Synergistic dual automaticity in sinoatrial node cell and tissue models.

Background: The mechanism of sinoatrial node (SAN) automaticity is traditionally attributed to membrane ion currents. Recent evidence indicates spontaneous sarcoplasmic reticulum (SR) Ca(2+) cycling also plays an important role.

Methods And Results: A computer simulation on SAN cell and 1D tissue model was performed.

Tachybradycardia in the isolated canine right atrium induced by chronic sympathetic stimulation and pacemaker current inhibition.

The mechanisms of sinoatrial node (SAN) dysfunction in patients with chronically elevated sympathetic tone and reduced pacemaker current (I(f); such as heart failure) are poorly understood. We simultaneously mapped membrane potential and intracellular Ca(2+) in the Langendorff-perfused canine right atrium (RA). Blockade of either I(f) (ZD-7288) or sarcoplasmic reticulum Ca(2+) release (ryanodine) alone decreased heart rate by 8% (n = 3) and 16% (n = 3), respectively.

Intrinsic cardiac nerve activity and paroxysmal atrial tachyarrhythmia in ambulatory dogs.

Background: Little is known about the relationship between intrinsic cardiac nerve activity (ICNA) and spontaneous arrhythmias in ambulatory animals.

Methods And Results: We implanted radiotransmitters to record extrinsic cardiac nerve activity (ECNA; including stellate ganglion nerve activity and vagal nerve activity) and ICNA (including superior left ganglionated plexi nerve activity and ligament of Marshall nerve activity) in 6 ambulatory dogs. Intermittent rapid left atrial pacing was performed to induce paroxysmal atrial fibrillation or atrial tachycardia.

Electrophysiological characteristics of the Marshall bundle in humans.

Background: Marshall bundles (MBs) are the muscle bundles within the ligament of Marshall.

Objective: This trial sought to the electrophysiological characteristics of the MB and the anatomical connections between MB and left atrium (LA) in patients with persistent atrial fibrillation (AF).

Methods: We enrolled 72 patients (male:female 59:13, age 59.

Induction of atrial ectopic beats with calcium release inhibition: Local hierarchy of automaticity in the right atrium.

Background: Recent evidence indicates that spontaneous sarcoplasmic reticulum (SR) calcium (Ca) release underlies the mechanism of sinoatrial node (SAN) acceleration during beta-stimulation, indicating the importance of the Ca clock in SAN automaticity. Whether or not the same mechanism applies to atrial ectopic pacemakers (AEPs) remains unclear.

Objective: The purpose of this study was to assess the mechanism of AEP.

The initiation of the heart beat.

During a normal lifetime, the heart may beat over 2 billion times, but the mechanisms by which the heart beats are initiated remain a subject of intense investigation. Since the discovery of a pacemaker current (I(f)) in 1978, multiple studies have shown that rhythmic changes in membrane voltage (the "membrane voltage clock") underlie the mechanisms of automaticity. The I(f) is a depolarization current activated during hyperpolarization.

LifeShirt acquisition system to monitor ECG from ambulatory swine and the implementation of an arrhythmia detection algorithm.

A wearable cardiopulmonary monitoring system, a LifeShirt, was used to acquire continuous electrocardiograms (ECGs) from ambulatory swine. The animals received intracoronary injections of autologous mesenchymal stem cells, and the LifeShirt was used for long-duration ECG monitoring in pre-defined periods post cell infusion. The system used here was developed for measurements from non-human primates and canines; however, we demonstrated that it could be used to non-invasively measure ECGs from swine without creating undue stress or restricting movement.

Cryoablation of stellate ganglia and atrial arrhythmia in ambulatory dogs with pacing-induced heart failure.

Background: There is an association between autonomic nerve discharges and atrial arrhythmias (including bradycardia and tachycardia) in ambulatory dogs with pacing-induced heart failure (HF).

Objective: The purpose of this study was to test the hypothesis that stellate ganglia ablation can reduce the incidence of atrial arrhythmias in a canine model of pacing-induced HF.

Methods: Cryoablation of the caudal half of the left and right stellate ganglia and T2-T4 thoracic sympathetic ganglia was performed in six dogs (experimental group).

The calcium and voltage clocks in sinoatrial node automaticity.

Recent evidence indicates that the voltage (cyclic activation and deactivation of membrane ion channels) and Ca(2+) clocks (rhythmic spontaneous sarcoplasmic reticulum Ca(2+) release) jointly regulate sinoatrial node (SAN) automaticity. Since the intact SAN is a heterogeneous structure that includes multiple different cell types interacting with each other, the relative importance of the voltage and Ca(2+) clocks for pacemaking may be variable in different regions of the SAN. Recently, we performed optical mapping in isolated and Langendorff-perfused canine right atria.

Ligament of Marshall: why it is important for atrial fibrillation ablation.

The ligament of Marshall (LOM) is located on the epicardium between the left atrial appendage and the left pulmonary veins. The corresponding endocardial structure is the left lateral ridge. LOM is a source of paroxysmal AF, and may activate at fast rates during persistent AF.

Diastolic intracellular calcium-membrane voltage coupling gain and postshock arrhythmias: role of purkinje fibers and triggered activity.

Rationale: Recurrent ventricular arrhythmias after initial successful defibrillation are associated with poor clinical outcome.

Objective: We tested the hypothesis that postshock arrhythmias occur because of spontaneous sarcoplasmic reticulum Ca release, delayed afterdepolarization (DAD), and triggered activity (TA) from tissues with high sensitivity of resting membrane voltage (V(m)) to elevated intracellular calcium (Ca(i)) (high diastolic Ca(i)-voltage coupling gains).

Methods And Results: We simultaneously mapped Ca(i) and V(m) on epicardial (n=14) or endocardial (n=14) surfaces of Langendorff-perfused rabbit ventricles.

Mechanisms of sinoatrial node dysfunction in a canine model of pacing-induced atrial fibrillation.

Background: The mechanism of sinoatrial node (SAN) dysfunction in atrial fibrillation (AF) is unclear.

Objective: The purpose of this study was to test the hypothesis that defective spontaneous sarcoplasmic reticulum (SR) Ca(2+) release (Ca(2+) clock) is in part responsible for SAN dysfunction in AF.

Methods: Arrhythmic events and SAN function were evaluated in pacing-induced AF dogs (n = 7) and in normal dogs (n = 19) with simultaneous intracellular calcium (Ca(i)) and membrane potential recording.

Increased susceptibility of aged hearts to ventricular fibrillation during oxidative stress.

Oxidative stress with hydrogen peroxide (H(2)O(2)) readily promotes early afterdepolarizations (EADs) and triggered activity (TA) in isolated rat and rabbit ventricular myocytes. Here we examined the effects of H(2)O(2) on arrhythmias in intact Langendorff rat and rabbit hearts using dual-membrane voltage and intracellular calcium optical mapping and glass microelectrode recordings. Young adult rat (3-5 mo, N = 25) and rabbit (3-5 mo, N = 6) hearts exhibited no arrhythmias when perfused with H(2)O(2) (0.

Autonomic nervous system activity measured directly and QT interval variability in normal and pacing-induced tachycardia heart failure dogs.

Objectives: This study sought to find out more about the relationship between sympathetic and vagal nerve activity and the cardiac repolarization in a canine model of pacing-induced tachycardia congestive heart failure (CHF).

Background: The QT variability index (QTVI), a noninvasive marker of temporal cardiac repolarization dispersion, is among the risk factors for sudden death during CHF. Among factors influencing this variable are the myocardial damage and the autonomic nervous system activity typical of dilated cardiomyopathy.

What have we learned about the contribution of autonomic nervous system to human arrhythmia?

Myocardial infarction results in denervation, followed by neural remodeling characterized by nerve sprouting and heterogeneous sympathetic hyperinnervation throughout the myocardium. There is an association between the density of sympathetic nerves and occurrence of cardiac arrhythmia in humans. Autonomic nerve recording in ambulatory dogs showed a close association between autonomic nerve activity and paroxysmal atrial and ventricular arrhythmias.

Mechanisms of recurrent ventricular fibrillation in a rabbit model of pacing-induced heart failure.

Background: Successful defibrillation may be followed by recurrent spontaneous ventricular fibrillation (VF). The mechanisms of postshock spontaneous VF are unclear.

Objective: The purpose of this study was to determine the mechanisms of spontaneous VF after initial successful defibrillation in a rabbit model of heart failure (HF).

Power spectral analysis of heart rate variability and autonomic nervous system activity measured directly in healthy dogs and dogs with tachycardia-induced heart failure.

Background: Heart rate variability (HRV), calculated in the frequency or time domain, decreases in congestive heart failure (CHF). In HRV power spectral analysis, the low-frequency (LF) component diminishes in patients with CHF and the decrease is related to an increased risk of sudden death.

Objective: Our aim was to clarify the nature of HRV power spectral analysis in normal and CHF dogs.

Histopathological substrate for chronic atrial fibrillation in humans.

Background: There is a lack of understanding of the substrate for microreentrant circuits and triggered activity of the pulmonary vein (PV) muscle sleeves and atria in patients with atrial fibrillation (AF).

Objective: This study sought to examine the histological substrate of patients with chronic AF.

Methods: We stained 23 biopsies taken from the PV-left atrium (LA) junction and right atrial appendage from 5 chronic AF patients and 3 sinus rhythm (SR) patients undergoing mitral valve surgery using periodic acid-Schiff (PAS) test, and antibodies to hyperpolarization-activated cyclic nucleotide-gated potassium channel 4 (HCN4), CD117/c-kit, myoglobin, tyrosine hydroxylase (TH), growth-associated protein 43, cholineacetyltransferase, and synaptophysin, as well as trichrome.

Prevention of atrial fibrillation: report from a national heart, lung, and blood institute workshop.

The National Heart, Lung, and Blood Institute convened an expert panel April 28 to 29, 2008, to identify gaps and recommend research strategies to prevent atrial fibrillation (AF). The panel reviewed the existing basic scientific, epidemiological, and clinical literature about AF and identified opportunities to advance AF prevention research. After discussion, the panel proposed the following recommendations: (1) enhance understanding of the epidemiology of AF in the population by systematically and longitudinally investigating symptomatic and asymptomatic AF in cohort studies; (2) improve detection of AF by evaluating the ability of existing and emerging methods and technologies to detect AF; (3) improve noninvasive modalities for identifying key components of cardiovascular remodeling that promote AF, including genetic, fibrotic, autonomic, structural, and electrical remodeling markers; (4) develop additional animal models reflective of the pathophysiology of human AF; (5) conduct secondary analyses of already-completed clinical trials to enhance knowledge of potentially effective methods to prevent AF and routinely include AF as an outcome in ongoing and future cardiovascular studies; and (6) conduct clinical studies focused on secondary prevention of AF recurrence, which would inform future primary prevention investigations.

Intracellular calcium dynamics and acceleration of sinus rhythm by beta-adrenergic stimulation.

Background: Recent evidence indicates that membrane voltage and Ca2+ clocks jointly regulate sinoatrial node (SAN) automaticity. Here we test the hypothesis that sinus rate acceleration by beta-adrenergic stimulation involves synergistic interactions between these clock mechanisms.

Methods And Results: We simultaneously mapped intracellular calcium (Ca(i)) and membrane potential in 25 isolated canine right atrium, using previously described criteria of the timing of late diastolic Ca(i) elevation (LDCAE) relative to the action potential upstroke to detect the Ca2+ clock.