Repolarization Currents Research Articles

Liquid Crystalline Electro-Optical Modulator of Submegahertz Range

A liquid crystalline (LC) electro-optical modulator providing an electro-optical response time up to 400 nanoseconds with a modulation frequency up to 500 kHz has been developed. The ferroelectric liquid crystal FLC-576 obtained by us was used as the electro-optical medium of the modulator. Its helix pitch р0 is much smaller than wavelengths of visible light (р0 < 100 nm). The liquid crystal operates in the deformed helix ferroelectric mode (DHF-effect) under the action of electric fields. The controlling electric fields are less than a critical field of helix unwinding. At high frequencies of the control voltage (over 10 kHz), the heating of electro-optical cell by repolarization currents of FLC can occur up to the temperature of phase transition from ferroelectric to paraelectric phase, which leads to the cessation of electro-optical modulation. The work experimentally and theoretically examines the self-heating issues of electro-optical modulators depending on the liquid crystal layer thickness, frequency and strength of applied electric field. The heat removal conditions from the liquid crystal cell have been determined and experimentally implemented. Under these conditions the LC is in the smectic C* ferroelectric phase temperature range, which is necessary to provide electro-optical modulation in submegaherts diapason.

Human-induced pluripotent stem cell-derived cardiomyocytes to study PUFA analogues as a potential treatment of long QT syndrome.

Long QT syndrome (LQTS) is an inheritable ventricular arrhythmia that predisposes patients to torsades de pointes and sudden cardiac death. Mutations in voltage-gated ion channels (VGC) and their regulatory β subunits involved in the cardiac action potential (AP) generate LQTS by prolonging the QT interval of the electrocardiogram. 15 types of LQTS has been described depending on the underlying gene mutated. LQT1 and LQT5 are described as loss-of-function mutations in genes that encode Kv7.1 (alpha pore-forming subunit) and its β-regulatory subunit KCNE1, respectively. Kv7.1/KCNE1 channels elicit one of the main repolarization currents (IKs) involved in the cardiac AP. Therefore, Kv7.1/KCNE1 channel-specific activators might be a potential treatment for LQTS. Polyunsaturated fatty acid (PUFA) analogues can broadly modulate cardiac VGC when applied on isolated channels in a heterologous system. In the present study, we measured the effects of these four compounds, Linoleoyl-taurine (LIN-Tau), docosahexaenoyl-Tau (DHA-Tau), Linoleoyl-Glycine (LIN-Gly), and DHA-Gly, on human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). DHA-analogues shortened the hiPSC-CMs AP duration (APD), while LIN-analogues prolonged hiPSC-CMs APD. DHA-analogues were also tested in isogenic hiPSC-CMs lines for two KCNQ1 (Kv7.1 gene) mutations that cause LQT1, R190Q, and G269S. R190Q is an autosomal dominant missense mutation characterized by a 70-80 % reduction of IKs because of a dominant negative traffic defect. Moreover, we also analyzed DHA-analogues in a heterozygous missense KCNQ1 mutation, G269S. G269S mutation shows a net effect of less than 50% reduction of IKs current (haploinsufficiency). We here use a combination of hiPSC-CM monolayers with a high-resolution, all-optical electrophysiology system for screening the anti-arrhythmic properties of diverse PUFA analogues. Moreover, the well-characterized hiPSC-CMs mutants show us whether PUFA analogues might be a potential treatment approach for more than one type of LQT1.

Repolarization Heterogeneity in Human Post-Infarct Ventricular Tachycardia.

Slow conduction, caused by fibrosis between surviving myocytes and connexin remodeling, is an important prerequisite for post-infarction ventricular tachycardia (VT); however, slow conduction is present throughout the infarct whereas VT circuits are finite in number and discrete. In a porcine model of VT, re-entrant circuits occur at region of significant repolarization heterogeneity caused by up-regulation of potassium channel β-subunits KCNE3 (increasing repolarization current) and KCNE4 (decreasing repolarization current), causing heterogeneous action potential durations. This study was designed to determine whether re-entrant circuits in human post-infarction VT are associated with repolarization heterogeneity. In 6 patients, left ventricular mapping was performed during induced VT to identify sites within the VT circuit. Subsequently, unipolar mapping (3.5-mm tip ablation catheter) was performed to characterize activation-recovery intervals (ARIs), which are surrogates for local action potential durations, at sites documented within the VT circuit isthmus (IN) compared to sites within the infarct scar but outside of the VT circuit (OUT). ARIs were significantly shorter in the IN compared with the OUT sites (420.2 ± 79.3 ms vs 462 ± 52.8ms; P=0.01). In all patients. sites that were associated with the circuit always had shorter ARI values than did those sampled from OUT regions. VT circuit sites in human post-infarct VT are associated with repolarization heterogeneity, similar to what was previously reported in a porcine model. This suggests the possibility of a common mechanism between humans and the porcine model of post-infarct VT, and that development of ablation strategies or small molecule or genetic therapies to restore normal repolarization kinetics may be antiarrhythmic.

Abstract P402: Caveolin-1 Upregulation Leads To Decreased Erg And Stress-induced Ventricular Tachycardia In Cystic Fibrosis Hearts

Background: Cardiac manifestations of cystic fibrosis are classically accepted as cor pulmonale, yet emerging evidence supports that cardiac abnormalities can develop early when respiratory function is preserved. Myocardial cystic fibrosis transmembrane regulator (CFTR) channels, inactive in normal conditions, are activated in response to catecholamine stress. Methods and Results: In multiple mouse models of homozygous CFTR mutations (S489X or F508d), we demonstrate increased susceptibility to ventricular tachycardia (VT) in response to epinephrine, and this is associated with prolongation of QTc intervals (repolarization). Despite having normal left ventricular ejection fraction and histology, CF S489X mut/mut hearts showed 460 proteins significantly altered compared with WT hearts by tandem mass tag (TMT) proteomics. The Ingenuity Pathway Analysis of proteomics data revealed mitochondrial dysfunction and increased caveolin-1 signaling among the top pathways affected in CF S489X mut/mut hearts. In mouse hearts and human induced pluripotent stem cells derived cardiomyocytes (iPS-CM) with CFTR mutations, we observed increased ER stress and caveolin-1 (cav-1). These changes are concomitant with reduced levels of the ERG channel, a K+ channel contributing to phase 3 repolarization, mutations of which cause long QT syndrome II and VT. Patch clamp analysis showed decreased phase 2-3 repolarization current (including hERG current) in CF F508d iPS-CM compared with control iPS-CM, consistent with the findings of decreased membranous hERG and elevated Cav-1. Suppression of Cav-1 successfully restores membranous hERG in two separate lines of mutant iPS-CM generated from CF patients with F508d mutation. In F508d mut/mut mice, suppression of cardiac Cav-1 upregulation by reducing ER stress using TUDCA or crossing with heterozygous Cav-1 +/- abolished the stress-induced VT. Our analysis of a large-scale real-world clinical database from TriNetX, including 4520 CF men, 3510 CF women and the same number of well-matched controls demonstrated novel findings of increased risk for QT prolongation and VT in CF patients. Retrospective analysis of 126 CF patients with available EKG in our hospital revealed significant QTc prolongation in CF patients compared with matched controls, for both males (CF 447.8±4.5 vs cont. 429.2±2.5) and females (CF 454.0±3.5 vs cont.437.5±2.4). The QTc interval is not affected by lung function (%predicted FEV1) and is an independent predictor of survival in CF patients. Conclusions: In mice and iPS-CM models of CF, we demonstrated impaired repolarization and increased susceptibility to stress-induced VT. This is mediated by ER-stress-induced upregulation of Cav-1, which leads to internalization of ERG and subsequent decrease in repolarization current.

Micro-RNA 133a-3p induces repolarization abnormalities in atrial myocardium and modulates ventricular electrophysiology affecting ICa,L and Ito currents

Mir-133a-3p is the most abundant myocardial microRNA. The impact of mir-133a-3p on cardiac electrophysiology is poorly explored. In this study, we investigated the effects of mir-133a-3p on the main ionic currents critical for action potential (AP) generation and electrical activity of the heart.We used conventional ECG, sharp microelectrodes and patch-clamp to clarify a role of mir-133a-3p in normal cardiac electrophysiology in rats after in vivo and in vitro transfection.Mir-133a-3p caused no changes to pacemaker APs and automaticity in the sinoatrial node. No significant changes in heart rate (HR) were observed in vivo; however, miR transfection facilitated HR increase in response to β-adrenergic stimulation. Mir-133a-3p induced repolarization abnormalities in the atrial working myocardium and the L-type calcium current (ICa,L) was significantly increased. The main repolarization currents, including the transient outward (Ito), ultra-rapid (IK,ur), and inward rectifier (IK1) remained unaffected in atrial cardiomyocytes. Mir-133a-3p affected both ICa,L and Ito in ventricular cardiomyocytes. Systemic administration of mir-133a-3p induced QT-interval prolongation.Bioinformatic analysis revealed protein phosphatase 2 (PPP2CA/B) and Kcnd3 (encoding Kv4.3 channels generating Ito) as the main miR-133a-3p targets in the heart. No changes in mRNA expression of Cacna1c (encoding Cav1.2 channels generating ICa,L) and Kcnd3 were seen in mir-133a-3p treated rats. However, the expression of Ppp2cA, encoding PPP2CA, and Kcnip2 encoding KChIP2, a Kv4.3 regulatory protein, were significantly decreased.The accumulation of mir-133a-3p in cardiac myocytes causes chamber-specific electrophysiological changes. The suppression of PPP2CA, involved in adrenergic signal transduction, and Kchip2 may indirectly mediate mir-133a-3p-induced augmentation of ICa,L and attenuation of Ito.

Polyunsaturated Fatty Acids Therapeutic Potential for Long QT Syndrome

Long QT syndrome (LQTS) is an inherited ventricular repolarization disorder. Patients with the QT interval prolonged might develop lethal ventricular arrhythmias such as Torsade des pointes and sudden cardiac death. There are two major currents involved in the ventricular repolarization, IKr and IKs currents. Loss-of-function mutations on any of the genes that encode the proteins involved in the generation of these two currents are directly related to LQTS. IKs channel is formed by four alpha subunits, coded by the KCNQ1 gene, co-assembled with regulatory beta subunits, encoded by the KCNE1 gene.

Electrophysiological Analysis of the Cardiac KV Channel with the New Point Mutation Found in the Patient with LQTS

Voltage-dependent cation channels Kv7.1 encoded by the KCNQ1 genes play an important role in the repolarization of cardiac cells and the maintenance of normal duration of cardiac action potential. In cardiac muscle tissue, Kv7.1 is expressed together with the accessory KCNE1 beta-subunit to form a functionally active channel that provides a slow repolarization current. To date, more than 100 mutations (mainly single nucleotide variations, SNV) are known to affect the activity of the Kv7.1 channel, altering the kinetics of activation and interaction with regulatory subunits, or disrupting traffic toward the cell membrane.

Different arrhythmia-associated calmodulin mutations have distinct effects on cardiac SK channel regulation.

Calmodulin (CaM) plays a critical role in intracellular signaling and regulation of Ca2+-dependent proteins and ion channels. Mutations in CaM cause life-threatening cardiac arrhythmias. Among the known CaM targets, small-conductance Ca2+-activated K+ (SK) channels are unique, since they are gated solely by beat-to-beat changes in intracellular Ca2+. However, the molecular mechanisms of how CaM mutations may affect the function of SK channels remain incompletely understood. To address the structural and functional effects of these mutations, we introduced prototypical human CaM mutations in human induced pluripotent stem cell-derived cardiomyocyte-like cells (hiPSC-CMs). Using structural modeling and molecular dynamics simulation, we demonstrate that human calmodulinopathy-associated CaM mutations disrupt cardiac SK channel function via distinct mechanisms. CaMD96V and CaMD130G mutants reduce SK currents through a dominant-negative fashion. By contrast, specific mutations replacing phenylalanine with leucine result in conformational changes that affect helix packing in the C-lobe, which disengage the interactions between apo-CaM and the CaM-binding domain of SK channels. Distinct mutant CaMs may result in a significant reduction in the activation of the SK channels, leading to a decrease in the key Ca2+-dependent repolarization currents these channels mediate. The findings in this study may be generalizable to other interactions of mutant CaMs with Ca2+-dependent proteins within cardiac myocytes.

Abstract 13743: A Tale of Syncope, Prolonged QT and ICD

Introduction: Long QT syndrome (LQTS) was first described in the 1960s. It manifests clinically as syncope, cardiac arrest or sudden cardiac death. LQTS can be caused by 15 different genes. These mutations lead to action potential prolongation by causing impaired repolarizing currents. Case Discussion: A 29-year-old previously healthy Caucasian woman was admitted after recurrent episodes of syncope that happened within 1-month prior to the presentation. She was hemodynamically stable with normal vitals. Her ECG showed normal sinus rhythm with corrected QT (QTc) of 598ms. In the ED, she suffered an episode of sustained monomorphic ventricular tachycardia (VT) and underwent cardioversion. She was started on amiodarone infusion. Serial ECGs showed prolonged QTc. She had another episode of pulseless VT that terminated without defibrillation. She was transferred to our facility for further care. Her family history was significant for paternal aunt who had died unexpectedly at the age of 39. All her lab work including electrolytes, thyroid panel, cardiac enzymes, inflammatory markers and extended drug screen was unrevealing. Transthoracic echocardiogram showed normal biventricular size and function. Decision making: She was started on propranolol for possible LQTS. Cardiac MR did not show any evidence of structural abnormalities. Genetic panel was sent. Since myocarditis or familial LQTS could not be ruled out, we proceeded with implantable cardioverter defibrillator (ICD) implantation for secondary prevention. She was discharged home on nadolol. Conclusion: In the absence of genetic information, LQTS can be diagnosed in symptomatic patients with QTc >480msec on serial ECGs after excluding secondary causes. Schwartz score comprising of ECG findings, symptoms, clinical & family history is diagnostic when greater than 3.5. Beta-blockers are indicated in all patients with a clinical diagnosis. Patients must avoid any QT prolonging agents and strenuous exercise. An ICD is indicated in patients who suffered cardiac arrest. ICD may also be considered for primary prevention in high risk patients.

Identification of Drug-Induced Multichannel Block and Proarrhythmic Risk in Humans Using Continuous T Vector Velocity Effect Profiles Derived From Surface Electrocardiograms.

We present continuous T vector velocity (TVV) effect profiles as a new method for identifying drug effects on cardiac ventricular repolarization. TVV measures the temporal change in the myocardial action potential distribution during repolarization. The T vector dynamics were measured as the time required to reach p percent of the total T vector trajectory length, denoted as Tr(p), with p in {1, …, 100%}. The Tr(p) values were individually corrected for heart rate at each trajectory length percentage p. Drug effects were measured by evaluating the placebo corrected changes from baseline of Tr(p)c jointly for all p using functional mixed effects models. The p-dependent model parameters were implemented as cubic splines, providing continuous drug effect profiles along the entire ventricular repolarization process. The effect profile distributions were approximated by bootstrap simulations. We applied this TVV-based analysis approach to ECGs available from three published studies that were conducted in the CiPA context. These studies assessed the effect of 10 drugs and drug combinations with different ion channel blocking properties on myocardial repolarization in a total of 104 healthy volunteers. TVV analysis revealed that blockade of outward potassium currents alone presents an effect profile signature of continuous accumulation of delay throughout the entire repolarization interval. In contrast, block of inward sodium or calcium currents involves acceleration, which accumulates during early repolarization. The balance of blocking inward versus outward currents was reflected in the percentage pzero of the T vector trajectory length where accelerated repolarization transitioned to delayed repolarization. Binary classification using a threshold pzero = 43% separated predominant hERG channel blocking drugs with potentially higher proarrhythmic risk (moxifloxacin, dofetilide, quinidine, chloroquine) from multichannel blocking drugs with low proarrhythmic risk (ranolazine, verapamil, lopinavir/ritonavir) with sensitivity 0.99 and specificity 0.97. The TVV-based effect profile provides a detailed view of drug effects throughout the entire ventricular repolarization interval. It enables the evaluation of drug-induced blocks of multiple cardiac repolarization currents from clinical ECGs. The proposed pzero parameter enhances identification of the proarrhythmic risk of a drug beyond QT prolongation, and therefore constitutes an important tool for cardiac arrhythmia risk assessment.

High-throughput discovery of trafficking-deficient variants in the cardiac potassium channel KV11.1

KCHN2 encodes the KV11.1 potassium channel responsible for IKr, a major repolarization current during the cardiomyocyte action potential. Variants in KCNH2 that lead to decreased IKr have been associated with long QT syndrome type 2 (LQT2). The mechanism of LQT2 is most often induced loss of KV11.1 trafficking to the cell surface. Accurately discriminating between variants with normal and abnormal trafficking would aid in understanding the deleterious nature of these variants; however, the volume of reported nonsynonymous KCNH2 variantsprecludes the use of conventional methods for functional study. The purpose of this study was to report a high-throughput, multiplexed screening method for KCNH2 genetic variants capable of measuring the cell surface abundance of hundreds of missense variants in the resulting KV11.1 channel. We developed a method to quantitate KV11.1 variant trafficking on a pilot region of 11 residues in the S5 helix. We generated trafficking scores for 220 of 231 missense variants in the pilot region. For 5 of 5 variants, high-throughput trafficking scores validated when tested in single variant flow cytometry and confocal microscopy experiments. We further explored these results with planar patch electrophysiology and found that loss-of-trafficking variants do not produce IKr. Conversely, but expectedly, some variants that traffic normally were still functionally compromised. We describe a new method for detecting KV11.1 trafficking-deficient variants in a multiplexed assay. This new method accurately generated trafficking data for variants in KV11.1 and is extendable both to all residues in KV11.1 and to other cell surface proteins.

Methylmercury Poisoning Induces Cardiac Electrical Remodeling and Increases Arrhythmia Susceptibility and Mortality.

This study aims to investigate the cardiac electrical remodeling associated with intoxication by methylmercury (MeHg). We evaluated the chronic effects of MeHg on in vivo electrocardiograms and on ex vivo action potentials and depolarizing (ICa-L) and repolarizing (Ito) currents. The acute effect of MeHg was evaluated on HEK293 cells expressing human ERG, Kv4.3 and KCNQ1/KCNE1 channels. Chronic MeHg treatment increased QTc and Tpeak–Tend interval duration, prolonged action potential duration and decreased amplitude of Ito and ICa-L. In addition, heterologously expressed IhKv4.3, IhERG or IhKCNQ1/KCNE1 decreased after acute exposure to MeHg at subnanomolar range. The introduction of the in vitro effects of MeHg in a computer model of human ventricular action potentials triggered early afterdepolarizations and arrhythmia. In conclusion, cardiac electrical remodeling induced by MeHg poisoning is related to the reduction of Ito and ICa-L. The acute effect of MeHg on hKv4.3; hERG and hKCNQ1/KCNE1 currents and their transposition to in silico models show an association between MeHg intoxication and acquired Long QT Syndrome in humans. MeHg can exert its high toxicity either after chronic or acute exposure to concentrations as low as picomolar.

Associations between QT interval subcomponents, HIV serostatus, and inflammation.

BackgroundThe total QT interval comprises both ventricular depolarization and repolarization currents. Understanding how HIV serostatus and other risk factors influence specific QT interval subcomponents could improve our mechanistic understanding of arrhythmias.MethodsTwelve‐lead electrocardiograms (ECGs) were acquired in 774 HIV‐infected (HIV+) and 652 HIV‐uninfected (HIV−) men from the Multicenter AIDS Cohort Study. Individual QT subcomponent intervals were analyzed: R‐onset to R‐peak, R‐peak to R‐end, JT segment, T‐onset to T‐peak, and T‐peak to T‐end. Using multivariable linear regressions, we investigated associations between HIV serostatus and covariates, including serum concentrations of inflammatory biomarkers such as interleukin‐6 (IL‐6), and each QT subcomponent.ResultsAfter adjustment for demographics and risk factors, HIV+ versus HIV− men differed only in repolarization phase durations with longer T‐onset to T‐peak by 2.3 ms (95% CI 0–4.5, p < .05) and T‐peak to T‐end by 1.6 ms (95% CI 0.3–2.9, p < .05). Adjusting for inflammation attenuated the strength and significance of the relationship between HIV serostatus and repolarization. The highest tertile of IL‐6 was associated with a 7.3 ms (95% CI 3.2–11.5, p < .01) longer T‐onset to T‐peak. Age, race, body mass index, alcohol use, and left ventricular hypertrophy were each associated with up to 2.2–12.5 ms longer T‐wave subcomponents.ConclusionsHIV seropositivity, in combination with additional risk factors including increased systemic inflammation, is associated with longer T‐wave subcomponents. These findings could suggest mechanisms by which the ventricular repolarization phase is lengthened and thereby contribute to increased arrhythmic risk in men living with HIV.

Charging and domain switching in ferroelectrics LiNbO3 by electron beam

Comprehensive experimental results on the kinetic characteristics of LiNbO3 charging process are reported. Secondary electron emission (SEE) yield, surface potential, and the sum of leakage and displacement currents were experimentally obtained during electron beam irradiation in the energy range from 200 eV to 10 keV for both sides of the Z-cut. We found that at the initial stage of charging, the SEE current that were collected by a hemispherical electrode changes its sign. It was explained by the emergence of a large displacement current on the collector. The direction of this current is opposite to the directions of SEE and backscattered electron currents. If a large positive charge arises on the surface of ferroelectrics, the positive displacement current dominates the secondary emission current; this fact was confirmed experimentally. Also, a high value of the negative surface potential in the electron energy range 200–700 eV for −Z cut of lithium niobate was found, though in this energy region, positive charging is observed for nonpolar dielectrics. The influence of domain repolarization currents on the measured emitted electrons and displacement current signals is shown.

Coupling of Smoothened to inhibitory G proteins reduces voltage-gated K+ currents in cardiomyocytes and prolongs cardiac action potential duration

SMO (Smoothened), the central transducer of Hedgehog signaling, is coupled to heterotrimeric Gi proteins in many cell types, including cardiomyocytes. In this study, we report that activation of SMO with SHH (Sonic Hedgehog) or a small agonist, purmorphamine, rapidly causes a prolongation of the action potential duration that is sensitive to a SMO inhibitor. In contrast, neither of the SMO agonists prolonged the action potential in cardiomyocytes from transgenic GiCT/TTA mice, in which Gi signaling is impaired, suggesting that the effect of SMO is mediated by Gi proteins. Investigation of the mechanism underlying the change in action potential kinetics revealed that activation of SMO selectively reduces outward voltage-gated K+ repolarizing (Kv) currents in isolated cardiomyocytes and that it induces a down-regulation of membrane levels of Kv4.3 in cardiomyocytes and intact hearts from WT but not from GiCT/TTA mice. Moreover, perfusion of intact hearts with Shh or purmorphamine increased the ventricular repolarization time (QT interval) and induced ventricular arrhythmias. Our data constitute the first report that acute, noncanonical Hh signaling mediated by Gi proteins regulates K+ currents density in cardiomyocytes and sensitizes the heart to the development of ventricular arrhythmias.

T112. Visualization of electrical activities in the carpal tunnel area by magnetoneurography of median nerve

Introduction In recent years, diagnosis of the carpal tunnel syndrome is mainly performed by electrophysiological examination. In particular, the utility and reliability of inching method were demonstrated by some reports. However, electrophysiological examination is affected by the surrounding tissues such as bone and soft tissue, and the inching method is not technically easy and requires many electrodes. On the other hand, the magnetic field is not affected by the surrounding tissue. We have developed the magnetometer for the spinal cord and the spinal nerve activity and succeeded in measuring electrophysiological activity in the spinal cord and spinal nerve roots. Now, we are working on magnetoneurography (MNG) which is measurement of magnetic fields generated by the peripheral nerve. In this study, we aimed to evaluate spatiotemporal spread of digital nerve-evoked currents in the median nerve at the carpal tunnel area using MNG. Methods Using a newly developed superconducting quantum interference device (SQUID) magnetometer, neuromagnetic fields of 9 healthy volunteers’ hands were measured at the surface of the carpal tunnel area after stimulation of the digital nerves at the index or middle finger. Current sources were estimated using spatial filter techniques and were superimposed on X-ray images of the hand. We set a virtual electrode in the carpal tunnel along the median nerve. We reconstructed the current waveform from the magnetic field and calculated the nerve conduction velocity from the peak latency. We also measured sensory nerve action potential just above the carpal tunnel, 3 cm distal and 3 cm proximal to the carpal tunnel in response to stimulation of the digital nerves of the index finger. The conduction velocity was calculated from the peak latency. Results Neuromagnetic fields propagating from the finger to the wrist were successfully measured in all subjects. Distribution of action currents calculated from MNG showed the axonal activity pattern showing the intra-axonal current and the depolarization/ repolarization current. Nerve conduction velocity estimated from the MNG was 55.3 m/s and corresponded with the sensory nerve conduction velocity. Conclusion We could visualize action current at any point in carpal tunnel with high resolution using MNG. Moreover, MNG is not affected by the surrounding bone and soft tissues and can be fused with morphological images such as X-rays. MNG is expected to contribute to the clinical diagnosis and treatment of carpal tunnel syndrome.

Molecular Insights into the Short QT Syndrome.

Short QT syndrome (SQTS) is a myocardial conduction disorder characterized by a short QT interval on electrocardiogram and predisposition to familial atrial fibrillation and/or sudden cardiac death. Genetic SQTS is primarily caused by one or more cardiac ion channelopathies, in which either impaired depolarization currents, or enhanced repolarization currents, shorten cardiac action potential duration. Given that QT interval duration is not always predictive of arrhythmia burden and risk of death in SQTS, there is a need to understand the molecular mechanisms of the condition to improve risk prognostication and potential pharmacologic treatment. In the last decade, several computational advances and in vitro preclinical studies have provided insight into the molecular mechanisms underlying congenital SQTS. In this review, we discuss recent findings in SQTS molecular mechanisms and correlate these advances with clinical guidelines for SQTS diagnosis and treatment.

Contribution of small conductance K+ channels to sinoatrial node pacemaker activity: insights from atrial-specific Na+ /Ca2+ exchange knockout mice.

Repolarizing currents through K+ channels are essential for proper sinoatrial node (SAN) pacemaking, but the influence of intracellular Ca2+ on repolarization in the SAN is uncertain. We identified all three isoforms of Ca2+ -activated small conductance K+ (SK) channels in the murine SAN. SK channel blockade slows repolarization and subsequent depolarization of SAN cells. In the atrial-specific Na+ /Ca2+ exchanger (NCX) knockout mouse, cellular Ca2+ accumulation during spontaneous SAN pacemaker activity produces intermittent hyperactivation of SK channels, leading to arrhythmic pauses alternating with bursts of pacing. These findings suggest that Ca2+ -sensitive SK channels can translate changes in cellular Ca2+ into a repolarizing current capable of modulating pacemaking. SK channels are a potential pharmacological target for modulating SAN rate or treating SAN dysfunction, particularly under conditions characterized by abnormal increases in diastolic Ca2+ . Small conductance K+ (SK) channels have been implicated as modulators of spontaneous depolarization and electrical conduction that may be involved in cardiac arrhythmia. However, neither their presence nor their contribution to sinoatrial node (SAN) pacemaker activity has been investigated. Using quantitative PCR (q-PCR), immunostaining and patch clamp recordings of membrane current and voltage, we identified all three SK isoforms (SK1, SK2 and SK3) in mouse SAN. Inhibition of SK channels with the specific blocker apamin prolonged action potentials (APs) in isolated SAN cells. Apamin also slowed diastolic depolarization and reduced pacemaker rate in isolated SAN cells and intact tissue. We investigated whether the Ca2+ -sensitive nature of SK channels could explain arrhythmic SAN pacemaker activity in the atrial-specific Na+ /Ca2+ exchange (NCX) knockout (KO) mouse, a model of cellular Ca2+ overload. SAN cells isolated from the NCX KO exhibited higher SK current than wildtype (WT) and apamin prolonged their APs. SK blockade partially suppressed the arrhythmic burst pacing pattern of intact NCX KO SAN tissue. We conclude that SK channels have demonstrable effects on SAN pacemaking in the mouse. Their Ca2+ -dependent activation translates changes in cellular Ca2+ into a repolarizing current capable of modulating regular pacemaking. This Ca2+ dependence also promotes abnormal automaticity when these channels are hyperactivated by elevated Ca2+ . We propose SK channels as a potential target for modulating SAN rate, and for treating patients affected by SAN dysfunction, particularly in the setting of Ca2+ overload.

Pressure-overload-induced angiotensin-mediated early remodeling in mouse heart.

Our previous work on angiotensin II-mediated electrical-remodeling in canine left ventricle, in connection with a long history of other studies, suggested the hypothesis: increases in mechanical load induce autocrine secretion of angiotensin II (A2), which coherently regulates a coterie of membrane ion transporters in a manner that increases contractility. However, the relation between load and A2 secretion was correlative. We subsequently showed a similar or identical system was present in murine heart. To investigate whether the relation between mechanical load and A2-mediated electrical remodeling was causal, we employed transverse aortic constriction in mice to subject the left ventricle to pressure overload for short-term (1 to 2 days) or long-term (1 to 2 weeks) periods. Heart-to-body weight ratios and cell capacitance measurements were used to determine hypertrophy. Whole-cell patch clamp recordings of the predominant repolarization currents Ito,fast and IK,slow were used to assess electrical remodeling. Hearts or myocytes subjected to long-term load displayed significant hypertrophy, which was not evident in short-term load. However, short-term load induced significant reductions in Ito,fast and IK,slow. Incubation of these myocytes with the angiotensin II type 1 receptor inhibitor saralasin for 2 hours restored Ito,fast and IK,slow to control levels. The number of Ito.fast or IK,slow channels did not change with A2 or long-term load, however the hypertrophic increase in membrane area reduced the current densities for both channels. For Ito,fast but not IK,slow there was an additional reduction that was reversed by inhibition of angiotensin receptors. These results suggest increased load activates an endogenous renin angiotensin system that initially reduces Ito,fast and IK,slow prior to the onset of hypertrophic growth. However, there are functional interactions between electrical and anatomical remodeling. First, hypertrophy tends to reduce all current densities. Second, the hypertrophic program can modify signaling between the angiotensin receptor and target current.

KChIP2 is a core transcriptional regulator of cardiac excitability.

Arrhythmogenesis from aberrant electrical remodeling is a primary cause of death among patients with heart disease. Amongst a multitude of remodeling events, reduced expression of the ion channel subunit KChIP2 is consistently observed in numerous cardiac pathologies. However, it remains unknown if KChIP2 loss is merely a symptom or involved in disease development. Using rat and human derived cardiomyocytes, we identify a previously unobserved transcriptional capacity for cardiac KChIP2 critical in maintaining electrical stability. Through interaction with genetic elements, KChIP2 transcriptionally repressed the miRNAs miR-34b and miR-34c, which subsequently targeted key depolarizing (INa) and repolarizing (Ito) currents altered in cardiac disease. Genetically maintaining KChIP2 expression or inhibiting miR-34 under pathologic conditions restored channel function and moreover, prevented the incidence of reentrant arrhythmias. This identifies the KChIP2/miR-34 axis as a central regulator in developing electrical dysfunction and reveals miR-34 as a therapeutic target for treating arrhythmogenesis in heart disease.