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(Stroke. 1996;27:1316-1318.)
© 1996 American Heart Association, Inc.

Articles

Autonomic Neuropathy Predicts the Development of Stroke in Patients With Non-Insulin-Dependent Diabetes Mellitus

Jari P. Toyry, MD; Leo K. Niskanen, MD; Esko A. Lansimies, MD; Kaarina P.L. Partanen, MD Matti I.J. Uusitupa, MD

the Departments of Clinical Physiology (J.P.T., E.A.L.), Clinical Nutrition (M.I.J.U.), Medicine (L.K.N.), and Clinical Radiology (K.P.L.P.), Kuopio University Hospital and University of Kuopio (Finland).

Correspondence to Jari Toyry, MD, Department of Clinical Physiology, Kuopio University Hospital, FIN 70210 Kuopio, Finland. E-mail jtoyry@messi.uku.fi.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose Our aim was to determine the predictive factors for stroke in patients with non–insulin-dependent diabetes mellitus (NIDDM).

Methods We studied 133 patients with NIDDM at the time of diagnosis and 5 and 10 years later.

Results The number of new fatal or nonfatal strokes was 19 (14.7%; 14 after 5-year examination). High initial fasting blood glucose (odds ratio [OR], 1.2; 95% confidence interval [CI], 1.04 to 1.4) and the use of ß-blocking agents (OR, 6.7; 95% CI, 2.1 to 21.5) at baseline and the presence of parasympathetic neuropathy (OR, 6.7; 95% CI, 1.5 to 29.9), or sympathetic autonomic nervous dysfunction (OR, 1.1; 95% CI, 1.01 to 1.2), hypertriglyceridemia (OR, 5.7; 95% CI, 1.1 to 31.0), or use of ß-blocking agents (OR, 6.4; 95% CI, 1.3 to 31.2), and high fasting plasma glucose (OR, 1.2; 95% CI, 1.0 to 1.5) determined at 5-year examination predicted the development of stroke.

Conclusions Autonomic neuropathy is an independent risk factor for stroke in NIDDM.

Key Words: autonomic dysfunctions • diabetes mellitus • neuropathies, hereditary sensory and autonomic • risk factors • stroke

	Introduction

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The frequency of ischemic stroke is increased in patients with NIDDM. In particular, diabetes has been associated with lacunar infarcts resulting from occlusion of small arteries.¹ The causes for this particular risk of stroke in diabetes are unclear, but some studies suggest that the duration and metabolic control of NIDDM could have an effect.² The role of autonomic neuropathy with respect to the development of stroke has not been studied, but autonomic neuropathy appears to be an independent risk factor for cardiovascular mortality.³ In the present study the impact of autonomic nervous function on the 10-year occurrence of stroke was examined in NIDDM patients diagnosed in 1979 to 1981.⁴

	Subjects and Methods

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Informed consent was given by the 133 subjects (70 men, 63 women) studied. The formation, representativeness, and methods of the baseline examination have been described previously.⁴ Approval for the study had been given by the Ethics Committee of Kuopio University Hospital.

For the present analysis, data from three examinations were used. At the baseline in 1979 to 1981, the following examinations were done: clinical history, anthropometric measurements, blood pressure, resting ECG, fasting blood glucose, serum lipids and lipoproteins, and parasympathetic nervous function. The 5-year examination performed in 1985 to 1986 included the same measurements and fasting plasma glucose, HbA_1C, and autonomic nervous function.³ At the 10-year examination in 1991 to 1992, the numbers of fatal and nonfatal strokes were ascertained from patient records and death certificates.⁵ CT had been performed in 18 cases. Body mass index was calculated as body weight (kilograms)/height (meters) squared. A conventional 12-lead resting ECG was interpreted according to the Minnesota code.⁶ Venous blood glucose was analyzed at baseline by the glucose-oxidase method (Glox, Kabi Ab), and plasma glucose at 5 years was analyzed by the glucose dehydrogenase method (Merck). Serum and lipoprotein lipids were determined from 12-hour fasting samples. Cholesterol and triglycerides were analyzed enzymatically.⁶ HbA_1C was measured by liquid cation chromatography (normal range, 4.0% to 6.0%).

Parasympathetic (deep breathing test at baseline and at 5-year examination) and sympathetic (orthostatic test at 5-year examination) tests were performed at approximately 9 to 10 AM after the subjects had fasted for 12 hours. In the deep breathing test, the subjects breathed with maximum vital capacity with a respiratory cycle of 10 seconds (0.1 Hz) while in the supine position. The ECG during breathing cycles was manually analyzed with a coordinate reader (Summagraphics 300), and the mean value of the ratios of the longest RR interval (expiration) to the shortest RR interval (inspiration) was considered the E/I ratio. In the orthostatic test, the subjects actively stood up after 5 minutes of rest in the supine position. Systolic blood pressure was measured at the end of rest and at 1 and 3 minutes of standing. Parasympathetic neuropathy was classified as an E/I ratio of 1.10 or less.³ Sympathetic autonomic nervous dysfunction was assessed as maximum decrease or minimum increase of systolic blood pressure (expressed in millimeters of mercury) during standing.³

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The total number of first strokes was 19 (10 lacunar infarcts on 17 blindly reanalyzed CTs) during the 10-year follow-up, of which 14 (9 lacunar infarcts on 14 CTs; 11 CTs after and 1 CT before the first stroke, 2 CTs after the second stroke) appeared after 5 years. The frequency of parasympathetic neuropathy was 19.6% and that of sympathetic neuropathy 6.8% at the 5-year examination.³ Factors associated with the development of stroke in univariate analysis are expressed in the Table. At the 5-year examination, HbA_1C did not differ between those who developed stroke and those who did not (9.6±2.7% versus 9.3±2.6%; P=.713).

View this table: [in this window] [in a new window]   Table 1. Factors Predicting the Development of Stroke in Univariate Analysis

The following baseline risk factors (associations in univariate analyses) were analyzed by forward stepwise multiple logistic regression: age, sex, body mass index, systolic blood pressure, the use of ß-blocking agents, fasting blood glucose, the prevalence of ischemic ECG changes, smoking history, serum high-density lipoprotein cholesterol, and serum total triglycerides (2.20 mmol/L or >2.20 mmol/L). The independent predictors for stroke were fasting blood glucose and the use of ß-blocking agents (19 strokes of 129). In the final model with parasympathetic neuropathy at 5-year examination, parasympathetic neuropathy, serum total triglycerides, and fasting plasma glucose emerged as independent predictors of stroke (Figure). The model with sympathetic autonomic nervous dysfunction showed that sympathetic autonomic nervous dysfunction (OR, 1.1; 95% CI, 1.01 to 1.2; P=.021; ie, a 10 mm Hg decline in systolic blood pressure in the orthostatic test doubles the risk), the use of ß-blocking agents (OR, 6.4; 95% CI, 1.3 to 31.2; P=.021), and fasting plasma glucose (OR, 1.3; 95% CI, 1.1 to 1.6; P=.013) were independent predictors of stroke (11 strokes of 98). In addition, parasympathetic neuropathy at 5-year examination was more frequent in stroke patients with lacunar infarct (3 of 6; 50%) than in patients without stroke (13 of 85; 15.3%; P=.032).

View larger version (28K): [in this window] [in a new window]   Figure 1. a, In forward stepwise multiple logistic regression analysis, fasting blood glucose (OR, 1.2; 95% CI, 1.04 to 1.4; P=.013) and the use of ß-blocking agents (OR, 6.7; 95% CI, 2.1 to 21.5; P=.001) independently predicted the development of stroke at baseline (n=19). b, Fasting plasma glucose (OR, 1.2; 95% CI, 1.0 to 1.5; P=.051), parasympathetic neuropathy (OR, 6.7; 95% CI, 1.5 to 29.9; P=.012), and hypertriglyceridemia (OR, 5.7; 95% CI, 1.1 to 31.0; P=.042) independently predicted the development of stroke at the 5-year examination (n=11). See text for factors included in the model.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Our novel finding was that both parasympathetic and sympathetic autonomic nervous dysfunctions determined after 5 years from the detection of NIDDM were independent predictors of stroke. Because autonomic nervous dysfunction is associated with obesity, coronary heart disease, and poor metabolic control,³ we cannot rule out the possibility that the observed association between autonomic nervous dysfunction and the development of stroke could be in part ascribed to these disorders. However, according to multiple logistic regression analyses, the impact of autonomic nervous dysfunction on the risk of stroke was not mediated by these factors alone. Other predictors of stroke were elevated glucose and triglyceride levels, which confirmed recent observations.² The use of ß-blocking agents also emerged as a risk factor, although most likely their use reflects underlying diseases, eg, hypertension and coronary heart disease.

Diabetic patients have defects in increasing blood flow to a vasodilating stimulus such as carbon dioxide.⁷ In animal models during cerebral ischemia, parasympathetic denervation of pial vessels predisposes to increased infarct size.^{8 9} Thus, our observations provide direct support for the suggestion that autonomic neuropathy through several mechanisms¹⁰ could markedly increase the risk of stroke in NIDDM. This study also suggests that lacunar infarcts, which are common in diabetes,¹ could be related to autonomic neuropathy.

	Selected Abbreviations and Acronyms

 

CI = confidence interval ECG = electrocardiogram HbA1C = glycosylated hemoblobin A1C NIDDM = non–insulin-dependent diabetes mellitus OR = odds ratio

	Acknowledgments

 
This study was supported by grants from the Finnish Foundation of Diabetes Research and Medical Council, Academy of Finland (Dr Uusitupa).

Received March 18, 1996; revision received May 9, 1996; accepted May 10, 1996.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 
1. Mast H, Thompson JLP, Lee SH, Mohr JP, Sacco RL. Hypertension and diabetes mellitus as determinants of multiple lacunar infarcts. Stroke. 1995;26:30-33.[Abstract/Free Full Text]

2. Kuusisto J, Mykkanen L, Pyorala K, Laakso M. Non–insulin-dependent diabetes and its metabolic control are important predictors of stroke in elderly subjects. Stroke. 1994;25:1157-1164.[Abstract]

3. Toyry JP, Niskanen LK, Mantysaari MJ, Lansimies EA, Uusitupa MIJ. Occurrence, predictors, and clinical significance of autonomic neuropathy in NIDDM: ten-year follow-up from the diagnosis. Diabetes. 1996;45:308-315.[Abstract]

4. Uusitupa M, Siitonen O, Pyorala K, Aro A, Hersio K, Penttila I, Voutilainen E. The relationship of cardiovascular risk factors to the prevalence of coronary heart disease in newly diagnosed type 2 (non-insulin-dependent) diabetes. Diabetologia. 1985;28:653-659.[Medline] [Order article via Infotrieve]

5. World Health Organization. International Classification of Diseases, 9th Revision, 1975: Manual of International Statistical Classification of Diseases, Injuries, and Causes of Death. Geneva, Switzerland: World Health Organization; 1977-1978.

6. Uusitupa MIJ, Niskanen LK, Siitonen O, Voutilainen E, Pyorala K. Ten-year cardiovascular mortality in relation to risk factors and abnormalities in lipoprotein composition in type 2 (non-insulin-dependent) diabetic and non-diabetic subjects. Diabetologia. 1993;36:1175-1184.[Medline] [Order article via Infotrieve]

7. Dandona P, James IM, Newburg PA, Wollard ML, Beckett AG. Cerebral blood flow in diabetes mellitus: evidence of abnormal cerebrovascular reactivity. Br Med J. 1978;2:325-326.

8. Kano M, Moskowitz MA, Yokota M. Parasympathetic denervation of rat pial vessels significantly increases infarction volume following middle cerebral artery occlusion. J Cereb Blood Flow Metab. 1991;11:628-637.[Medline] [Order article via Infotrieve]

9. Koketsu N, Moskowitz MA, Kontos HA, Yokota M, Shimizu T. Chronic parasympathetic sectioning decreases regional cerebral blood flow during hemorrhagic hypotension and increases infarct size after middle cerebral artery occlusion in spontaneously hypertensive rats. J Cereb Blood Flow Metab. 1992;12:613-620.[Medline] [Order article via Infotrieve]

10. Bell DSH. Stroke in the diabetic patient. Diabetes Care. 1994;17:213-219.[Abstract]

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