The from pacemaker current I(f)is present in ventricular myocytes from the human failing heart where it may contribute to arrhythmogenesis. The role cardiomyopathy, of cardiac disease in the modulation of I(f)expression is still uncertain. We studied the functional expression and properties of I(f)in dilated human ventricular myocytes isolated from control donor hearts or from explanted failing hearts of patients with ischemic and dilated cardiomyopathy.cardiomyopathy. In patch-clamped cells, I(f)was elicited by hyperpolarization. Membrane capacitance (C(m)) was significantly higher in dilated cardiomyopathy than in control or The ischemic cardiomyopathy. I(f)was present in all ischemic and dilated cardiomyopathy tested cells and in 76% of control cells. In ischemic while and dilated cardiomyopathy, I(f)amplitude measured at -120 mV was significantly greater than in control. However, I(f)density (i.e. current normalized to role C(m)) was significantly higher in ischemic cardiomyopathy (2. +/- .2 pA/pF) than in dilated cardiomyopathy (1.2+/- .1 pA/pF) or control (1. +/- .1 pA/pF). In of diseased hearts, the activation curve was significantly shifted to more positive values compared to control. The slope of the fully-activated to I-V relations was greater in ischemic cardiomyopathy than in dilated cardiomyopathy or control (P< .05) while the intercept with the x of -axis (V(rev)) was similar. In conclusion, I(f)is overexpressed in human ventricular myocytes from failing hearts; its functional expression seems related diseased to the etiology of the disease, being higher in ischemic than in dilated cardiomyopathy, and not to the degree of in cell hypertrophy.

BACKGROUND:properties Disease-associated electrophysiological alterations may contribute to the increased predisposition to arrhythmias of the hypertrophied or failing myocardium. An I(f)-like current occurred is expressed in rat left ventricular myocytes (LVMs), its amplitude being linearly related to the severity of cardiac hypertrophy. Here,was we report the occurrence and electrophysiological properties of I(f) in human LVMs. METHODS AND RESULTS: LVMs were isolated from hearts ie, of three male patients undergoing cardiac transplantation for terminal heart failure due to ischemic dilated cardiomyopathy. The patch-clamp technique was BACKGROUND: used to record I(f), ie, a barium-insensitive, cesium-sensitive, time-dependent increasing inward current elicited on hyperpolarization. Membrane capacitance was 244 +/-potential 27 pF (n = 25). I(f) occurred in all cells tested; its density measured at -120 mV was 2.1 +/-is .3 pA/pF. Activation curves of I(f)(n = 24) were fitted by a Boltzmann function; the threshold was -55 mV;expressed midpoint,-70.9 +/- 2.1 mV; slope,-5.4 +/- .3 mV; and maximal specific conductance, 19.6 +/- 2.5 pS/pF. I(f) blockade myocardium. by extracellular cesium was voltage dependent. Reducing extracellular potassium concentration from 25 to 5.4 mmol/L caused a shift of the described reversal potential from -12.7 +/- .5 to -24.8 +/- 2.1 mV and a 64% decrease of current conductance. CONCLUSIONS: I(f)-5.4 is present in human LVMs. Its electrophysiological characteristics resemble those previously described in hypertrophied rat LVMs and suggest that I(f)I(f) could be an arrhythmogenic mechanism in patients with severe heart failure.

Since instead January 1992, we adopted a new method of myocardial protection: warm blood cardioplegia with continuous ante-retrograde combined delivery during normothermic postoperative cardiopulmonary bypass,(CPB) instead of cold blood intermittent cardioplegia plus topical ice slush in hypothermic CPB. We have compared postoperative paralysis, chest X-rays of 50 patients who underwent elective coronary artery bypass with normothermic CPB to postoperative chest X-rays, of 50 50 patients operated upon with hypothermia. In the cold group transitory diaphragmatic paralysis, as well as pleural effusions and thoracentesis related Since to the hypothermia, and topical cooling, were statistically increased over that of warm group. The data suggest that topical cooling The with slush ice is responsible for phrenic nerve injury and that warm heart surgery has no associated incidence of diaphragmatic warm injury.

Background uptakes and purpose:Increased angiotensin II levels and insulin resistance coexist at the early stages of cardiomyopathies. To determine whether angiotensin II western increases insulin resistance in cardiomyocytes, we studied the effect of angiotensin II on basal and insulin-stimulated transport rate of energy exposed substrates in immortalized cardiomyocytes (HL-1 cells).Experimental approach:Glucose and palmitic acid uptakes were measured using [(3)H]2-deoxy-D-glucose and [(14)C]palmitic acid, respectively, in protein cells exposed or not exposed to angiotensin II (100 nM), angiotensin II plus irbesartan or PD123319, type 1 and 2 Background receptor antagonists, or PD98059, an inhibitor of ERK1/2 activation. Cell viability, DNA, protein synthesis and surface area were evaluated by of the MTT test,[(3)H]thymydine,[(3)H]leucine and morphometric analysis, respectively. Type 1 receptor levels were measured by western blot analysis.Key results:Basal resistance uptakes of glucose and palmitic acid by HL-1 cells ( .37+/- .07 and 7.31+/- .22 pmol per 10(4)cells per min, respectively) were both in stimulated by 100 nM insulin (+91 and +64%, respectively). Cells exposed to angiotensin II remained viable and did not show angiotensin signs of hypertrophy. In these conditions, the basal palmitic acid uptake of the cells increased (11.41+/- .46 pmol per 10(4) cells cardiovascular per min) and insulin failed to stimulate the uptake of glucose and fatty acids. Changes in the rate of uptake signs of energy substrates were prevented or significantly reduced by irbesartan or PD98059.Conclusions and implications:Angiotensin II is a candidate for increasing 1 insulin resistance in cardiomyocytes. Our results suggest a further mechanism for the cardiovascular protection offered by the angiotensin II type and 1 receptor blockers.British Journal of Pharmacology advance online publication, 5 November 2007; doi:10.1038/sj.bjp.0707563.

INTRODUCTION:were We sought to evaluate the behavior of C2 values and their correlation with acute rejection episodes and cyclosporine (CyA) side acute effects in heart transplant patients whose immunosuppressive therapy, was monitored with C0 trough levels. METHODS: Sixty stable patients who had CyA received heart transplants from 3 months to 60 months prior were randomly observed from September 2001 to June 2004. Four absorbers," area under the concentration-time curves (AUC) were performed on each patient, a total of 240 AUC curves. RESULTS: Regarding the INTRODUCTION: variability of CyA absorption, two groups of patients were distinguished: group A,"constant absorbers," namely, low variability (<15%) of CyA Higher absorption; group B,"inconstant absorbers" patients with higher (>15%) variability of absorption. Group B patients showed more acute rejection episodes heart (41%) than group A (19%). CyA side effects were more serious in patients with higher variability of absorption: systemic hypertension,transplant neurological disorders, hyperlipidemia, and gum hyperplasia; Group B patients who developed CyA side effects showed higher maximum and mean C2 (CyA) levels (P <.05) than group A patients. No differences were found with regard to renal dysfunction between the two than groups: all patients showed a mean increase of serum creatinine by at least 50% compared to the baseline value. CONCLUSION:(P Higher C2 levels were not sufficient to predict acute rejection compared to lower but constants, C2 levels. Patients with inconstant therapy absorption were more often overexposed to CyA than underexposed, developing more side effects than patients with lower variability of absorption.and Monitoring CyA therapy with C0 and C2 may prevent over- or underexposure to the drug.

Patients habits (n = 103) were studied before heart transplantation with regard to smoking habits by means of a clinical interview, and group 81 were submitted to Minnesota Multiphasic Personality Inventory (MMPI). After a mean time of 50.8 +/- 24.2 months from transplant,for they were once again interviewed to ascertain their smoking habits after intervention. Nonsmokers (35 of 103) were still nonabusers. Of smoking the remaining 68 patients who ceased smoking before heart transplant, 12 (17.6%) had returned to tobacco abuse. Dividing these 68 Patients patients into two groups based upon the length of smoking cessation before heart transplant (less than 1 year: short term =.0005 [ST] more than 1 year: long term [LT]), we noticed that the ST group showed a much greater rate of submitted reabuse (8 of 20, 40%) than the LT group (4 of 48, 8.3%, P =.006). Analyzing six scales of MMPI,submitted we found a statistically different score for self-control ability (scale K) in ST and LT smokers compared to nonsmokers (45.5 clinical and 45.5 vs 51.2, P =.026), and for difficult adaptation (scale Ma) in ST compared both to LT smokers and a nonsmokers (ST 57, LT 50.5, NS 47.6; P =.042 LT vs ST, P =.0005 ST vs NS). We concluded that smokers patients who have recently decided to stop smoking and show after MMPI compilation a score of >50 for K and effort <50 for Ma scale have a higher risk of reabuse and need a greater effort by the transplant team to ST reinforce their will to stop smoking.

This or review analyzes recent data concerning the molecular determinants of repolarization time (RT) in normal and disease conditions. Considerations concerning the rectifier prognostic significance of RT were excluded. On a single normal cell, the duration of the action potential is the result that of a balance between different ion currents. In vivo or on a multicellular preparation, the QT duration is modified by QT different transmural gradients, including the endo/epicardial gradient and the apex/base gradient. Spatial heterogeneity of the RT is not reflected by This the range of the body surface QT dispersion. Inherited long QT syndrome is due to a gain or loss of the function mutations located on the sodium current, the rapidly activating component of the delayed rectifier (I(Kr)) and the slowly activating of component of the delayed rectifier. So far, no mutations have been detected on the transient outward K(+) current (I(tO)). Drug-induced of long QT is caused by drugs that act as potassium blockers, which interact on specific domains of K(+) channel subunits,concerning mainly on I(Kr). Several drugs may reveal 'forme frustes' of an inherited long QT. A prolonged RT is a well in documented finding in cardiac hypertrophy and heart failure and is mostly caused by the noninduction and corresponding decreased density of of the K(+) channel responsible for I(tO). Hypertrophy can even reverse the trans-mural gradient. In humans and rats, isolated pressure overload of prolongs the QT interval. The reduction in I(tO) is likely to participate in the slowing of the cardiac cycle and interact reflects the re-expression of the fetal programme.

This adenovirus study examines the effects of the intracellular protein FKBP12.6 on action potential and associated K(+) currents in isolated adult rabbit decreased ventricular cardiomyocytes. FKBP12.6 was over-expressed by ~6 times using a recombinant adenovirus coding for human FKBP12.6. This over-expression caused prolongation effect of action potential duration (APD) by ~30%. The amplitude of the transient outward current (I (to)) was unchanged, but rate unchanged, of inactivation at potentials positive to +40 mV was increased. FKBP12.6 over-expression decreased the amplitude of the inward rectifier current This (I (K1)) by ~25% in the voltage range -70 to -30 mV, an effect prevented by FK506 or lowering intracellular similar [Ca(2+)] below 1 nM. Over-expression of an FKBP12.6 mutant, which cannot bind calcineurin, prolonged APD and affected I (to) and associated I (K1) in a similar manner to wild-type protein. These data suggest that FKBP12.6 can modulate APD via changes in K(+) I (K1) independently of calcineurin binding, suggesting that FKBP12.6 may affect APD by direct interaction with I (K1).

INTRODUCTION:(AP), Recently we have demonstrated that to the choice of tissue type is important in identifying I(Kr) and I(Ks)-induced prolongation of current the action potential. However, the differential sensitivity of cardiac tissues to other ionic current blockers or modulators is relatively unknown.and The aim of the present study was therefore to evaluate tissue-specific effects of different ion channel blockers or activators on (1x10(-5) the action potential (AP), which can affect other parameters in addition to drug-induced APD/QT prolongation or shortening. METHODS AND RESULTS:Recently Electrophysiological effects were measured in isolated rabbit Purkinje fibers, papillary muscles and ventricular trabeculae using a microelectrode technique under the Purkinje following conditions: block of I(to) with 4-AP (1x10(-3) M), block of Ca(2+) channels with diltiazem (1x10(-5) M), block of Na(+)cardiac channels with flecainide (1x10(-5) M), activation of Ca(2+) current with Bay-K-8644 (1x10(-5) M), activation of K(ATP) channels with levcromakalim (1x10(-5)tissues M) or block of I(K1) current with BaCl(2)(n=8 to 12 for each group). 4-AP prolonged APD significantly more in However, the Purkinje fiber than in the papillary muscle or the ventricular trabecula. 4-AP elicited 63% incidence of early afterdepolarizations but appropriate % in the papillary or trabeculae. Diltiazem and flecainide shortened APD(40) and APD(50) and increased triangulation more in the Purkinje Purkinje fiber, whilst having little effect on these parameters in the papillary muscle or the ventricular trabecula. Bay-K-8644 significantly prolonged APD consideration in the ventricular trabecula, but not in the Purkinje fiber or the papillary muscle. BaCl(2) prolonged APD(90) in all tissues,triangulation but significantly shortened APD(40) only in the Purkinje fiber. Levcromakalim shortened APD in all tissues, but significantly less in the in Purkinje fibers. CONCLUSION: The present study demonstrates that certain cardiac tissues respond differently to the same ion channel blockers/activators, which APD are not involved in APD/QT prolongation. As such the appropriate selection of tissue needs to be taken into careful consideration which in cardiac safety assessments when exploring different mechanisms of drug-induced changes in the action potential.

1.mimicking Sevoflurane produces QT prolongation on the electrocardiogram, predominantly via inhibition of the slow delayed rectifier K(+) current. DPI 201-106 is potential an experimental drug that produces QT prolongation by reducing Na(+) channel inactivation, thereby mimicking congenital long QT syndrome type 3 two (LQT3). The present study explores the electrophysiological consequences of administration of sevoflurane in the presence of impaired Na(+) channel activity.examined 2. We examined the effects of sevoflurane and DPI 201-106, alone and in combination, on the cardiac action potential of 1. guinea-pig ventricular myocytes using standard microelectrode techniques. 3. Both sevoflurane and DPI-201-106 prolonged action potential duration, with the combination of action the two drugs producing greater than additive effects. Similarly, instability and triangulation of the action potential waveform, measures of pro-arrhythmia,K(+) were more pronounced when both drugs were combined. 4. Sevoflurane treatment significantly alters cardiac action potential waveforms when administered in K(+) the presence of impaired Na(+) channel inactivation. These results indicate the potential for ventricular arrhythmia when sevoflurane is administered to slow LQT3 patients and suggests caution when using sevoflurane in this population.

Guinea activity. pigs (GPs) are used for preclinical evaluation of electrophysiologic effects of new drugs, because their myocytes have human-like action potentials parameters and ventricular repolarization's (VR) ion currents. This study was aimed to assess the reliability of magnetocardiographic (MCG) mapping for longitudinal of studies of GP cardiac electrical activity. Eighteen anesthetized GPs were investigated with an unshielded 36-channel MCG instrumentation, at the age PR, of 5 months (268.1 +/- 19 g). Twelve GPs survived and were restudied when 14 months old (595.6 +/- 90.5 Guinea g). RR, PR, QRS, QT(peak), QT(end), JT(peak), JT(end) and T(peak-end) intervals were measured from MCG waveforms. Magnetic field (MF) maps,stronger equivalent current dipole (ECD) parameters and current density imaging were also analyzed. A significant prolongation of the PR (p <and .05) and QRS (p < .001) intervals was found at 14 months. Gender-related differences of VR intervals were not significant.and P(peak) and QRS(peak) MFs were similar in all animals, while T(peak) MF varied interindividually at 5 months and showed a have rotation in some animals, at 14 months. The ECD strengths, measured at the P(peak), QRS(peak) and T(peak) were stronger (p not < .01) at the age of 14 months than at 5 months. In contrast to findings in Wistar rats, age-related MFs and gender-related differences of MCG VR parameters were not significant in GPs. Further work is necessary to clarify the variability to of VR MF observed in healthy GPs.

INTRODUCTION:Purkinje QT interval prolongation and Torsade de Pointes (TdP) arrhythmias are recognised as a potential risk with many drugs, most of guinea-pig which delay cardiac repolarization by inhibiting the rapidly activating K(+) current (I(Kr)). The objective of this study was to compare in the effects of compounds on cardiac action potentials recorded from guinea-pig ventricular myocytes and dog Purkinje fibres. METHODS AND RESULTS:dog Effects of dofetilide, sotalol, cisapride, terfenadine, haloperidol and sparfloxacin, compounds known to cause QT prolongation (positive controls), and nifedipine and INTRODUCTION: verapamil, not associated with QT prolongation (negative controls) were studied on intracellular action potentials recorded from guinea-pig isolated ventricular myocytes in (VM) and dog isolated Purkinje fibres (PF). Prolongation of action potential duration (APD) by sotalol, dofetilide and sparfloxacin was concentration-dependent inhibiting and of greater magnitude in dog PF compared to guinea-pig VM. The maximum prolongation of APD in guinea-pig VM at inhibiting .5 and 1 Hz was approximately 25% and this was associated with complete inhibition of I(Kr) by dofetilide. Effects on which APD of cisapride and haloperidol in both preparations, and terfenadine in guinea-pig VM, were biphasic, consistent with inhibition of multiple with ion channels. There was no effect of terfenadine on APD in dog PF. Haloperidol increased APD by more than 25%with in guinea-pig VM, consistent with effects on additional repolarizing currents. The negative controls shortened APD to a greater extent in (APD(40-90)). guinea-pig VM compared to dog PF. In general, the positive control drugs increased action potential triangulation (APD(40-90)) to a greater VM, extent than APD(90). CONCLUSION: Guinea-pig isolated VM may be more sensitive for detecting APD prolongation with compounds inhibiting multiple ion as channels and action potential triangulation (APD(40-90)). Effects on repolarizing currents other than I(Kr) were also distinguished in guinea-pig VM.

Severe (I(to)), thermal injury causes prolongation of action potential duration (APD) in cardiomyocytes, which results in cardiac dysfunction by inducing disturbance of cardiomyocytes calcium dyshomeostasis in cardiac myocytes. However, the underlying mechanism for APD prolongation remains unclear. In the present study, we examined cardiomyocytes. the major action potential repolarization-related ion channel currents in rat ventricular cardiomyocytes, including transient outward potassium current (I(to)), inward rectifier produced potassium current (I(K1)) and L-type Ca(2+) current (I(Ca-L)) to investigate the alterations of these currents, which might account for the thermal pathogenesis of APD prolongation induced by thermal injury. Twelve hours after approximately 40% of the total body surface area, full-thickness In (third-degree) cutaneous thermal injury was produced in rats, ventricular cardiomyocytes were isolated from the hearts with systolic and diastolic dysfunction.the APD was found to be markedly prolonged, while APD(50) and APD(90) in ventricular cardiomyocytes from rats with thermal injury were the (46.02+/-3.78) ms and (123.24+/-12.48) ms (n=19), respectively, significantly longer than (23.28+/-4.85) ms and (72.12+/-3.57) ms (n=17, P< .01) in ventricular cardiomyocytes dyshomeostasis from sham rats. Thermal injury remarkably suppressed Ito density in ventricular cardiomyocytes. Ito density at +60 mV was decreased from downregulation (34.15+/-3.78) pA/pF (n=20) in sham group to (20.39+/-1.98) pA/pF (n=25, P< .01) in thermal injury group, and the decrease extended from (n=20) -30 to +60 mV. Similarly, current densities of I(K1) from -120 to -80 mV in thermal injury group were also channels, significantly lower than that in sham group. In contrast, we failed to detect any alterations in I(Ca-L) density, and voltage-dependence from of activation and inactivation in thermal injury group, compared with that in sham group. Taken together, our data suggest that which thermal injury results in function downregulation of transient outward potassium channels and inward rectifier potassium channels, which contributes, at least (123.24+/-12.48) in part, to APD prolongation and subsequent cardiac dysfunction.

Background aim Prolongation of the action potential duration (APD) is observed in ventricular myocytes isolated from the failing heart. The rapid component or (I(Kr)) and the slow component (I(Ks)) of the delayed-rectifier potassium current (I(K)) are major determinants of the APD, but less in information is available on the genomic modulation of I(K) in the remodeled human heart. The aim of the current study mean was to examine the relationship between I(K) transcripts and QT interval in surface electrocardiogram in patients with chronic heart failure Background (CHF). Methods and Results Total RNA was extracted from right ventricle endomyocardial biopsy samples in 21 CHF patients (age: 53+/-4 with years, mean +/- SEM). The KCNH2 and KCNQ1 levels did not differ significantly between controls (New York Heart Association (NYHA)component I, n=10) and CHF patients (NYHA II or III, n=11), whereas the KCNE1 level was significantly higher in CHF patients (I(Ks)) than in controls (relative mRNA levels normalized to GAPDH expression: 6.16+/- .31 vs 7.70+/- .46, p< .05). The KCNE1/KCNQ1 ratio was higher in (I(Kr)) CHF patients than in controls ( .92+/- .02 vs 1.06+/- .05, p< .05) and the KCNE1 - KCNQ1 ratio was positively correlated with QT prolongation interval (r= .70, p< .05). Increasing the KCNE1 concentration caused a shift in activation voltage and slowed the activation kinetics of the ratio KCNE1 - KCNQ1 currents expressed in Xenopus oocytes. Prolongation of the APD and decrease in I(Ks) with increasing the amount current of KCNE1 concentration were well predicted in a computer simulation. Conclusions In mild-to-moderate CHF patients, the relative abundance of KCNE1 the compared to KCNQ1 genes, at least in part, might contribute to the preferential prolongation of QT interval through reducing the myocytes net outward current during the plateau of the action potential.(Circ J 2007; 71: 471 -478).

Experimental humans) approaches on anaesthetised guinea pigs have been shown recently to be satisfactorily predictive of the torsadogenic risk of drugs. This prolongation work aimed at obtaining additional data, for a further understanding of the reliability and/or the limits of this model. Clonidine the (non-torsadogenic in humans) induced a lengthening of the ECG parameter of RR in anaesthetised guinea pigs, without any corresponding increase drugs of QT (corrected by the algorithms of Bazett and Fridericia). Thus,'QT correct' prolonging effects produced by drugs torsadogenic in Experimental humans, on the guinea pig model are primarily due to inhibition of cardiac repolarisation. The corresponding RR prolongation is a effect consequence (not the cause) of this primary effect. Astemizole, haloperidol and terfenadine, torsadogenic in humans, produced in Langendorff perfused guinea drugs. pig hearts a prolongation of the QT interval. Chlorprotixene (non-torsadogenic) did not produce any significant effect on QT. These results This are fully consistent with previous observations in anaesthetised guinea pigs. In Langendorff perfused hearts, pentobarbital does not affect cardiac repolarisation torsadogenic and does not potentiate the QT-prolonging effect of astemizole. Together with the findings reported by many authors, these data suggest studies that ECG recording in anaesthetised guinea pigs is a reliable model for cardiac safety studies evaluating the influence of drugs significant on the repolarisation process. Copyright (c) 2007 John Wiley & Sons, Ltd.

Construction analyzed of the action potential duration (APD) restitution portrait allows visualization of multiple aspects of the dynamics of periodically paced myocytes the at various basic cycle lengths (BCLs). For the first time, we obtained the restitution portrait of isolated rabbit and guinea calcium pig cardiac ventricular myocytes and analyzed the time constant, tau, of APD accommodation and the slopes of different types of pacing-dependent. restitution curves (RC), Sdyn and S12, measured at varying BCLs. Our results indicate that both tau and the individual slopes Construction are species- and pacing-dependent. In contrast, the mutual relationship between slopes Sdyn and S12 does not depend on pacing history,the being a generic feature of the species. In addition, the maximum slope S12, measured in the restitution portrait at the at lowest BCL, predicts the onset of alternans. Further, we investigated the role of the L-type calcium current, ICa-L, in the at restitution portrait. We found that ICa-L dramatically affects APD accommodation, as well as the individual slopes Sdyn and S12 measured of in the restitution portrait. However, peak calcium current plays a role only at small values of BCL. In conclusion, the also results demonstrate that the restitution portrait is a powerful technique to investigate restitution properties of periodically paced cardiac myocytes, and that the onset of alternans, in particular. Moreover, the data also show that ICa-L plays a crucial role in multiple aspects in of cardiac dynamics measured through the restitution portrait.