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08-02-2018 | Cardiovascular disorders | Article

Progression of cardiovascular autonomic neuropathy and cardiovascular disease in type 2 diabetes

Journal: Cardiovascular Diabetology

Authors: Jae-Seung Yun, Yong-Moon Park, Seon-Ah Cha, Yu-Bae Ahn, Seung-Hyun Ko

Publisher: BioMed Central




To examine whether the progression rate of cardiovascular autonomic neuropathy (CAN) stage is an independent predictive factor for cardiovascular disease (CVD) in type 2 diabetes.


Standardized cardiovascular autonomic reflex tests (CARTs) using traditional Ewing method were performed at baseline. The follow-up CARTs was recommended once every two years. We estimated the primary CVD endpoint, defined as coronary artery disease and ischemic stroke. The association between the progression rate of CAN stage and CVD was examined using time-dependent Cox proportional hazard models.


At baseline, 578 patients completed follow-up CARTs; the cohort comprised 329 women (56.9%) with a mean age of 58.3 ± 10.3 years and a mean diabetes duration of 10.1 ± 6.2 years. One hundred and seventy-six patients (30.4%) developed CAN progression between baseline and follow-up CARTs. In the multivariable Cox proportional hazards regression analysis, patients with CAN progression demonstrated a 3.32 times higher risk (95% confidence interval, CI 1.81–6.14, P < 0.001) of CVD than those without CAN progression. Patients who experienced CAN progression from the normal to definite stage had the greatest risk of CVD compared to other patients (hazard ratio 4.91, 95% CI 2.05–11.77, P for trend = 0.001).


CAN stage progression was associated with an increased risk of CVD in this type 2 diabetes cohort. Patients with rapid CAN progression had the greatest risk of CVD. Thus, regular screening and risk management of CAN progression is necessary to prevent CVD.
Vinik AI, Ziegler D. Diabetic cardiovascular autonomic neuropathy. Circulation. 2007;115(3):387–97. CrossRefPubMed
Pop-Busui R. Cardiac autonomic neuropathy in diabetes: a clinical perspective. Diab Care. 2010;33(2):434–41. CrossRef
Kuehl M, Stevens MJ. Cardiovascular autonomic neuropathies as complications of diabetes mellitus. Nat Rev Endocrinol. 2012;8(7):405–16. CrossRefPubMed
Maser RE, Lenhard MJ. Cardiovascular autonomic neuropathy due to diabetes mellitus: clinical manifestations, consequences, and treatment. J Clin Endocrinol Metabol. 2005;90(10):5896–903. CrossRef
Fisher VL, Tahrani AA. Cardiac autonomic neuropathy in patients with diabetes mellitus: current perspectives. Diab Metab Syndr Obes. 2017;10:419–34. CrossRef
Tesfaye S, Boulton AJ, Dyck PJ, Freeman R, Horowitz M, Kempler P, Lauria G, Malik RA, Spallone V, Vinik A, et al. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diab Care. 2010;33(10):2285–93. CrossRef
Spallone V, Ziegler D, Freeman R, Bernardi L, Frontoni S, Pop-Busui R, Stevens M, Kempler P, Hilsted J, Tesfaye S, et al. Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management. Diabetes/metabolism research and reviews. 2011;27(7):639–53. CrossRefPubMed
Vinik AI, Maser RE, Mitchell BD, Freeman R. Diabetic autonomic neuropathy. Diab Care. 2003;26(5):1553–79. CrossRef
Ewing DJ, Campbell IW, Clarke BF. Assessment of cardiovascular effects in diabetic autonomic neuropathy and prognostic implications. Ann Intern Med. 1980;92(2 Pt 2):308–11. CrossRefPubMed
Pop-Busui R, Evans GW, Gerstein HC, Fonseca V, Fleg JL, Hoogwerf BJ, Genuth S, Grimm RH, Corson MA, Prineas R. Effects of cardiac autonomic dysfunction on mortality risk in the action to control cardiovascular risk in diabetes (ACCORD) trial. Diab Care. 2010;33(7):1578–84. CrossRef
Yun JS, Ahn YB, Song KH, Yoo KD, Kim HW, Park YM, Ko SH. The association between abnormal heart rate variability and new onset of chronic kidney disease in patients with type 2 diabetes: a 10-year follow-up study. Diab Res Clin Pract. 2015;108(1):31–7. CrossRef
Yun JS, Kim JH, Song KH, Ahn YB, Yoon KH, Yoo KD, Park YM, Ko SH. Cardiovascular autonomic dysfunction predicts severe hypoglycemia in patients with type 2 diabetes: a 10-year follow-up study. Diab Care. 2014;37(1):235–41. CrossRef
Cha SA, Yun JS, Lim TS, Min K, Song KH, Yoo KD, Park YM, Ahn YB, Ko SH. Diabetic cardiovascular autonomic neuropathy predicts recurrent cardiovascular diseases in patients with type 2 diabetes. PLoS ONE. 2016;11(10):e0164807. CrossRefPubMedPubMedCentral
Wackers FJ, Young LH, Inzucchi SE, Chyun DA, Davey JA, Barrett EJ, Taillefer R, Wittlin SD, Heller GV, Filipchuk N, et al. Detection of silent myocardial ischemia in asymptomatic diabetic subjects: the DIAD study. Diab Care. 2004;27(8):1954–61. CrossRef
Miettinen H, Lehto S, Salomaa V, Mahonen M, Niemela M, Haffner SM, Pyorala K, Tuomilehto J. Impact of diabetes on mortality after the first myocardial infarction. The FINMONICA Myocardial Infarction Register Study Group. Diab Care. 1998;21(1):69–75. CrossRef
Boulton AJ, Vinik AI, Arezzo JC, Bril V, Feldman EL, Freeman R, Malik RA, Maser RE, Sosenko JM, Ziegler D. Diabetic neuropathies: a statement by the American Diabetes Association. Diab Care. 2005;28(4):956–62. CrossRef
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek JW, Eggers P, Van Lente F, Greene T, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604–12. CrossRefPubMedPubMedCentral
Koivisto VA, Stevens LK, Mattock M, Ebeling P, Muggeo M, Stephenson J, Idzior-Walus B. Cardiovascular disease and its risk factors in IDDM in Europe. EURODIAB IDDM Complications Study Group. Diab Care. 1996;19(7):689–97. CrossRef
Desouza CV, Bolli GB, Fonseca V. Hypoglycemia, diabetes, and cardiovascular events. Diab Care. 2010;33(6):1389–94. CrossRef
Jun JE, Lee SE, Lee YB, Ahn JY, Kim G, Jin SM, Hur KY, Lee MK, Kim JH. Glycated albumin and its variability as an indicator of cardiovascular autonomic neuropathy development in type 2 diabetic patients. Cardiovasc Diabetol. 2017;16(1):127. CrossRefPubMedPubMedCentral
Shimabukuro M, Tanaka A, Sata M, Dai K, Shibata Y, Inoue Y, Ikenaga H, Kishimoto S, Ogasawara K, Takashima A, et al. alpha-Glucosidase inhibitor miglitol attenuates glucose fluctuation, heart rate variability and sympathetic activity in patients with type 2 diabetes and acute coronary syndrome: a multicenter randomized controlled (MACS) study. Cardiovasc Diabetol. 2017;16(1):86. CrossRefPubMedPubMedCentral
Jaiswal M, Divers J, Urbina EM, Dabelea D, Bell RA, Pettitt DJ, Imperatore G, Pihoker C, Dolan LM, Liese AD, et al. Cardiovascular autonomic neuropathy in adolescents and young adults with type 1 and type 2 diabetes: the SEARCH for Diabetes in Youth Cohort Study. Pediatr Diab. 2018;19(4):680–9. CrossRef
Chung JO, Park SY, Han JH, Cho DH, Chung DJ, Chung MY. Serum apolipoprotein A-1 concentrations and the prevalence of cardiovascular autonomic neuropathy in individuals with type 2 diabetes. J Diab Compl. 2018;32(4):357–61. CrossRef
Low PA, Benrud-Larson LM, Sletten DM, Opfer-Gehrking TL, Weigand SD, O’Brien PC, Suarez GA, Dyck PJ. Autonomic symptoms and diabetic neuropathy: a population-based study. Diab Care. 2004;27(12):2942–7. CrossRef
Pop-Busui R, Low PA, Waberski BH, Martin CL, Albers JW, Feldman EL, Sommer C, Cleary PA, Lachin JM, Herman WH. Effects of prior intensive insulin therapy on cardiac autonomic nervous system function in type 1 diabetes mellitus: the diabetes control and complications trial/epidemiology of diabetes interventions and complications study (DCCT/EDIC). Circulation. 2009;119(22):2886–93. CrossRefPubMedPubMedCentral
Valensi P, Paries J, Attali JR. Cardiac autonomic neuropathy in diabetic patients: influence of diabetes duration, obesity, and microangiopathic complications–the French multicenter study. Metab Clin Exp. 2003;52(7):815–20. CrossRefPubMed
Gaede P, Vedel P, Parving HH, Pedersen O. Intensified multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: the Steno type 2 randomised study. Lancet. 1999;353(9153):617–22. CrossRefPubMed
Boulton AJ, Malik RA, Arezzo JC, Sosenko JM. Diabetic somatic neuropathies. Diab Care. 2004;27(6):1458–86. CrossRef
Ko SH, Song KH, Park SA, Kim SR, Cha BY, Son HY, Moon KW, Yoo KD, Park YM, Cho JH, et al. Cardiovascular autonomic dysfunction predicts acute ischaemic stroke in patients with Type 2 diabetes mellitus: a 7-year follow-up study. Diab Med. 2008;25(10):1171–7. CrossRef
Shakespeare CF, Katritsis D, Crowther A, Cooper IC, Coltart JD, Webb-Peploe MW. Differences in autonomic nerve function in patients with silent and symptomatic myocardial ischaemia. Br Heart J. 1994;71(1):22–9. CrossRefPubMedPubMedCentral
Schonauer M, Thomas A, Morbach S, Niebauer J, Schonauer U, Thiele H. Cardiac autonomic diabetic neuropathy. Diab Vasc Dis Res. 2008;5(4):336–44. CrossRefPubMed
Paulson DJ, Light KE. Elevation of serum and ventricular norepinephrine content in the diabetic rat. Res Commun Chem Pathol Pharmacol. 1981;33(3):559–62. PubMed
Felten SY, Peterson RG, Shea PA, Besch HR Jr, Felten DL. Effects of streptozotocin diabetes on the noradrenergic innervation of the rat heart: a longitudinal histofluorescence and neurochemical study. Brain Res Bull. 1982;8(6):593–607. CrossRefPubMed
Givertz MM, Sawyer DB, Colucci WS. Antioxidants and myocardial contractility: illuminating the “Dark Side” of beta-adrenergic receptor activation? Circulation. 2001;103(6):782–3. CrossRefPubMed
Eichhorn EJ, Bristow MR. Medical therapy can improve the biological properties of the chronically failing heart. A new era in the treatment of heart failure. Circulation. 1996;94(9):2285–96. CrossRefPubMed
Bristow MR. Mechanistic and clinical rationales for using beta-blockers in heart failure. J Cardiac Fail. 2000;6(2 Suppl 1):8–14.
Morita-Tsuzuki Y, Hardebo JE, Bouskela E. Interaction between cerebrovascular sympathetic, parasympathetic and sensory nerves in blood flow regulation. J Vasc Res. 1993;30(5):263–71. CrossRefPubMed
Gorst C, Kwok CS, Aslam S, Buchan I, Kontopantelis E, Myint PK, Heatlie G, Loke Y, Rutter MK, Mamas MA. Long-term glycemic variability and risk of adverse outcomes: a systematic review and meta-analysis. Diab Care. 2015;38(12):2354–69. CrossRef

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