Cardiovascular Dysfunction Induced by Combined Exposure to Nicotine Inhalation and High Fat Diet

Anna K. Whitehead¹, Zhen Li^2,3, Kyle B. LaPenna^2,3, Thomas E. Sharp^3,4, Eric Lazartigues^2,3,5,6, David J. Lefer^2,3, and Xinping Yue^1,3

¹Department of Physiology, ²Department of Pharmacology and Experimental Therapeutics, ³Cardiovascular Center of Excellence, and ⁴Department of Medicine Section of Cardiology, ⁵Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, and ⁶Southeast Louisiana Veterans Health Care Systems New Orleans, LA, USA

Cardiovascular diseases (CVD) are the leading cause of death worldwide, and cigarette smoking remains the most significant preventable risk factor. The contribution of nicotine, the addictive component of all tobacco products, to smoking-related CVD remains generally unknown. In addition to smoking, consumption of a high fat diet (HFD) and obesity are risk factors for the development of CVD. Little is known about the combined effects of nicotine and consumption of HFD; thus, this study investigates the impact of their combined use on cardiovascular function. C57BL/6N mice fed either standard chow (SC) (22 kcal% Fat) or HFD (60 kcal% Fat) were exposed to room air or nicotine vapor inhalation for 12 weeks. Left heart catheterization showed that mice exposed to both nicotine and HFD had elevated left ventricular (LV) end diastolic pressure (14.1±0.7 mmHg vs. 4.5±0.8 mmHg in air controls fed SC, 2.8±0.7 mmHg in air controls fed HFD, and 3.9±1.3 mmHg in nicotine exposed mice fed SC) and increased time constant of LV relaxation (Tau). RNA sequencing (RNA-seq) analysis of left ventricles revealed that combined exposure to nicotine and HFD resulted in 70 differentially expressed genes (DEG) (36 upregulated and 34 downregulated) unique from either treatment alone. The DEG were associated with multiple signaling pathways, including dilated cardiomyopathy, and select genes of interest such as Nppa and Nppb (encoding A- and B-type natriuretic peptide, respectively) were confirmed with qPCR. In addition, combined exposure to nicotine and HFD led to greater impairment of endothelium-dependent vasodilation in thoracic aortas than nicotine or HFD alone. In summary, the negative cardiovascular impacts of combined exposure to nicotine and HFD were greater than either treatment alone. These findings provide evidence that obesity, which has reached epidemic levels in the United States, may influence cardiovascular outcomes in patients with a history of chronic nicotine inhalation.