Transient outward current, Ito1, is altered in cardiac memory.

BACKGROUND: Cardiac memory refers to an altered T-wave morphology induced by ventricular pacing or arrhythmias that persist for variable intervals after resumption of sinus rhythm. METHODS AND RESULTS: We induced long-term cardiac memory (LTM) in conscious dogs by pacing the ventricles at 120 bpm for 3 weeks. ECGs were recorded daily for 1 hour, during which time pacing was discontinued. At terminal study, the heart was removed and the electrophysiology of left ventricular epicardial myocytes was investigated. Control (C) and LTM ECG did not differ, except for T-wave amplitude, which decreased from 0.12+/-0.18 to -0.34+/-0.21 mV (+/-SEM, P<0.05), and T-wave vector, which shifted from -37+/-12 degrees to -143+/-4 degrees (P<0.05). Epicardial action potentials revealed loss of the notch and lengthening of duration at 20 days (both P<0.05). Calcium-insensitive transient outward current (Ito) was investigated by whole-cell patch clamp. No difference in capacitance was seen in C and LTM myocytes. Ito activated on membrane depolarization to -25+/-1 mV in C and -7+/-1 mV (P<0.05) in LTM myocytes, indicating a positive voltage shift of activation. Ito density was reduced in LTM myocytes, and a decreased mRNA level for Kv4.3 was observed. Recovery of Ito from inactivation was significantly prolonged: it was 531+/-80 ms (n=10) in LTM and 27+/-6 ms (n=9) in C (P<0.05) at -65 mV. CONCLUSIONS: Ito changes are associated with and can provide at least a partial explanation for action-potential and T-wave changes occurring with LTM.

Vagal release of vasoactive intestinal peptide can promote vagotonic tachycardia in the isolated innervated rat heart.

OBJECTIVE: The aim was to determine the extent to which endogenous release of vasoactive intestinal polypeptide (VIP) might be implicated in the modulation of sinoatrial rate in the presence and absence of muscarinic blockade or beta blockade. METHODS: Langendorff perfused rat hearts were studied with the right vagus intact. The hearts were maintained in sinus rhythm and subjected to right vagal stimuli of 5, 10, 20, and 30 Hz. RESULTS: Administration of exogenous VIP, 10(-8) M, increased sinus rate by 20% (p < 0.05). This increase in heart rate was reduced significantly to 8% by the VIP antagonist [D-p-Cl-Phe6, Leu17]VIP, 10(-7) M, which alone had no effect on sinus rate. Vagal stimulation reduced sinus rate from a control of 254(SEM 2) to 164(17) beats.min-1 (p < 0.05) at 20 Hz. VIP, 10(-8) M, increased these rates to 284(6) and 220(21) beats.min-1 (p < 0.05). In another eight vagally stimulated hearts, frequencies of 5-20 Hz reduced sinus rate. At 30 Hz heart rate increased in five, and the resultant rate was significantly faster in these [154(10) beats.min-1] than in the remainder [98(12) beats.min-1, p < 0.05]. Vagal stimulation also increased sinus rate (p < 0.05) in four of seven additional hearts perfused with atropine, 2 x 10(-6) M. This increase was completely abolished by [D-p-Cl-Phe6, Leu17]VIP. That the effect was not beta adrenergic was demonstrated in eight experiments using atropine plus propranolol, 1 x 10(-7) M. A vagally induced increment in rate still occurred (p < 0.05) and was abolished by [D-p-CL-Phe6, Leu17]VIP. The ability to ascribe a rate change to VIP release was maximal in the presence of propranolol and atropine, intermediate in the presence of atropine alone, and minimal in the absence of muscarinic or beta blockade. CONCLUSIONS: Vagally released VIP is capable of limiting the decrement in sinus rate that occurs at high frequencies of vagal stimulation, and in some circumstances can actually increment sinus rate. Its role as an endogenous modulator of vagal effects on heart rate and as a possible cause of vagal and postvagal tachycardias should be further explored.

Steady-state and nonsteady-state action potentials in fibrillating canine atrium: abnormal rate adaptation and its possible mechanisms.

OBJECTIVE: Our goal was to study rate adaptation of atrial action potentials in non-steady and steady states to further our understanding of mechanisms determining inducibility and stability of atrial fibrillation. METHODS: We used standard microelectrode techniques to examine the characteristics of steady-state action potentials paced at regular cycle lengths (CL) and of nonsteady-state action potentials observed after an abrupt change of CL in atria from canine hearts that had been rapidly paced. RESULTS: We compared action potential characteristics among normal atria, atria in which chronic atrial fibrillation (cAF, lasting more than 3 days) had been induced and atria in which only nonsustained atrial fibrillation (nAF, lasting less than 12 h) had been induced. In steady-state, the rate adaptation of maximum diastolic potential (MDP) and action potential duration (APD) and markedly reduced in both cAF and nAF. Action potential characteristics did not differ between cAF and nAF atria, suggesting that factors other than electrophysiological properties determine the chronicity of AF. The time course of change in APD after an abrupt change of CL was altered in nAF/cAF atria; i.e., when CL was prolonged, APD also prolonged at the first beat, and then shortened during several subsequent beats (initial phase). Thereafter, APD slowly prolonged to a new steady-state (slow phase). In nAF/cAF atria, the initial phase was enhanced (greater shortening of APD) and the slow phase was reduced (less prolongation of APD). This latter phase was modified by ryanodine. CONCLUSIONS: Thus the reduced rate adaptation of steady-state APD is explained mainly by the loss of a slow phase of APD adaptation in nAF/cAF which is reversed in the presence of ryanodine. Therefore, in both nAF and cAF atria, rate adaptation of MDP as well as APD are reduced, nonsteady state as well as steady state, AP characteristics are markedly altered and these changes are partially explicable by Ca, -dependent processes.

Interactions between antiarrhythmic drugs and cardiac memory.

OBJECTIVE: Ventricular pacing or arrhythmias can induce cardiac memory (CM). We hypothesized that clinically administered antiarrhythmic drugs alter the expression of CM, and that the repolarization changes characteristic of CM can modulate the effects of antiarrhythmic drugs. METHODS: We studied conscious, chronically-instrumented dogs paced for two 1-h periods to study the effects of drugs on the evolution of memory (protocol 1) or for 21 days (protocol 2) to observe the effects of steady-state memory on drug actions. Dogs were treated in both settings with quinidine, lidocaine or E4031, in random order, and within therapeutic serum concentration ranges. RESULTS: Pacing, alone, for 2 h significantly prolonged ERP only near the left ventricular pacing site, whereas pacing alone for 21 days prolonged ERP at all sites (P<0.05). Quinidine and E4031, but not lidocaine, prolonged repolarization and ERP and suppressed evolution of CM in protocol 1. However, quinidine's effect in prolonging repolarization was diminished in both protocols, while its effect in prolonging ERP was diminished in the 21-day protocol only. In contrast, the effects of E4031 were additive to those of CM, prolonging repolarization and ERP in both protocols, while lidocaine showed no changes in effect at all. CONCLUSIONS: Pacing to induce CM significantly affects ventricular repolarization and refractoriness, and there are interactions between CM, quinidine and E4031. Depending on the specific drug, these interactions have the potential to be anti- or proarrhythmic, and may impact importantly on the clinical efficacy of drugs as well as on electrophysiologic testing of drug actions.

Abnormal cardiac repolarization and impulse initiation in German shepherd dogs with inherited ventricular arrhythmias and sudden death.

OBJECTIVE: We tested the hypothesis that delayed afterdepolarization (DAD)-associated rhythms in German shepherd dogs with reduced anteroseptal left ventricular (LV) sympathetic innervation derive from abnormal beta-adrenergic receptor effector coupling. METHODS AND RESULTS: In anteroseptal LV midmyocardium of afflicted dogs, beta-receptor density was greater than that in normal dogs (P < .05), with affinity being equal in both groups. Basal and maximum isoproterenol (ISO) stimulated adenylyl cyclase activity of anteroseptal LV of afflicted dogs was greater than that in normal dogs (P < .05). Isolated anteroseptal M cell preparations of afflicted dogs studied with microelectrodes showed abnormal lengthening, rather than shortening of action potential duration in response to ISO, as well as a 61% incidence of 10(-7) mol/l ISO-induced triggered activity as compared to 12% in normals (P < .05). In contrast, there was no difference between afflicted and control dogs in triggered activity, beta-receptors or adenylyl cyclase activity in a normally innervated region of the ventricles. CONCLUSION: In this model there is an increase in beta-receptor density and beta-adrenergic stimulation of adenylyl cyclase and of triggered activity in anteroseptal myocardium but not in a normally innervated region of the heart. Hence, abnormal beta-adrenergic signal transduction appears associated with the neural abnormality identified in dogs with inherited VT.

[A method of modeling of occlusion-reperfusion induced myocardial infarction and quantitative evaluation of the effectiveness of limitation of its size]. / Metod modelirovaniia okkliuzionno-reperfuzionnogo infarkta miokarda i kolichestvennoi otsenki éffektivnosti ogranicheniia ego razmerov.

An experimental mathematical model was proposed to assess the efficiency of experimental myocardial infarction (MI) size limitation. A canine model of occlusion-reperfusion myocardial lesion was used in an acute experiment with an open chest. 90-minute occlusion and 4-hour reperfusion were performed by carotid coronary bypass surgery. The necrotic zone and the risk area were visualized by double perfusion with tetrazolium staining. Retrograde coronary blood flow was used as a measure of collateral blood flow. The multiple linear regression equation with values of the risk zone and retrograde blood flow/risk area ratio used as independent variables enabled the size of myocardial infarction to be highly accurately predicted. Comparison of the true size of MI with the "expected" one provided methods for quantitative assessment of pharmacological limitation of MI sizes. Calculating an individual value for each animal made it possible to examine its relation to coronary circulation parameters and facilitated comparison of benefits from various agents.

[Impact of exercise test on signal-averaged ECG in patients with myocardial infarction]. / Vliianie nagruzochnogo testa na signal-usrednennuiu EKG u bolnykh infarktom miokarda.

To examine the impact of exercise test (bicycle ergometry) and exercise-induced transient ischemic changes in ST segment on signal-averaged ECG parameters, the authors studied a homogeneous group including 65 patients (62 males and 3 females) with a 2-3-week history of primary myocardial infarction. The findings showed that induced myocardial ischemia caused no significant changes in signal-averaged ECG and late potentials, exercise might induce late potentials without clear-cut ECG signs of myocardial ischemia. It was also indicated that exercise-labile late potentials were significantly more frequently associated with the development of ventricular arrhythmias than steady late potentials.

[Dynamic signal-averaged ECG during spontaneous stenocardia attacks in patients with ischemic heart disease]. / Dinamika sigtnal-usrednennoi EKG vo vremia spontannykh pristupov stenokardii u bol'nykh ishemicheskoi bolezn'iu serdtsa.

The dynamics of signal-averaged ECG and late potentials was studied in 19 patients with coronary heart disease during spontaneous anginal episodes. Baseline late potentials were observed in 9 (45%) patients, they remaining in all during and after anginal episodes. The occurrence of new late potentials was recorded in none of them. There were no significant differences in some parameters of signal-averaged ECG before, during, and after an anginal episode, though the duration of low-amplitude signals tended to increase at the end of the QRS complex and the mean square amplitude of late 40 msec of QRS complex decreased during transient myocardial ischemia. The differences did not achieve their statistical significance. It was concluded that transient myocardial ischemia during spontaneous anginal episodes failed to lead to the appearance of a substrate for the occurrence of late potentials.

[The effect of transient myocardial ischemia on the late potentials during transluminal coronary angioplasty in patients with ischemic heart disease]. / Vliianie prekhodiashchei ishemii miokarda na pozdnie potentsialy pri transliuminal'noi koronarnoi angioplastike u bol'nykh ishemicheskoi bolezn'iu serdtsa.

The frequency of recording late potentials and their dynamics were studied in 25 patients with coronary heart disease before, during, and after transluminal angioplasty (TAP). Baseline late potentials were observed in 6 (20.7%) cases. During TAP, late potentials were recorded significantly more frequently (48.3%) than the baseline ones (p < 0.03), in 6 (20.7%) patients, late potentials appeared only in arterial dilatation and disappeared after TAP. There was a profound decrease in root-mean-square amplitude of late 40 msec in the QRS complex and an increase in the duration of low-amplitude (less than 40 microV) signals at the end of the QRS complex as compared to the baseline values. In ST-segment elevation, the parameters of the ECG signal-average become deteriorated to a greater degree than those in ST-segment depression.

[The dynamics of the signal-averaged ECG in myocardial infarct patients]. / Dinamika signal-usrednennoi EKG u bol'nykh infarktom miokarda.

To study the dynamics of signal-averaged ECG and late potentials (LP) in the first month of myocardial infarction (MI) and the impact of coronary reperfusion on them, examinations were made of 98 patients with primary myocardial infarction, in 69 of whom coronary reperfusion was achieved. LP was found to be detectable just in the first hours of MI, their stabilization (steady-state appearance or cessation) mainly occurred at day 3 of the onset. LP detection at this time allowed them to be predicted before the patients' discharge (70% sensitivity and 95% specificity, 82% predictive value in the first 24 hours of MI, LPs are characterized by more instability than those in the subsequent period of the patients' hospitalization. Thrombolytic therapy and coronary artery patency have no impact on the frequency of LP recording and parameters of signal-averaged ECG. No significant difference was found in the frequency of recording LP in anterior and inferior MI before discharge. The frequency of LP recording does not depend on the sex and age of a patient, the maximum creatine phosphokinase levels, and the presence of postinfarction angina pectoris and heart failure.

[Effect of echinochrom on experimental myocardial reperfusion injury]. / Vliianie ekhinokhroma na éksperimental'noe reperfuzionnoe povrezhdenie miokarda.

Echinochrom, a new antioxidant of the polyhydroxynaphthaquinone class, was tested for its cardioprotective activity in a model of occlusive reperfusion myocardial infarction (90-min occlusion and 4-hour reperfusion) in the acute experiments with open-chest dogs. The bolus intravenous injection of echinochrom in a dose of 1 mg/kg 5 min before reperfusion caused a significant (over 40%) reduction in the size of a necrotic focus. A supplementary administration of echinochrom 5 min after the onset of ischemia failed to contribute to a significant enhancement of its protective effect, suggesting that there is no substantial effect of the agent on ischemic lesion. The efficacy of echinochrom given after prolonged ischemia, low effective doses, and no adverse effects create prerequisites for using the drug in the clinical setting.

Developmental changes in modulation of cardiac repolarization by sympathetic stimulation: the role of beta- and alpha-adrenergic receptors.

INTRODUCTION: Our goals were to study the role of development in determining the cardiac effects of sympathetic neural activation, and to identify the roles of alpha- and beta-adrenergic receptor-mediated pathways in modulating the effects of sympathetic stimulation. METHODS AND RESULTS: We compared responses of young and adult canine hearts in situ to right, left, and bilateral stellate ganglion stimulation. We focused on changes in heart rate, rhythm, QT interval, rate-corrected QT interval (QTc), and T wave amplitude. Right stellate stimulation (RSS) induced more pronounced sinus tachycardia in adult than young animals. Left stellate stimulation (LSS) induced junctional tachycardia in adult more than young animals. In adults, LSS and RSS prolonged QTc (LSS > RSS), whereas 1-week-olds manifested QTc shortening with RSS. LSS also increased T wave amplitude, most markedly in adults. In all studies, bilateral stellate stimulation induced responses intermediate between those seen with RSS and LSS. beta-Adrenergic blockade (propranolol) abolished all responses to LSS in adult hearts, but alpha-blockade (prazosin) attenuated only the LSS-induced prolongation in QTc. CONCLUSION: In the postnatal modulation of cardiac rhythm, rate, and repolarization by the sympathetic nervous system, beta-adrenergic receptors play a major role at all ages, whereas alpha-adrenergic receptors play a lesser role, which is manifested only in adults. Moreover, expression of junctional tachycardias, which are beta-adrenergically modulated, is seen only in the adults.

Altering ventricular activation remodels gap junction distribution in canine heart.

INTRODUCTION: Prolonged arrhythmic or paced ventricular activation causes persistent changes in myocardial conduction and repolarization that may result from altered electrotonic current flow, for which gap junctional coupling is the principal determinant. Remodeling of gap junctions and their constituent connexins modifies conduction and has been causally implicated in reentrant arrhythmogenesis. We hypothesized conversely that altering the pattern of ventricular activation causes gap junctional remodeling. METHODS AND RESULTS: Seven dogs were paced from the left ventricular (LV) epicardium (VVO, approximately 120 beats/min) for 21 days before excision of transmural LV samples that were divided into endomyocardial, mid-myocardial, and epimyocardial layers. Another five paced dogs had recording electrodes attached to multiple LV sites. All 12 dogs developed characteristic pacing-induced persistent T wave changes of cardiac memory. After 21 days of pacing, the ventricularly paced QRS duration prolonged by a mean of 4 msec over baseline (P < 0.05), a change that was associated with significant slowing of intraventricular conduction to local sites. These changes in QRS duration and repolarization were associated with a reduction in epimyocardial connexin43 expression on quantitative Western blotting of LV myocardium from close to, but not distant from, the pacing site (61.7+/-18.4 vs 100.9+/-34.0; P < 0.02) and a marked disruption in immunolabeled connexin43 distribution in epimyocardium only. CONCLUSION: Spatially distinct transmural and regional gap junctional remodeling is a consequence of abnormal ventricular activation and is associated with consistent changes in activation that may alter patterns of repolarization and facilitate reentrant arrhythmogenesis.

Evolution and resolution of long-term cardiac memory.

BACKGROUND: Cardiac memory (CM) refers to T-wave changes induced by ventricular pacing or arrhythmia that accumulate in magnitude and duration with repeated episodes of abnormal activation. We report herein the kinetics of long-term CM and its association with the ventricular action potential. METHODS AND RESULTS: Dogs were paced from the ventricles at rates of 110 to 120 bpm for approximately 3 weeks. CM characterized by gradual sinus rhythm T vector rotation toward the paced QRS vector evolved in all dogs regardless of pacing site (left ventricular [LV] anterior apex or base, posterior LV, or right ventricular free wall). Cardiac hemodynamics and myocardial flow (microsphere studies) were unaltered by the pacing. Recovery time for the memory T wave to return to control increased with duration of the previous pacing. The protein synthesis inhibitor cycloheximide markedly (P<.05) and reproducibly attenuated evolution of CM. When pacing was performed from the atrium, CM did not occur. Standard microelectrode techniques were used to study action potential from the LV free wall of control and CM dogs. CM was associated with increased action potential duration in epicardial and endocardial but not midmyocardial cells, significantly altering the transmyocardial gradient for repolarization. CONCLUSIONS: CM is a dynamic process for which the final T vector is predicted by the paced QRS vector and which is associated with significant changes in epicardial and endocardial but not midmyocardial cell action potential duration, such that the transmural gradient of repolarization is altered. It is unaccompanied by evidence of altered hemodynamics or flow, requires a change in pathway of activation, and appears to require new protein synthesis.

Synthesis of some hydroxynaphthazarins and their cardioprotective effects under ischemia-reperfusion in vivo.

A series of hydroxynaphthazarins has been synthesized. Some of them were found in in vivo experiments to be protectors of myocardium under ischemia-reperfusion and to reduce the infarction zone by 50% without any adverse effect. All compounds exhibit a moderate or small toxicity and are active in low doses.