Proliferative diabetic retinopathy is related to cardiovascular autonomic neuropathy in non-insulin-dependent diabetes mellitus

Diabetes Research and Clinical Practice 29 (1995) 163-168

Proliferative diabetic retinopathy is related to cardiovascular autonomic neuropathy in non-insulin-dependent diabetes mellitus Helena Schmid*, Beatriz Schaan, Flavia Cecconello, Tatiana Maestri, Cristina Neumann Endocrinology Division, Hospital de Clinicas de Porto Alegre, Federal University of Rio Grande do SU/ Porto Alegre, R.‘j, Brazil Received 19 April

1995; revision received IO July 1995; accepted 25 July 1995

Abstract

The aim of the study was to define the relationship between the presenceof proliferative diabetic retinopathy and nephropathy with objectively defined autonomic neuropathy in non-insulin-dependent diabetes mellitus (NIDDM) patients. The research design used was a cross-sectional, case control study. A cohort of NIDDM patients was classified, according to live cardiovascular autonomic tests described by Ewing, as: (1) no involvement - no abnormal tests (n = 17); (2) cardiovascular autonomic neuropathy - two out of five abnormal tests (n = 18). Age, age at diagnosis, plasma creatinine, fasting plasma glucose, glycated haemoglobin and blood pressure measurementswere not statistically different among the two groups. According to indirect ophthalmoscopy and the presenceof macroproteinuria and microalbuminuria, respectively, patients were also classified as having proliferative, non-proliferative or no retinopathy and with or without nephropathy. The results showed a striking relationship between cardiovascular autonomic neuropathy and proliferative diabetic retinopathy. Relative odds for nephropathy, non-proliferative diabetic retinopathy and proliferative retinopathy were, respectively, 16.0, 10.1 and 34.7. When odds ratios were adjusted for the presenceof nephropathy, hypertension, non-proliferative and proliferative retinopathy, only proliferative retinopathy was significantly associated(odds ratio, 7.1). It was concluded that in NIDDM the presenceof cardiovascular autonomic neuropathy is strongly associated with proliferative retinopathy. Long-term prospective studies on large cohorts of patients must be done to evaluate if having autonomic dysfunction would be a risk factor or a risk indicator of an etiologic process underlying the development of proliferative retinopathy. Keywords: Autonomic neuropathy; Cardiovascular autonomic neuropathy; Diabetes mellitus; Proliferative retinopathy; Non-insulin-dependent diabetes mellitus

1. Introduction l

Corresponding author, Curso de P6s-Graduaqao em Medicina, Clinica MCdica, Hospital de Clinicas de Porto Alegre, Rua Ramiro Barcelos 2350, Port0 Alegre, 90410, RS, Brazil. Fax: +55 51 3328324.

Elsevier Science Ireland Ltd. SSDI Ol68-8227(95)01120-3

It is well known that among insulin-dependent diabetes mellitus (IDDM) patients the prevalence

of non-proliferative diabetic retinopathy increases

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H. Schmid et al. /Diabetes

Research and Clinical Practice 29 (1995) 163-168

as the duration of diabetes increases and that, usually, somedegreeof this complication develops during the first 10 years of diabetes [ 1,2]. Although 25% of IDDM patients develop proliferative lesions during the 2nd decade, others never present it, even after 20 years of diabetes [2]. Among the factors indicated as causing the progression of non-proliferative retinopathy to proliferative retinopathy in IDDM are diabetic kidney diseaseand cardiovascular autonomic neuropathy [2-61. Those studies suggest that in IDDM patients cardiovascular autonomic neuropathy may be a risk factor for the development of early onset proliferative retinopathy. In non-IDDM (NIDDM) the relationship between diabetic retinopathy and the duration of diabetes is not clear, probably becauseit is rarely possible to determine when the metabolic disturbance began. In NIDDM there is also little information regarding the degree of association between cardiovascular autonomic neuropathy and proliferative retinopathy and nephropathy. This study examines the relationship between the presence of proliferative retinopathy and autonomic neuropathy in an inception cohort of NIDDM patients with cardiovascular autonomic neuropathy (cases) and without cardiovascular autonomic neuropathy (controls). The two groups show no differences in age, age at diagnosis, blood pressure,plasma creatinine, fasting plasma glucose and glycated haemoglobin.

2. Subjects and methods

Between March 1991and October 1991,all outpatients with NIDDM attending the Endocrinology Unit, Hospital de Clinicas de Porto Alegre, were screened for inclusion in the study. Those using anti-hypertensive medication, presenting problems such as alcohol abuse, cardiac rhythm disturbances and acute infectious disease were excluded. The remaining ones constituted a population of 60 subjects,all of them performed cardiovascular autonomic function tests. Nineteen of them had two or more than two abnormal responsesto cardiovascular tests and since one of them was excluded becausehe had glaucoma, 18 patients were included in the study as cases.Of the remaining 41 patients, 9 were not included because they had only one autonomic test abnormal, 7 because they had a cataract(s) and/or glaucoma and 8 becausetheir age was more advanced than the age of the casesgroup. The clinical characteristics of the patients are presented in Table 1. The criteria used to define the presence of nephropathy was a urinary excretion of proteins > 550 mg/24 h or the presence of microalbuminuria (defined as a urinary albumin excretion rate ~20 pg/min) in urinary samples obtained from nocturnal collections of 3 consecutive weeks by electroimmunoassay [7]. Retinopathy was classified as absent, proliferative or non-proliferative according to the results of

Table 1 Clinical characteristics of studied patients Controls n= 17 Insulin treatment Age (years) Age at diagnosis (years) Plasma creatinine (mg/dl) Fasting plasma glucose (mg/dl) Glycated haemoglobin (%) Mean blood pressure (mmHg)

11 55.3 * 48.6 + 1.0 f 151.8 zt 7.8 zt 103.3 *

11.0 11.1 0.2 56.7 1.9 12.0

Cases n= 18

P

7 59.6 f 11.6 48.3 zt 11.1 1.1 f 0.4 150.9 f 75.8 8.7 zt 2.6 105.9 l 17.3

0.234 0.270 0.520 0.260 0.970 0.350 0.530

NS NS NS NS NS NS NS

H. Schmid et al. / Diaberes Research and Clinical Practice 29 (1995) 163-168

indirect ophthalmoscopy. The fimdoscopic examination was performed through dilated pupils. The presenceor absencein each retina of red lesions, exudates,and neovascularization, as defined in the WHO’s MSVDD [8] was recorded. Small, medium, and large red spots included those referred to as microaneurysms and small or large hemorrhages, respectively. Exudates were defined as yellow or gray-white patches usually referred to as hard and soft exudates. Proliferative retinopathy was defined by the presenceof neovascularization, vitreous hemorrhage, or any evidence of scars of photocoagulation, presumably directed at new vessels.Fundi that could not be graded becauseof hemorrhage obscuring the retina were assumedto represent proliferative retinopathy. The subjects underwent cardiovascular tests, always during the afternoon. The tests were supervised by a researcher who was blind to the other results. The electrocardiographically monitored, heart rate response (HRR), was evaluated after deep breathing, Valsalva maneuver and standing. Blood pressureresponse(BPR) to a sustained handgrip and to standing was measured with an aneroid sphygmomanometer. The tests were performed as follows - (a) HRR to deep breathing: the subject breathes deeply and evenly at 6 breaths/mm (the examiner tells the subject when each period of 5 s is ending and whether he must make an inspiratory or expiratory movement). The maximum and minimum heart rates during each breathing cycle were measuredand the mean of the differences during three successive breathing cycleswas taken as the response.(b) HRR to standing: the subject lies quietly and then gets up unaided. The ratio of the longest RR interval (around the 30th beat) to the shortest RR (around the 15th beat) was recorded. (c) HRR to the Valsalva maneuver: the subject blows into a mouthpiece at a pressure of 40 mmHg for 15 s (the examiner must seejugular engorgement during the test). The ratio of the longest RR interval shortly after the maneuver to the shortest RR interval during the maneuver was measured and called the Valsalva ratio. (d) BPR to standing: the maneuver was the sameas described in b. The blood pressure variation when the person was lying down and 1 min after standing was taken as the measure of

165

postural blood pressure change. (e) BPR to sustained handgrip: the handgrip was maintained at 30% of the maximum voluntary contraction using a handgrip dynamometer up to a maximum of 5 min and the BPR was measuredevery minute. The difference between the diastolic blood pressure just before beginning the contraction and the maximal one during the maneuver was taken as the response.The normal value responsesto those tests were standardized in our laboratory in 97 healthy controls and were: (a) > 13 beats/min for subjects under 30 years old and > 6 beats/min for people 30 years or over; (b) > 1.21; (c) > 1.06; (d) < -20 mmHg; (e) > 10 mmHg. 2.1. Statistical Tests

Comparisons betweenthe clinical characteristics of studied patients were made using the Student’s t-test (for age, age at diagnosis, plasma creatinine, fasting plasma glucose, glycated haemoglobin, mean blood pressure) or Fisher’s exact test (for number of patients using insulin) or MannWhitney (for HRR to Valsalva, HRR to deep breathing and HRR on rising). Statistical significance of associations between each complication in the two groups was evaluated by logistic regression analysis. Univariate analysis was initially performed to identify significant associations with autonomic neuropathy. Stepwise linear logistic regression was used to test the associations between independent variables (presence of autonomic neuropathy) and other complications. Maximum-likelihood methods were used to estimate the regression coefficients, and likelihood ratio tests were selected to test the significance of the coefficients. The likelihood ratio test performed at each step determined whether the last variable that entered the regression added significantly to the variables already selected.The stepwise procedures resulted in ranking the variables according to their relative importance.

3.Resdts Mean cardiovascular test results of studied patients are presentedin Table 2. As was expected by the study design, differences were observed in the mean of responses to all tests among cases and

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H. Schmid et al. /Diabetes Research and Clinical Practice 29 (1995) 163-168

Table 2 Cardiovascular test results of the studied patients

Basal heart rate (bpm) HRR to Valsalva

Controls

Cases

n=17

n=18

77.5 zt 11.6 1.65 * 0.33

P

86.4 zt 15.9 1.19 l 0.22

0.069
(bpmhin)

HRR to deep breathing (bpmknin) HRR responseon rising (bpmknin) Systolic blood pressure on rising (mmHg)

18.6 f

0.03

4.35 zt 3.18


1.20

0.11

1.06 zt 0.04


l

3.30 +

9.6

-22.2

f 23.0

<0.004

Table 3

Relative odds for the presence of nephropathy according to cardiovascular autonomic dysfunction in controls (NIDDM patients without autonomic neuropathy) and cases(NIDDM patients with autonomic neuropathy) Degree of Nephropathy None Overt proteinuria

Controls n=17

Cases n= 18

16 I

9 9

Odds ratio 1.0 16.0

95% confidence intervals 1.73-147.2

Table 4 Relative odds for the presence of retinopathy according to cardiovascular autonomic dysfunction in controls (NIDDM patients without autonomic neuropathy) and cases(NIDDM patients with autonomic neuropathy) Degree of Retinopathy None Non-proliferative Proliferative

Controls

Cases

II=17

n=18

13

3 7 8

3

1

Odds ratio 1.0

95% confidence intervals -

10.11

1.60-64.0

34.67

3.06-393.2

Table 5 Regression of determinants for the presence of diabetic autonomic neuropathy in NIDDM patients Cases ?I= 18

Odds ratio

II=17

95% confidence intervals

Nephropathy Overt and MA x None

1 x 16

9x9

12.54

0.56-278.91

Hypertension Diastolic pressure ~-90 mmHg

6x

9x9

1.58

0.21-

7x3 8x3

0.49 7.11

0.08- 3.17 1.24- 40.59

Independent variables

Retinopathy Non-proliferative x none Proliferative x none

Controls

II

3 x 13

I x 13

12.21

H. Schmid et al. /Diabetes

Research and Clinical Practice 29 (1995) 163-168

controls; only the basal heart rate was similar between the two groups. The relationship between two stages of nephropathy and the presence of autonomic neuropathy are summarized in Table 3. Presence of nephropathy (microalbuminuria or overt proteinuria) was significantly related to the presence of cardiovascular autonomic dysfunction. The relationship between two stages of retinopathy and the presence of autonomic neuropathy is summarized in Table 4. Both nonproliferative and proliferative retinopathy were related to autonomic dysfunction. To investigate the independence of the associations that were identified in univariate analyses, a multiple logistic regression model was examined. The model is summarized in Table 5. The odds ratio for proliferative retinopathy remained the same as in the previous model but nephropathy was no more significantly related to autonomic dysfunction. Hypertension (defined as a diastolic pressure > 90 mmHg) and non-proliferative retinopathy were also not related to autonomic dysfunction.

4. Discussion

In this study the number of patients using insulin, age,age at diagnosis, plasma creatinine, fasting plasma glucose, glycated haemoglobin and mean blood pressurewere similar in casesand controls; if differences in the prevalence of complications are observed among the two groups, they probably are not related to differences in the degree of kidney dysfunction, aging, duration of diabetes and insulin use. Although at the time the study was made both, the metabolic control and the number of patients treated with insulin, were similar among the two groups, it is impossible to exclude the possibility that differences in the past metabolic control are contributing to differences in the prevalence of complications (an index of previous hyperglycemia was not obtained). Retinopathy and neuropathy frequently coexist in diabetic patients, as was shown in the comprehensive study by Pirart [9] but it is not known whether one complication predisposes to the others or

167

whether all of them will occur if the duration of diabetes is long enough. In the case of diabetic nephropathy it has been observed that the majority of IDDM patients will not present this complication [9] and that some factors such as microalbuminuria can be considered risk factors for nephropathy development [lo]. More recently autonomic neuropathy was also suggested as a risk factor for nephropathy progression [ 111. Proliferative retinopathy is not always present in diabetes patients with a long history of the diseaseand in somepersons it occurs after a short period of diabetes; the risk and protective factors are not well understood [ 121but somefactors such as impaired renal function, poor glycemic control and hypertension, have been described in IDDM [6] and NIDDM patients [13,14]. For autonomic neuropathy, both the prevalence and risk factors and their relationship to other complications are not well known. In the present study a striking relationship between cardiovascular autonomic neuropathy and the presenceof proliferative retinopathy is shown in NIDDM patients. If these results are correct it is possible to imagine that in NIDDM patients autonomic neuropathy could play a permissive role in the obstruction of retinal vessels which could produce more retinal ischemia and trigger a stimulus for the proliferation of new vessels. Another possibility is that severe microangiopathy presenting as proliferative retinopathy could be a risk indicator of an etiologic processthat promotes ischemia of vasa nervorum and may contribute to autonomic neuropathy development. Ischemia of peripheral nerves has been suggested as a possible mechanism to explain the development of peripheral neuropathy [ 151. The findings of the present study also suggest that long-term prospective studies on larger cohorts of patients with and without autonomic neuropathy, followed up for the development of proliferative retinopathy, should be done. References [l] Klein, R., Klein, B.E.K., Moss, SE., Davis, M.D. and DeMets, D.L. (1984) The Wisconsin Epidemiologic

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Research and Clinical Practice 29 (1995) 163-168

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