Reduced Conduction Velocity Research Articles

65. Peripheral nerve ultrasonography: Clinical use

Charcot–Marie–Tooth disease (CMT) is an heterogeneous group of hereditary neuropathies characterized by weakness and atrophy of the limbs, loss of sensation and absent or reduced tendon reflexes. Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) causes progressive or recurrent weakness and numbness of the limbs. Both CMT and CIDP share similar nerve conduction study abnormalities (reduced amplitude of sensory and motor potentials, and reduced conduction velocity). The aim of our study was to compare the ultrasound (US) data recorded in genetic neuropathy (CMT) and inflammatory neuropathy (CIDP). We enrolled 10 patients with CMT type 1A and 10 patients with CIDP. In this study we compared left and right median nerve cross-sectional area (CSA) and echogenicity nerve in the forearm, between two groups of patients to evaluate a possible difference. Three US classes were identified based on CSA and echogenicity. For all patient included neurophysiological assessment was used to estimate a possible correlation between the nerve conduction study variables and US data. US of the nerve can be a tool of significant value in the differential diagnosis in different neuropathies.

TMEM43 mutation p.S358L alters intercalated disc protein expression and reduces conduction velocity in arrhythmogenic right ventricular cardiomyopathy.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a myocardial disease characterized by fibro-fatty replacement of myocardium in the right ventricular free wall and frequently results in life-threatening ventricular arrhythmias and sudden cardiac death. A heterozygous missense mutation in the transmembrane protein 43 (TMEM43) gene, p.S358L, has been genetically identified to cause autosomal dominant ARVC type 5 in a founder population from the island of Newfoundland, Canada. Little is known about the function of the TMEM43 protein or how it leads to the pathogenesis of ARVC. We sought to determine the distribution of TMEM43 and the effect of the p.S358L mutation on the expression and distribution of various intercalated (IC) disc proteins as well as functional effects on IC disc gap junction dye transfer and conduction velocity in cell culture. Through Western blot analysis, transmission electron microscopy (TEM), immunofluorescence (IF), and electrophysiological analysis, our results showed that the stable expression of p.S358L mutation in the HL-1 cardiac cell line resulted in decreased Zonula Occludens (ZO-1) expression and the loss of ZO-1 localization to cell-cell junctions. Junctional Plakoglobin (JUP) and α-catenin proteins were redistributed to the cytoplasm with decreased localization to cell-cell junctions. Connexin-43 (Cx43) phosphorylation was altered, and there was reduced gap junction dye transfer and conduction velocity in mutant TMEM43-transfected cells. These observations suggest that expression of the p.S358L mutant of TMEM43 found in ARVC type 5 may affect localization of proteins involved in conduction, alter gap junction function and reduce conduction velocity in cardiac tissue.

Analysis of short-term effects of World Trade Center dust on rat sciatic nerve.

The purpose of this study was to investigate the short-term effects of residual dust from the World Trade Center (WTC) on rat sciatic nerve. Nerve action potentials were recorded in nerves exposed to dust from the WTC as well as control nerves. There was a reduction in the conduction velocity of nerves exposed to a high concentration of the dust from the WTC when compared with controls. Although there are statistically significant reductions in conduction velocity when exposed to the WTC dust in this pilot study, additional studies both clinical and basic will be needed to further understand the significance of these results.

15 * Early pharmacological enhancement of gap junction coupling with rotigaptide reduces arrhythmia vulnerability and modulates structural remodelling in reperfused myocardial infarction

Introduction: Survivors of myocardial infarction (MI) are at increased risk of late ventricular arrhythmias and sudden cardiac death with infarct size and scar heterogeneity as key determinants of arrhythmic risk. Current preventative strategies are limited to few, select antiarrhythmic drugs or an implantable cardioverter-defibrillator. Cardiac gap junctions (GJ) have a key role in allowing the passage of small molecules between cells and may mediate the spread of acute myocardial infarction. We hypothesised that enhancing GJ coupling in the acute phase of MI may beneficially modify the extent and pattern of necrosis and infarction acutely, thus affording a protective effect against late arrhythmogenesis. Methods: A small-animal model of infarction-reperfusion, mimicking clinical reperfusion, was used to study the effects of Rotigaptide on arrhythmogenicity and structural remodelling in a four-week healed model of MI. Male Sprague-Dawley rats (250–300g) underwent infarction-reperfusion surgery with either Rotigaptide (n=15) or Saline (n=15) via minipump. The arrhythmia phenotype was characterised at four-weeks with in-vivo telemetry, 6-lead ECG, ex-vivo arrhythmia provocation studies and dual optical mapping. Structural changes post-MI were studied with diffusion-weighted MRI (DWI) and Masson's Trichrome histology. Results: Rotigaptide resulted in a significant reduction in arrhythmias induced by programmed stimulation (arrhythmia score ROT 3.2 vs. CON 1.4, p<0.05), driven by a reduction in sustained VT (20% vs. 53%, p<0.06). Rotigaptide had no effect on mortality or the incidence of spontaneous arrhythmias or ECG parameters. Remodelling of the optical action potential (AP) was similar between groups a reduction in conduction velocity at the border zone and slowing of the AP upstroke. DWI provided quantifiable measures of structural remodelling in the remote, IBZ and infarct. In control hearts, the infarct demonstrated a significant reduction in fractional anisotropy, and a significant increase in mean diffusivity, compared to remote, partially reversed by Rotigaptide (FA: CON -15% vs. ROT -5%, p<0.05, MD: 6% vs. 2%, p<0.05). The 3D laminar structure of the IBZ was remodelled by Rotigaptide, with a reduction in mean (ROT 16 degrees vs. CON 19 degrees, p<0.05) and dispersion (9 degrees vs. 12 degrees, p<0.05) of the transverse angle. There was no remodelling of helix or transverse angle in remote of either treatment group. Conclusions: Pharmacological GJ enhancement in the early healing phase in reperfused infarction modifies the infarct scar morphology to render myocardium less vulnerable to arrhythmias during programmed stimulation, without affecting the properties of the cardiac action potential or calcium transient. The effects of Rotigaptide were limited to at-risk regions with attenuation of remodelling in the infarct and reduced fibre dispersion in the IBZ offering potential mechanistic explanations for the reduced arrhythmic risk.

Acute nerve stretch and the compound motor action potential

In this paper, the acute changes in the compound motor action potential (CMAP) during mechanical stretch were studied in hamster sciatic nerve and compared to the changes that occur during compression.In response to stretch, the nerve physically broke when a mean force of 331 gm (3.3 N) was applied while the CMAP disappeared at an average stretch force of 73 gm (0.73 N). There were 5 primary measures of the CMAP used to describe the changes during the experiment: the normalized peak to peak amplitude, the normalized area under the curve (AUC), the normalized duration, the normalized velocity and the normalized velocity corrected for the additional path length the impulses travel when the nerve is stretched. Each of these measures was shown to contain information not available in the others.During stretch, the earliest change is a reduction in conduction velocity followed at higher stretch forces by declines in the amplitude of the CMAP. This is associated with the appearance of spontaneous EMG activity. With stretch forces < 40 gm (0.40 N), there is evidence of increased excitability since the corrected velocities increase above baseline values. In addition, there is a remarkable increase in the peak to peak amplitude of the CMAP after recovery from stretch < 40 gm, often to 20% above baseline.Multiple means of predicting when a change in the CMAP suggests a significant stretch are discussed and it is clear that a multifactorial approach using both velocity and amplitude parameters is important. In the case of pure compression, it is only the amplitude of the CMAP that is critical in predicting which changes in the CMAP are associated with significant compression.

Circulation : Clinical Summaries

<i>Circulation</i> : Clinical Summaries

Initiation of Ventricular Fibrillation by a Single Ectopic Beat in Three Dimensional Numerical Models of Ischemic Heart Disease: Abrupt Transition to Chaos

Background: To explore the conditions most dangerous for the emergence of sustained Ventricular Tachycardia or Ventricular Fibrillation (VT/VF) a new computational model of ventricular myocardium including 2592 finite elements in three dimensions was created. Methods: The fully three dimensional model of right and left ventricular muscle was used to simulate the spread of electrical activation and the resulting electrocardiogram. Localized zones of ischemic muscle tissue were characterized by reduced conduction velocity and reduced refractory period, and VT/VF was initiated by single ectopic beats. The simulated body surface Electrocardiogram (ECG) was also computed. Results: In this system clinically realistic VT/VF is readily produced by single stimuli. Reduced conduction velocity and reduced effective refractory period in localized abnormal muscle predispose to VT/VF. Transition to chaos was abrupt. No one specific pattern of re-entry, spiral waves, or vortices could be identified that later decomposed into VT/VF. Instead, there was a wide variety of activation patterns leading to chaos, depending sensitively on initial conditions. Nonetheless, a clear border between stable vs. chaotic behavior was defined by a critical threshold impulse wavelength, the product of conduction velocity and refractory period, γ*, in local ischemic tissue. This threshold, separating stable and chaotic regimes, can be specified precisely as γ*=FV1/3 , where V is the local volume of diseased tissue and 0 γ F γ 1 is a shape factor, near 1 for compact volumes and progressively smaller for flattened volumes. When the impulse wavelength is ≤γ*, VT/VF happens. Typical values for γ* range from 1 to 3 cm. Such behavior is characteristic of classical chaotic systems. Conclusions: The patterns of muscle activation leading to self-sustaining VT/VF observed in three dimensional diseased hearts are much more complex and variable than traditional re-entry in two dimensions. Instead a model of abrupt transition to chaos emerges from the application of first-principles cardiac electrophysiology, realistic ventricular anatomy, and the pathophysiology of ischemic cardiac muscle. This phenomenon may represent a higher order form of mathematical chaos than has been previously studied.

Effect Of Hyperlipidemia On Nerve Conduction Velocity In Type II Diabetes Mellitus

Objectives: The pathogenesis of neuropathy in type II Diabetes Mellitus is multifactorial. Hyperlipidemia may contribute to the development of diabetic neuropathy. This study aimed to assess the correlation between hyperlipidemia and diabetic neuropathy. Material And Method: The study included 60 known cases of Type II diabetes mellitus attending diabetic OPD at GMCH, Aurangabad of age 30-60 years with duration of 5-10 years. The cases were divided into two groups; Group I included diabetic patients with normolipidemia and Group II included diabetic patients with hyperlipidemia. Biochemical investigations included HbA1c, total cholesterol and triglycerides. Nerve conduction velocity was done by computerized Micromed RMSEMG system.Statistical analysis was done by unpaired student’s t test. Results: The study revealed significant reduction in conduction velocity in diabetic patients with hyperlipidemia.

Ranolazine Reduces Arrhythmogenic Calcium Waves in Ventricular Cardiomyocytes

We have previously shown that reducing Na+ influx by a reduction in peak Na+ current (INa,peak) in isolated cardiac myocytes leads to a decrease in pro-arrhythmic Ca2+ waves. However, INa,peak inhibition can result in reduced conduction velocity and promote wavebreak leading to enhanced arrhythmia in vivo. Here we test if ranolazine, an inhibitor of late Na+ current (INa,late) could also reduce the occurrence of Ca2+ waves without potentially problematic reductions in INa,peak. Cells, loaded with fluo-4AM to monitor intracellular Ca2+, were stimulated at different pacing rates followed by a one-minute rest period for wave detection.10μM ranolazine reduced Ca2+ wave frequency in cells following pacing at 5Hz although less potently than 5μM flecainide (0.13±0.02 waves.s−1 (flecainide) vs 0.16±0.02 waves.s−1 (ranolazine), P<0.01). Comparable effects were achieved when the concentration of ranolazine was increased to 20μM (0.14±0.02 waves.s−1 (flecainide) and 0.18±0.03 waves.s−1 (ranolazine) vs 0.22±0.03 waves.s−1 (control), P<0.001 and 0.05 respectively) although at this concentration there is a significant reduction in INa,peak. Ranolazine's ability to reduce wave occurrence was tested further under two conditions in which enhancement of INa,late, would be expected; in the presence of anemone toxin II and in cells from an established model of chronic heart failure (HF). In both conditions wave frequency was increased (e.g. 0.08±0.01 waves.s−1 (HF) vs 0.06±0.01 waves.s−1 (control), P<0.05) but ranolazine was not effective at reducing frequency (0.19±0.04 waves.s−1 (ranolazine 10μM) vs 0.19±0.04 waves.s−1 (control), P=0.92).Ranolazine decreased Ca2+ wave frequency in isolated cardiomyocytes, particularly at concentrations where INa,peak is reduced. The lack of efficacy in states of enhanced INa,late suggests specific effects of the drug are less important than off-target effects on INa,peak. Thus similar dose-limiting side effects as with conventional INa blockers are expected.

Letter to the Editor Complex-I defect with minimal manifestations

Letter to the Editor Complex-I defect with minimal manifestations

Uncoupling the mitochondria facilitates alternans formation in the isolated rabbit heart

Alternans of action potential duration (APD) and intracellular calcium ([Ca²⁺]i) transients in the whole heart are thought to be markers of increased propensity to ventricular fibrillation during ischemia-reperfusion injuries. During ischemia, ATP production is affected and the mitochondria become uncoupled, which may affect alternans formation in the heart. The aim of our study was to investigate the role of mitochondria on the formation of APD and [Ca²⁺]i alternans in the isolated rabbit heart. We performed dual voltage and [Ca²⁺]i optical mapping of isolated rabbit hearts under control conditions, global no-flow ischemia (n = 6), and after treatment with 50 nM of the mitochondrial uncoupler FCCP (n = 6). We investigated the formation of alternans of APD, [Ca²⁺]i amplitude (CaA), and [Ca²⁺]i duration (CaD) under different rates of pacing. We found that treatment with FCCP leads to the early occurrence of APD, CaD, and CaA alternans; an increase of intraventricular APD but not CaD heterogeneity; and significant reduction in conduction velocity compared with that of control. Furthermore, we demonstrated that FCCP and global ischemia have similar effects on the prolongation of [Ca²⁺]i transients, whereas ischemia induces a significantly larger reduction of APD compared with that in FCCP treatment. In conclusion, our results demonstrate that uncoupling of mitochondria leads to an earlier occurrence of alternans in the heart. Thus, in conditions of mitochondrial stress, as seen during myocardial ischemia, uncoupled mitochondria may be responsible for the formation of both APD and [Ca²⁺]i alternans in the heart, which in turn creates a substrate for ventricular arrhythmias.

Mesenchymal Stem Cell Transplantation Mitigates Electrophysiological Remodeling in a Rat Model of Myocardial Infarction

Transplantation of mesenchymal stem cells (MSCs) has shown therapeutic potential for cardiovascular diseases, but the electrophysiological implications are not understood. The purpose of this study was to evaluate the impact of MSC transplantation on adverse electrophysiological remodeling in the heart following myocardial infarction (MI). Three weeks after coronary ligation to induce MI in rats, MSCs or culture medium were directly injected into each infarct. One to two weeks later, hearts were excised, Langendorff-perfused, and optically mapped using the potentiometric fluorescent dye Di-4-ANEPPS. Quantitative real-time PCR was also performed to assess gene expression. Optical mapping showed that post-MI reduction in conduction velocity (from 0.70 ± 0.04 m/s in 12 normal controls to 0.47 ± 0.02 m/s in 11 infarcted hearts, P < 0.05) was attenuated with MSC transplantation (0.65 ± 0.04 m/s, n = 18, P < 0.05). Electrophysiological changes correlated with higher vascular density and better-preserved ventricular geometry in MSC-transplanted hearts. A number of ion channel genes showed changes in RNA expression following infarction. In particular, the expression of Kir2.1, which mediates the inward rectifier potassium current, I(K1), was reduced in infarcted tissues (n = 7) to 13.8 ± 3.7% of normal controls, and this post-MI reduction was attenuated with MSC transplantation (44.4 ± 11.2%, n = 7, P < 0.05). In addition to promoting angiogenesis and limiting adverse structural remodeling in infarcted hearts, MSC transplantation also alters ion channel expression and mitigates electrophysiological remodeling. Further understanding of the electrophysiological impact of MSC transplantation to the heart may lead to the development of cell-based therapies for post-MI arrhythmias.

Functional interaction between charged nanoparticles and cardiac tissue: a new paradigm for cardiac arrhythmia?

To investigate the effect of surface charge of therapeutic nanoparticles on sarcolemmal ionic homeostasis and the initiation of arrhythmias. Cultured neonatal rat myocytes were exposed to 50 nm-charged polystyrene latex nanoparticles and examined using a combination of hopping probe scanning ion conductance microscopy, optical recording of action potential characteristics and patch clamp. Positively charged, amine-modified polystyrene latex nanoparticles showed cytotoxic effects and induced large-scale damage to cardiomyocyte membranes leading to calcium alternans and cell death. By contrast, negatively charged, carboxyl-modified polystyrene latex nanoparticles (NegNPs) were not overtly cytotoxic but triggered formation of 50-250-nm nanopores in the membrane. Cells exposed to NegNPs revealed pro-arrhythmic events, such as delayed afterdepolarizations, reduction in conduction velocity and pathological increment of action potential duration together with an increase in ionic current throughout the membrane, carried by the nanopores. The utilization of charged nanoparticles is a novel concept for targeting cardiac excitability. However, this unique nanoscopic investigation reveals an altered electrophysiological substrate, which sensitized the heart cells towards arrhythmias.

Effect of Electrical Field Stimulation on Dorsal Root Ganglion Neuronal Function

Neural stimulation may provide analgesia for a variety of painful conditions. Activation of primary sensory neurons, which underlies pain relief by spinal cord stimulation, also may be achieved by stimulation at the level of the dorsal root ganglion (DRG). The DRG also is a site of pain pathogenesis, particularly in neuropathic pain. We therefore examined the hypothesis that field stimulation of the DRG directly suppresses excitability of sensory neurons. Intercellular Ca2+ level (Fura-2 microfluorimetry) and membrane potential were recorded in excised rat DRGs with ganglionic field stimulation (GFS) delivered by wire electrodes in the bath solution adjacent to the DRG. Neuronal excitability was evaluated by number of action potentials (APs) generated during neuronal depolarization, conduction velocity during axonal stimulation, and AP propagation failure. These were measured before and after 90 sec of GFS at 60 Hz. Data analysis employed chi-square, paired t-test, and analysis of variance. GFS using 400-μsec pulses and 30 V generated Ca2+ influx, indicative of DRG neuronal activation. Fewer neurons were able to fire one or more APs after GFS (N = 23) than in control neurons without GFS (N = 24, p < 0.05), and fewer neurons were able to generate multiple APs after GFS compared with time controls (p < 0.05). GFS significantly reduced conduction velocity compared with baseline before GFS (N = 16, p < 0.05) while there was no change in the controls (N = 18). The peak rate at which APs could be propagated was reduced in 9 of 16 neurons by GFS, but propagation efficiency was reduced in only 4 of 18 control neurons (p < 0.05), and the total number of APs generated in an ensemble of stimuli at different frequencies was reduced by GFS (N = 16, p < 0.05) but not in time controls (N = 18). Our findings indicate that direct excitation of the DRG by electrical fields reduces neuronal excitability and may provide a new analgesic approach.

Atrial arrhythmogenesis in catecholaminergic polymorphic ventricular tachycardia – is there a mechanistic link between sarcoplasmic reticulum Ca2+ leak and re‐entry?

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is caused by mutations in the genes encoding the cardiac ryanodine receptor channel (RyR2) or the major sarcoplasmic reticulum (SR) Ca2+ buffer calsequestrin-2 (Casq2) (Leenhardt et al., 2012). Traditionally, CPVT has been described as a bi-directional or polymorphic ventricular arrhythmia occurring during conditions of increased sympathetic tone, which may originate from ectopic activity due to abnormal (sub)cellular Ca2+ handling (Leenhardt et al., 2012). Recent studies, however, have suggested that CPVT mutations in RyR2 are also associated with atrial arrhythmias. In this edition of Acta Physiologica, King et al. (King et al., 2012) show for the first time that atria from mice homozygous for the CPVT-associated mutation P2328S in RyR2 (RyR2S/S) have a reduced conduction velocity (CV) and lower maximum rates of action potential (AP) upstroke velocity compared to wild-type (WT) mice. Moreover, these parameters correlated strongly with arrhythmia susceptibility suggesting a potential novel arrhythmogenic mechanism due to RyR2 mutations.

Abnormal Ca(2+) homeostasis, atrial arrhythmogenesis, and sinus node dysfunction in murine hearts modeling RyR2 modification.

Ryanodine receptor type 2 (RyR2) mutations are implicated in catecholaminergic polymorphic ventricular tachycardia (CPVT) thought to result from altered myocyte Ca2+ homeostasis reflecting inappropriate “leakiness” of RyR2-Ca2+ release channels arising from increases in their basal activity, alterations in their phosphorylation, or defective interactions with other molecules or ions. The latter include calstabin, calsequestrin-2, Mg2+, and extraluminal or intraluminal Ca2+. Recent clinical studies additionally associate RyR2 abnormalities with atrial arrhythmias including atrial tachycardia (AT), fibrillation (AF), and standstill, and sinus node dysfunction (SND). Some RyR2 mutations associated with CPVT in mouse models also show such arrhythmias that similarly correlate with altered Ca2+ homeostasis. Some examples show evidence for increased Ca2+/calmodulin-dependent protein kinase II (CaMKII) phosphorylation of RyR2. A homozygotic RyR2-P2328S variant demonstrates potential arrhythmic substrate resulting from reduced conduction velocity (CV) in addition to delayed afterdepolarizations (DADs) and ectopic action potential (AP) firing. Finally, one model with an increased RyR2 activity in the sino-atrial node (SAN) shows decreased automaticity in the presence of Ca2+-dependent decreases in ICa, L and diastolic sarcoplasmic reticular (SR) Ca2+ depletion.

Chlorpyrifos toxicity causing delayed myeloneuropathy

Dear Sir, Chlorpyrifos is an organophosphate insecticide which can cause delayed neurological toxicity following a high dose exposure. Delayed neuropathy has been often reported; but here we report delayed myeloneuropathy, following chlorpyrifos poisoning. A 25-year-old man who had consumed about 50 mL of pesticide preparation containing chlorpyrifos 50% was treated with stomach wash, injection atropine, injection pralidoxime, and other supportive medical care. His pseudocholinesterase level was below 1000 U/L (normal being 4650–10440 U/L). By day 7, he started having breathing difficulty and required mechanical ventilation for 2 weeks. By about 6 weeks after poisoning, he started requiring support to stand and to walk and also had urinary urgency and urge incontinence. At 6 month postexposure, he still required support to walk. He improved very gradually in ability to walk. At 5 years postexposure, he was able to walk independently. He was found to have significant spasticity in the lower limbs with brisk deep tendon reflexes. The plantar reflexes showed extensor response bilaterally. There was no sensory loss of any of the modalities. He had weakness of foot dorsiflexion bilaterally which was 4/5 on medical research council grading. The small muscles of the foot were wasted with hammer toes and pes cavus bilaterally. The combination of foot drop, scissoring, and ankle clonus gave his gait a peculiar bobbing character. The upper limbs were essentially normal on neurological examination. He still had mild bladder symptoms in the form of urgency. His higher mental functions and cranial nerves were normal. He had no history or findings suggestive of autoimmune disorder. His systemic examination revealed no abnormality. The hemoglobin, complete blood counts, blood sugar, renal function test, liver function tests, and electrolytes were within normal limits. The serum human immunodeficiency virus and VDRL (Venereal disease research laboratory) testing were negative. The serum B12 levels were normal. The magnetic resonance imaging of the whole spine was within normal limits. Nerve conduction study revealed reduced compound muscle action potential amplitudes and reduced conduction velocities in bilateral tibial and peroneal nerves. Upper limb motor nerve conduction study did not reveal any abnormality. The sensory nerve conduction studies were normal. He was managed with physiotherapy and supportive care. Very few cases like this one have been described in literature following chlorpyrifos exposure.[12] The earlier hypothesis of inhibition of neurotoxicity target esterase as a causative factor is being replaced by implication of aberrant phosphorylation of cytoskeletal proteins leading to axonal instability and degeneration.[3] The combination of upper and lower motor neuron features in our patient bears superficial resemblance to the motor neuron disease. The possible link may be paraoxonase enzyme which is required for chlorpyrifos oxon hydrolysis and its mutation has been linked to the motor neuron disease.[4] Precise reporting of such neurotoxicities in human may help us in gaining more insight into the mechanism of these toxicities and possibly enhance our understanding of related neurodegenerative diseases.

Sudden arrhythmic death: from basic science to clinical practice

EDITORIAL article Front. Physiol., 25 November 2013Sec. Cardiac Electrophysiology Volume 4 - 2013 | https://doi.org/10.3389/fphys.2013.00339

Nerve damage in leprosy: An electrophysiological evaluation of ulnar and median nerves in patients with clinical neural deficits: A pilot study

Background:Leprosy involves peripheral nerves sooner or later in the course of the disease leading to gross deformities and disabilities. Sadly, by the time it becomes clinically apparent, the nerve damage is already quite advanced. However, if the preclinical damage is detected early in the course of disease, it can be prevented to a large extent.Materials and Methods:We conducted an electrophysiological pilot study on 10 patients with clinically manifest leprosy, in the Dermatology Department of Mahatma Gandhi Institute of Medical Sciences, Sewagram. This study was done to assess the nerve conduction velocity, amplitude and latency of ulnar and median nerves.Results and Conclusion:We found reduced conduction velocities besides changes in latency and amplitude in the affected nerves. Changes in sensory nerve conduction were more pronounced. Also, sensory latencies and amplitude changes were more severe than motor latencies and amplitude in those presenting with muscle palsies. However, further studies are going on to identify parameters to detect early nerve damage in leprosy.

Mitochondrial dysfunction causing cardiac sodium channel downregulation in cardiomyopathy

Cardiomyopathy is associated with cardiac Na+ channel downregulation that may contribute to arrhythmias. Previously, we have shown that elevated intracellular NADH causes a decrease in cardiac Na+ current (INa) signaled by an increase in mitochondrial reactive oxygen species (ROS). In this study, we tested whether the NADH–mitochondria ROS pathway was involved in the reduction of INa in a nonischemic cardiomyopathic model and correlated the findings with myopathic human hearts. Nonischemic cardiomyopathy was induced in C57BL/6 mice by hypertension after unilateral nephrectomy, deoxycorticosterone acetate (DOCA) pellet implantation, and salt water substitution. Sham operated mice were used as controls. After six weeks, heart tissue and ventricular myocytes isolated from mice were utilized for whole cell patch clamp recording, NADH/NAD+ level measurements, and mitochondrial ROS monitoring with confocal microscopy. Human explanted hearts were studied using optical mapping. Compared to the sham mice, the arterial blood pressure was higher, the left ventricular volume was significantly enlarged (104.7±3.9 vs. 87.9±6.1μL, P<0.05), and the ejection fraction was reduced (37.1±1.8% vs. 49.4±3.7%, P<0.05) in DOCA mice. Both the whole cell and cytosolic NADH level were increased (279±70% and 123±2% of sham, respectively, P<0.01), INa was decreased (60±10% of sham, P<0.01), and mitochondrial ROS overproduction was observed (2.9±0.3-fold of sham, P<0.01) in heart tissue and myocytes of myopathic mice vs. sham. Treatment of myocytes with NAD+ (500μM), mitoTEMPO (10μM), chelerythrine (50μM), or forskolin (5μM) restored INa back to the level of sham. Injection of NAD+ (100mg/kg) or mitoTEMPO (0.7mg/kg) twice (at 24h and 1h before myocyte isolation) to animals also restored INa. All treatments simultaneously reduced mitochondrial ROS levels to that of controls. CD38 was found to transduce the extracellular NAD+ signal. Correlating with the mouse model, failing human hearts showed a reduction in conduction velocity that improved with NAD+. Nonischemic cardiomyopathy was associated with elevated NADH level, PKC activation, mitochondrial ROS overproduction, and a concomitant decrease in INa. Reducing mitochondrial ROS by application of NAD+, mitoTEMPO, PKC inhibitors, or PKA activators, restored INa. NAD+ improved conduction velocity in human myopathic hearts.