Action Potential Conduction Velocity Research Articles

Common SYNE2 Genetic Variant Associated With Atrial Fibrillation Lowers Expression of Nesprin-2α1 With Downstream Effects on Nuclear and Electrophysiological Traits.

Atrial fibrillation GWAS (genome-wide association studies) identified significant associations for rs1152591 and linked variants in the SYNE2 gene encoding Nesprin-2, which connects the nuclear membrane with the cytoskeleton. Reporter gene vector transfection and CRISPR-Cas9 editing were used to identify the causal variant regulating the expression of SYNE2α1. After SYNE2 knockdown or SYNE2α1 overexpression in human stem cell-derived cardiomyocytes, nuclear phenotypes were assessed by imaging and atomic force microscopy. Gene expression was assessed by RNAseq and gene set enrichment analysis. Fura-2 AM staining assessed calcium transients. Optical mapping assessed action potential duration and conduction velocity. The risk allele of rs1152591 had lower promoter and enhancer activity and was significantly associated with lower expression of the short SYNE2α1 isoform in human stem cell-derived cardiomyocytes, without an effect on the expression of the full-length SYNE2 mRNA. SYNE2α1 overexpression had dominant negative effects on the nucleus with its overexpression or SYNE2 knockdown leading to increased nuclear area and decreased nuclear stiffness. Gene expression results from SYNE2α1 overexpression demonstrated both concordant and nonconcordant effects with SYNE2 knockdown. SYNE2α1 overexpression had a gain of function on electrophysiology, leading to significantly faster calcium reuptake and decreased assessed action potential duration, while SYNE2 knockdown showed both shortened assessed action potential duration and decreased conduction velocity. rs1152591 was identified as a causal atrial fibrillation variant, with the risk allele decreasing SYNE2α1 expression. Downstream effects of SYNE2α1 overexpression include changes in nuclear stiffness and electrophysiology, which may contribute to the mechanism for the risk allele's association with AF.

CAMP reduces action potential amplitude and conduction velocity over long axonal distance.

cAMP reduces action potential amplitude and conduction velocity over long axonal distance.

New findings about neuropathological outcomes in the PKU mouse throughout lifespan

Phenylketonuria (PKU, OMIM 261600) is a genetic disorder caused by a deficiency of the hepatic enzyme phenylalanine hydroxylase (PAH). If left untreated, PKU leads to systemic phenylalanine (Phe) accumulation, which can result in irreversible brain damage and intellectual disabilities. In the last 60 years, early and strict dietary restriction of phenylalanine (Phe) intake proved to prevent the severe clinical phenotype of untreated PKU. While the specific mechanisms through which phenylalanine causes brain damage are still poorly understood, preclinical models have been deeply explored to characterize the neurotoxic effect of Phe on neurodevelopmental processes. At the same time, that on the aging brain still needs to be explored. In the brain of untreated PAHEnu2(−/−) mouse, we previously reported a reduction of myelin basic protein (MBP) during postnatal development up to 60 PND. Later in the diseased mouse's life, a spontaneous and persistent restoration of MBP was detected. In this present longitudinal study, ranging from 14 to 540 post-natal days (PND) of untreated PAHEnu2(−/−) mice, we further investigated: a) the long-life consistency of two Phe-related brain metabolic alterations, such as large neutral amino acids (LNAA) and biogenic amine neurotransmitters' depletion; b) the outcome of locomotor functions during the same life span; c) the integrity of myelin as assessed ex vivo by central (hippocampus) and peripheral (extensor digitorum longus-sciatic nerve) action potential conduction velocities. In contrast with the results of other studies, brain Leu, Ile, and Val concentrations were not significantly altered in the brain PAHEnu2(−/−) mouse. On the other hand, 3-O-Methyldopa (3-OMD, a biomarker of L-DOPA), serotonin, and its associated metabolites were reduced throughout most of the considered time points, with consistent reductions observed prevalently from 14 to 60 PND. Normal saltatory conduction was restored after 60 PND and remained normal at the last examination at 360 PND, resulting nonetheless in a persistent locomotor impairment throughout a lifetime. These new findings contribute to laying the foundations for the preclinical characterization of aging in PKU, confirming neurotransmitter defects as consistent metabolic traits. LNAAs have a minor role, if any, in brain damage pathogenesis. Transient myelin synthesis failure may impact brain connectivity during postnatal development but not nervous signal conduction.

Male and female atria exhibit distinct acute electrophysiological responses to sex steroids

The electrophysiological properties of the hearts of women and men are different. These differences are at least partly mediated by the actions of circulating estrogens and androgens on the cardiomyocytes. Experimentally, much of our understanding in this field is based on studies focusing on ventricular tissue, with considerably less known in the context of atrial electrophysiology. The aim of this investigation was to compare the electrophysiological properties of male and female atria and assess responses to acute sex steroid exposure. Age-matched adult male and female C57BL/6 mice were anesthetized (4 % isoflurane) and left atria isolated. Atria were loaded with Di-4-ANEPPS voltage sensitive dye and optical mapping performed to assess action potential duration (APD; at 10 %, 20 %, 30 %, 50 %, and 70 % repolarization) and conduction velocity in the presence of 1 nM and 100 nM 17β-estradiol or testosterone. Male and female left atria demonstrated similar baseline action potential duration and conduction velocity, with significantly greater APD70 spatial heterogeneity evident in females. 17β-estradiol prolonged action potential duration in both sexes – an effect that was augmented in females. Atrial conduction was slowed in the presence of 100 nM 17β-estradiol in both males and females. Testosterone prolonged action potential duration in males only and did not modulate conduction velocity in either sex. This study provides novel insights into male and female atrial electrophysiology and its regulation by sex steroids. As systemic sex steroid levels change and intra-cardiac estrogen synthesis capacity increases with aging, these actions may have an increasingly important role in determining atrial arrhythmia vulnerability.

Nonalcoholic Fatty Liver Disease in Shift Workers and Its Effect on Peripheral Nerve Conduction: A Cross-Sectional Study.

Introduction Nonalcoholic fatty liver disease (NAFLD) presents as a multisystem disorder, heightening the risk of developing type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVDs). Occupation emerges as a significant factor influencing the occurrence of NAFLD. Research indicates that individuals engaged in shift work face an elevated risk of NAFLD, alongside obesity and T2DM, attributed to disruptions in their circadian rhythm, which precipitate hepatic steatosis and inflammation. Remarkably, peripheral neuropathy has been observed in conjunction with advanced liver disorders and NAFLD in the general population. However, the correlation between NAFLD and peripheral neuropathy remains unestablished in shift workers. Objective To identify NAFLD in seemingly healthy rotating shift workers and assess any potential impact of NAFLD on nerve function in this demographic. Methods This cross-sectional study involved 73 apparently healthy nonalcoholic security guards (aged 35 to 60 years) working in rotating shifts. The study included a comprehensive assessment, beginning with a medical history, an evaluation of physical activity, and anthropometric measurements. Confirmation of NAFLD was achieved through abdominal ultrasonography (USG), followed by the analysis of biochemical parameters. Motor and sensory nerve conduction studies (NCS) were conducted on participants with normal vitamin B12 levels using the Aleron electromyograph (EMG) machine (Recorders and Medicare Systems Private Ltd, Budanpur, India). The evaluation encompassed the Median and Common Peroneal motor nerves, as well as Median and Sural sensory nerves. Recorded parameters for motor nerves included distal motor latency (DML), compound muscle action potential (CMAP) amplitude, conduction velocity (CV), and F-wave minimum latency (F-wave), while sensory nerve parameters comprised sensory onset latency (SOL), sensory nerve action potential (SNAP) amplitude, and CV. Results Among 73 healthy security guards working in rotating shifts, 76.1% were diagnosed with NAFLD through abdominal ultrasound. Following participant withdrawals and exclusions due to vitamin B12 deficiency, a comparison of NCS parameters between NAFLD (n=24) and Non-NAFLD (n=12) groups revealed no significant disparities in motor or sensory parameters, except for a slightly diminished CMAP amplitude in the peroneal nerve of NAFLD subjects (8.21±2.83mV vs ±10.22±2.30 mV, p< 0.040). However, these differences fell within normal ranges, indicating no notable impact on peripheral nerve conduction in the presence of NAFLD. Conclusion The results indicate a high prevalence of NAFLD among individuals working rotating shifts. Moreover, the investigation suggests that despite the presence of NAFLD, there is no discernible influence on motor and sensory peripheral nerve conduction, particularly in common peroneal, median, and sural nerves.

Ex-vivo systems for neuromodulation: A comparison of ex-vivo and in-vivo large animal nerve electrophysiology

BackgroundLittle research exists on extending ex-vivo systems to large animal nerves, and to the best of our knowledge, there has yet to be a study comparing these against in-vivo data. This paper details the first ex-vivo system for large animal peripheral nerves to be compared with in-vivo results. New MethodDetailed ex-vivo and in-vivo closed-loop neuromodulation experiments were conducted on pig ulnar nerves. Temperatures from 20 °C to 37 °C were evaluated for the ex-vivo system. The data were analysed in the time and velocity domains, and a regression analysis established how evoked compound action potential amplitude and modal conduction velocity (CV) varied with temperature and time after explantation. Main resultsPig ulnar nerves were sustained ex-vivo up to 5 h post-explantation. CV distributions of ex-vivo and in-vivo data were compared, showing closer correspondence at 37 °C. Regression analysis results also demonstrated that modal CV and time since explantation were negatively correlated, whereas modal CV and temperature were positively correlated. Comparison with Existing MethodsPrevious ex-vivo systems were primarily aimed at small animal nerves, and we are not aware of an ex-vivo system to be directly compared with in-vivo data. This new approach provides a route to understand how ex-vivo systems for large animal nerves can be developed and compared with in-vivo data. ConclusionThe proposed ex-vivo system results were compared with those seen in-vivo, providing new insights into large animal nerve activity post-explantation. Such a system is crucial for complementing in-vivo experiments, maximising collected experimental data, and accelerating neural interface development.

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.

Effect of High-Intensity Laser Therapy on Carpal Tunnel Syndrome Patients: A Systematic Review and Meta-analysis.

To provide a strong foundation for the use of high-intensity laser therapy in carpel tunnel syndrome, we conducted a systematic review and meta-analysis to investigate the outcomes of short- and long-term follow-up studies. This is a systematic review and meta-analysis. Sample sizes of included studies ranged from 16 to 98 patients ( N = 308). Overall, a significant difference between the treatment and control groups were found across majority of the measures. Studies using a 4-wk follow-up period, however, only found significantly greater benefits for high-intensity laser therapy in visual analog scale compared with placebo ( P = 0.0191), transcutaneous electrical nerve stimulation ( P = 0.0026), and low-intensity laser therapy 20 J/cm 2 ( P < 0.0002), and exercise ( P < 0.0001). For improvement in visual analog scale score over a long treatment period, high-intensity laser therapy was also preferred over control group ( P < 0.0071). Insufficient evidence exists to determine effect of high-intensity laser therapy on nerve conduction examinations. The only statistically significant differences observed in examinations were in relation to sensory nerve action potential ( P = 0.0083) and sensory nerve conduction velocity ( P = 0.0468). Moderate evidence exists regarding efficacy of high-intensity laser therapy compared with placebo, high-intensity laser therapy + wrist splint, and exercise in a short period of follow-up time but evidence on long-term follow-up is limited.

Development of myelination and axon diameter for fast and precise action potential conductance.

Axons of globular bushy cells in the cochlear nucleus convey hyper-accurate signals to the superior olivary complex, the initial site of binaural processing via comparably thick axons and the calyx of the Held synapse. Bushy cell fibers involved in hyper-accurate binaural processing of low-frequency sounds are known to have an unusual internode length-to-axon caliber ratio (L/d) correlating with higher conduction velocity and superior temporal precision of action potentials. How the L/d-ratio develops and what determines this unusual myelination pattern is unclear. Here we describe a gradual developmental transition from very simple to complex, mature nodes of Ranvier on globular bushy cell axons during a 2-week period starting at postnatal day P6/7. The molecular composition of nodes matured successively along the axons from somata to synaptic terminals with morphologically and molecularly mature nodes appearing almost exclusively after hearing onset. Internodal distances are initially coherent with the canonical L/d-ratio of ~100. Several days after hearing onset, however, an over-proportional increase in axon caliber occurs in cells signaling low-frequency sounds which alters their L/d ratio to ~60. Hence, oligodendrocytes initially myelinating axons according to their transient axon caliber but a subsequent differential axon thickening after hearing onset results in the unusual myelination pattern.

Sural nerve involvement in patients with acute inflammatory demyelinating polyneuropathy variant of Guillain-Barre syndrome with sural sparing at initial presentation

Introduction: Neurophysiological testing is a valuable tool in the diagnosis of Guillain-Barre syndrome (GBS). Sural sparing is a usual feature of acute inflammatory demyelinating polyneuropathy (AIDP) type GBS. However, sural involvement has been reported in later stages of GBS. It is important to identify patterns of sural nerve involvement to differentiate GBS from its mimickers and to stage the disease. This research aimed to detect the pattern of sural nerve involvement in AIDP-GBS cases with normal electrophysiological responses in the sural nerve at the beginning.Objectives: To determine the location and timing of sural nerve involvement in AIDP-GBS.Methods: This prospective follow up study included diagnosed cases of AIDP-GBS with preserved bilateral sural responses. Nerve conduction and somatosensory evoked potentials (SSEP) were done on admission and weekly thereafter for four consecutive weeks. The last evaluation was done four weeks after the fourth study.Results: All patients (100%) showed normal distal sural responses over the initial four weeks of follow up. They continued to remain normal up to eight weeks in eight patients (53.3%). Two patients had gradual prolongation of their sural SSEP on consecutive studies. One of them had gradual reduction of sural sensory nerve action potential and nerve conduction velocity along with the prolongation of sural SSEP latencies. The difference of SSEP latency increments in the left sural nerve of these two patients was statistically significant (p&lt;0.05). The right sural SSEP latency difference was not significant.Conclusion: Sparing of the distal sural sensory response was demonstrated in 100% of AIDP-GBS cases during the first four weeks of follow up. More than 50% of the cohort demonstrated preserved sural sensory responses for eight weeks from the initial presentation. Two out of fifteen patients showed statistically significant proximal sural sensory pathway involvement with increasing SSEP latencies. This finding suggests that in some patients, the sural sensory pathway may get affected at its proximal segments or at the central nervous system before the distal nerve is affected.

Filtering property of myelinated internode can change neural information representability and might trigger a compensatory action during demyelination

In this paper, for the first time, we showed that an Internode Segment (INS) of a myelinated axon acts as a lowpass filter, and its filter characteristics depend on the number of myelin turns. Consequently, we showed how the representability of a neural signal could be altered with myelin loss in pathological conditions involving demyelinating diseases. Contrary to the traditionally held viewpoint that myelin geometry of an INS is optimised for maximising Conduction Velocity (CV) of Action Potential (AP), our theory provides an alternative viewpoint that myelin geometry of an INS is optimised for maximizing representability of the stimuli a fibre is meant to carry. Subsequently, we show that this new viewpoint could explain hitherto unexplained experimentally observed phenomena such as, shortening of INS length during demyelination and remyelination, and non-uniform distribution of INS in the central nervous system fibres and associated changes in diameter of nodes of ranvier along an axon. Finally, our theory indicates that a compensatory action could take place during demyelination up to a certain number of loss of myelin turns to preserve the neural signal representability by simultaneous linear scaling of the length of an INS and the inner radius of the fibre.

Unraveling the pathogenesis of novel ANKRD1 missense mutation causing familial dilated cardiomyopathy using human-induced pluripotent stem cells derived cardiomyocytes

Abstract Introduction Familial dilated cardiomyopathy(f-DCM) can be caused by mutations in 30 different genes encoding sarcomeric, cytoskeletal, mechanotransducers and transcription factors. One of the genes ANKRD1 encode Cardiac ankyrin repeat protein (CARP) which is involved in the mechanosensory unit located on the I-band of the sarcomere. Here we demonstrate a novel mutation in ANKRD1 gene causing f-DCM, and the usage of human-induced pluripotent(hiPSC) technology unraveling the pathogenesis of the disease. Purpose of the study: 1) Establishing patient specific hiPSC-derived cardiomyocytes from a family harboring a mutation in ANKRD1 gene causing f-DCM; 2) Phenotypical assessment of the morphological and ultrastructural properties of the diseased cells upon CARP activation; 3) Functional assessment of the 3 component of excitation-contraction coupling at the single-cell and tissue level. Methods and Results Patient-specific hiPSC were generated from a family harboring missense mutation in the ANKRD1 gene, with a substitution of the amino acid arginine to cysteine at position 182 of the Cardiac ankyrin repeat protein (CARP). ANKRD1-mut hiPSC were differentiated into cardiomyocytes and later matured using hormonal treatment. Morphological assessment using immunofluorescence(IF) techniques revealed that ANKRD1-mut hiPSC-CMs demonstrate an attenuated response to hypertrophy (upon Angiotensin-2 and Phenylephrine treatment). In addition ANKRD1-mut hiPSC-CMs displayed a higher cellular death rate upon increasing substrate stiffness and starvation. Electrophysiological assessment of the ANKRD1-mut cardiac tissues exhibit no alternations in action potential durations and conduction velocities while assessment of calcium transients demonstrated slower kinetics. In addition forces were quantified at the single-cell and tissue level , and demonstrated reduced active tension values and abnormal post-extrasystolic potentiation, while only single-cell experiments have demonstrated decreased passive tensions. These phenotypical alternations might be attributed to decreased nuclear translocation of CARP upon phenylephrine treatment as detected in IF experiments. Conclusion Novel mutation in ANKRD1 were found and validated to be causing f-DCM, by revealing phenotypical alternation using hiPSC-CM technology. Increased cellular death rate and impaired nuclear translocation of CARP might be the underlying causes of the morphological and contractile abnormalities detected in-vitro, leading to systolic dysfunction in the affected family.

The effect of polyneuropathy severity on nerve conduction and pain syndrome in patients with type 2 diabetes

Background. The article examines the relationship between nerve conduction indicators and polyneuropathy severity in patients with type 2 diabetes. The influence of polyneuropathy severity on nerve conduction was studied, as well as the effect of insulin therapy on these indicators. Objective: to determine the influence of polyneuropathy severity and the need for additional insulin administration in patients with type 2 diabetes on nerve conduction indicators and the development of pain syndrome. Materials and methods. Eighty patients with type 2 diabetes were examined, 49 men and 31 women. All of them underwent general clinical and biochemical laboratory tests to evaluate the hematopoietic system, li-ver, kidneys, fat and carbohydrate metabolism. The need for insulin therapy was assessed by the C-peptide level. To verify the diagnosis of diabetic polyneuropathy, complaints, clinical and instrumental examination data were evaluated. The main indicators of nerve conduction were taken into account when determining polyneuritis disorders, namely: рeroneal motor nerve conduction velocity, sensory nerve action potential of the sural nerve, sensory nerve conduction velocity of the sural nerve. Results. A dependence of nerve conduction on polyneuropathy severity was revealed, рeroneal motor nerve conduction velocity was the lowest in the group with severe polyneuropathy. A correlation was also found between the levels of sensory indicators (sensory nerve action potential and sensory nerve conduction velocity) and polyneuropathy severity, nerve conduction velocity decreases with an increase in the latter. The influence of polyneuropathy severity on the painful or painless form has been found. Among patients with severe polyneuropathy, the painful form was observed more often. No relationship was found between the need for insulin therapy and the painful or painless form of polyneuropathy. Conclusions. Indicators of nerve conduction depend on polyneuropathy severity. The presence and severity of pain syndrome directly depends on polyneuropathy severity. The need for additional insulin administration affects sensory indicators but has no effect on the development of the painful form of polyneuropathy.

Yüzme Egzersizinin Siyatik Sinir Hasarı Sonrasında Elektrofizyolojik Parametreler Üzerindeki İyileştirici Etkisi

The sciatic nerve damage can cause symptoms such as loss of muscle strength and pain as a result of trauma to the nerve due to pressure, stretching or cutting, as well as lifelong disability. Despite the increasing knowledge about sciatic nerve regeneration mechanisms, full functional recovery is still insufficient. It is well known that exercise improves overall health. The current study aimed to reveal the therapeutic effects of swimming exercises using electrophysiological methods in rats with experimental sciatic nerve injury. Eighteen male Wistar Albino rats were used in this study. The subjects were randomly divided into three groups (n=6): 1-Control (C), 2-Intact Exercise (IntE), 3-Operated Exercise (OpE) groups. Sciatic nerve injury was performed by inducing experimental damage to the left hind extremity sciatic nerve of rats. Swimming exercise was applied for 45 minutes a day, five days a week (25°C) for four weeks. The level of regeneration was evaluated by taking motor function test-sciatic function index and EMG recording performed at the beginning of the experiment (day 0), after nerve damage (day 3), and at the end of the experiment (day 35). It was determined that sciatic function index, amplitude of motor and sensory nerves, peak-peak amplitude, percentage of compound muscle action potential, motor and sensory nerve conduction velocities, which decreased after sciatic nerve injury, increased with swimming exercise (p

Chronic diastolic stretch unmasks conduction defects in an in vitro model of arrhythmogenic cardiomyopathy.

We seek to elucidate the precise nature of mechanical loading that precipitates conduction deficits in a concealed-phase model of arrhythmogenic cardiomyopathy (ACM). ACM is a progressive disorder often resulting from mutations in desmosomal proteins. Exercise has been shown to worsen disease progression and unmask arrhythmia vulnerability, yet the underlying pathomechanisms may depend on the type and intensity of exercise. Because exercise causes myriad changes to multiple inter-dependent hemodynamic parameters, it is difficult to isolate its effects to specific changes in mechanical load. Here, we use engineered heart tissues (EHTs) with iPSC-derived cardiomyocytes expressing R451G desmoplakin, an ACM-linked mutation, which results in a functionally null model of desmoplakin (DSP). We also use a novel bioreactor to independently perturb tissue strain at different time points during the cardiac cycle. We culture EHTs under three strain regimes: normal physiological shortening; increased diastolic stretch, simulating high preload; and isometric culture, simulating high afterload. DSPR451G EHTs that have been cultured isometrically undergo adaptation, with no change in action potential parameters, conduction velocity, or contractile function, a phenotype confirmed by global proteomic analysis. However, when DSPR451G EHTs are subjected to increased diastolic stretch, they exhibit concomitant reductions in conduction velocity and the expression of connexin-43. These effects are rescued by inhibition of both lysosome activity and ERK signaling. Our results indicate that the response of DSPR451G EHTs to mechanical stimuli depends on the strain and the timing of the applied stimulus, with increased diastolic stretch unmasking conduction deficits in a concealed-phase model of ACM.

Trunk extensor muscle endurance and its relationship to action potential conduction velocity and spectral parameters estimated using high-density electromyography

Trunk extensor muscle fatigue typically manifests as a decline in spectral content of surface electromyography. However, previous research on the relationship of this decline with trunk extensor muscle endurance have shown inconsistent results. The decline of spectral content mainly reflects the decrease in average motor unit action potential conduction velocity (CV). We evaluated whether the rate of change in CV, as well as two approaches employing the change in spectral content, are related to trunk extensor muscle endurance. Fourteen healthy male participants without a low-back pain history performed a non-strictly controlled static forward trunk bending trial until exhaustion while standing. For 13 participants, physiologically plausible CV estimates were obtained from high-density surface electromyography bilaterally from T6 to L5. Laterally between L1 and L2, the linear rate of CV change was strongly correlated to endurance time (R2 = 0.79), whereas analyses involving the linear rate of change in spectral measures showed a lower (R2 = 0.38) or no correlation. For medial electrode locations, estimating CV and its relationship with endurance time was less successful, while the linear rate of change in spectral measures correlated moderately to endurance time (R2 = 0.44; R2 = 0.56). This study provides guidance on monitoring trunk extensor muscle fatigue development using electromyography.

Nerve conduction studies through landmark based recording and effects of hand length

As per existing guidelines, the distance between stimulator and recording electrodes in nerve conduction studies (NCS) should be the same (fixed) in all the subjects, i.e., it should not be based on anatomical landmarks. However, there are no studies comparing fixed distance recordings with landmark based NCS. We postulated that hand length can influence the NCS parameters in fixed distance recordings and this can be nullified using landmark based recordings. To test this theory, we performed NCS in 48 normal subjects as per standard guidelines (standard protocol) and then compared it to NCS with ulnar styloid as the landmark (modified protocol). NCS were performed on median and ulnar nerves of the right upper limb. Three motor NCS parameters including distal latency, compound muscle action potential (CMAP) amplitudes and nerve conduction velocities were measured. Sensory nerve action potential (SNAP) amplitudes and conduction velocities were the two sensory parameters measured. On analysis, ulnar motor conduction velocity was the only parameter affected by hand length in both standard and modified protocols. Modified protocol did not have any additional advantage to the standard protocol advised by NDTF. We conclude that the NDTF guidelines are therefore reasonable when considering the effects of hand length. Possible reasons for this result including anatomical and anthropometric explanations are discussed.

A Novel Quantitative Electrocardiography Strategy Reveals the Electroinhibitory Effect of Tamoxifen on the Mouse Heart.

Tamoxifen, a selective estrogen receptor modulator, was initially used to treat cancer in women and more recently to induce conditional gene editing in rodent hearts. However, little is known about the baseline biological effects of tamoxifen on the myocardium. In order to clarify the short-term effects of tamoxifen on cardiac electrophysiology of myocardium, we applied a single-chest-lead quantitative method and analyzed the short-term electrocardiographic phenotypes induced by tamoxifen in the heart of adult female mice. We found that tamoxifen prolonged the PP interval and caused a decreased heartbeat, and further induced atrioventricular block by gradually prolonging the PR interval. Further correlation analysis suggested that tamoxifen had a synergistic and dose-independent inhibition on the time course of the PP interval and PR interval. This prolongation of the critical time course may represent a tamoxifen-specific ECG excitatory-inhibitory mechanism, leading to a reduction in the number of supraventricular action potentials and thus bradycardia. Segmental reconstructions showed that tamoxifen induced a decrease in the conduction velocity of action potentials throughout the atria and parts of the ventricles, resulting in a flattening of the P wave and R wave. In addition, we detected the previously reported prolongation of the QT interval, which may be due to a prolonged duration of the ventricular repolarizing T wave rather than the depolarizing QRS complex. Our study highlights that tamoxifen can produce patterning alternations in the cardiac conduction system, including the formation of inhibitory electrical signals with reduced conduction velocity, implying its involvement in the regulation of myocardial ion transport and the mediation of arrhythmias. A Novel Quantitative Electrocardiography Strategy Reveals the Electroinhibitory Effect of Tamoxifen on the Mouse Heart（Figure 9）. A working model of tamoxifen producing acute electrical disturbances in the myocardium. SN, sinus node; AVN, atrioventricular node; RA, right atrium; LA, left atrium; RV, right ventricle; LV, left ventricle.

The interactive effects of age and sex on the neuro-cardiovascular responses during fatiguing rhythmic handgrip exercise.

The impact of age on exercise pressor responses is equivocal, likely because of sex-specific neuro-cardiovascular changes with age. However, assessments of the interactive effects of age and sex on muscle sympathetic nerve activity (MSNA) responses to exercise are lacking. We tested the hypothesis that older females would exhibit exaggerated increases in blood pressure (BP) and MSNA discharge patterns during handgrip exercise compared with similarly aged males and young adults. Twenty-five young (25 (2) years; mean (SD)) males (YM; n=12) and females (YF; n=13) and 23 older (71 (5) years) males (OM; n=11) and females (OF; n=12) underwent assessments of BP, total peripheral resistance (TPR; Modelflow) and MSNA action potential (AP) discharge patterns (microneurography) during incremental rhythmic handgrip exercise and post-exercise circulatory occlusion (PECO). OM demonstrated larger ∆BP and ∆TPR from baseline than YM (both P < 0.001) despite smaller increases in ∆APs/burst (OM: 0.4 (3) vs. YM: 5 (3) spikes/burst, P < 0.001) and ∆AP clusters/burst (OM: 0.1 (1) vs. YM: 1.8 (1) clusters/burst, P < 0.001) during exercise. Testosterone was lower in OM than YM (P < 0.001) and was inversely related to ∆BP but positively related to ∆AP clusters/burst in males (both P=0.03). Conversely, YF and OF demonstrated similar ∆BP and ∆AP discharge during exercise (range: P=0.75-0.96). Age and sex did not impact haemodynamics or AP discharge during PECO (range: P=0.08-0.94). Altogether, age-related changes in neuro-cardiovascular reactivity exist in males but not females during fatiguing exercise and seem to be related to testosterone. This sex-specific impact of age underscores the importance of considering biological sex when assessing age-related changes in neuro-cardiovascular control during exercise. KEY POINTS: Older males have the largest increase in blood pressure despite having the smallest increases in sympathetic vasomotor outflow during rhythmic handgrip exercise. Young males demonstrate greater increases in sympathetic action potential (AP) discharge compared with young females during rhythmic handgrip exercise. Older adults (regardless of sex) demonstrate smaller increases in muscle sympathetic nerve activity (MSNA) burst amplitude and total AP clusters compared with young adults during exercise, as well as smaller increases in integrated MSNA burst frequency, incidence and total MSNA activity during post-exercise circulatory occlusion (i.e. independent effect of age). Males, but not females (regardless of age), reflexively modify AP conduction velocity during exercise. Our results indicate that age and sex independently and interactively impact the neural and cardiovascular homeostatic adjustments to fatiguing small muscle mass exercise.

PO-01-180 MECHANISMS OF PULMONARY ARTERIAL HYPERTENSION-INDUCED ATRIAL FIBRILLATION IN THE RIGHT HEART: INSIGHTS FROM MULTI-SCALE MODELS OF THE HUMAN ATRIA

Pulmonary arterial hypertension (PAH) is one of the common conditions primarily affecting the right heart and promoting atrial fibrillation (AF), but the mechanisms are poorly understood. This study aimed to use multi-scale atrial models to investigate mechanisms by which right atrial (RA) remodeling facilitates and perpetuates atrial arrhythmias. We have developed single-cell-to-tissue-level computer models to mimic control and disease conditions by incorporating the most recent experimental data on PAH-induced electrical and structural remodeling (Hiram et al., JACC, 2019). The effects of PAH-induced remodeling in both RA and left atria (LA) on action potential duration (APD), calcium transient (CaT), conduction velocity (CV), and dynamics of re-entrant excitation waves were assessed using the multi-scale computer models. Our computer simulation results suggested that at the single cell level, although PAH-induced remodeling prolonged action potential (ΔAPD: 49.6 ms in the RA vs. 41.6 ms in the LA) and increased calcium transient (ΔCaT: 7.5e-2 μM in the RA vs. 0.9e-3 μM in the LA), heterogeneous remodeling increased susceptibility to afterdepolarizations only in the RA (Fig. A). At the tissue level, dramatically reduced CV (ΔCV: -0.5 m/s in the RA vs. -0.05 m/s in the LA) abbreviated wavelength inthe RA but not inthe LA. In addition, afterdepolarizations in the RA increased repolarization dispersion and promoted unidirectional conduction block (Fig B). Finally, the upregulated fibrosis increased the chance of breakdown of excitation waves and sustained reentries in in the RA (Fig C). These results demonstrated that PAH-induced AF is mainly in RA not LA, due to a higher degree of cardiac remodeling. RA remodeling increases arrhythmias risk due to elevated susceptibility to afterdepolarizations, reduced wavelength, increased repolarization heterogeneity and upregulation of fibrosis, which together facilitate initiation and maintenance of re-entrant circuits in the right heart.