Electrical Dysfunction Research Articles

Cardiac arrhythmias induced by glutathione oxidation can be inhibited by preventing mitochondrial depolarization

We have previously proposed that the heterogeneous collapse of mitochondrial inner membrane potential (ΔΨm) during ischemia and reperfusion contributes to arrhythmogenesis through the formation of metabolic sinks in the myocardium, wherein clusters of myocytes with uncoupled mitochondria and high KATP current levels alter electrical propagation to promote reentry. Single myocyte studies have also shown that cell-wide ΔΨm depolarization, through a reactive oxygen species (ROS)-induced ROS release mechanism, can be triggered by global depletion of the antioxidant pool with diamide, a glutathione oxidant. Here we examine whether diamide causes mitochondrial depolarization and promotes arrhythmias in normoxic isolated perfused guinea pig hearts. We also investigate whether stabilization of ΔΨm with a ligand of the mitochondrial benzodiazepine receptor (4′-chlorodiazepam; 4-ClDzp) prevents the formation of metabolic sinks and, consequently, precludes arrhythmias. Oxidation of the GSH pool was initiated by treatment with 200 μM diamide for 35 min, followed by washout. This treatment increased GSSG and decreased both total GSH and the GSH/GSSG ratio. All hearts receiving diamide transitioned from sinus rhythm into ventricular tachycardia and/or ventricular fibrillation during the diamide exposure: arrhythmia scores were 5.5±0.5; n=6 hearts. These arrhythmias and impaired LV function were significantly inhibited by co-administration of 4-ClDzp (64 μM): arrhythmia scores with diamide+4-ClDzp were 0.4±0.2 (n=5; P<0.05 vs. diamide alone). Imaging ΔΨm in intact hearts revealed the heterogeneous collapse of ΔΨm beginning 20 min into diamide, paralleling the timeframe for the onset of arrhythmias. Loss of ΔΨm was prevented by 4-ClDzp treatment, as was the increase in myocardial GSSG. These findings show that oxidative stress induced by oxidation of GSH with diamide can cause electromechanical dysfunction under normoxic conditions. Analogous to ischemia–reperfusion injury, the dysfunction depends on the mitochondrial energy state. Targeting the mitochondrial benzodiazepine receptor can prevent electrical and mechanical dysfunction in both models of oxidative stress.

Modeling Cardiac Action Potential Shortening Driven by Oxidative Stress-Induced Mitochondrial Oscillations in Guinea Pig Cardiomyocytes

Ischemia-induced shortening of the cardiac action potential and its heterogeneous recovery upon reperfusion are thought to set the stage for reentrant arrhythmias and sudden cardiac death. We have recently reported that the collapse of mitochondrial membrane potential (ΔΨ m) through a mechanism triggered by reactive oxygen species (ROS), coupled to the opening of sarcolemmal ATP-sensitive potassium (K ATP) channels, contributes to electrical dysfunction during ischemia-reperfusion. Here we present a computational model of excitation-contraction coupling linked to mitochondrial bioenergetics that incorporates mitochondrial ROS-induced ROS release with coupling between the mitochondrial energy state and electrical excitability mediated by the sarcolemmal K ATP current ( I K,ATP). Whole-cell model simulations demonstrate that increasing the fraction of oxygen diverted from the respiratory chain to ROS production triggers limit-cycle oscillations of ΔΨ m, redox potential, and mitochondrial respiration through the activation of a ROS-sensitive inner membrane anion channel. The periods of transient mitochondrial uncoupling decrease the cytosolic ATP/ADP ratio and activate I K,ATP, consequently shortening the cellular action potential duration and ultimately suppressing electrical excitability. The model simulates emergent behavior observed in cardiomyocytes subjected to metabolic stress and provides a new tool for examining how alterations in mitochondrial oxidative phosphorylation will impact the electrophysiological, contractile, and Ca 2+ handling properties of the cardiac cell. Moreover, the model is an important step toward building multiscale models that will permit investigation of the role of spatiotemporal heterogeneity of mitochondrial metabolism in the mechanisms of arrhythmogenesis and contractile dysfunction in cardiac muscle.

Physiology, Injury, and Recovery of Interstitial Cells of Cajal: Basic and Clinical Science

In the last 15 years, our understanding of the cellular basis of gastrointestinal function has been altered irreversibly by the discovery that normal gastrointestinal (GI) motility requires interstitial cells of Cajal (ICC). Research in this relatively short time period has modified our original concept that the core unit that controls motility is made up of nerves and smooth muscle, to one that now includes ICC. This concept has now expanded to beyond the GI tract, suggesting that it may be a fundamental property of the regulation of smooth muscle function that requires rhythmic contraction. ICC are distributed throughout the GI tract, have important functions in the control of GI motility, and are often abnormal in diseased states. Recently, significant steps forward have been made in our understanding of the physiology of ICC as well as mechanisms of injury and recovery. These advances are the focus of this review. The Physiology of ICC Unique motor patterns are intrinsic to every organ of the GI tract, which suit their functions related to mixing, absorption, and anally directed movement. The ICC are an integral part of the control of these motor activities. The distribution of ICC throughout the musculature is associated with nerve structures. Myenteric pacemaker ICC surround the myenteric or Auerbach’s plexus and intramuscular ICC are associated with nerve varicosities throughout the muscle layers (Figures 1 and 2). Other subpopulations of ICC are associated with nonganglionated plexuses of nerve varicosities at the inner borders of the circular muscle layers in the intestine and colon (Figures 1 and 2). The best understood function is that of pacemaker activity in the stomach and small intestine where the ICC generate a periodic depolarization at a characteristic frequency in each of these organs that is called the slow wave or pacemaker activity.

Lethal Effect of Electric Fields on Isolated Ventricular Myocytes

Defibrillator-type shocks may cause electric and contractile dysfunction. In this study, we determined the relationship between probability of lethal injury and electric field intensity (E in isolated rat ventricular myocytes, with emphasis on field orientation and stimulus waveform. This relationship was sigmoidal with irreversible injury for E > 50 V/cm . During both threshold and lethal stimulation, cells were twofold more sensitive to the field when it was applied longitudinally (versus transversally) to the cell major axis. For a given E, the estimated maximum variation of transmembrane potential (Delta V(max)) was greater for longitudinal stimuli, which might account for the greater sensitivity to the field. Cell death, however, occurred at lower maximum Delta V(max) values for transversal shocks. This might be explained by a less steep spatial decay of transmembrane potential predicted for transversal stimulation, which would possibly result in occurrence of electroporation in a larger membrane area. For the same stimulus duration, cells were less sensitive to field-induced injury when shocks were biphasic (versus monophasic). Ours results indicate that, although significant myocyte death may occur in the E range expected during clinical defibrillation, biphasic shocks are less likely to produce irreversible cell injury.

Impaired Ca2+ homeostasis is associated with atrial fibrillation in the α1D L-type Ca2+ channel KO mouse

The novel alpha1D Ca2+ channel together with alpha1C Ca2+ channel contribute to the L-type Ca2+ current (I(Ca-L)) in the mouse supraventricular tissue. However, its functional role in the heart is just emerging. We used the alpha1D gene knockout (KO) mouse to investigate the electrophysiological features, the relative contribution of the alpha1D Ca2+ channel to the global I(Ca-L), the intracellular Ca2+ transient, the Ca2+ handling by the sarcoplasmic reticulum (SR), and the inducibility of atrial fibrillation (AF). In vivo and ex vivo ECG recordings from alpha1D KO mice demonstrated significant sinus bradycardia, atrioventricular block, and vulnerability to AF. The wild-type mice showed no ECG abnormalities and no AF. Patch-clamp recordings from isolated alpha1D KO atrial myocytes revealed a significant reduction of I(Ca-L) (24.5%; P < 0.05). However, there were no changes in other currents such as I(Na), I(Ca-T), I(K), I(f), and I(to) and no changes in alpha1C mRNA levels of alpha1D KO atria. Fura 2-loaded atrial myocytes showed reduced intracellular Ca2+ transient (approximately 40%; P < 0.05) and rapid caffeine application caused a 17% reduction of the SR Ca2+ content (P < 0.05) and a 28% reduction (P < 0.05) of fractional SR Ca2+ release in alpha1D KO atria. In conclusion, genetic deletion of alpha1D Ca2+ channel in mice results in atrial electrocardiographic abnormalities and AF vulnerability. The electrical abnormalities in the alpha1D KO mice were associated with a decrease in the total I(Ca-L) density, a reduction in intracellular Ca2+ transient, and impaired intracellular Ca2+ handling. These findings provide new insights into the mechanism leading to atrial electrical dysfunction in the alpha1D KO mice.

Rescue peri-operative management of the patient with giant electrical storm and severe left ventricular dysfunction: support by levosimendan and intraaortic balloon counterpulsation☆

We present a case of a 62-year-old male patient (coronary heart disease, and stenosis of aortic valve) with severe left ventricular dysfunction (left ventricular ejection fraction 20%, left ventricular end-diastolic diameter 80 mm, end-diastolic volume 329 ml) who developed giant electrical storm (on the whole 115 episodes of pulseless ventricular tachycardia treated by antiarrhythmics and electrical discharges) with low-elevation of cardiac biomarkers. The patient was referred to emergent cardiac surgery (double coronary bypass grafting, aortic valve replacement, and implantation of left ventricular epicardial electrode). Levosimendan and intraaortic balloon counterpulsation were used for successful weaning from the cardiopulmonary bypass; no other arrhythmia appeared in the post-bypass period. Postoperatively no arrhythmic events were detected, and repeated echocardiographic examinations of the patient in good general condition showed gradual improvement of left ventricular ejection fraction (30-35%), likewise in other parameters (left ventricular end-diastolic diameter 72 mm, end-diastolic volume 285 ml).

Low-Intensity Laser Irradiation Improves the Mitochondrial Dysfunction of C2C12 Induced by Electrical Stimulation

We investigated the effects of electrical stimulation and low-intensity laser (LIL) energy on the mitochondrial function of cultured C2C12 myotubes in order to find a dosage that could be used to improve the function of mitochondria, and then rehabilitate exercise-induced damage and fatigue. Many other studies in the past demonstrated that LIL had a cytoprotective effect, and a recent study also found that LIL could reduce muscular fatigue during tetanic contractions in rats. Cultured C2C12 myotubes were subjected to electrical stimulation or/and LIL irradiation at various intensities. Reactive oxygen species (ROS) were detected with a fluorescent probe (DCFH-DA) and mitochondrial function was assessed with an MTT assay. The results showed that electrical stimulation at 20 ms, 5 Hz, and 45 V for 75 min can induce mitochondrial dysfunction in cultured C2C12 myotubes. Electrical stimulation-induced mitochondrial dysfunction was improved, but degeneration occurred with LIL at doses of 0.33-8.22 and 11.22-14.16 J/cm2, respectively, and these changes were markedly increased with LIL at 0.33 and 1.34 J/cm2, respectively. We conclude that treatment of myotubes with the proper dosage of LIL irradiation significantly diminished production of ROS and restored mitochondrial function, and this may provide a foundation for the use of photobiomodulation to treat exercise-induced mitochondrial dysfunction or skeletal muscular fatigue.

Dilated Cardiomyopathy due to Sodium Channel Dysfunction

The cardiac sodium channel mediates the rapid upstroke of the cardiac action potential and thereby constitutes a critical determinant of cardiac excitability and conduction. Mutations in the SCN5A gene encoding the α-subunit of this channel have been linked to a broad clinical spectrum of arrhythmia disorders, including long QT syndrome, Brugada syndrome, sick sinus syndrome, conduction disease, and most recently, atrial fibrillation.1,2 These primary arrhythmia syndromes were originally considered pure electrical entities occurring in the absence of structural heart disease, and the presence of myocardial abnormalities in these disorders was originally actually excluded by definition. Evidence is now accumulating, however, that sodium channelopathy can also be associated with the development of cardiac fibrosis, dilatation, and hypertrophy.3–8 Such structural changes within the myocardium may in turn further predispose to the development of ventricular arrhythmias. These findings have led to reevaluation of the initial view that mutations in a cardiac ion channel would only lead to pure electrical dysfunction and raised the intriguing possibility that the structural alterations could be a direct consequence of sodium channel dysfunction rather than a consequence of long-standing arrhythmia. The mechanism by which a dysfunctional sodium channel leads to structural changes in myocardial tissue, however, remains unclear. Article p 83 In this issue of Circulation: Arrhythmia and Electrophysiology , Ge et al8 report on a novel SCN5A mutation (A1180V) linked to dilated cardiomyopathy (DCM), expanding the repertoire of SCN5A mutations associated with DCM. Previously, the D1275N mutation was discovered independently by McNair et al5 and Olson et al6 in the same large family with the syndrome of DCM, atrial arrhythmias, sinus node dysfunction, and conduction disease. This family had been originally described by Greenlee et al9 in 1986. The D1275N mutation has also been associated with mild ventricular structural alterations in …

Risk Stratification for Recurrent Heart Failure in Patients Post-Myocardial Infarction With Electrocardiographic and Echocardiographic Left Atrial Abnormality

Left atrial enlargement is predictive of cardiovascular events. The predictive power, however, of the combination of electrocardiographic (LAE-ECG) and echocardiographic left atrial enlargement (LAE-Echo) has not been extensively evaluated. We prospectively identified patients admitted with non-ST-segment elevation myocardial infarction (NSTEMI) who developed new-onset heart failure during admission. Baseline electrocardiograms obtained < or =12 months before admission were evaluated for LAE-ECG, such as prolonged P-wave duration or positive P-wave terminal force in lead V1, and in-hospital echocardiographic reports obtained < or =1 month after admission were assessed for linear, anteroposterior LAE-Echo. Follow-up was directed toward pertinent cardiovascular events and death. Of the 462 patients with NSTEMI, 108 developed new-onset heart failure (23%); 71 patients had LAE-Echo. Follow-up was 23.2 months (mean 22.1 months). Although in-hospital (early) cardiovascular complications (other than heart failure) were not significantly higher in patients with LAE-Echo, these patients demonstrated more postdischarge (late) cardiovascular complications, predominantly recurrent heart failure. In addition, those with a combination of LAE-Echo and LAE-ECG demonstrated significantly higher recurrence of heart failure (hazard ratio 1.52, 95% confidence interval 1.12 to 4.35; p = 0.02 for interatrial conduction delay, and hazard ratio 1.07, 95% confidence interval 1.01 to 3.27 for P-wave terminal force in lead V1; p = 0.03) and increased mortality compared with those with LAE-Echo alone. In conclusion, our data suggest that a combination of electrical and mechanical left atrial dysfunction is significantly more predictive of increased cardiovascular events and mortality compared with left atrial mechanical dysfunction alone.

Inhibition of late sodium current to reduce electrical and mechanical dysfunction of ischaemic myocardium

This commentary on the review by DA Saint in the current issue of the British Journal of Pharmacology focuses on the pathological role of late I(Na) in the heart, the evidence supporting inhibition of late I(Na) as a therapeutic target in ischaemic heart disease, and the therapeutic applications and challenges for development of new late I(Na) inhibitors. Recent reports from a large clinical outcome trial (MERLIN) of ranolazine, a drug known to inhibit late I(Na), indicated that it was safe and reduced recurrent ischaemia and arrhythmic activity. In combination with other results indicating that inhibition of late I(Na) reduces ischaemia, myocardial Ca(2+) overload, and electrical and mechanical dysfunction when late I(Na) is increased, the new clinical trial results suggest that reduction of cardiac late I(Na) is safe and therapeutically beneficial.

A ligand to the mitochondrial benzodiazepine receptor prevents ventricular arrhythmias and LV dysfunction after ischemia or glutathione depletion

We examined how instability of mitochondrial membrane potential (ΔΨm) contributed to arrhythmogenesis and left ventricular dysfunction in intact hearts subjected to metabolic challenge. In isolated myocytes, oxidative stress was previously shown to elicit oscillations in ΔΨm which were stabilized by 4′‐chlorodiazepam (4‐ClDzp), a ligand to the mitochondrial benzodiazepine receptor. Guinea pig hearts were stressed either with global ischemia/reperfusion (I/R) or normoxic perfusion with diamide (to deplete the reduced glutathione pool). In both groups, overwhelming the anti‐oxidant defenses led to severe electrical and contractile dysfunction. Hearts exposed to I/R had high propensity for arrhythmias (score of 6.0 ± 0.7) and contractile dysfunction (LV developed pressure (LVDP) and LV minimum pressure at end of I/R: 10 ± 3 mmHg and 58 ± 1 mmHg, respectively). Stabilizing ΔΨm with 4‐ClDzp reduced arrhythmias (score 1.25 ± 0.25; P &lt; 0.01) and contractile dysfunction (LVDP and LVP min were 23 ± 1 and 18 ± 3 mmHg at the end of I/R, respectively; P &lt; 0.01). Similarly, diamide induced arrhythmias (score of 6.0 ± 1.1) that were prevented by co‐treatment with 4‐ClDzp (score of 1.0 ± 0.6; P &lt; 0.01). LVDP also recovered significantly in diamide‐treated hearts plus 4‐Cldzp. These data provide further evidence that stabilizing ΔΨm in the face of oxidative stress has significant clinical implications for myocardial I/R injury.

Trimetazidine Protective Effect Against Ischemia-Induced Susceptibility to Ventricular Fibrillation in Pigs

Ventricular fibrillation (VF) is a possible consequence of brief myocardial ischemia. Such a short ischemia does not provoke cell damage, but induces changes in intracellular cardiac metabolism due to diminished oxygen supply to the heart. Trimetazidine (TMZ) is a drug able to restore the metabolic balance between fatty acid and glucose oxidation in ischemic myocardial cells. The aim of this double-blind study was to investigate TMZ effect on VF in pigs during short-term ischemia. Ischemia was induced after thoracotomy by complete, but brief (1 min) occlusion of the left anterior descending coronary artery under electrical stimulation. The ventricular fibrillation threshold (VFT), heart rate (HR), various hemodynamic parameters and malondialdehyde (MDA) blood levels were measured before and during ischemia in two groups of eight anesthetized pigs. The mass of ischemic myocardial tissue was also evaluated. No effects on either the HR or the hemodynamic parameters were observed during myocardial ischemia, whereas TMZ increased the VFT and decreased both MDA blood levels (an index of lipid peroxidation) and the ischemic area. TMZ limited ischemia-induced electrical dysfunction leading to cardiac susceptibility to VF by decreasing lipid peroxidation and maintaining ionic homeostasis. TMZ could therefore provide protection against ischemia-induced VF.

Regulation of ion channels and arrhythmias in the ischemic heart

Ventricular arrhythmias in the setting of ischemic heart disease is a leading cause of mortality in the United States. A better understanding of the complex changes associated with ischemic injury is likely to improve our ability to design better treatment strategies for patients who have coronary events. A major difficulty in treating those patients arises from the complexity of the electrophysiological changes that occur with varying time courses during the ischemic episode and the reperfusion phase. Here, we discuss some of the key cellular and network electrophysiological changes that are associated with ischemic injury and highlight the link between alterations in the energetic/metabolic substrate of the heart and electrical dysfunction.

Abstract 798: Ca 2+ Sparks are Modulated by the Mitochondrial Energy State

Mitochondria produce reactive oxygen species (ROS) but are also a target of oxidative stress that can induce rapid oscillations of mitochondrial inner membrane potential (ΔΨ m ). The proximity of mitochondria to SR Ca 2+ release sites suggests that the mitochondrial energy state will determine the local redox and energetic status of the Ca 2+ handling subsystem. Because ryanodine receptors, SERCA, and L-type Ca 2+ channels are all sensitive to ATP, Mg 2+ and thiol oxidation, we investigated whether laser flash-triggered mitochondrial ΔΨ m oscillations influence resting Ca 2+ spark frequency in fluo-4 + TMRE-loaded cardiomyocytes using two-photon microscopy to monitorΔΨ m , cytosolic [Ca 2+ ], and [NADH]. The correlation between resting Ca 2+ spark frequency and ΔΨ m was analyzed over several cycles of ΔΨ m oscillation in each cell. Notably, Ca 2+ spark frequency increased with ΔΨ m depolarization and decreased withΔΨ m repolarization, indicative of close coupling between energetics and Ca 2+ cycling (See Figure ). Moreover, spontaneous Ca 2+ waves were often observed when mitochondria were depolarized but not whenΔΨ m recovered. There were no significant effects on Ca 2+ spark durations or rise times. In conclusion, the results show that stress-induced mitochondrial depolarization (involving NADH oxidation, ROS release, and depletion of glutathione) leads to increased Ca 2+ spark frequency, most likely as a result of modification of the local redox status near the dyad. These findings provide important insights into the connection between metabolism and Ca 2+ cycling in the heart with relevance to the mechanism of contractile and electrical dysfunction in cardiac disease states.

Abstract 552: Mitochondrial KCa and Anion Channels Influence Mitochondrial Volume and Respiratory Rate: Relevance to Cardioprotection

Ion channels in the mitochondrial inner membrane influence the response of the heart to ischemia and reperfusion - the opening of mitochondrial K + channels (mitoK Ca or mitoK ATP ) induce cardioprotection while the excessive activation of an inner membrane anion channel (IMAC) contributes to post-ischemic contractile and electrical dysfunction. Here we examined the effects of K Ca channel openers and inhibitors on mitochondrial volume and respiration in KCl-based medium in energized isolated guinea-pig heart mitochondria. Inhibition of IMAC with a mitochondrial benzodiazepine ligand was also assessed. Mitochondrial swelling and contraction were evoked by the sequential addition of 5mM glutamate (Glu) and 5mM malate (Mal), respectively. Both the swelling and contraction responses involved energy-dependent fluxes of K + and Cl − . The Glu-induced swelling response was suppressed by preincubation with either the K Ca channel toxin paxilline, or by the IMAC blocker 4′-chlorodiazepam (4-Cl-DZP). The K Ca opener NS1619, at concentrations &lt;10μM, initiated mitochondrial swelling responses either in the absence or presence of substrates. This effect was blocked by paxilline or charybdotoxin. Massive and irreversible swelling was induced by [NS1619] &gt;10μM. Under similar conditions, mitochondrial respiratory control (State3/State4 VO 2 ratio) was maintained at &gt;15 for [NS1619] &lt;10μM, but was strongly suppressed above 20μM due to an increase in state4- and a decrease in state3-respiration. 4-Cl-DZP did not affect respiration and only slightly increased the K 0.5 for ADP. The findings indicate that mitochondrial matrix volume is modulated by mitoK Ca channel activity under normal conditions and in the presence of K Ca channel openers, while IMAC channels underlie compensatory anion movements in response to K + flux. Physiological regulation of mitochondrial volume by ion transport is in turn linked to altered respiratory flux, with important implications for cardioprotection and recovery of mitochondrial function in the post-ischemic heart.

The Perfect Storm

See related articles, pages 1039–1048 and 1049–1057 Primary electrical diseases of the heart such as the Long QT Syndrome (LQTS), Short QT Syndrome (SQTS), Brugada Syndrome (BrS), and Catecholaminergic polymorphic ventricular tachycardia (CPVT) are inherited monogenic disorders caused by mutations in ion channel genes (ie, channelopathies), calcium handling proteins, or related molecules that occur in the absence of overt structural abnormalities.1 Because these disorders are typically associated with a high incidence of ventricular tachyarrhythmias and sudden cardiac death (SCD), they are the subject of intense investigation. Although collectively, monogenic diseases underlie a minority of SCD cases in the general population, elucidation of the underlying mechanisms by which they promote electrical instability has provided a wealth of knowledge regarding the role of ion channel dysfunction in electrical remodeling and arrhythmogenesis at multiple levels of integration, linking single amino acid mutations in ion channel genes to electrical dysfunction at the intact cell, organ, and system levels. In recent years, numerous investigations have focused on mechanisms by which altered ion channel function and action potential properties can promote arrhythmias at the multi-cellular network level in various animal models of LQTS, SQTS, and BrS.2 In this issue of Circulation Research , Cerrone et al3 provide a strong mechanistic link between a known CPVT causing mutation and electrical instability arising from the His-Purkinje network of the intact heart in a tour de force study using high-resolution optical mapping, cellular electrophysiological measurements, a variety of pharmacological tools, and numerical simulations. CPVT is a heritable disorder that presents clinically as exercise- or stress- induced ventricular arrhythmias, syncope, or SCD.1 Electrocardiographically, patients with CPVT exhibit polymorphic VT (PVT), bidirectional VT with an alternating QRS axis (Bi-VT), and ventricular fibrillation (VF). Several mutations in the cardiac Ryanodine Receptor (RyR2) and Calsequestrin (CSQ) have been …

Evolution of paced QRS and QTc intervals in children with epicardial pacing leads

Permanent ventricular pacing in children is associated with ventricular dysfunction due to asynchronous activation. It is unclear whether paced QRS intervals increase disproportionately over time, which could potentially cause ventricular dysfunction. A total of 52 children, with bipolar steroideluting epicardial leads implanted at a median age of 5.6 years (0.0-17.4), was analyzed and followed up to 12.2 years (median 3.7). Patients were subdivided in two groups: right (RV, n = 21) and left (LV, n = 31) ventricular pacing. To correct for age, standard deviation scores (Z-scores) for paced QRS and QTc intervals were calculated from published standard-ECG norm-values. As a measure for individual paced QRS and QTc interval changes, a regression slope coefficient (incline(i)) was calculated for each patient's course. Mean Z-scores for paced QRS intervals at first and last follow-up were 4.7 +/- 1.2 and 4.9 +/- 0.9 for group RV, 4.4 +/- 1.1 and 4.8 +/- 1.1 for group LV. Incline(i) of paced QRS (group RV: 0.038 [-0.27-0.12], group LV: 0.147 [-0.05-0.30]; p = 0.07) and QTc intervals (group RV: 0.026 [-0.08-0.06], group LV: 0.023 [-0.04-0.09]; p = 0.63) did not differ between both groups and indicated limited interval changes over time. Neither epicardial pacing of the right nor left ventricle caused disproportionate paced QRS or QTc interval increases over time. An age-related prolongation of the electrical activation unlikely causes ventricular dysfunction.

Propagation of the cardiac impulse in the diabetic rat heart: reduced conduction reserve.

Diabetes mellitus is a growing epidemic with severe cardiovascular complications. Although much is known about mechanical and electrical cardiac dysfunction in diabetes, few studies have investigated propagation of the electrical signal in the diabetic heart and the associated changes in intercellular gap junctions. This study was designed to investigate these issues, using hearts from control and diabetic rats. Diabetic conditions were induced by streptozotocin (STZ), given i.v. 7-14 days before experiments. Optical mapping with the voltage-sensitive dye di-4-ANEPPS, using hearts perfused on a Langendorff apparatus, showed little change in baseline conduction velocity in diabetic hearts, reflecting the large reserve of function. However, both the gap junction uncoupler heptanol (0.5-1 mM) and elevated potassium (9 mM, to reduce cell excitability) produced a significantly greater slowing of impulse propagation in diabetic hearts than in controls. The maximal action potential upstroke velocity (an index of the sodium current) and resting potential was similar in single ventricular myocytes from control and diabetic rats, suggesting similar electrical excitability. Immunoblotting of connexin 43 (Cx43), a major gap junction component, showed no change in total expression. However, immunofluorescence labelling of Cx43 showed a significant redistribution, apparent as enhanced Cx43 lateralization. This was quantified and found to be significantly larger than in control myocytes. Labelling of two other gap junction proteins, N-cadherin and beta-catenin, showed a (partial) loss of co-localization with Cx43, indicating that enhancement of lateralized Cx43 is associated with non-functional gap junctions. In conclusion, conduction reserve is smaller in the diabetic heart, priming it for impaired conduction upon further challenges. This can desynchronize contraction and contribute to arrhythmogenesis.

Re-thinking angina.

William Heberden in 1772 published "some account of the disorder of the breast" which contains the essential elements of angina pectoris as we understand it today. The number of existing cases in the U.S. population today is 6.4 million. Myocardial ischemia manifested by angina pectoris can be either acute or chronic. Patients with chronic stable angina will be the focus of this supplement. The majority of patients are symptomatic but approximately 25% can be asymptomatic. The clinical manifestations of myocardial ischemia generally are chest discomfort, arrhythmias, and LV dysfunction. Myocardial ischemia is a result of imbalance between myocardial oxygen supply and myocardial oxygen demand. High grade coronary stenosis are the usual cause of decreased oxygen supply. The classic hemodynamic factors increasing myocardial oxygen demand include hypertension and increased heart rate due to tachyarrhythmias of any etiology. Exertion is the usual precipitating cause of chronic myocardial ischemia. New information has come forward indicating that myocardial ischemia is associated with disruption of cellular sodium and calcium homeostasis. Ischemia results in a rise of intracellular sodium concentration and thus sodium overload which then activates the sodium calcium exchanger and leads to increased intracellular calcium. When this occurs there is electrical instability and mechanical dysfunction which increases oxygen demand and decreases oxygen supply. The compound Ranolazine is thought to selectively inhibit the late sodium current and attenuates the abnormalities of ventricular repolarization and contractility associated with myocardial ischemia. This compound is the first new class of anti-anginal medication approved in 25 years which may provide physicians with additional therapy for chronic stable angina along with the other anti-angina agents, beta blockers, calcium antagonists and nitrates.

Treating Erectile Dysfunction through Electronic Consultation: A Pilot Study

We investigated a group of men suffering from electric dysfunction (ED) who visited the website www.erectie.info and who had received consultation through the Internet (n = 219). We measured the treatment's effectiveness using the 5-item version of the International Index of Erectile Function (IIEF-5; Rosen et al., 1996; Rosen, Cappelleri, Smith, Lipsky, & Pena, 1999) and a global assessment question (GAQ). We investigated the motives and characteristics of the users of electronics consultation using a questionnaire. After a few months, the consultation group showed a considerably higher IIEF-5 score compared with their baseline score. Eighty-one percent replied in the affirmative to the GAQ. E-consultation is likely to be effective when treating ED, especially among men who find the medium convenient and for men who experience much embarrassment.