Incidentally Induced Atrial Fibrillation During Programmed Electrical Stimulation in Patients With Depressed Left Ventricular Systolic Function After an Acute Myocardial Infarction.

BACKGROUND: The aim of this study was to investigate the clinical implication of incidentally induced atrial fibrillation (AF) during programmed electrical stimulation (PES) in patients with left ventricular systolic dysfunction (≤40%) after an acute myocardial infarction (MI). METHODS: In this study, we included 231 patients from the Cardiac Arrhythmias and RIsk Stratification after Myocardial InfArction (CARISMA) study with left ventricular ejection fraction ≤40% and no prior history of AF. These patients underwent PES 6 weeks post-MI as part of the study protocol. Patients all received an implantable cardiac monitor (ICM) 3-21 days post-MI and were continuously monitored for cardiac arrhythmias for 2 years. Induction of AF was unwanted but reported if this incidentally occurred. RESULTS: A total of 61 patients (26%) developed AF within 2 years of follow-up, in which n = 10 (29%) had incidental AF during PES at baseline. The overall risk of AF was not significantly increased in patients with incidental AF (n = 34) during PES compared to patients without incidental AF (n = 197) (HR 1.6 [0.9-3.0], p = 0.14). The risk of bradyarrhythmia (HR = 0.2 [0.0-1.2], p = 0.07), ventricular arrhythmias (HR = 0.7 [0.1-5.8], p = 0.77), and major cardiovascular events (MACE) (HR 0.5 [0.2-1.7], p = 0.28) was not significantly different in patients with versus without incidental AF. CONCLUSIONS: Incidentally induced AF during PES in post-MI patients with reduced LVEF was not significantly associated with a higher risk of long-term atrial fibrillation, other cardiac arrhythmias, or major cardiac events. TRIAL REGISTRATION: NCT00145119.

Late life-threatening arrhythmia in patients with Brugada syndrome: Results from long-term follow-up in a large Japanese cohort.

INTRODUCTION: Most patients with Brugada syndrome (BrS) are first diagnosed in their 40s, with sudden cardiac death (SCD) often occurring in their 50s. Ventricular fibrillation (VF) may occur in some patients with BrS despite having been asymptomatic for a long period. This study aimed to assess the incidence and risk factors for late life-threatening arrhythmias in patients with BrS. METHODS: Patients with BrS (n = 523; mean age, 51 ± 13 years; male, n = 497) were enrolled. The risk of late life-threatening arrhythmia was investigated in 225 patients who had experienced no cardiac events (CEs: SCD or ventricular tachyarrhythmia) for at least 10 years after study enrollment. The incidence of CEs during the follow-up period was examined. RESULTS: During the follow-up of the 523 patients, 59 (11%) experienced CEs. The annual incidences of CEs were 2.87%, 0.77%, and 0.09% from study enrollment to 3, 3-10, and after 10 years, respectively. Among 225 patients who had experienced no CEs for at least 10 years after enrollment, four patients (1.8%) subsequently experienced CEs. Kaplan-Meier analysis revealed significant differences in the incidence of late CEs between patients with and without a history of symptoms (p = .032). The positive and negative predictive values of late CEs for the programmed electrical stimulation (PES) test were 2.9% and 100%, respectively. CONCLUSION: Our results suggest that patients with BrS who are asymptomatic and have no ventricular tachycardia/VF inducibility by PES are at extremely low risk of experiencing late life-threatening arrhythmias.

In Vivo Cardiac Electrophysiology in Mice: Determination of Atrial and Ventricular Arrhythmic Substrates.

Cardiac arrhythmias are a common cardiac condition that might lead to fatal outcomes. A better understanding of the molecular and cellular basis of arrhythmia mechanisms is necessary for the development of better treatment modalities. To aid these efforts, various mouse models have been developed for studying cardiac arrhythmias. Both genetic and surgical mouse models are commonly used to assess the incidence and mechanisms of arrhythmias. Since spontaneous arrhythmias are uncommon in healthy young mice, intracardiac programmed electrical stimulation (PES) can be performed to assess the susceptibility to pacing-induced arrhythmias and uncover the possible presence of a proarrhythmogenic substrate. This procedure is performed by positioning an octopolar catheter inside the right atrium and ventricle of the heart through the right jugular vein. PES can provide insights into atrial and ventricular electrical activity and reveal whether atrial and/or ventricular arrhythmias are present or can be induced. Here, we explain detailed procedures used to perform this technique, possible troubleshooting scenarios, and methods to interpret the results obtained. © 2024 Wiley Periodicals LLC. Basic Protocol: Programmed electrical stimulation in mice.

Intracardiac electrophysiology to characterize susceptibility to ventricular arrhythmias in murine models.

Introduction: Sudden cardiac death (SCD) and ventricular fibrillation are rare but severe complications of many cardiovascular diseases and represent a major health issue worldwide. Although the primary causes are often acute or chronic coronary diseases, genetic conditions, such as inherited channelopathies or non-ischemic cardiomyopathies are leading causes of SCD among the young. However, relevant experimental models to study the underlying mechanisms of arrhythmias and develop new therapies are still needed. The number of genetically engineered mouse models with cardiac phenotype is growing, making electrophysiological studies in mice essential tools to study arrhythmogenicity and arrhythmia mechanisms and to test novel treatments. Recently, intracardiac catheterization via the jugular vein was described to induce and record ventricular arrhythmias in living anesthetized mice. Several strategies have been reported, developed in healthy wild-type animals and based on aggressive right ventricular stimulation. Methods: Here, we report a protocol based on programmed electrical stimulation (PES) performed in clinical practice in patients with cardiac rhythm disorders, adapted to two transgenic mice models of arrhythmia - Brugada syndrome and cardiolaminopathy. Results: We show that this progressive protocol, based on a limited number of right ventricular extrastimuli, enables to reveal different rhythmic phenotypes between control and diseased mice. In this study, we provide detailed information on PES in mice, including catheter positioning, stimulation protocols, intracardiac and surface ECG interpretation and we reveal a higher susceptibility of two mouse lines to experience triggered ventricular arrhythmias, when compared to control mice. Discussion: Overall, this technique allows to characterize arrhythmias and provides results in phenotyping 2 arrhythmogenic-disease murine models.

Cardiac electrophysiology studies in mice via the transjugular route: a comprehensive practical guide.

Cardiac arrhythmias are associated with cardiovascular morbidity and mortality. Cardiac electrophysiology studies (EPS) use intracardiac catheter recording and stimulation for profound evaluation of the heart's electrical properties. The main clinical application is investigation and treatment of rhythm disorders. These techniques have been translated to the murine setting to open opportunities for detailed evaluation of the impact of different characteristics (including genetics) and interventions on cardiac electrophysiology and -pathology. Currently, a detailed description of the technique of murine transjugular EPS (which is the standard route of catheter introduction) is lacking. This article provides detailed information on EPS in mice via the transjugular route. This includes catheter placement, stimulation protocols, intracardiac tracing interpretation, artifact reduction, and surface ECG recording. In addition, reference values as obtained in C57BL/6N mice are presented for common electrophysiological parameters. This detailed methodological description aims to increase accessibility and standardization of EPS in mice. Ultimately, also human research and patient care may benefit from translation of the knowledge obtained in preclinical models using this technique.NEW & NOTEWORTHY Electrophysiology studies (EPS) allow in-depth evaluation of cardiac electrophysiology and -pathology. These techniques have been adapted to the murine setting for (translational) studies, mainly focusing on arrhythmogenesis. Despite the frequent application of EPS via the transjugular route, a thorough description of the technique is currently lacking. This article aims to function as a comprehensive guide, also elaborating (for the first time) on nonsurgical aspects such as catheter positioning, tracing artifacts, stimulation protocols, and reference values.

Utility of electrophysiologic testing for sudden death risk stratification in cardiac sarcoidosis patients with mildly impaired left ventricular function.

BACKGROUND: Ventricular arrhythmias (VA) account for at least 25% of deaths caused by cardiac sarcoidosis (CS) and may arise in patients with mildly impaired LVEF (>35%). OBJECTIVE: In the current study, we examine whether EP study may be used for sudden death risk stratification in CS patients who have mildly impaired LVEF and a diagnosis of highly probable or probable CS according to the World Association of Sarcoidosis and Other Granulomatous Diseases Sarcoidosis Organ Assessment Instrument (WASOGI). METHODS: All patients: (1) exhibited a diagnosis of highly probable or probable CS according to the WASOGI, (2) exhibited cardiac MRI findings consistent with CS, (3) exhibited LVEF >45% and (4) underwent EP study. Device interrogations, transmissions and medical records were reviewed for all patients. RESULTS: We identified 46 CS patients with mildly impaired LVEF. VA were induced in 11 patients and 10/11 patients underwent ICD placement. Thirty-five patients had no VA and 24/35 patients underwent placement of an ILR. During the follow-up period, the VA event rate was 6.5%. The negative and positive predictive values of the EP study for the development of VA were 100% and 27.2%, respectively. CONCLUSIONS: In CS patients with mildly impaired LVEF and a diagnosis of highly probable or probable CS, a negative EP study was highly predictive of the absence of VA. The successful execution of future prospective studies is contingent upon enrollment of phenotypically homogenous cardiac sarcoidosis patients.

Pacing site- and rate-dependent shortening of retrograde conduction time over the slow pathway after atrial entrainment of fast-slow atrioventricular nodal reentrant tachycardia.

INTRODUCTION: We tested our hypothesis that atrial entrainment pacing (EP) of a) the common-type (com-) fast-slow (F/S-) atypical atrioventricular nodal reentrant tachycardia (AVNRT) using a typical slow pathway (SP), or b) the superior-type (sup-) F/S-AVNRT using a superior SP, both modify the retrograde conduction time across the SP immediately after termination of EP (retro-SP-time). METHODS: We measured the difference in the His-atrial interval (HA difference) immediately after cessation of EP, performed at 2 ± 2 rates from the high right atrium (HA[1]-HRA) versus from the proximal coronary sinus (HA[1]-CS) in 17 patients with com-F/S-AVNRT and 11 patients with sup-F/S-AVNRT. We also measured the atrial-His and HA intervals of the first and second cycles immediately after cessation of EP and during stable tachycardia. RESULTS: Unequal responses, defined as a ≥ 20-ms HA difference at ≥1 EP rates, were observed in 16 patients (57%), including 7 with com- and 9 with sup-F/S-AVNRT. Irrespective of the EP rate, all unequal responses of com-F/S-AVNRT were due to a shorter HA[1]-CS than HA[1]-HRA, with a mean 34 ± 11 ms HA difference, whereas all unequal responses of sup-F/S-AVNRT were due to a longer HA[1]-CS than HA[1]-HRA, with a mean 49 ± 25 ms HA difference. The unequal responses resolved within two cycles after the cessation of EP. CONCLUSIONS: We have identified a little-known pacing site- and pacing rate-dependent shortening of the retro-SP-time.

Risk stratification in asymptomatic patients with Brugada syndrome: Utility of multiple risk factor combination rather than programmed electrical stimulation.

BACKGROUND: The prognostic value of programmed electrical stimulation (PES) in Brugada syndrome (BrS) remains controversial. Asymptomatic BrS patients generally have a better prognosis than those with symptoms. The purpose of this study was to evaluate the value of nonaggressive PES with up to two extra stimuli and predict clinical factors for risk stratification in asymptomatic BrS patients. METHODS: The study enrolled 193 consecutive asymptomatic BrS patients with type 1 ECG (mean age: 50 ± 13 years, 180 males) who underwent PES using a nonaggressive uniform protocol. Cardiac events (CEs: sudden cardiac death or ventricular tachyarrhythmia) during the follow-up period were examined. RESULTS: During a mean follow-up of 101 ± 48 months, seven asymptomatic patients (3.6%) had a CE. The incidence of CEs was not different between patients with and without inducible ventricular tachyarrhythmia by PES (p = .51). The clinical significance of risk factor combinations, including spontaneous type 1 ECG, family history of sudden cardiac death, QRS duration in lead V2 , and presence of J wave, was evaluated. Using the Kaplan-Meier method according to the number of risk factors, the prevalence of CE in patients with three or four risk factors was determined to be significantly higher than in those with one risk factor (p = .02 and p = .004, respectively). CONCLUSIONS: The present study suggests that inducibility of ventricular tachyarrhythmia does not predict future CEs in asymptomatic BrS patients. Combination analysis of the other four clinical risk parameters may be effective for risk assessment.

Impact of atrial programmed electrical stimulation techniques on unipolar electrogram morphology.

INTRODUCTION: Intra-atrial conduction abnormalities are associated with the development of atrial fibrillation (AF) and cause morphological changes of the unipolar atrial electrogram (U-AEGM). This study examined the impact of different atrial programmed electrical stimulation (APES) protocols on U-AEGM morphology to identify the most optimal APES protocol provoking conduction abnormalities. METHODS: APES techniques (14 protocols) were applied in 30 patients referred for an electrophysiology study, consisting of fixed rate, extra, and decremental stimuli at different frequencies. U-AEGM morphologies including width, amplitude, and fractionation for patients without (control group) and with a history of AF (AF group) were examined during APES. In addition, sinus rhythm (SR) U-AEGMs preceding different APES protocols were compared to evaluate the morphology stability over time. RESULTS: U-AEGM morphologies during SR before the APES protocols were comparable (all P > .396). Atrial refractoriness was longer in the AF group compared to the control group (298 ± 48 vs 255 ± 33 ms; P ≤ .020), but did not differ between AF patients with and without amiodarone therapy (278 ± 48 vs 311 ± 40 ms; P ≥ .126). Compared to the initial SR morphology, U-AEGM width, amplitude, and fractionation changed significantly during the 14 different APES protocols, particularly in the AF group. In both groups, U-AEGM changes in morphology were most pronounced during fixed-rate stimulation with extra stimuli (8S1-S2 = 400-250 ms). CONCLUSION: APES results in significant changes in U-AEGM morphology, including width, amplitude, and fractionation. The impact of APES differed between APES sequence and between patients with and without AF. These findings suggest that APES could be useful to identify AF-related conduction abnormalities in the individual patient.

A model for human action potential dynamics in vivo.

Computational modeling based on experimental data remains an important component in cardiac electrophysiological research, especially because clinical data such as human action potential (AP) dynamics are scarce or limited by practical or ethical concerns. Such modeling has been used to develop and test a variety of mechanistic hypotheses, with the majority of these studies involving the rate dependence of AP duration (APD) including APD restitution and conduction velocity (CV). However, there is very little information regarding the complex dynamics at the boundary of repolarization (or refractoriness) and reexcitability. Here, we developed a "minimal" ionic model of the human AP, based on in vivo human monophasic AP (MAP) recordings obtained during clinical programmed electrical stimulation (PES) to address the progressive decrease in AP take-off potential (TOP) and associated CV slowing seen during three tightly spaced extrastimuli. Recent voltage-clamp data demonstrating the effect of intracellular calcium on sodium current availability were incorporated and were required to reproduce large (>15 mV) elevations in take-off potential and progressive encroachment. Introducing clinically observed APD gradients into the model enabled us to replicate the dynamic response to PES in patients leading to conduction block and reentry formation for the positive, but not the negative, APD gradient. Finally, we modeled the dynamics of reentry and show that spiral waves follow a meandering trajectory with a period of ~180 ms. We conclude that our model reproduces a variety of electrophysiological behavior including the response to sequential premature stimuli and provides a basis for studies of the initiation of reentry in human ventricular tissue.NEW & NOTEWORTHY This work presents a new model of the action potential of the human which reproduces the complex dynamics during premature stimulation in patients.

Systematic Review for the 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society.

BACKGROUND: Although large randomized clinical trials have found that primary prevention use of an implantable cardioverter-defibrillator (ICD) improves survival in patients with cardiomyopathy and heart failure symptoms, patients who receive ICDs in practice are often older and have more comorbidities than patients who were enrolled in the clinical trials. In addition, there is a debate among clinicians on the usefulness of electrophysiological study for risk stratification of asymptomatic patients with Brugada syndrome. AIM: Our analysis has 2 objectives. First, to evaluate whether ventricular arrhythmias (VAs) induced with programmed electrostimulation in asymptomatic patients with Brugada syndrome identify a higher risk group that may require additional testing or therapies. Second, to evaluate whether implantation of an ICD is associated with a clinical benefit in older patients and patients with comorbidities who would otherwise benefit on the basis of left ventricular ejection fraction and heart failure symptoms. METHODS: Traditional statistical approaches were used to address 1) whether programmed ventricular stimulation identifies a higher-risk group in asymptomatic patients with Brugada syndrome and 2) whether ICD implantation for primary prevention is associated with improved outcomes in older patients (>75 years of age) and patients with significant comorbidities who would otherwise meet criteria for ICD implantation on the basis of symptoms or left ventricular function. RESULTS: Evidence from 6 studies of 1138 asymptomatic patients were identified. Brugada syndrome with inducible VA on electrophysiological study was identified in 390 (34.3%) patients. To minimize patient overlap, the primary analysis used 5 of the 6 studies and found an odds ratio of 2.3 (95% CI: 0.63-8.66; p=0.2) for major arrhythmic events (sustained VAs, sudden cardiac death, or appropriate ICD therapy) in asymptomatic patients with Brugada syndrome and inducible VA on electrophysiological study versus those without inducible VA. Ten studies were reviewed that evaluated ICD use in older patients and 4 studies that evaluated unique patient populations were identified. In our analysis, ICD implantation was associated with improved survival (overall hazard ratio: 0.75; 95% confidence interval: 0.67-0.83; p<0.001). Ten studies were identified that evaluated ICD use in patients with various comorbidities including renal disease, chronic obstructive pulmonary disease, atrial fibrillation, heart disease, and others. A random effects model demonstrated that ICD use was associated with reduced all-cause mortality (overall hazard ratio: 0.72; 95% confidence interval: 0.65-0.79; p<0.0001), and a second "minimal overlap" analysis also found that ICD use was associated with reduced all-cause mortality (overall hazard ratio: 0.71; 95% confidence interval: 0.61-0.82; p<0.0001). In 5 studies that included data on renal dysfunction, ICD implantation was associated with reduced all-cause mortality (overall hazard ratio: 0.71; 95% confidence interval: 0.60-0.85; p<0.001).

Systematic review for the 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society.

BACKGROUND: Although large randomized clinical trials have found that primary prevention use of an implantable cardioverter-defibrillator (ICD) improves survival in patients with cardiomyopathy and heart failure symptoms, patients who receive ICDs in practice are often older and have more comorbidities than patients who were enrolled in the clinical trials. In addition, there is a debate among clinicians on the usefulness of electrophysiological study for risk stratification of asymptomatic patients with Brugada syndrome. AIM: Our analysis has 2 objectives. First, to evaluate whether ventricular arrhythmias (VAs) induced with programmed electrostimulation in asymptomatic patients with Brugada syndrome identify a higher risk group that may require additional testing or therapies. Second, to evaluate whether implantation of an ICD is associated with a clinical benefit in older patients and patients with comorbidities who would otherwise benefit on the basis of left ventricular ejection fraction and heart failure symptoms. METHODS: Traditional statistical approaches were used to address 1) whether programmed ventricular stimulation identifies a higher-risk group in asymptomatic patients with Brugada syndrome and 2) whether ICD implantation for primary prevention is associated with improved outcomes in older patients (>75 years of age) and patients with significant comorbidities who would otherwise meet criteria for ICD implantation on the basis of symptoms or left ventricular function. RESULTS: Evidence from 6 studies of 1138 asymptomatic patients were identified. Brugada syndrome with inducible VA on electrophysiological study was identified in 390 (34.3%) patients. To minimize patient overlap, the primary analysis used 5 of the 6 studies and found an odds ratio of 2.3 (95% CI: 0.63-8.66; p=0.2) for major arrhythmic events (sustained VAs, sudden cardiac death, or appropriate ICD therapy) in asymptomatic patients with Brugada syndrome and inducible VA on electrophysiological study versus those without inducible VA. Ten studies were reviewed that evaluated ICD use in older patients and 4 studies that evaluated unique patient populations were identified. In our analysis, ICD implantation was associated with improved survival (overall hazard ratio: 0.75; 95% confidence interval: 0.67-0.83; p<0.001). Ten studies were identified that evaluated ICD use in patients with various comorbidities including renal disease, chronic obstructive pulmonary disease, atrial fibrillation, heart disease, and others. A random effects model demonstrated that ICD use was associated with reduced all-cause mortality (overall hazard ratio: 0.72; 95% confidence interval: 0.65-0.79; p<0.0001), and a second "minimal overlap" analysis also found that ICD use was associated with reduced all-cause mortality (overall hazard ratio: 0.71; 95% confidence interval: 0.61-0.82; p<0.0001). In 5 studies that included data on renal dysfunction, ICD implantation was associated with reduced all-cause mortality (overall hazard ratio: 0.71; 95% confidence interval: 0.60-0.85; p<0.001).

Systematic Review for the 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society.

BACKGROUND: Although large randomized clinical trials have found that primary prevention use of an implantable cardioverter-defibrillator (ICD) improves survival in patients with cardiomyopathy and heart failure symptoms, patients who receive ICDs in practice are often older and have more comorbidities than patients who were enrolled in the clinical trials. In addition, there is a debate among clinicians on the usefulness of electrophysiological study for risk stratification of asymptomatic patients with Brugada syndrome. AIM: Our analysis has 2 objectives. First, to evaluate whether ventricular arrhythmias (VAs) induced with programmed electrostimulation in asymptomatic patients with Brugada syndrome identify a higher risk group that may require additional testing or therapies. Second, to evaluate whether implantation of an ICD is associated with a clinical benefit in older patients and patients with comorbidities who would otherwise benefit on the basis of left ventricular ejection fraction and heart failure symptoms. METHODS: Traditional statistical approaches were used to address 1) whether programmed ventricular stimulation identifies a higher-risk group in asymptomatic patients with Brugada syndrome and 2) whether ICD implantation for primary prevention is associated with improved outcomes in older patients (>75 years of age) and patients with significant comorbidities who would otherwise meet criteria for ICD implantation on the basis of symptoms or left ventricular function. RESULTS: Evidence from 6 studies of 1138 asymptomatic patients were identified. Brugada syndrome with inducible VA on electrophysiological study was identified in 390 (34.3%) patients. To minimize patient overlap, the primary analysis used 5 of the 6 studies and found an odds ratio of 2.3 (95% CI: 0.63-8.66; P=0.2) for major arrhythmic events (sustained VAs, sudden cardiac death, or appropriate ICD therapy) in asymptomatic patients with Brugada syndrome and inducible VA on electrophysiological study versus those without inducible VA. Ten studies were reviewed that evaluated ICD use in older patients and 4 studies that evaluated unique patient populations were identified. In our analysis, ICD implantation was associated with improved survival (overall hazard ratio: 0.75; 95% confidence interval: 0.67-0.83; P<0.001). Ten studies were identified that evaluated ICD use in patients with various comorbidities including renal disease, chronic obstructive pulmonary disease, atrial fibrillation, heart disease, and others. A random effects model demonstrated that ICD use was associated with reduced all-cause mortality (overall hazard ratio: 0.72; 95% confidence interval: 0.65-0.79; P<0.0001), and a second "minimal overlap" analysis also found that ICD use was associated with reduced all-cause mortality (overall hazard ratio: 0.71; 95% confidence interval: 0.61-0.82; P<0.0001). In 5 studies that included data on renal dysfunction, ICD implantation was associated with reduced all-cause mortality (overall hazard ratio: 0.71; 95% confidence interval: 0.60-0.85; P<0.001).

Effect of flecainide on atrial fibrillatory rate in a large animal model with induced atrial fibrillation.

BACKGROUND: Atrial fibrillatory cycle length has been considered one of the indices of atrial electrical remodelling during atrial fibrillation (AF), which can be assessed from surface ECG by computer-assisted calculation of atrial fibrillatory rate (AFR). Horses have been suggested as a bona fide model for AF studies since horses too, develop lone AF, however data on AF characteristics in horses are extremely sparse and non-invasive characterization of AF complexity using surface ECG processing has not been reported. AIM: The aim was to study characteristics of induced AF and its modification by flecainide. METHODS: The study group consisted on 3 horses with spontaneous persistent AF and 13 with pace-induced AF. Seven horses were treated with saline (control) and eight with flecainide (2 mg/kg). ECGs were analysed using spatiotemporal cancellation of QRST complexes and calculation of AFR from the residual atrial signal. RESULTS: At AF onset, AFR was 295 ± 52 fibrillations per minute (fpm) in the horses with induced AF treated with flecainide, 269 ± 36 fpm in the control group (ns), and 364 ± 26 fpm in the horses with spontaneous persistent AF (P < 0.05 compared to the control group). Flecainide caused a decrease in AFR in all animals and restored sinus rhythm in the animals with induced AF. In the control animals, AFR increased from 269 ± 36 fpm to a plateau of 313 ± 14 fpm before decreasing to 288 ± 28 fpm during the last 10% of the AF episodes preceding spontaneous conversion (P < 0.05). CONCLUSION: AFR in horses with induced AF resembles AFR in humans with paroxysmal AF. Flecainide caused a rapid decrease in AFR in all horses, further supporting the method to be a non-invasive technique to study the effect of antiarrhythmic compounds.

Enhancement of Gap Junction Function During Acute Myocardial Infarction Modifies Healing and Reduces Late Ventricular Arrhythmia Susceptibility.

OBJECTIVES: The purpose of this study was to investigate the effects of enhancing gap junction (GJ) coupling during acute myocardial infarction (MI) on the healed infarct scar morphology and late post-MI arrhythmia susceptibility. BACKGROUND: Increased heterogeneity of myocardial scarring after MI is associated with greater arrhythmia susceptibility. We hypothesized that short-term enhancement of GJ coupling during acute MI can produce more homogeneous infarct scars, reducing late susceptibility to post-MI arrhythmias. METHODS: Following arrhythmic characterization of a rat 4-week post-MI model (n = 24), another 27 Sprague-Dawley rats were randomized to receive rotigaptide to enhance GJ coupling (n = 13) or to saline control (n = 14) by osmotic minipump immediately prior to and for the first 7 days following surgically induced MI. At 4 weeks post-MI, hearts were explanted for ex vivo programmed electrical stimulation (PES) and optical mapping. Heterogeneity of infarct border zone (IBZ) scarring was quantified by histomorphometry. RESULTS: Despite no detectable differences in infarct size at 4 weeks post-MI, rotigaptide-treated hearts had reduced arrhythmia susceptibility during PES (inducibility score for rotigaptide: 2.4 ± 0.8; for control: 5.0 ± 0.6; p = 0.02) and less heterogeneous IBZ scarring (dispersion of IBZ complexity score: rotigaptide: 1.1 ± 0.1; control: 1.4 ± 0.1; p = 0.04), associated with an improvement in IBZ conduction velocity (rotigaptide: 43.1 ± 3.4 cm/s; control: 34.8 ± 2.0 cm/s; p = 0.04). CONCLUSIONS: Enhancement of GJ coupling for only 7 days at the time of acute MI produced more homogeneous IBZ scarring and reduced arrhythmia susceptibility at 4 weeks post-MI. Short-term GJ modulation at the time of MI may represent a novel treatment strategy to modify the healed infarct scar morphology and reduce late post-MI arrhythmic risk.

Programmed electrical stimulation for risk stratification of patients with ischemic cardiomyopathy.

BACKGROUND: Patients with ischemic cardiomyopathy (ICM) are at an increased risk for sudden death. Although earlier trials used programmed electrical stimulation (PES) for risk stratification, more recent data demonstrate the benefit of implantable cardiac defibrillators (ICDs) in selected patients with reduced left ventricular ejection fraction (LVEF) without performing PES. However, little is known about the outcome of non-inducible patients. The purpose of this study was to evaluate the efficacy of PES for mortality risk stratification in patients with ICM. METHODS: All consecutive patients who met the inclusion criteria (history of coronary artery disease, LVEF≤35%, and absence of documented spontaneous sustained ventricular tachycardia or aborted sudden cardiac death) were included in the study. The stimulation protocol involved up to three extrastimuli from two different sites in the right ventricle, with 180 ms as the shortest coupling interval. The primary endpoint was overall survival. RESULTS: A total of 198 patients were included in the study; of these, 60 exhibited negative (-)PES, and 138 had positive (+)PES and also underwent ICD implantation. The mean follow-up duration was 4.5 years. There was no difference in age or LVEF between the patient groups. We found a trend towards an increased 5-year survival rate in the (+)PES group in whom ICD implantation had been performed (p=0.058). Survival was significantly better in patients under 68 year olds in the (+)PES group in whom ICD implantation was performed (hazard ratio=0.3, p=0.01). The survival rate of patients ≥68 years old was similar in both groups (p=0.95). CONCLUSIONS: Non-inducibility during PES does not predict the prognosis of patients with ischemic cardiomyopathy.

Transplantation of adipose tissue-derived stem cells improves cardiac contractile function and electrical stability in a rat myocardial infarction model.

The transplantation of adipose tissue-derived stem cells (ADSCs) improves cardiac contractility after myocardial infarction (MI); however, little is known about the electrophysiological consequences of transplantation. The purpose of this study was to clarify whether the transplantation of ADSCs increases or decreases the incidence of ventricular tachyarrhythmias (VT) in a rat model of MI. MI was induced experimentally by permanent occlusion of the left anterior descending artery of Lewis rats. ADSCs were harvested from GFP-transgenic rats, and were cultured until passage four. ADSCs (10×10(6)) resuspended in 100µL saline or pro-survival cocktail (PSC), which enhances cardiac graft survival, were injected directly into syngeneic rat hearts 1week after MI. The recipients of ADSCs suspended in PSC had a larger graft area compared with those receiving ASDCs suspended in saline at 1week post-transplantation (number of graft cells/section: 148.7±10.6 vs. 22.4±3.4, p<0.05, n=5/group). Thereafter, all ADSC recipients were transplanted with ASDCs in PSC. ADSCs were transplanted into infarcted hearts, and the mechanical and electrophysiological functions were assessed. Echocardiography revealed that ADSC recipients had improved contractile function compared with those receiving PSC vehicle (fractional shortening: 21.1±0.9 vs. 14.1±1.2, p<0.05, n≥12/group). Four weeks post-transplantation, VT was induced via in vivo programmed electrical stimulation. The recipients of ADSCs showed a significantly lower incidence of induced VT compared with the control (31.3% vs. 83.3%, p<0.05, n≥12/group). To understand the electrical activity following transplantation, we performed ex vivo optical mapping using a voltage sensitive dye, and found that ADSC transplantation decreased conduction velocity and its dispersion in the peri-infarct area. These results suggest that ADSC transplantation improved cardiac mechanical and electrophysiological functions in subacute MI.

Pharmacologic inhibition of small-conductance calcium-activated potassium (SK) channels by NS8593 reveals atrial antiarrhythmic potential in horses.

BACKGROUND: Small-conductance calcium-activated potassium (SK) channels have been found to play an important role in atrial repolarization and atrial fibrillation (AF). OBJECTIVE: The purpose of this study was to investigate the existence and functional role of SK channels in the equine heart. METHODS: Cardiac biopsies were analyzed to investigate the expression level of the most prominent cardiac ion channels, with special focus on SK channels, in the equine heart. Subcellular distribution of SK isoform 2 (SK2) was assessed by immunohistochemistry and confocal microscopy. The electrophysiologic and anti-AF effects of the relative selective SK channel inhibitor NS8593 (5 mg/kg IV) were evaluated in anesthetized horses, focusing on the potential of NS8593 to terminate acute pacing-induced AF, drug-induced changes in atrial effective refractory period, AF duration and vulnerability, and ventricular depolarization and repolarization times. RESULTS: Analysis revealed equivalent mRNA transcript levels of the 3 SK channel isoforms in atria compared to ventricles. Immunohistochemistry and confocal microscopy displayed a widespread distribution of SK2 in both atrial and ventricular cardiomyocytes. NS8593 terminated all induced AF episodes (duration ≥15 minutes), caused pronounced prolongation of atrial effective refractory period, and reduced AF duration and vulnerability. QRS duration and QTc interval were not affected by treatment. CONCLUSION: SK channels are widely distributed in atrial and ventricular cardiomyocytes and contribute to atrial repolarization. Inhibition by NS8593 terminates pacing-induced AF of short duration and decreases AF duration and vulnerability without affecting ventricular conduction and repolarization. Thus, inhibition by NS8593 demonstrates clear atrial antiarrhythmic properties in healthy horses.