Hrayr S. Karagueuzian

Nerve Sprouting and Sudden Cardiac Death

The factors that contribute to the occurrence of sudden cardiac death (SCD) in patients with chronic myocardial infarction (MI) are not entirely clear. The present study tests the hypothesis that augmented sympathetic nerve regeneration (nerve sprouting) increases the probability of ventricular tachycardia (VT), ventricular fibrillation (VF), and SCD in chronic MI. In dogs with MI and complete atrioventricular (AV) block, we induced cardiac sympathetic nerve sprouting by infusing nerve growth factor (NGF) to the left stellate ganglion (experimental group, n=9). Another 6 dogs with MI and complete AV block but without NGF infusion served as controls (n=6). Immunocytochemical staining revealed a greater magnitude of sympathetic nerve sprouting in the experimental group than in the control group. After MI, all dogs showed spontaneous VT that persisted for 5.8+/-2.0 days (phase 1 VT). Spontaneous VT reappeared 13.1+/-6.0 days after surgery (phase 2 VT). The frequency of phase 2 VT was 10-fold higher in the experimental group (2.0+/-2.0/d) than in the control group (0.2+/-0.2/d, P<0.05). Four dogs in the experimental group but none in the control group died suddenly of spontaneous VF. We conclude that MI results in sympathetic nerve sprouting. NGF infusion to the left stellate ganglion in dogs with chronic MI and AV block augments sympathetic nerve sprouting and creates a high-yield model of spontaneous VT, VF, and SCD. The magnitude of sympathetic nerve sprouting may be an important determinant of SCD in chronic MI.

Chaos and the Transition to Ventricular Fibrillation: A New Approach to Antiarrhythmic Drug Evaluation

Sudden cardiac death resulting from ventricular fibrillation can be separated into 2 components: initiation of tachycardia and degeneration of tachycardia to fibrillation. Clinical drug studies such as CAST and SWORD demonstrated that focusing exclusively on the first component is inadequate as a therapeutic modality. The hope for developing effective pharmacological therapy rests on a comprehensive understanding of the second component, the transition from tachycardia to fibrillation. We summarize evidence that the transition from tachycardia to fibrillation is a transition to spatiotemporal chaos, with similarities to the quasiperiodic transition to chaos seen in fluid turbulence. In this scenario, chaos results from the interaction of multiple causally independent oscillatory motions. Simulations in 2-dimensional cardiac tissue suggest that the destabilizing oscillatory motions during spiral-wave reentry arise from restitution properties of action potential duration and conduction velocity. The process of spiral-wave breakup in simulated cardiac tissue predicts remarkably well the sequence by which tachycardia degenerates to fibrillation in real cardiac tissue. Modifying action potential duration and conduction velocity restitution characteristics can prevent spiral-wave breakup in simulated cardiac tissue, suggesting that drugs with similar effects in real cardiac tissue may have antifibrillatory efficacy (the Restitution Hypothesis). If valid for the real heart, the Restitution Hypothesis will support a new paradigm for antiarrhythmic drug classification, incorporating an antifibrillatory profile based on effects on cardiac restitution and the traditional antitachycardia profile (classes 1 through 4).

The Dynamics of Cardiac Fibrillation

Reentry occurs when the electrical wave propagating through the atria or ventricles breaks locally and forms a rotor (also called a scroll wave or functional reentry). If the waves propagating outward from a rotor develop additional wavebreaks (which may form new rotors), fibrillation results. Tissue heterogeneity, exacerbated by electrical and structural remodeling from cardiac disease, has traditionally been considered the major factor promoting wavebreak and its degeneration to fibrillation. Recently, however, dynamic factors have also been recognized to play a key role. Dynamic factors refer to cellular properties of the cardiac action potential and Ca(i) cycling, which dynamically generate wave instability and wavebreak, even in tissue that is initially completely homogeneous. Although the latter situation can only be created in computer simulations, its relevance to real (heterogeneous) cardiac tissue has been unequivocally demonstrated. Dynamic factors are related to membrane voltage (Vm) and Ca(i). Vm factors include electrical restitution of action potential duration and conduction velocity, short-term cardiac memory, and electrotonic currents. Ca(i) factors are related to dynamic Ca(i) cycling properties. They act synergistically, as well as with tissue heterogeneity, to promote wavebreak and fibrillation. As global properties, rather than local electrophysiological characteristics, dynamic factors represent an attractive target for novel therapies to prevent ventricular fibrillation.

Sympathetic nerve sprouting, electrical remodeling and the mechanisms of sudden cardiac death

The purpose of this article is to review the nerve sprouting hypothesis of sudden cardiac death. It is known that sympathetic stimulation is important in the generation of sudden cardiac death. For example, there is a diurnal variation of sudden death rate in patients with myocardial infarction. Beta blockers, or drugs with beta blocking effects, are known to prevent sudden cardiac death. It was unclear if the cardiac nerves in the heart play only a passive role in the mechanisms of sudden death. To determine if nerve sprouting and neural remodeling occur after myocardial infarction, we performed immunocytochemical studies of cardiac nerves in explanted native hearts of transplant recipients. We found that there was a positive correlation between nerve density and a clinical history of ventricular arrhythmia. Encouraged by these results, we performed a study in dogs to determine whether or not nerve growth factor (NGF) infusion to the left stellate ganglion can facilitate the development of ventricular tachycardia (VT), ventricular fibrillation (VF), and sudden cardiac death (SCD). The results showed that augmented myocardial sympathetic nerve sprouting through NGF infusion plus atrioventricular (AV) block and MI result in a 44% incidence (four of nine dogs) of SCD and a high incidence of VT in the chronic phase of MI. In contrast, none of the six dogs (with AV block and MI) without NGF infusion died suddenly or had frequent VT episodes. Based on these findings, we propose the nerve sprouting hypothesis of ventricular arrhythmia and SCD. The hypothesis states that MI results in nerve injury, followed by sympathetic nerve sprouting and regional (heterogeneous) myocardial hyperinnervation. The coupling between augmented sympathetic nerve sprouting with electrically remodeled myocardium results in VT, VF and SCD. Modification of nerve sprouting after MI may provide a novel opportunity for arrhythmia control.

Spatiotemporal Heterogeneity in the Induction of Ventricular Fibrillation by Rapid Pacing Importance of Cardiac Restitution Properties

The mechanism by which rapid pacing induces ventricular fibrillation (VF) is unclear. We performed computerized epicardial mapping studies in 10 dogs, using 19-beat pacing trains. The pacing interval (PI) of the first train was 300 ms and then was progressively shortened until VF was induced. For each PI, we constructed restitution curves for the effective refractory period (ERP). When the PI was long, the activation cycle length (CL) was constant throughout the mapped region. However, as the PI shortened, there was an increase in the spatiotemporal complexity of the CL variations and an increase in the slope of the ERP restitution curve. In 5 dogs, we documented the initiation of VF by wavebreak at the site of long-short CL variations. Computer simulation studies using the Luo-Rudy I ventricular action potential model in simulated 2-dimensional tissue reproduced the experimental results when normal ERP and conduction velocity (CV) restitution properties were intact. By altering CV and ERP restitutions in this model, we found that CV restitution creates spatial CL variations, whereas ERP restitution underlies temporal, beat-to-beat variations in refractoriness during rapid pacing. Together, the interaction of CV and ERP restitutions produces spatiotemporal oscillations in cardiac activation that increase in amplitude as the PI decreases, ultimately causing wavebreak at the site of intrinsic heterogeneity. This initial wavebreak then leads to the formation of spiral waves and VF. These findings support a key role for both CV and ERP restitutions in the initiation of VF by rapid pacing.

Ventricular Fibrillation How Do We Stop the Waves From Breaking

Abstract— Combined experimental and theoretical developments have demonstrated that in addition to preexisting electrophysiological heterogeneities, cardiac electrical restitution properties contribute to breakup of reentrant wavefronts during cardiac fibrillation. Developing therapies that favorably alter electrical restitution properties have promise as a new paradigm for preventing fibrillation.

Nerve Sprouting and Sympathetic Hyperinnervation in a Canine Model of Atrial Fibrillation Produced by Prolonged Right Atrial Pacing

Background—Long-term rapid atrial pacing may result in atrial fibrillation (AF) in dogs. Whether there is histological evidence for neural remodeling is unclear. Method and Results—We performed rapid right atrial pacing in 6 dogs for 111±76 days to induce sustained AF. Tissues from 6 healthy dogs were used as controls. Immunocytochemical staining of cardiac nerves was performed using anti–growth-associated protein 43 (GAP43) and anti–tyrosine hydroxylase (TH) antibodies. In dogs with AF, the density of GAP43-positive and TH-positive nerves in the right atrium was 470±406 and 231±126 per mm2, respectively, which was significantly (P <0.001) higher than the nerve density in control tissues (25±32 and 88±40 per mm2, respectively). The density of GAP43-positive and TH-positive nerves in the atrial septum was 317±36 and 155±85 per mm2, respectively, and was significantly (P <0.001) higher than the nerve density in control tissues (9±13 and 30±7 per mm2, respectively). Similarly, the density of GAP43-positive and TH-positive nerves in the left atrium of dogs with AF was 119±61 and 91±40 per mm2, respectively, which was significantly (P <0.001) higher than the nerve density in control tissues (10±15 and 38±39 per mm2, respectively). Furthermore, in dogs with AF, the right atrium had a significantly higher nerve density than the left atrium. Microscopic examinations revealed an inhomogeneous distribution of cardiac nerves within each sampling site. Conclusions—Significant nerve sprouting and sympathetic hyperinnervation are present in a canine model of sustained AF produced by prolonged right atrial pacing. The magnitude of nerve sprouting and hyperinnervation was higher in the right atrium than in the left atrium.

Relation Between Ligament of Marshall and Adrenergic Atrial Tachyarrhythmia

BACKGROUND The mechanism of the adrenergic atrial tachyarrhythmia is unclear. We hypothesize that the ligament of Marshall (LOM) is sensitive to adrenergic stimulation and may serve as a source of the adrenergic atrial tachyarrhythmia. METHODS AND RESULTS We performed computerized mapping studies in isolated-perfused canine left atrial tissues from normal dogs (n=9) and from dogs with chronic atrial fibrillation (AF) induced by 10 to 41 weeks of rapid pacing (n=3). Before isoproterenol, spontaneous activity occurred in only one normal tissue (cycle length, CL >1300 ms). During isoproterenol infusion, automatic rhythm was induced in both normal tissues (CL=578+/-172 ms) and AF tissues (CL=255+/-29 ms, P<0.05). The origin of spontaneous activity was mapped to the LOM. In the AF tissues, but not the normal tissues, we observed the transition from rapid automatic activity to multiple wavelet AF. Ablation of the LOM terminated the spontaneous activity and prevented AF. Immunocytochemical studies of the LOM revealed muscle tracts surrounded by tyrosine hydroxylase-positive (sympathetic) nerves. CONCLUSIONS We conclude that the LOM is richly innervated by sympathetic nerves and serves as a source of isoproterenol-sensitive focal automatic activity in normal canine atrium. The sensitivity to isoproterenol is upregulated after long-term rapid pacing and may contribute to the development of AF in this model.

Simultaneous Biatrial Computerized Mapping During Permanent Atrial Fibrillation in Patients with Organic Heart Disease

Activations in Permanent Atrial Fibrillation. Introduction: Activation patterns during permanent atrial fibrillation (AF) in patients with organic heart diseases are unclear.

Aging-related increase to inducible atrial fibrillation in the rat model.

Aging and Atrial Fibrillation. Introduction: Aging is associated with atrial interstitial fibrosis and increased incidence of atrial fibrillation (AF). We hypothesized that aged rats are suitable for study of aging‐related AF and that partial atrial cellular uncoupling induced with heptanol in young rats mimics aging‐related AF.