies in the treatment of chemotherapy-induced peripheral neuropathy: A study protocol for a randomized controlled trial.

IntroductionChemotherapy-induced peripheral neuropathy (CIPN) is a common complication in patients with cancer during chemotherapy. It mainly leads to severe numbness of the hands and feet and causes great pain in patients. Electroacupuncture (EA) is considered to be beneficial in improving peripheral neuropathy and relieving numbness of the hands and feet. This trial aims to evaluate the therapeutic effect of different frequencies of EA on CIPN in patients with cancer.Methods and analysisThis study is a randomized controlled trial. In total, 160 eligible CIPN patients are randomly assigned to the 2 Hz EA group, 100 Hz EA group, 2/100 Hz EA group, and control group in the ratio of 1:1:1:1. All patients in the EA treatment groups receive treatment with EA three times a week for 4 weeks and following up for 4 weeks. The patients in the control group are given Mecobalamin (MeCbl) tablets orally, one tablet at a time, three times a day, for 4 weeks, and following up for 4 weeks. The primary outcome measures are the participant neurotoxicity questionnaire (PNQ) and the peripheral neurotoxicity assessment rating (NCI CTCAE V5.0). Secondary outcomes are the quality of life scale (EORTC QLQ-C30) and the measurement of peripheral nerve conduction velocity (NCV). The results are evaluated at baseline, post-treatment phase, and following up for 4 weeks. All major analyses are based on the intention to treat principle.Ethics/disseminationThis protocol was approved by the Medical Ethics Committee of the Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital) on 7 December 2021. The license number is IRB-2021-458. This study provides clinical efficacy data of different frequencies of EA in the treatment of CIPN. The results help to prove whether EA is an effective therapy for CIPN and optimize the frequency of EA for CIPN. The results of this study are shared with health care professionals, the public, and relevant organizations through the publication of manuscripts and conference reports.Trial registration numberChiCTR2100054458.

Dynamic voltage attenuation identifies atrial fibrosis in a rabbit model: simultaneous assessment with optical mapping and contact electrogram mapping

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): British Heart Foundation. Academy of Medical Sciences. Background Bipolar voltage amplitude is a widely-used clinical parameter in atrial electrophysiology procedures. However, voltage amplitude is variable, and it has been shown that increasing activation rate decreases bipolar voltage amplitude in patients with atrial fibrillation. It is not known whether such voltage attenuation is a marker of the presence of atrial fibrosis which could therefore be used to improve intra-procedural assessment of atrial cardiomyopathy. Purpose We sought to investigate the effect of increasing activation rate on bipolar voltage amplitude in both healthy and fibrotic left atrial tissue. Methods 10 New Zealand Rabbits were fed a high cholesterol diet (0.75%) for a period of 12 weeks to create an atrial fibrosis model. 10 Animals were fed normal chow. After terminal anaesthesia the heart was excised, and optical and voltage mapping of the excised left atrial tissue was performed. Blebbistatin was used to maintain cardiac stasis and the voltage sensitive dye RH237 was used for optical mapping. Voltage and optical recordings were made during pacing was from 3 different directions at rates from 2-6Hz and at 3 sites across the atrial tissue. Voltage amplitude was recorded as the mean amplitude over 10 beats during steady-state pacing. Optical recordings were used to measure conduction velocity and action potential characteristics. Only pacing runs showing 1:1 conduction were included in analysis. Atrial fibrosis was assessed using Masson’s Trichrome staining. Results The degree of atrial fibrosis was significantly greater in the atrial fibrosis model compared to healthy controls (15±3.24% vs. 9.74±4.98%, p=0.0069). Median voltage at base rate pacing of 2Hz was not significantly different between control and fibrotic atria (11.63mV, IQR 6.35mV vs. 10.3mV, IQR 6.81mV, p=0.71, respectively). Median voltage was significantly lower at 6Hz than at 2Hz in the control group (9.84mV, IQR 6.87mV, p=0.046). The degree of voltage attenuation between study groups was not significantly different between when pacing at 3hz or 4hz, whereas pacing at 5Hz and 6Hz showed significantly greater attenuation in fibrotic atria. At 5Hz the median reduction in amplitude from baseline in control vs fibrotic atria was 0.88mV, IQR 2.36mV vs 1.92mV, IQR 1.63mV (p=0.031). At 6 Hz the median reduction was 0.94mV, IQR 1.69mV vs 2.68mV, IQR 1.11mV, p=0.013 in control and fibrotic groups respectively. Discussion High cholesterol diet increased atrial fibrosis in a rabbit model. Bipolar voltage amplitude attenuation occurred in both control and fibrotic atria however the degree of voltage attenuation was significantly greater in fibrotic atria. These findings support the further evaluation of dynamic voltage attenuation for intraprocedural identification of atrial fibrosis.

Melatonin treatment improves ventricular conduction via upregulation of Nav1.5 channel proteins and sodium current in the normal rat heart

Melatonin treatment was reported to reduce the risk of cardiac arrhythmias, and crucial for this antiarrhythmic action was the effect of melatonin on activation spread. The aim of the present study was evaluation of the mechanisms of this activation enhancement.Experiments were performed in a total of 123 control and melatonin-treated (10 mg/kg, daily, for 7 days) male Wistar rats. In epicardial mapping studies (64 leads, interlead distance 0.5 mm) in the anesthetized animals, activation times (ATs) were determined in each lead as dV/dt minimum during QRS complex under sinus rhythm. Epicardial pacing was performed to measure conduction velocity (CV) across the mapped area. Average left ventricular ATs were shorter in the treated animals as compared to the controls, whereas the minimal epicardial ATs indicating the duration of activation propagation via the ventricular conduction system did not differ between the groups. CV was higher in the treated groups indicating that melatonin affected conduction via contractile myocardium The area of Cx43-derived fluorescence, as well as the expression of Cx43 protein, was similar in ventricles in the control and melatonin-treated groups. Expression of Gja1 gene transcripts encoding Cx43, was increased in the last group. An uncoupling agent octanol modified myocardial conduction properties (time of activation, action potential upstroke velocity, passive electrotonic phase duration) similarly in both groups. On the other hand, the expression of both Scn5a gene transcripts encoding Nav1.5 proteins, as well as peak density of transmembrane sodium current were increased in the ventricular myocytes from the melatonin-treated animals. Thus, a week-long melatonin treatment caused the increase of conduction velocity via enhancement of sodium channel proteins expression and increase of sodium current in the ventricular myocytes.

Open-source low-cost cardiac optical mapping system.

Fluorescent imaging with voltage- or calcium-sensitive dyes, known as optical mapping, is one of the indispensable modern techniques to study cardiac or neural electrophysiology, unsurpassed by temporal and spatial resolution. High-speed CMOS cameras capable of optical registration of action potential propagation are in general very costly. We present a complete solution priced below US$1,000 (including camera and lens) at the moment of publication with an open-source image acquisition and processing software. We demonstrate that the iDS UI-3130CP rev.2 camera we used in this study is capable of 200x200 977 frames per second (FPS) action potential recordings from rodent hearts, with the signal-to-noise-ratio of a conditioned signal of 16 ± 10. A comparison with a specialized MiCAM Ultimate-L camera has shown that signal-to-noise ratio (SNR) while lower is sufficient for accurate measurements of AP waveform, conduction velocity (± 0.04 m/s) and action potential duration (± 7ms) in mouse and rat hearts. We used 4-aminopyridine to prolong the action potential duration in mouse heart, thus demonstrating that the proposed system is adequate for pharmacological studies.