Social Stress and Cardiovascular Disease in Primates

  • Carol A. ShivelyEmail author


Atherosclerosis of the coronary arteries (CAA) and its complications are the ­principal pathological processes that result in coronary heart disease (CHD). Cynomolgus monkeys (Macaca fascicularis) are a well-characterized animal model of susceptibility to diet-induced atherogenesis. Cynomolgus monkeys imported as adults have little or no atherosclerosis.


Social stress Coronary artery atherosclerosis Social reorganization Social isolation Social strangers Social status Cholesterol Ovarian function Ovariectomy Depression Autonomic nervous system Sympathetic nervous ­system Hypothalamic–pituitary–adrenal axis Visceral obesity Inuslin resistance Hyperglycemia Dyslipidemia Proinflammatory cytokines 


  1. 1.
    Armstrong ML, Trillo A, Prichard RW. Naturally occurring and experimnetally induced atherosclerosis in nonhumna primates. In: Kalter SS, ed. The Use of Nonhuman Primates in Cardiovascular Diseases. Auistin: University of Texas Press; 1980:58-101.Google Scholar
  2. 2.
    Clarkson TB. Symposium summary. In: Kalter SS, ed. The Use of Nonhuman Primates in Cardiovascular Diseases. Austin: University of Texas Press; 1980:452-473.Google Scholar
  3. 3.
    Bond MD, Bullock BC, Bellinger DA, et al. Myocardial infarction in a large colony of nonhuman primates with coronary artery atherosclerosis. Am J Pathol. 1980;101:675-692.PubMedGoogle Scholar
  4. 4.
    Kirschbaum C, Pirke KM, Hellhammer DH. The ‘Trier Social Stress Test’–a tool for investigating psychobiological stress responses in a laboratory setting. Neuropsychobiology. 1993;28(1–2):76-81.PubMedCrossRefGoogle Scholar
  5. 5.
    Rozanski A, Blumenthal JA, Kaplan J. Impact of psychological factors on the pathogenesis of cardiovascular disease and implications for therapy. Circulation. 1999;99(16):2192-2217.PubMedCrossRefGoogle Scholar
  6. 6.
    O’Donovan A, Hughes BM. Access to social support in life and in the laboratory: combined impact on cardiovascular reactivity to stress and state anxiety. J Health Psychol. 2008;13(8):1147-1156.PubMedCrossRefGoogle Scholar
  7. 7.
    Adler NE, Boyce T, Chesney MA, et al. Socioeconomic status and health. The challenge of the gradient. Am Psychol. 1994;49(1):15-24.PubMedCrossRefGoogle Scholar
  8. 8.
    Kaplan JR, Manuck SB, Clarkson TB, Lusso FM, Taub DM. Social status, environment, and atherosclerosis in cynomolgus monkeys. Arteriosclerosis. 1982;2(5):359-368.PubMedCrossRefGoogle Scholar
  9. 9.
    Kaplan JR, Manuck SB, Clarkson TB, Lusso FM, Taub DM, Miller EW. Social stress and ­atherosclerosis in normocholesterolemic monkeys. Science. 1983;220(4598):733-735.PubMedCrossRefGoogle Scholar
  10. 10.
    Kaplan JR, Manuck SB, Adams MR, et al. Inhibition of coronary atherosclerosis by propranolol in behaviorally predisposed monkeys fed an atherogenic diet. Circulation. 1987;76:1364-1372.PubMedCrossRefGoogle Scholar
  11. 11.
    Kaplan JR, Manuck SB. The effect of propranolol on social interactions among adult male cynomolgus monkeys (Macaca fascicularis) housed in disrupted social groupings. Psychosom Med. 1989;51:449-462.PubMedGoogle Scholar
  12. 12.
    Shively CA. Social subordination stress, behavior and central monoaminergic function in female cynomolgus monkeys. Biol Psychiatry. 1998;44:882-891.PubMedCrossRefGoogle Scholar
  13. 13.
    Berga SL, Loucks TL. The diagnosis and treatment of stress-induced anovulation. Minerva Ginecol. 2005;57(1):45-54.PubMedGoogle Scholar
  14. 14.
    Shively CA. Reproduction, effects of social stress on. In: Fink G, ed. Encyclopedia of Stress. 2nd ed. Oxford: Elsevier; 2007:360-365.Google Scholar
  15. 15.
    Mahoney CJ. A study of the menstrual cycle in Macaca irus with special reference to the detection of ovulation. J Reprod Fertil. 1970;21:153-163.PubMedCrossRefGoogle Scholar
  16. 16.
    Wilks JW, Hodgen GD, Ross GT. Endocrine characteristics of ovulatory and anovulatory ­menstrual cycles in the rhesus monkey. In: Hafez ESE, ed. Human Ovulation. Amsterdam: ElsevierMorth-Holland Biomedical Press; 1979:205-218.Google Scholar
  17. 17.
    Kaplan JR, Manuck SB. Ovarian dysfunction, stress, and disease: a primate continuum. ILAR J. 2004;45:89-115.PubMedCrossRefGoogle Scholar
  18. 18.
    Shively CA, Kaplan JR. Stability of social status rankings of female cynomolgus monkeys, of varying reproductive condition, in different social groups. Am J Primatol. 1991;23:239-245.CrossRefGoogle Scholar
  19. 19.
    Adams MR, Kaplan JR, Clarkson TB, Koritnik DR. Ovariectomy, social status, and atherosclerosis in cynomolgus monkeys. Arteriosclerosis. 1985;5:192-200.PubMedCrossRefGoogle Scholar
  20. 20.
    Hamm TE Jr, Kaplan JR, Clarkson TB, Bullock BC. Effects of gender and social behavior on the development of coronary artery atherosclerosis in cynomolgus macaques. Atherosclerosis. 1983;48:221-233.PubMedCrossRefGoogle Scholar
  21. 21.
    Kaplan JR, Adams MR, Clarkson TB, Koritnik DR. Psychosocial influences on female ‘­protection’ among cynomolgus macaques. Atherosclerosis. 1984;53(3):283-295.PubMedCrossRefGoogle Scholar
  22. 22.
    Adams MR, Kaplan JR, Manuck SR, et al. Inhibition of coronary artery atherosclerosis by 17-beta estradiol in ovariectomized monkeys. Arteriosclerosis. 1990;10:1051-1057.PubMedCrossRefGoogle Scholar
  23. 23.
    Kaplan JR. Origins and health consequences of stress-induced ovarian dysfunction. Interdiscip Top Gerontol. 2008;36:162-185.PubMedCrossRefGoogle Scholar
  24. 24.
    Solomon CG, Hu FB, Dunaif A, et al. Menstrual cycle irregularity and risk for future ­cardiovascular disease. J Clin Endocrinol Metab. 2002;87:2013-2017.PubMedCrossRefGoogle Scholar
  25. 25.
    Ahmed B, Bairey Merz CN, Johnson BD, et al. Diabetes mellitus, hypothalamic hypoestrogenemia, and coronary artery disease in premenopausal women (from the National Heart, Lung, and Blood Institute sponsored WISE study). Am J Cardiol. 2008;102:150-154.PubMedCrossRefGoogle Scholar
  26. 26.
    Kaplan JR, Chen H, Manuck SB. The relationship between social status and atherosclerosis in male and female monkeys as revealed by meta-analysis. Am J Primatol. 2009;71(9):732-741.PubMedCrossRefGoogle Scholar
  27. 27.
    Shively CA, Clarkson TB, Kaplan JR. Social deprivation and coronary artery atherosclerosis in female cynomolgus monkeys. Atherosclerosis. 1989;77:69-76.PubMedCrossRefGoogle Scholar
  28. 28.
    Shively CA, Laber-Laird K, Anton RF. The behavior and physiology of social stress and depression in female cynomolgus monkeys. Biol Psychiatry. 1997;41:871-882.PubMedCrossRefGoogle Scholar
  29. 29.
    Shively CA, Williams JK, Laber-Laird K, Anton RF. Depression and coronary artery atherosclerosis and reactivity in female cynomolgus monkeys. Psychosomatic Med. 2002;64(5):699-706.CrossRefGoogle Scholar
  30. 30.
    Shively CA, Register TC, Adams MR, Golden DL, Willard SL, Clarkson TB. Depressive behavior and coronary artery atherogenesis in adult female cynomolgus monkeys. Psychosom Med. 2008;70(6):637-645.PubMedCrossRefGoogle Scholar
  31. 31.
    Strawn WB, Bondjers G, Kaplan JR, et al. Endothelial dysfunction in response to psychosocial stress in monkeys. Circ Res. 1991;68(5):1270-1279.PubMedCrossRefGoogle Scholar
  32. 32.
    Skantze HB, Kaplan J, Pettersson K, et al. Psychosocial stress causes endothelial injury in cynomolgus monkeys via a1-adrenoceptor activation. Atherosclerosis. 1998;136:153-161.PubMedCrossRefGoogle Scholar
  33. 33.
    Broadley AJ, Korszun A, Abdelaal E, et al. Inhibition of cortisol production with metyrapone prevents mental stress-induced endothelial dysfunction and baroreflex impairment. J Am Coll Cardiol. 2005;46:344-350.PubMedCrossRefGoogle Scholar
  34. 34.
    Broadley AJ, Korszun A, Abdelaal E, et al. Metyrapone improves endothelial dysfunction in patients with treated depression. J Am Coll Cardiol. 2006;48(1):170-175.PubMedCrossRefGoogle Scholar
  35. 35.
    Pozzi AO, Bernardo E, Coronado MT, Punchard MA, González P, Fantidis P. Acute arterial thrombosis in the absence of inflammation: the stress-related anti-inflammatory hormone ACTH participates in platelet-mediated thrombosis. Atherosclerosis. 2009;204(1):79-84.PubMedCrossRefGoogle Scholar
  36. 36.
    Fantidis P. The role of the stress-related anti-inflammatory hormones ACTH and cortisol in atherosclerosis. Curr Vasc Pharmacol. 2010;8(4):517-525.PubMedCrossRefGoogle Scholar
  37. 37.
    Cohen S, Line S, Manuck SB, Heise E, Kaplan JR. Chronic social stress, social dominance and susceptibility to upper respiratory infections in nonhuman primates. Psychosom Med. 1997;59:213-221.PubMedGoogle Scholar
  38. 38.
    Williams JK, Kaplan JR, Suparto IH, Fox JL, Manuck SB. Effects of exercise on cardiovascular outcomes in monkeys with risk factors for coronary heart disease. Arterioscler Thromb Vasc Biol. 2003;23(5):864-871.PubMedCrossRefGoogle Scholar
  39. 39.
    Després JP, Lemieux I. Abdominal obesity and metabolic syndrome. Nature. 2006;444:881-887.PubMedCrossRefGoogle Scholar
  40. 40.
    Després JP. Cardiovascular disease under the influence of excess visceral fat. Crit Pathw Cardiol. 2007;6:51-59.PubMedCrossRefGoogle Scholar
  41. 41.
    Shively CA, Clarkson TB, Miller LC, Weingand KW. Body fat distribution as a risk factor for coronary artery atherosclerosis in female cynomolgus monkeys. Arteriosclerosis. 1987;7:226-231.PubMedCrossRefGoogle Scholar
  42. 42.
    Shively CA, Kaplan JR, Clarkson TB. Carotid artery atherosclerosis in cholesterol-fed ­cynomolgus monkeys: the effects of oral contraceptive treatments, social factors and regional adiposity. Arteriosclerosis. 1990;10:358-366.PubMedCrossRefGoogle Scholar
  43. 43.
    Shively CA, Register TC, Clarkson TB. Social stress, visceral obesity, and coronary artery atherosclerosis in female primates. Obesity (Silver Spring). 2009;17(8):1513-1520.CrossRefGoogle Scholar
  44. 44.
    Shively CA, Register TC, Clarkson TB. Social stress, visceral obesity, and coronary artery atherosclerosis: product of a primate adaptation. Am J Primatol. 2009;71(9):742-751.PubMedCrossRefGoogle Scholar
  45. 45.
    Jayo JM, Shively CA, Kaplan JR. Effects of exercise and stress on body fat distribution in male cynomolgus monkeys. Int J Obesity. 1993;17:597-604.Google Scholar
  46. 46.
    Shively CA, Clarkson TB. Regional obesity and coronary artery atherosclerosis in females: a non-human primate model. Acta Med Scand Suppl. 1988;723:71-78.PubMedGoogle Scholar
  47. 47.
    Anagnostis P, Athyros VG, Tziomalos K, Karagiannis A, Mikhailidis DP. Clinical review: the pathogenetic role of cortisol in the metabolic syndrome: a hypothesis. J Clin Endocrinol Metab. 2009;94:2692-2701.PubMedCrossRefGoogle Scholar
  48. 48.
    Mayes JS, Watson GH. Direct effects of sex steroid hormones on adipose tissues and obesity. Obes Rev. 2004;5:197-216.PubMedCrossRefGoogle Scholar
  49. 49.
    Kyrou I, Tsigos C. Stress mechanisms and metabolic complications. Horm Metab Res. 2007;39:430-438.PubMedCrossRefGoogle Scholar
  50. 50.
    Kyrou I, Tsigos C. Chronic stress, visceral obesity and gonadal dysfunction. Hormones. 2008;7:287-293.PubMedGoogle Scholar

Copyright information

© Springer-Verlag London Limited 2011

Authors and Affiliations

  1. 1.Department of Pathology/Comparative MedicineWake Forest University School of MedicineWinston-SalemUSA

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