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Nicotine and cardiac vulnerability to fibrillation

Institution: Cedars-Sinai Medical Center
Investigator(s): Hrayr Karagueuzian, Ph.D.
Award Cycle: 1997 (Cycle 6) Grant #: 6RT-0020 Award: $370,057
Subject Area: Cardiovascular Disease
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
It is known that tobacco smoke aggravates the outcome (prognosis) of a disease in man. Patients with a history of a heart attack (myocardial infarction or MI) are perhaps the most vulnerable to the worsening effect of tobacco smoke. A recent carefully designed study involving a large number of patients with a history of MI, showed that smoking not only significantly increased the incidence of sudden cardiac death, but that quitting the habit also led to a significant reduction in the mortality rate in this patient population.

Sudden cardiac death in man is often caused by irregular beating (arrhythmia) of the heart. The most common cause of these potentially lethal cardiac arrhythmias is cardiac fibrillation, an irregular and rapid cardiac rhythm that resembles fluid turbulence. During fibrillation the orderly normal beatings of the heart, (like target waves that travel in sequence in a pond) is completely lost. If fibrillation occurs in the lower chambers (i.e., ventricular fibrillation of VF) the patient suddenly collapses (sudden death) requiring emergency resuscitation with electrical shock. If on the other hand, fibrillation occurs in the upper chambers of the heart (atrial fibrillation or AF) although death is not as imminent as in VF, however, AF in the long run carries significant risk of sudden cardiac death and brain stroke. At the present, it is not known by what mechanism(s) smoking precipitates these potentially lethal cardiac rhythms. The major cardiac effects of smoking are mimicked by the intake of nicotine, a major constituent of tobacco smoke, and chewing nicotine gum has been shown to directly trigger AF in susceptible patients. The aim of our research proposal, therefore, is to elucidate the mechanism(s) by which nicotine triggers cardiac fibrillation in diseased hearts.

We will determine nicotine’s effect on cardiac vulnerability to fibrillation in animal models with diseased hearts that bear close resemblance to diseased human hearts prone to AF and VF. In these models, we will show, using computer generated images how nicotine converts the regular normal rhythm (target wave pattern) to fibrillation (turbulent wave pattern). In this proposal we will specifically determine nicotine’s pro-fibrillatory mechanisms in diseased hearts and the conditions under which nicotine promotes the conversion of normal cardiac rhythm (regular target waves) to fibrillation (irregular vortex-like waves). Nicotine’s pro-fibrillatory potential will also be evaluated under conditions of increased heart rates, an event that accompanies physical activity.

The result of this study will provide, for the first time, fundamental and new knowledge on the mechanism by which nicotine promotes cardiac fibrillation. This new knowledge is most relevant to the problem of smoking-induced increase in sudden cardiac death in man. It is anticipated that the results of this study will provide new and effective therapeutic strategies and encourage preventive measures designed to minimize the incidence of sudden cardiac death in smokers.

Final Report
The objectives of this project were to determine the vulnerability of the diseased ventricles (lower chambers of the heart) to nicotine in promoting ventricular fibrillation (VF) a rapid and disorganized rhythm that is incompatible with life. VF is the major precursor of sudden cardiac death that claims more that 300,000 lives each year in the United States.

We created myocardial infarction (MI) in the dogs by permanent occlusion of a branch of the left coronary artery to mimic the phenomenon of heart attack that occurs in humans. We evaluated the vulnerability of the infracted ventricles to nicotine in this model during a period considered to be “stable” in humans (i.e. the healed phase). Vulnerability to VF was evaluated by testing the restitution hypothesis of vulnerability to wavebreak. This hypothesis determines activation wave stability by measuring the rate of recovery of ventricular excitability.

Using computerized activation map with several hundred simultaneous recordings from the diseased ventricle, we discovered that nicotine, at concentrations found in the blood of the smokers, increased activation wave instability (wavebreak or wave splitting). The instability was immediately followed by complete loss of regular activation pattern leading to a very rapid and irregular activity that signaled the onset of VF. The effect of nicotine was most apparent in the diseased area of the ventricle compared to adjoining normal non-diseased areas of the infracted left ventricle. We also found that nicotine at concentrations often found the blood of smokers did not have significant effect on ventricular vulnerability to fibrillation in normal hearts with no MI. Nicotine’s pro-VF influence was most apparent during increases in the heat rate.

These results provide mechanistic insight into nicotine’s profibrillatory influence on the diseased ventricle and indicated that the use of nicotine and nicotine products in patients with chronic MI during a period considered “stable” carries high risk of sudden cardiac death caused by VF. It is suggested that nicotine not be used in such high risk patients and that in such patients increases in heart rate carries a particularly ominous outcome.

We also found that nicotine increases activation wave front complexity during the VF. Since activation wave complexity bears an influence on the level of electrical energy requirement for successful ventricular defibrillation (the only affective form of therapy) it is possible that nicotine use in patients with MI may also be accompanied by grater incidence of failed defibrillation shocks.
Publications

Transmembrane potential properties of atrial cells at different sites of a spiral wave reentry. Cellular _x000d_ evidence for an excitable but non-excited core.
Periodical: Pacing and Clinical Electrophysiology Index Medicus:
Authors: Karagueuzian HS, Athill CA, Yashima M, et al ART
Yr: 1998 Vol: Nbr: Abs: Pg: 2360-2365

Mechanism of acceleration of functional reentry in the ventricle
Periodical: Circulation Index Medicus:
Authors: Uchida T, Yashima M, Gotoh M, et al ART
Yr: 1999 Vol: 99 Nbr: Abs: Pg: 704-712

Nicotine increases spatiotemporal complexity of ventricular fibrillation wave fronts on the epicardial border zone of healed canine infarcts
Periodical: Journal of Cardiovascular Pharmacology Index Medicus:
Authors: Ohara T, Yashima M, Hamzei A, et al ART
Yr: 1999 Vol: 4 Nbr: Abs: Pg: 121-127

Idiopathic paroxysmal atrial fibrillation induced by a focal discharge mechanism in the left superior pulmonary vein. Possible role of the ligament of Marshall
Periodical: Journal of Cardiovascular Electrophysiology Index Medicus:
Authors: Hwang C, Karagueuzian HS, Chen P-S ART
Yr: 1999 Vol: 10 Nbr: Abs: Pg: 636-648

Role of papillary muscle in the generation and maintenance of reentry during ventricular tachycardia and fibrillation in isolated swine right ventricle
Periodical: Circulation Index Medicus:
Authors: Kim Y-H, Xie F, Yashima M, et al ART
Yr: 1999 Vol: Nbr: Abs: Pg:

Mechanism of procainamide-induced prevention of spontaneous wave break during ventricular fibrillation. Insight into the fibrillation wave fronts
Periodical: Circulation Index Medicus:
Authors: Kim Y-H, Yashima M, Wu T-J, Chen P-S, Karagueuzian HS ART
Yr: 1999 Vol: Nbr: Abs: Pg:

Current concept of ventricular defibrillation
Periodical: Journal of Cardiovascular Electrophysiology Index Medicus:
Authors: Chen P-S, Swerldow CD, Hwang C, Karagueuzian HS ART
Yr: 1998 Vol: 9 Nbr: Abs: Pg: 553-562

Focal source hypothesis of atrial fibrillation
Periodical: Journal of Electrocardiology Index Medicus:
Authors: Chen P-S, Wu T-J, Ikeda T, et al ART
Yr: 1999 Vol: 31 Nbr: Suppl Abs: Pg: 32-34

Chaos and the transition to ventricular fibrillation: A new approach to antiarrhythmic drug evaluation
Periodical: Circulation Index Medicus:
Authors: Weiss JN, Garfinkel A, Karagueuzian HS, Qu Z, Chen P-S ART
Yr: 1999 Vol: Nbr: Abs: Pg:

Atrial cell action potentials recorded from different sites of a reentrant wave front
Periodical: Archives des Maladies du Coeur et des Vaisseaux Index Medicus:
Authors: Karagueuzian HS, Athill C, Yashima M, Ikeda T, Mandel WJ, Chen P-S ABS
Yr: 1998 Vol: 91 Nbr: Spec III Abs: Pg: 276

The importance of endocardial structure in chronic atrial fibrillation
Periodical: Circulation Index Medicus:
Authors: Wu T-J, Huang H-H, Ong JCO ABS
Yr: 1998 Vol: Nbr: Abs: Pg:

Relation between the cellular repolarization characteristics and the critical mass for human ventricular fibrillation
Periodical: American Journal of Cardiology Index Medicus:
Authors: Wu T-J, Yashima M, Doshi R, et al ABS
Yr: 1999 Vol: 33 Nbr: 2 Suppl A Abs: 151A Pg:

Upregulation of catecholamine-sensitive focal automaticity from the Ligament of Marshall in a canine model of chronic atrial fibrillation
Periodical: American Journal of Cardiology Index Medicus:
Authors: Doshi R, Wu T-J, Yashima M, et al ABS
Yr: 1999 Vol: 33 Nbr: 2 Suppl A Abs: 167A Pg:

Approximate entropy as an index for ventricular fibrillation stratification. Implications for mechanism
Periodical: American Journal of Cardiology Index Medicus:
Authors: Hamzei A, Ohara T, Lee M-H, Voroshilovsky O, Chen P-S, Karagueuzian HS ABS
Yr: 1999 Vol: 33 Nbr: 2 Suppl A Abs: 126A Pg:

Decreased connexin45 distribution decreases the core of functional reentry on the epicardial border zone of healed infarcts during ventricular fibrillation
Periodical: Pacing and Clinical Electrophysiology Index Medicus:
Authors: Ohara T, Cao J, Mandel WJ, Chen P-S, Karagueuzian HS ABS
Yr: 1999 Vol: 22 Nbr: 4 Part II Abs: 753 Pg:

Mass and approximate entropy as determinants of ventricular defibrillation threshold
Periodical: Pacing and Clinical Electrophysiology Index Medicus:
Authors: Hamzei A, Ohara T, Lee M-H, Voroshilovski O, Chen P-S, Karagueuzian HS ABS
Yr: 1999 Vol: 22 Nbr: 4 Part II Abs: 747 Pg:

Mechanism of Procainamide-induced prevention of spontaneous wave break during ventricular fibrillation
Periodical: Pacing and Clinical Electrophysiology Index Medicus:
Authors: Kim Y-H, Yashima M, Wu T-J, Doshi RN, Chen P-S, Karagueuzian HS ABS
Yr: 1999 Vol: 22 Nbr: 4 Part II Abs: 731 Pg:

Single cell transmembrane action potential recorded near the phase singularity during ventricular fibrillation
Periodical: Pacing and Clinical Electrophysiology Index Medicus:
Authors: Lee M-H, Voroshilovsky O, Ohara T, et al ABS
Yr: 1999 Vol: 22 Nbr: 4 Part II Abs: 833 Pg:

Action potential duration restitution and the maintenance of ventricular fibrillation in isolated swine right ventricle: validation of the restitution hypothesis
Periodical: Pacing and Clinical Electrophysiology Index Medicus:
Authors: Voroshilovsky O, Lee M-H, Ohara T, et al ABS
Yr: 1999 Vol: 22 Nbr: 4 Part II Abs: 759 Pg:

Cardiac action potential recorded with pure iridium metal microelectrode
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

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 T-J, Ong J-JC, 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, Fishbein MC, Mandel WJ, Chen P-S, Karagueuzian HS ART
Yr: 2001 Vol: 103 Nbr: Abs: Pg: 1465-1472