Relation of sympathetic activation and stress-induced hypertension in atherosclerosis of the thoracic aorta: a cadaveric study


  • Apostolos S. Gogakos Department of Forensic Medicine and Toxicology, Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece Department of Thoracic Surgery, Theagenio Cancer Hospital, Thessaloniki, Greece
  • Triantafyllia D. Koletsa Department of Pathology, Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
  • Leonidas C. Pavlidis Department of Plastic and Reconstructive Surgery, Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
  • Dimitrios A. Paliouras Department of Thoracic Surgery, Theagenio Cancer Hospital, Thessaloniki, Greece
  • Thomas S. Rallis Department of Thoracic Surgery, Theagenio Cancer Hospital, Thessaloniki, Greece
  • Achilleas A. Lazopoulos Department of Thoracic Surgery, Theagenio Cancer Hospital, Thessaloniki, Greece
  • Nikolaos G. Barbetakis Department of Thoracic Surgery, Theagenio Cancer Hospital, Thessaloniki, Greece
  • Fotios G. Chatzinikolaou Department of Forensic Medicine and Toxicology, Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece



Atherosclerosis, Hypertension, Stress, Sympathetic nervous system, Thoracic aorta, Cadaveric, Neuron terminals


Background: The autonomic nervous system (ANS) has been associated with numerous atherosclerosis-induced cardiovascular events, such as myocardial infarction and aortic disease. Although evidence suggests a relationship between autonomic dysfunction and atherosclerotic disease, the underlying mechanisms are still under investigation. The purpose of this study is to investigate the effect of ANS to the development of atherosclerosis and vice versa, in human thoracic aorta.

Methods: An autopsy analysis from three segments of the thoracic aorta was performed; ascending aorta, aortic arch, descending aorta, using 52 unselected adult cadavers (38 male, 14 female – mean age 64.4 years; age range 19-90 years). Subjects were divided in two age groups (<65 years – N=26, >65 years – N=26). Tissue specimens were macroscopically examined and histopathologically divided into 7 grades of scoring for atherosclerosis (ATHERO, from 0=intact, to 6=thrombi formation). The relationship between ANS and atherosclerosis was depicted by further immunohistochemical analysis for detection of neuron terminals onto the aortic wall. All data were evaluated according to the subjects’ demographic and clinical characteristics.

Results: Total 96.2% of all subjects had atherosclerosis of variable degree in one or more segments. No aneurismal change was found. The presence of atheromas were common in all subjects regardless of age and segment, with atherosclerosis increasing by age; ascending aorta (r=0.571, p<0.001), aortic arch (r=0.655, p<0.001), descending aorta (r=0.659, p<0.001). Hypertension was a significant factor in the development of atherosclerosis in adults >65 years (r=0.450, p=0.023). In addition, a positive history of hypertension was statistically significant regarding both the presence of atherosclerosis and neuron terminals in all three aortic wall segments; ascending aorta (p=0.037), Aaortic arch (p=0.046), descending aorta (p=0.045). Furthermore, there was a strong negative correlation between the ATHERO score and the presence of neuron terminals in all three aortic segments; ascending aorta (r=-0.264, p=0.041), aortic arch (r=-0.400, p=0.003), descending aorta (r=-0.234, p=0.047).

Conclusions: Human cadaveric studies are extremely useful in understanding the pathophysiology of ANS, along with clinical and animal studies that are most commonly performed. These data suggest that there is a link between autonomic disfunction and the presence of atherosclerosis in human thoracic aorta, especially when hypertension is present. It is therefore possible that stress-induced hypertension can be considered as a potential risk factor for the development of atherosclerosis.


Low PA, Engstom JW. Disorders of the autonomic nervous system. Harrison’s principles of internal medicine 16th ed. McGraw-Hill, USA. 2006;3351-60.

Kenney MJ, Ganta CK. Autonomic nervous system and immune system interactions. Compr Physiol. 2014;4:1177-200.

Purves D, Augustine GJ, Fitzpatrick D, Hall WC, LaMantia AS, McNamara JO, et al. The Visceral Motor System Neuroscience. 3rd ed. Sunderland, USA. 2004;469-98.

WHO. World Health Organization: Global status report on noncommunicable diseases, 2014. Available at: /ncd-status-report-2014/en/. Accessed on: 08 August 2020.

Yulan S, Li Z. The crosstalk between autonomic nervous system and blood vessels. Int J Physiol Pathophysiol Pharmacol. 2018;10(1):17-28.

Johansen K, Kohler TR, Nicholls SC, Zieler RE, Clowes AW, Kazimers A. Ruptured aortic aneurysm: the Harborview experience. J Vasc Surg. 1991;13:240-7.

Amiya E, Watanabe M, Komuro I. The Relationship between Vascular Function and the Autonomic Nervous System. Ann Vasc Dis. 2014;7(2):109-19.

Manuck SB, Kaplan JR, Clarkson TB. Behaviorally induced heart rate reactivity and atherosclerosis in cynomolgus monkeys. Psychosom. 1983;45:95-108.

Rozanski A, Blumenthal JA, Davidson KW, Saab PG, Kubzansky L. The epidemiology, pathophysiology, and management of psychosocial risk factors in cardiac practice: The emerging field of behavioral cardiology. J Am Coll Cardiol. 2005;45:637-51.

Liao D, Cai J, Rosamond WD, Barnes RW, Hutchinson RG, Whitsel EA, et al. Cardiac Autonomic Function and Incident Coronary Heart Disease: A Population-based Case-Cohort Study: The ARIC Study. Am J Epidemiol. 1997;145:696-706.

Kawachi I, Colditz GA, Ascherio A, Rimm EB, Giovannucci E, Stampfer MJ, et al. A prospective study of social networks in relation to total mortality and cardiovascular disease in men in the USA. J Epidemiol Comm Health. 1996;50:245-51.

Endo S, Goldsmith HL, Karino T. Flow patterns and preferred sites of atherosclerotic lesions in the human aorta - I. Aortic arch. Biorheology. 2014;51(4-5):239-55.

Stary HC, Chandler AB, Dinsmore RE, Fuster V, Glagov S, Insull W Jr, Rosenfeld ME, Schwartz CJ, Wagner WD, Wissler RW. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the committee on vascular lesions of the council on atherosclerosis, American Heart Association. Circulation. 1995;92:1355-74.

Hansson GK, Libby P. The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol. 2006;6:508-19.

Silverman S. Diagnostic Imaging. In: Mader DR, editor. Reptile Medicine and Surgery. 2nd ed. St. Louis: Saunders Elsevier. 2006;471-89.

Willecke F, Yuan C, Oka K, Chan L, Hu Y, Barnhart S, et al. Effects of High Fat Feeding and Diabetes on Regression of Atherosclerosis Induced by Low-Density Lipoprotein Receptor Gene Therapy in LDL Receptor-Deficient Mice. PLoS One. 2015;10(6).

Smith SC, Smith EC, Taylor RL. Susceptibility to spontaneous atherosclerosis in pigeons: an autosomal recessive trait. J Heredity. 2001;92:439-42.

Asakura T, Karino T. Flow patterns and spatial distributions of atherosclerotic lesions in human coronary arteries. Circ Res. 1990;66:1045-66.

Caro CG, Fitz-Gerald JM, Schroter RC. Arterial wall shear and distribution of early atheroma in man. Nature. 1969;223:1159-61.

Cornhill JF, Herderick EE, Stary HC. Topography of human aortic sudanophilic lesions. Monogr Atheroscler. 1990;15:13-9.

Kjaernes M, Svindland A, Walloe L, Wille SØ. Localization of early atherosclerotic lesions in an arterial bifurcation in humans. Acta Path Microbiol Scand. 1981;A89:35-40.

Allaire E, Schneider F, Saucy F. New insight in aetiopathogenesis of aortic diseases, Eur J Vasc Endovasc Surg. 2009;37:531-7.

Hagan PG, Nienaber CA, Isselbacher EM, Bruckman D, Karavite DJ, Russman PL, et al., The international registry of acute aortic dissection (IRAD): new insights into an old disease. JAMA. 2000;283:897-903.

Allison MA, Criqui MH, Wright CM. Patterns and risk factors for systemic calcified atherosclerosis. Arterioscler Thromb Basc Biol. 2004;24:331-6.

Miwa Y, Tsushima M, Arima H, Kawano Y, Sasaguri T. Pulse pressure is an independent predictor for the progression of aortic wall calcification in patients with controlled hyperlipidemia. Hypertension. 2004;43:536-40.

Stetter MD. Ultrasonography. In: Mader DR, editor. Reptile Medicine and Surgery. 2nd ed. St. Louis: Saunders Elsevier. 2006;665-74.

Pearson TA, Blair SN, Daniels SR, Eckel RH, Fair JM, Fortmann SP. AHA guidelines for primary prevention of cardiovascular disease and stroke: 2002 update: Consensus panel guide t comprehensive risk reduction for adult patients without coronary or other atherosclerotic vascular diseases. American Heart Association Science Advisory and Coordinating Committee. Circulation. 2002;106:388-91.

Amarenco P, Duyckaerts C, Tzourio C, Henin D, Bousser MG, Hauw JJ. The prevalence of ulcerated plaques in the aortic arch in patients with stroke. N Engl J Med. 1992;326:221-5.

Tunick PA, Kronzon I. Protruding atherosclerotic plaque in the aortic arch of patients with systemic embolization: a new finding seen by transesophageal echocardiography. Am Heart J. 1990;120:658-60.

Corti R, Fuster V, Fayad ZA, Worthley SG, Helft G, Chaplin WF, et al. Effects of aggressive versus conventional lipid-lowering therapy by simvastatin on human atherosclerotic lesions: a prospective, randomized, double-blind trial with high-resolution magnetic resonance imaging. J Am Coll Cardiol. 2005;46:106-12.

Amarenco P, Cohen A. Atherosclerotic disease of the aortic arch. In: Barnett HJM, Mohr JP, Stein BM, Yatsu FM, editors. Stroke: Pathophysiology, Diagnosis and Management. 3rd edition. New York, NY: Churchill Livingstone. 1998;895-920.

Barbetseas J, Alexopoulos N, Brili S, Aggeli C, Chrysohoou C, Frogoudaki A, et al. Atherosclerosis of the aorta in patients with acute thoracic aortic dissection. Circ J. 2008;72(11):1773-6.

Kallikazaros IE, Tsioufis CP, Stefanadis CI, Pitsavos CE, Toutouzas PK. Closed relation between carotid and ascending aortic atherosclerosis in cardiac patients. Circulation. 2000;102(19).

Kostopoulos CG, Spiroglou SG, Varakis JN, Apostolakis E, Papadaki HH. Chemerin and CMKLR1 expression in human arteries and periadventitial fat: A possible role for local chemerin in atherosclerosis? BMC Cardiovasc Disord. 2014;14.

Vallbo AB, Hagbarth KE, Torebjork HE, Wallin BG. Somatosensory, proprioceptive, and sympathetic activity in human peripheral nerves. Physiol Rev. 1979;59:919-57.

Esler MD, Hasking GJ, Willett IR, Leonard PW, Jennings GL, Esler MD, Jennings GL, Johns J, Burke F, Little PJ, Leonard P. Estimation of ‘total’ renal, cardiac and splanchnic sympathetic nervous tone in essential hypertension from measurements of noradrenaline release. J Hypertens. 1985;3:117-29.

Mark AL. The sympathetic nervous system in hypertension: a potential long-term regulator of arterial pressure. J Hypertens Suppl. 1996;14:159-65.

Grassi G, Ram VS. Evidence for a critical role of the sympathetic nervous system in hypertension. J Am Soc Hypertens. 2016;10:457-66.

Gamboa A, Okamoto LE, Diedrich A, Choi L, Robertson D, Farley G, et al. Sympathetic activation and nitric oxide function in early hypertension. Am J Physiol Heart Circ Physiol. 2012;302:1438-43.

Julius S. The evidence for a pathophysiologic significance of the sympathetic overactivity in hypertension. Clin Exp Hypertens. 1996;18:305-21.

Pizzi C, Manzoli L, Mancini S, Bedetti G, Fontana F, Costa GM. Autonomic nervous system, inflammation and preclinical carotid atherosclerosis in depressed subjects with coronary risk factors. Atherosclerosis. 2010;212:292-8.

Libby P. Inflammation in Atherosclerosis. Arterioscler Thromb Vasc Biol. 2012;32:2045-51.

Aronson D, Mittleman MA, Burger AJ. Interleukin-6 levels are inversely correlated with heart rate variability in patients with decompensated heart failure. J Cardiovasc Electrophysiol. 2001;12:294-300.

Janszky I, Ericson M, Lekander M, Blom M, Buhlin K, Georgiades A, et al. Inflammatory markers and heart rate variability in women with coronary heart disease. J Intern Med. 2004;256:421-8.

Lanza GA, Sgueglia GA, Cianflone D, Rebuzzi AG, Angeloni G, Sestito A, et al. Relation of heart rate variability to serum levels of C-reactive protein in patients with unstable angina pectoris. Am J Cardiol. 2006;97:1702-6.

Anderson EA, Wallin BG, Mark AL. Dissociation of sympathetic nerve activity in arm and leg muscle during mental stress. Hypertension. 1987;9(III):114-9.

Ghiadoni L, Donald AE, Cropley M, Mullen MJ, Oakley G, Taylor M, et al. Mental stress induces transient endothelial dysfunction in humans. Circulation. 2000;102:2473-8.

Bernberg E, Ulleryd MA, Johansson ME, Bergstrom GM. Social disruption stress increases IL-6 levels and accelerates atherosclerosis in ApoE-/- mice. Atherosclerosis. 2012;221:359-65.

Kaplan JR, Manuck SB, Clarkson TB, Lusso FM, Taub DM. Social status, environment, and atherosclerosis in cynomolgus monkeys. Arteriosclerosis. 1982;2:359-68.

Kaplan JR, Manuck SB, Clarkson TB, Lusso FM, Taub DM, Miller EW. Social stress and atherosclerosis in normocholesterolemic monkeys. Science. 1983;220:733-5.

Hjalmarson A, Goldstein S, Fagerberg B, Wedel H, Waagstein F, Kjekshus J, et al. Effects of controlled-release metoprolol on total mortality, hospitalizations, and wellbeing in patients with heart failure: the Metoprolol CR/XL Randomized Intervention Trial in congestive heart failure (MERIT-HF). MERIT-HF Study Group. JAMA. 2000;283:1295-302.

Wikstrand J, Kendall M. The role of beta receptor blockade in preventing sudden death. Eur Heart J. 1992;13(D):111-20.

Heidt T, Sager HB, Courties G, Dutta P, Iwamoto Y, Zaltsman A, et al. Chronic variable stress activates hematopoietic stem cells. Nat Med. 2014;20:754-8.

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;23:742-9.

Tesfamariam B, Weisbrod RM, Cohen RA. Cyclic GMP modulators on vascular adrenergic neurotransmission. J Vasc Res. 1992;29:396-404.

Aubineau P. Role of the adventitial innervation in establishing and maintaining the structural and functional properties of the arterial wall. Effects during aging. Ann Cardiol Angeiol (Paris). 1991;40:285-91.

Sobey CG, Sozzi V, Woodman OL. Ischaemia/reperfusion enhances phenylephrine induced contraction of rabbit aorta due to impairment of neuronal uptake. J Cardiovasc Pharmacol. 1994;23:562-8.






Original Research Articles