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Fulltext Solitonic conduction of electrotonic signals in neuronal branchlets with polarized microstructure

Poznanski RR, Cacha LA, Al-Wesabi YMS, Ali J, Bahadoran M, Yupapin PP, et al.

Sci Rep, 2017 May 31;7(1):2746.
PMID: 28566682 DOI: 10.1038/s41598-017-01849-3

A model of solitonic conduction in neuronal branchlets with microstructure is presented. The application of cable theory to neurons with microstructure results in a nonlinear cable equation that is solved using a direct method to obtain analytical approximations of traveling wave solutions. It is shown that a linear superposition of two oppositely directed traveling waves demonstrate solitonic interaction: colliding waves can penetrate through each other, and continue fully intact as the exact pulses that entered the collision. These findings indicate that microstructure when polarized can sustain solitary waves that propagate at a constant velocity without attenuation or distortion in the absence of synaptic transmission. Solitonic conduction in a neuronal branchlet arising from polarizability of its microstructure is a novel signaling mode of electrotonic signals in thin processes (<0.5 μm diameter).

Matched MeSH terms: Action Potentials/physiology
Evolving spatio-temporal data machines based on the NeuCube neuromorphic framework: Design methodology and selected applications

Kasabov N, Scott NM, Tu E, Marks S, Sengupta N, Capecci E, et al.

Neural Netw, 2016 Jun;78:1-14.
PMID: 26576468 DOI: 10.1016/j.neunet.2015.09.011

The paper describes a new type of evolving connectionist systems (ECOS) called evolving spatio-temporal data machines based on neuromorphic, brain-like information processing principles (eSTDM). These are multi-modular computer systems designed to deal with large and fast spatio/spectro temporal data using spiking neural networks (SNN) as major processing modules. ECOS and eSTDM in particular can learn incrementally from data streams, can include 'on the fly' new input variables, new output class labels or regression outputs, can continuously adapt their structure and functionality, can be visualised and interpreted for new knowledge discovery and for a better understanding of the data and the processes that generated it. eSTDM can be used for early event prediction due to the ability of the SNN to spike early, before whole input vectors (they were trained on) are presented. A framework for building eSTDM called NeuCube along with a design methodology for building eSTDM using this is presented. The implementation of this framework in MATLAB, Java, and PyNN (Python) is presented. The latter facilitates the use of neuromorphic hardware platforms to run the eSTDM. Selected examples are given of eSTDM for pattern recognition and early event prediction on EEG data, fMRI data, multisensory seismic data, ecological data, climate data, audio-visual data. Future directions are discussed, including extension of the NeuCube framework for building neurogenetic eSTDM and also new applications of eSTDM.

Matched MeSH terms: Action Potentials/physiology
Fulltext In vitro differentiation between oxytocin- and vasopressin-secreting magnocellular neurons requires more than one experimental criterion

da Silva MP, Merino RM, Mecawi AS, Moraes DJ, Varanda WA

Mol Cell Endocrinol, 2015 Jan 15;400:102-11.
PMID: 25451978 DOI: 10.1016/j.mce.2014.11.004

The phenotypic differentiation between oxytocin (OT)- and vasopressin (VP)-secreting magnocellular neurosecretory cells (MNCs) from the supraoptic nucleus is relevant to understanding how several physiological and pharmacological challenges affect their electrical activity. Although the firing patterns of OT and VP neurons, both in vivo and in vitro, may appear different from each other, much is assumed about their characteristics. These assumptions make it practically impossible to obtain a confident phenotypic differentiation based exclusively on the firing patterns. The presence of a sustained outward rectifying potassium current (SOR) and/or an inward rectifying hyperpolarization-activated current (IR), which are presumably present in OT neurons and absent in VP neurons, has been used to distinguish between the two types of MNCs in the past. In this study, we aimed to analyze the accuracy of the phenotypic discrimination of MNCs based on the presence of rectifying currents using comparisons with the molecular phenotype of the cells, as determined by single-cell RT-qPCR and immunohistochemistry. Our results demonstrated that the phenotypes classified according to the electrophysiological protocol in brain slices do not match their molecular counterparts because vasopressinergic and intermediate neurons also exhibit both outward and inward rectifying currents. In addition, we also show that MNCs can change the relative proportion of each cell phenotype when the system is challenged by chronic hypertonicity (70% water restriction for 7 days). We conclude that for in vitro preparations, the combination of mRNA detection and immunohistochemistry seems to be preferable when trying to characterize a single MNC phenotype.

Matched MeSH terms: Action Potentials/drug effects; Action Potentials/physiology*
Reliability of measurement of muscle fiber conduction velocity using surface EMG

Harba MI, Teng LY

Front Med Biol Eng, 1999;9(1):31-47.
PMID: 10354908

Cross-correlating two surface EMG signals detected at two different locations along the path of flow of action potential enables the measurement of the muscle fiber average conduction velocity in those active motor units monitored by the electrodes. The position of the peak of the cross-correlation function is the time delay between the two signals and hence the velocity may be deduced. The estimated velocity using this technique has been observed previously to depend on the location of the electrodes on the muscle surface. Different locations produced different estimates. In this paper we present a measurement system, analyze its inherent inaccuracies and use it for the purpose of investigating the reliability of measurement of conduction velocity from surface EMG. This system utilizes EMG signals detected at a number of locations on the biceps brachii, when under light tension, to look for any pattern of variations of velocity as a function of location and time. It consists of a multi-electrode unit and a set of eight parallel on-line correlators. The electrode unit and the parallel correlators ensure that these measurements are carried out under the same physical and physiological conditions of the muscle. Further, the same detected signals are used in different measurement configurations to try to understand the reasons behind the observed variations in the estimated velocity. The results obtained seem to suggest that there will always be an unpredictable random component superimposed on the estimated velocity, giving rise to differences between estimates at different locations and differences in estimates with time at the same location. Many factors contribute to this random component, such as the non-homogeneous medium between the muscle fibers and the electrodes, the non-parallel geometry and non-uniform conduction velocity of the fibers, and the physical and physiological conditions of the muscle. While it is not possible to remove this random component completely from the measurement, the user must be aware of its presence and how to reduce its effects.

Matched MeSH terms: Action Potentials/physiology*
Effects of demographic and physical factors on nerve conduction study values of healthy subjects in a multi-ethnic Asian population

Fong SY, Goh KJ, Shahrizaila N, Wong KT, Tan CT

Muscle Nerve, 2016 08;54(2):244-8.
PMID: 26790132 DOI: 10.1002/mus.25029

INTRODUCTION: We investigated the effects of demographic and physical factors on nerve conduction studies (NCS) in a multi-ethnic Asian population.
METHODS: One hundred sixty-six healthy Malaysians of different ethnicities (51.2% women, aged 21-77 years) underwent NCS using a standard protocol. Correlations of various factors to NCS were determined, and multiple linear regression analysis was used to develop predictive equations for each parameter.
RESULTS: Age and ethnicity were the commonest independent factors influencing NCS followed by gender, height, weight, and body mass index. Increasing age predicted a reduction in lower limb motor and all sensory nerve action potential amplitudes and decrease in motor and sensory (except sural) conduction velocities. Ethnic Indians had slower motor and sensory conduction velocities in several nerves and also had differences in action potential amplitudes.
CONCLUSIONS: NCS parameters in multi-ethnic Malaysians were influenced independently by various demographic and physical factors, including ethnicity. Muscle Nerve 54: 244-248, 2016.

Matched MeSH terms: Action Potentials/physiology*
Phenomenological analysis of simple ion channel block in large populations of uncoupled cardiomyocytes

Simitev RD, Al Dawoud A, Aziz MHN, Myles R, Smith GL

Math Med Biol, 2023 Jun 14;40(2):175-198.
PMID: 36689769 DOI: 10.1093/imammb/dqad001

Current understanding of arrhythmia mechanisms and design of anti-arrhythmic drug therapies hinges on the assumption that myocytes from the same region of a single heart have similar, if not identical, action potential waveforms and drug responses. On the contrary, recent experiments reveal significant heterogeneity in uncoupled healthy myocytes both from different hearts as well as from identical regions within a single heart. In this work, a methodology is developed for quantifying the individual electrophysiological properties of large numbers of uncoupled cardiomyocytes under ion channel block in terms of the parameters values of a conceptual fast-slow model of electrical excitability. The approach is applied to a population of nearly 500 rabbit ventricular myocytes for which action potential duration (APD) before and after the application of the drug nifedipine was experimentally measured (Lachaud et al., 2022, Cardiovasc. Res.). To this end, drug action is represented by a multiplicative factor to an effective ion conductance, a closed form asymptotic expression for APD is derived and inverted to determine model parameters as functions of APD and $\varDelta $APD (drug-induced change in APD) for each myocyte. Two free protocol-related quantities are calibrated to experiment using an adaptive-domain procedure based on an original assumption of optimal excitability. The explicit APD expression and the resulting set of model parameter values allow (a) direct evaluation of conditions necessary to maintain fixed APD or $\varDelta $APD, (b) predictions of the proportion of cells remaining excitable after drug application, (c) predictions of stimulus period dependency and (d) predictions of dose-response curves, the latter being in agreement with additional experimental data.

Matched MeSH terms: Action Potentials/physiology
Fulltext Chia Seed Oil Ameliorates Doxorubicin-Induced Cardiotoxicity in Female Wistar Rats: An Electrocardiographic, Biochemical and Histopathological Approach

Ahmed AZ, Mumbrekar KD, Satyam SM, Shetty P, D'Souza MR, Singh VK

Cardiovasc Toxicol, 2021 Jul;21(7):533-542.
PMID: 33740233 DOI: 10.1007/s12012-021-09644-3

Doxorubicin (DOX) is a potent anti-cancer antibiotic that was widely used for treatment of various cancers. It produces free radicals which result in extreme dose-limiting cardiotoxicity. This study investigated the cardioprotective potential of chia seed oil, an active polyphenolic nutraceutical against doxorubicin-induced cardiotoxicity in Wistar rats. Twenty-four female Wistar rats were divided into four groups (n = 6) which consist of normal control, DOX control, test-A and test-B group. Animals were prophylactically treated with two different doses of test drug, i.e. chia seed oil 2.5 ml/kg/day and 5 ml/kg/day in test-A and test-B groups orally for 7 days. Doxorubicin (25 mg/kg; single dose) was administered intraperitoneally to DOX control, Test-A and Test-B animals on the seventh day to induce cardiotoxicity. ECG analysis was done before and after treatment. Besides ECG, CK, CK-MB, LDH, AST, MDA and GSH were analyzed. DOX had significantly altered ECG, CK, CK-MB, LDH, AST, MDA and GSH. Pre-treatment with chia seed oil significantly alleviated DOX-induced ECG changes and also guarded against DOX-induced rise of serum CK, CK-MB and AST levels. Chia seed oil alleviated histopathological alteration in DOX-treated rats. It also significantly inhibited DOX-induced GSH depletion and elevation of MDA. The present study revealed that chia seed oil exerts cardioprotection against doxorubicin-induced cardiotoxicity in female Wistar rats. Our study opens the perspective to clinical studies to precisely consider chia seed oil as a potential chemoprotectant nutraceutical in the combination chemotherapy with doxorubicin to limit its cardiotoxicity.

Matched MeSH terms: Action Potentials/drug effects
Fulltext Evaluation of the cardiotoxicity of mitragynine and its analogues using human induced pluripotent stem cell-derived cardiomyocytes

Lu J, Wei H, Wu J, Jamil MF, Tan ML, Adenan MI, et al.

PLoS One, 2014;9(12):e115648.
PMID: 25535742 DOI: 10.1371/journal.pone.0115648

INTRODUCTION: Mitragynine is a major bioactive compound of Kratom, which is derived from the leave extracts of Mitragyna speciosa Korth or Mitragyna speciosa (M. speciosa), a medicinal plant from South East Asia used legally in many countries as stimulant with opioid-like effects for the treatment of chronic pain and opioid-withdrawal symptoms. Fatal incidents with Mitragynine have been associated with cardiac arrest. In this study, we determined the cardiotoxicity of Mitragynine and other chemical constituents isolated using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).
METHODS AND RESULTS: The rapid delayed rectifier potassium current (IKr), L-type Ca2+ current (ICa,L) and action potential duration (APD) were measured by whole cell patch-clamp. The expression of KCNH2 and cytotoxicity was determined by real-time PCR and Caspase activity measurements. After significant IKr suppression by Mitragynine (10 µM) was confirmed in hERG-HEK cells, we systematically examined the effects of Mitragynine and other chemical constituents in hiPSC-CMs. Mitragynine, Paynantheine, Speciogynine and Speciociliatine, dosage-dependently (0.1∼100 µM) suppressed IKr in hiPSC-CMs by 67%∼84% with IC50 ranged from 0.91 to 2.47 µM. Moreover, Mitragynine (10 µM) significantly prolonged APD at 50 and 90% repolarization (APD50 and APD90) (439.0±11.6 vs. 585.2±45.5 ms and 536.0±22.6 vs. 705.9±46.1 ms, respectively) and induced arrhythmia, without altering the L-type Ca2+ current. Neither the expression, and intracellular distribution of KCNH2/Kv11.1, nor the Caspase 3 activity were significantly affected by Mitragynine.
CONCLUSIONS: Our study indicates that Mitragynine and its analogues may potentiate Torsade de Pointes through inhibition of IKr in human cardiomyocytes.

Matched MeSH terms: Action Potentials/drug effects
Fulltext The RyR2-P2328S mutation downregulates Nav1.5 producing arrhythmic substrate in murine ventricles

Ning F, Luo L, Ahmad S, Valli H, Jeevaratnam K, Wang T, et al.

Pflugers Arch., 2016 Apr;468(4):655-65.
PMID: 26545784 DOI: 10.1007/s00424-015-1750-0

Catecholaminergic polymorphic ventricular tachycardia (CPVT) predisposes to ventricular arrhythmia due to altered Ca(2+) homeostasis and can arise from ryanodine receptor (RyR2) mutations including RyR2-P2328S. Previous reports established that homozygotic murine RyR2-P2328S (RyR2 (S/S)) hearts show an atrial arrhythmic phenotype associated with reduced action potential (AP) conduction velocity and sodium channel (Nav1.5) expression. We now relate ventricular arrhythmogenicity and slowed AP conduction in RyR2 (S/S) hearts to connexin-43 (Cx43) and Nav1.5 expression and Na(+) current (I Na). Stimulation protocols applying extrasystolic S2 stimulation following 8 Hz S1 pacing at progressively decremented S1S2 intervals confirmed an arrhythmic tendency despite unchanged ventricular effective refractory periods (VERPs) in Langendorff-perfused RyR2 (S/S) hearts. Dynamic pacing imposing S1 stimuli then demonstrated that progressive reductions of basic cycle lengths (BCLs) produced greater reductions in conduction velocity at equivalent BCLs and diastolic intervals in RyR2 (S/S) than WT, but comparable changes in AP durations (APD90) and their alternans. Western blot analyses demonstrated that Cx43 protein expression in whole ventricles was similar, but Nav1.5 expression in both whole tissue and membrane fractions were significantly reduced in RyR2 (S/S) compared to wild-type (WT). Loose patch-clamp studies similarly demonstrated reduced I Na in RyR2 (S/S) ventricles. We thus attribute arrhythmogenesis in RyR2 (S/S) ventricles resulting from arrhythmic substrate produced by reduced conduction velocity to downregulated Nav1.5 reducing I Na, despite normal determinants of repolarization and passive conduction. The measured changes were quantitatively compatible with earlier predictions of linear relationships between conduction velocity and the peak I Na of the AP but nonlinear relationships between peak I Na and maximum Na(+) permeability.

Matched MeSH terms: Action Potentials*
Dual-action potential of cationic cryptides against infections and cancers

Abd El-Aal AAA, Jayakumar FA, Reginald K

Drug Discov Today, 2023 Nov;28(11):103764.
PMID: 37689179 DOI: 10.1016/j.drudis.2023.103764

Cryptides are a subfamily of bioactive peptides embedded latently in their parent proteins and have multiple biological functions. Cationic cryptides could be used as modern drugs in both infectious diseases and cancers because their mechanism of action is less likely to be affected by genetic mutations in the treated cells, therefore addressing a current unmet need in these two areas of medicine. In this review, we present the current understanding of cryptides, methods to mine them sustainably using available online databases and prediction tools, with a particular focus on their antimicrobial and anticancer potential, and their potential applicability in a clinical setting.

Matched MeSH terms: Action Potentials
Fulltext Inhibitory effects of cardamonin on compound action potentials in frog sciatic nerves and the possible involvement of opioidergic pathway

Sambasevam, Yogesvari, Wong, Siong Jiun, Farihah Hanani Ghazali, Ammar Izzati Amir Ramadan, Mohd Roslan Sulaiman, Mohd Khairi Hussain, et al.

Life Sciences, Medicine and Biomedicine, 2017;1(1):18-24.
MyJurnal

Introduction: Active compounds derived from plants are able to inhibit nerve conduction. Cardamonin, a naturally occurring chalcone, manifests anti-nociceptive, anti-inflammatory and anti-neuropathy properties. Consequently, cardamonin may potentially inhibit nerve action potential, whereby, it affects the nerve conduction. Compound action potential is the sum of the activity which is measured from a nerve trunk. Objective: The experiment was carried out to investigate the inhibitory effect of cardamonin on compound action potentials and its possible mechanism of action on frog sciatic nerve. Methodology: LabTutor software was used to record compound action potentials in frog sciatic nerve. Sciatic nerve was isolated from the frog and soaked in Ringer’s solution. Stimulating electrodes were used to stimulate the nerve and recording electrodes were used to record compound action potentials. Compound action potential of the nerve were recorded before and after treatments [vehicle, cardamonin (0.5, 1 & 2 mg/ml) & morphine (3mg/ml)]. Participation of opioid system was investigated by pre-treating the nerve with naloxone and followed by cardamonin. All the data were recorded and analysed via LabTutor software. The data were analysed by using Two-way ANOVA followed by Bonferonni’s post hoc test with significant value at P < 0.05. Results: The outcomes showed that all the doses of cardamonin significantly reduced the peak amplitude of compound action potential in frog sciatic nerves. Besides, co-treatment of naloxone and cardamonin significantly (P < 0.001) reversed the effect of cardamonin on peak amplitude of compound action potential, suggesting the involvement of opioid receptors to inhibit nerve conduction. Conclusion: Cardamonin reduces the nerve signal conduction via activation of opioid receptors to modulate pain and contribute to the analgesic effects.

Matched MeSH terms: Action Potentials
Fulltext Effects of sulbutiamine on diabetic polyneuropathy: an open randomised controlled study in type 2 diabetics

Kiew KK, Wan Mohamad WB, Ridzuan A, Mafauzy M

Malays J Med Sci, 2002 Jan;9(1):21-7.
PMID: 22969314 MyJurnal

Thirty patients with diabetic polyneuropathy were recruited from the diabetic clinic in Hospital Universiti Sains Malaysia from 1996 to 1998. They were randomly assigned either sulbutiamine (Arcalion(®)) (15 patients) or no treatment (control group; 15 patients). Glycaemic control was assessed by blood glucose and HbA1. Severity of neuropathy was assessed by symptom and sign score, and electrophysiological parameters (nerve conduction velocity and compound muscle action potential) at entry to the study and after 6 weeks. There were improvements in the electrophysiological parameters in the treatment group when compared to the controls with significant improvement in the median nerve conduction velocity (p<0.001), median compound muscle action potential (p<0.001), peroneal nerve conduction velocity (p<0.001), and peroneal compound muscle action potential (p<0.001). No significant improvement in symptom and sign scores were noted between the groups but a significant improvement compared to base line was noted for the sulbutiamine treated group. (p< 0.05). The glycaemic control in both groups was not significantly different at base line and was stable throughout the study. Sulbutiamine objectively improved peripheral nerve function in diabetic polyneuropathy although the symptom score did not improve, possibly due to the short duration of the study.

Matched MeSH terms: Action Potentials
Response to: Depolarization vs. repolarization: what is the mechanism of ventricular arrhythmogenesis underlying sodium channel haploinsufficiency in mouse hearts?

Jeevaratnam K, Guzadhur L, Goh YM, Grace AA, Huang CL

Acta Physiol (Oxf), 2016 12;218(4):236-238.
PMID: 27272698 DOI: 10.1111/apha.12731
Matched MeSH terms: Action Potentials
Fulltext Epac-induced ryanodine receptor type 2 activation inhibits sodium currents in atrial and ventricular murine cardiomyocytes

Valli H, Ahmad S, Sriharan S, Dean LD, Grace AA, Jeevaratnam K, et al.

Clin Exp Pharmacol Physiol, 2018 03;45(3):278-292.
PMID: 29027245 DOI: 10.1111/1440-1681.12870

Acute RyR2 activation by exchange protein directly activated by cAMP (Epac) reversibly perturbs myocyte Ca2+ homeostasis, slows myocardial action potential conduction, and exerts pro-arrhythmic effects. Loose patch-clamp studies, preserving in vivo extracellular and intracellular conditions, investigated Na+ current in intact cardiomyocytes in murine atrial and ventricular preparations following Epac activation. Depolarising steps to varying test voltages activated typical voltage-dependent Na+ currents. Plots of peak current against depolarisation from resting potential gave pretreatment maximum atrial and ventricular currents of -20.23 ± 1.48 (17) and -29.8 ± 2.4 (10) pA/μm2 (mean ± SEM [n]). Challenge by 8-CPT (1 μmol/L) reduced these currents to -11.21 ± 0.91 (12) (P .05). Assessment of the inactivation that followed by applying subsequent steps to a fixed voltage 100 mV positive to resting potential gave concordant results. Half-maximal inactivation voltages and steepness factors, and time constants for Na+ current recovery from inactivation in double-pulse experiments, were similar through all the pharmacological conditions. Intracellular sharp microelectrode membrane potential recordings in intact Langendorff-perfused preparations demonstrated concordant variations in maximum rates of atrial and ventricular action potential upstroke, (dV/dt)max . We thus demonstrate an acute, reversible, Na+ channel inhibition offering a possible mechanism for previously reported pro-arrhythmic slowing of AP propagation following modifications of Ca2+ homeostasis, complementing earlier findings from chronic alterations in Ca2+ homeostasis in genetically-modified RyR2-P2328S hearts.

Matched MeSH terms: Action Potentials
Fulltext Ion channels, long QT syndrome and arrhythmogenesis in ageing

Jeevaratnam K, Chadda KR, Salvage SC, Valli H, Ahmad S, Grace AA, et al.

Clin Exp Pharmacol Physiol, 2017 12;44 Suppl 1:38-45.
PMID: 28024120 DOI: 10.1111/1440-1681.12721

Ageing is associated with increased prevalences of both atrial and ventricular arrhythmias, reflecting disruption of the normal sequence of ion channel activation and inactivation generating the propagated cardiac action potential. Experimental models with specific ion channel genetic modifications have helped clarify the interacting functional roles of ion channels and how their dysregulation contributes to arrhythmogenic processes at the cellular and systems level. They have also investigated interactions between these ion channel abnormalities and age-related processes in producing arrhythmic tendency. Previous reviews have explored the relationships between age and loss-of-function Nav 1.5 mutations in producing arrhythmogenicity. The present review now explores complementary relationships arising from gain-of-function Nav 1.5 mutations associated with long QT3 (LQTS3). LQTS3 patients show increased risks of life-threatening ventricular arrhythmias, particularly after 40 years of age, consistent with such interactions between the ion channel abnormailities and ageing. In turn clinical evidence suggests that ageing is accompanied by structural, particularly fibrotic, as well as electrophysiological change. These abnormalities may result from biochemical changes producing low-grade inflammation resulting from increased production of reactive oxygen species and superoxide. Experimental studies offer further insights into the underlying mechanisms underlying these phenotypes. Thus, studies in genetically modified murine models for LQTS implicated action potential recovery processes in arrhythmogenesis resulting from functional ion channel abnormalities. In addition, ageing wild type (WT) murine models demonstrated both ion channel alterations and fibrotic changes with ageing. Murine models then suggested evidence for interactions between ageing and ion channel mutations and provided insights into potential arrhythmic mechanisms inviting future exploration.

Matched MeSH terms: Action Potentials/genetics*
Fulltext Age-dependent atrial arrhythmic phenotype secondary to mitochondrial dysfunction in Pgc-1β deficient murine hearts

Valli H, Ahmad S, Chadda KR, Al-Hadithi ABAK, Grace AA, Jeevaratnam K, et al.

Mech Ageing Dev, 2017 Oct;167:30-45.
PMID: 28919427 DOI: 10.1016/j.mad.2017.09.002

INTRODUCTION: Ageing and several age-related chronic conditions including obesity, insulin resistance and hypertension are associated with mitochondrial dysfunction and represent independent risk factors for atrial fibrillation (AF).
MATERIALS AND METHODS: Atrial arrhythmogenesis was investigated in Langendorff-perfused young (3-4 month) and aged (>12 month), wild type (WT) and peroxisome proliferator activated receptor-γ coactivator-1β deficient (Pgc-1β-/-) murine hearts modeling age-dependent chronic mitochondrial dysfunction during regular pacing and programmed electrical stimulation (PES).
RESULTS AND DISCUSSION: The Pgc-1β-/- genotype was associated with a pro-arrhythmic phenotype progressing with age. Young and aged Pgc-1β-/- hearts showed compromised maximum action potential (AP) depolarization rates, (dV/dt)max, prolonged AP latencies reflecting slowed action potential (AP) conduction, similar effective refractory periods and baseline action potential durations (APD90) but shortened APD90 in APs in response to extrasystolic stimuli at short stimulation intervals. Electrical properties of APs triggering arrhythmia were similar in WT and Pgc-1β-/- hearts. Pgc-1β-/- hearts showed accelerated age-dependent fibrotic change relative to WT, with young Pgc-1β-/- hearts displaying similar fibrotic change as aged WT, and aged Pgc-1β-/- hearts the greatest fibrotic change. Mitochondrial deficits thus result in an arrhythmic substrate, through slowed AP conduction and altered repolarisation characteristics, arising from alterations in electrophysiological properties and accelerated structural change.

Matched MeSH terms: Action Potentials
Fulltext Sodium channel biophysics, late sodium current and genetic arrhythmic syndromes

Chadda KR, Jeevaratnam K, Lei M, Huang CL

Pflugers Arch., 2017 06;469(5-6):629-641.
PMID: 28265756 DOI: 10.1007/s00424-017-1959-1

Arrhythmias arise from breakdown of orderly action potential (AP) activation, propagation and recovery driven by interactive opening and closing of successive voltage-gated ion channels, in which one or more Na+ current components play critical parts. Early peak, Na+ currents (I Na) reflecting channel activation drive the AP upstroke central to cellular activation and its propagation. Sustained late Na+ currents (I Na-L) include contributions from a component with a delayed inactivation timecourse influencing AP duration (APD) and refractoriness, potentially causing pro-arrhythmic phenotypes. The magnitude of I Na-L can be analysed through overlaps or otherwise in the overall voltage dependences of the steady-state properties and kinetics of activation and inactivation of the Na+ conductance. This was useful in analysing repetitive firing associated with paramyotonia congenita in skeletal muscle. Similarly, genetic cardiac Na+ channel abnormalities increasing I Na-L are implicated in triggering phenomena of automaticity, early and delayed afterdepolarisations and arrhythmic substrate. This review illustrates a wide range of situations that may accentuate I Na-L. These include (1) overlaps between steady-state activation and inactivation increasing window current, (2) kinetic deficiencies in Na+ channel inactivation leading to bursting phenomena associated with repetitive channel openings and (3) non-equilibrium gating processes causing channel re-opening due to more rapid recoveries from inactivation. All these biophysical possibilities were identified in a selection of abnormal human SCN5A genotypes. The latter presented as a broad range of clinical arrhythmic phenotypes, for which effective therapeutic intervention would require specific identification and targeting of the diverse electrophysiological abnormalities underlying their increased I Na-L.

Matched MeSH terms: Action Potentials
Fulltext Cardiomyocyte ionic currents in intact young and aged murine Pgc-1β-/- atrial preparations

Valli H, Ahmad S, Jiang AY, Smyth R, Jeevaratnam K, Matthews HR, et al.

Mech Ageing Dev, 2018 01;169:1-9.
PMID: 29197478 DOI: 10.1016/j.mad.2017.11.016

INTRODUCTION: Recent studies reported that energetically deficient murine Pgc-1β-/- hearts replicate age-dependent atrial arrhythmic phenotypes associated with their corresponding clinical conditions, implicating action potential (AP) conduction slowing consequent upon reduced AP upstroke rates.
MATERIALS AND METHODS: We tested a hypothesis implicating Na+ current alterations as a mechanism underlying these electrophysiological phenotypes. We applied loose patch-clamp techniques to intact young and aged, WT and Pgc-1β-/-, atrial cardiomyocyte preparations preserving their in vivo extracellular and intracellular conditions.
RESULTS AND DISCUSSION: Depolarising steps activated typical voltage-dependent activating and inactivating inward (Na+) currents whose amplitude increased or decreased with the amplitudes of the activating, or preceding inactivating, steps. Maximum values of peak Na+ current were independently influenced by genotype but not age or interacting effects of genotype and age on two-way ANOVA. Neither genotype, nor age, whether independently or interactively, influenced voltages at half-maximal current, or steepness factors, for current activation and inactivation, or time constants for recovery from inactivation following repolarisation. In contrast, delayed outward (K+) currents showed similar activation and rectification properties through all experimental groups. These findings directly demonstrate and implicate reduced Na+ in contrast to unchanged K+ current, as a mechanism for slowed conduction causing atrial arrhythmogenicity in Pgc-1β-/- hearts.

Matched MeSH terms: Action Potentials*
Fulltext Effects of ageing on pro-arrhythmic ventricular phenotypes in incrementally paced murine Pgc-1β -/- hearts

Ahmad S, Valli H, Edling CE, Grace AA, Jeevaratnam K, Huang CL

Pflugers Arch., 2017 Dec;469(12):1579-1590.
PMID: 28821956 DOI: 10.1007/s00424-017-2054-3

A range of chronic clinical conditions accompany cardiomyocyte energetic dysfunction and constitute independent risk factors for cardiac arrhythmia. We investigated pro-arrhythmic and arrhythmic phenotypes in energetically deficient C57BL mice with genetic ablation of the mitochondrial promoter peroxisome proliferator-activated receptor-γ coactivator-1β (Pgc-1β), a known model of ventricular arrhythmia. Pro-arrhythmic and cellular action potential (AP) characteristics were compared in intact Langendorff-perfused hearts from young (12-16 week) and aged (> 52 week), wild-type (WT) and Pgc-1β -/- mice. Simultaneous electrocardiographic and intracellular microelectrode recordings were made through successive trains of 100 regular stimuli at progressively incremented heart rates. Aged Pgc-1β -/- hearts displayed an increased incidence of arrhythmia compared to other groups. Young and aged Pgc-1β -/- hearts showed higher incidences of alternans in both AP activation (maximum AP upshoot velocity (dV/dt)max and latency), recovery (action potential duration (APD90) and resting membrane potential (RMP) characteristics compared to WT hearts. This was particularly apparent at lower pacing frequencies. These findings accompanied reduced (dV/dt)max and increased AP latency values in the Pgc-1β -/- hearts. APs observed prior to termination of the protocol showed lower (dV/dt)max and longer AP latencies, but indistinguishable APD90 and RMPs in arrhythmic compared to those in non-arrhythmic hearts. APD restitution analysis showed that Pgc-1β -/- and WT hearts showed similar limiting gradients. However, Pgc-1β -/- hearts had shortened plateau AP wavelengths, particularly in aged Pgc-1β -/- hearts. Pgc-1β -/- hearts therefore show pro-arrhythmic instabilities attributable to altered AP conduction and activation rather than recovery characteristics.

Matched MeSH terms: Action Potentials/physiology
Fulltext Pro-arrhythmic atrial phenotypes in incrementally paced murine Pgc1β-/- hearts: effects of age

Valli H, Ahmad S, Fraser JA, Jeevaratnam K, Huang CL

Exp Physiol, 2017 12 01;102(12):1619-1634.
PMID: 28960529 DOI: 10.1113/EP086589

NEW FINDINGS: What is the central question of this study? Can we experimentally replicate atrial pro-arrhythmic phenotypes associated with important chronic clinical conditions, including physical inactivity, obesity, diabetes mellitus and metabolic syndrome, compromising mitochondrial function, and clarify their electrophysiological basis? What is the main finding and its importance? Electrocardiographic and intracellular cardiomyocyte recording at progressively incremented pacing rates demonstrated age-dependent atrial arrhythmic phenotypes in Langendorff-perfused murine Pgc1β-/- hearts for the first time. We attributed these to compromised action potential conduction and excitation wavefronts, whilst excluding alterations in recovery properties or temporal electrophysiological instabilities, clarifying these pro-arrhythmic changes in chronic metabolic disease. Atrial arrhythmias, most commonly manifesting as atrial fibrillation, represent a major clinical problem. The incidence of atrial fibrillation increases with both age and conditions associated with energetic dysfunction. Atrial arrhythmic phenotypes were compared in young (12-16 week) and aged (>52 week) wild-type (WT) and peroxisome proliferative activated receptor, gamma, coactivator 1 beta (Ppargc1b)-deficient (Pgc1β-/- ) Langendorff-perfused hearts, previously used to model mitochondrial energetic disorder. Electrophysiological explorations were performed using simultaneous whole-heart ECG and intracellular atrial action potential (AP) recordings. Two stimulation protocols were used: an S1S2 protocol, which imposed extrasystolic stimuli at successively decremented intervals following regular pulse trains; and a regular pacing protocol at successively incremented frequencies. Aged Pgc1β-/- hearts showed greater atrial arrhythmogenicity, presenting as atrial tachycardia and ectopic activity. Maximal rates of AP depolarization (dV/dtmax ) were reduced in Pgc1β-/- hearts. Action potential latencies were increased by the Pgc1β-/- genotype, with an added interactive effect of age. In contrast, AP durations to 90% recovery (APD90 ) were shorter in Pgc1β-/- hearts despite similar atrial effective recovery periods amongst the different groups. These findings accompanied paradoxical decreases in the incidence and duration of alternans in the aged and Pgc1β-/- hearts. Limiting slopes of restitution curves of APD90 against diastolic interval were correspondingly reduced interactively by Pgc1β-/- genotype and age. In contrast, reduced AP wavelengths were associated with Pgc1β-/- genotype, both independently and interacting with age, through the basic cycle lengths explored, with the aged Pgc1β-/- hearts showing the shortest wavelengths. These findings thus implicate AP wavelength in possible mechanisms for the atrial arrhythmic changes reported here.

Matched MeSH terms: Action Potentials

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