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Nicotine & cardiac vulnerability to fibrillation

Institution: Cedars-Sinai Medical Center
Investigator(s): Hrayr Karagueuzian, Ph.D.
Award Cycle: 2000 (Cycle 9) Grant #: 9RT-0041 Award: $120,000
Subject Area: Cardiovascular Disease
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
Epidemiological studies have shown that the incidence of atrial fibrillation (AF), rapid and irregular electrical activation of the upper chambers of the heart (disorganized wave front activity), increases with increasing age and is more prevalent in male than in female. While not lethal in and itself, AF if remained untreated causes heart failure, chest pain, stroke and increases the risk of sudden cardiac death caused by ventricular fibrillation (VF). In the US, AF remains the most common cardiac arrhythmia requiring hospitalization. Recent studies have shown that smoking increases the incidence of AF in diseased (remodeled) atria of various causes. It is however, not known how smoking influences the incidence of AF in aged atria known to manifest various forms of remodeling. Furthermore, the mechanisms by which nicotine promotes AF in the aged atria and gender differences, if at all, for enhanced vulnerability to AF with nicotine use remains undefined. The purpose of this study is to elucidate the mechanism by which nicotine promotes AF in the remodeled atria induced by aging and to determine gender differences to nicotine sensitivity for the induction of AF.

The studies will be conducted on atria isolated from rats of different ages and gender. (The National Institute on Aging maintains colonies of rats of different ages for the specific purpose of studying the effects of aging on various body functions). The effects of nicotine on atrial electrical activation patterns and properties will be visualized dynamically during heart rate acceleration using high-resolution computerized optical mapping techniques. By this method we will determine how a normal electrical activation wave front undergoes breakup leading to disorganized and irregular atrial activation, i.e., AF.

We have developed two hypotheses of activation wave front breakups: the Restitution Hypothesis and the altered cellular (junctional) coupling hypothesis of vulnerability. The first hypothesis states that when the recovery rate of cardiac excitability speeds up (slope >1) a beat-to-beat cardiac instability develops during heart rate acceleration. When an atrial beat becomes unstable (i.e., too weak to propagate), a wavebreak results, leading to AF. The second hypothesis states that in the remodeled atria cell-to-cell coupling (conductance) becomes altered in aged atria and, when the heart rate is accelerated, the defective cellular communication leads to wavebreak and AF. Nicotine's ability to modulate atrial vulnerability to AF will systematically be evaluated by testing these two hypotheses in aged atria of different genders.

The elucidation of the mechanism by which nicotine promotes and maintains AF in aged atria and the determination of gender differences in the sensitivity to nicotine's pro-AF effect assume a considerable clinical significance as it helps identify subjects at high risk of developing AF with nicotine use.

Final Report
Nicotine (N) has been implicated as a potential cause of a broad spectrum of cardiac arrhythmias including atrial fibrillation (AF). The potential factors responsible for N's variable influence on AF vulnerability remain undefined. We hypothesized that aging is one factor that modulates AF vulnerability to N. Twelve male rats (Fisher-344) were grouped into young (2-4 months, N=6) and old (22-24 months, N=6). The isolated hearts were perfused (through the aorta) and superfused with oxygenated Tyrode's at 37°C. Atrial effective refractory period (ERP), interatrial conduction time (CT) and AF vulnerability (tested by burst atrial pacing) were then determined in both groups before and after 10-100 ng/ml N perfusion. [The arterial blood level of N in smokers is between 30-85 ng/ml]. The epicardial surface of the atria was optically mapped using CCD camera. At baseline, CT was significantly greater in the old than in the young rats (52±32 vs. 25±5 ms, P<0.05), however, there was no significant difference in the ERP between the two groups (19.2±4.8 vs. 19.3±7.6 ms). Burst pacing induced AF (CLs of 26-50 ms) in 5 of the 6 old rats. However, no AF could be induced in any of the 6 young rats. N increased interatrial CT and ERP in a concentration-dependent manner that was significantly (P<0.05) higher in the old than in the young rats (90±34 ms vs. 35±9 ms and 24±4 ms vs. 27±3 ms respectively during 80 ng/ml N perfusion). N at 10-30 ng/ml prevented AF induction in the old rats, however atrial tachycardia (AT) at CLs of 84-110 ms could still be induced in 5/6 old rats. N at 50 ng/ml and above prevented AF and AT induction in the old rats. In contrast however N at 10-100 ng/ml significantly (P<0.01) increased AF (N=3) and AT (N=3) induction in the young rats. Optical mapping showed the presence of 2-3 independent wave fronts during AF but only one large periodic wave front during AT. Old rats had significantly (P<0.05) greater interstitial atrial fibrosis compared to young rats (1.72±0.81 vs. 0.38±0.45%).

We conclude that the mechanism of N-induced modulation of AF vulnerability is compatible with changes in interatrial CT and ERP. In atria with less than a critical increase in the CT/ERP (young rats at baseline) or excessive increase in CT/ERP (aged atria exposed to N >50 ng/ml) AF/AT can not be induced.

IMPACT. In young and normal atria .N at blood levels found in smokers increases AF and AT vulnerability. Such effects may increase the incidence of sudden death. In aged atria prone to AF with preexisting tissue abnormality and conduction defects (interstitial fibrosis) N at blood levels found in smokers increases AF/AT vulnerability. However at higher concentrations, N causes complete intraatrial conduction block and inexcitability (No AF/AT) causing loss of atrial contraction ("atrial kick").
Publications

Cardiac action potential recorded with pure iridium metal microelectrode: a comparative study with glass microelectrode studies
Periodical: American Journal of Physiology Index Medicus:
Authors: Omichi C, Lee M-H, Ohara T, Naik AM, Karagueuzian HS, Chen P-S ART
Yr: 2000 Vol: 279 Nbr: Abs: Pg: H3113-H3117

Obstacle-induced transition from ventricular fibrillation to ventricular tachycardia in isolated swine right ventricles
Periodical: Journal of the American College of Cardiology Index Medicus:
Authors: Vladerrabano M, Kim Y-H, Yashima M, Wu T-J, Karagueuzian HS, Chen P-S ART
Yr: 2000 Vol: 36 Nbr: Abs: Pg: 2000-2008

Co-localization of tenascin and sympathetic nerves in a canine model of nerve sprouting and sudden cardiac death
Periodical: Journal of Cardiovascular Electrophysiology Index Medicus:
Authors: Lai AC, Wallner K, Cao J-M, et al ART
Yr: 2000 Vol: 11 Nbr: Abs: Pg: 1345-1351

Nerve sprouting and sympathetic hyperinnervation in a canine model of atrial fibrillation produced by prolonged right atrial pacing
Periodical: Circulation Index Medicus:
Authors: Chang C-M, Wu T-J, Zhou S-M, et al ART
Yr: 2001 Vol: 103 Nbr: Abs: Pg: 22-25

Pulmonary veins and ligament of Marshall as sources of rapid activations in a canine model of sustained atrial fibrillation
Periodical: Circulation Index Medicus:
Authors: Wu TJ, Ong JJC, Chang C-M, et al ART
Yr: 2001 Vol: 103 Nbr: Abs: Pg: 1157-1163

Increased wavebreak during ventricular fibrillation in the epicardial border zone of hearts with healed myocardial infarction
Periodical: Circulation Index Medicus:
Authors: Ohara T, Cao J-M, Fishbeine MC, Mandel WJ, Chen P-S, Karagueuzian HS ART
Yr: 2001 Vol: 103 Nbr: Abs: Pg: 1465-1472

The effects of diacetyl monoxime and cytochalasin D on action potential duration restitution and the dynamics of ventricular fibrillation in isolated swine right ventricles
Periodical: American Journal of Physiology Index Medicus:
Authors: Lee M-H, Lin S-F, Ohara T, et al ART
Yr: 2001 Vol: Nbr: Abs: Pg: H253-H265

Dynamics of intramural and transmural reentry during ventricular fibrillation in isolated swine ventricles
Periodical: Circulation Research Index Medicus:
Authors: Valderrabano M, Lee M-H, Ohara T, et al ART
Yr: 2001 Vol: 88 Nbr: Abs: Pg: 839-848

Mechanisms of ventricular defibrillation in isolated swine right ventricles
Periodical: Circulation Index Medicus:
Authors: Wang NC, Lee M-H, Ohara, Voroshilovski, Karagueuzian HS ART
Yr: 2001 Vol: 104 Nbr: Abs: Pg: 227-233

Modulation of QT interval by cardiac sympathetic nerve sprouting and the mechanisms of ventricular arrhythmia in a canine model of sudden cardiac death
Periodical: Journal of Cardiovascular Electrophysiology Index Medicus:
Authors: Zhou S, Cao J-M, Tebb ZD, et al ART
Yr: 2001 Vol: Nbr: Abs: Pg: