Prevalence of metabolic syndrome, insulin resistance, and microvascular angina pectoris in 500 consecutive patients referred to coronarography.

OBJECTIVE: This work was aimed to evaluate the prevalence of insulin resistance (IR) and metabolic syndrome in a large cohort of 40-60 years old patients with cardiovascular symptoms. METHODS: A total of 500 consecutive males and females referred to coronarography and coronary catheterization, because of spontaneous or after load precordial pain plus denivelisation of ST segment by electrocardiography, were included. Besides standard clinical examinations, ergometry, echocardiography, fundamental laboratory tests, and several other laboratory examinations were also performed, including oral glucose toleration test (OGTT), total and high-density lipoprotein (HDL) cholesterol, triglycerides, apoprotein A1 and B, apolipoprotein (a), uric acid, fibrinogen, plasminogen activator inhibitor-1 (PAI-1), cytokines (tumor necrosis factor α, TNFα, interleukin-1, IL-1, interleukin-6, IL-6), endothelin-1, as well as hormones (insulin, C peptide, leptin, growth hormone, cortisol). RESULTS: In 81.6% of patients, IR syndrome with compensatory hyperinsulinemia was found in a positive correlation with various symptoms of metabolic syndrome, including abdominal obesity, increased body mass index (BMI), dysglycemia, dyslipoproteinemia, coronary stenosis, decreased HDL level, and hypertension. Hirsutism with polycystic ovarian syndrome was found in 52% of examined women with IR. However, a normal coronary angiogram, called as a microvascular form of the angina pectoris (MIV-AP), was found in 14% of predominantly periclimacteric and benign hirsutic females with long-term disorders of menstrual cycle. Since these patients showed the same symptoms as their gender, age, BMI, and degree of coronary stenoses adjusted pairs with the macrovascular form (such as the same levels of several lipids, hormones and obesity measures), our data strongly support the view that MIV-AP might belong to the IR syndrome. CONCLUSIONS: Hyperinsulinemia and high prevalence of various symptoms of metabolic syndrome (MS) were found in high percentage of patients with after load precordial pain who were referred to coronarography. Similarly, in several women, MIV-AP was detected and its affiliation to MS suggested.

The levels of soluble adhesion molecules in diabetic and nondiabetic patients with combined hyperlipoproteinemia and the effect of ciprofibrate therapy.

Cell adhesion molecules are thought to play a role in atherosclerosis. Several clinical trials have shown that fibrate treatment leads to a reduction in coronary events, although the mechanisms are not fully understood. Soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1) and soluble E-selectin plasma concentrations were measured in 10 obese dyslipidemic men (group A), in 10 obese dyslipidemic type 2 diabetic men without coronary artery disease (CAD) (group B), and in 10 dyslipidemic type 2 diabetic men with angiographically documented CAD (group C) before and after 12 weeks of treatment with ciprofibrate. Compared with nondiabetic dyslipidemic men, diabetic patients with CAD or without documented CAD had significantly increased levels of sVCAM-1 (512 +/-39 versus 750 +/-139 ng/mL; p<0.0001 and 566 +/-78 ng/mL; p<0.01, respectively) and sE-selectin (54.8 +/-6.9 versus 65.9 +/-8.8 ng/mL; p<0.001 and 62.6 +/-9.4 ng/mL; p=0.056, respectively). The levels of sICAM-1 were similar in all 3 groups. Multivariate analyses showed that the higher sCAM levels in patients occurred independently of lipoprotein levels. Waist circumference as a marker of abdominal adiposity was the only independent predictor of elevated concentrations of all 3 cell adhesion molecules in multivariate analyses. sE-selectin was associated with HbA1C levels (p<0.01) in diabetic men at baseline. After 12 weeks of ciprofibrate therapy, sVCAM-1 levels were reduced by 13.5 +/-2.1%, sICAM-1 levels by 11.8 +/-2.2%, and sE-selectin levels by 17.1 +/-3.5% (p<0.01 for all) with the greatest sE-selectin reduction in the diabetic subgroups (p<0.001). There was no correlation between the lowering of soluble adhesion molecules and the magnitude of lipid-lowering effect. An increased level of circulating adhesion molecules may be a mechanism by which dyslipidemia and/or diabetes mellitus promotes atherogenesis, and treatment with ciprofibrate may alter vascular cell activation.

[Thallium scintigraphy of the myocardium in evaluation of patients with insulin resistance syndrome and microvascular angina pectoris]. / Táliová spect scintigrafia myokardu v hodnotení pacientov so syndrómom inzulínovej rezistencie a mikrovaskulárnou anginou pectoris.

Insulin resistance syndrom (IR) is often associated with the syndrome of microvascular angina pectoris (MVAP) or with coronary artery disease (CAD). The authors quantified distribution and washout of 201Tl in heart (C), lungs (L) and liver (H) to evaluate the results 201Tl stress (s) and redistribution SPECT in 50 patients. They compared 2 groups of patients with laboratory verified IR (MVAP and CAD) and control group (CG) of patients with normal coronarography without any symptoms of IR. In Patients with IR and MVAP were found significantly more frequent local perfusion abnormalities then in CG. The index sL/C calculated by ROI analysis is significantly lower in controls, then in CAD. The index sC/H is lower in patients with IR (MVAP significantly) then in CG. The washout of 201Tl in CAD myocardium decreased and in MVAP liver increased. 201thalium scintigraphy is useful for separation of patients with MVAP and local perfusion abnormalities. This findings had probably prognostic value in patients with IR.

[Insulin resistance and the coronary syndrome]. / Inzulínová rezistencia a koronárny syndróm.

The different diseases associated with the insulin resistance syndrome--diabetes mellitus or impaired carbohydrate tolerance, atherogenic lipoprotein phenotype, arterial hypertension and central type of obesity are the main risk factors of atherosclerosis. The reduced sensitivity of target tissues to the metabolic action of insulin (insulin resistance) is considered at present a separate risk factor. The authors analyze on the basis of a group of 210 coronarographic patients the influence of insulin resistance and associated etiopathogenetic risk factors on coronary lesions evaluated by the method of quantitative coronarography. From the results of the investigation ensues that insulin resistance is the most frequent metabolic deviation in patients with coronary disease whereby in the macrovascular group it was found in 74.3% and in the group with microvascular angina pectoris in 64.3% of the patients. Changes in the lipoprotein spectrum were a more frequent and earlier manifestation of insulin resistance than impaired carbohydrate metabolism. The change from functional changes of the vascular wall (impaired endothelium-dependent vasodilatation) to the development of an atheromatous plaque depends on the total number of cholesterol conveying lipoproteins assessed by means of the apoprotein B level and on the capacity of the reverse cholesterol transport, whereby both mechanisms are greatly influenced by insulin sensitivity. The degree of coronary affection evaluated by means of a coronary score, is in patients with manifest diabetes comparable with the affection in patients with insulin resistance without manifest diabetes and these two groups differ very significantly as to the extent and degree of affection from patients with a normal sensitivity to the effect of insulin.

[Relation between cytokines (TNF-alpha, IL-1 and 6) and homocysteine in android obesity and the phenomenon of insulin resistance syndromes]. / Vzt'ah cytokínov (TNF-alfa, IL-1 a 6) a homocysteínu k androidnej obezite a k fenoménom syndrómu inzulínovej rezistencie.

TNF-alpha (so-called cachectin), IL-1 and 6 are important regulating agents in the homeostasis of energy in the organism, as among others they control processes of apoptosis and thus also the volume of adipose and muscular tissues. They are produced not only in immunocompetent cells but also in adipocytes and muscle cells. The cytokine system is then activated not only in tumours and infections but elevated values were found also in obesity, NIDDM, in myocardial infarction and in advanced decompensated cardiac patients. By acting on phosphorylation of IRS-1 and PI-3 kinase TNF-alpha promotes significantly insulin resistance, causes deterioration of diabetes, as well as elevated body temperature, sleepiness and anorexia. In a group of 65 patients, mostly with android obesity, in hyperleptinaemic and insulin resistant probands with coronarographically confirmed microvascular angina pectoris (n = 22) or IHD, mostly after a myocardial infarction (n = 43) with one or more significant stenoses on the epicardial coronary arteries in half the patients positive or elevated TNF-alpha was found and in 28% also IL-6. This increase did not correlate however with BMI, the percentage of body fat, IRI and C peptide levels nor with cortisol and leptin levels. Insulin resistant subjects had more frequently elevated homocysteine and Lp(a) values which are further two independent risk factors of atherothrombogenesis. Hyperhomocysteinaemia can be favourably influenced by vitamin fortification of the diet or by administration of folate and pyridoxine (1 tablet per day) involving negligible financial costs.

[Relation between levels of leptin, insulin and cortisol in persons with the 5H (X) syndrome]. / Vzt'ah hladín leptínu k hladinám inzulínu a kortizolu u l'udí so syndrómom 5H (X).

Leptin levels in subjects with android obesity with the insulin resistance syndrome (syndrome X, 5H) are in general elevated, as compared with non-obese subjects and correlate with the BMI, with the percentage of body fat, WHR, IRI levels and sex (they are higher in women), as it is the case in the general population. In the elevated leptin level in syndrome 5H (association of hyperinsulinism, hyperglycaemia-NIDDM, hyperlipoproteinaemia with android obesity, arterial hypertension and hirsutism in females with the polycystic ovaries syndrome) participate in a significant way also elevated basal IRI and cortisol levels as well as an elevated postprandial IRI response during oGTT despite the fact that leptin and endothelin-1 levels do not rise significantly during oGTT despite hyperinsulinaemia. Leptin levels were however higher in men (liminally significant in women) with an hyperinsulinaemic response during oGTT, as compared with probands with a normal insulin response. Optimal insulin and glucocorticoid levels are the prerequisite for a rise of leptin because proadipocytes in vitro begin to produce leptin as soon as insulin is added to the medium and this effect is trebled, if cortisol is added. It appears that the insulin and leptin resistance in syndrome 5H are parallel phenomena which potentiate each other. Elevated insulin and cortisol levels maintain elevated leptin levels which in turn enhances the insulin resistance in muscles and at the same time has an impact on the IRI response to postprandial hyperglycaemia. In the background of this insulin and leptin resistance in the majority of subjects with the 5H syndrome there is apparently no actual molecular defect of the hormone and its receptors in target tissues but a possible defect in mechanisms of postreceptor transduction of the hormonal signal. In the hormonal resistance participate moreover also two general and non-specific mechanisms such as: 1. increased consumption or uptake of hormonal receptors by elevated levels of the appropriate hormone ("down regulation" phenomenon), 2. disorders of paracrine endothelial mechanisms of the vascular wall which determine via the control of the inflow in the regional microcirculation the availability of insulin, leptin and metabolic substrates to target tissues. Impaired vasodilatation reserves and the development of paradoxical vascular spasms in response to stimuli which normally cause vasodilatation (strain, administration of acetylcholine, histamine, ATP etc.) are constant, associated phenomena in hyperlipoproteinaemias, arterial hypertension and in type 2 diabetics. These phenomena are the syndrome of insulin resistance and syndrome 5H-X resp. Endothelin-1 levels assessed in the systemic circulation are however due to their short biological half-life and the paracrine action of endothelin-1 not sensitive markers of endothelial dysfunction in syndrome X.

Funkcie a dysfunckie cievneho endotelu.

Endothelium represents a large paracrine gland with an enormous reactive surface. By means of its numerous vasodilation and vasospastic factors it manages the basal and working tonus of vessels and thus also the regional flow and the access of target tissues to hormones and metabolic substrates. It manages also the proliferation and migration of myocytes of the vascular wall and thus its adaptation to overload. The dysfunctional states of endothelium are observed in arterial hypertensions, diabetes, dyslipoproteinaemia and they grow with age. They are the first stage of atherothrombogenic processes. They manifest themselves by a decreased vasodilation reserve of the vascular wall to strain, insulin and many other stimuli. On the contrary, quite frequently they paradoxically react to physical strain, acetylcholine, histamine, ATP etc. by vascular spasms which can determine vasospastic and microvascular angina pectoris including spasms and occlusions of e.g. coronary arteries in sites of insignificant stenoses with the origin of infarctions. The damaged endothelium, so to explain, conceives these stimuli in accordance with the encoded programme as a stimulus to the protection from haemorrhage during stress (fight or flight) and develops "suicidal" defensive reaction against them which we are nowadays able to modulate by administration of ACE-inhibitors, beta-blockers, hypolipidaemic drugs, inhibitors of cyclooxygenase-1 (30--100 mg of aspirin), Ca-antagonists and antioxidants including numerous nonpharmacological procedures. We can retard or halt the process of atherothrombogenesis and avoid or lower thus the number of sudden vascular ventricular as well as brain episodes, including the congestive heart failures, limb amputations and ischaemic damage of the brain. (Fig. 4, Ref. 70.).

[Functions and dysfunctions of the vascular endothelium]. / Funkcie a dysfunkcie cievneho endotelu.

Endothelium represents a large paracrine gland with an enormous reactive surface. By means of its numerous vasodilation and vasospastic factors it manages the basal and working tonus of vessels and thus also the regional flow and the access of target tissues to hormones and metabolic substrates. It manages also the proliferation and migration of myocytes of the vascular wall and thus its adaptation to overload. The dysfunctional states of endothelium are observed in arterial hypertensions, diabetes, dyslipoproteinaemia, and they grow with age. They are the first stage of atherothrombogenic processes. They manifest themselves by a decreased vasodilation reserve of the vascular wall to strain, insulin and many other stimuli. On the contrary, quite frequently they paradoxically react to physical strain, acetylcholine, histamine, ATP etc. by vascular spasms which can determine vasospastic and microvascular angina pectoris including spasms and occlusions of e.g. coronary arteries in sites of insignificant stenoses with the origin of infarctions. The damaged endothelium, so to explain, conceives these stimuli in accordance with the encoded programme as a stimulus to the protection from haemorrhage during stress (fight or flight) and develops "suicidal" defensive reaction against them which we are nowadays able to modulate by administration of ACE-inhibitors, beta-blockers, hypolipidaemic drugs, inhibitors of cyclooxygenase-1 (30-100 mg of aspirin), Ca-antagonists and antioxidants including numerous non-pharmacological procedures. We can retard or halt the process of atherothrombogenesis and avoid or lower thus the number of sudden vascular ventricular as well as brain episodes, including the congestive heart failures, limb amputations and ischaemic damage of the brain. (Fig. 4, Ref. 70.)

[The insulin resistance syndrome and fibrinolysis disorders]. / Syndróm inzulínovej rezistencie a poruchy fibrinolýzy.

The high atherogenic potential of the insulin resistance syndrome can be only partly explained by the association of "classical" risk factors of atherosclerosis which are considered part of it, i.e. impaired carbohydrate tolerance/diabetes mellitus type II, dyslipidaemia, hypertension and obesity. Impaired fibrinolysis due to excessive production of the plasminogen activator inhibitor-1 (PAI-1) are further risk factors which participate in the process of atherogenesis from the beginning of formation of the atheromatous plaque to the thrombotic occlusion of the vascular lumen. The authors present a group of 25 patients with different grades of glucose resistance, evaluated by theinsulin response to a glucose load. The insulin resistant group (n = 15) differed significantly from the non-resistant one (n = 10) as regards body weight and the central type of obesity (< 0.01 and 0.001 resp.) insulin level on fasting and after a load (< 0.0001 and 0.001 resp.), triglyceride levels (< 0.01), the incidence of diabetes or impaired carbohydrate tolerance (66.7 vs. 20%) and hypertension (53.3 vs. 20%), but also as regards the PAI-1 activity (.0001). As regards blood sugar levels, total and HDL cholesterol the groups did not differ. The authors investigated also the relationship between PAI-1 activity and different components of the insulin resistance syndrome in the whole group. The closest correlation was found between the PAI-1 activity and the general insulinaemic response to a glucose load (< 0.001) and between PAI-1 and triglycerides (< 0.001). Based on the presented results it may be stated that hypofibnrinolysis as a result of excessive production of PAI.1 is part of the insulin resistance syndrome and potentiates its high atherogenic risk.

[The effects of nicotine on leptin levels in patients with android obesity]. / Vplyv nikotínu na hladiny leptínu u androidne obéznych jedincov.

In insulin resistant subjects with android obesity the leptin levels are, as compared with non-obese subjects, elevated in proportion to their BMI, WHR and their percentage of body fat. Generally independent on obesity, leptin levels are significantly higher in women than in men as in women the percentage of adipose tissue is higher. After administration of 2 mg nicotine in Nicorette chewing gum to 36 android obese non-smokers the elevated baseline values of leptin did not change and thus the observation that cigarettes suppress hunger or that smoking promotes weight reduction is untrue or else this effect is not mediated by nicotine stimulation of leptin secretion or formation in adipose tissue, leptin being the adipose tissue hormone which controls food intake, the sensation of satiety and via neuropeptide Y also other hypothalamic functions such as muscular and sexual activity, gonadoliberin output, thermoregulation etc. Leptin thus offers no alibi to smokers. Conversely smoking in android obese hyperinsulinaemic hyperleptinaemic subjects with syndrome X (5H) potentiates significantly the risk of cardiovascular death.

[Ischemic heart disease with significant coronary stenosis and insulin resistance]. / Ischemická choroba srdca so signifikantnými koronárnymi stenózami a inzulínová rezistencia.

The authors examined a group of 22 patients with significant stenoses revealed on coronarographic examination. None of the patients were diabetic. Hyperinsulinaemia was found in 12 patients (54.5%). The hyperinsulinaemic and normoinsulinaemic groups differed significantly as to the type of obesity expressed by the W/H ratio, the incidence of hypertension and triglyceride levels. The authors discuss the direct participation of insulin resistance and compensatory hyperinsulinism in the pathogenesis of atherosclerosis and its participation in the manifestation of associated risk factors (dyslipidaemia, hypertension, obesity and NIDDM).

[How should we implement the basic principles of treatment of type 2 diabetes mellitus from the aspect of the hormono-metabolic syndrome X (5H)?]. / Aké by sme mali prijat zásady liecenia diabetes mellitus 2. typu (NIDDM) z hladiska hormonálno-metabolického syndrómu X (5H)?

The authors summarize the principles of the therapeutic approach to the 5H syndrome [1. hyperinsulinism, 2. hyperglycaemia (NIDDM), 3. hyperlipoproteinaemia (obesity), 4. hypertension, 5. hirsutism], in particular its two components, i.e. NIDDM and arterial hypertension. The authors found that early treatment of hyperinsulinism, e.g. already in the stage of impaired glucose tolerance or NIDDM with oral antidiabetics, their disproportionate increase with regard to the blood sugar level and glycosylated haemoglobin without making "hygienic" provisions (radical weight reduction; increased physical activity to the maximum possible individual level; energy restricted diet in particular as regards carbohydrates and fat) does not prevent progression of the components of the 5H syndrome to the clinical stage. In treatment of arterial hypertension associated with 5H syndrome non-selective beta-blockers and thiazide diuretics are unsuitable because they worsen the HPLP and enhance insulin resistance. Suitable preparations are combinations of ACE-inhibitors, calcium antagonists, selective beta-blockers in particular with ISA and beta-blockers with a partial selective sympathomimetic activity (devalol and celiprolol). Hygienic provisions must be started in childhood, or when hyperinsulinism is detected.

[Hyperinsulinism as a major etiopathogenic link with arterial hypertension, hyperlipoproteinemia and hirsutism. II]. / Hyperinzulinizmus ako vedûci etiopatogenetický clánok artériovej hypertenzie, hyperlipoproteinémií a hirzutizmu. II. cast'.

The authors analyze mechanism by which hyperinsulinism causes NIDDM, hypertension, hyperlipoproteinaemia and hirsutism (5H syndrome). They demonstrate on a group of their 100 patients with NIDDM and arterial hypertension that, as compared with matched pairs without arterial hypertension, they have significantly higher levels of C-peptide and less favourable parameters of dyslipoproteinaemia. Hirsutism occurs in 10-15% of the adult female population, but in 18.4% women with NIDDM. However, in a group of 48 hirsutic women with NIDDM they did not find, as compared with matched pairs (i.e. women with NIDDM of analogous age, BMI and BP) significantly higher C-peptide and lipid levels. According to the authors congenital insulin resistance modified by numerous endogenous and exogenous factors is eventually manifested in the phenotype, in particular via hyperinsulinism as NIDDM, hypertension, associated with dyslipoproteinaemia and obesity which then, as the main risk factors, condition a high cardiovascular morbidity and mortality. Although hirsutism and the polycystic ovary syndrome are associated with hyperinsulinism, their interrelation is probably less close and thus has not such a negative impact on national health.

[Clinical manifestations of insulin resistance. The hormonal-metabolic syndrome X (5H), its prevalence and impact on cardiovascular morbidity and mortality. I]. / Klinické prejavy inzulínovej rezistencie. Hormonálno-metabolický syndróm X (5H), jeho výskyt a dopad na kardiovaskulárnu morbiditu a mortalitu. I.cast'.

Insulin resistance (prereceptor, receptor, postreceptor) is a complex phenomenon. It penetrates into the clinical picture via hyperinsulinism as impaired glucose tolerance, or NIDDM, as hyperlipoproteinaemia, arterial hypertension and hirsutism in women (syndrome 5H) associated with the polycystic ovary syndrome or the HAIR-AN syndrome. Based on a group of their 480 patients with NIDDM, 108 women with hirsutism, 320 patients with myocardial infarction and the results of the national cardiovascular programme the authors estimate the prevalence of the 5H syndrome as follows: in the general population 5-10%, in patients with arterial hypertension 15-30%, in NDDM 65-90%, in hirsutic women 10-20% and in patients with myocardial infarction 30-50%. These figures could be, however, substantially higher if as the criterion the IRI response was taken or that of C-peptide in OGTT or the results of the hyperinsulinaemic euglycaemic clamp. The clinical 5H syndrome is a phenomenon of latent insulin resistance perceived late by doctors and patients.