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Since its initial description by Jervell and Lange-Nielsen in 1957, the congenital long QT syndrome (LQTS) has been the most investigated cardiac ion channelopathy. A prolonged QT interval in the surface electrocardiogram is the sine qua non of the LQTS and is a surrogate measure of the ventricular action potential duration (APD). Congenital as well as acquired alterations in certain cardiac ion channels can affect their currents in such a way as to increase the APD and hence the QT interval. The inhomogeneous lengthening of the APD across the ventricular wall results in dispersion of APD. This together with the tendency of prolonged APD to be associated with oscillations at the plateau level, termed early afterdepolarizations (EADs), provides the substrate of ventricular tachyarrhythmia associated with LQTS, usually referred to as torsade de pointes (TdP) VT. This review will discuss the genetic, molecular, and phenotype characteristics of congenital LQTS as well as current management strategies and future directions in the field. [ABSTRACT FROM AUTHOR]

Abstract: Since its initial description by Jervell and Lange‐Nielsen in 1957, the congenital long QT syndrome (LQTS) has been the most investigated cardiac ion channelopathy. Although congenital LQTS continues to remain the domain of cardiologists, cardiac electrophysiologists, and specialized centers, the by far more frequent acquired drug‐induced LQTS is the domain of all physicians and other members of the health care team who are required to make therapeutic decisions. This report will review the electrophysiological mechanisms of LQTS and torsade de pointes, electrocardiographic characteristics of acquired LQTS, its clinical presentation, management, and future directions in the field. [ABSTRACT FROM AUTHOR]

Ambulatory ECG (AECG) is very commonly employed in a variety of clinical contexts to detect cardiac arrhythmias and/or arrhythmia patterns which are not readily obtained from the standard ECG. Accurate and timely characterization of arrhythmias is crucial to direct therapies that can have an important impact on diagnosis, prognosis or patient symptom status. The rhythm information derived from the large variety of AECG recording systems can often lead to appropriate and patient-specific medical and interventional management. The details in this document provide background and framework from which to apply AECG techniques in clinical practice, as well as clinical research. [ABSTRACT FROM AUTHOR]

Background. Takotsubo cardiomyopathy (TCM) is sudden and reversible myocardial dysfunction often attributable to physical or emotional triggers. Case Report. We describe a 51-year-old man presented to emergency department with sepsis from urinary tract infection (UTI). He was placed on cefepime for UTI and non-ST-elevation myocardial infarction protocol given elevated troponins with chest pain. Subsequently, patient was pulseless with torsades de pointes (TdP) and then converted to sinus rhythm with cardioversion. An echocardiogram revealed low ejection fraction with hypokinesis of the apical wall. Over 48 hours, the patient was extubated and stable on 3 L/min nasal cannula. He underwent a cardiac catheterization to evaluate coronary artery disease (CAD) and was found to have mild nonobstructive CAD with no further findings. Conclusion. TCM is a rare disorder presenting with symptoms similar to acute coronary syndrome. Though traditionally elicited by physical and emotional triggers leading to transient left ventricular dysfunction, our case suggests that it may also be triggered by a urinary tract infection and lead to severe QT prolongation and a malignant ventricular arrhythmia in TdP. [ABSTRACT FROM AUTHOR]

Background The aim of the study is to contrast the role of conventional ambulatory electrocardiographic monitoring (AEM) artifacts with a less emphasized problem with potentially more serious implications, that is, the failure to recognize, and therefore misinterpret, a genuine arrhythmia episode in the AEM recording. Methods The study material included 500 Holter recordings and 500 recordings from the cardiac telemetry unit. Results Electrocardiographic (ECG) artifacts were more common in telemetry recordings (5.6%) compared to Holter recordings (4%) for a total of 4.8%. There were 35 examples of misinterpretation of AEM recordings (3.5%). These were significantly more common in telemetry recordings (2.6%) compared to Holter recordings (0.9%). The most common ECG artifacts were examples of pseudo ventricular tachyarrhythmia (VT). The majority of misinterpretation (26 of 35 examples) were fast supraventricular tachyarrhythmias with aberrant QRS (including six examples of atrial flutter with periods of 1:1 atrioventricular conduction) that were misdiagnosed as ventricular VT. Other examples were misinterpretation of arrhythmic episodes consistent with sick sinus syndrome, pacemaker malfunction, and long QT syndrome. Only 5 of 48 examples of AEM artifacts resulted in management errors of commission or errors of omission compared to all 35 examples of misinterpretation. Conclusions Compared to conventional artifacts in AEM, misinterpretation of nonartifactual arrhythmic episodes consistently resulted in management errors. Misinterpretation was significantly more common with telemetry recordings compared to Holter ECG. This highlights the need for more appropriate training of the entire clinical team in charge of the management of the cardiac telemetry unit. [ABSTRACT FROM AUTHOR]

Key points Early afterdepolarizations (EADs) are a known trigger for arrhythmias, but the effect of surrounding tissue on EADs is poorly understood., Neurotoxin anthopleurin-A (AP-A) increases action potential duration and gives rise to EADs in isolated myocytes. We investigate the effect of AP-A on connected networks of cultured cardiac cells., We show that EADs are markedly suppressed in well-coupled neonatal rat ventricular monolayers treated with AP-A, but reappear when gap junction connectivity is blocked., The ability of cell coupling to electrotonically damp EADs is confirmed in a two-cell simulation where connectivity is systematically varied., Taken together, these results suggest that cell-cell coupling can act to suppress EADs in normal cardiac tissue. Results also suggest that EADs may emerge and propagate in poorly coupled tissue., Abstract Pathologies that result in early afterdepolarizations (EADs) are a known trigger for tachyarrhythmias, but the conditions that cause surrounding tissue to conduct or suppress EADs are poorly understood. Here we introduce a cell culture model of EAD propagation consisting of monolayers of cultured neonatal rat ventricular myocytes treated with anthopleurin-A (AP-A). AP-A-treated monolayers display a cycle length dependent prolongation of action potential duration (245 ms untreated, vs. 610 ms at 1 Hz and 1200 ms at 0.5 Hz for AP-A-treated monolayers). In contrast, isolated single cells treated with AP-A develop prominent irregular oscillations with a frequency of 2.5 Hz, and a variable prolongation of the action potential duration of up to several seconds. To investigate whether electrotonic interactions between coupled cells modulates EAD formation, cell connectivity was reduced by RNA silencing gap junction Cx43. In contrast to well-connected monolayers, gap junction silenced monolayers display bradycardia-dependent plateau oscillations consistent with EADs. Further, simulations of a cell displaying EADs electrically connected to a cell with normal action potentials show a coupling strength-dependent suppression of EADs consistent with the experimental results. These results suggest that electrotonic effects may play a critical role in EAD-mediated arrhythmogenesis. [ABSTRACT FROM AUTHOR]

Aims: The present study attempts to develop an objective, statistically based set of criteria for activation time determination from unipolar electrograms (U-EGMs) using a standard of activation related to biophysical theory. Methods: A high-resolution assembly of U-EGMs obtained from the epicardial surface of the canine postinfarction heart were analyzed in order to achieve the best prediction of local versus distant activation. An activation time standard (ATS) consisted of three properties: (1) propagation of activation, evidenced by a linear temporal shift of waveforms from closely spaced U-EGMs with little or no decay in amplitude; (2) cycle length-dependent changes of those propagating waveforms; and (3) evidence of electrotonic deflections, seen as nonpropagating potentials having decaying amplitude with distance. Results: A number of U-EGM features were calculated and subjected to analysis by comparing their occurrence with the ATS. A discriminant function analysis incorporating multiple features (Voltage, −dV/dt and Ratio) of major U-EGM deflections improved prediction of activation time of complex fractionated EMGs from ischemic canine epicardium to 90%. Conclusion: A unique discriminant function based on sound biophysical principles markedly improved prediction of activation time of complex U-EGMs from ischemic canine epicardium. A computerized version of the algorithm could be developed to provide more accurate activation maps for both basic and clinical use. (PACE 2011; 34:1105-1115) [ABSTRACT FROM AUTHOR]

A 74-year-old man with past history of near syncope presented with frequent periods of second-degree atrioventricular block (2° AVB). An electrophysiological study revealed prolonged atrial-His and His-ventricular (HV) intervals and frequent His bundle (H) extrasystoles. The latter manifested in the surface electrocardiogram as premature atrial, junctional, or ventricular beats, as well as 2° AVB that mimicked Wenckebach or Mobitz II block. Procainamide markedly suppressed H extrasystole. However, because of the presence of prolonged HV interval and history of presyncope, a permanent pacemaker was inserted. The case illustrates the varied manifestation of H extrasystole and presents guidelines for management. (PACE 2010; 1-4) [ABSTRACT FROM AUTHOR]

Management of Sudden Cardiac Death (SCD) is undergoing a radical change in direction. It is becoming increasingly appreciated that besides depressed left ventricular systolic function and the conventional risk stratification tools, new markers for plaque vulnerability, enhanced thrombogenesis, specific genetic alterations of the autonomic nervous system, cardiac sarcolemmal and contractile proteins, and familial clustering may better segregate patients with atherosclerotic coronary artery disease who are at high risk for SCD from those who may suffer from nonfatal ischemic events. Better understanding of pathophysiological processes, such as postmyocardial infarction remodeling, the transition from compensated hypertrophy to heart failure, and the increased cardiovascular risk of coronary artery disease in the presence of diabetes or even a prediabetic state will help to improve both risk stratification and management. The rapidly developing fields of microchips technology and proteomics may allow rapid and cost-effective mass screening of multiple risk factors for SCD. The ultimate goal is to identify novel methods for risk stratification, risk modification, and prevention of SCD that could be applied to the general public at large. [Copyright &y& Elsevier]

Aims: To compare patients with atrial flutter (AFl) and 1:1 atrioventricular conduction (AVC) with patients with AFl and higher AVC. Methods: The characteristics of 19 patients with AFl and 1:1 AVC (group A) were compared with those of 116 consecutive patients with AFl and 2:1 AVC or higher degree AV block (group B). Results: Age, gender, and left ventricular function were similar in the two groups. In group A versus group B, more patients had no structural heart disease (42% vs 17%, P < 0.05) and syncope/presyncope (90% vs 12%, P < 0.05). The AFl cycle length (CL) in group A was longer than in group B (265 ± 24 ms vs 241 ± 26 ms, P < 0.01). The transition from AFl with 1:1 to 2:1 AVC or vice versa was associated with small but definite changes in AFl CL, which showed larger variations in response to sympathetic stimulation. In group A patients who were studied off drugs, the atrial-His interval was not different from group B, but maximal atrial pacing rate with 1:1 AVC was faster. In group A, five patients were misdiagnosed as ventricular tachyarrhythmias, and three with a defibrillator received inappropriate shocks. Four patients had ablation of AVC and six had ablation of AFl circuit. Conclusions: The main difference between groups A and B may be an inherent capacity of the AV node for faster conduction, especially in response to increased sympathetic tone. The latter affects not only AVC but also the AFl CL. One should be aware of the different presentations of AFl with 1:1 AVC to avoid misdiagnosis/mismanagement and to consider the diagnosis in patients with narrow or wide QRS tachycardia and rates above 220/min. [ABSTRACT FROM AUTHOR]

Introduction: Atrial standstill is a rare heterogeneous arrhythmia characterized by electrical and mechanical standstill and electrical inexcitability. A long-lasting progressive form is seen with cardiac and neuromuscular diseases, and a familial or idiopathic form may have a genetic basis. A transient form was described secondary to drug intoxication, electrolyte imbalance, cardiac inflammation, and ischemia. Methods: We investigated three patients with long-standing atrial tachyarrhythmia (AT) (atrial flutter in two, and focal atrial tachycardia in one). All patients underwent a complete electrophysiological study with mapping of right and left atrial activity and radiofrequency ablation (RF Abl) of AT. Results: Following RF Abl of AT, all three patients manifested transient atrial electrical silence in the absence of known reversible causes. Atrial electrical silence was observed when, following AT termination, an escape atrioventricular (AV) junctional rhythm (in two patients) and an escape VVI pacemaker rhythm (in one patient) showed transient ventriculo-atrial (VA) conduction block (up to 30 seconds). A dominant sinus rhythm was observed to return 30 minutes, 90 minutes, and 12 hours, respectively, in the three patients. Two patients received a dual chamber pacemaker and a decision was made not to upgrade the patient with VVI pacemaker. Discussion and Conclusions: The present report expands the spectrum of the syndrome of atrial standstill and raises interesting questions regarding possible electrophysiologic mechanism(s) of prolonged post overdrive atrial standstill. The report suggests that chronic overdrive of sinus and subsidiary atrial pacemakers may result in calcium overloading of cardiac cells, which is known to cause suppression of pacemaker activity as well as increased intracellular resistance. These mechanisms can possibly result in either prolonged suppression of sinus and atrial pacemaker activity and/or pacemaker exit block. [ABSTRACT FROM AUTHOR]

Available evidence supports the hypothesis that cardiac resynchronization therapy (CRT) results in favorable structural as well as electrical remodeling. Electrical remodeling seems to be related, to a large extent, to structural remodeling, usually referred to as reverse remodeling of left ventricular (LV) dysfunction. This can lead to amelioration of the arrhythmogenic substrate associated with depressed LV systolic function and heart failure. However, a direct electrophysiological effect due to favorable remodeling of repolarization with reduction of the dispersion of repolarization cannot be ruled out. On the other hand, in a small subgroup of patients, CRT could increase the dispersion of repolarization and induce malignant ventricular tachyarrhythmias. Clinical trials have consistently shown improved outcome with CRT-defibrillators (CRT-D) and more trials have demonstrated the benefits of the defibrillator in the population with depressed LV function. However, some physicians argue that implanting the less expensive and less complicated CRT-pacemaker (CRT-P) may be appropriate in certain groups of patients. Before this position is accepted, it is imperative that criteria for the selection of this group of patients with presumably low risk for sudden arrhythmic death as well as the proarrhythmic effect of CRT be clearly defined. [ABSTRACT FROM AUTHOR]

The cardiovascular drug carvedilol is characterized by multiple pharmacological actions, which translate into a wide-spectrum therapeutic potential. Its major molecular targets are membrane adrenoceptors, ion channels, and reactive oxygen species. Carvedilol's favorable hemodynamic effects are due to the fact that the drug competitively blocks β1-, β2-, and α1- adrenoceptors. Several additional properties have been documented and may be clinically important, including antioxidant, antiproliferative/antiatherogenic, anti-ischemic, and antihypertrophic effects. The antiarrhythmic action of carvedilol may be related to a combination of its β-blocking effects with its modulating effects on a variety of ion channels and currents. Several studies suggest that the drug may be useful in reducing cardiac death in high-risk patients with prior myocardial infarction and/or heart failure, as well as for primary and secondary prevention of atrial fibrillation. This article will review experimental data available on the electrophysiologic properties of carvedilol, with a focus on their clinical relevance. [ABSTRACT FROM AUTHOR]

Repolarization Distribution in LQT3. Introduction: The occurrence of significant spatial dispersion of repolarization in vivo as it relates to the mechanism of arrhythmia formation in the long QT syndrome (LQTS) continues to be questioned. Methods and Results: We investigated a guinea pig model of LQT3 using anthopleurin-A (AP-A) to study the contribution of rate-dependent spatial dispersion of repolarization in the intact heart to the arrhythmogenicity of LQTS. Optical action potentials were measured using potentiometric fluorescent dye di-4ANEPPS in Langendorff-perfused hearts with induced AV block. AP-A exacerbated the normal uniform epicardial apex-base action potential duration (APD) gradient, resulting in rate-dependent increased APD dispersion and nonuniform APD gradient. Spontaneous focal premature beats induced functional conduction block along boundaries where large nonuniform APD gradient occurred setting the stage for circulating wavefronts and ventricular tachyarrhythmia (VT). Endocardial ablation abolished spontaneous VT, but nonuniform epicardial APD gradient persisted and could be challenged by a stimulated premature stimulus to induce VT. Conclusion: The study shows that in LQT3, spatial variations in steady-state properties result in zones of nonuniform APD gradients. These provide a substrate for functional conduction block and reentrant excitation when challenged by subendocardial “early afterdepolarization-triggered” premature beats. The study emphasizes the key importance of spatial dispersion of repolarization, whether located in epicardial or intramyocardial layers, in arrhythmia formation in LQTS. (J Cardiovasc Electrophysiol, Vol. 15, pp. 323-331, March 2004) [ABSTRACT FROM AUTHOR]

Risk Stratification and Management of SCD. Management of SCD is undergoing radical change in direction. It is becoming increasingly appreciated that besides depressed left ventricular systolic function and the conventional risk stratification tools, new markers for plaque vulnerability, enhanced thrombogenesis, specific genetic alterations of the autonomic nervous system, cardiac sarcolemmal and contractile proteins, and familial clustering may better segregate patients with atherosclerotic coronary artery disease who are at high risk for SCD from those who may suffer from nonfatal ischemic events. Better understanding of pathophysiologic processes, such as postmyocardial infarction remodeling, the transition from compensated hypertrophy to heart failure, and the increased cardiovascular risk of coronary artery disease in the presence of diabetes or even a prediabetic state will help to improve both risk stratification and management. The rapidly developing fields of microchips technology and proteomics may allow rapid and cost-effective mass screening of multiple risk factors for SCD. The ultimate goal is to identify novel methods for risk stratification, risk modification, and prevention of SCD that could be applied to the general public at large. (J Cardiovasc Electrophysiol, Vol. 14, pp. 1113-1119, October 2003) [ABSTRACT FROM AUTHOR]

Introduction: Compared to concordant T wave alternans (CA), discordant T wave alternans (DA) may be associated with an increased dispersion of repolarization (DR) and a greater propensity to develop reentrant ventricular tachyarrhythmias. The electrophysiologic mechanisms of DA in the in vivo heart are not well understood. Methods and Results: The mechanisms of DA were investigated in the canine anthopleurin-A surrogate model of long QT3 syndrome using tridimensional analysis of activation and repolarization patterns from 256 to 384 unipolar electrograms. Cardiac repolarization was evaluated as the activation-recovery interval (ARI) of local electrograms. Two mechanisms for the development of DA were observed. (1) Stepwise shortening of cycle length (CL) superimposed on preexisting DR resulted in different diastolic intervals (DI) at midmyocardial sites compared to epicardial and endocardial sites. The dispersion of DI coupled with different restitution kinetics at those sites induced DA. (2) The dependence of conduction velocity on DI as the CL is abruptly shortened could result in differential conduction delays at mid sites. This enhanced the dispersion of DI between sites and, coupled with the different restitution kinetics, induced DA. The critical step for the development of DA in both mechanisms was the occurrence of short ARI in two consecutive beats either at epicardial sites in the first mechanism or at mid sites in the second mechanism. Sites with DA had significantly more DR compared to sites with concordant T wave alternans, and ventricular tachyarrhythmias developed mainly in the presence of DA. Conclusion: In the in vivo heart, DA developed due to critical interaction between dispersion of DI and differences in restitution kinetics at different myocardial sites. The dispersion of DI could result from preexisting DR or differential conduction delay at a critical short CL. DA is critically linked to the development of malignant tachyarrhythmias. (J... [ABSTRACT FROM AUTHOR]

Introduction: Microvolt T wave alternans (TWA) has been proposed as a strong independent predictor of malignant ventricular tachyarrhythmias and sudden cardiac death. TWA reproducibility during bicycle stress test has not been previously investigated. We sought to assess the short-term reproducibility of TWA, as well as heart rate (HR) threshold for TWA, and its spatial distribution and magnitude. Methods and Results: The study enrolled 42 patients who were able to complete two bicycle stress tests with HR at peak exercise > 110 beats/min within 4 hours of each other and who had technically adequate recordings for TWA analysis during both tests. Concordant results for TWA determination were obtained in 39 (93%) of 42 cases. TWA was present during both tests in 23 patients and was absent during both tests in 16 patients. In the 23 patients with two positive tests, HR at the onset of TWA was not significantly different during the two tests. Further, the number of leads showing TWA and the magnitude of TWA were not significantly different between the two tests. Conclusion: TWA is characterized by satisfactory short-term reproducibility and, when present, by high temporal and spatial stability. [ABSTRACT FROM AUTHOR]

Introduction: Azimilide dihydrochloride blocks both the rapid (IKr) and slow (IKs) components of the delayed rectified K+ current; dofetilide blocks only IKr. Their efficacies were assessed on atrial flutter reentrant circuits in dogs with surgically induced right atrial enlargement. Methods and Results: Multiple biopsies of the tricuspid valve and banding of the pulmonary artery in male mongrel dogs made them susceptible, about 3 weeks postoperatively, to stimulation-induced sustained (5 min or longer) atrial flutter. Azimilide 3 mg/kg administered intravenously (IV) terminated flutter in 8 of 8 dogs, but a slower, nonsustained arrhythmia could be reinduced in 5. In these 5 dogs, azimilide 10 mg/kg terminated flutter and prevented reinduction. This dose increased effective refractory period significantly more in the slow conduction zone (25%) than in the normal zone (17%) and increased flutter cycle length (37%). Termination followed progressive conduction delay in the slow zone of the reentrant circuit. Dofetilide 1 μg/kg IV terminated flutter in 6 of 6 dogs, but the arrhythmia could be reinduced. At 3 μg/kg, flutter terminated in all dogs and could not be reinduced. Dofetilide also increased the effective refractory period significantly more in the slow zone (17%) than in the normal zone (12%) and increased cycle length (33%), leading to interruption of the arrhythmia circuit. Conclusion: In the canine right atrial enlargement model of circus movement atrial flutter, both azimilide 10 mg/kg IV and dofetilide 3 μg/kg IV were 100% effective in terminating flutter and preventing reinduction. Efficacy relied on a similar mechanism of differentially prolonged refractoriness in the slow conduction component of the reentrant circuit where drug-induced termination occurred. [ABSTRACT FROM AUTHOR]

Previous tridimensional activation mapping showed that the development of functional conduction block at the onset of torsades de pointes was regionally heterogeneous; conduction block was frequently observed in the L V and the interventricular septum (IVS) but not in the RV, in the canine anthopleurin-A (AP-A) model of long QT syndrome (LQTS). This may be related to the distribution of mvocytes with M celllike electrophysiological characteristics. To better understand the regional difference of arrhythmogenicity in LQTS, the authors investigated cycle length related modulation of ventricular repolarization among three different layers: the endocardium (End), mid-myocardium (Mid), and epicardium (Epi) of the LV and RV and at two different areas: the Epi and septum (Sep) in the IVS. The LQT3 model was produced by AP-A in dogs. Using constant pacing and single premature stimulation (S1S2), the ventricular repolarization pattern was analyzed from 256 unipolar electrograms. Activation-recovery intervals (ARIs) were used to estimate local repolarization. In seven experiments, AP-A increased regional AW dispersion to 88.1 ± 36.0 ins in the LV, to 72.9 ± 35.7ms in the IVS. and to 23.0 ± 8.7 ms in the RV at the pacing cycle length (CL) of 7,000 ms. Development of the large ARI dispersion was due to greater ARI prolongation at the Mid site in the LV and at Sep site in the IVS. As the S1S2 interval was shortened, regional ARI dispersion decreased gradually, and finally, ARI dispersion showed a reversal gradient of repobarization between the Mid and Epi sites in the LV and between the Sep and Epi sites in the IVS. Two factors contributed to create the reversal gradient of repolarization: (1) a difference in restitution kinetics at the Mid site in the LV and at the Sep site in the IVS, characterized by a larger Δ ARI and slower time constant (τ), and (2) a difference in diastolic intervals at each site resulting in different input to restitution at the same CL. However, the RV showed small alteration in the transmural dispersion of repolarization in the S1S2 protocol. S2 created heterogeneous functional conduction block in the LV and IVS but not in the RV. In the LQT3 model, the arrhvthmogenicity of torsades do pointes is primarily due to dispersion of repolarizatian in the LV and IVS because of prominent distribution of M cells. The RV seems to participate passively in reentrant excitation during torsades de pointes. [ABSTRACT FROM AUTHOR]

Both the congenital and acquired long QT syndrome are due to abnormalities (intrinsic and/or acquired) of the ionic currents underlying repolarization. The prolongation of repolarization acts as a priming step for the generation of early afterdepolarizations. In the long QT syndrome, it also is associated with increased dispersion of repolarization. Focal early afterdepolarization-induced triggered beat(s) can infringe on the underlying substrate of inhomogeneous repolarization to initiate polymorphic reentrant ventricular tachycardia that sometimes has a characteristic twisting of the QRS axis, referred to as torsades de pointes. [ABSTRACT FROM AUTHOR]

Objectives: This study was conducted to determine the optimal target heart rate (HR) for the use of exercise-induced T-wave alternans (TWA) as an index for risk of malignant ventricular tachyarrhythmias. Background: Rate-dependent TWA is an index of vulnerability to ventricular tachyarrhythmias. However, false positive TWA was reported to occur in normal subjects at high HR. Methods: Two groups were evaluated: Group I: 50 patients with malignant ventricular tachyarrhythmias, who received an implantable cardioverter-defibrillator (ICD); and Group II: 55 agematched normal subjects. In both Groups, TWA was evaluated during symptom-limited bicycle exercise test. Results: Peak HR during exercise test was 103 ± 17 beats/min in Group I, versus 124 ± 18 beats/min in Group II (P < 0.001). In Group I, 4 patients were excluded from analysis, due to high noise level or frequent ectopy during exercise. Out of the remaining 46 patients, TWA was present in 28 patients (61%), and absent in 18 (39%). In group II, TWA was present in four subjects (7%), and absent in 51 (93%). HR at the onset of TWA was 91 ± 11/min in Group I, and 119 ± 12/min in Group II (P < 0.001). Receiver operated characteristics curves demonstrated that a HR of 115 beats/min was the cutoff with the best sensitivity and specificity for TWA (100 and 96%, respectively). None of the patients in Group I developed TWA at HR > 115 beats/min, while two out of four in Group II had TWA at HR > 115/minutes. However, 13 patients in Group I who had no TWA were unable to exercise to a peak HR > 115 beats/min, compared to nine subjects in Group II. Conclusions: A target HR of 115 beats/min was highly sensitive and specific for determination of exercise-induced TWA as an index of risk of malignant ventricular tachyarrhythmias. However, a significant number of patients may not be able to achieve this target HR, resulting in an indeterminate test. The value of pharmacologic testing in this group should be assessed. A.N.E. 2001;6(2):123-128 [ABSTRACT FROM AUTHOR]

Introduction: After a myocardial infarction (MI), the heart undergoes a remodeling process that includes hypertrophy of noninfarcted left ventricular myocytes. Alterations in the genetic expression, including reexpression of fetal isogene patterns, can result in electrophysiologic changes that contribute to the arrhythmogenicity of post-MI heart. The present study investigated possible alterations in gene expression of Na+ channel subtypes, as well as the kinetics of the Na+ current (INa), in 3- to 4-week-old post-MI rat remodeled left ventricular myocardium. Methods and Results: Using a macropatch technique, we showed increased Na+ channel bursting activity during sustained depolarization in post-MI remodeled myocytes resulting in a large slow component of the INa decay. A tetrodotoxin-sensitive current contributed 18% to the prolonged APD90 of isolated post-MI myocytes compared with 6% in control myocytes . Our molecular studies revealed that, in addition to the rat heart I (rH I) subtype, thought to be the predominant subtype that encodes a tetrodotoxin-resistant isoform, the brain subtypes NaCh I and NaCh Ia also are expressed in the rat myocytes. Post-MI remodeled myocardium showed increased expression of NaCh I protein with reversion of the NaCh Ia/NaCh I isoform ratio toward the fetal phenotype. Conclusion: Our findings raise the possibility that the increase in the slow component of INa in post-MI remodeled myocytes is secondary to the increased expression of NaCh I. Additional studies are required to address these questions and to characterize the functional role of the NaCh I subtypes in cardiac myocytes. [ABSTRACT FROM AUTHOR]

Introduction: Down-regulation of key K+ channel subunit gene expression and K+ currents is a universal response to cardiac hypertrophy, whatever the cause, Including the postmyocardial Infarction (post-MI) remodeled heart. Methods and Results: We investigated the hypothesis that down-regulation of K+ channel genes and currents post-MI occurs early and before significant remodeled hypertrophy of the noninfarcted myocardium could be detected. We investigated (1) the Incidence of induced ventricular tachyarrhythmias (VT) in 3-day post-MI rat heart; (2) action potential (AP) characteristics of isolated left ventricular (LV) myocytes from sham-operated and 3-day post-MI head; (3) time course of changes in outward K+ currents Ito-fast(f) and IK in isolated myocytes from 3-day and 4-week post-MI noninfarcted LV and compared the changes with sham-operated animals; and (4) changes in the messenger and protein levels of Kv2.1, Kv4.2, and Kv4.3 In the LV and right ventricle of 3-day post-MI heart. Sustained VT was Induced in 6 of 10 3-day post-MI rats and in none of 8 sham rats. The membrane capacitance of myocytes isolated from 3-day post-MI noninfarcted LV was not significantly different from control, whereas membrane capacitance 4-week post-MI was significantly higher, reflecting the development of hypertrophy. At duration was increased and the density of Ito-f and IK were significantly decreased In 3-day post-MI LV myocytes compared with sham The reduced density of IK, did not significantly differ in 4-week post-MI LV myocytes, whereas the density of IK was decreased further at 4 weeks post-MI. The changes in Ito-f and IK correlated with decreased messenger and protein levels of Kv4.2/Kv4.3 and Kv2.1, respectively. Conclusion: These results support the hypothesis that down-regulation of K+ channel gene expression and current In the post-MI LV occurs early and may be dissociated from the slower time course of post-MI remodeled hypertrophy. These changes may contribute to early arrhythmogenesis of the post-MI head. [ABSTRACT FROM AUTHOR]

Introduction: L-type calcium channels were studied in cell-attached patches from ventricular cell membranes of human fetal heart. Methods and Results: Experiments were performed in the presence of 70 mM Ba2+ as the charge carrier at 22°C to 24°C. Unitary current sweeps were evoked by 300-msec depolarizing pulses to 0 mV from a holding potential of -50 mV at 0.5 Hz. Recorded currents were blocked by nisoldipine (1 μM) and stimulated by (-)Bay K 8644 (1 μM). During control, channel activity was seen in 13.9% ± 4.2% of the total 200 sweeps. Ensemble average current amplitude was 0.03 ± 0.01 pA (n = 6) and average conductance was 20.4 ± 0.2 pS (n = 5). Analysis of single channel kinetics showed open time and closed time histograms were best fit by one and two exponentials, respectively. Mean open time was To = 0.99 ± 0.05 msec (n = 6). Mean closed time fast (Tcf) and slow (Tcs) component values were Tcf = 0.85 ± 0.09 msec and Tcs = 8.0 ± 0.94 msec (n = 6), respectively. With intrapipette (-)Bay K 8644 (1 μM), mean open time was best fit by two exponentials, Tcf = 0.9 ± 0.2 msec (n = 10) and Tos = 134 ± 2.6 msec (n = 10); mean close time values were Tcf = 0.6 ± 0.1 msec (n = 10) and Tcs = 9.8 ± 1.9 msec (n = 10), respectively. With (-)Bay K 8644, channel activity was 66.5% ± 7.4%, the ensemble average current was 0.52 ± 0.04 pA (n = 10) and the conductance 20.7 ± 0.5 pS (n = 5). conclusion: (1) the data establishes the characteristics of L-type Ca channels of human fetal hearts and their modulation by dihydropyridines; (2) the open time kinetics differ from those of avian embryonic and rat fetal hearts; and (3) the findings provide new and relevant information for understanding the physiologic behavior of unitary Ca2+ channels in the developing human heart and the baseline comparison for diseases that implicate Ca2+ channels in their etiology, such as autoimmune-associated congenital heart block. [ABSTRACT FROM AUTHOR]

Currently, three prognostic indicators of ventricular vulnerability are commonly utilized: ambulatory monitoring, programmed electrical stimulation, and signal averaging of late potentials. All three are limited by the fact that they represent electrophysiological phenomena in a fixed stable substrate, and might therefore be of questionable value in long-term prediction. Programmed stimulation, however, appears useful in stratifying patients with complex ventricular arrhythmias, into law- or high-risk groups. This technique may be further enhanced by the addition of-signal-averaged data to better predict future arrhythmic events. [ABSTRACT FROM AUTHOR]

The effects of a single intravenous infusion of 750 mg of procainamide was studied in 12 patients with symptomatic chronic recurrent venlricular tachycardia in whom arrhythmias could reproducibly be initiated and terminated by programmed electrical stimulation of the heart. Sustained ventricular tachycardia was induced in 6 patients and non-sustained tachycardia was induced in the remaining 6 patients during control studies. Following procainamide (plasma level 10.3 ± 3.7 mcg/ml], ventricular tachycardia could be induced in 10/12 patients, sustained in 4 patients and non-sustained in the remaining 6 patients. In 8/12 patients (66%). induction of ventricular tachycardia was facilitated as demonstrated by: (1) tachycardia zone was widened in 4 patients and was unchanged in another 3 patients; (2) non-sustained ventricular tachycardia was changed to sustained ventricular tachycardia in one patient. The ventricular tachycardia had a faster rate and a different QRS morphology; [3] in 4 patients tachycardia was inducible with a lesser number of extrastimuli and/ or by spontaneously occurring ventricular premature depolarization and; (4) increase of the number of induced ventricular responses of non-sustained ventricular tachycardia. In 4/12 patients )(33%), procainamide abolished or modified the induction of ventricular tachycardia as demonstrated by: (1) inability to induce ventricular tachycardia in 2 patients; (2) narrowing of the tachycardia zone and conversion from sustained into non-sustained ventricular tachycardia (one patient) and; (3) decrease in the number of induced ventricular responses in one patient. The response to procainamide could not be predicted from rates of spontaneous ventricular tachycardia, induced ventricular tachycardia during control studies, degree of slowing of ventricular tachycardia or from prolongation of the coupling interval after procainamide. These results suggest that instead of abolishing the arrhythmia, procainamide in frequently employed doses in patients with chronic recurrent ventricular tachycardia can facilitate its initiation sometimes at even faster rates. Patients not responsive to the usual doses of procainamide should undergo acute drug testing trials to determine the optimal dose/drug levels. [ABSTRACT FROM AUTHOR]

A case is described in which ventricular pacing from the middle cardiac vein produced an electrocardiographic pattern which mimicked the morphology of the normally conducted beats. The possible etiologies of this unusual phenomenon and its implications concerning the functional anatomy of the normal conduction system in the human heart are discussed. [ABSTRACT FROM AUTHOR]

Malfunction of both temporary and permanent demand transvenous pacemakers was caused by contact between the two endocardial electrodes. Contact between these electrodes created spurious potentials which resulted in irregular inhibition of both demand units. The potentials were demonstrated by recording from the temporary wire. There was no interference with either pacemaker in the fixed rate mode and malfunction ceased when the temporary wire was removed. [ABSTRACT FROM AUTHOR]

Background: Lack of standardization of software algorithms to identify the end of QRS for time-domain analysis of the signal-averaged electrocardiogram may limit the comparison of results obtained with different machines. Methods: To study this problem, 50 normal volunteers underwent signal-averaged electrocardiogram with ART 1200 EPX and Corazonix Predictor units in random sequence, collecting an equal number of beats. Data were analyzed with five different commercial softwares by ART and Corazonix. Results: Comparison of QRS duration, duration of low amplitude signals, and root mean square voltage of last 40 ms of QRS at two high-pass filter settings (25 and 40 Hz) showed significant differences among softwares. Conclusions: Standardization of software for time-domain analysis of the signal averaged electrocardiogram is warranted; until then, normal values for signal averaged electrocardiogram parameters will have to be appropriately selected for each study, according to the software utilized. [ABSTRACT FROM AUTHOR]

The LQTS is a prime example of bow molecular biology, ion channel, cellular, and organ physiology, coupled with clinical observations, promise to be the future paradigm for advancement of medical knowledge. Both the congenital and acquired LQTS are due to abnormalities (intrinsic and/or acquired) of the ionic currents underlying cardiac repolarization. In this review, the continually unraveling molecular biology of congenital LQTS is discussed. The various pharmacological agents associated with the acquired LQTS are listed. Although it is difficult to predict which patients are at risk for TdP, careful assessment of the risk-benefit ratio is important before prescribing drugs known to be able to cause QT prolongation. The in vivo electrophysiological mechanism of TdP in the LQTS is described using, as a paradigm, the anthopleurin-A canine model, a surrogate for LQT3. In the LQTS, prolonged repolarization is associated with increased spatial dispersion of repolarization. Prolongation of repolarization also acts as a primary step for the generation of EADs. The focal EAD induced triggered beat(s) can infringe on the underlying substrate of inhomogeneous repolarization to initiate polymorphic reentrant VT, sometimes having the characteristic twisting QHS configuration known as TdP. The review concludes by discussion of the clinical manifestations and current management of both the congenital and acquired LQTS. The initial therapy of choice for the large majority of patients with the congenital LQTS is a beta-blocking drug. This therapy seems to be effective in LQT1 and LQT2 patients, but may not be as effective in LQT3 patients. Other therapeutic options include pacemakers, cervicothoracic sympathectomy, and the implantable cardioverter defibrillator. Recent molecular genetic studies have suggested several genotype specific therapies; however, long-term efficacy data are not available. [ABSTRACT FROM AUTHOR]

The value of signal-averaged P-wave electrocardiogram and echocardiography for predicting recurrent atrial tachyarrhythmias was prospectively investigated in 60 patients presenting with paroxysmal atrial fibrillation or flutter. All patients were followed up for 1 year after restoration of sinus rhythm. A stepwise discriminant function analysis sac used to identify variables predicting recurrent atrial tachyarrhythmias. Analyzed variables included signal-averaged P-wave duration in 3 bipolar orthogonal leads (X,Y,Z) and their vector magnitude as well as left and right atrial dimensions and volumes. During follow-up, 25 patients had recurrent curial tachyarrhythmias, while 35 did not. Using discriminant function analysis, the left atrial antero-superior dimension was found to be the only variable predicting the recurrence of atrial tachyarrhythmias (P< 0.0038) and was able to correctly classify 65% of the study patients. It was concluded that, in patients with paroxysmal atrial fibrillation or flutter, the traditionally used determination of left atrial dimension was the variable most closely associated with a high risk for recurrent tacharrhythmias. The signal-averaged P-wave duration did plot improve tachyarrhythmia prediction. [ABSTRACT FROM AUTHOR]

T or U wave alternans in association with long QTU and torsade de pointes (TdP) is uncommon and its mechanism(s) is unknown. We studied three patients with TU alternans, long QTU, and TdP: patient 1 was a newborn with congenital long QTU; patient 2 had marked hypokalemia and hypomagnesemia; and patient 3 was receiving procainamide. In the three patients, TU alternans was tachycardia dependent and preceded the onset of TdP. In the patient on procainamide, TU alternans and TdP occurred at long cardiac cycles. In this patient, endocardial monophasic action potential (MAP) recordings showed that TU alternans was associated with alternation of the duration of the plateau. A deflection consistent with early afterdepolarization (EAD) arose at a constant time interval from phase 0 but alternated from high and low levels of phase 3. The first ectopic heat of TdP arose on the descending limb of the EAD. TU alternans was investigated by MAP recordings in six normal dogs, following the administration of anthopleurin-A (AP-A), a drug shown to delay sodium inactivation and to induce bradycardia dependent long QTU, EADs, and TdP. In two dogs TU alternans was associated with 2:1 recordings of EAD and nearly constant plateau duration. In three dogs, TU alternans was associated with EAD that occurred in consecutive beats at constant time intervals from phase 0, but alternated from high and low phase 3 because of alternation of the duration of the plateau. In one dog, alternation of EAD and plateau duration occurred. In 36 separate episodes of TdP that were analyzed in the six dogs, 32 were bradycardia dependent but four developed on abrupt shortening of the cardiac cycle associated with alternation of action potential duration. Our results suggest: (1) TU alternans may be due to 2:1 propagation of an EAD or to alternation of the recovery kinetics of u repolarization current; (2) The constant occurrence of EAD in relation to phase 0 in spite of alternation of plateau duration suggests an ionic mechanism synchronized to depolarization; (3) Tachycardia dependent TdP in clinical and experimental examples of long QTU seems to be characteristically associated with TU alternans. Dispersion of repolarization may underlie the increased ventricular electrical instability in these cases. [ABSTRACT FROM AUTHOR]

The signal averaged electrocardiogram (SA-ECG), programmed electrical stimulation (PES), and left ventricular ejection fraction (EF) studies were utilized for risk stratification and management of patients with complex ventricular arrhythmias and nonsustained ventricular tachycardia (VT). The study population included 90 patients (63 with coronary artery disease and 27 with dilated cardiomyopathy). Sustained monomorphic VT was induced in 22 cases (24%), ventricular fibrillation (VF) in 10 (11%), and no sustained VT/VF in 58 (64%). An abnormal SA-ECG was recorded in 23 patients (26%) and was more common in patients with than in those without induced sustained VT (68% vs 12%, P < 0.0001). None of 33 patients with normal SA-ECG and EF ≥ 40% had induced VT. Patients were followed-up for 2.5 ± 0.8 years off antiarrhythmic therapy, unless they had induced sustained VT. The 3-year sudden death rate was 19% in the group with induced sustained VT, 0 in that with induced VF, and 9% in that without induced VT/VF (P = NS). The 3-year total cardiac mortality was higher in patients with than in those without EF < 40% (27% vs 7%, P < 0.05). It is concluded that patients with organic heart disease and spontaneous nonsustained VT may not need PES or antiarrhythmic therapy if SA-ECG is normal and EF is ≥ 40%, since their risk of induced VT and sudden death is low. On the other hand, patients with abnormal SA-ECG and/or EF < 40% may require PES, since their risk for induced VT is high. Antiarrhythmic therapy may also be considered in these patients. [ABSTRACT FROM AUTHOR]

The presence of late potentials on the body surface recording was correlated with ventricular activation maps of reentrant circuits in the postinfarction canine model of reentrant excitation. Late potentials were found to correlate with delayed myocardial activation. However, during a reentrant rhythm complete diastolic activity on the body surface could not be detected if the mass of electrically active cells was too small and/or if very slow conduction in part of the reentrant circuit generated low amplitude extracellular potentials. Myocardial zones responsible for late potentials during a basic rhythm (e.g., sinus rhythm) may not necessarily be part of the critical zone of slow conduction during reentrant activation. Dynamic changes in late potentials are not amenable to temporal signal averaging techniques but could be detected by a high resolution beat-to-beat recording. A thorough understanding of the electrophysiological limitations of late potentials in the signal-averaged ECG could result in better utilization of the technique in clinical practice as well as in the development of new approaches for the detection of the arrhythmogenic substrate. [ABSTRACT FROM AUTHOR]

The article focuses on percutaneous cardiac mapping and ablation registry. After the first published reports of therapeutic electrode catheter ablation appeared in 1982, the Percutaneous Cardiac Mapping and Ablation Registry was formed to collect and disseminate information relative to these nonpharmacological techniques for control of refractory cardiac tachyarrhythmias. Thus, the Registry allows physicians to assess the risks and benefits of these procedures. Because this field is evolving, it was considered important to devise a central registry for tracking the course of not only catheter electrode ablation techniques but also those catheter techniques using alternative forms of energy.

Asynchronous pacing during the presence of electromagnetic interference or other sources of "noise" is a protective mechanism available to prevent pacemaker output inhibition. We describe a patient with a DDD pacemaker who had asynchronous dual chamber or noise reversion pacing as a consequence of repetitive signals (QRS complexes) falling into the noise sampling period (NSP) of the pacemaker ventricular refractory period. During supraventricular tachycardi at a rate of 215 bpm, noise reversion mode pacing occurred when QRS complexes were well detected immediately after the termination of a normal pacemaker ventricular refractory period and treated as a premature ventricular depolarization, resulting in automatic refractory period extension. Recycling of this extended refractory period occurred when consecutive QRS complexes were detected during the NSP and forced asynchronous dual chamber pacing at the programmed lower rate. The mechanism is presented and was supported by subthreshold esophageal pacing simulating the tachycadia and initiating the noise reversion response. [ABSTRACT FROM AUTHOR]

Focuses on the importance of reentrant excitation as a mechanism for cardiac arrhythmia. Difficulty of obtaining information on the electrophysiological requirements for reentry; Role of reflection in clinical arrhythmia; Demonstration of the multiple muscular connections between the atrium and ventricle in the human heart.

Presents summaries of pertinent data on attempted ablation of the atrioventricular juntion and ventricular tachycardia foci. Catheter ablation of the atrioventricular junction; Analysis of catheter ablation of ventricular tachycardia foci.

The mechanisms of resetting, entrainment. acceleration, or termination of reentrant ventricular tachycardia by programmed electrical stimulation were studied in the canine post-infarction model. In this model, reentrant circuits were localized in the epicardial layer overlying the infarction and were accessible to detailed mapping by multiplexer techniques. The reentrant circuit has a characteristic figure-eight configuration in the form of two circulating wavefronts around arcs of functional conduction block that coalesce into a slow common reentrant wavefront. Termination of reentrant tachy-cardia occurred when a stimulated wavefront arrived earlier to a strategically located area in the proximal portion of the zone of slow conduction, before refractoriness expired distally, resulting in conduction block. The three factors that determined if the stimulated wavefront could reach this zone in time for conduction block were: (1) the cycle length of stimulation; (2) the number of stimulated beats, and (3) the site of stimulation. The most optimal situation for stimulated termination of reentry was a critically coupled single stimulus applied to the ischemic zone close to the proximal side of the zone of slow conduction that captured locally and conducted prematurely to the strategic zone for conduction block. When a single stimulated wavefront failed to terminate reentry, one or more subsequent wavefronts succeeded. However, the stimulated train had to be terminated following the beat that interrupted reentry. Otherwise, a subsequent stimulated beat could reinitiate the same reentrant circuit or induce a different circuit. The new circuit could have a shorter revolution time, resulting in tachycardia acceleration , and occasionally degeneration into ventricular fibrillation. Overdrive termination of reentry required both a critical cycle length of stimulation and a critical number of beats in a stimulated train. Otherwise, the stimulated train could establish a new.. [ABSTRACT FROM AUTHOR]

Catheter ablation of ventricular tachycardia is a procedure of last resort in critically III patients. The Percutaneous Cardiac Mapping and Ablation Registry was able to collect data on 88 patients undergoing ablation of ventricular tachycardia foci. The mean following interval for the group was 10 ± 8 months. Results were divided into three categories: Group I patients remained asymptomatic and were on no antiarrhythmic medications (33%); Group 11 remained asymptomatic and took antiarrhythmic agents (38%); Group III patients were considered unsuccessful and consisted of 29 percent of the total. More than one-third of patients received two shocks; the remainder received from one to five shocks. Overall mortality included four procedure-related deaths and total follow- up mortality was 25 percent. Catheter ablation for ventricular tachycardia should be undertaken only in highly specialized centers with an expert and experienced electrophysiologist with immediate surgical back-up available. [ABSTRACT FROM AUTHOR]

Provides information about the Percutaneous Cardiac Mapping and Ablation Registry in the U.S. in 1982. Executive management of the registry; Purpose of the registry; Responsibilities of the registry.

There are three current prognostic indicators of ventricular electrical instability: (1) categorization and stratification of spontaneous ventricular arrhythmias from standard EGG recordings; (2) programmed electrical stimulation; (3) direct recording of delayed depolarization potentials, usually referred to as late potentials. Of the three, the latter offers a new and promising approach. Late potentials represent delayed activation potentials of diseased myocardial zones and may prove to be a strong independent marker of the propensity to develop reentrant ventricular arrhythmias and sudden cardiac electrical death. The problem in identifying late potentials on the body surface is that the signal is smaller than the electrical noise produced by various sources. Two different techniques have been utilized to improve the signal-to-noise ratio: first, signal averaging, which is applicable to regular repetitive electrocardiographic signals but cannot detect moment-to-moment dynamic changes in the signal; second, low-noise or high-resolution electrocardiography that utilizes spatial averaging techniques as well as other noise-reducing measures to record the late potentials on a heat-to-beat basis. This technique has the potential of directly identifying malignant "reentrant" versus benign "focal" ventricular rhythms. The present report discusses the electrophysiologic basis of late potentials and the clinical results of both signal-averaged and low-noise recordings for evaluation of ventricular electrical instability, particularly in patients with ischemic heart disease. [ABSTRACT FROM AUTHOR]

A 44-year-old man developed recurrent pulmonary embolization after implantation of a permanent transvenous DVI pacemaker connected to polyurethane leads. Thrombus was found in the left innominate and subclavian veins around the pacemaker leads, but not in the right atrium or in the venous system of the pelvis and the lower extremities. The recurrence of pulmonary embalization followed discontinuation of treatment with Coumadin. This case demonstrates that lifelong anticoagulation is indicated in patients who have had pulmonary, embolization and/or venous thrombosis around the pacemaker leads. [ABSTRACT FROM AUTHOR]

Introduction: The effects of a Class III agent, azimilide dihydrochloride, on atrial flutter circuits were studied in a functional model of single loop reentrant atrial flutter using dogs, 3 to 5 days after production of sterile pericarditis. Methods and Results: A computerized mapping system was used to construct activation maps from 138 to 222 epicardial sites in the right atrium. Doses of 3, 10, and 30 mg/kg IV azimilide dihydrochloride were analyzed in 8 dogs in which sustained atrial flutter lasting more than 30 minutes was induced by burst pacing. Atrial flutter was always due to a single loop circus movement reentry in the lower right atrium. At 3 mg/kg, azimilide dihydrochloride terminated atrial flutter in 2 dogs; however, atrial flutter was reinduced. At 10 mg/kg, atrial flutter was terminated in all 8 dogs but was reinduced in 4 dogs with slower rate. At 30 mg/kg. atrial flutter was terminated in the remaining 4 dogs and could not be reinduced. Atrial flutter cycle length always increased prior to termination. Isochronal activation maps showed that the increase in cycle length was due to additional conduction delays in the slow zone of the reentrant circuit. The site of termination was always located within the slow conduction zone situated in the lower right atrium between the line of functional conduction block and the AV ring. Reflective refractory periods (ERPs) were measured at selected sites in the slow zone and normal zone at twice diastolic threshold for the 10 mg/kg dose. Azimilide preferentially prolonged ERP in the slow zone (42.4 ± 20.1 msec, mean ± SD) compared with the normal zone (23.3 ± 15.4 msec, P < 0.0001). The increase in cycle length corresponded with the increase in ERP in the slow zone. Conclusions: In a functional model of circus movement atrial flutter, azimilide dihydrochloride terminates and prevents reinduction of atrial flutter by a preferential increase in refractoriness leading to further conduction delay and conduction block in the slow zone of the functional reentrant circuit. [ABSTRACT FROM AUTHOR]