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Bruce Sheldon Stambler,1 Leonard M Ngunga2 1Department of Cardiac Electrophysiology, Piedmont Heart Institute Cardiology/Electrophysiology, Atlanta, GA, USA; 2Department of Cardiology, Aga Khan University Hospital, Nairobi, Kenya Abstract: Health care in Sub-Saharan Africa is being challenged by a double burden of disease as lifestyle diseases common in the developed world, such as stroke and atrial fibrillation (AF), increase, while, simultaneously, health issues of the developing world in terms of communicable disease persist. The prevalence of AF is lower in Africa than in the developed world but is expected to increase significantly over the next few decades. Patients with AF in Africa tend to be younger and have a higher prevalence of rheumatic valvular heart disease than patients with AF in other regions. Permanent AF is the most prevalent type of AF in Africa, possibly due to the lower use of rhythm control strategies than in the developed world. Mortality rates of patients with AF in Africa are high, due largely to poor health care access and suboptimal therapy. The risk of stroke in AF, which is moderate to high in Africans as in the developed world, contributes to the high mortality rate. Patients with AF in Africa are often undertreated with antithrombotics, as cost and access to monitoring are major barriers. Vitamin K antagonists, including warfarin, are the most commonly available oral anticoagulants, but regular monitoring can be challenging, especially for patients in remote areas. Several non-vitamin K antagonist oral anticoagulants (NOACs) have been approved for use in countries across Sub-Saharan Africa and have the potential to reduce stroke burden. The higher cost of newer agents may be offset by the reduced need for regular monitoring, fixed dosing, and lower risk of intracranial bleeding; NOACs could provide a treatment option for patients in remote areas with limited access to regular monitoring. However, NOACs are not indicated in valvular AF. More work is needed to increase understanding of the epidemiology of AF and stroke, as well as to improve management strategies to reduce the burden of cardiovascular disease predicted for Africa. Keywords: stroke, real-world treatment, treatment guidelines, barriers to care, non-vitamin K antagonist oral anticoagulants

BackgroundStandard clinical practice permits the use of either single-chamber ventricular pacemakers or dual-chamber pacemakers for most patients who require cardiac pacing. Ventricular pacemakers are less expensive, but dual-chamber pacemakers are believed to be more physiologic. However, it is not known whether either type of pacemaker results in superior clinical outcomes.MethodsThe Pacemaker Selection in the Elderly study was a 30-month, single-blind, randomized, controlled comparison of ventricular pacing and dual-chamber pacing in 407 patients 65 years of age or older in 29 centers. Patients received a dual-chamber pacemaker that had been randomly programmed to either ventricular pacing or dual-chamber pacing. The primary end point was health-related quality of life as measured by the 36-item Medical Outcomes Study Short-Form General Health Survey.ResultThe average age of the patients was 76 years (range, 65 to 96), and 60 percent were men. Quality of life improved significantly after pacemaker implantation (P

Studies of atrial fibrillation (AF) have demonstrated that a stable rhythm of very short cycle length in the left atrium (LA) can cause fibrillatory conduction in the rest of the atria. We tested the hypothesis that fast Fourier transform (FFT) analysis of atrial electrograms (AEGs) during this AF will rapidly and reliably identify LA-to-right atrium (RA) conduction pathway(s) generated by the driver. Methods and Results: During induced atrial tachyarrhythmias in the canine sterile pericarditis and rapid ventricular pacing-induced congestive heart failure models, 380-404 AEGs were recorded simultaneously from epicardial electrodes on both atria. FFT analysis of AEGs during AF demonstrated a dominant frequency peak in the LA (driver), and multiple frequency peaks in parts of the LA and the most of the RA. Conduction pathways from the LA driver to the RA varied from study-to-study. They were identified by the presence of multiple frequency peaks with one of the frequency peaks at the same frequency as the driver, and traveled (1) inferior to the inferior vena cava (IVC); (2) between the superior vena cava and the right superior pulmonary vein (RSPV); (3) between the RSPV and the right inferior pulmonary vein (RIPV); (4) between the RIPV and the IVC; and (5) via Bachmann's bundle. Conduction pathways identified by FFT analysis corresponded to the conduction pathways found in classical sequence of activation mapping. Computation time for FFT analysis for each AF episode took less than 5 minutes. Conclusion: FFT analysis allowed rapid and reliable detection of the LA-to-RA conduction pathways in AF generated by a stable and rapid LA driver. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Different analysis techniques have been developed to help understand and characterize the mechanisms responsible for atrial arrhythmias. We tested the hypothesis that Fast Fourier Transform (FFT) analysis of recorded atrial electrograms (AEGs) will rapidly and accurately identify regular and irregular patterns of atrial activation, and, thereby, may provide evidence suggestive of underlying mechanisms of atrial tachyarrhythmias. METHODS AND RESULTS: During induced atrial tachyarrhythmias in both the canine sterile pericarditis model and canine rapid ventricular pacing-induced congestive heart failure model; 380-404 AEGs were recorded simultaneously from epicardial electrodes on both atria. From AEGs, atrial activation sequences were determined during atrial flutter (AFL), focal atrial tachycardia (AT), and atrial fibrillation (AF). Four-second recording segments of each AEG were subjected to FFT analysis. Frequencies found during FFT analyses in all studies precisely corresponded to the cycle lengths of the AEGs. In AFL and AT, one dominant frequency peak was found throughout both atria. In AF due to multiple unstable reentry circuits, multiple and broad frequency peaks were found in both atria. In AF due to a stable rapid rhythm (driver) in the left atrium with fibrillatory conduction to the rest of the atria, one dominant frequency peak in areas with 1:1 conduction from the driver, and multiple and/or broad frequency peaks in areas with fibrillatory conduction produced by the driver were found. Computation time for all FFT analyses took <5 minutes. CONCLUSION: FFT analysis accurately and rapidly identifies global atrial activation patterns during AFL, AT, and AF, thereby assisting in determining arrhythmia mechanisms. [ABSTRACT FROM AUTHOR]

INTRODUCTION: This study examined the relationship between dobutamine facilitation of ventricular tachyarrhythmia (VT) inducibility with programmed electrical stimulation (PES) and dobutamine stress-induced myocardial ischemia. METHODS AND RESULTS: Twenty patients with prior myocardial infarction and cardiac arrest or sustained VT but no sustained VT induced at baseline electrophysiologic testing underwent repeat PES during dobutamine infusion. Ischemia (new or worsened wall-motion abnormality) was documented by echocardiography performed in conjunction with PES. Eight patients were receiving Class I or III antiarrhythmic drugs and seven beta-blockers. Dobutamine facilitated induction of sustained VT in 16 patients (80%) and provoked ischemia in 13 patients (65%). Induction of VT was associated with ischemia in 9 patients (56%). VTs associated with ischemia were induced at higher dobutamine doses (26 +/- 11 vs 11 +/- 10 microg/kg per min, P = 0.02) than were VTs without ischemia (n = 7). Among 13 patients with provoked ischemia, 9 (69%) had VTs induced and 4 remained noninducible. The onset of ischemia occurred at the same dose as induction of VT in 5 patients and at a lower dose in 4 patients. Monomorphic VT (318 +/- 59 ms) was induced in 13 patients, of whom 8 (62%) had ischemia. The ECG morphology of VT suggested an origin in a myocardial segment that demonstrated initial viability at low doses then ischemic dysfunction at higher doses preceding VT induction in 7 (88%) of 8 patients. CONCLUSION: Dobutamine enhances inducibility of sustained VTs during PES. The temporal and anatomic association of dobutamine-induced ischemia and VT suggests that at high dobutamine doses, ischemia may contribute to ventricular arrhythmia inducibility in some patients. [ABSTRACT FROM AUTHOR]

We compared 1-year survival in patients receiving implantable cardioverter defibrillators (ICDs) that provide only shock therapy with more advanced ICDs that provide antitachycardia pacing, bradycardia pacing, low-energy cardioversion, and advanced detection algorithms. Outcome in patients with advanced-generation ICD systems was similar or improved compared with outcome in patients receiving ICDs with only monophasic shock. [ABSTRACT FROM AUTHOR]

Etripamil, a fast-acting nondihydropyridine L-type calcium channel blocker, is under investigation for potential self-administration for the acute treatment of supraventricular tachyarrhythmias in a medically unsupervised setting. We report detailed pharmacokinetics and pharmacodynamics of intranasally administered etripamil in healthy adults from 2 Phase 1, randomized, double-blind studies: Study MSP-2017-1096 (sequential dose-escalation, crossover study design, n = 64) and NODE-102 (single dose, 4-way crossover study, n = 24). Validated bioanalytical assays determined plasma concentrations of etripamil and its inactive metabolite. Noncompartmental pharmacokinetic parameters were calculated. Pharmacodynamic parameters were determined for PR interval, blood pressure, and heart rate. Etripamil was rapidly absorbed intranasally, with time to maximal plasma concentration of 5-8.5 minutes, corresponding to a rapid greater than 10% increase in mean maximum PR interval from baseline within 4-7 minutes of doses of 60 mg or greater. Following peak plasma concentrations, systemic etripamil levels declined rapidly within the first 15 minutes following dosing and decreased more gradually thereafter. PR interval prolongation greater than 10% from baseline was generally sustained for about 45 minutes at doses of 60 mg or greater. The mean terminal half-life ranged from about 1.5 hours with 60 mg to about 2.5-3 hours for the 70- and 105-mg doses. Etripamil was generally well tolerated without symptomatic hypotension. Adverse events were primarily mild to moderate and related to the administration site; no serious adverse events or episodes of atrioventricular block occurred. Intranasal etripamil administration, at doses of 60 mg or greater, produced rapidly occurring slowing of atrioventricular nodal conduction with a limited duration of effect without hemodynamic or electrocardiographic safety signals in healthy volunteers., (© 2024 Milestone Pharma. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

What Is This Summary About?: This is a plain language summary of a clinical research study called RAPID. The study looked at the potential for how safe and effective etripamil was at stopping an episode of rapid heartbeats in people with atrioventricularnodal-dependent supraventricular tachycardia (AV-node-dependent SVT). An episode is used to describe the period of time when a person experiences an abnormally very fast heartbeat. This was done by comparing an investigational drug called etripamil with a placebo, each administered via a rapidly acting nasal spray. AV-node-dependent SVT affects the rhythm of the heart, causing it to suddenly beat rapidly. The condition often requires medical treatment to help return the heart to its normal, healthy heartbeat pattern and speed, called 'sinus rhythm'. Researchers are looking at ways of improving the management of supraventricular tachycardias (SVT) by reducing the need for patients to attend an urgent care clinic, emergency ward or hospital for treatment. In the RAPID study, participants used a nasal spray containing either 70 mg etripamil or a placebo solution when they experienced an episode of SVT. The researchers wanted to know how long it took for each participant's rapid heartbeat to return to sinus rhythm after administering the etripamil or placebo nasal spray. Participants in the study were considered successfully treated if their heartbeats returned to sinus rhythm for at least 30 seconds within 30 minutes of using the nasal spray. Although 30 seconds may seem brief, it's medically important because it shows that a person's heartbeat has been temporarily stabilized and returned to normal functioning., What Were the Results?: Out of 99 people who used etripamil during an SVT episode, 63 participants (64%) experienced a return to sinus rhythm for at least 30 seconds within 30 minutes after using the nasal spray. In contrast, 26 out of 85 participants (31%) who used the placebo nasal spray experienced a return to sinus rhythm for at least 30 seconds within 30 minutes after use. Furthermore, the average time taken for the return to sinus rhythm was 17 minutes for the etripamil group which was 3-times faster than the placebo group at 53 minutes. Also, in the study no serious side effects occurred that were related to etripamil., What Do the Results of the Study Mean?: The RAPID study supports the potential that etripamil may be safe and well tolerated by participants as a treatment for episodes of rapid heartbeat in people with AV-node-dependent SVT. The results also showed a significant improvement in symptoms following treatment with etripamil.

Background: Despite chronic therapies, atrial fibrillation (AF) leads to rapid ventricular rates (RVR) often requiring intravenous treatments. Etripamil is a fast-acting, calcium-channel blocker administered intranasally affecting the atrioventricular node within minutes., Methods: Reduction of Ventricular Rate in Patients with Atrial Fibrillation evaluated the efficacy and safety of etripamil for the reduction of ventricular rate (VR) in patients presenting urgently with AF-RVR (VR ≥110 beats per minute [bpm]), was randomized, double-blind, placebo-controlled, and conducted in Canada and the Netherlands. Patients presenting urgently with AF-RVR were randomized (1:1, etripamil nasal spray 70 mg: placebo nasal spray). The primary objective was to demonstrate the effectiveness of etripamil in reducing VR in AF-RVR within 60 minutes of treatment. Secondary objectives assessed achievement of VR <100 bpm, reduction by ≥10% and ≥20%, relief of symptoms and treatment effectiveness; adverse events; and additional measures to 360 minutes., Results: Sixty-nine patients were randomized, 56 dosed with etripamil (n=27) or placebo (n=29). The median age was 65 years; 39% were female patients; proportions of AF types were similar between groups. The difference of mean maximum reductions in VR over 60 minutes, etripamil versus placebo, adjusting for baseline VR, was -29.91 bpm (95% CI, -40.31 to -19.52; P <0.0001). VR reductions persisted up to 150 minutes. Significantly greater proportions of patients receiving etripamil achieved VR reductions <100 bpm (with longer median duration <100 bpm), or VR reduction by ≥10% or ≥20%, versus placebo. VR reduction ≥20% occurred in 66.7% of patients in the etripamil arm and no patients in placebo. Using the Treatment Satisfaction Questionnaire for Medication-9, there was significant improvement in satisfaction on symptom relief and treatment effectiveness with etripamil versus placebo. Serious adverse events were rare; 1 patient in the etripamil arm experienced transient severe bradycardia and syncope, assessed as due to hypervagotonia., Conclusions: Intranasal etripamil 70 mg reduced VR and improved symptom relief and treatment satisfaction. These data support further development of self-administered etripamil for the treatment of AF-RVR., Registration: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT04467905., Competing Interests: Disclosures Dr Camm has received grants and personal fees from Boehringer Ingelheim, Bayer, Pfizer, Bristol-Myers Squibb, and Daiichi Sankyo; personal fees from Medtronic, Boston Scientific, Menarini, and Biotronik; and support from Anthos, Sanofi, Abbott, GlaxoSmithKline, and Johnson & Johnson. Dr Piccini has received grants for clinical research from Abbott, the American Heart Association, the Association for the Advancement of Medical Instrumentation, Bayer, Boston Scientific, iRhythm, and Philips and serves as a consultant to Abbott, AbbVie, ARCA biopharma, Bayer, Boston Scientific, Bristol-Myers Squibb (Myokardia), Element Science, Itamar Medical, LivaNova, Medtronic, ElectroPhysiology Frontiers, ReCor, Sanofi, Philips, and UpToDate. Dr Alings has no disclosures to report. Drs Dorian, Ip, and Stambler serve on the steering committee for Milestone Pharmaceuticals. Dr Gosselin has no disclosures to report. Drs Kowey and Mondésert are consultants for Milestone Pharmaceuticals. Drs Prins, Roux, van Eck, and Al Windy have no disclosures to report. Drs Thermil, Shardonofsky, and Bharucha are employees of Milestone Pharmaceuticals. Dr Roy has no disclosures to report.

Background Self-administration of investigational intranasal L-type calcium channel blocker etripamil during paroxysmal supraventricular tachycardia (PSVT) appeared safe and well-tolerated in the phase 3 NODE-301 (Multi-Centre, Randomized, Double-Blind, Placebo-Controlled, Efficacy, and Safety Study of Etripamil Nasal Spray for the Termination of Spontaneous Episodes of Paroxysmal Supraventricular Tachycardia) trial of adults with sustained atrioventricular nodal-dependent PSVT. The NODE-302 open-label extension further characterized etripamil safety and efficacy. Methods and Results Eligible patients were monitored via self-applied cardiac monitoring system for 5 hours after etripamil self-administration. The primary end point was time-to-conversion of positively adjudicated PSVT to sinus rhythm after etripamil treatment. Probability of conversion to sinus rhythm was reported via Kaplan-Meier plot. Adverse events were based on self-reported symptoms and clinical evaluations. Among 169 patients enrolled, 105 self-administered etripamil ≥1 time for perceived PSVT (median [range], 232 [8-584] days' follow-up). Probability of conversion within 30 minutes of etripamil was 60.2% (median time to conversion, 15.5 minutes) among 188 PSVT episodes (92 patients) positively adjudicated as atrioventricular nodal dependent by independent ECG analysis. Among 40 patients who self-treated 2 episodes, 75% had a significantly consistent response by 30 minutes; 9 did not convert on either episode, and 21 converted on both episodes (χ 2 =8.09; P =0.0045). Forty-five of 105 patients (42.9%) had ≥1 treatment-emergent adverse event, generally transient and mild-to-moderate, including nasal congestion (14.3%), nasal discomfort (14.3%), or rhinorrhea (12.4%). No serious cardiac safety events were observed within 24 hours of etripamil. Conclusions In this extension study, investigational etripamil nasal spray was well tolerated for self-treating recurrent episodes of PSVT without medical supervision. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03635996.

Background: Etripamil is a fast-acting, intranasally administered calcium-channel blocker in development for on-demand therapy outside a health-care setting for paroxysmal supraventricular tachycardia. We aimed to evaluate the efficacy and safety of etripamil 70 mg nasal spray using a symptom-prompted, repeat-dose regimen for acute conversion of atrioventricular-nodal-dependent paroxysmal supraventricular tachycardia to sinus rhythm within 30 min., Methods: RAPID was a multicentre, randomised, placebo-controlled, event-driven trial, conducted at 160 sites in North America and Europe as part 2 of the NODE-301 study. Eligible patients were aged at least 18 years and had a history of paroxysmal supraventricular tachycardia with sustained, symptomatic episodes (≥20 min) as documented by electrocardiogram. Patients were administered two test doses of intranasal etripamil (each 70 mg, 10 min apart) during sinus rhythm; those who tolerated the test doses were randomly assigned (1:1) using an interactive response technology system to receive either etripamil or placebo. Prompted by symptoms of paroxysmal supraventricular tachycardia, patients self-administered a first dose of intranasal 70 mg etripamil or placebo and, if symptoms persisted beyond 10 min, a repeat dose. Continuously recorded electrocardiographic data were adjudicated, by individuals masked to patient assignment, for the primary endpoint of time to conversion of paroxysmal supraventricular tachycardia to sinus rhythm for at least 30 s within 30 min after the first dose, which was measured in all patients who administered blinded study drug for a confirmed atrioventricular-nodal-dependent event. Safety outcomes were assessed in all patients who self-administered blinded study drug for an episode of perceived paroxysmal supraventricular tachycardia. This trial is registered at ClinicalTrials.gov, NCT03464019, and is complete., Findings: Between Oct 13, 2020, and July 20, 2022, among 692 patients randomly assigned, 184 (99 from the etripamil group and 85 from the placebo group) self-administered study drug for atrioventricular-nodal-dependent paroxysmal supraventricular tachycardia, with diagnosis and timing confirmed. Kaplan-Meier estimates of conversion rates by 30 min were 64% (63/99) with etripamil and 31% (26/85) with placebo (hazard ratio 2·62; 95% CI 1·66-4·15; p<0·0001). Median time to conversion was 17·2 min (95% CI 13·4-26·5) with the etripamil regimen versus 53·5 min (38·7-87·3) with placebo. Prespecified sensitivity analyses of the primary assessment were conducted to test robustness, yielding supporting results. Treatment-emergent adverse events occurred in 68 (50%) of 99 patients treated with etripamil and 12 (11%) of 85 patients in the placebo group, most of which were located at the administration site and were mild or moderate, and all of which were transient and resolved without intervention. Adverse events occurring in at least 5% of patients treated with etripamil were nasal discomfort (23%), nasal congestion (13%), and rhinorrhea (9%). No serious etripamil-related adverse events or deaths were reported., Interpretation: Using a symptom-prompted, self-administered, initial and optional-repeat-dosing regimen, intranasal etripamil was well tolerated, safe, and superior to placebo for the rapid conversion of atrioventricular-nodal-dependent paroxysmal supraventricular tachycardia to sinus rhythm. This approach could empower patients to treat paroxysmal supraventricular tachycardia themselves outside of a health-care setting, and has the potential to reduce the need for additional medical interventions, such as intravenous medications given in an acute-care setting., Funding: Milestone Pharmaceuticals., Competing Interests: Declaration of interests BSS, PTS, BM, MC, PRK, JPP, SDP, and AJC are consultants for Milestone Pharmaceuticals. AJC has received grants and personal fees from Boehringer Ingelheim, Bayer, Pfizer, Bristol-Myers Squibb, and Daiichi Sankyo; personal fees from Medtronic, Boston Scientific, Menarini, and Biotronik; and support from Anthos, Sanofi, Abbott, GlaxoSmithKline, and Johnson & Johnson. PRK has received personal fees from Acesion Pharma, Allergan, Astellas Pharma, AstraZeneca, AtriCure, Boehringer Ingelheim, Bristol-Myers Squibb, Chattem, Correvio, Daiichi Sankyo, GlaxoSmithKline, InCarda Therapeutics, Johnson & Johnson, Medtronic, Merck, Novartis, Pfizer, Roche, and Sanofi-Aventis; serves on a data safety monitoring board for Eli Lilly; and has equity in CardioNet. SDP has received personal fees from Medtronic, Boston Scientific, Pfizer, Bristol-Myers Squibb, Janssen Pharmaceuticals, Philips, Zoll, and Sanofi-Aventis and research grants from Boston Scientific, Gilead Sciences, Pfizer, Bristol-Myers Squibb, the US Food and Drug Administration, Janssen Pharmaceuticals, Philips, Medtronic, and Sanofi-Aventis. HH has received lecture and consultancy fees from Abbott, Biotronik, Daiichi Sankyo, Pfizer-BMS, Medscape, and Springer Healthcare and unconditional research grants through the University of Antwerp and/or the University of Hasselt from Abbott, Bayer, Biotronik, Biosense Webster, Boston Scientific, Boehringer Ingelheim, Daiichi Sankyo, Fibricheck/Qompium, Medtronic, and Pfizer-BMS, all outside of the scope of this work. JLM has received grants and personal fees from Medtronic, Microport, and Sanofi. JPP has received grants for clinical research from Abbott, the American Heart Association, the Association for the Advancement of Medical Instrumentation, Bayer, Boston Scientific, iRhythm, and Philips and serves as a consultant to Abbott, AbbVie, ARCA biopharma, Bayer, Boston Scientific, Bristol Myers Squibb (Myokardia), Element Science, Itamar Medical, LivaNova, Medtronic, ElectroPhysiology Frontiers, ReCor, Sanofi, Philips, and UpToDate. AV has received personal fees from MedLumics and Adagio Medical and research grants from Bayer, Biosense Webster, and Medtronic. JMW has received personal fees from Sanofi-Aventis, Bristol-Myers Squibb, and Janssen Pharmaceuticals and a research grant from Milestone Pharmaceuticals. PTS has equity in Milestone Pharmaceuticals. DBB, FP, and SS are employees of Milestone Pharmaceuticals. JEI, MA, BSS, PD, and AJC serve on the steering committee for Milestone Pharmaceuticals. JH declares no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Pharmacologic termination of paroxysmal supraventricular tachycardia (PSVT) often requires medically supervised intervention. Intranasal etripamil, is an investigational fast-acting, nondihydropyridine, L-type calcium channel blocker, designed for unsupervised self-administration to terminate atrioventricular nodal-dependent PSVT. Phase 2 results showed potential safety and efficacy of etripamil in 104 patients with PSVT., Methods: NODE-301, a phase 3, multicenter, double-blind, placebo-controlled study evaluated the efficacy and safety of etripamil nasal spray administered, unsupervised in patients with symptomatic sustained PSVT. After a medically supervised etripamil test dose while in sinus rhythm, patients were randomized 2:1 to receive etripamil 70 mg or placebo. When PSVT symptoms developed, patients applied a cardiac monitor and attempted a vagal maneuver; if symptoms persisted, they self-administered blinded treatment. An independent Adjudication Committee reviewed continuous electrocardiogram recordings. The primary efficacy endpoint was termination of adjudicated PSVT within 5 hours after study drug administration., Results: NODE-301 accrued 156 positively adjudicated PSVT events treated with etripamil (n=107) or placebo (n=49). The hazard ratio for the primary endpoint, time-to-conversion to sinus rhythm during the 5-hour observation period, was 1.086 (95% CI, 0.726-1.623; P =0.12). In predefined sensitivity analyses, etripamil effects (compared with placebo) occurred at 3, 5, 10, 20, and 30 minutes ( P <0.05). For example, at 30 minutes, there was a 53.7% of SVT conversion in the treatment arm compared to 34.7% in the placebo arm (hazard ratio, 1.87 [95% CI, 1.09-3.22]; P =0.02). Etripamil was well tolerated; adverse events were mainly related to transient nasal discomfort and congestion (19.6% and 8.0%, respectively, of randomized treatment-emergent adverse events., Conclusions: Although the primary 5-hour efficacy endpoint was not met, analyses at earlier time points indicated an etripamil treatment effect in terminating PSVT. Etripamil self-administration during PSVT was safe and well tolerated. These results support continued clinical development of etripamil nasal spray for self-administration during PSVT in a medically unsupervised setting., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT03464019.

Presently, acute pharmacological termination of paroxysmal supraventricular tachycardia (PSVT) unresponsive to patient-initiated vagal maneuvers requires in-hospital intervention. Etripamil, a fast-acting, nondihydropyridine, L-type calcium channel blocker, is formulated as an intranasal spray to rapidly terminate atrioventricular (AV) nodal-dependent PSVT in a medically unsupervised setting. The NODE-301 study did not meet its prespecified primary end point of PSVT conversion over 5 hours following a single dose of etripamil 70 mg. However, analysis at earlier time points demonstrated etripamil treatment effect during the first 30 minutes, consistent with its expected rapid onset and short duration of action. This led to the design of the RAPID study, which includes a new dosing regimen (up to 2 etripamil 70 mg doses separated by 10 minutes) to increase the exposure and pharmacodynamic effect of etripamil. The primary objective of RAPID (NCT03464019) is to determine if etripamil self-administered by patients is superior to placebo in terminating PSVT in an at-home setting. The secondary objective is to evaluate the safety of etripamil when self-administered by patients without medical supervision. Additional efficacy end points include the proportion of patients requiring additional medical intervention in an emergency department to terminate PSVT and patient-reported outcomes. After successfully completing a test dose to assess the safety of 2 70 mg doses of etripamil during sinus rhythm, approximately 500 patients will be randomized 1:1 to etripamil or placebo to accrue 180 positively adjudicated AV nodal-dependent PSVT events for treatment with the study drug. Etripamil may offer a new alternative to the current in-hospital treatment modality, providing for safe and effective at-home termination of PSVT., (Copyright © 2022. Published by Elsevier Inc.)

Competing Interests: Conflict of interest: The authors have provided declaration of interest information for all relationships that might be perceived as real or potential sources of conflicts of interest. The full disclosures can be viewed in the supplementary material for this article, available online at http://academic.oup.com/europace/article-lookup/doi/10.1093/europace/euac066#supplementary-data.

This international multidisciplinary document is intended to guide electrophysiologists, cardiologists, other clinicians, and health care professionals in caring for patients with arrhythmic complications of neuromuscular disorders (NMDs). The document presents an overview of arrhythmias in NMDs followed by detailed sections on specific disorders: Duchenne muscular dystrophy, Becker muscular dystrophy, and limb-girdle muscular dystrophy type 2; myotonic dystrophy type 1 and type 2; Emery-Dreifuss muscular dystrophy and limb-girdle muscular dystrophy type 1B; facioscapulohumeral muscular dystrophy; and mitochondrial myopathies, including Friedreich ataxia and Kearns-Sayre syndrome, with an emphasis on managing arrhythmic cardiac manifestations. End-of-life management of arrhythmias in patients with NMDs is also covered. The document sections were drafted by the writing committee members according to their area of expertise. The recommendations represent the consensus opinion of the expert writing group, graded by class of recommendation and level of evidence utilizing defined criteria. The recommendations were made available for public comment; the document underwent review by the Heart Rhythm Society Scientific and Clinical Documents Committee and external review and endorsement by the partner and collaborating societies. Changes were incorporated based on these reviews. By using a breadth of accumulated available evidence, the document is designed to provide practical and actionable clinical information and recommendations for the diagnosis and management of arrhythmias and thus improve the care of patients with NMDs., (Copyright © 2022 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Background: Atrial natriuretic peptide (ANP), which is released by the heart in response to acute cardiac stretch, possesses cardiac electrophysiological properties that include modulation of ion channel function and repolarization. However, data regarding whether ANP can directly modulate electrical instability or arrhythmias are largely lacking., Objective: This study sought to determine whether ANP modifies onset or electrophysiological characteristics of ventricular fibrillation (VF) induced by severe hypokalemia in an isolated heart model., Methods: Langendorff-perfused rabbit hearts in the absence and presence of 10 nM ANP (n = 9 in each group) were subjected to a low potassium (K + ) perfusate (1.2 mM K + ). Left ventricular (LV) epicardial monophasic action potential (MAP) and pressure were monitored continuously. Incidence and time to onset of VF and dominant frequency during VF determined by spectral analysis were evaluated., Results: ANP did not alter ventricular repolarization (MAP duration) or LV pressure during perfusion with physiologic, K + -containing solution. Within the first 30 s after low K + perfusion, ANP accelerated the onset of beat-to-beat repolarization alternans (100% vs. 33% in ANP-treated vs. non-treated hearts, p < 0.01). During low K + perfusion, the incidence of VF did not differ between ANP-treated and non-treated hearts (8 of 9 [89%] in each group). However, VF occurred sooner (3.75 ± 0.33 vs. 5.78 ± 0.70 min, P < 0.05) and immediately after VF onset, peak dominant frequency was higher (24.1 ± 7.3 vs. 14.2 ± 2.3 Hz, P = 0.01) in ANP-treated than in non-treated hearts., Conclusions: ANP accelerates initiation of VF and increases maximum dominant frequency during VF in isolated hearts subjected to severe hypokalemia., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Ventricular arrhythmia (VA) is a rare complication of cardiac resynchronization therapy (CRT). Little is known about ventricular proarrhythmia related to the pacing vector of CRT. This case report describes the elimination of ventricular arrythmia using biventricular pacing in a patient with VT-storm related to LV only pacing as part of the AdaptivCRT algorithm (Medtronic Inc). Simultaneous biventricular pacing was effective in eliminating polymorphic ventricular tachycardia. Changing the pacing vector is a noninvasive treatment strategy that should be considered to manage VA due to CRT., (© 2020 Wiley Periodicals LLC.)

Background: There is no nonparenteral medication for the rapid termination of paroxysmal supraventricular tachycardia., Objectives: The purpose of this study was to assess the efficacy and safety of etripamil nasal spray, a short-acting calcium-channel blocker, for the rapid termination of paroxysmal supraventricular tachycardia (SVT)., Methods: This phase 2 study was performed during electrophysiological testing in patients with previously documented SVT who were induced into SVT prior to undergoing a catheter ablation. Patients in sustained SVT for 5 min received either placebo or 1 of 4 doses of active compound. The primary endpoint was the SVT conversion rate within 15 min of study drug administration. Secondary endpoints included time to conversion and adverse events., Results: One hundred four patients were dosed. Conversion rates from SVT to sinus rhythm were between 65% and 95% in the etripamil nasal spray groups and 35% in the placebo group; the differences were statistically significant (Pearson chi-square test) in the 3 highest active compound dose groups versus placebo. In patients who converted, the median time to conversion with etripamil was <3 min. Adverse events were mostly related to the intranasal route of administration or local irritation. Reductions in blood pressure occurred predominantly in the highest etripamil dose., Conclusions: Etripamil nasal spray rapidly terminated induced SVT with a high conversion rate. The safety and efficacy results of this study provide guidance for etripamil dose selection for future studies involving self-administration of this new intranasal calcium-channel blocker in a real-world setting for the termination of SVT. (Efficacy and Safety of Intranasal MSP-2017 [Etripamil] for the Conversion of PSVT to Sinus Rhythm [NODE-1]; NCT02296190)., (Copyright © 2018 Milestone Pharmaceuticals Inc. Published by Elsevier Inc. All rights reserved.)

Background: This continuing medical education (CME) curriculum utilizes the Learner Assessment Platform (LAP), providing learners with personalized educational pathways related to atrial fibrillation treatment., Hypothesis: There are improvements in knowledge among physician learners after CME, especially among LAP learners., Methods: In this LAP-based curriculum, an evaluation of learner deficits on designated learning objectives was conducted in tier 1 and used to direct learners to individualized tier 2 activities. Performance was assessed across learner tracks from baseline to learners' final intervention. Retention data were measured by the postcurriculum assessment, completed 8 weeks after the learners last intervention. Additionally, each activity included a unique matched set of pretest and post-test questions assessing the 4 learner domains: knowledge, competence, confidence, and practice patterns., Results: Significant learner improvement was measured across the curriculum over all 4 learner-domains: 48% (P < 0.0005), 78% (P < 0.0005), 21% (P < 0.0005), and 20% (P < 0.0005) improvements for knowledge, competence, confidence, and practice, respectively. Significant gains in participant performance scores (28% increase, P < 0.0005) by the final activity was observed. Learners who participated in the LAP (N = 989) demonstrated greater improvement in performance from baseline compared to non-LAP learners (41% increase for LAP vs 23% and 26% increase for non-LAP learners who completed 1 (N = 1899) or ≥2 (N = 533) activities, respectively, P = 0.003)., Conclusions: The participant population (N = 3421) achieved statistically significant improvement across the curriculum, with LAP learners showing greater performance gains compared to non-LAP learners. These findings support the value of the LAP methodology in providing a cumulative and individualized CME experience., (© 2017 Wiley Periodicals, Inc.)

Traditionally, warfarin has been used to prevent stroke in patients with atrial fibrillation (AF), but data from large, multinational, prospective, randomized studies suggest that novel oral anticoagulants (NOACs) may be suitable alternatives. These include the direct thrombin inhibitor dabigatran and the factor Xa inhibitors rivaroxaban, apixaban, and edoxaban. These data showed that dabigatran 150 mg twice daily was more effective at preventing stroke than warfarin, with similar rates of major bleeding, while rivaroxaban 20 mg once daily was noninferior to warfarin, with no difference in major bleeding rates. In addition, apixaban 5 mg twice daily was shown to be superior to warfarin for preventing stroke, with lower bleeding rates. Currently, edoxaban is still in clinical trials. NOACs offer more predictable anticoagulant effects than warfarin and do not require regular monitoring; however, different NOACs are associated with varied drug interactions and limitations related to use in certain patient populations. Overall, the clinical data suggest that these novel agents will offer new options for stroke prevention in patients with AF.

Introduction: Mineralocorticoid receptor antagonism reduces sudden cardiac death in heart failure, but the underlying mechanism is unclear. Our previous studies indicate that treatment with a mineralocorticoid receptor antagonist prevents adverse ventricular electrophysiological remodeling and reduces ventricular tachyarrhythmia inducibility in the rapid ventricular pacing-induced heart failure model. This study's aim was to determine whether chronic spironolactone treatment prevents formation of local electrical activation delays in the cardiomyopathic ventricle by attenuating inflammatory pathways and myocardial fibrosis., Methods and Results: Dogs subjected to rapid ventricular pacing at 220 bpm for 5 weeks in the absence or presence of spironolactone treatment were assessed by echocardiography, electrophysiology study, ventricular fibrosis measurements and inflammatory cytokine mRNA expression analysis. Spironolactone failed to prevent LV systolic dysfunction or chamber enlargement in dogs that underwent rapid ventricular pacing. Spironolactone prevented ventricular electrogram widening after premature stimulation at short coupling intervals, electrogram fractionation, interstitial fibrosis, and inflammatory cytokine (interleukin-6, tumor necrosis factor-α) gene overexpression in ventricular paced dogs with heart failure., Conclusions: Our findings establish an important link between inflammatory cytokine gene expression, interstitial fibrosis and myocardial electrical activation delays during premature excitation and provide insight into the mechanisms by which mineralocorticoid receptor antagonism may prevent development of an arrhythmogenic ventricular substrate in systolic heart failure., (© 2013 Wiley Periodicals, Inc.)

Background: Twelve lead ECGs have limited value in precisely identifying atrial and ventricular activation during arrhythmias, including accessory atrioventricular conduction activation. The aim of this study was to report a single center's clinical experience validating a novel, noninvasive, whole heart, beat-by-beat, 3-dimensional mapping technology with invasive electrophysiological studies, including ablation, where applicable., Methods and Results: Using an electrocardiographic mapping (ECM) system in 27 patients, 3-dimensional epicardial activation maps were generated from >250 body surface ECGs using heart-torso geometry obtained from computed tomographic images. ECM activation maps were compared with clinical diagnoses, and confirmed with standard invasive electrophysiological studies mapping. (1) In 6 cases of Wolff-Parkinson-White syndrome, ECM accurately identified the ventricular insertion site of an accessory atrioventricular connection. (2) In 10 patients with premature ventricular complexes, ECM accurately identified their ventricular site of origin in 8 patients. In 2 of 10 patients transient premature ventricular complex suppression was observed during ablation at the site predicted by ECM as the earliest. (3) In 10 cases of atrial tachycardia/atrial flutter, ECM accurately identified the chamber of origin in all 10, and distinguished isthmus from nonisthmus dependent atrial flutter. (4) In 1 patient with sustained exercise induced ventricular tachycardia, ECM accurately identified the focal origin in the left ventricular outflow tract., Conclusions: ECM successfully provided valid activation sequence maps obtained noninvasively in a variety of rhythm disorders that correlated well with invasive electrophysiological studies.

Background: Focal atrial tachycardia (AT) originates from preferential sites, including the tricuspid and mitral annuli. AT arising from the atrioventricular annuli is initiated and terminated with programmed stimulation and is, in general, adenosine and verapamil sensitive. Para-Hisian AT arising from the apex of the triangle of Koch has been considered to be a distinct entity, characterized by unique electrophysiological properties., Objective: We sought to more fully delineate the electrophysiological and electrocardiographic properties of para-Hisian AT in a large series of patients., Methods: The study population consisted of 38 patients (63 ± 15 years; 23 female) with AT from the para-Hisian region. The ATs were focal and originated from the anteroseptal tricuspid annulus, in close proximity to the His bundle recording. Proximity to the His bundle was confirmed by electrogram recordings, fluoroscopy, and centrifugal activation during three-dimensional mapping., Results: The mean AT cycle length was 421 ± 69 ms. AT was associated with a distinct P-wave morphology that was significantly narrower than the P wave during sinus rhythm. Adenosine (5.0 ± 1.5 mg) terminated AT in 34/35 patients. Intravenous verapamil terminated AT in three of three patients. Catheter ablation was attempted in 30 patients and was successful in 26 (87%)., Conclusion: The para-Hisian region is a source of focal AT, with properties consistent with AT arising circumferentially along the tricuspid and mitral annuli, and should be considered a subset of this broader group of "annular" ATs. The electropharmacologic findings in para-Hisian AT are mechanistically consistent with cyclic AMP-mediated triggered activity., (Copyright © 2011. Published by Elsevier Inc.)

In this review, we examine the data evaluating the role of adjuvant therapy with antiarrthymic drugs (AADs) in chronic suppression of ventricular tachyarrhythmias in the patient with an ICD. It must be noted that all uses of AADs for this indication represent "off-label" prescription. No AAD is approved by the Food and Drug Administration (FDA) specifically as a therapy to reduce ICD shocks., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Background: Aldosterone blockade reduces sudden cardiac death in heart failure, but the underlying mechanism is unclear., Objective: This study's aim was to determine whether chronic eplerenone treatment protects against detrimental ventricular electrical remodeling and development of an arrhythmogenic substrate in a rapid ventricular pacing (RVP)-induced heart failure model., Methods: Dogs were assigned randomly to oral placebo or eplerenone treatment and divided into 4 groups: 2 sham-operated (no RVP) and 2 RVP groups. After 5 weeks of no RVP or RVP along with concurrent placebo or eplerenone treatment, dogs underwent echocardiographic assessments of systolic function and chamber size and electrophysiologic measurements of ventricular repolarization, refractoriness, conduction, tachyarrhythmia inducibility, and myocardial activation delays after premature stimulation., Results: Eplerenone failed to prevent left ventricular systolic dysfunction or chamber enlargement in RVP dogs. Eplerenone attenuated prolongation of ventricular repolarization and refractoriness, increases in dispersion of repolarization and refractoriness, fractionation of ventricular electrograms, and delays in myocardial activation after premature stimulation at short coupling intervals and improved arrhythmia vulnerability score in RVP dogs with heart failure. Ventricular tachyarrhythmia inducibility in heart failure dogs was predicted by activation delays after premature stimulation at short coupling intervals, which were prevented by eplerenone. Eplerenone did not alter electrophysiological parameters in no-RVP dogs without heart failure., Conclusions: Eplerenone attenuates heart failure-related ventricular electrical remodeling and tachyarrhythmia vulnerability. Inhibition of myocardial activation delays during premature excitation may contribute to preventing development of an arrhythmogenic ventricular substrate in heart failure.

Background: The optimal site to permanently pace the right ventricle (RV) has yet to be determined. To address this issue, three randomized prospective multicenter clinical trials are in progress comparing the long-term effects of RV apical versus septal pacing on left ventricular (LV) function. The three trials are Optimize RV Selective Site Pacing Clinical Trial (Optimize RV), Right Ventricular Apical and High Septal Pacing to Preserve Left Ventricular Function (Protect Pace), and Right Ventricular Apical versus Septal Pacing (RASP)., Methods: Patients that require frequent or continuous ventricular pacing are randomized to RV apical or septal pacing. Optimize RV excludes patients with LV ejection fraction <40% prior to implantation, whereas the other trials include patients regardless of baseline LV systolic function. The RV septal lead is positioned in the mid-septum in Optimize RV, the high septum in Protect Pace, and the mid-septal inflow tract in RASP. Lead position is confirmed by fluoroscopy in two planes and adjudicated by a blinded panel. The combined trials will follow approximately 800 patients for up to 3 years., Results: The primary outcome in each trial is LV ejection fraction evaluated by radionuclide ventriculography or echocardiography. Secondary outcomes include echo-based measurements of ventricular/atrial remodeling, 6-minute hall walk distance, brain natriuretic peptide levels, and clinical events (atrial tachyarrhythmias, heart failure, stroke, or death)., Conclusion: These selective site ventricular pacing trials should provide evidence of the importance of RV pacing site in the long-term preservation of LV function in patients that require ventricular pacing and help to clarify the optimal RV pacing site.

Introduction: Renin-angiotensin-aldosterone system activation may be involved in the pathogenesis of atrial arrhythmias in congestive heart failure (CHF). The effects of aldosterone blockade on atrial tachyarrhythmias have not been evaluated. This study's aim was to determine whether selective aldosterone blockade suppresses atrial tachyarrhythmia inducibility and modifies atrial electrical and/or structural remodeling in a canine model of rapid ventricular pacing (RVP)-induced CHF., Methods and Results: Dogs were assigned randomly to treatment with oral placebo or eplerenone (50 mg/day) and divided into four groups: two sham-operated (no RVP) and two RVP groups. After 5 weeks of no RVP or RVP at 230 beats/min along with concurrent placebo or eplerenone treatment, dogs underwent electrophysiologic and echocardiographic studies. Sustained atrial tachyarrhythmia inducibility (>10-minute duration), atrial effective refractory periods (ERPs), systolic and diastolic function, and left atrial and left ventricular (LV) chamber sizes were assessed. Placebo-treated RVP dogs developed CHF with LV systolic and diastolic dysfunction, left atrial and LV enlargement, increased atrial ERPs, and inducible sustained atrial tachyarrhythmias. Eplerenone treatment in RVP dogs significantly suppressed sustained atrial tachyarrhythmia inducibility, nonuniformly prolonged atrial ERPs and attenuated LV diastolic dysfunction without modifying left atrial or LV dilation or ejection fractions in CHF. Isoproterenol (2-4 microg/min) reversed eplerenone's atrial antiarrhythmic and ERP prolonging effects in CHF. Eplerenone did not alter atrial ERPs in sham (no RVP) dogs without CHF., Conclusions: Eplerenone suppresses inducibility of sustained atrial tachyarrhythmias, selectively prolongs atrial ERPs, and attenuates LV diastolic remodeling in RVP-induced CHF. Aldosterone blockade may be a promising new approach for atrial tachyarrhythmia prevention in CHF.

Introduction: Atrial natriuretic peptide (ANP) may alter electrophysiological properties of the heart and possibly have a role in arrhythmogenesis. However, previous studies have yielded conflicting results and have not fully considered whether ANP's cardiac electrophysiological effects are mediated via direct actions and/or indirectly via the autonomic nervous system. This study's aim was to establish whether ANP infused at pathophysiological and pharmacological doses has significant in vivo cardiac electrophysiological effects and to determine whether these effects are directly or autonomically mediated., Methods and Results: Electrophysiologic and hemodynamic effects of ANP infusion (human ANP at 15-600 ng/kg per minute) were examined in chloralose-anesthetized dogs under conditions of varying autonomic blockade. In autonomically intact dogs (n = 12), low-dose ANP (15 ng/kg per minute) shortened atrial effective refractory period (ERP) (P < 0.001) and monophasic action potential duration (MAPD90) (P < 0.05) at 600, 500, and 400 msec atrial paced cycle lengths and reduced right atrial pressure (P < 0.05) but did not alter mean arterial pressure. After either combined vagal and beta-adrenergic blockade (vagotomy plus atropine plus propranolol, n = 7) or selective vagal blockade (n = 9), low-dose ANP no longer altered atrial ERP or MAPD90. Higher ANP doses (150 and 600 ng/kg per minute) decreased mean arterial and right atrial pressures (P < 0.001) but did not alter atrial ERP, MAPD90, or other electrophysiological parameters including atrial fibrillation threshold, ventricular ERP, and MAPD90., Conclusion: ANP has dose-dependent, autonomically mediated effects on atrial refractoriness and repolarization.

Introduction: Dogs with rapid ventricular pacing (RVP)-induced congestive heart failure (CHF) have inducible atrial tachycardia, flutter, and fibrillation (AF). We tested the hypothesis that rapid atrial activation in multiple regions and at different rates is responsible for sustained AF in this CHF model., Methods and Results: We studied 12 episodes of sustained (>10 minutes) AF induced in 12 dogs with CHF produced by 3-6 weeks of RVP at 230 beats/minute. High-density mapping of AF was performed using 382 unipolar atrial electrograms recorded simultaneously from epicardial electrodes on the right (RA) and left atria (LA) and Bachmann's bundle. AF mechanisms were based on Fast Fourier Transform (FFT) analysis and activation sequence mapping. A driver was defined as a rapid stable activation region with a single dominant frequency peak in FFT analysis. During AF, three FFT and activation patterns were seen: (1) a single LA driver (7.8 +/- 1.1 Hz) near the pulmonary veins (PVs) with irregular activation in the rest of the atria (n = 4); (2) simultaneous, multisite, biatrial drivers at differing frequencies (LA vs RA dominant frequency gradient: 1.3 +/- 0.8 Hz) near the PVs (8.4 +/- 0.3 Hz) and high RA (8.5 +/- 1.5 Hz) (n = 7); and (3) biatrial irregular activation with multiple and/or broadband frequency peaks without a dominant frequency. (LA: 7.1-11.4 Hz; RA: 5.9-7.7 Hz) (n = 1). Atrial drivers had either a focal activation pattern or were due to a macroreentrant circuit around the PVs., Conclusions: In this CHF model, FFT analysis and activation sequence mapping demonstrate that sustained AF is characterized by single and multiple, stable LA and RA drivers with predominant sources in the PVs and high RA causing fibrillatory conduction.

Enhanced understanding of the mechanisms underlying atrial fibrillation (AF) and advent of catheter-based therapy for AF has altered the approach to patients with this most common arrhythmia. However, despite the success of aggressive procedural techniques, pharmacologic therapy remains the first-line and mainstay approach in the treatment of AF. This review of new antiarrhythmic drug (AAD) therapy for AF provides an in-depth overview of recently available classic and new investigational drugs being considered for AF treatment. Currently available AADs are associated with less than satisfactory efficacy in preventing AF and a significant side effect profile, including ventricular proarrhythmia. Recent investigations have focused on development of new AADs that, hopefully, will be more effective and safer even in patients with structural heart disease. These new AADs include selective multi-ion channel and atrial specific blockers and agents that target the underlying etiologies and substrate alterations that lead to AF. Included among the latter new category are agents that suppress activation of the renin-angiotensin-aldosterone system or inflammation, which represent novel targets for drug therapy for AF. Finally, new selective A1 adenosine receptor agonists may offer the possibility of more specific and successful ventricular rate control during AF. There is considerable hope and interest that improved understanding of AF mechanisms ultimately will result in more effective and less dangerous pharmacologic therapy becoming available in the future.

We report the first clinical application of electrocardiographic imaging (ECGI), a new, noninvasive imaging modality for arrhythmias, in an athlete with focal ventricular tachycardia (VT) originating from a left ventricular (LV) diverticulum. A reconstructed map of the epicardial activation sequence during a single premature ventricular complex (PVC) of an identical QRS morphology to the clinical VT, generated from 224-electrode body surface ECGs and a chest CT (ECGI), localized the PVC to the site of the diverticulum. This correlated with subsequent maps obtained using standard techniques. We describe the first case that used ECGI to guide diagnosis and therapy of a clinical tachyarrhythmia.

Advances in left ventricular transvenous lead delivery systems for biventricular pacing are leading to more refined techniques, shorter procedure times and higher implant success rates. Despite these advances, the inability to successfully cannulate the coronary sinus and deliver a lead to a distal location are still major causes of prolonged procedures times and implant failures. The pathophysiologic process of heart failure results in dilatation of the right atrium as well as other morphological changes in cardiac anatomy. Additionally, cannulation can be further complicated by congenital anomalous cardiac anatomy. This report describes the implant of a biventricular pacing system using a novel, steerable 7 French catheter system developed to aid in the cannulation of the coronary sinus ostium and its venous branches. The steerable catheter is used in conjunction with a 9 French braided sheath and guide-wire to create a telescoping system. The use of new tools and methods as described provides insight into available options for left ventricular transvenous lead implantation and dealing with difficult anatomy.

Pacing impedance has been proposed to monitor the clinical status of patients with congestive heart failure (CHF). This study examined whether changes in right ventricular (RV) pacing impedance correlate with changes in left ventricular ejection fraction (LVEF) and New York Heart Association (NYHA) functional class during long-term follow-up in pacemaker recipients with CHF. The study included 67 patients, 70 +/- 12 years of age, in NYHA class II or III, and with a mean LVEF = 29 +/- 8% at implant. LVEF, NYHA class, and bipolar pacing impedance at the RV outflow tract (RVOT) and apex (RVA) were measured at implant and at 3, 6, 9, and 12 months of follow-up. At implant, impedance was similar in RVOT (548 +/- 115 Omega) and RVA (571 +/- 174 Omega). Between implant and 3 months, mean impedance decreased (P < 0.0001) at both the RVOT (472 +/- 62 Omega) and RVA (488 +/- 86 Omega), LVEF increased (43 +/- 14%, P < 0.0001), and the NYHA class decreased from 2.4 +/- 0.5 to 2.1 +/- 0.6 (P = 0.0001). Changes in RVA impedance correlated with changes in LVEF (r = 0.45, P = 0.002). A 50 Omega decrease in RVA impedance corresponded to a 3% decrease in LVEF. RVA impedance decreased significantly as NYHA class increased from I to IV (P = 0.04). There was no correlation between impedance measured at the RVOT and LVEF or NYHA class. A decrease in bipolar pacing impedance at the RVA was associated with worsening LVEF and the NYHA class. The use of pacing impedance to monitor the clinical status in CHF is dependent on the RV pacing site.