Epicardial adipose tissue (EAT) is present in close proximity to the adventitia of the coronary arteries and the underlying myocardium, and functions as both endocrine organ and inflammatory tissue, secreting hormones, cytokines and chemokines. Since atherosclerotic lesions result from inflammation and extracellular matrix formation that are exaggerated by obesity, there is a poor outcome in obese atherosclerotic patients following contrary intervention. We hypothesize that obesity-induced inflammatory phenotype of epicardial fat is exacerbated by vitamin D deficiency leading to endothelial dysfunction and enhanced intimal hyperplasia following coronary intervention.
Aim 1 : Our hypothesis predicts that high fructose and high fat diet will increase thickness and the inflammatory phenotype of EAT accompanied with impairment of coronary vasodilatation and increased reoccurrence of cardiovascular events following coronary artery intervention.
Aim 2 : Our hypothesis predicts that vitamin D deficiency will exacerbate and vitamin D supplementation will decrease thickness and the inflammatory phenotype of EAT and restore coronary vasodilatation and this will correlate with decreased reoccurrence of cardiovascular events following coronary artery intervention.
Aim 3 : Our hypothesis predicts that enhanced inflammatory phenotype of EAT in obese and atherosclerotic swine is due to increased translocation of NF-?B to the nucleus via increased transcription and translation of importin-?3 and decreased prohibitin and SOCS3, and vitamin D suppresses pro-inflammatory responses in EAT. Hypercholesterolemic swine on high fructose diet will undergo balloon angioplasty and stenting. Effect of vitamin D will be examined in vitamin D-deficient, -sufficient and supplemented swine fed with high cholesterol and high fructose diet. Epicardial fat thickness will be measured by cardiac CT. Angiogram and Optical Coherence Tomography will be done to assess cardiac function and quantify in-segment minimal luminal diameter and intimal hyperplasia. Endothelium-dependent and -independent coronary vasodilatation will be measured by intracoronary administration of adenosine and acetylcholine. Biochemical parameters in epicardial fat will include the changes in adipocyte size, M1/M2 macrophage polarity, T-lymphocyte subsets, levels of pro- and anti-inflammatory mediators and cytokines. Histologically, intimal thickness and intimal hyperplasia, lumen area, intima-media ratio, plaque development, and re-occlusion will be examined. The proposed studies will provide conceptual support of our hypothesis and position us to translate our investigation into a clinical study in obese patients with coronary artery disease.

Public Health Relevance

The prevalence and significant rise in obesity is a major health problem. There is a poor outcome in obese patients with atherosclerosis following coronary intervention, such as angioplasty and intravascular stenting. Fat tissue on the anterior surface of the heart become inflamed due to obesity and this could be exacerbated by vitamin D deficiency, which is prevalent in our population. In this project, we proposed to examine the underlying cellular and molecular mechanisms of inflammation and vascular dysfunction in obese and hypercholesterolemic model and to determine if vitamin D supplementation will reduce fat deposits on outside of the heart and on re-narrowing of coronary arteries following angioplasty and stenting. The proposed studies will provide conceptual support of our hypothesis and position us to translate our investigation into a clinical study in patients with coronary artery disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
3R01HL120659-01S1
Application #
8775002
Study Section
Special Emphasis Panel (ZRG1-VH-B (03))
Program Officer
Ershow, Abby
Project Start
2014-01-01
Project End
2018-05-31
Budget Start
2014-01-01
Budget End
2014-05-31
Support Year
1
Fiscal Year
2014
Total Cost
$25,797
Indirect Cost
$6,294
Name
Creighton University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
053309332
City
Omaha
State
NE
Country
United States
Zip Code
68178
Thankam, Finosh G; Boosani, Chandra S; Dilisio, Matthew F et al. (2018) MicroRNAs associated with inflammation in shoulder tendinopathy and glenohumeral arthritis. Mol Cell Biochem 437:81-97
Hall, Sannette; Agrawal, Devendra K (2018) Delivery of viral vectors for gene therapy in intimal hyperplasia and restenosis in atherosclerotic swine. Drug Deliv Transl Res 8:918-927
Agarwal, Shreya; Kovilam, Oormila; Agrawal, Devendra K (2018) Vitamin D and its impact on maternal-fetal outcomes in pregnancy: A critical review. Crit Rev Food Sci Nutr 58:755-769
Rosenberg, John H; Werner, John H; Moulton, Michael J et al. (2018) Current Modalities and Mechanisms Underlying Cardioprotection by Ischemic Conditioning. J Cardiovasc Transl Res 11:292-307
Werner, John H; Rosenberg, John H; Keeley, Kristen L et al. (2018) Immunobiology of periprosthetic inflammation and pain following ultra-high-molecular-weight-polyethylene wear debris in the lumbar spine. Expert Rev Clin Immunol 14:695-706
Ludwig, Parker E; Thankam, Finosh G; Patil, Arun A et al. (2018) Brain injury and neural stem cells. Neural Regen Res 13:7-18
Plitt, Gilman D; Spring, Jordan T; Moulton, Michael J et al. (2018) Mechanisms, diagnosis, and treatment of heart failure with preserved ejection fraction and diastolic dysfunction. Expert Rev Cardiovasc Ther 16:579-589
Addula, Mounika; Wilson, Victoria E D; Reddymasu, Savio et al. (2018) Immunopathological and molecular basis of functional dyspepsia and current therapeutic approaches. Expert Rev Clin Immunol 14:831-840
Agarwal, Shreya; Agrawal, Devendra K (2017) Kawasaki disease: etiopathogenesis and novel treatment strategies. Expert Rev Clin Immunol 13:247-258
Rudick, Courtney P; Cornell, David L; Agrawal, Devendra K (2017) Single versus combined immunoregulatory approach using PD-1 and CTLA-4 modulators in controlling sepsis. Expert Rev Clin Immunol 13:907-919

Showing the most recent 10 out of 60 publications