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Nicotine Exposure In Aging Hearts

13.11.2003


New study in rats suggests that nicotine at concentrations found in the blood of smokers may increase atrial vulnerability to inducible atrial tachycardia and atrial fibrillation in normal adult atria with no atrial disease.



Large numbers of Americans still smoke cigarettes or use over-the-counter nicotine products such as patches and gums to satisfy their craving for nicotine. However, serious and sometime fatal cases of atrial fibrillation (AF) have been reported in patients who use a nicotine product. This is particularly true when the individual has smoked while using a nicotine patch. AF is the most common type of disturbance of the normal rhythm of the heart and affects some two million people annually. At its most devastating, AF results in stroke (brain attack) and congestive heart failure. Previous studies have concluded that transdermal nicotine patches should be used cautiously because of the high risk of AF they carry for patients with heart disease.

How specific atrial substrates control and modulate atrial vulnerability, which can induce atrial tachycardia (AT) and AF (AT/AF) in response to acute doses of nicotine, is poorly understood. One substrate known to modulate atrial vulnerability to inducible AT/AF is enhanced atrial interstitial fibrosis, commonly found among the aging. Against this backdrop a team of researchers has hypothesized that nicotine concentrations found in the blood of certain smokers exerts a differential influence on the atria and on different substrates for AT/AF. They tested their hypothesis by determining atrial sensitivity to nicotine by inducible AT/AF in young and old rats.


A New Study

The authors of a new study entitled, “Age-related Sensitivity to Nicotine for Inducible Atrial Tachycardia and Atrial Fibrillation,” are Hideki Hayashi, Chikaya Omichi, Yasushi Miyauchi, William J. Mandel, Shien-Fong Lin, Peng-Sheng Chen and Hrayr S. Karagueuzian, all of the Division of Cardiology, Department of Medicine, Cedars-Sinai Medical Center and David Geffen School of Medicine, University of California, Los Angeles, CA. Their findings appear in the November 2003 edition of the American Journal of Physiology—Heart and Circulatory Physiology, one of 14 journals published each month by the American Physiological Society (APS).

Methodology

The investigators studied male Fischer 344 rats, a strain that has been extensively used as a model of aging without the presence of other confounding factors such as coronary, vascular, or valvular abnormalities that often accompany growing old. Twelve male rats consisting of six young (2-3 mo old) and six old (22-24 mo old) were anesthetized, and a thoracotomy was performed. The pulmonary artery and aorta were cut and the pulmonary veins ligated. The isolated heart was perfused through the aorta, immersed in a tissue bath, and later superperfused with warm and oxygenated solution. Two pairs of bipolar electrodes were place on the right atrium (RA) and two pairs on the left atrium (LA) for arterial pacing and recording. The fifth pair was placed on the left ventricle.

Atrial vulnerability to inducible AT/AF was tested by a rapid, 3-s burst atrial pacing at cycle lengths (CL) of 100 ms with a pulse duration of 2 ms and twice-diastolic current threshold. The effective refractory period (ERP) was measured by the S2 extrastimulus method using eight regularly paced S1-S1 at a pacing CL of 200 ms in the right atrium (RA). After baseline studies, nicotine (Sigma) at concentrations of 10, 30, 50, 80, and 100 ng/ml in solution was perfused through the aorta to determine its effects on the interatrial conduction time (IACT), atrial ERP, atrial vulnerability to inducible AT/AF, and atrial activation wavefront patterns during induced AT and AF. The hearts were stained with a voltage-sensitive dye that was injected through the aorta and illuminated.

All statistical analyses were performed using GB-Stat. The data were expressed as means + SD. Statistical tests were performed using Student’s t-test, ÷2 test, and one-way ANOVA for repeated measures. A value of P <0.05 was considered significant.

Results

The researchers found the following:
  • Weights: The body and heart weights were significantly smaller in the young compared with the old rats.

  • AT in young rats: At baseline, no AT could be induced in the young rats. During nicotine perfusion at 10-30 ng/ml, burst atrial pacing induced AT in five of the six rats. Yet, when the nicotine concentration was raised >30 ng/ml, a significant decrease (33%) (P<0.01) in pacing-induced AT developed (two of six rats). These findings indicate that nicotine exerts a biphasic effect on inducible AT in young rats, causing facilitation at low -- and inhibition at high -- nicotine concentrations.

  • AF in young rats: No AF could be induced in any of the young rats at baseline. However, nicotine perfusion at 10-100 ng/ml caused the burst atrial pacing to induce AF in four of six young rats (85%, P< 0.05). The range of nicotine concentrations during with AF could be induced varied in each rat and encompassed the entire 10-100 ng/ml range tested.

  • AT/AF in old rats: The incidences of inducible AT/AF at baseline and during nicotine exposure in the old rats were significantly different from young rats. At baseline, burst atrial pacing induced AT and AF in five of the six old rats. The influence of nicotine on AT inducibility in the old rats was concentration dependent. At 10-30 ng/ml, nicotine preserved AT inducibility as at baseline. However, when the nicotine concentration was raised >30 ng/ml, nicotine suppressed the induction of AT in all the old rats. Furthermore, nicotine perfusion at concentrations of 10-100 ng/ml prevented burst atrial pacing-induced AF in all the old rats.

  • AT/AF Cycle Length: The CL of the induced AT in the presence of nicotine was insensitive to nicotine concentrations in both young and old rats. The mean CL of the AF in the young and old rats was insensitive to nicotine concentrations as well.

  • Effective Refractory Period: In the young rats, nicotine had a biphasic effect on atrial ERP. In the old rats, nicotine at 10 ng/ml had no effect, although when nicotine concentrations were raised >30 ng/ml, a significant progressive increase in the ERP developed.

  • Interatrial Conduction Time: Nicotine significantly increased the IACT in a CL-dependent and concentration-dependent manner in both the young and old rats. The increase in the IACT was significantly higher in the old rats than that in the young ones all nicotine concentration levels.

  • High-Resolution Optical Mapping: During an induced AT, a periodic single large activation wavefront originating from the junction between the LA and the pulmonary vein was present in both the young and old rats that propagated from the LA to the RA. During induced AF, multiple independent waterfronts separated by recovered atria tissues were present in both the young and old rats. These AF wavelets propagated in all direction.

Conclusions and Discussion

The results of this study show that atrial sensitivity to nicotine for inducible AT/AF is different in young vs. old rats. Nicotine significantly increased atrial vulnerability to inducible AT/AF in the young rats while suppressing AT/AF induction in the old rats, causing complete prevention of inducible AT/AF and high degrees of interartrial conduction block. These results also suggest that nicotine at concentrations found in the blood of smokers (30-85 ng/ml) might increase atrial vulnerability to inducible AT/AF in normal adult atria with no atrial disease.

Limitations of the Study

This study was done using Landendorff-perfused normal young and aged hearts with no other detectable confounding atrial disease. Applicability of these findings to human clinical settings may not be possible – particularly the potential use of nicotine as an anti- AT/AF agent in the aged population -- because of the detrimental effects of nicotine in causing high degrees of interatrial conduction block.


Source: November 2003 edition of the American Journal of Physiology—Heart and Circulatory Physiology.

Donna Krupa | APS
Further information:
http://www.the-aps.org/press/journal/20.htm

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