Chronic Nicotine Inhalation Promotes Differential Remodeling of the Right and Left Ventricles in Mice

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Introduction Cigarette smoking continues to decline in the United States, but a rise in e‐cigarette use poses a threat to human health. E‐cigarettes, oft marketed as a healthier alternative to traditional forms of tobacco consumption, still contain nicotine. Cigarette smoking is a major risk factor in a vast array of pathological conditions including cancer and cardiovascular disease. Despite knowledge regarding the risks of cigarettes, the effects of inhaled nicotine have been poorly characterized. In this study, we sought to investigate the effects of inhaled nicotine on cardiac function and remodeling. Methods Male C57BL6/J mice were exposed to air (control) or nicotine vapor (daily, 12 hours on/12 hours off) for 8 weeks. Nicotine exposure was assessed by weekly measurement of serum cotinine levels, which showed an average of 599±54 ng/ml in nicotine‐exposed mice. A subset of mice were implanted with an Angiotensin‐II (AngII) osmotic minipump (450 ng/kg/min) for 4 weeks. Cardiac structure and function were assessed using echocardiography and cardiac catheterization, followed by tissue collection for analysis. Results Nicotine exposure produced a significant increase in right ventricular systolic pressure (RVSP; 39.6±4.2 mmHg, n=7) compared to air‐exposed controls (22.3±1.7 mmHg, n=8, p<0.01). Nicotine‐associated RVSP elevation was similar to AngII infusion (38.0±2.0 mmHg, n=7). RVSP changes were associated with RV hypertrophy (free wall thickness of 0.50±0.02 mm in nicotine exposure versus 0.42±0.03 mm in air‐exposed control, n=8–9, p<0.05) and increased angiotensin converting enzyme expression (3.87‐fold increase in nicotine exposure versus air‐exposed control, n=5, p<0.05). Nicotine exposure alone produced no significant changes in left ventricular (LV) structure or angiotensin converting enzyme expression. Interestingly, co‐administeration of nicotine and AngII resulted in blunting of AngII‐mediated LV hypertrophy (posterior wall thickness; 0.83±0.03 mm versus 0.93±0.02 mm for AngII alone, n=19–23, p<0.01). Furthermore, we have found preliminary evidence of blunted LV hypertrophic signaling in nicotine‐exposed, AngII‐infused mice which exhibited reduced phosphorylated mTOR/mTOR compared to AngII alone (n=5, p=0.076). Discussion Taken together, these findings led us to conclude that chronic nicotine inhalation promotes differential remodeling of the right and left heart. Nicotine inhalation alone promotes hypertrophic remodeling of the RV, but produces no significant changes in the LV. Nicotine inhalation does, however, abrogate AngII‐induced hypertrophic LV remodeling. Ongoing experiments within our laboratory are exploring the mechanisms underlying this differential remodeling and anti‐hypertrophic effect. Support or Funding Information National Institutes of Health R01HL135635 (JG/EL/XY).

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