Purpose of Review
In this review, we summarize evidence on the risk factor psychological stress in the context of coronary heart disease (CHD) in humans and explore the role of inflammation as a potential underlying mechanism.
While chronic stress increases the risk of incident CHD and poor cardiovascular prognosis, acute emotional stress can trigger acute CHD events in vulnerable patients. Evidence supporting a potential role for inflammation as a promising biological mechanism comes from population-based studies showing associations between chronic stress and increased inflammation. Similarly, experimental studies demonstrate acute stress-induced increases in inflammatory markers and suggest modulatory potential for pharmacological and biobehavioral interventions. So far, studies investigating patients with cardiovascular disease are few and the full sequence of events from stress to inflammation to CHD remains to be established.
Psychological stress is an independent CHD risk factor associated with increased inflammation. Although promising, causality needs to be further explored.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major Importance
Gaziano JM. Global burden of cardiovascular disease. In: Zipes DP, Libby P, Bonow RO, Braunwald RO, editors. Braunswald’s heart disease—a textbook of Cardiovacular medicine. 7. Philadelphia: Elsevier Saunders; 2005. p. 1–19.
Townsend N, Wilson L, Bhatnagar P, Wickramasinghe K, Rayner M, Nichols M. Cardiovascular disease in Europe: epidemiological update 2016. Eur Heart J. 2016;37(42):3232–45.
Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, et al. Heart disease and stroke statistics—2017 update: a report from the American Heart Association. Circulation. 2017;135(10):e146–603.
Zipes DP, Libby P, Bonow RO, Braunwald E. Braunwald's Heart Disease. A Textbook of Cardiovascular Medicine. 7th ed. Philadelphia: Elsevier Saunders; 2005. 2183 p
Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005;352(16):1685–95.
Libby P. Inflammation in atherosclerosis. Arterioscler Thromb Vasc Biol. 2012;32(9):2045–51.
• Hansson GK, Hermansson A. The immune system in atherosclerosis. Nat Immunol. 2011;12(3):204–12. This review article provides an excellent overview on the role of the innate as well as the adaptive immune response in atherosclerosis, including circulating markers of inflammation.
Ridker PM, Libby P. Risk factors for atherothrombotic disease. In: Zipes DP, Libby P, Bonow RO, Braunwald E, editors. Heart disease—a textbook of cardiovascular medicine. 7. Philadelphia: Elsevier Saunders; 2005. p. 939–58.
Ridker PM. From C-reactive protein to interleukin-6 to interleukin-1: moving upstream to identify novel targets for atheroprotection. Circ Res. 2016;118(1):145–56.
Kaptoge S, Seshasai SR, Gao P, Freitag DF, Butterworth AS, Borglykke A, et al. Inflammatory cytokines and risk of coronary heart disease: new prospective study and updated meta-analysis. Eur Heart J. 2014;35(9):578–89.
Emerging Risk Factors C, Kaptoge S, Di Angelantonio E, Lowe G, Pepys MB, Thompson SG, et al. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet. 2010;375(9709):132–40.
Kop WJ. Chronic and acute psychological risk factors for clinical manifestations of coronary artery disease. Psychosom Med. 1999;61(4):476–87.
von Kanel R. Psychosocial stress and cardiovascular risk: current opinion. Swiss Med Wkly. 2012;142:w13502.
Lagraauw HM, Kuiper J, Bot I. Acute and chronic psychological stress as risk factors for cardiovascular disease: insights gained from epidemiological, clinical and experimental studies. Brain Behav Immun. 2015;50:18–30.
Selye H. The stress of life. New York: McGraw Hill; 1937.
Lazarus RS, Folkman S. Stress, appraisal, and coping. New York: Springer Publishing Company; 1984.
Dimsdale JE. Psychological stress and cardiovascular disease. J Am Coll Cardiol. 2008;51(13):1237–46.
Hansel A, Hong S, Camara RJ, von Kanel R. Inflammation as a psychophysiological biomarker in chronic psychosocial stress. Neurosci Biobehav Rev. 2010;35(1):115–21.
Appels A. Inflammation and the mental state before an acute coronary event. Ann Med. 1999;31(Suppl 1):41–4.
Melamed S, Ugarten U, Shirom A, Kahana L, Lerman Y, Froom P. Chronic burnout, somatic arousal and elevated salivary cortisol levels. J Psychosom Res. 1999;46(6):591–8.
Melamed S, Shirom A, Toker S, Berliner S, Shapira I. Burnout and risk of cardiovascular disease: evidence, possible causal paths, and promising research directions. Psychol Bull. 2006;132(3):327–53.
• Steptoe A, Kivimaki M. Stress and cardiovascular disease: an update on current knowledge. Annu Rev Public Health. 2013;34:337–54. This review article elegantly summarizes the abundant research on the role of psychosocial factors in coronary heart disease and the various mechanisms that are involved in this link.
• Kivimaki M, Nyberg ST, Batty GD, Fransson EI, Heikkila K, Alfredsson L, et al. Job strain as a risk factor for coronary heart disease: a collaborative meta-analysis of individual participant data. Lancet. 2012;380(9852):1491–7. This impressive meta-analysis pooled data from published and unpublished prospective studies and found that job strain is associated with a small but consistent increased risk of an incident CHD event.
Kivimaki M, Jokela M, Nyberg ST, Singh-Manoux A, Fransson EI, Alfredsson L, et al. Long working hours and risk of coronary heart disease and stroke: a systematic review and meta-analysis of published and unpublished data for 603,838 individuals. Lancet. 2015;386(10005):1739–46.
Virtanen M, Nyberg ST, Batty GD, Jokela M, Heikkila K, Fransson EI, et al. Perceived job insecurity as a risk factor for incident coronary heart disease: systematic review and meta-analysis. BMJ. 2013;347:f4746.
Valtorta NK, Kanaan M, Gilbody S, Ronzi S, Hanratty B. Loneliness and social isolation as risk factors for coronary heart disease and stroke: systematic review and meta-analysis of longitudinal observational studies. Heart. 2016;102(13):1009–16.
Power C, Hypponen E, Smith GD. Socioeconomic position in childhood and early adult life and risk of mortality: a prospective study of the mothers of the 1958 British birth cohort. Am J Public Health. 2005;95(8):1396–402.
Backholer K, Peters SAE, Bots SH, Peeters A, Huxley RR, Woodward M. Sex differences in the relationship between socioeconomic status and cardiovascular disease: a systematic review and meta-analysis. J Epidemiol Community Health. 2017;71(6):550–7.
Manrique-Garcia E, Sidorchuk A, Hallqvist J, Moradi T. Socioeconomic position and incidence of acute myocardial infarction: a meta-analysis. J Epidemiol Community Health. 2011;65(4):301–9.
Appels A, Kop W, Bar F, de Swart H, Mendes de Leon C. Vital exhaustion, extent of atherosclerosis, and the clinical course after successful percutaneous transluminal coronary angioplasty. Eur Heart J. 1995;16(12):1880–5.
Schnohr P, Marott JL, Kristensen TS, Gyntelberg F, Gronbaek M, Lange P, et al. Ranking of psychosocial and traditional risk factors by importance for coronary heart disease: the Copenhagen City heart study. Eur Heart J. 2015;36(22):1385–93.
Nawrot TS, Perez L, Kunzli N, Munters E, Nemery B. Public health importance of triggers of myocardial infarction: a comparative risk assessment. Lancet. 2011;377(9767):732–40.
•• Mostofsky E, Penner EA, Mittleman MA. Outbursts of anger as a trigger of acute cardiovascular events: a systematic review and meta-analysis. Eur Heart J. 2014;35(21):1404–10. A landmark meta-analysis showing that feelings of intense anger are a triggering factor for acute myocardial infarction and other cardiovascular events within a critical time interval of a few hours.
Mostofsky E, Maclure M, Sherwood JB, Tofler GH, Muller JE, Mittleman MA. Risk of acute myocardial infarction after the death of a significant person in one’s life: the determinants of myocardial infarction onset study. Circulation. 2012;125(3):491–6.
Fang F, Fall K, Mittleman MA, Sparen P, Ye W, Adami HO, et al. Suicide and cardiovascular death after a cancer diagnosis. N Engl J Med. 2012;366(14):1310–8.
Steptoe A, Brydon L. Emotional triggering of cardiac events. Neurosci Biobehav Rev. 2009;33(2):63–70.
Linden W, Gerin W, Davidson K. Cardiovascular reactivity: status quo and a research agenda for the new millennium. Psychosom Med. 2003;65(1):5–8.
Schwartz AR, Gerin W, Davidson KW, Pickering TG, Brosschot JF, Thayer JF, et al. Toward a causal model of cardiovascular responses to stress and the development of cardiovascular disease. Psychosom Med. 2003;65(1):22–35.
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.
• Dickerson SS, Kemeny ME. Acute stressors and cortisol responses: a theoretical integration and synthesis of laboratory research. Psychol Bull. 2004;130(3):355–91. This meta-analysis shows that social evaluative threat and uncontrollability of stress are important determinants of the cortisol reactivity in the context of acute stress.
Henze GI, Zankert S, Urschler DF, Hiltl TJ, Kudielka BM, Pruessner JC, et al. Testing the ecological validity of the trier social stress test: association with real-life exam stress. Psychoneuroendocrinology. 2017;75:52–5.
McEwen BS. Protective and damaging effects of stress mediators. N Engl J Med. 1998;338(3):171–9.
Chida Y, Steptoe A. Greater cardiovascular responses to laboratory mental stress are associated with poor subsequent cardiovascular risk status: a meta-analysis of prospective evidence. Hypertension. 2010;55(4):1026–32.
Panaite V, Salomon K, Jin A, Rottenberg J. Cardiovascular recovery from psychological and physiological challenge and risk for adverse cardiovascular outcomes and all-cause mortality. Psychosom Med. 2015;77(3):215–26.
Brotman DJ, Golden SH, Wittstein IS. The cardiovascular toll of stress. Lancet. 2007;370(9592):1089–100.
Hamer M, Endrighi R, Venuraju SM, Lahiri A, Steptoe A. Cortisol responses to mental stress and the progression of coronary artery calcification in healthy men and women. PLoS One. 2012;7(2):e31356.
•• Marsland AL, Walsh C, Lockwood K, John-Henderson NA. The effects of acute psychological stress on circulating and stimulated inflammatory markers: a systematic review and meta-analysis. Brain Behav Immun. 2017;64:208–19. This meta-analysis investigated circulating inflammatory markers before and after exposure to laboratory stress induction and found significant increases in IL-1β, IL-6, and TNF-α.
Steptoe A, Hamer M, Chida Y. The effects of acute psychological stress on circulating inflammatory factors in humans: a review and meta-analysis. Brain Behav Immun. 2007;21(7):901–12.
• Kuebler U, Zuccarella-Hackl C, Arpagaus A, Wolf JM, Farahmand F, von Kanel R, et al. Stress-induced modulation of NF-kappaB activation, inflammation-associated gene expression, and cytokine levels in blood of healthy men. Brain Behav Immun. 2015;46:87–95. In this randomized controlled trial in healthy men, we investigated stress kinetics and interrelations of pro- and anti-inflammatory measures on both the transcriptional (transcription factor DNA binding activity and gene expression) and protein level.
• Bierhaus A, Wolf J, Andrassy M, Rohleder N, Humpert PM, Petrov D, et al. A mechanism converting psychosocial stress into mononuclear cell activation. Proc Natl Acad Sci U S A. 2003;100(4):1920–5. This study disentangled for the first time the adrenergic mechanisms on the cellular level that underlie the production of proinflammatory cytokines by immunocompetent cells in response to acute psychosocial stress.
Wolf JM, Rohleder N, Bierhaus A, Nawroth PP, Kirschbaum C. Determinants of the NF-kappaB response to acute psychosocial stress in humans. Brain Behav Immun. 2009;23(6):742–9.
Pace TW, Mletzko TC, Alagbe O, Musselman DL, Nemeroff CB, Miller AH, et al. Increased stress-induced inflammatory responses in male patients with major depression and increased early life stress. Am J Psychiatry. 2006;163(9):1630–3.
Brydon L, Edwards S, Jia H, Mohamed-Ali V, Zachary I, Martin JF, et al. Psychological stress activates interleukin-1beta gene expression in human mononuclear cells. Brain Behav Immun. 2005;19(6):540–6.
McInnis CM, Wang D, Gianferante D, Hanlin L, Chen X, Thoma MV, et al. Response and habituation of pro- and anti-inflammatory gene expression to repeated acute stress. Brain Behav Immun. 2015;46:237–48.
Kop WJ, Weissman NJ, Zhu J, Bonsall RW, Doyle M, Stretch MR, et al. Effects of acute mental stress and exercise on inflammatory markers in patients with coronary artery disease and healthy controls. Am J Cardiol. 2008;101(6):767–73.
Rooks CR, Ibeanu I, Shah A, Pimple P, Murrah N, Shallenberger L, et al. Young women post-MI have higher plasma concentrations of interleukin-6 before and after stress testing. Brain Behav Immun. 2016;51:92–8.
Brydon L, Strike PC, Bhattacharyya MR, Whitehead DL, McEwan J, Zachary I, et al. Hostility and physiological responses to laboratory stress in acute coronary syndrome patients. J Psychosom Res. 2010;68(2):109–16.
• Strike PC, Magid K, Whitehead DL, Brydon L, Bhattacharyya MR, Steptoe A. Pathophysiological processes underlying emotional triggering of acute cardiac events. Proc Natl Acad Sci U S A. 2006;103(11):4322–7. This study found that ACS survivors who experienced acute negative emotions in the 2h before symtom onset show increased immune cell-platelet aggregate reactivity to acute stress induction as compared to control patients without acute negative emotions before ACS onset.
Reid GJ, Seidelin PH, Kop WJ, Irvine MJ, Strauss BH, Nolan RP, et al. Mental-stress-induced platelet activation among patients with coronary artery disease. Psychosom Med. 2009;71(4):438–45.
Rohleder N. Stimulation of systemic low-grade inflammation by psychosocial stress. Psychosom Med. 2014;76(3):181–9.
Brouwers CJ, Wolf JM, von Kanel R. Inflammatory biomarkers in PTSD. In: Martin CR, Preedy VR, Patel VB, editors. Comprehensive Guide to Post-Traumatic Stress Disorder. 1st ed. Berlin: Springer; 2016. p. 979–93.
• Danese A, Pariante CM, Caspi A, Taylor A, Poulton R. Childhood maltreatment predicts adult inflammation in a life-course study. Proc Natl Acad Sci U S A. 2007;104(4):1319–24. The study showed that after a follow-up of 20 years, adults with childhood adversities had higher levels of C-reactive protein and other inflammatory markers than those without maltreatment, independendent of health behaviors and stress in adulthood.
von Kanel R, Mills PJ, Mausbach BT, Dimsdale JE, Patterson TL, Ziegler MG, et al. Effect of Alzheimer caregiving on circulating levels of C-reactive protein and other biomarkers relevant to cardiovascular disease risk: a longitudinal study. Gerontology. 2012;58(4):354–65.
Potier F, Degryse JM, de Saint-Hubert M. Impact of caregiving for older people and pro-inflammatory biomarkers among caregivers: a systematic review. Aging Clin Exp Res 2017. https://doi.org/10.1007/s40520-017-0765-0.
Xu W, Chen B, Guo L, Li Z, Zhao Y, Zeng H. High-sensitivity CRP: possible link between job stress and atherosclerosis. Am J Ind Med. 2015;58(7):773–9.
Emeny RT, Zierer A, Lacruz ME, Baumert J, Herder C, Gornitzka G, et al. Job strain-associated inflammatory burden and long-term risk of coronary events: findings from the MONICA/KORA Augsburg case-cohort study. Psychosom Med. 2013;75(3):317–25.
von Kanel R, Bellingrath S, Kudielka BM. Association between burnout and circulating levels of pro- and anti-inflammatory cytokines in schoolteachers. J Psychosom Res. 2008;65(1):51–9.
Marteinsdottir I, Ernerudh J, Jonasson L, Kristenson M, Garvin P. Psychological resources are independently associated with markers of inflammation in a middle-aged community sample. Int J Behav Med. 2016;23(5):611–20.
Wirtz PH, von Kanel R, Schnorpfeil P, Ehlert U, Frey K, Fischer JE. Reduced glucocorticoid sensitivity of monocyte interleukin-6 production in male industrial employees who are vitally exhausted. Psychosom Med. 2003;65(4):672–8.
Appels A, Bar FW, Bar J, Bruggeman C, de Baets M. Inflammation, depressive symptomtology, and coronary artery disease. Psychosom Med. 2000;62(5):601–5.
Nazmi A, Victora CG. Socioeconomic and racial/ethnic differentials of C-reactive protein levels: a systematic review of population-based studies. BMC Public Health. 2007;7:212.
Deverts DJ, Cohen S, Kalra P, Matthews KA. The prospective association of socioeconomic status with C-reactive protein levels in the CARDIA study. Brain Behav Immun. 2012;26(7):1128–35.
Cho HJ, Seeman TE, Kiefe CI, Lauderdale DS, Irwin MR. Sleep disturbance and longitudinal risk of inflammation: moderating influences of social integration and social isolation in the coronary artery risk development in young adults (CARDIA) study. Brain Behav Immun. 2015;46:319–26.
Hackett RA, Hamer M, Endrighi R, Brydon L, Steptoe A. Loneliness and stress-related inflammatory and neuroendocrine responses in older men and women. Psychoneuroendocrinology. 2012;37(11):1801–9.
Passos IC, Vasconcelos-Moreno MP, Costa LG, Kunz M, Brietzke E, Quevedo J, et al. Inflammatory markers in post-traumatic stress disorder: a systematic review, meta-analysis, and meta-regression. Lancet Psychiatry. 2015;2(11):1002–12.
von Kanel R, Begre S, Abbas CC, Saner H, Gander ML, Schmid JP. Inflammatory biomarkers in patients with posttraumatic stress disorder caused by myocardial infarction and the role of depressive symptoms. Neuroimmunomodulation. 2010;17(1):39–46.
Elenkov IJ. Neurohormonal-cytokine interactions: implications for inflammation, common human diseases and well-being. Neurochem Int. 2008;52(1–2):40–51.
Huston JM, Tracey KJ. The pulse of inflammation: heart rate variability, the cholinergic anti-inflammatory pathway and implications for therapy. J Intern Med. 2011;269(1):45–53.
• von Kanel R, Kudielka BM, Metzenthin P, Helfricht S, Preckel D, Haeberli A, et al. Aspirin, but not propranolol, attenuates the acute stress-induced increase in circulating levels of interleukin-6: a randomized, double-blind, placebo-controlled study. Brain Behav Immun. 2008;22(2):150–7. In this randomized controlled trial in healthy men, we could demonstrate that 100 mg of daily aspirin for a total of 5 days signficantly attenuated the increase in the interleukin-6 response to acute psychosocial stress up to 2 h after stress cesssation.
Kuebler U, Arpagaus A, Meister RE, von Kanel R, Huber S, Ehlert U, et al. Dark chocolate attenuates intracellular pro-inflammatory reactivity to acute psychosocial stress in men: a randomized controlled trial. Brain Behav Immun. 2016;57:200–8.
Pace TW, Negi LT, Adame DD, Cole SP, Sivilli TI, Brown TD, et al. Effect of compassion meditation on neuroendocrine, innate immune and behavioral responses to psychosocial stress. Psychoneuroendocrinology. 2009;34(1):87–98.
Pace TW, Negi LT, Dodson-Lavelle B, Ozawa-de Silva B, Reddy SD, Cole SP, et al. Engagement with cognitively-based compassion training is associated with reduced salivary C-reactive protein from before to after training in foster care program adolescents. Psychoneuroendocrinology. 2013;38(2):294–9.
Moore RC, Chattillion EA, Ceglowski J, Ho J, von Kanel R, Mills PJ, et al. A randomized clinical trial of behavioral activation (BA) therapy for improving psychological and physical health in dementia caregivers: results of the pleasant events program (PEP). Behav Res Ther. 2013;51(10):623–32.
Oken BS, Fonareva I, Haas M, Wahbeh H, Lane JB, Zajdel D, et al. Pilot controlled trial of mindfulness meditation and education for dementia caregivers. J Altern Complement Med. 2010;16(10):1031–8.
Creswell JD, Taren AA, Lindsay EK, Greco CM, Gianaros PJ, Fairgrieve A, et al. Alterations in resting-state functional connectivity link mindfulness meditation with reduced Interleukin-6: a randomized controlled trial. Biol Psychiatry. 2016;80(1):53–61.
Malarkey WB, Jarjoura D, Klatt M. Workplace based mindfulness practice and inflammation: a randomized trial. Brain Behav Immun. 2013;27(1):145–54.
Creswell JD, Irwin MR, Burklund LJ, Lieberman MD, Arevalo JM, Ma J, et al. Mindfulness-based stress reduction training reduces loneliness and pro-inflammatory gene expression in older adults: a small randomized controlled trial. Brain Behav Immun. 2012;26(7):1095–101.
Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, Catapano AL, et al. 2016 European guidelines on cardiovascular disease prevention in clinical practice: the sixth joint task force of the European Society of Cardiology and Other Societies on cardiovascular disease prevention in clinical practice (constituted by representatives of 10 societies and by invited experts)developed with the special contribution of the European Association for Cardiovascular Prevention & rehabilitation (EACPR). Eur Heart J. 2016;37(29):2315–81.
This work was funded by research grants from the Swiss National Science Foundation (PP00P1_128565/1) and from the German Research Foundation (INST 38/550-1) (all to PHW). The funding sources had no impact on the writing of the manuscript, or the decision to submit the manuscript for publication.
Conflict of Interest
Petra H. Wirtz declares no conflict of interest.
Roland von Känel reports personal fees from Vifor AG Switzerland.
Human and Animal Rights and Informed Consent
This article reviews published studies and does not present original data with human or animal subjects performed by any of the authors.
This article is part of the Topical Collection on Psychological Aspects of Cardiovascular Diseases
About this article
Cite this article
Wirtz, P.H., von Känel, R. Psychological Stress, Inflammation, and Coronary Heart Disease. Curr Cardiol Rep 19, 111 (2017). https://doi.org/10.1007/s11886-017-0919-x
- Psychosocial stress
- Coronary heart disease
- C-reactive protein
- Inflammatory stress response
- Job burnout