Skip to main content

The Role of Perivascular Adipose Tissue in Microvascular Function and Coronary Atherosclerosis

  • Chapter
  • First Online:
Microcirculation

Abstract

Microvascular function is an independent risk factor for cardiovascular events, but the causes of microvascular dysfunction remain poorly understood. The role of perivascular adipose tissue (PVAT) in the regulation of vascular function is now a well-established concept supported by ample evidence from animal and translational studies. Importantly, contrary to the traditional notion of PVAT as the cause of vascular dysfunction, recent translational studies have demonstrated that there is a bidirectional communication between the vascular wall and PVAT, the latter playing a key role in diverse aspects of microvascular function and vascular disease, from endothelial dysfunction and microvascular angina to atherosclerosis development and plaque rupture. Although the associations between visceral or subcutaneous adipose tissue with cardiovascular disease risk have been largely explored in clinical studies, the role of PVAT in human atherosclerosis has remained elusive, mainly because of the lack of appropriate tools to study it. However, thanks to recent advances in the field of cardiovascular imaging, noninvasive phenotyping of human coronary PVAT is now feasible. Coronary computed tomography angiography and the use of perivascular Fat Attenuation Index has emerged as a valuable noninvasive biomarker to characterize PVAT and to risk stratify patients for cardiovascular disease risk. In this review we provide an overview of the role of PVAT in microvascular function, the findings of the recent clinical studies in the field, and the role of PVAT as a biomarker in cardiovascular disease.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 79.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 99.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Kissebah AH, Krakower GR. Regional adiposity and morbidity. Physiol Rev. 1994;74(4):761–811.

    Article  CAS  PubMed  Google Scholar 

  2. Gesta S, Tseng YH, Kahn CR. Developmental origin of fat: tracking obesity to its source. Cell. 2007;131(2):242–56.

    Article  CAS  PubMed  Google Scholar 

  3. Bastien M, et al. Overview of epidemiology and contribution of obesity to cardiovascular disease. Prog Cardiovasc Dis. 2014;56(4):369–81.

    Article  PubMed  Google Scholar 

  4. Nazare JA, et al. Usefulness of measuring both body mass index and waist circumference for the estimation of visceral adiposity and related cardiometabolic risk profile (from the INSPIRE ME IAA study). Am J Cardiol. 2015;115(3):307–15.

    Article  PubMed  Google Scholar 

  5. Subirana I, et al. Prediction of coronary disease incidence by biomarkers of inflammation, oxidation, and metabolism. Sci Rep. 2018;8(1):3191.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Antonopoulos AS, Tousoulis D. The molecular mechanisms of obesity paradox. Cardiovasc Res. 2017;113(9):1074–86.

    Article  CAS  PubMed  Google Scholar 

  7. Cirulli ET, et al. Profound perturbation of the metabolome in obesity is associated with health risk. Cell Metab. 2019;29(2):488–500.e2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Margaritis M, et al. Interactions between vascular wall and perivascular adipose tissue reveal novel roles for adiponectin in the regulation of endothelial nitric oxide synthase function in human vessels. Circulation. 2013;127(22):2209–21.

    Article  CAS  PubMed  Google Scholar 

  9. Guzik TJ, et al. Perivascular adipose tissue as a messenger of the brain-vessel axis: role in vascular inflammation and dysfunction. J Physiol Pharmacol. 2007;58(4):591–610.

    CAS  PubMed  Google Scholar 

  10. Greenstein AS, et al. Local inflammation and hypoxia abolish the protective anticontractile properties of perivascular fat in obese patients. Circulation. 2009;119(12):1661–70.

    Article  CAS  PubMed  Google Scholar 

  11. Mahabadi AA, et al. Association of pericoronary fat volume with atherosclerotic plaque burden in the underlying coronary artery: a segment analysis. Atherosclerosis. 2010;211(1):195–9.

    Article  CAS  PubMed  Google Scholar 

  12. Goeller M, et al. Pericoronary adipose tissue computed tomography attenuation and high-risk plaque characteristics in acute coronary syndrome compared with stable coronary artery disease. JAMA Cardiol. 2018;3(9):858–63.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Ohyama K, et al. Coronary adventitial and perivascular adipose tissue inflammation in patients with vasospastic angina. J Am Coll Cardiol. 2018;71(4):414–25.

    Article  PubMed  Google Scholar 

  14. Antonopoulos AS, et al. Detecting human coronary inflammation by imaging perivascular fat. Sci Transl Med. 2017;9(398):eaal2658.

    Article  PubMed  CAS  Google Scholar 

  15. Oikonomou EK, et al. Non-invasive detection of coronary inflammation using computed tomography and prediction of residual cardiovascular risk (the CRISP CT study): a post-hoc analysis of prospective outcome data. Lancet. 2018;392(10151):929–39.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Antonopoulos AS, Antoniades C. The role of epicardial adipose tissue in cardiac biology: classic concepts and emerging roles. J Physiol. 2017;595(12):3907–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sharma AM. Adipose tissue: a mediator of cardiovascular risk. Int J Obes Relat Metab Disord. 2002;26(Suppl 4):S5–7.

    Article  CAS  PubMed  Google Scholar 

  18. Marchington JM, Mattacks CA, Pond CM. Adipose tissue in the mammalian heart and pericardium: structure, foetal development and biochemical properties. Comp Biochem Physiol B. 1989;94(2):225–32.

    Article  CAS  PubMed  Google Scholar 

  19. Iacobellis G, et al. Epicardial fat from echocardiography: a new method for visceral adipose tissue prediction. Obes Res. 2003;11(2):304–10.

    Article  PubMed  Google Scholar 

  20. Szasz T, Bomfim GF, Webb RC. The influence of perivascular adipose tissue on vascular homeostasis. Vasc Health Risk Manag. 2013;9:105–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Siegel-Axel DI, Haring HU. Perivascular adipose tissue: an unique fat compartment relevant for the cardiometabolic syndrome. Rev Endocr Metab Disord. 2016;17(1):51–60.

    Article  CAS  PubMed  Google Scholar 

  22. Saely CH, Geiger K, Drexel H. Brown versus white adipose tissue: a mini-review. Gerontology. 2012;58(1):15–23.

    Article  PubMed  Google Scholar 

  23. Gil-Ortega M, et al. Regional differences in perivascular adipose tissue impacting vascular homeostasis. Trends Endocrinol Metab. 2015;26(7):367–75.

    Article  CAS  PubMed  Google Scholar 

  24. Antonopoulos AS, et al. Adiponectin as a link between type 2 diabetes and vascular NADPH oxidase activity in the human arterial wall: the regulatory role of perivascular adipose tissue. Diabetes. 2015;64(6):2207–19.

    Article  CAS  PubMed  Google Scholar 

  25. Antonopoulos AS, et al. Mutual regulation of epicardial adipose tissue and myocardial redox state by PPAR-gamma/adiponectin signalling. Circ Res. 2016;118(5):842–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Aghamohammadzadeh R, et al. Perivascular adipose tissue from human systemic and coronary vessels: the emergence of a new pharmacotherapeutic target. Br J Pharmacol. 2012;165(3):670–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Akoumianakis I, Antoniades C. The interplay between adipose tissue and the cardiovascular system: is fat always bad? Cardiovasc Res. 2017;113(9):999–1008.

    Article  CAS  PubMed  Google Scholar 

  28. Rajsheker S, et al. Crosstalk between perivascular adipose tissue and blood vessels. Curr Opin Pharmacol. 2010;10(2):191–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Emilova R, et al. Diabetes converts arterial regulation by perivascular adipose tissue from relaxation into H(2)O(2)-mediated contraction. Physiol Res. 2016;65(5):799–807.

    CAS  PubMed  Google Scholar 

  30. Kagota S, et al. Time-dependent differences in the influence of perivascular adipose tissue on vasomotor functions in metabolic syndrome. Metab Syndr Relat Disord. 2017;15(5):233–9.

    Article  CAS  PubMed  Google Scholar 

  31. Antonopoulos AS, Antoniades C. Perivascular fat attenuation index by computed tomography as a metric of coronary inflammation. J Am Coll Cardiol. 2018;71(23):2708–9.

    Article  PubMed  Google Scholar 

  32. Antonopoulos AS, Antoniades C, Tousoulis D. Unravelling the “adipokine paradox”: when the classic proatherogenic adipokine leptin is deemed the beneficial one. Int J Cardiol. 2015;197:125–7.

    Article  PubMed  Google Scholar 

  33. Antonopoulos AS, et al. Reciprocal effects of systemic inflammation and brain natriuretic peptide on adiponectin biosynthesis in adipose tissue of patients with ischemic heart disease. Arterioscler Thromb Vasc Biol. 2014;34(9):2151–9.

    Article  CAS  PubMed  Google Scholar 

  34. Lee S, et al. Exercise training improves endothelial function via adiponectin-dependent and independent pathways in type 2 diabetic mice. Am J Physiol Heart Circ Physiol. 2011;301(2):H306–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Antonopoulos AS, et al. Novel therapeutic strategies targeting vascular redox in human atherosclerosis. Recent Pat Cardiovasc Drug Discov. 2009;4(2):76–87.

    Article  CAS  PubMed  Google Scholar 

  36. Axelsson J, et al. Adipose tissue and its relation to inflammation: the role of adipokines. J Ren Nutr. 2005;15(1):131–6.

    Article  PubMed  Google Scholar 

  37. Lau DC, et al. Adipokines: molecular links between obesity and atheroslcerosis. Am J Physiol Heart Circ Physiol. 2005;288(5):H2031–41.

    Article  CAS  PubMed  Google Scholar 

  38. Zavaritskaya O, et al. Role of KCNQ channels in skeletal muscle arteries and periadventitial vascular dysfunction. Hypertension. 2013;61(1):151–9.

    Article  CAS  PubMed  Google Scholar 

  39. Kohn C, et al. Hydrogen sulfide: potent regulator of vascular tone and stimulator of angiogenesis. Int J Biomed Sci. 2012;8(2):81–6.

    PubMed  PubMed Central  Google Scholar 

  40. Ardanaz N, Pagano PJ. Hydrogen peroxide as a paracrine vascular mediator: regulation and signaling leading to dysfunction. Exp Biol Med (Maywood). 2006;231(3):237–51.

    Article  CAS  Google Scholar 

  41. Xu X, et al. Molecular mechanisms of ghrelin-mediated endothelial nitric oxide synthase activation. Endocrinology. 2008;149(8):4183–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Beltowski J. Leptin and the regulation of endothelial function in physiological and pathological conditions. Clin Exp Pharmacol Physiol. 2012;39(2):168–78.

    Article  CAS  PubMed  Google Scholar 

  43. Haynes WG, et al. Receptor-mediated regional sympathetic nerve activation by leptin. J Clin Invest. 1997;100(2):270–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Rahmouni K, et al. Role of selective leptin resistance in diet-induced obesity hypertension. Diabetes. 2005;54(7):2012–8.

    Article  CAS  PubMed  Google Scholar 

  45. Belin de Chantemele EJ, et al. Impact of leptin-mediated sympatho-activation on cardiovascular function in obese mice. Hypertension. 2011;58(2):271–9.

    Article  CAS  PubMed  Google Scholar 

  46. Lu C, et al. Alterations in perivascular adipose tissue structure and function in hypertension. Eur J Pharmacol. 2011;656(1-3):68–73.

    Article  CAS  PubMed  Google Scholar 

  47. Prinzmetal M, et al. Angina pectoris. I. A variant form of angina pectoris; preliminary report. Am J Med. 1959;27:375–88.

    Article  CAS  PubMed  Google Scholar 

  48. Ong P, et al. Coronary artery spasm as a frequent cause of acute coronary syndrome: the CASPAR (coronary artery spasm in patients with acute coronary syndrome) study. J Am Coll Cardiol. 2008;52(7):523–7.

    Article  PubMed  Google Scholar 

  49. Li J, Zhang H, Zhang C. Role of inflammation in the regulation of coronary blood flow in ischemia and reperfusion: mechanisms and therapeutic implications. J Mol Cell Cardiol. 2012;52(4):865–72.

    Article  CAS  PubMed  Google Scholar 

  50. Shimokawa H. 2014 Williams Harvey Lecture: importance of coronary vasomotion abnormalities-from bench to bedside. Eur Heart J. 2014;35(45):3180–93.

    Article  CAS  PubMed  Google Scholar 

  51. Brown NK, et al. Perivascular adipose tissue in vascular function and disease: a review of current research and animal models. Arterioscler Thromb Vasc Biol. 2014;34(8):1621–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kandabashi T, et al. Inhibition of myosin phosphatase by upregulated rho-kinase plays a key role for coronary artery spasm in a porcine model with interleukin-1beta. Circulation. 2000;101(11):1319–23.

    Article  CAS  PubMed  Google Scholar 

  53. Ohyama K, et al. Association of Coronary Perivascular Adipose Tissue Inflammation and Drug-Eluting Stent-Induced Coronary Hyperconstricting Responses in pigs: (18)F-Fluorodeoxyglucose positron emission tomography imaging study. Arterioscler Thromb Vasc Biol. 2017;37(9):1757–64.

    Article  CAS  PubMed  Google Scholar 

  54. Cheang WS, et al. The peroxisome proliferator-activated receptors in cardiovascular diseases: experimental benefits and clinical challenges. Br J Pharmacol. 2015;172(23):5512–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Ketonen J, et al. Periadventitial adipose tissue promotes endothelial dysfunction via oxidative stress in diet-induced obese C57Bl/6 mice. Circ J. 2010;74(7):1479–87.

    Article  CAS  PubMed  Google Scholar 

  56. Pasarica M, et al. Adipose tissue collagen VI in obesity. J Clin Endocrinol Metab. 2009;94(12):5155–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Greenstein AJ, et al. Prevalence of adverse intraoperative events during obesity surgery and their sequelae. J Am Coll Surg. 2012;215(2):271–7.e3.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Lumeng CN, Bodzin JL, Saltiel AR. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest. 2007;117(1):175–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008;8(12):958–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Gurses KM, et al. Netrin-1 is associated with macrophage infiltration and polarization in human epicardial adipose tissue in coronary artery disease. J Cardiol. 2017;69(6):851–8.

    Article  PubMed  Google Scholar 

  61. Takaoka M, et al. Endovascular injury induces rapid phenotypic changes in perivascular adipose tissue. Arterioscler Thromb Vasc Biol. 2010;30(8):1576–82.

    Article  CAS  PubMed  Google Scholar 

  62. Bussey CE, et al. Obesity-related perivascular adipose tissue damage is reversed by sustained weight loss in the rat. Arterioscler Thromb Vasc Biol. 2016;36(7):1377–85.

    Article  CAS  PubMed  Google Scholar 

  63. Gil-Ortega M, et al. Imbalance between pro and anti-oxidant mechanisms in perivascular adipose tissue aggravates long-term high-fat diet-derived endothelial dysfunction. PLoS One. 2014;9(4):e95312.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Antoniades C, et al. Adiponectin: from obesity to cardiovascular disease. Obes Rev. 2009;10(3):269–79.

    Article  CAS  PubMed  Google Scholar 

  65. Wang Y, et al. Childhood obesity prevention programs: comparative effectiveness review and meta-analysis. Rockville: Agency for Healthcare Research and Quality; 2013.

    Google Scholar 

  66. Fesus G, et al. Adiponectin is a novel humoral vasodilator. Cardiovasc Res. 2007;75(4):719–27.

    Article  PubMed  CAS  Google Scholar 

  67. Marchesi C, et al. Endothelial nitric oxide synthase uncoupling and perivascular adipose oxidative stress and inflammation contribute to vascular dysfunction in a rodent model of metabolic syndrome. Hypertension. 2009;54(6):1384–92.

    Article  CAS  PubMed  Google Scholar 

  68. Payne GA, et al. Epicardial perivascular adipose-derived leptin exacerbates coronary endothelial dysfunction in metabolic syndrome via a protein kinase C-beta pathway. Arterioscler Thromb Vasc Biol. 2010;30(9):1711–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Owen MK, et al. Perivascular adipose tissue potentiates contraction of coronary vascular smooth muscle: influence of obesity. Circulation. 2013;128(1):9–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Sarin S, et al. Clinical significance of epicardial fat measured using cardiac multislice computed tomography. Am J Cardiol. 2008;102(6):767–71.

    Article  PubMed  Google Scholar 

  71. Natale F, et al. Visceral adiposity and arterial stiffness: echocardiographic epicardial fat thickness reflects, better than waist circumference, carotid arterial stiffness in a large population of hypertensives. Eur J Echocardiogr. 2009;10(4):549–55.

    Article  PubMed  Google Scholar 

  72. Adolph TE, et al. Adipokines and non-alcoholic fatty liver disease: multiple interactions. Int J Mol Sci. 2017;18:8.

    Google Scholar 

  73. J. P. Morgan 32nd annual healthcare conference. J Diabetes. 2014;6(4):275–6.

    Google Scholar 

  74. Jeong JW, et al. Echocardiographic epicardial fat thickness and coronary artery disease. Circ J. 2007;71(4):536–9.

    Article  PubMed  Google Scholar 

  75. Summaries for patients. The obesity paradox in type 2 diabetes mellitus. Ann Intern Med. 2015;162(9):I–26.

    Google Scholar 

  76. Silaghi A, et al. Epicardial adipose tissue extent: relationship with age, body fat distribution, and coronaropathy. Obesity (Silver Spring). 2008;16(11):2424–30.

    Article  Google Scholar 

  77. Iacobellis G, et al. Relation between epicardial adipose tissue and left ventricular mass. Am J Cardiol. 2004;94(8):1084–7.

    Article  PubMed  Google Scholar 

  78. Retraction note to: the ‘obesity paradox’ and survival after colorectal cancer: true or false? Cancer Causes Control. 2015;26(8):1203.

    Google Scholar 

  79. Antonopoulos AS, Antoniades C. Cardiac magnetic resonance imaging of epicardial and intramyocardial adiposity as an early sign of myocardial disease. Circ Cardiovasc Imaging. 2018;11(8):e008083.

    Article  PubMed  Google Scholar 

  80. Marwan M, et al. CT attenuation of pericoronary adipose tissue in normal versus atherosclerotic coronary segments as defined by intravascular ultrasound. J Comput Assist Tomogr. 2017;41(5):762–7.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Antonopoulos, A.S., Papanikolaou, P., Tousoulis, D. (2020). The Role of Perivascular Adipose Tissue in Microvascular Function and Coronary Atherosclerosis. In: Dorobantu, M., Badimon, L. (eds) Microcirculation. Springer, Cham. https://doi.org/10.1007/978-3-030-28199-1_6

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-28199-1_6

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-28198-4

  • Online ISBN: 978-3-030-28199-1

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics