Endocrinol Metab.  2013 Dec;28(4):309-319. 10.3803/EnM.2013.28.4.309.

Association between Cardiac Autonomic Neuropathy, Diabetic Retinopathy and Carotid Atherosclerosis in Patients with Type 2 Diabetes

• Jung CH
• Baek AR
• Kim KJ
• Kim BY
• Kim CH
• Kang SK
• Mok JO

• KMID: 2169309
• DOI: http://doi.org/10.3803/EnM.2013.28.4.309

Abstract

BACKGROUND
It is not clear whether microangiopathies are associated with subclinical atherosclerosis in type 2 diabetes mellitus (T2DM). We investigated the relation of cardiac autonomic neuropathy (CAN) and other microangiopathies with carotid atherosclerosis in T2DM.
METHODS
A total of 131 patients with T2DM were stratified by mean carotid intima-media thickness (CIMT) > or = or <1.0 mm and the number of carotid plaques. CAN was assessed by the five standard cardiovascular reflex tests according to the Ewing's protocol. CAN was defined as the presence of at least two abnormal tests or an autonomic neuropathy points > or =2. Diabetic microangiopathies were assessed.
RESULTS
Patients with CAN comprised 77% of the group with mean CIMT > or =1.0 mm, while they were 29% of the group with CIMT <1.0 mm (P=0.016). Patients with diabetic retinopathy (DR) comprised 68% of the group with CIMT > or =1.0 mm, while they were 28% of the group without CIMT thickening (P=0.003). Patients with CAN comprised 51% of the group with > or =2 carotid plaques, while they were 23% of the group with < or =1 carotid plaque (P=0.014). In multivariable adjusted logistic regression analysis, the patients who presented with CAN showed an odds ratio [OR] of 8.6 (95% confidence interval [CI], 1.6 to 44.8) for CIMT thickening and an OR of 2.9 (95% CI, 1.1 to 7.5) for carotid plaques. Furthermore, patients with DR were 3.8 times (95% CI, 1.4 to 10.2) more likely to have CIMT thickening.
CONCLUSION
These results suggest that CAN is associated with carotid atherosclerosis, represented as CIMT and plaques, independent of the traditional cardiovascular risk factors in T2DM. CAN or DR may be a determinant of subclinical atherosclerosis in T2DM.

Keyword

Cardiac autonomic neuropathy; Diabetic angiopathies; Carotid intima-media thickness; Carotid plaque; Diabetes mellitus, type 2

MeSH Terms

Atherosclerosis
Carotid Artery Diseases*
Carotid Intima-Media Thickness
Diabetes Mellitus, Type 2
Diabetic Angiopathies
Diabetic Neuropathies*
Diabetic Retinopathy
Humans
Logistic Models
Odds Ratio
Reflex
Risk Factors

Reference

1. Geiss LS, Herman WH, Smith PJ. National Diabetes Data Group. Diabetes in America. Bethesda: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney diseases;1995. p. 233–257.

2. Fuller JH, Stevens LK, Wang SL. Risk factors for cardiovascular mortality and morbidity: the WHO Mutinational Study of Vascular Disease in Diabetes. Diabetologia. 2001; 44:Suppl 2. S54–S64.

3. de Kreutzenberg SV, Coracina A, Volpi A, Fadini GP, Frigo AC, Guarneri G, Tiengo A, Avogaro A. Microangiopathy is independently associated with presence, severity and composition of carotid atherosclerosis in type 2 diabetes. Nutr Metab Cardiovasc Dis. 2011; 21:286–293.

4. Malecki MT, Osmenda G, Walus-Miarka M, Skupien J, Cyganek K, Mirkiewicz-Sieradzka B, damek-Guzik TA, Guzik TJ, Sieradzki J. Retinopathy in type 2 diabetes mellitus is associated with increased intima-media thickness and endothelial dysfunction. Eur J Clin Invest. 2008; 38:925–930.

5. Yokoyama H, Aoki T, Imahori M, Kuramitsu M. Subclinical atherosclerosis is increased in type 2 diabetic patients with microalbuminuria evaluated by intima-media thickness and pulse wave velocity. Kidney Int. 2004; 66:448–454.

6. Bots ML, Hoes AW, Koudstaal PJ, Hofman A, Grobbee DE. Common carotid intima-media thickness and risk of stroke and myocardial infarction: the Rotterdam Study. Circulation. 1997; 96:1432–1437.

7. Fleg JL, Mete M, Howard BV, Umans JG, Roman MJ, Ratner RE, Silverman A, Galloway JM, Henderson JA, Weir MR, Wilson C, Stylianou M, Howard WJ. Effect of statins alone versus statins plus ezetimibe on carotid atherosclerosis in type 2 diabetes: the SANDS (Stop Atherosclerosis in Native Diabetics Study) trial. J Am Coll Cardiol. 2008; 52:2198–2205.

8. Wyman RA, Fraizer MC, Keevil JG, Busse KL, Aeschlimann SE, Korcarz CE, Stein JH. Ultrasound-detected carotid plaque as a screening tool for advanced subclinical atherosclerosis. Am Heart J. 2005; 150:1081–1085.

9. Maser RE, Lenhard MJ. Cardiovascular autonomic neuropathy due to diabetes mellitus: clinical manifestations, consequences, and treatment. J Clin Endocrinol Metab. 2005; 90:5896–5903.

10. Gerritsen J, Dekker JM, TenVoorde BJ, Kostense PJ, Heine RJ, Bouter LM, Heethaar RM, Stehouwer CD. Impaired autonomic function is associated with increased mortality, especially in subjects with diabetes, hypertension, or a history of cardiovascular disease: the Hoorn Study. Diabetes Care. 2001; 24:1793–1798.

11. Meyer C, Milat F, McGrath BP, Cameron J, Kotsopoulos D, Teede HJ. Vascular dysfunction and autonomic neuropathy in Type 2 diabetes. Diabet Med. 2004; 21:746–751.

12. Gottsater A, Ahlgren AR, Taimour S, Sundkvist G. Decreased heart rate variability may predict the progression of carotid atherosclerosis in type 2 diabetes. Clin Auton Res. 2006; 16:228–234.

13. Ito H, Komatsu Y, Mifune M, Antoku S, Ishida H, Takeuchi Y, Togane M. The estimated GFR, but not the stage of diabetic nephropathy graded by the urinary albumin excretion, is associated with the carotid intima-media thickness in patients with type 2 diabetes mellitus: a cross-sectional study. Cardiovasc Diabetol. 2010; 9:18.

14. Nomura M, Kasami R, Ohashi M, Yamada Y, Abe H. Significantly higher incidence of carotid atherosclerosis found in Japanese type 2 diabetic patients with early nephropathy. Diabetes Res Clin Pract. 2004; 66:Suppl 1. S161–S163.

15. Juutilainen A, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Retinopathy predicts cardiovascular mortality in type 2 diabetic men and women. Diabetes Care. 2007; 30:292–299.

16. Cheung N, Wang JJ, Klein R, Couper DJ, Sharrett AR, Wong TY. Diabetic retinopathy and the risk of coronary heart disease: the Atherosclerosis Risk in Communities Study. Diabetes Care. 2007; 30:1742–1746.

17. Klein R, Sharrett AR, Klein BE, Moss SE, Folsom AR, Wong TY, Brancati FL, Hubbard LD, Couper D. ARIC Group. The association of atherosclerosis, vascular risk factors, and retinopathy in adults with diabetes: the atherosclerosis risk in communities study. Ophthalmology. 2002; 109:1225–1234.

18. Rema M, Mohan V, Deepa R, Ravikumar R. Chennai Urban Rural Epidemiology Study-2. Association of carotid intima-media thickness and arterial stiffness with diabetic retinopathy: the Chennai Urban Rural Epidemiology Study (CURES-2). Diabetes Care. 2004; 27:1962–1967.

19. Kawasaki R, Cheung N, Islam FM, Klein R, Klein BE, Cotch MF, Sharrett AR, O'Leary D, Wong TY. Multi-Ethnic Study of Atherosclerosis. Is diabetic retinopathy related to subclinical cardiovascular disease? Ophthalmology. 2011; 118:860–865.

20. Chambless LE, Folsom AR, Clegg LX, Sharrett AR, Shahar E, Nieto FJ, Rosamond WD, Evans G. Carotid wall thickness is predictive of incident clinical stroke: the Atherosclerosis Risk in Communities (ARIC) study. Am J Epidemiol. 2000; 151:478–487.

21. Chambless LE, Heiss G, Folsom AR, Rosamond W, Szklo M, Sharrett AR, Clegg LX. Association of coronary heart disease incidence with carotid arterial wall thickness and major risk factors: the Atherosclerosis Risk in Communities (ARIC) Study, 1987-1993. Am J Epidemiol. 1997; 146:483–494.

22. Valensi P, Paries J, Attali JR. French Group for Research and Study of Diabetic Neuropathy. Cardiac autonomic neuropathy in diabetic patients: influence of diabetes duration, obesity, and microangiopathic complications: the French multicenter study. Metabolism. 2003; 52:815–820.

23. Ewing DJ, Martyn CN, Young RJ, Clarke BF. The value of cardiovascular autonomic function tests: 10 years experience in diabetes. Diabetes Care. 1985; 8:491–498.

24. Bellavere F, Bosello G, Fedele D, Cardone C, Ferri M. Diagnosis and management of diabetic autonomic neuropathy. Br Med J (Clin Res Ed). 1983; 287:61.

25. O'Brien IA, O'Hare JP, Lewin IG, Corrall RJ. The prevalence of autonomic neuropathy in insulin-dependent diabetes mellitus: a controlled study based on heart rate variability. Q J Med. 1986; 61:957–967.

26. Levey AS, Coresh J, Balk E, Kausz AT, Levin A, Steffes MW, Hogg RJ, Perrone RD, Lau J, Eknoyan G. National Kidney Foundation. National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med. 2003; 139:137–147.

27. Lorenz MW, Markus HS, Bots ML, Rosvall M, Sitzer M. Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis. Circulation. 2007; 115:459–467.

28. Gottsater A, Ryden-Ahlgren A, Szelag B, Hedblad B, Persson J, Berglund G, Wroblewski M, Sundkvist G. Cardiovascular autonomic neuropathy associated with carotid atherosclerosis in Type 2 diabetic patients. Diabet Med. 2003; 20:495–499.

29. Gottsater A, Szelag B, Berglund G, Wroblewski M, Sundkvist G. Changing associations between progressive cardiovascular autonomic neuropathy and carotid atherosclerosis with increasing duration of type 2 diabetes mellitus. J Diabetes Complications. 2005; 19:212–217.

30. Klein R, Marino EK, Kuller LH, Polak JF, Tracy RP, Gottdiener JS, Burke GL, Hubbard LD, Boineau R. The relation of atherosclerotic cardiovascular disease to retinopathy in people with diabetes in the Cardiovascular Health Study. Br J Ophthalmol. 2002; 86:84–90.

31. Miyamoto M, Kotani K, Okada K, Fujii Y, Konno K, Ishibashi S, Taniguchi N. The correlation of common carotid arterial diameter with atherosclerosis and diabetic retinopathy in patients with type 2 diabetes mellitus. Acta Diabetol. 2012; 49:63–68.

32. Bonithon-Kopp C, Touboul PJ, Berr C, Leroux C, Mainard F, Courbon D, Ducimetiere P. The Vascular Aging (EVA) Study. Relation of intima-media thickness to atherosclerotic plaques in carotid arteries. Arterioscler Thromb Vasc Biol. 1996; 16:310–316.

33. Ebrahim S, Papacosta O, Whincup P, Wannamethee G, Walker M, Nicolaides AN, Dhanjil S, Griffin M, Belcaro G, Rumley A, Lowe GD. Carotid plaque, intima media thickness, cardiovascular risk factors, and prevalent cardiovascular disease in men and women: the British Regional Heart Study. Stroke. 1999; 30:841–850.

34. Sun Y, Lin CH, Lu CJ, Yip PK, Chen RC. Carotid atherosclerosis, intima media thickness and risk factors: an analysis of 1781 asymptomatic subjects in Taiwan. Atherosclerosis. 2002; 164:89–94.

35. Bedi US, Singh M, Singh PP, Bhuriya R, Bahekar A, Molnar J, Khosla S, Arora R. Effects of statins on progression of carotid atherosclerosis as measured by carotid intimal: medial thickness: a meta-analysis of randomized controlled trials. J Cardiovasc Pharmacol Ther. 2010; 15:268–273.

36. Kalinowski L, Matys T, Chabielska E, Buczko W, Malinski T. Angiotensin II AT1 receptor antagonists inhibit platelet adhesion and aggregation by nitric oxide release. Hypertension. 2002; 40:521–527.

37. Wang JG, Staessen JA, Li Y, Van Bortel LM, Nawrot T, Fagard R, Messerli FH, Safar M. Carotid intima-media thickness and antihypertensive treatment: a meta-analysis of randomized controlled trials. Stroke. 2006; 37:1933–1940.

38. Taniwaki H, Nishizawa Y, Kawagishi T, Ishimura E, Emoto M, Okamura T, Okuno Y, Morii H. Decrease in glomerular filtration rate in Japanese patients with type 2 diabetes is linked to atherosclerosis. Diabetes Care. 1998; 21:1848–1855.

39. Mattock MB, Morrish NJ, Viberti G, Keen H, Fitzgerald AP, Jackson G. Prospective study of microalbuminuria as predictor of mortality in NIDDM. Diabetes. 1992; 41:736–741.

40. Park SW, Kim SK, Cho YW, Kim DJ, Song YD, Choi YJ, Huh BW, Choi SH, Jee SH, Cho MA, Lee EJ, Huh KB. Insulin resistance and carotid atherosclerosis in patients with type 2 diabetes. Atherosclerosis. 2009; 205:309–313.

41. Ishizaka N, Ishizaka Y, Takahashi E, Unuma T, Tooda E, Nagai R, Togo M, Tsukamoto K, Hashimoto H, Yamakado M. Association between insulin resistance and carotid arteriosclerosis in subjects with normal fasting glucose and normal glucose tolerance. Arterioscler Thromb Vasc Biol. 2003; 23:295–301.

42. Shinozaki K, Hattori Y, Suzuki M, Hara Y, Kanazawa A, Takaki H, Tsushima M, Harano Y. Insulin resistance as an independent risk factor for carotid artery wall intima media thickening in vasospastic angina. Arterioscler Thromb Vasc Biol. 1997; 17:3302–3310.

43. Zureik M, Touboul PJ, Bonithon-Kopp C, Courbon D, Ruelland I, Ducimetiere P. Differential association of common carotid intima-media thickness and carotid atherosclerotic plaques with parental history of premature death from coronary heart disease: the EVA study. Arterioscler Thromb Vasc Biol. 1999; 19:366–371.

44. Cruickshank K, Riste L, Anderson SG, Wright JS, Dunn G, Gosling RG. Aortic pulse-wave velocity and its relationship to mortality in diabetes and glucose intolerance: an integrated index of vascular function? Circulation. 2002; 106:2085–2090.

45. van Popele NM, Grobbee DE, Bots ML, Asmar R, Topouchian J, Reneman RS, Hoeks AP, van der Kuip DA, Hofman A, Witteman JC. Association between arterial stiffness and atherosclerosis: the Rotterdam Study. Stroke. 2001; 32:454–460.

46. Taniwaki H, Kawagishi T, Emoto M, Shoji T, Kanda H, Maekawa K, Nishizawa Y, Morii H. Correlation between the intima-media thickness of the carotid artery and aortic pulse-wave velocity in patients with type 2 diabetes. Vessel wall properties in type 2 diabetes. Diabetes Care. 1999; 22:1851–1857.