BACKGROUND: Vaping is touted as a safer alternative to traditional cigarette smoking, but the full spectrum of harm reduction versus comparable risk remains unresolved. Elevated bioavailability of nicotine in vape aerosol together with known risks of nicotine exposure may result in previously uncharacterized cardiovascular consequences of vaping. The objective of this study is to assess the impact of nicotine exposure via vape aerosol inhalation upon myocardial response to infarction injury. METHODS AND RESULTS: Flavored vape juice containing nicotine (5 mg/mL) or vehicle alone (0 mg) was delivered using identical 4-week treatment protocols. Mice were subjected to acute myocardial infarction injury and evaluated for outcomes of cardiac structure and function. Findings reveal that nicotine exposure leads to worse outcomes with respect to contractile performance regardless of sex. Nonmyocyte interstitial cell accumulation following infarction significantly increased with exposure to vape aerosol alone, but a comparable increase was not present when nicotine was included. CONCLUSIONS: Myocardial function after infarction is significantly decreased after exposure to nicotine vape aerosol irrespective of sex. Comparable loss of contractile function was not observed in mice exposed to vape aerosol alone, highlighting the essential role of nicotine in loss of contractile function. Increased vimentin immunoreactivity was observed in the vape alone group compared with control and vape nicotine. The correlation between vaping, interstitial cell responses, and cardiac remodeling leading to impaired contractility warrants further investigation. Public health experts seeking to reduce vaping-related health risks should consider messaging that highlights the increased cardiovascular risk especially with nicotine-containing aerosols.