Chronic nicotine exposure is associated with electrophysiological and sympathetic remodeling in the intact rabbit heart

Guevara, A.; Smith, C. E. R.; Caldwell, J. L.; Ngo, L.; Mott, L. R.; Lee, I.-J.; Tapa, S.; Wang, Z.; Wang, L.; Woodward, W. R.; Ng, G. A.; Habecker, B. A.; Ripplinger, C. M.

doi:10.1101/2023.11.23.567754

bioRxiv · 10.1101/2023.11.23.567754

Chronic nicotine exposure is associated with electrophysiological and sympathetic remodeling in the intact rabbit heart

Guevara, A.·Smith, C. E. R.·Caldwell, J. L.·Ngo, L.·Mott, L. R.·Lee, I.-J.·Tapa, S.·Wang, Z.·Wang, L.·Woodward, W. R.·Ng, G. A.·Habecker, B. A.·Ripplinger, C. M.

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Abstract

Nicotine is the primary addictive component in tobacco products. Through its actions on the heart and autonomic nervous system, nicotine exposure is associated with electrophysiological changes and increased arrhythmia susceptibility. However, the underlying mechanisms are unclear. To address this, we treated rabbits with transdermal nicotine (NIC, 21 mg/day) or control (CT) patches for 28 days prior to performing dual optical mapping of transmembrane potential (RH237) and intracellular Ca2+ (Rhod-2 AM) in isolated hearts with intact sympathetic innervation. Sympathetic nerve stimulation (SNS) was performed at the 1st - 3rd thoracic vertebrae, and {beta}-adrenergic responsiveness was additionally evaluated as changes in heart rate (HR) following norepinephrine (NE) perfusion. Baseline ex vivo HR and SNS stimulation threshold were increased in NIC vs. CT (P = 0.004 and P = 0.003 respectively). Action potential duration alternans emerged at longer pacing cycle lengths (PCL) in NIC vs. CT at baseline (P = 0.002) and during SNS (P = 0.0003), with similar results obtained for Ca2+ transient alternans. SNS reduced the PCL at which alternans emerged in CT but not NIC hearts. NIC exposed hearts also tended to have slower and reduced HR responses to NE perfusion. While fibrosis was unaltered, NIC hearts had lower sympathetic nerve density (P = 0.03) but no difference in NE content vs. CT. These results suggest both sympathetic hypo-innervation of the myocardium and diminished {beta}-adrenergic responsiveness with NIC. This autonomic remodeling may underlie the increased risk of arrhythmias associated with nicotine exposure, which may be further exacerbated with continued long-term usage. NEW & NOTEWORTHYHere we show that chronic nicotine exposure was associated with increased heart rate, lower threshold for alternans and reduced sympathetic electrophysiological responses in the intact rabbit heart. We suggest that this was due to the sympathetic hypo-innervation of the myocardium and diminished {beta}- adrenergic responsiveness observed following nicotine treatment. Though these differences did not result in increased arrhythmia propensity in our study, we hypothesize that prolonged nicotine exposure may exacerbate this pro-arrhythmic remodeling.

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Guevara, A., Smith, C. E. R., Caldwell, J. L., Ngo, L., Mott, L. R., Lee, I.-J., Tapa, S., Wang, Z., Wang, L., Woodward, W. R., Ng, G. A., Habecker, B. A., Ripplinger, C. M.. 2023-11-23. Chronic nicotine exposure is associated with electrophysiological and sympathetic remodeling in the intact rabbit heart. https://doi.org/10.1101/2023.11.23.567754

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