Electrical Properties Of Myocardium Research Articles

Magnetocardiographic recognition of abnormal depolarization and repolarization in patients with coronary artery lesions caused by Kawasaki disease.

Myocardial ischemia changes the electrophysiological properties of the myocardium, but it is difficult to detect the abnormalities of depolarization and repolarization noninvasively in patients with coronary artery disease. Depolarization and repolarization abnormalities were retrospectively investigated in 61 patients (48 males and 13 females) with coronary artery lesions (CALs) caused by Kawasaki disease (KD) from 2007 to 2014 using magnetocardiography (MCG). CAL had been diagnosed by selective coronary angiography. Current arrow maps (CAMs) were constructed during depolarization and repolarization [corrected]. The MCG findings were compared between the stenotic lesions group (SL group) and the non-stenotic lesions group (non-SL group). The incidence of MCG abnormalities was significantly higher in the SL group than in the non-SL group (p < 0.0001). The incidence of abnormal repolarization was significantly higher than that of abnormal depolarization (p < 0.0001). The number of coronary artery occlusions significantly affected the severity of abnormal repolarization (p = 0.02). Six (75%) of the patients with abnormal depolarization had a previous anteroseptal myocardial infarction. The transmural myocardial infarction affects on abnormalities of depolarization, and the non-transmural myocardial infarction might relate on abnormalities of repolarization. The myocardial electrical properties were preserved in patients except very severe coronary stenosis. MCG is possible to detect electrical myocardial abnormalities noninvasively in patients with CALs caused by KD.

Editorial: Cardiac electronic remodeling and susceptibility to arrhythmias: an introduction and brief historical overview.

Editorial: Cardiac electronic remodeling and susceptibility to arrhythmias: an introduction and brief historical overview.

ECG imaging of altered electrical properties of myocardium in myocardial infarction

Temporal complexity of depolarization indicates myocardial sympathetic denervation and predicts sudden cardiac arrest in patients with ischemic cardiomyopathy and poor left ventricular ejection fraction Salah Al-Zaiti, CRNP, PhD, Amit Sethi, OTR/L, PhD, Mary Carey, RN, PhD, FAHA, John Canty,MD, FAHA, James Fallavollita, MD, FAHA University of Pittsburgh, Pittsburgh, PA, USA University of Rochester Medical Center, Rochester NY, USA VA WNY Health Care System at Buffalo, Buffalo, NY, USA The Center for Research in Cardiovascular Medicine, Buffalo, NY, USA The State University of New York at Buffalo, Buffalo, NY, USA

Abstract 9164: Low Doses of Ranolazine and Dronedarone in Combination Exert Potent Protection against Atrial Fibrillation and Vulnerability to Ventricular Arrhythmias during Acute Myocardial Ischemia

Background: Coronary artery disease carries dual risk for atrial fibrillation (AF) and sudden cardiac death. We examined whether low-dose ranolazine and/or dronedarone can protect against AF and vulnerability to ventricular tachyarrhythmias. Methods, Results: In chloralose-anesthetized, open-chest Yorkshire pigs (N=19), proximal segment of left circumflex (LCx) coronary artery was occluded to reduce flow by 75%. Electrode catheter was positioned on left atrial appendage to measure AF threshold (AFT) before and during LCx coronary artery stenosis prior to and at one hour after dronedarone (0.5 mg/kg i.v. bolus over 5 min) and/or ranolazine (0.6 mg/kg, i.v. bolus, followed by 0.035 mg/kg/min). Without drugs, LCx coronary artery stenosis lowered AFT from 25.2±1.7 control (mean±SEM) to 4.9±1.0 mA baseline (p&lt;0.01). At these low doses, neither ranolazine (plasma concentration: 2.4±0.6 μ M) nor dronedarone (plasma concentration: 20.9±3.5 nM) alone blunted ischemia-induced reduction in AFT, but combination was effective (from 25.2±1.7 control to 22.0±3.0 mA, NS). Combined but not separate administration blunted ischemia-induced surge in T-wave heterogeneity (TWH), a marker of risk for ventricular tachyarrhythmias. Without drug, TWH increased from 43.1±11.1 control to 149.7±15.1 μ V baseline during stenosis (p&lt;0.001); with both agents, TWH increased only from 61.7±13.7 control to 83.7±15.8 μ V during stenosis (NS) (Fig.). Conclusions: Combined administration of low doses of ranolazine and dronedarone exerts a potent, antiarrhythmic action consistent with synergy due to direct effects on myocardial electrical properties not on coronary flow, which was controlled.

Low doses of ranolazine and dronedarone in combination exert potent protection against atrial fibrillation and vulnerability to ventricular arrhythmias during acute myocardial ischemia

Coronary artery disease carries dual risk for atrial tachyarrhythmias and sudden cardiac death. To examine whether low-dose ranolazine and/or dronedarone can protect against vulnerability to atrial fibrillation (AF) and ventricular tachyarrhythmias. In chloralose-anesthetized, open-chest Yorkshire pigs (n = 15), the proximal segment of left circumflex (LCx) coronary artery was occluded to reduce flow by 75%. An electrode catheter was positioned on the left atrial appendage to measure AF threshold (AFT) before and during LCx coronary artery stenosis before and at 1 hour after dronedarone (0.5 mg/kg intravenous bolus over 5 minutes) and/or ranolazine administration (0.6 mg/kg intravenous bolus followed by 0.035 mg/kg/min). Before drug administration, LCx coronary artery stenosis lowered AFT from 25.2 ± 1.7 mA control (mean ± SEM) to 4.9 ± 1.0 mA baseline (P<.01). At the low doses, neither ranolazine (plasma concentration 2.4 ± 0.6 μM) nor dronedarone (plasma concentration 20.9 ± 3.5 nM) alone blunted the ischemia-induced reduction in AFT but were effective together (from 25.2 ± 1.7 mA control to 22.0 ± 3.0 mA during stenosis; P = not significant). AF duration (P<.03) and AF inducibility (P = .012) were reduced by ranolazine and dronedarone together but not by either drug alone. Concurrently, combined but not separate administration blunted the ischemia-induced surge in T-wave heterogeneity, a marker of risk for ventricular tachyarrhythmias (from 43.1 ± 11.1 μV control to 149.7 ± 15.1 μV during stenosis, P<.001, compared to 61.7 ± 13.7 μV control to 83.7 ± 15.8 μV during stenosis, P = not significant). Combined administration of low doses of ranolazine and dronedarone exerts a potent antiarrhythmic action on ischemia-induced vulnerability to AF and ventricular tachyarrhythmias due to direct effects on myocardial electrical properties.

KCNE2 modulation of Kv4.3 current and its potential role in fatal rhythm disorders

The transient outward current I(to) is of critical importance in regulating myocardial electrical properties during the very early phase of the action potential. The auxiliary beta subunit KCNE2 recently was shown to modulate I(to). The purpose of this study was to examine the contributions of KCNE2 and its two published variants (M54T, I57T) to I(to). The functional interaction between Kv4.3 (alpha subunit of human I(to)) and wild-type (WT), M54T, and I57T KCNE2, expressed in a heterologous cell line, was studied using patch-clamp techniques. Compared to expression of Kv4.3 alone, co-expression of WT KCNE2 significantly reduced peak current density, slowed the rate of inactivation, and caused a positive shift of voltage dependence of steady-state inactivation curve. These modifications rendered Kv4.3 channels more similar to native cardiac I(to). Both M54T and I57T variants significantly increased I(to) current density and slowed the inactivation rate compared with WT KCNE2. Moreover, both variants accelerated the recovery from inactivation. The study results suggest that KCNE2 plays a critical role in the normal function of the native I(to) channel complex in human heart and that M54T and I57T variants lead to a gain of function of I(to), which may contribute to generating potential arrhythmogeneity and pathogenesis for inherited fatal rhythm disorders.

Electrocardiographic diagnosis of left ventricular hypertrophy: depolarization changes

Electrocardiographic signs of left ventricular hypertrophy (LVH) are on one hand accepted as independent cardiovascular risk factors and indicators of target organ damage in hypertensive patients, but, on the other hand they are strongly criticized for their low sensitivity. In this paper, a historic perspective on the ECG dignosis of LVH is presented, showing the development of current views on the role of ECG in LVH detection. Based on the fact that ECG provides information on the electrical properties of myocardium and on new knowledge about electrical remodeling in LVH, a shift of paradigm in our consideration of the diagnosis of left ventricular hypertrophy is proposed, based on changes in the electrical properties of hypertrophied myocardium. This new paradigm could explain the broad spectrum of QRS patterns seen in LVH, including increased QRS voltage, prolonged duration of QRS complex, left axis deviation, prolonged intrinsicoid deflection, LBBB and LAFB patterns, as well as pseudo-normal ECG findings.

Altered expression of Na+ transporters at the mRNA level in rat normal and hypertrophic myocardium

Intracellular Na(+) ([Na(+)](i)) regulation plays a crucial role in the structural, mechanical, and electrical properties of myocardium. It is assumed that the [Na(+)](i) handling system may differ not only between normal and diseased hearts but also regionally within a heart. To gain new insight concerning disease- and region-dependent differences in the [Na(+)](i)-regulatory system, we investigated mRNA expression of Na+ transporters, the principal determinants of [Na(+)](i). Nonischemic pressure-overloaded hypertrophy was created by suprarenal abdominal aortic constriction of 50% for 7 weeks. mRNA abundances of Na(+)-Ca(2+) exchanger (NCX1), Na(+)-H(+) exchanger (NHE1), Na(+)-K(+)-2Cl(-) exchanger (NKCC1) and Na(+), K(+)-ATPase multigene family(alpha(1), alpha(2), alpha(3), and beta(1) isoforms) were measured by the real-time quantitative polymerase chain reaction method. mRNA abundance of all transporters mediating Na(+) influx (NCX1, NHE1, and NKCC1) was significantly upregulated as compared to normal. In contrast, Na(+)-efflux-mediating transporter (Na(+), K(+)-ATPase) mRNA expression was unaltered between normal and hypertrophic hearts. Losartan, an angiotensin II AT1 receptor antagonist, significantly attenuated upregulation of Na(+)-influx-mediating transporters induced by aortic constriction. The onset of Na(+)-influx-mediating transporter upregulation occurred within 5 days following constriction. In normal and hypertrophied hearts, mRNA of all Na(+)-influx-mediating transporters was expressed in order of abundance as: apex > septum approximately free wall of left ventricles. A transmural gradient in expression was also evident in normal hearts (midcardium > endo- and epicardium), which was attenuated under hypertrophic development. Myocardial hypertrophy is associated with significant changes in the spatial distribution and expression levels of Na(+) transporters. The upregulation of Na influx transporters during hypertrophy may contribute to the remodeling process, modulate contractility and promote arrhythmias.

Variety is the spice of life: searching for the substrates of regional myocardial electrical properties

Variety and diversity as well as regional specificity of gene expression are the basis of normal cardiac function. Transcriptional regulation has been demonstrated to be an essential compensatory response to structural and functional changes in the heart. In order to understand transcriptional regulation in defined disease states it is essential to have a detailed knowledge of expression patterns in non-diseased myocardial tissue. In this issue of The Journal of PhysiologyGaborit et al. (2007) give a detailed analysis of differentially expressed ion channel genes controlling regional diversity of myocardial electrical properties in non-diseased human hearts. High-throughput real-time RT-PCR in a hypothesis driven approach allowed for a comprehensive description of 79 ion channels and related genes in specific regions of the human heart. Differential expression of a variety of genes is giving clues to the molecular substrates controlling distinct myocardial electrical properties of specific regions in the heart and has been demonstrated in anatomically distinct regions of the heart such as atrial versus ventricular myocardium (Barth et al. 2005) or ventricular endocardium versus ventricular epicardium (Rosati et al. 2001). Genome wide expression studies in heart failure resulted in a description of deregulated gene clusters that can be attributed and sorted by functional groups such as metabolism, inflammation and signal transduction. While regional differences in deregulation of ion channels in normal and failing heart has been noted (Ellinghaus et al. 2005; Kaab et al. 2004), this study, in an unprecedented way, investigates a comprehensive set of ion channel genes and related genes in atria, ventricular epicardium and endocardium as well as in Purkinje fibres. The authors present and discuss their data in the context of previous findings and highlight novel findings of potential functional significance. Among the wealth of data, the detailed analysis of the Purkinje fibre system deserves special attention. The participation of Nav1.7 in TTX-sensitive Purkinje fibre INa, and the importance of low-level Na+,K+-ATPase and high-level inositol-trisphosphate receptor expression in the Purkinje system warrant further functional studies with respect to arrhythmogenesis. These data add to the discussion on Ca2+ signalling in the Purkinje system that was substantiated by the recent discovery of the molecular substrates of T- and L-type Ca2+ currents in Purkinje fibres in dog (Rosati et al. 2007). In comparison to previous pan-genomic approaches on regional specific gene expression in the heart this quantitative RT-PCR based study allowed for the detection of low-abundance mRNAs and unmasked differences in expression levels to a greater extent than pan-genomic arrays (Kaab et al. 2004; Ellinghaus et al. 2005). These data provide an important reference with a focus on low abundance ion channel genes for other studies aiming at: genes exclusively expressed in atrial or ventricular tissue; genes controlling electrical properties that may play an important functional role in arrhythmogenesis; transcriptional deregulation contributing to a remodelling process in defined disease states in the human heart (e.g. hypertrophy, heart failure). To link deregulation of ion channel genes to other potentially more global gene deregulation processes in the course of specific disease states more information especially on transcription factors involved will be needed. More sophisticated and meticulous dissecting methods as well as a combination with functional studies have recently led to the detailed characterization of ion channel expression in rabbit atria and sinus node, linking the variety of gene expression on a microscopic level to specific electrical properties that guarantee physiological excitation and conduction (Tellez et al. 2006). This holds out the promise that we will see a detailed analysis and understanding of the transcriptional control of key anatomical substrates of excitation and conduction such as sinus node, atrio-ventricular node, and crista terminalis in the human heart in the future.

Electrical and Structural Remodeling in Left Ventricular Hypertrophy—A Substrate for a Decrease in QRS Voltage?

Electrical remodeling in advanced stages of cardiovascular diseases creates a substrate for triggering and maintenance of arrhythmias. The electrical remodeling is a continuous process initiated already in the early stages of cardiological pathology. The aim of this opinion article was to discuss the changes in electrical properties of myocardium in left ventricular hypertrophy (LVH), with special focus on its early stage, as well as their possible reflection in the QRS amplitude of the electrocardiogram. It critically appraises the classical hypothesis related to the QRS voltage changes in LVH. The hypothesis of the relative voltage deficit is discussed in the context of supporting evidence from clinical studies, animal experiments, and simulation studies. The underlying determinants of electrical impulse propagation which may explain discrepancies between "normal" ECG findings and increased left ventricular size/mass in LVH are reviewed.

Sotalol testing unmasks altered repolarization in patients with suspected acquired long-QT-syndrome?a case-control pilot study using i.v. sotalol

The aim of this pilot study was to evaluate provocative sotalol testing to unmask abnormal repolarization due to altered myocardial electrical properties as the key feature in acquired Long-QT-Syndrome. Reliable diagnosis and risk stratification for the individual patient are complicated by the multitude of mechanisms involved in acquired QT-prolongation. The combined influence of all components determines susceptibility to arrhythmias related to QT-prolongation. Twenty consecutive patients who had experienced torsades de pointes in association with QT-prolonging drugs were tested with i.v. D,L-sotalol (2mg/kg) with 24-h intensive care monitoring to evaluate the repolarization process by determining QT- and QTc-prolongations. Results were compared to age and sex matched controls. At baseline, no differences between control and study population with regard to QT and QTc were detected. After sotalol infusion, QTc increased from 422+/-17 to 450+/-22ms in controls and from 434+/-20 to 541+/-37ms in the study population. Torsades de pointes occurred in three out of 20 patients (15%) in the study population but in none of the control patients following i.v. sotalol testing. Controlled exposure to sotalol successfully identifies patients with normal QTc intervals but altered myocardial repolarization. This may be useful for clarifying diagnosis and pathogenesis of acquired Long-QT-Syndrome.

Comparative studies of ATP sensitive potassium channels in heart and pancreatic beta cells using Vaughan-Williams class Ia antiarrhythmics.

Actions of cibenzoline and disopyramide, agents with Vaughan-Williams class Ia antiarrhythmic action, on ATP sensitive K+ (KATP) channels were examined in heart and pancreatic beta cells. Single ventricular myocytes and beta cells were prepared enzymatically from adult Wistar rat hearts and pancreatic islets. Using patch clamp techniques, KATP channel activities were recorded in whole cell and single channel modes. In whole cell experiments, myocytes were bathed with Tyrode's medium (34 degrees C); inside out patches were bathed with internal solutions (22-24 degrees C) containing 1 microM ATP and varying concentrations of cibenzoline or disopyramide. Myocytes were voltage clamped at -40 mV and glibenclamide blockade conductance was produced by cromakalim. Micromolar concentrations of both cibenzoline and disopyramide suppressed cromakalim induced conductance. When applied to the cytosolic surface of the cell membrane in inside out configuration, both drugs reversibly inhibited single KATP channel activities. Neither unitary conductance nor intraburst fast kinetics was affected by the compounds. At a holding potential of -40 mV under symmetrical approximately 150 mM K+ conditions, half maximum doses (IC50) were 0.9 microM [Hill coefficient (h) = 1.3] for cibenzoline induced block of cardiac KATP channels and 1.8 microM (h = 1.0) for disopyramide block. At +40 mV, IC50 for cibenzoline block was 1.4 microM (h = 0.9). Thus there was little voltage dependence in cibenzoline induced channel block. A similar IC50 value of 2.5 microM (h = 1.2 at -60 mV under symmetrical approximately 150 mM K+) was observed for cibenzoline induced block of KATP channels. Near therapeutic concentrations of cibenzoline and disopyramide inhibit KATP channel activities in both heart and pancreatic beta cells. This may be causally related to the fasting hypoglycaemia which is sometimes reported in patients receiving the drugs. These antiarrhythmic agents may also modulate myocardial electrical properties during hypoxia or ischaemia.

Interaction of amiodarone and its analogs with calmodulin

Benzofurans have important actions on the electrical properties of myocardium; the biochemical basis of those actions is not known. Crystallographic examination of these compounds has revealed that benzofurans share structural homologies with the traditional calmodulin antagonists N-(6-aminohexyl)-5-chloro-1-naphthalene and trifluoperazine. In the present study, the ability of amiodarone, desethylamiodarone, and benziodarone to displace the fluorescent ligand 8-anilino-1-napthalene sulfonic acid (ANS) from calmodulin, to modulate the fluorescence emission of dansylcalmodulin, and to inhibit the activation by calmodulin of bovine brain cyclic nucleotide phosphodiesterase and human erythrocyte membrane Ca 2+-ATPase were investigated at concentrations ranging from 10 −8 to 10 −6 m. These benzofurans displaced ANS from calmodulin with nearly equal efficiency upon forming a 1:1 complex with that protein. Each of these compounds also produced a decreased fluorescence emission of dansylcalmodulin, but with relative efficiencies being desethylamiodarone > amiodarone > benziodarone. Amiodarone and desethylamiodarone inhibited calmodulin-stimulable phosphodiesterase activity with similar potencies. Amiodarone and benziodarone inhibited calmodulin-stimulable Ca 2+-ATPase activity equally, but desethylamiodarone had no effect. The observed differential effects of the amiodarone analogs suggest that calmodulin may possess multiple benzofuran-binding sites that are recognized by specific targets and ligands of this Ca 2+-binding protein and that the cellular action of amiodarone and its analogs may reflect calmodulin antagonism.

Influence of Beta2-Adrenoceptor Stimulation and Blockade on Cardiac Electrophysiologic Properties and Serum Potassium Concentration in the Anesthetized Dog

The influence of selective beta 2-adrenoceptor stimulation and blockade on cardiac electrophysiologic properties was studied in 18 anesthetized dogs. Selective beta 2-adrenoceptor activation by salbutamol failed to alter myocardia excitability but significantly lowered serum potassium concentration. Excitability, refractoriness, and ventricular fibrillation threshold were also not changed after administration of 100 and 200 micrograms/kg of the selective beta 2-antagonist ICI 118,551. However, at a dose of 500 micrograms/kg, refractoriness was prolonged and ventricular fibrillation threshold increased. These changes appear to be due to blockade of beta 1-adrenoceptors rather than to membrane stabilizing effects, since in catecholamine-depleted animals even the highest dose of ICI 118,551 did not alter myocardial electrical properties. It is concluded that beta 2-adrenoceptors do not influence electrophysiologic properties of the canine myocardium.

Influence of beta 2-adrenoceptor stimulation and blockade on cardiac electrophysiologic properties and serum potassium concentration in the anesthetized dog

The influence of selective β 2-adrenoceptor stimulation and blockade on cardiac electrophysiologic properties was studied in 18 anesthetized dogs. Selective β 2-adrenoceptor activation by salbutamol failed to alter myocardial excitability but significantly lowered serum potassium concentration. Excitability, refractoriness, and ventricular fibrillation threshold were also not changed after administration of 100 and 200 μg/kg of the selective β 2-antagonist ICI 118,551. However, at a dose of 500 μg/kg, refractoriness was prolonged and ventricular fibrillation threshold increased. These changes appear to be due to blockade of β 1-adrenoceptors rather than to membrane stabilizing effects, since in catecholamine-depleted animals even the highest dose of ICI 118,551 did not alter myocardial electrical properties. It is concluded that β 2-adrenoceptors do not influence electrophysiologic properties of the canine myocardium.

1981 APhA Exposition and Annual Meeting Update

Coronary artery disease carries dual risk for atrial tachyarrhythmias and sudden cardiac death.To examine whether low-dose ranolazine and/or dronedarone can protect against vulnerability to atrial fibrillation (AF) and ventricular tachyarrhythmias.In chloralose-anesthetized, open-chest Yorkshire pigs (n = 15), the proximal segment of left circumflex (LCx) coronary artery was occluded to reduce flow by 75%. An electrode catheter was positioned on the left atrial appendage to measure AF threshold (AFT) before and during LCx coronary artery stenosis before and at 1 hour after dronedarone (0.5 mg/kg intravenous bolus over 5 minutes) and/or ranolazine administration (0.6 mg/kg intravenous bolus followed by 0.035 mg/kg/min).Before drug administration, LCx coronary artery stenosis lowered AFT from 25.2±1.7 mA control (mean±SEM) to 4.9±1.0 mA baseline (P<.01). At the low doses, neither ranolazine (plasma concentration 2.4±0.6 μM) nor dronedarone (plasma concentration 20.9±3.5 nM) alone blunted the ischemia-induced reduction in AFT but were effective together (from 25.2±1.7 mA control to 22.0±3.0 mA during stenosis; P = not significant). AF duration (P<.03) and AF inducibility (P = .012) were reduced by ranolazine and dronedarone together but not by either drug alone. Concurrently, combined but not separate administration blunted the ischemia-induced surge in T-wave heterogeneity, a marker of risk for ventricular tachyarrhythmias (from 43.1±11.1 μV control to 149.7±15.1 μV during stenosis, P<.001, compared to 61.7±13.7 μV control to 83.7±15.8 μV during stenosis, P = not significant).Combined administration of low doses of ranolazine and dronedarone exerts a potent antiarrhythmic action on ischemia-induced vulnerability to AF and ventricular tachyarrhythmias due to direct effects on myocardial electrical properties.