Silent myocardial ischaemia episodes in non-insulin dependent diabetes mellitus: relationship with haemostatic alterations

libnnolws (IYYl) 5, 121-126 01991 Longman Group UK I.rd

Silent Myocardial Ischaemia Episodes in Non-insulin Dependent Diabetes Mellitus: Relationship

M. C. Torrado, la Calle

with Haemostatic

Alterations

L. J. Garcia Frade, J. I. Lara, I. Rayo, L. Cuellar, E. Marin, A. Garcia Avello, H. de

SUMMARY.

A hypercoagulable state possibly associated with metabolic alterations may contribute to the development of vascular damage in diabetes mellitus. The aim of this study was to evaluate the coagulation-fibrinolysis system in patients with non-insulin dependent diabetes mellitus (NIDDM), silent myocardial ischaemia (SMI). Fifty NIDDM patients were studied (24 men and 26 women) age S&3&0.9 (mean2M.S.E.) years and diabetes duration 9.2f0.8 (mean*M.S.E.) years. None of the patients showed basal ECG alterations and all were under continuous ambulatory electrocardiographic monitoring for 48 h. A SMI episode was defined as an asymptomatic downslope of ST segment30.1 mV with a duration 30.08s after J point of QRS complex, remaining at least for 1 min. Peripheral vasculopathy was evaluated from clinical data and physical examination. Pre and post venous occlusion blood samples were collected, measuring tissue-type plasminogen activator (t-PA) levels, tissue plasminogen activator fast acting inhibitor (PAI) activity, antithrombin III (AT-III) and glycosylated haemoglobin (Hb A,,). Ninety-eight control persons matched by age and sex were studied. Twenty-nine patients showed SMI, 7 had peripheral vasculopathy; none of the patients without SMI had peripheral vasculopathy (p
KEYWORDS.

Silent myocardial

ischaemia.

Diabetes

mellitus.

Haemostatic

alterations.

Peripheral

vasculo-

pathy.

an autonomic heart neuropathy has been considered the responsible for the absence of pain due to a defect in the nervous afferent path.” A hypercoagulable state, possibly associated to metabolic alterations,’ may contribute to the onset and/or progression of vascular lesions that have been found in diabetic disease.*-’ Disorders in lipidic metabolism, haemostasi@ and hyperviscosity, seem to contribute to the development of vascular damage. Predictive value of cholesterolaemia on the coronary risk is widely accepted and it has been demonstrated that increases of plasma cholesterol levels carry a proportional risk of coronary disease.30

Cardiovascular pathology is responsible for a 75% rate of mortality in diabetic patients3’ and non-painful myocardial ischaemia episodes are frequently found in them. The mechanisms by which no pain appears in silent myocardial ischaemia (SMI) are unknown.‘.s It has been implied as possible causes the existence of a failure in the heart ‘alarm system’,’ an altered threshold in pain perception’ and, in diabetic patients M. C. Torrado, L. J. Garcia Frade, A. Garcia Avello, Department of Haematology, J. I. Lara, L. Cuellar, H. de la Calle, Department of Endocrinology. I. Rayo, E. Marin, Department of Cardiology, Hospital ‘Ramh y Cajal’, Madrid. Spain. 121

122

Silent Myocardial

Ischaemia

Episodes

in Non Insulin-dependent

Diabetes

Mellitus:

SMI showed

peripheral

Relationship

with Haemostatic

Alterations

SbfI. NO VAWULOP. L

Fig. 1 Distribution

of studied

groups.

None of the patients

without

In diabetic patients, either a normal or low spontaneous fibrinolytic activity,“~” platelet hyperaggregability, ’ increased plasmatic levels of fibrinogen (Fg), factor VIII coagulant (VIII:C), factor VIIIrelated antigen (VIIIR:Ag), and von Willebrand/ Ristocetin. co-factor (VIII:Rcof)‘7-2n have been found. A decrease in fibrinogen survival, rapidly reversible with correction of hyperglycaemia21 has been found; so hyperfibrinogenaemia in diabetics is associated with a glycaemic level as there is a correlation between Fg levels in plasma and haemoglobin Ai,, which is used as a blood glucose control.‘s The plasma concentration of tissue-type plasminogen activator (t-PA) antigen and PA1 activity has been described as being higher in both non-insulin dependent diabetes mellitus (NIDDM) and insulin dependent diabetes mellitus (IDDM) patients as related to controls. 22 Release of plasminogen activator from vascular endothelium is abnormal in some cases.i4.” It has been described that reduced plasma fibrinolytic activity in diabetic patients is negatively correlated with PA1 activity levels, which is indicative of the importance of this inhibitor in the regulation of fibrinolysis. 22 Increased levels of PA1 produce an inhibition of t-PA so a decreased fibrinolytic capacity is found.2”-2’ Diabetes, mainly non-insulin dependent, shows several factors such as obesity, hypertension, hyperinsulinism and old age, all associated with a decreased plasma fibrinolytic capacity, probably mediated by an increase in PA1 levels; all these factors could predispose to the development of thrombosis and vasculopathy, due to its abnormal fibrinolysis.22 Alterations of PA1 levels in these patients seem to be independent of diabetes control as no correlation has been found with Hb Ai, levels.22 An elevated body mass index (BMI) is often associated with

vasculopathy

(p
NIDDM, which predisposes both to a resistance to insulin and to an hyperinsulinism rather than to a insulin deficiency. 2h.27This hyperinsulinism can have a tendency to cause vascular damage.28 A positive correlation has been described between insulin concentration and PAI.*” The aim of this study was to evaluate the coagulation-fibrinolysis system in patients with NIDDM, SMI and/or peripheral vasculopathy.

MATERIALS AND METHODS Fifty non-insulin dependent diabetic patients (26 women and 24 men) aged between 45 and 74 years (58.3k0.9 mean5M.S.E.) without alterations of the ST segment in the basal electrocardiogram were studied. The mean duration of diabetes was 9.24k0.8, with a range from 1 to 25 years. Thirty-nine patients were treated with insulin (33.53t2.79 SIU/ day), 9 with hypoglycaemic agents and 2 with diet. According to WHO criteria, 14 patients had arterial

Table 1 Distribution of patients and mean valueskmean standard errors of blood pressure, diabetes duration and insulin doses in diabetics with and without SMI

Number Males Females SAP (mm Hg) DAP (mm Hg) Dtes. D. (years) I.D. (units/day)

D+SMI

D-SMI

Total Diabetics

29 12 17 140.3f4.5 85.5f1.9 10.2+1.2 36.2*4.1

21 12 9 132.6k4.1 79.5k2.4 7.9kl.l 30.Of3.5

50 24 26 137.04f3.15 X2.95+1.52 9.24+0.88 33.53zb2.79

D+SMI: diabetics with silent myocardial ischaemia D-SMI: diabetics without silent myocardial ischaemia SAP: systolic arterial pressure DAP: diastolic arterial pressure Dtes. D: diabetes duration I.D.: insulin doses

Fibrinolysia

the enzyme linked immunospecific assay (ELISA) described by Rijken et al” with the exception that the 96-well polyvinyl plates were coated with goat IgG antibodies to t-PA and stored at -40°C until use; each subsequent assay was confined to 1 h incubations at 37°C. PA1 activity was evaluated by a functional method described by Speisser et al.” Fg was measured by the Clauss method.“J AT-III level by a chromogenic substrate method.” HB Al, was evaluated by an ‘Auto Al, HA-8110 DIC Daiichi’@ Hb Al, analyser (Kyoto, Japan) and total cholesterol, HDLcholesterol, LDL-cholesterol and triglycerides by an Hitachi@ autoanalyser. All values are expressed as mean-tM.S.E. Statistical analysis was performed using the Student’s t-test. Correlation coefficients were calculated by the Pearson test.

PAI (SI\J/ml) 70

c[.

1=Cont.rol Z=SMI

Mean

S=without

123

SMI

60

RESULTS

1

2

Fifty-eight per cent of the studied patients showed SMI episodes, 14% showed peripheral vasculopathy; (24.14% of the patients with SMI presented peripheral vasculopathy). None of the patients without SMI showed peripheral vasculopathy (p
3

Fig. 2 PA1 activity levels of studied patients. There is an increase in levels in the SMI group compared to the controls (p
hypertension. Diabetes control was assessed by measuring glycosylated haemoglobin (HbAI,). Ninety-eight controls matched by age and sex were studied. All patients were under continuous ambulatory electrocardiographic monitoring for 48h. SMI episodes were defined as an asymptomatic downslope of ST segment 20.1 mV after 0.08s from J point, with a minimal duration of lmin. Peripheral vasculopathy was evaluated from clinical data and physical examination. Blood samples from fasting patients, overnight and before receiving their insulin, were collected pre and post venous stasis (lOmin, midway between systolic and diastolic pressure) into ‘Vacuumtainers’@ with 0.1 M trisodium citrate (9:l v/v) after an observed supine rest for 15min. Platelet-poor plasma was obtained by centrifuging at 3OOOXg for 15min and stored at -20°C until processed. Blood samples were obtained and mixed with 3.2% sodium EDTA in order to evaluate HB Al, level. Pre and post venous stasis t-PA was measured by

Table 2 Mean valueskmean standard errors of fibrinogen, difference Antithromhin-III levels in diabetics with and without SMI

FgW At-PA (SW/ml) PA1 (AU/ml) AT-III (%) D+SMI: diabetics D-SMI: diabetics At-PA: difference

1). There was an increase of PA1 activity levels (49.08k4.85 AU/ml) in the SMI group related to the PAI activity levels of controls (30.40+_2.40 AU/ml) statistical differences (p
between

higher serum T-Chol

t-PA post and pre venous

occlusion.

(p
PA1 and

Controls

D+SMI

D-SMI

Total diabetics

2.62fO.18 2.08kO.14 30.4Ok2.39 100.22+2.44

3.5OiO.17 0.92t0.31 49.08k4.85 102.7922.92

3.727tO.30 1.18f0.33 39.64+4.45 86.22+6.02

3.59+0.16 1.03SO.23 4.5.1443.42 96.44k3.12

with silent myocardial ischaemia without silent myocardial ischaemia between t-PA post and pre venous occlusion

(t-PA post-t-PA

pre)

124

Silent Myocardial

Ischaemia

Episodes

in Non Insulin-dependent

AT III (%) 1 =Control 2=SMI 3=without

SMI

110 100 90 80 70 I 60

50 40

i

Diabetes

Mellitus:

Relationship

with Haemostatic

Alterations

The increase of PA1 activity levels in diabetics as compared to controls means, according to previous studies,22 a decrease in fibrinolytic activity. High levels of PA1 produce an inhibition of t-PA, resulting in a decrease of fibrinolytic capacity23-25 which may contribute to the development of vascular disease.22 Hyperinsulinaemia presented in NIDDM may increase the liver synthesis of PAI.2” No correlation between PA1 activity levels and other risk factors such as hypercholesterolaemia and metabolic control state was found. We have found a positive correlation between the fibrinogen concentration and the number of SMI episodes. The association of an increase in fibrinogen concentration and subsequent hyperviscosity to SMI can contribute, linked to a hypofibrinolytic state, to the development of coronary disease in NIDDM. In our results is shown a decreased hbrinolytic response to stimulous in patients with peripheral

Fibrinogen

(gr,/l)

6

Fig. 3 AT-III levels of studied patients. Levels in diabetics SMI are higher than the ones without SMI (p
with

5

and LDL-Chol (~~0.05) levels were found when matched to the ones without it. Also, higher levels of Hb Al, (p
I-

DISCUSSION The tendency of diabetic patients to develop vascular pathology is produced by several factors, like the existence of a hypercoagulable state, metabolic alterations, age, obesity and hypertension. Our patients with SMI showed an increase of diastolic arterial a worse metabolic control (with higher pressure, levels of Hb Al, than in the non-ischaemic group) and an increase of T-Chol and LDL-Chol levels when matched to those without SMI.

2 0

D+SMI: D-SMI:

diabetics diabetics

I 20

! 30

I 40

n. of Fig. 4 Correlation between ischaemic episodes without p
Table 3 Mean valueskmean standard errors of Hb Ai,, triglycerides, LDL-cholesterol in diabetics with and without SMI

Hb Ai, (%) TG (mg/dl) T-Chol (mg/dl) HDL-Chol (mg/dl) LDL-Chol (mg/dl)

I 10

total cholesterol,

/ 50

I 60

70

/ 80

I 100

S.M.I. episodes

fibrinogen level gr/l and number of changes in the beat rate. (r=0.53

HDL-cholesterol

and

Controls

D+SMI

D-SMI

Total diabetics

<5.7 12Ozk3.0 200f5.0 4Okl.O 125k2.5

8.4f0.3 149.4f20.0 248.4k9.7 43.4+2.3 178.4L8.6

7.3TO.4 128.9k14.2 221.828.4 43.7k2.7 152.5+8.0

7.98f0.28 140.8213.34 237.326.98 43.5k1.72 167.9f6.22

with silent myocardial ischaemia without silent myocardial ischaemia

I 90

Fibrinolysls

vasculopathy and this abnormal response does not occur in patients with electrocardiographic alterations only; this suggest that there are different pathologic situations in vascular damage. On the other hand, the presence of increased levels of AT-III in patients with SMI episodes related to diabetics in general, that showed lower levels of AT-III, may be considered as a response to a hypercoagulable situation. In conclusion, 58% of the patients with NIDDM showed episodes of SMI, possibly related with coronary thrombosis. A hypercoaguable state is suggested by the AT-III and Fg concentrations and increased PAI activity levels. These alterations, together with a worse metabolic control and hypercholesterolaemia may be markers of coronary disease.

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Received: 24 November 1989 Accepted after revision: 15 March 1YYO Offprint orders to: M.C. Torrado, Department Hospital ‘Ram6n y Cajal’, Madrid, Spain.

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