Correlation between adolescent chronic emotional stress and incidence of adult cardiovascular disease in female rats

Document Type: Original Article


1 Laboratory of Neuro-Organic Chemistry, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran

2 Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran


Objective(s): Association of adolescent emotional stress (ES) with the incidence of cardiovascular disease (CVD) at older age was investigated.
Materials and Methods: 21 female rats were divided into three groups of 7 each; ES, foot-shock, and control. Chronic ES was induced by exposing the rats to witness foot-shock of their neighboring counterparts in the stress-box system in 5 successive days. 6 weeks after the last stress exposure, M-Mode echocardiographic assessment, qRT-PCR, and western blotting were performed in adult rats to determine the persistent effect of adolescent ES on cardiac performance and gene/protein expression levels of cardiac natriuretic peptide receptor 3 (NPR3) as a biomarker of CVD.
Results: Interventricular septum thicknesses in diastole (IVSd) increased from 0.152±0.007 cm to 0.197±0.016 cm (P<0.05), left ventricular posterior wall thickness in diastole (LVPWd) significantly enlarged from 0.169±0.006 cm to 0.288±0.033 cm (P<0.01), left ventricular posterior wall thickness in systole (LVPWs) enlarged from 0.223±0.012 cm to 0.318±0.038 cm (P<0.05), left ventricular mass increased from 1.000±0.024 g to 1.283±0.084 g (P<0.01), and mean heart rate elevated from 229.42±6.57 bpm to 280.29±10.45 bpm (P<0.01). Moreover, ES significantly upregulated the expression levels of cardiac NPR3 gene (P<0.01) and protein (P<0.01).
Conclusion: The incidence of adult CVD seemed to be increased under the influence of adolescent ES. Consequently, we suggest that mental healthcare during adolescence would be a critical factor for adult CVD prevention.


Main Subjects

1. Mendis S, Puska P, Norrving B. Global atlas on cardiovascular disease prevention and control: World Health Organization; 2011.
2. Kivimäki M, Steptoe A. Effects of stress on the development and progression of cardiovascular disease. Nat Rev Cardiol 2018; 15:215-299.
3. Steptoe A, Kivimäki M. Stress and cardiovascular disease: an update on current knowledge. Annu Rev Public Health 2013; 34:337-354.
4. Dayas CV, Buller KM, Crane JW, Xu Y, Day TA. Stressor categorization: acute physical and psychological stressors elicit distinctive recruitment patterns in the amygdala and in medullary noradrenergic cell groups. Eur J Neurosci 2001; 14:1143-1152.
5. Pyter LM, Kelly SD, Harrell CS, Neigh GN. Sex differences in the effects of adolescent stress on adult brain inflammatory markers in rats. Brain Behav Immun 2013; 30:88-94.
6. Watanabe H, Kodama M, Tanabe N, Nakamura Y, Nagai T, Sato M, et al. Impact of earthquakes on risk for pulmonary embolism. Int J Cardiol 2008; 129:152-154.
7. Strike P, Steptoe A. Systematic review of mental stress-induced myocardial ischaemia. Eur Heart J 2003; 24:690-703.
8. Wittstein IS, Thiemann DR, Lima JA, Baughman KL, Schulman SP, Gerstenblith G, et al. Neurohumoral features of myocardial stunning due to sudden emotional stress. N Engl J Med 2005; 352:539-548.
9. James P, Taggart P, McNally S, Newman S, Sporton S, Hardman S. Acute psychological stress and the propensity to ventricular arrhythmias. Evidence for a linking mechanism. Eur Heart J 2000; 21:1023-1028.
10. Peters MN, Seliger SL, Christenson RH, Hong‐Zohlman SN, Daniels LB, Lima JA, et al. “Malignant” left ventricular hypertrophy identifies subjects at high risk for progression to asymptomatic left ventricular dysfunction, heart failure, and death: MESA (Multi‐Ethnic Study of Atherosclerosis). J Am Heart Assoc 2018; 7:e006619.
11. Garg S, Drazner MH. Refining the classification of left ventricular hypertrophy to provide new insights into the progression from hypertension to heart failure. Curr Opin Cardiol 2016; 31:387-393.
12. McCullough PA, Chan CT, Weinhandl ED, Burkart JM, Bakris GL. Intensive hemodialysis, left ventricular hypertrophy, and cardiovascular disease. Am J Kidney Dis 2016; 68:S5-S14.
13. Potter LR, Yoder AR, Flora DR, Antos LK, Dickey DM. Natriuretic peptides: their structures, receptors, physiologic functions and therapeutic applications.  cGMP: Generators, Effectors and Therapeutic Implications: Springer; 2009. p. 341-366.
14. Pagel-Langenickel I. Evolving Role of Natriuretic Peptides from Diagnostic Tool to Therapeutic Modality.  2018.
15. Zayed MA, Harring SD, Abendschein DR, Vemuri C, Lu D, Detering L, et al. Natriuretic peptide Receptor-C is up-regulated in the intima of advanced carotid artery atherosclerosis. J Med Surg Pathol 2016; 1.
16. Egom EE-A, Feridooni T, Pharithi RB, Khan B, Maher V, El Hiani Y, et al. New insights and new hope for pulmonary arterial hypertension: natriuretic peptides clearance receptor as a novel therapeutic target for a complex disease. Int J Physiol Pathophysiol Pharmacol 2017; 9:112-118.
17. Venkatesan B, Tumala A, Subramanian V, Vellaichamy E. Transient silencing of Npr3 gene expression improved the circulatory levels of atrial natriuretic peptides and attenuated β-adrenoceptor activation-induced cardiac hypertrophic growth in experimental rats. Eur J Pharmacol 2016; 782:44-58.
18. Abuzaanona A, Lanfear D. Pharmacogenomics of the Natriuretic Peptide System in Heart Failure. Curr Heart Fail Rep 2017; 14:536-542.
19. Van den Berg CL, Lamberts RR, Wolterink G, Wiegant VM, Van Ree JM. Emotional and footshock stimuli induce differential long-lasting behavioural effects in rats; involvement of opioids. Brain Res 1998; 799:6-15.
20. Pijlman FT, Wolterink G, van Ree JM. Cueing unavoidable physical but not emotional stress increases long-term behavioural effects in rats. Behav Brain Res 2002; 134:393-401.
21. Campbell T, Lin S, DeVries C, Lambert K. Coping strategies in male and female rats exposed to multiple stressors. Physiol Behav 2003; 78:495-504.
22. Mora O, Cabrera M. Pheromonal male-induced diestrus and cyclicity in aging intact and young estrogenized female rats. Biol Reprod 1994; 50:603-606.
23. Marcondes FK, Miguel KJ, Melo LL, Spadari-Bratfisch RC. Estrous cycle influences the response of female rats in the elevated plus-maze test. Physiology & behavior 2001; 74:435-440.
24. Tousi SMTR, Faghihi M, Nobakht M, Molazem M, Kalantari E, Azar AD, et al. Improvement of heart failure by human amniotic mesenchymal stromal cell transplantation in rats. J Tehran Heart Cent 2016; 11:123-138.
25. Moult EM, Choi W, Boas DA, Baumann B, Clermont AC, Feener EP, et al. Evaluating anesthetic protocols for functional blood flow imaging in the rat eye. J Biomed Opt 2017; 22:016005.
26. Brown L, Fenning A, Chan V, Loch D, Wilson K, Anderson B, et al. Echocardiographic assessment of cardiac structure and function in rats. Heart Lung Circ 2002; 11:167-173.
27. Azar AD, Tavakoli F, Moladoust H, Zare A, Sadeghpour A. Echocardiographic evaluation of cardiac function in ischemic rats: value of m-mode echocardiography. Res Cardiovasc Med 2014; 3:1-5.
28. Parsa H, Imani A, Faghihi M, Riahi E, Badavi M, Shakoori A, et al. Acute sleep deprivation preconditions the heart against ischemia/reperfusion injury: the role of central GABA-A receptors. Iran J Basic Med Sci 2017; 20:1232-1241.
29. Mard SA, Veisi A, Ahangarpour A, Gharib-Naseri MK. Mucosal acidification increases hydrogen sulfide release through up-regulating gene and protein expressions of cystathionine gamma-lyase in the rat gastric mucosa. Iran J Basic Med Sci 2016; 19:172-177.
30. Berntson J, Patel JS, Stewart JC. Number of recent stressful life events and incident cardiovascular disease: Moderation by lifetime depressive disorder. J Psychosom Res 2017; 99: 149-154.
31. Bomhof-Roordink H, Seldenrijk A, van Hout HP, van Marwijk HW, Diamant M, Penninx BW. Associations between life stress and subclinical cardiovascular disease are partly mediated by depressive and anxiety symptoms. J Psychosom Res 2015; 78:332-339.
32. McEwen BS, Bowles NP, Gray JD, Hill MN, Hunter RG, Karatsoreos IN, et al. Mechanisms of stress in the brain. Nature neuroscience 2015; 18:1353-1363.
33. Chrousos GP, Loriaux DL, Gold PW. Mechanisms of physical and emotional stress: Springer Science & Business Media; 2013.
34. Dimsdale JE. Psychological stress and cardiovascular disease. J Am Coll Cardiol 2008; 51:1237-1246.
35. Roy MP, Kirschbaum C, Steptoe A. Psychological, cardiovascular, and metabolic correlates of individual differences in cortisol stress recovery in young men. Psychoneuroendocrinology 2001; 26:375-391.
36. Jafari M, Salehi M, Zardooz H, Rostamkhani F. Response of liver antioxidant defense system to acute and chronic physical and psychological stresses in male rats. EXCLI J 2014; 13:161-171.
37. Kalil B, Leite C, Carvalho-Lima M, Anselmo-Franci J. Role of sex steroids in progesterone and corticosterone response to acute restraint stress in rats: sex differences. Stress 2013; 16:452-460.
38. Katholi RE, Couri DM. Left ventricular hypertrophy: major risk factor in patients with hypertension: update and practical clinical applications. Int J Hypertens 2011; 2011.
39. Palatini P, Julius S. Elevated heart rate: a major risk factor for cardiovascular disease. Clin Exp Hypertens 2004; 26:637-644.
40. Cooney MT, Vartiainen E, Laakitainen T, Juolevi A, Dudina A, Graham IM. Elevated resting heart rate is an independent risk factor for cardiovascular disease in healthy men and women. Am Heart J 2010; 159:612-619. e613.
41. Koren MJ, Devereux RB, Casale PN, Savage DD, Laragh JH. Relation of left ventricular mass and geometry to morbidity and mortality in uncomplicated essential hypertension. Ann Intern Med 1991; 114:345-352.
42. Bluemke DA, Kronmal RA, Lima JA, Liu K, Olson J, Burke GL, et al. The relationship of left ventricular mass and geometry to incident cardiovascular events: the MESA (Multi-Ethnic Study of Atherosclerosis) study. J Am Coll Cardiol 2008; 52:2148-2155.
43. Slavich GM, Irwin MR. From stress to inflammation and major depressive disorder: A social signal transduction theory of depression. Psychol Bull 2014; 140:774-815.
44. Altekin E. Natriuretic peptide family as a” novel candidate marker” for the assessment of diagnosis, therapeutic response and prognosis in cardiovascular disease. Anadolu Kardiyol Derg 2007; 7:452-454.
45. Cruz FC, Duarte JO, Leão RM, Hummel LF, Planeta CS, Crestani CC. Adolescent vulnerability to cardiovascular consequences of chronic social stress: Immediate and long‐term effects of social isolation during adolescence. Dev Neurobiol 2016; 76:34-46.
46. Duarte JO, Planeta CS, Crestani CC. Immediate and long-term effects of psychological stress during adolescence in cardiovascular function: comparison of homotypic vs heterotypic stress regimens. Int J Dev Neurosci 2015; 40:52-59.
47. Meknatkhah S, Sharif Dashti P, Mousavi MS, Zeynali A, Ahmadian S, Karima S, et al. Psychological stress effects on myelin degradation in the cuprizone‐induced model of demyelination. Neuropathology 2019; 39:14-21.
48. Mousavi M-S, Riazi G, Imani A, Meknatkhah S, Fakhraei N, Pooyan S, et al. Comparative evaluation of adolescent repeated psychological or physical stress effects on adult cognitive performance, oxidative stress, and heart rate in female rats. Stress  2019; 22:123-132.