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 effect of Pycnogenol on the erythrocyte membrane fluidity.

In the present study, the in vitro effect of polyphenol rich plant extract, flavonoid--Pycnogenol (Pyc), on erythrocyte membrane fluidity was studied. Membrane fluidity was determined using 1-[4-trimethyl-aminophenyl]-6-phenyl-1,3,5-hexatriene (TMA-DPH), 1,6-diphenyl-1,3,5-hexatriene (DPH) and 12-(9-anthroyloxy) stearic acid (12-AS) fluorescence anisotropy. After Pyc action (50 microg/ml to 300 microg/ml), we observed decreases in the anisotropy values of TMA-DPH and DPH in a dose-dependent manner compared with the untreated erythrocyte membranes. Pyc significantly increased the membrane fluidity predominantly at the membrane surface. Further, we observed the protective effect of Pyc against lipid peroxidation, TBARP generation and oxidative hemolysis induced by H2O2. Pyc can reduce the lipid peroxidation and oxidative hemolysis either by quenching free radicals or by chelating metal ions, or by both. The exact mechanism(s) of the positive effect of Pyc is not known. We assume that Pyc efficacy to modify effectively some membrane dependent processes is related not only to the chemical action of Pyc but also to its ability to interact directly with cell membranes and/or penetrate the membrane thus inducing modification of the lipid bilayer and lipid-protein interactions.

Inhibition of nonenzymatic protein glycation and lipid peroxidation by drugs with antioxidant activity.

We studied the effects of aminoguanidine (AG), beta-resorcylidene aminoguanidine (RAG), DL-penicillamine (PNCA) and captopril on early and advanced glycation of human serum albumin (HSA). We also assessed inhibition of lipid peroxidation by AG and RAG in erythrocytes. Incubation of HSA with D-glucose (20 mM, 37 degrees C for 21 days) led to the formation of Amadori products and fluorescent advanced glycation end-products (AGE). Only PNCA markedly reduced the formation of Amadori products, while all tested compounds markedly reduced the formation of AGE. AG and RAG also inhibited malondialdehyde formation in erythrocytes incubated with hydrogen peroxide. Addition of AG at concentrations from 1 microM to 1 mM caused a 10-80% inhibition of lipid peroxidation. Thus, AG and RAG inhibit toxic oxidative processes and may have therapeutic potential in a number of human diseases.

[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.

[Inhibition of lipid peroxidation in erythrocytes by aminoguanidine, resorcylidine aminoguanidine and their oxygen and sulfur analogs in diabetic rats]. / Inhibícia peroxidácie lipidov v erytrocytoch diabetických potkanov aminoguanidínom, rezorcylidénaminoguanid ínom a ich kyslíkovými a sírnymi analógmi.

This study examined the effect of aminoguanidine (AG) and its structural analogs semicarbazide (SK) and thiosemicarbazide (TSK), as well as their condensation products with 2,4-dihydroxybenzaldehyde-resorcylidene aminoguanidine (RAG), resorcylidene thiosemicarbazone (RTSKon), and resorcylidene semicarbazone (RSKon) on erythrocyte lipid peroxidation in rats with diabetes mellitus induced by hydrogen peroxide. All of the tested compounds at concentrations 1 mmol.l-1 in incubation mixture significantly inhibited the formation of malondialdehyde (MDA), an end product of lipid peroxidation, as assessed by its thiobarbituric acid reactivity. AG and RAG were the most effective inhibitors of lipid peroxidation 90%). It was also found, that RSKon and RTSKon were more potent inhibitors of lipid peroxidation (70 and 80%) compared to Sk and TSK (50%). We suppose that this increase of inhibitory effect by compounds with resorcylidene group may be due to the formation of quinone structure.

[Importance of advanced glycation end products--AGE products]. / Význam koncových produktov pokrocilej glykácie--AGE-produktov.

Recent experimental findings suggest that free oxygen radicals and AGEs may be significantly involved in the onset and development of chronic diabetic complications and Alzheimer's disease. The presented review summarizes knowledge on structure and rise of these products in vitro and in vivo and the chemical and biological properties of advanced glycation endproducts are discussed. Strategy of influencing development and prevention of diabetic complications in the near future involves a potentially promising antiglycation therapy and supplementation by antioxidants.

[The role of calcium inhibitors in the treatment of arterial hypertension]. / Miesto Ca-inhibitorov v liecbe artériovej hypertenzie.

Base on their own experience with isradipine and results of a multicentric study with amplodipine in the Slovak Republic, as well as based on data in the literature the authors conclude that: 1. In the treatment of arterial hypertension associated in the syndrome of insulin resistance (syndrome X and 5H resp.) with type 2 diabetes, hyperlipiproteinaemia and hyperinsulinism drugs of first choice include ACE-inhibitors and Ca antagonist of the second generation, dihydropiridine type, such as amplodipine, isradipine, fellodipine, nirtendipine etc. ACE inhibitors and Ca antagonist of the dihydropyridine type with prolonged effect have a good tolerance, few undesirable effect, a favourable effect on the decline of BP, regression of hypertrophy of the left ventricle and vascular wall; they do not cause deterioration of insulin resistance and thus do not interfere with compensation of diabetes and associated hyperlipoproteinaemia. 2. ACE inhibitors moreover reduce glomerular filtration and albuminuria and thus retard along with the effect on BP the progression of diabetic nephropathy. 3. In pre-existing hyporeninemic hypoaldosteronism (cca in 18% diabetic subjects) they can however cause dangerous hyperkalinaemia by further inhibition of the damaged renin-angiotensin-aldosterone system. In instances Ca inhibitors are indicated. The latter activate RAAS and do not have an impact on albuminuria. By their effect on the vas deferens they can increase glomerular filtration. 4. Diuretics are not suitable for the treatment of hypertension in X syndrome and the use of beta-blocking agents even with ISA and beta-1-selective preparations in restricted in particular when insulin is administered or other numerous contraindications are present (cardiac failure, bradyarrythmias, bronchitis etc.). Perhaps a combination of ACE-inhibitors and Ca antagonists of the 2nd generation with an alpha-blocking agent or hybrid alpha-beta-blocking agent is a suitable solution.

[The effect of long-term treatment of arterial hypertension with Ca antagonists on the renin-angiotensin-aldosterone system in diabetics. Hyporeninemic hypoaldosteronism]. / Vplyv dlhodobej liecby artériovej hypertenzie Ca-antagonistami na aktivitu renín-angiotenzín-aldosterónového systému (RAAS) u diabetikov. Hyporenínový hypoaldosteronizmus.

During long-term treatment of arterial hypertension with calcium antagonists of the dihydropyridine type activation of the sympathetic nervous system and subsequently also of the renin-angiotensin-aldosterone system persists, while the haemodynamic reaction to vasodilatation, manifested by an elevated pulse rate and minute volume from the initial stage of therapy, recedes. In type II diabetics the basal and stimulated response of the renin-angiotensin-aldosterone system is reduced. The administration of calcium antagonists of the dihydropyridine type does not stimulate significantly the renin-angiotensin-aldosterone system as the starting function of the sympathetic nervous system is impaired within the framework of vegetative neuropathy. In almost 20% NIDDM plasma renin activity and aldosterone do not respond to furosemide administration and the vertical posture. In others the response is found but takes place at reduced levels. Hyporeninaemic hypoaldosteronism is thus manifested not so much by a drop of plasma renin and aldosterone beneath the lower range of reference values as by a reduced response to stimulation. Functional hyporeninaemic hypoaldosteronism is another, frequent late complication of diabetes. In advanced forms a further block of the renin-angiotensin-aldosterone system by ACE inhibitors can then produce, even in the absence of diabetic nephropathy, in the stage of chronic renal failure dangerous hyperkaliaemia which may threaten the patient. Dynamic examination of the sympathetic nerve and the renin-angiotensin-aldosterone system makes it possible to predict this condition. In practice it is necessary in diabetics with arterial hypertension after starting with ACE inhibitors during the first days to monitor repeatedly plasma potassium and creatinine. ACE inhibitors and calcium antagonists are otherwise for diabetics drugs of first choice which can arrest the progression of nephropathy, effectively reduced the blood pressure without causing deterioration of insulin resistance and hyperlipoproteinaemia and lead even to regression of hypertrophy of the vascular wall and left ventricle.

[Insulin resistance and arterial hypertension]. / Inzulínová rezistencia a artériová hypertenzia.

The hypothesis of insulin resistance in the pathogenesis of arterial hypertension as part of the hormonal metabolic X syndrome and our 5H syndrome resp. (association of hyperinzulinism with hyperglycaemia-NIDDM-hyperlipoproteinaemia, hypertension and a hyperandrogenic state in women) is based on sympathomimetic, sodium retention and trophic effects of insulin. In the submitted paper the authors review opinions supporting and refuting the validity of this hypothesis. Based on the results of different studies in recent years another genetic predisposition comes also to the foreground, i.e. reduced vascularization of the skeletal muscles which on the background of insulin resistance leads to enhanced development of hypertension with subsequent hypertrophy of the vascular wall and left ventricle and to the development of arteriosclerosis. From the clinical aspect this stimulating pathogenetic concept within the framework of the hormonal and metabolic X syndrome and 5H syndrome makes it possible to use a more adequate approach to prevention and treatment not only of arterial hypertension but also of associated phenomena which enhance the risk of cardiovascular morbidity and mortality in the population. The authors summarize factors which during non-pharmacological treatment promote insulin resistance and those which improve it. When drugs are selected for pharmacological treatment, priority is given to those which improve the insulin sensitivity index (ACE-inhibitors, alpha blockers) or are at least neutral in this respect (Ca antagonists, beta blockers with ISA and cardioselective). The drugs must not enhance associated hyperlipoproteinaemia, hypercoagulability, hyperviscosity, hyperuricaemia) and they should exert a positive effect on the regression of hypertrophic vascular walls and the left ventricle.

[The importance of studying the renin-angiotensin-aldosterone system in essential arterial hypertension in clinical practice. Activity of the renin-angiotensin-aldosterone system during treatment of hypertension with ACE-inhibitors and beta blockers]. / Význam vysetrovania renín-angiotenzín-aldosterónového systému u esenciálnej artériovej hypertenzie v klinickej praxi. Chovanie sa renín-angiotenzín-aldoesterónového systému v priebehu liecby hypertenzie ACE--inhibitormi a betablokátormi.

The authors assessed in 20 subjects with mild or medium severe arterial hypertension basal and stimulated values of plasma renin activity (PRA) and aldosterone before onset of treatment and after 6-week therapy with enalapril (ENAP KRKA) or metoprolol (Vasocardin Slovakofarma). PRA and aldosterone secretion was stimulated by a vertical position and by administration of 40 mg furosemide by the i.v. This test proved suitable for assessment of secondary arterial hypertension in different forms of primary hyperaldosteronism and for expressing suspicion of renovascular hypertension and hypertension with affection of the renal arteries resp. Based on PRA levels, arterial hypertension can be divided into normorenin, high-renin and low-renin hypertension. This classification is, however, of no value for selection of treatment and the prognosis of hypertension. Each level of PRA can be associated with three different aldosterone levels. PRA and aldosterone did not correlate with urinary K, Na excretion nor with blood pressure. During treatment with ACE inhibitor PRA rose while basal as well as stimulated aldosterone levels declined. After administration of betablockers basal as well as stimulated PRA and aldosterone levels declined.

[Insulin resistance and arterial hypertension. Hyperinsulinism as a basic etiopathogenic factor in essential arterial hypertension and associated phenomena]. / Inzulínová rezistencia a artériová hypertenzia. Hyperinzulinizmus ako základný etiopatogenetický clánok esenciálnej artériovej hypertenzie a pridruzených fenoménov.

In 50 normotonic patients with type 2 diabetes (NIDDM) and controls matched for sex and age with NIDDM and hypertension a statistically significant difference was found as regards S-peptide values on fasting, cholesterol, triglycerides, BMI and atherogenic index (cholesterol/HDL, p < 0.01). C-peptide values correlated positively with values of the systolic and median BP and the atherogenic index in both groups. In normotonic diabetics there was also a positive correlation with the BMI and in hypertonic subjects with the triglyceride levels. The results confirm the hypothesis that in NIDDM there is a direct relationship between arterial hypertension, unfavourable lipid parameters and insulin resistance and compensatory hyperinsulinism resp. The authors discuss possible mechanisms by which hyperinsulinism mediates a rise of BP, hyperlipoproteinaemia, hyperglycaemia and hirsutism (hormonal metabolic syndrome X and 5H resp.). These phenomena are the main risk factors of cardiovascular diseases and lead via heart attacks and cerebrovascular attacks (IHD and stroke) to a high cardiovascular morbidity and mortality in our population. The morbidity and mortality is steadily increasing and thus we are among civilized countries among those with the highest morbidity and mortality.

[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.

[Autoimmune mechanisms in endocrinology--the polyglandular autoimmune endocrine syndrome]. / Autoimúnne mechanizmy v endokrinológii--polyglandulárny autoimúnny endokrinný syndróm (PAES).

Autoimmune endocrinopathies belong to so-called organ specific autoimmune diseases. These diseases combine very often and from the polyglandular autoimmune endocrine syndrome (PAES), where autoantibodies either destroy or stimulate individual endocrine glands or hormone receptors in target tissues. Thus a wide range of combinations of hypofunctional or hyperfunctional clinical syndromes develops. PAES is a good natural model of endocrine polyautoaggressiveness. In its development the following aetiopathogenetic factors participate: 1. Hereditary familial disposition, expressed e.g. by certain inherited HHS genes (e.g. A1, B8, DR 3, 4). 2. Aberrant expression of these DR genes on endocrine organs due to bacterial or viral infections, pregnancy, stimulation of the thyroid gland by TSH or immunoglobulins (TSIg). 3. Antigenic mimicri and the presentation of autoantigens to immunocompetent cells. 4. Impaired immunoregulation--antigen specific insufficiency of suppressor T lymphocytes. 5. Local and general amplification reaction to an autoimmune process. 6. The development and autoreproduction of organ specific autoimmune endocrine disease and its development into the final stage of endocrine disease where autoantibodies may disappear. The diagnosis of PAES in clinical practice is difficult. Common immunological tests are not very conclusive. To assess a polyglandular affection we found useful the multiaxial synchronous test where stimulation of several hypothalamic releasing hormones combined with a hypoglycaemic stimulus is used. Autoimmune lymphocytic hypophysitis is part of PAES. In clinical practice this syndrome is therefore frequently incorrectly diagnosed and then incorrectly treated.