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Previous Research from P50 grant

Research Project: Cardiovascular Toxicity of Tobacco Products


Sanjay Srivastava, Ph.D. - ATRAC Principal Investigator
Sanjay Srivastava, Ph.D.
University of Louisville

This project led to the development of an animal model to establish standard toxicity changes and identification of biomarkers of cardiovascular injury that can be associated with tobacco exposure. The project also provided baseline information about the contribution of reactive aldehydes to the cardiovascular toxicity of cigarette smoke and smokeless tobacco that are now being used in our current study on CV toxicity of tobacco products. The detailed aims of this project were to:

  1. Examine tobacco-induced endothelial injury. To examine tobacco-induced endothelial injury: In adult mice exposed to varying intensities of tobacco smoke and smokeless tobacco, we identified urinary metabolites of tobacco-derived aldehydes and determined how these relate to the extent and duration of exposure. We also looked into the changes of these markers based on gender, time, and duration of exposure. We aimed to identify specific indices of endothelial function and damage that would robustly and sensitively reflect endothelial injury and thrombosis and demonstrate how these biomarkers of injury are related to the biomarkers of exposure.
     
  2. Delineate the contribution of harmful and potentially harmful (HPHC) constituents, such as aldehydes, to endothelial injury induced by tobacco exposure. To identify which constituents of tobacco and tobacco smoke contribute to endothelial damage, we examined changes in the biomarkers of endothelial injury in mice exposed to individual constituents of exposure: nicotine, acrolein and crotonaldehyde. We also demonstrated how removing them affects endothelial injury from exposure to tobacco smoke and whether increases in the extent of exposure to these aldehydes and related reactive chemicals increases the extent of endothelial injury.  

Research Project: Cardiovascular Injury Due to Tobacco Use (1.0)


A-TRAC: Aruni Bhatnagar Headshot
Aruni Bhatnagar, Ph.D.
University of Louisville

This project focused on the identification and validation of novel biomarkers of endothelial injury that are associated with exposure to tobacco and tobacco constituents. From these studies, we attempted to assess which tobacco-associated biomarkers of injury indicated the extent and progression of cardiovascular disease and how the magnitude of changes in these biomarkers translates into meaningful impacts on CVD outcomes. This project has been expanded into a longitudinal study that will follow participants to determine how these markers are affected by changes in individuals’ tobacco use patterns over time.

  1. Elucidate the relationship between biomarkers of cardiovascular injury and exposure to tobacco smoke and smokeless tobacco. We evaluated biomarkers of endothelial damage and predilection for thrombosis in a cohort of cigarette smokers, smokeless tobacco users and non-smokers without overt CVD.
     
  2. Identify and compare the dose-dependent associations between tobacco exposure, measures of subclinical cardiovascular disease, and clinical cardiovascular events.  Using data from the Multi-Ethnic Study of Atherosclerosis (MESA) prospective cohort, we examined associations between tobacco exposure and subclinical vascular disease as assessed by carotid intima-media thickness, coronary artery calcification, ankle brachial index, flow mediated dilation and arterial stiffening, and biomarkers of inflammation.
     
  3. Validate candidate biomarkers associated with tobacco exposure in independent human cohorts. Candidate bio-measures reflective of tobacco-induced cardiovascular injury, identified in Aims 1 and 2 were independently validated in The Jackson Heart Study (JHS) cohort and assessed for their association with urinary metabolites of nicotine and aldehydes. 

Participating Studies

Research Project: Perception of Tobacco Use in Vulnerable Populations


Thomas J. Payne, Ph.D. - ATRAC Principal Investigator
Thomas J. Payne, Ph.D.
University of Mississippi Medical Center

In this project, we examined the role of knowledge and perception of tobacco products in individuals’ decision to start and continue tobacco use. We examined channel use frequency (i.e., what are the most frequent channels for seeking tobacco-related communication and what are the most frequent channels for communicating with others about tobacco?) and the influence of several factors that modify these choices. For example, modifying factors included age, gender, race, knowledge about tobacco, tobacco use or intention, family tobacco use and peer tobacco use.

  1. Evaluate communication channel use, knowledge, risk perception, and intention for tobacco use in vulnerable populations.The populations studied differed by race/ethnicity, SES and sexual orientation, with an overall focus on the disadvantaged and underserved across the United States. All participants were assessed regarding combustible cigarette use (i.e., whether they were smokers, former smokers, or non-smokers), and their use of vaping devices and other tobacco products (in some studies, tobacco use status was a selection criteria).
     
  2. Provide evidence to facilitate the development of communication campaigns to aid tobacco users in understanding the risks of tobacco product use. The data from this project will be used to inform public education and communication campaign strategies such that the messaging resonates more strongly with the intended audience.  

Research Project: Administrative Supplements for Tobacco Regulatory Research on Tobacco Flavors and Flavorings


ATRAC PI - Daniel Conklin
Daniel Conklin, Ph.D.
University of Louisville

This study provided valuable information about the chemicals generated from the thermal degradation of tobacco product flavorings, helped establish their concentrations at different temperatures and determine which in vitro assays can effectively compare the cardiovascular toxicity of different flavorings used in cigarettes, cigars and e-cigarettes. This information could prove critical to the FDA when determining the regulations affecting product standards. This project lead to a larger flagship project focused on the cardiovascular toxicity of tobacco products.

  1. Identify and quantify the chemical products generated due to thermal degradation when tobacco product flavorings and additives are heated or burned; Major classes of commonly used flavor chemicals currently used in tobacco products (alcohols, phenols, aldehydes, esters, ethers, hydrocarbons, ketones, lactones, organic acids, pyrazines, pyridines, and pyrones) were burned and heated at temperatures achieved by conventional pyrolysis and non-conventional heating methods used in aerosol formation, to determine the extent of degradation of parent compounds, identify structures of the products and estimate the relative concentration of products generated during such thermal degradation;
     
  2. Compare the relative toxicity of different flavorings commonly used in tobacco products with those flavorings after burning or heating. In in vitro assays we measured the EC50 of each of the major classes of commonly used flavor chemicals (listed in Aim 1) in affecting platelet adhesion, endothelial activation and myocardial excitability, particularly Q-T prolongation and compare the sensitivity of these assays vis-à-vis assays for pulmonary and immune cell toxicity. We then compared the results from these assays to determine which in vitro assay is capable of comparative toxicological assessments that can examine the harm potential between different flavorings currently used in tobacco products.