Statin therapy modulates thickness and inflammatory profile of human epicardial adipose tissue

[en] Background: Epicardial adipose tissue (EAT) thickness and pro-inflammatory status has been shown to be associated with several cardiac diseases, including aortic stenosis (AS). Thus, cardiac visceral fat could represent a potential new target for drugs. In the present study we evaluate the effect of statin therapy on EAT accumulation and inflammation. Methods: Echocardiographic EAT thickness was assessed in 193 AS patients taking (n.87) and not taking (n.106) statins, undergoing cardiac surgery. To explore the association between statin therapy and EAT inflammation, EAT biopsies were obtained for cytokines immunoassay determination in EAT secretomes. An in vitro study was also conducted and the modulation of EAT and subcutaneous adipose tissue (SCAT) secretomes by atorvastatin was assessed in paired biopsies. Results: Statin therapy was significantly associated with lower EAT thickness (p < 0.0001) and with lower levels of EAT-secreted inflammatory mediators (p < 0.0001). Of note, there was a significant correlation between EAT thickness and its pro-inflammatory status. In vitro, atorvastatin showed a direct anti-inflammatory effect on EAT which was significantly higher compared to the SCAT response to statin incubation (p < 0.0001). Conclusions: The present study indicates a robust association between statin therapy and reduced EAT accumulation in patients with AS. The present data also suggest a direct relationship between EAT thickness and its inflammatory status, both modulated by statin therapy. The in vitro results support the hypothesis of a direct action of statins on EAT secretory profile. Overall our data suggest EAT as a potential new therapeutic target for statin therapy. © 2018 Elsevier B.V.

Disciplines :

Cardiovascular & respiratory systems

Author, co-author :

Parisi, V.; Department of Translational Medical Science, University of Naples Federico II, Italy

Petraglia, L.; Department of Translational Medical Science, University of Naples Federico II, Italy

D'Esposito, V.; Department of Translational Medical Science, University of Naples Federico II, Italy

Cabaro, S.; Department of Translational Medical Science, University of Naples Federico II, Italy

Rengo, G.; Department of Translational Medical Science, University of Naples Federico II, Italy

Caruso, A.; Casa di Cura San Michele, MaddaloniCE, Italy

Grimaldi, M. G.; Casa di Cura San Michele, MaddaloniCE, Italy

Baldascino, F.; Casa di Cura San Michele, MaddaloniCE, Italy

De Bellis, A.; Casa di Cura San Michele, MaddaloniCE, Italy

Vitale, D.; Casa di Cura San Michele, MaddaloniCE, Italy

More authors (9 more)

Language :

English

Title :

Statin therapy modulates thickness and inflammatory profile of human epicardial adipose tissue

Publication date :

2019

Journal title :

International Journal of Cardiology

ISSN :

0167-5273

eISSN :

1874-1754

Publisher :

Elsevier Ireland Ltd

Peer reviewed :

Peer Reviewed verified by ORBi

Available on ORBi :

since 21 December 2018

Statistics

Number of views

327 (7 by ULiège)

Number of downloads

591 (0 by ULiège)

More statistics

Scopus citations^®

Scopus citations^®
without self-citations

OpenCitations

OpenAlex citations

Bibliography

Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet, 334, 1994, 1383–1389.
Sacks, F.M., Pfeffer, M.A., Moye, L.A., The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N. Engl. J. Med. 335 (1996), 1001–1009.
Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and broad range of initial cholesterol levels. The long-term intervention with pravastatin in Ischaemic disease (LIPID) study group. N. Engl. J. Med., 339, 1998, 1349–1357.
West of Scotland coronary prevention study: identification of high-risk groups and comparison with other cardiovascular intervention trials. Lancet, 346, 1996, 1339–1342.
Downs, J.R., Clearfield, M., Weis, S., Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels. N. Engl. J. Med. 339 (1999), 1615–1622.
Corsini, A., Bellosta, S., Baetta, R., Fumagalli, R., Paoletti, R., Bernini, F., New insights into the pharmacodynamic and pharmacokinetic properties of statins. Pharmacol. Ther. 84 (1999), 413–428.
Rocha, V.Z., Libby, P., Obesity, inflammation, and atherosclerosis. Nat. Rev. Cardiol. 6 (2009), 399–409.
Tedgui, A., Mallat, Z., Cytokines in atherosclerosis: pathogenic and regulatory pathways. Physiol. Rev. 86 (2006), 515–581.
Parisi, V., Leosco, D., Ferro, G., Bevilacqua, A., Pagano, G., de Lucia, C., PerroneFilardi, P., Caruso, A., Rengo, G., Ferrara, N., The lipid theory in the pathogenesis of calcific aortic stenosis. Nutr. Metab. Cardiovasc. Dis. 25 (2015), 519–525.
Saito, S., Fujiwara, T., Matsunaga, T., Minagawa, K., Fukui, K., Fukuda, I., Osanai, T., Okumura, K., Increased adiponectin synthesis in the visceral adipose tissue in men with coronary artery disease treated with pravastatin: a role of the attenuation of oxidative stress. Atherosclerosis 199 (2008), 378–383.
Łabuzek, K., Bułdak, Ł., Duława-Bułdak, A., Bielecka, A., Krysiak, R., Madej, A., Okopień, B., Atorvastatin and fenofibric acid differentially affect the release of adipokines in the visceral and subcutaneous cultures of adipocytes that were obtained from patients with and without mixed dyslipidemia. Pharmacol. Rep. 63 (2011), 1124–1136.
Mazurek, T., Zhang, L., Zalewski, A., Mannion, J.D., Diehl, J.T., Arafat, H., Sarov-Blat, L., O'Brien, S., Keiper, E.A., Johnson, A.G., Martin, J., Goldstein, B.J., Shi, Y., Human epicardial adipose tissue is a source of inflammatory mediators. Circulation 108 (2003), 2460–2466.
Baker, A.R., Silva, N.F., Quinn, D.W., Harte, A.L., Pagano, D., Bonser, R.S., Kumar, S., McTernan, P.G., Human epicardial adipose tissue expresses a pathogenic profile of adipocytokines in patients with cardiovascular disease. Cardiovasc. Diabetol., 5, 2006, 1.
Parisi, V., Rengo, G., Pagano, G., D'Esposito, V., Passaretti, F., Caruso, A., Grimaldi, M.G., Lonobile, T., Baldascino, F., De Bellis, A., Formisano, P., Ferrara, N., Leosco, D., Epicardial adipose tissue has an increased thickness and is a source of inflammatory mediators in patients with calcific aortic stenosis. Int. J. Cardiol. 186 (2015), 167–169.
Baumgartner, H., Falk, V., Bax, J.J., De Bonis, M., Hamm, C., Holm, P.J., Iung, B., Lancellotti, P., Lansac, E., Muñoz, D.R., Rosenhek, R., Sjögren, J., Tornos Mas, P., Vahanian, A., Walther, T., Wendler, O., Windecker, S., Zamorano, J.L., ESC Scientific Document Group, 2017 ESC/EACTS guidelines for the management of valvular heart disease. Eur. Heart J. 38 (2017), 2739–2791.
Royston, P., Ambler, G., Sauerbrei, W., The use of fractional polynomials to model continuous risk variables in epidemiology. Int. J. Epidemiol. 28 (1999), 964–974.
Shorrocks, A.F., Decomposition procedures for distributional analysis: a unified framework based on the Shapley value. J. Econ. Inequal. 11 (2013), 99–126.
Royston, P., Sauerbrei, W., Multivariate Model Building. A Pragmatic Approach to Regression Analysis Based On Fractional Polynomials for Modeling Continuous Variables. 2008, Wiley, Chichester. UK, 183–186.
Kutner, M.H., Nachtsheim, C.J., Neter, J., Li, W., Applied Linear Statistical Models. 5th edition, 2005, McGraw Hill, Irwin, New York. NY, 409.
Suleiman, A.A., Analysis of multicollinearity in multiple regressions. Int. J. Adv. Technol. Eng. Sci. 3 (2015), 571–578.
Iacobellis, G., Ribaudo, M.C., Assael, F., Vecci, E., Tiberti, C., Zappaterreno, A., Di Mario, U., Leonetti, F., Echocardiographic epicardial adipose tissue is related to anthropometric and clinical parameters of metabolic syndrome: a new indicator of cardiovascular risk. J. Clin. Endocrinol. Metab., 88, 2003, 5163e8.
Iacobellis, G., Leonetti, F., Epicardial adipose tissue and insulin resistance in obese subjects. J. Clin. Endocrinol. Metab. 90 (2005), 6300–6302.
Ahn, S.G., Lim, H.S., Joe, D.Y., Kang, S.J., Choi, B.J., Choi, S.Y., Yoon, M.H., Hwang, G.S., Tahk, S.J., Shin, J.H., Relationship of epicardial adipose tissue by echocardiography to coronary artery disease. Heart, 94, 2008, e7.
Parisi, V., Rengo, G., Perrone-Filardi, P., Pagano, G., Femminella, G.D., Paolillo, S., Petraglia, L., Gambino, G., Caruso, A., Grimaldi, M.G., Baldascino, F., Nolano, M., Elia, A., Cannavo, A., De Bellis, A., Coscioni, E., Pellegrino, T., Cuocolo, A., Ferrara, N., Leosco, D., Increased epicardial adipose tissue volume correlates with cardiac sympathetic denervation in patients with heart failure. Circ. Res. 118 (2016), 1244–1253.
Park, J.H., Park, Y.S., Kim, Y.J., Lee, I.S., Kim, J.H., Lee, J.H., Choi, S.W., Jeong, J.O., Seong, I.W., Effects of statins on the epicardial fat thickness in patients with coronary artery stenosis underwent percutaneous coronary intervention: comparison of atorvastatin with simvastatin/ezetimibe. J. Cardiovasc. Ultrasound 18 (2010), 121–126.
Soucek, F., Covassin, N., Singh, P., Ruzek, L., Kara, T., Suleiman, M., Lerman, A., Koestler, C., Friedman, P.A., Lopez-Jimenez, F., Somers, V.K., Effects of atorvastatin (80 mg) therapy on quantity of epicardial adipose tissue in patients undergoing pulmonary vein isolation for atrial fibrillation. Am. J. Cardiol. 116 (2015), 1443–1446.
Alexopoulos, N., Melek, B.H., Arepalli, C.D., Hartlage, G.R., Chen, Z., Kim, S., Stillman, A.E., Raggi, P., Effect of intensive versus moderate lipid-lowering therapy on epicardial adipose tissue in hyperlipidemic post-menopausal women: a substudy of the BELLES trial (beyond endorsed lipid lowering with EBT scanning). J. Am. Coll. Cardiol. 61 (2013), 1956–1961.
Abe, M., Matsuda, M., Kobayashi, H., Miyata, Y., Nakayama, Y., Komuro, R., Fukuhara, A., Shimomura, I., Effects of statins on adipose tissue inflammation: their inhibitory effect on MyD88-independent IRF3/IFN-beta pathway in macrophages. Arterioscler. Thromb. Vasc. Biol. 28 (2008), 871–877.
Hartman, J., Frishman, W.H., Inflammation and atherosclerosis: a review of the role of interleukin-6 in the development of atherosclerosis and the potential for targeted drug therapy. Cardiol. Rev. 22 (2014), 147–151.
Gualtero, D.F., Viafara-Garcia, S.M., Morantes, S.J., Buitrago, D.M., Gonzalez, O.A., Lafaurie, G.I., Rosuvastatin inhibits interleukin (IL)-8 and IL-6 production in human coronary artery endothelial cells stimulated with Aggregatibacter actinomycetemcomitans serotype b. J. Periodontol. 88 (2017), 225–235.
Blyme, A., Asferg, C., Nielsen, O.W., Sehestedt, T., Kesäniemi, Y.A., Gohlke-Bärwolf, C., Boman, K., Willenheimer, R., Ray, S., Nienaber, C.A., Rossebø, A., Wachtell, K., Olsen, M.H., High sensitivity C reactive protein as a prognostic marker in patients with mild moderate aortic valve stenosis during lipid-lowering treatment: an SEAS substudy. Open Heart, 2, 2015, e000152.
Ridker, P.M., From C-Reactive Protein to Interleukin-6 to Interleukin-1: moving upstream to identify novel targets for atheroprotection. Circ. Res. 118 (2016), 145–156.
Iacobellis, G., Willens, H.J., Echocardiographic epicardial fat: a review of research and clinical applications. J. Am. Soc. Echocardiogr. 22 (2009), 1311–1319.
Iacobellis, G., Willens, H.J., Barbaro, G., Sharma, A.M., Threshold values of high-risk echocardiographic epicardial fat thickness. Obesity 16 (2008), 887–892.