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Increased cardiovascular morbidity and mortality in diabetes mellitus: identification of the high risk patient
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Diabetes Research and Clinical Practice 30 Suppl. (1996) $85-$88
Increased cardiovascular morbidity and mortality in diabetes mellitus: identification of the high risk patient Hans Uwe Janka ZKH Bremen-Nord, Hammersbecker Strasse 228, 28755 Bremen, Germany
Abstract
Cardiovascular diseases are the major cause of morbidity and mortality in the diabetic paticnt. Acute myocardial infarction carries twice the mortality of that in the general population. Although in the thrombolytic era, in-hospital survival for both diabetic and non-diabetic patients have improved considerably, the overall case fatality rate due to out-of-hospital death is still more than 50%. Screening relates particularly to the systematic search for cardiovascular risk factors and asymptomatic atherosclerosis. The individual risk cannot exactly be described by the level of risk factors alone. Today, diagnosis of preclinical cardiovascular disease can identify the high risk patient for severe cardiovascular events. The presence of asymptomatic or 'preclinical' cardiovascular disease such as left ventricular hypertrophy, peripheral arterial vessel disease, carotid atherosclerosis, autonomic neuropathy, and renal dysfunction carries a markedly increased risk for symptomatic morbidity as well as cardiovascular mortality. The unfavorable connection between autonomic neuropathy and coronary heart disease risk has just recently been reported. Therefore, diabetic patients with existing cardiovascular disease should be investigated and managed as vigorously as is warranted by existing evidence. Keywords: Cardiovascular disease; Morbidity; Mortality; Diabetic patient
I. I n t r o d u c t i o n
Cardiovascular diseases are the major cause of morbidity and mortality in the diabetic patient, especially in developed countries where atherosclerosis is the most common complication of diabetes. It occurs at a younger age and progresses more rapidly in diabetic than in non-diabetic subjects and frequently culminates in such fatal or disabling complications as myocardial infarction, stroke, and gangrene [1,2]. Women with diabetes are at particularly increased risk [3].
The acceleration of atherogenesis occurs in all types of diabetes. In population-based epidemiologic studies, diabetic subjects exhibited a 3--4 times higher rate of cardiovascular mortality than non-diabetic subjects and diabetic patients with cardiovascular disease have a much poorer prognosis [3]. Survival rate after myocardial infarction is markedly reduced in comparison to the non-diabetic subjects. The prevalence of cardiovascular disease is clearly age-dependent: it is rather infrequent below the age of 40 years, but increases thereafter and also with the duration of diabetes [4].
0168-8227/96/$15.00 © 1996 Elsevier Science Ireland Ltd. All rights reserved SSDI 0304-3835(95)01176-5
86
H.U. Janka / Diabetes Research and Clinical Practice 30 Suppl. (1996) $85-$88
2. Myocardial infarction
4. Preclinical cardiovascular disease (PVD)
Acute myocardial infarction carries twice the mortality of that in the general population [5-7]. Contributory factors may include coexistent diabetic cardiomyopathy, blunting of cardiac reflexes by autonomic neuropathy, ventricular arrhythmias and complete heart block, as well as adverse metabolic effects [8]. In the thrombolytic era, in-hospital survival for both diabetic and non-diabetic patients have improved considerably [7]. The benefit of fibrinolytic therapy appears to be greater among the diabetic patients. This therapy saves a substantial amount of lives in the younger and middle age group. The overall case fatality rate, however, due to out-ofhospital death is still more than 50% [6,9]. Silent myocardial ischemia and silent myocardial infarction are more common in people with diabetes, and have a worse prognosis in diabetes than in the general population [10]. Early diagnosis and preventive measures, therefore, are mandatory in middle aged and elderly diabetic patients.
Advances in diagnostic methodology now make possible accurate non-invasive detection of asymptomatic or 'preclinical' cardiovascular disease such as left ventricular hypertrophy [14], peripheral arterial vessel disease [15], autonomic neuropathy [16], and renal dysfunction [ 17,18]. The presence of one of these abnormalities carries a markedly increased risk for symptomatic morbidity as well as cardiovascular mortality. It has been recommended that all physician offices providing routine care to adult diabetic patients should be able to measure ankle and brachial blood pressure for ankle brachial index (ABI) to detect PVD [19]. All patients with confirmed preclinical cardiovascular disease should be especially carefully screened and monitored for risk factors and accordingly aggressively treated.
3. Screening for cardiovascular risk Screening relates particularly to the systematic search for cardiovascular risk factors and asymptomatic atherosclerosis. Traditional risk factors (especially hypertension, elevated cholesterol levels and cigarette smoking) are important predictors of morbid atherosclerotic and hypertensive events, and their control reduces the incidence of events [I1]. Recent evidence suggests that for the diabetic patient in addition dyslipidemia (low HDL-cholesterol, increased triglycerides), upper body obesity, clotting abnormalities (high fibrinogen levels), insulin resistance, proteinuria as well as poor glycemic control (high glycated hemoglobin levels) are important risk factors. A typical feature of diabetic patients (those with NIDDM particular) is that they tend to have several risk factors simultaneously and the effect of these risk factor clusters may be synergistic [ 12]. However, the individual risk cannot exactly be described by the level of risk factors alone. Today, diagnosis of preclinical cardiovascular disease can identify the high risk patient for severe cardiovascular events [ 13].
5. Cardiovascular autonomic neuropathy Several reports have suggested the existence of a specific diabetic heart muscle disease which may progress to chronic heart failure [20]. Although microangiopathy of the heart capillaries have been repeatedly demonstrated the clinical significance of these findings remain to be shown. More convincing are reports of a detrimental effect of diabetic neuropathy of the heart. Prospective studies have shown an increased mortality in diabetic patients with cardiovascular autonomic neuropathy [ 16,21 ]. A number of unexpected sudden deaths were observed in these patients. Sudden death could primarily be due to cardiac arrhythmias. Prolongation of the QT interval has been proposed to be associated with an increased risk of ventricular arrhythmias and sudden death [22]. The predictive value of prolonged QT for sudden death as well as coronary heart disease death [23] can be explained by ventricular electrical instability, particularly in the presence of high sympathetic activity. Such instability is hypothesized to result from left sympathetic predominance. Since coronary artery disease is frequently associated with abnormalities in the parasympathetic heart-rate control [24], there is an unfavorable connection between autonomic neuropathy and coronary heart disease risk.
H.U. Janka / Diabetes Research and Clinical Practice 30 Suppl. (1996) $85-$88
6. Secondary prevention Evidence of cardiovascular disease should be specifically sought by clinical enquiry, physical examination and non-invasive techniques, such as electrocardiography (including recording of heart rate variability) and Doppler sonographic devices. Diabetic patients with existing cardiovascular disease should be investigated and managed as vigorously as is warranted by existing evidence. Special procedures may be used, such as duplex sonographic examinations, radionuclide scanning, echocardiography, and coronary angiography. Since a considerable number of NIDDM patients have already significant coronary artery disease at diabetes diagnosis, intervention should be started early, probably already in the prediabetic state. There is evidence that primary risk factors continue to operate, although their effect is proportionately less, depending on the degree of cardiac and vascular damage (which ultimately dominates prognosis). Thus, risk factors should still be sought and corrected to a degree compatible with the patient's age and physical condition. In addition, measures to revascularize the myocardium should always be considered. Preventive measures for the diabetic patient should also include physical retraining programs and the use of low doses of aspirin. Particularly at this stage, all diabetic patients should be offered education including the individual patient's problem, the options for investigation and treatment, and secondary prevention advice.
References [1] Keen, H. (1986) Diagnosis and classification of diabetes mellitus. In: L.P. Krall (Ed.), World Book of Diabetes in Practice, Vol. 2, Elsevier, Amsterdam, pp. 8-15. [2] Jarrett, R.J. (1985) Risk factors of macrovascular disease in diabetes mellitus. Horm. Metab. Res. (Suppl. 15), 1-3. [3] Donahue, R.P. and Orchard, T.J. (1992) Diabetes mellitus and macrovascular complications. An epidemiological perspective. Diabetes Care 15, 1141-1155. [4] Krolewski, A.S., Kosinski, E.J., Warram, J.H. et al. (1987) Magnitude and determinants of coronary artery disease in juvenile-onset, insulin-dependent diabetes mellitus. Am. J. Cardiol. 59, 750--755. [5l Smith, J.W., Marcus, F.E. and Serokman, R. (1984) Prognosis of patients with diabetes mellitus after myocardial infarction. Am. J. Cardiol. 54, 718.
87
[6] Miihonen, M., Tuomilehto, J. and the FINMONICA Study Group (1992) Acute myocardial infarction (AMI) in diabetic patients: clinical findings and case fatality in the FINMONICA AMI register. Eur. Heart J. (Abstract Suppl.) 13, 279. [7] Fibrinolytic Therapy Trialists' (FIT) Collaborative Group (1994) Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality results from all randomised trials of more than 1000 patients. Lancet 343, 311-322. [8] Rytter, L., Troelsen, S. and Beck-Nielsen, H. (1985) Prevalence and mortality of acute myocardial infarction in patients with diabetes. Diabetes Care 8, 230--234. [9] LOwel, H., Dobson, A., Keil, U. et al. (1993) Coronary heart disease case fatality in four countries: a community study. Circulation 88, 2524-2531. [10] Nesto, R.W. and Phillips, R.T. (1986) Asymptomatic myocardial ischemia in diabetic patients. Am. J. Med. 80 (Suppl. 4c) 40--47. [11] Yudkin, J.S. (1993) How can we best prolong life? Benefits of coronary risk factor reduction in non-diabetic and diabetic subjects. Br. Med. J. 306, 1313-1318. [12] Janka, H.U., Balletshofer, B., Becker, A., Giek, M.R., Hartmannn, J., Jung, D., Miickelmann, S. and M61tner, A (1992) Das metabolische Syndrom als potenter kardiovaskuliirer Risikofaktor fur vorzeitigen Tod bei Typ-lI-Diabetikern. Diab./Stoffw. !, 2-7. [13] Devereux, R.B. and Aldermann, M.H. (1993) Role of preclinical cardiovascular disease in the evolution from risk factor exposure to development of morbid events. Circulation 88, IA.A.A, 1455. [14] Levy, D., Garrison, R.J., Savage, D.D. et al. (1990) Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N. Engl. J. Med. 322, 1561-1566. [15] Criqui, M.H., Langer, R.D., Fronek, A., Feigelson, H.S., Klauber, M.R., McCann, T.J. and Browner, D., Mortality over a period of 10 years in patients with peripheral arterial disease. N. Engl. J. Med. 326 (1992) 381-386. [16] Ewing, D.J., Campbell, 1.W. and Clarke, B.F. (1980) The natural history of diabetic autonomic neuropathy. Q. J. Med. 49, 95-108. [17] Schmitz, A. and Vaeth, M. (1988) Mieroalbuminuria and mortality in non-insulin dependent diabetes. Diabete Metab. 14, 193. [18] M61gaard, H., Christensen, P.D., Hermansen, K. et al. (1994) Early recognition of autonomic dysfunction in microalbuminuria: significance for cardiovascular mortality in diabetes mellitus? Diabetologia 37, 788-796. [19] Orchard, T.J. and Strandness, D.E. (1993) Assessment of peripheral vascular disease in diabetes: report and recommendations of an international workshop. Circulation 88, 819-828. [20] Park, J.-W., Ziegler, A.G., Janka, H.U. et al. (1988) Left ventrieular relaxation and filling pattern in diabetic heart muscle disease: an echocardiographic study. Klin. Wochenschr. 66, 773-778. [21] Rathmann, W., Ziegler, D., Jahnke, M., Haastert, B. and
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H.U. Janka / Diabetes Research and Clinical Practice 30 Suppl. (1996) $85-$88
Gries, F.A. (1993) Mortality in diabetic patients with cardiovascular autonomic neuropathy. Diab. Med. 10, 820824. [22] Kahn, J.K., Sisson, J.C. and Vinik, A.I. (1987) QT interval prolongation and sudden cardiac death in diabetic autonomic neuropathy. J. Clin. Endocrinol. Metab. 64, 751-754. [23] Dekker, .1.M., Schouten, E.G., Klootwijk, P., Pool, J. and
Kromhout, D. (1994) Association between QT interval and coronary heart disease in middle-aged and elderly men: the Zutphen Study. Circulation 90, 779-785. [24] Airaksinen, K.E., Koistinen, M.J., Ik~iheimo, M.J. et al. (1990) Effect of coronary artery disease on parasympathetic cardiovascular reflexes in NIDDM patients. Diabetes Care 13, 83-86.
Diabetes Research and Clinical Practice 30 Suppl. (1996) $85-$88
Increased cardiovascular morbidity and mortality in diabetes mellitus: identification of the high risk patient Hans Uwe Janka ZKH Bremen-Nord, Hammersbecker Strasse 228, 28755 Bremen, Germany
Abstract
Cardiovascular diseases are the major cause of morbidity and mortality in the diabetic paticnt. Acute myocardial infarction carries twice the mortality of that in the general population. Although in the thrombolytic era, in-hospital survival for both diabetic and non-diabetic patients have improved considerably, the overall case fatality rate due to out-of-hospital death is still more than 50%. Screening relates particularly to the systematic search for cardiovascular risk factors and asymptomatic atherosclerosis. The individual risk cannot exactly be described by the level of risk factors alone. Today, diagnosis of preclinical cardiovascular disease can identify the high risk patient for severe cardiovascular events. The presence of asymptomatic or 'preclinical' cardiovascular disease such as left ventricular hypertrophy, peripheral arterial vessel disease, carotid atherosclerosis, autonomic neuropathy, and renal dysfunction carries a markedly increased risk for symptomatic morbidity as well as cardiovascular mortality. The unfavorable connection between autonomic neuropathy and coronary heart disease risk has just recently been reported. Therefore, diabetic patients with existing cardiovascular disease should be investigated and managed as vigorously as is warranted by existing evidence. Keywords: Cardiovascular disease; Morbidity; Mortality; Diabetic patient
I. I n t r o d u c t i o n
Cardiovascular diseases are the major cause of morbidity and mortality in the diabetic patient, especially in developed countries where atherosclerosis is the most common complication of diabetes. It occurs at a younger age and progresses more rapidly in diabetic than in non-diabetic subjects and frequently culminates in such fatal or disabling complications as myocardial infarction, stroke, and gangrene [1,2]. Women with diabetes are at particularly increased risk [3].
The acceleration of atherogenesis occurs in all types of diabetes. In population-based epidemiologic studies, diabetic subjects exhibited a 3--4 times higher rate of cardiovascular mortality than non-diabetic subjects and diabetic patients with cardiovascular disease have a much poorer prognosis [3]. Survival rate after myocardial infarction is markedly reduced in comparison to the non-diabetic subjects. The prevalence of cardiovascular disease is clearly age-dependent: it is rather infrequent below the age of 40 years, but increases thereafter and also with the duration of diabetes [4].
0168-8227/96/$15.00 © 1996 Elsevier Science Ireland Ltd. All rights reserved SSDI 0304-3835(95)01176-5
86
H.U. Janka / Diabetes Research and Clinical Practice 30 Suppl. (1996) $85-$88
2. Myocardial infarction
4. Preclinical cardiovascular disease (PVD)
Acute myocardial infarction carries twice the mortality of that in the general population [5-7]. Contributory factors may include coexistent diabetic cardiomyopathy, blunting of cardiac reflexes by autonomic neuropathy, ventricular arrhythmias and complete heart block, as well as adverse metabolic effects [8]. In the thrombolytic era, in-hospital survival for both diabetic and non-diabetic patients have improved considerably [7]. The benefit of fibrinolytic therapy appears to be greater among the diabetic patients. This therapy saves a substantial amount of lives in the younger and middle age group. The overall case fatality rate, however, due to out-ofhospital death is still more than 50% [6,9]. Silent myocardial ischemia and silent myocardial infarction are more common in people with diabetes, and have a worse prognosis in diabetes than in the general population [10]. Early diagnosis and preventive measures, therefore, are mandatory in middle aged and elderly diabetic patients.
Advances in diagnostic methodology now make possible accurate non-invasive detection of asymptomatic or 'preclinical' cardiovascular disease such as left ventricular hypertrophy [14], peripheral arterial vessel disease [15], autonomic neuropathy [16], and renal dysfunction [ 17,18]. The presence of one of these abnormalities carries a markedly increased risk for symptomatic morbidity as well as cardiovascular mortality. It has been recommended that all physician offices providing routine care to adult diabetic patients should be able to measure ankle and brachial blood pressure for ankle brachial index (ABI) to detect PVD [19]. All patients with confirmed preclinical cardiovascular disease should be especially carefully screened and monitored for risk factors and accordingly aggressively treated.
3. Screening for cardiovascular risk Screening relates particularly to the systematic search for cardiovascular risk factors and asymptomatic atherosclerosis. Traditional risk factors (especially hypertension, elevated cholesterol levels and cigarette smoking) are important predictors of morbid atherosclerotic and hypertensive events, and their control reduces the incidence of events [I1]. Recent evidence suggests that for the diabetic patient in addition dyslipidemia (low HDL-cholesterol, increased triglycerides), upper body obesity, clotting abnormalities (high fibrinogen levels), insulin resistance, proteinuria as well as poor glycemic control (high glycated hemoglobin levels) are important risk factors. A typical feature of diabetic patients (those with NIDDM particular) is that they tend to have several risk factors simultaneously and the effect of these risk factor clusters may be synergistic [ 12]. However, the individual risk cannot exactly be described by the level of risk factors alone. Today, diagnosis of preclinical cardiovascular disease can identify the high risk patient for severe cardiovascular events [ 13].
5. Cardiovascular autonomic neuropathy Several reports have suggested the existence of a specific diabetic heart muscle disease which may progress to chronic heart failure [20]. Although microangiopathy of the heart capillaries have been repeatedly demonstrated the clinical significance of these findings remain to be shown. More convincing are reports of a detrimental effect of diabetic neuropathy of the heart. Prospective studies have shown an increased mortality in diabetic patients with cardiovascular autonomic neuropathy [ 16,21 ]. A number of unexpected sudden deaths were observed in these patients. Sudden death could primarily be due to cardiac arrhythmias. Prolongation of the QT interval has been proposed to be associated with an increased risk of ventricular arrhythmias and sudden death [22]. The predictive value of prolonged QT for sudden death as well as coronary heart disease death [23] can be explained by ventricular electrical instability, particularly in the presence of high sympathetic activity. Such instability is hypothesized to result from left sympathetic predominance. Since coronary artery disease is frequently associated with abnormalities in the parasympathetic heart-rate control [24], there is an unfavorable connection between autonomic neuropathy and coronary heart disease risk.
H.U. Janka / Diabetes Research and Clinical Practice 30 Suppl. (1996) $85-$88
6. Secondary prevention Evidence of cardiovascular disease should be specifically sought by clinical enquiry, physical examination and non-invasive techniques, such as electrocardiography (including recording of heart rate variability) and Doppler sonographic devices. Diabetic patients with existing cardiovascular disease should be investigated and managed as vigorously as is warranted by existing evidence. Special procedures may be used, such as duplex sonographic examinations, radionuclide scanning, echocardiography, and coronary angiography. Since a considerable number of NIDDM patients have already significant coronary artery disease at diabetes diagnosis, intervention should be started early, probably already in the prediabetic state. There is evidence that primary risk factors continue to operate, although their effect is proportionately less, depending on the degree of cardiac and vascular damage (which ultimately dominates prognosis). Thus, risk factors should still be sought and corrected to a degree compatible with the patient's age and physical condition. In addition, measures to revascularize the myocardium should always be considered. Preventive measures for the diabetic patient should also include physical retraining programs and the use of low doses of aspirin. Particularly at this stage, all diabetic patients should be offered education including the individual patient's problem, the options for investigation and treatment, and secondary prevention advice.
References [1] Keen, H. (1986) Diagnosis and classification of diabetes mellitus. In: L.P. Krall (Ed.), World Book of Diabetes in Practice, Vol. 2, Elsevier, Amsterdam, pp. 8-15. [2] Jarrett, R.J. (1985) Risk factors of macrovascular disease in diabetes mellitus. Horm. Metab. Res. (Suppl. 15), 1-3. [3] Donahue, R.P. and Orchard, T.J. (1992) Diabetes mellitus and macrovascular complications. An epidemiological perspective. Diabetes Care 15, 1141-1155. [4] Krolewski, A.S., Kosinski, E.J., Warram, J.H. et al. (1987) Magnitude and determinants of coronary artery disease in juvenile-onset, insulin-dependent diabetes mellitus. Am. J. Cardiol. 59, 750--755. [5l Smith, J.W., Marcus, F.E. and Serokman, R. (1984) Prognosis of patients with diabetes mellitus after myocardial infarction. Am. J. Cardiol. 54, 718.
87
[6] Miihonen, M., Tuomilehto, J. and the FINMONICA Study Group (1992) Acute myocardial infarction (AMI) in diabetic patients: clinical findings and case fatality in the FINMONICA AMI register. Eur. Heart J. (Abstract Suppl.) 13, 279. [7] Fibrinolytic Therapy Trialists' (FIT) Collaborative Group (1994) Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality results from all randomised trials of more than 1000 patients. Lancet 343, 311-322. [8] Rytter, L., Troelsen, S. and Beck-Nielsen, H. (1985) Prevalence and mortality of acute myocardial infarction in patients with diabetes. Diabetes Care 8, 230--234. [9] LOwel, H., Dobson, A., Keil, U. et al. (1993) Coronary heart disease case fatality in four countries: a community study. Circulation 88, 2524-2531. [10] Nesto, R.W. and Phillips, R.T. (1986) Asymptomatic myocardial ischemia in diabetic patients. Am. J. Med. 80 (Suppl. 4c) 40--47. [11] Yudkin, J.S. (1993) How can we best prolong life? Benefits of coronary risk factor reduction in non-diabetic and diabetic subjects. Br. Med. J. 306, 1313-1318. [12] Janka, H.U., Balletshofer, B., Becker, A., Giek, M.R., Hartmannn, J., Jung, D., Miickelmann, S. and M61tner, A (1992) Das metabolische Syndrom als potenter kardiovaskuliirer Risikofaktor fur vorzeitigen Tod bei Typ-lI-Diabetikern. Diab./Stoffw. !, 2-7. [13] Devereux, R.B. and Aldermann, M.H. (1993) Role of preclinical cardiovascular disease in the evolution from risk factor exposure to development of morbid events. Circulation 88, IA.A.A, 1455. [14] Levy, D., Garrison, R.J., Savage, D.D. et al. (1990) Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N. Engl. J. Med. 322, 1561-1566. [15] Criqui, M.H., Langer, R.D., Fronek, A., Feigelson, H.S., Klauber, M.R., McCann, T.J. and Browner, D., Mortality over a period of 10 years in patients with peripheral arterial disease. N. Engl. J. Med. 326 (1992) 381-386. [16] Ewing, D.J., Campbell, 1.W. and Clarke, B.F. (1980) The natural history of diabetic autonomic neuropathy. Q. J. Med. 49, 95-108. [17] Schmitz, A. and Vaeth, M. (1988) Mieroalbuminuria and mortality in non-insulin dependent diabetes. Diabete Metab. 14, 193. [18] M61gaard, H., Christensen, P.D., Hermansen, K. et al. (1994) Early recognition of autonomic dysfunction in microalbuminuria: significance for cardiovascular mortality in diabetes mellitus? Diabetologia 37, 788-796. [19] Orchard, T.J. and Strandness, D.E. (1993) Assessment of peripheral vascular disease in diabetes: report and recommendations of an international workshop. Circulation 88, 819-828. [20] Park, J.-W., Ziegler, A.G., Janka, H.U. et al. (1988) Left ventrieular relaxation and filling pattern in diabetic heart muscle disease: an echocardiographic study. Klin. Wochenschr. 66, 773-778. [21] Rathmann, W., Ziegler, D., Jahnke, M., Haastert, B. and
88
H.U. Janka / Diabetes Research and Clinical Practice 30 Suppl. (1996) $85-$88
Gries, F.A. (1993) Mortality in diabetic patients with cardiovascular autonomic neuropathy. Diab. Med. 10, 820824. [22] Kahn, J.K., Sisson, J.C. and Vinik, A.I. (1987) QT interval prolongation and sudden cardiac death in diabetic autonomic neuropathy. J. Clin. Endocrinol. Metab. 64, 751-754. [23] Dekker, .1.M., Schouten, E.G., Klootwijk, P., Pool, J. and
Kromhout, D. (1994) Association between QT interval and coronary heart disease in middle-aged and elderly men: the Zutphen Study. Circulation 90, 779-785. [24] Airaksinen, K.E., Koistinen, M.J., Ik~iheimo, M.J. et al. (1990) Effect of coronary artery disease on parasympathetic cardiovascular reflexes in NIDDM patients. Diabetes Care 13, 83-86.