Inflammation markers are associated with metabolic syndrome and ventricular arrhythmia in patients with coronary artery disease.

BACKGROUND: Inflammation plays a major role in the development and progression of atherosclerosis and coronary artery disease (CAD). Inflammation markers, including white blood cell (WBC) count, C-reactive protein (CRP) and interleukin-6 (IL-6), are widely used for cardiovascular risk prediction. The aim of the study was to establish factors associated with WBC, CRP and IL-6 in patients with CAD. Two functional polymorphisms in genes encoding enzymes participating in adenosine metabolism were analyzed (C34T AMPD1, G22A ADA). METHODS: Plasma concentrations of IL-6 were measured using high-sensitivity ELISA kits, and the nephelometric method was used for high-sensitivity CRP (hs-CRP) measurement in 167 CAD patients. RESULTS: Presence of metabolic syndrome (MS) and its components, presence of heart failure, severity of CAD symptoms, severe past ventricular arrhythmia (sustained ventricular tachycardia [sVT] or ventricular fibrillation [VF]), lower left ventricle ejection fraction, higher left ventricle mass index, higher end-diastolic volume and higher number of smoking pack-years were significantly associated with higher WBC, CRP and IL-6. Strong associations with arrhythmia were observed for IL-6 (median 3.90 vs 1.89 pg/mL, p<0.00001) and CRP concentration (6.32 vs 1.47 mg/L, p=0.00009), while MS was associated most strongly with IL-6. CRP and IL-6 were independent markers discriminating patients with sVT or VF. There were no associations between AMPD1 or ADA genotypes and inflammation markers. CONCLUSIONS: WBC, CRP and IL-6 are strongly associated with components of the metabolic syndrome. Their strong association with life-threatening ventricular arrhythmia emphasizes the proarrhythmic role of inflammation in the increased cardiovascular risk of CAD patients.

Association between low-dose folic acid supplementation and blood lipids concentrations in male and female subjects with atherosclerosis risk factors.

BACKGROUND: Folic acid (FA) is one of the B complex vitamins. It is thought that FA deficiency promotes atherosclerosis formation in arterial endothelium. FA, acting through reducing homocysteine (Hcy) levels, may contribute to decreased cholesterol (Ch) synthesis. The aim of this study was to analyze the association of low-dose folic acid supplementation with blood lipids concentrations in subjects with atherosclerosis risk factors. MATERIAL/METHODS: The study enrolled 124 Caucasian individuals (60 M, ages 20-39; and 64 F, ages 19-39) with atherosclerosis risk factors (family history of premature ischemic stroke, arterial hypertension, dyslipidemia, overweight and obesity, cigarette smoking, and low level of physical activity). The participants were asked to take FA at a low dose of 0.4 mg/24 h for 12 weeks. RESULTS: FA levels increased in females (6.3 vs. 12.5 ng/dL; p=0.001) and males (6.4 vs. 11.4 ng/dL; p=0.001) and Hcy levels decreased (10.6 vs. 8.3 µmol/L; p=0.001 and 11.5 vs. 9.3; p=0.001, respectively). A significant reduction in mean concentration of total cholesterol in females (203.4 vs. 193.1 mg/dL; p=0.001) and in males (209.5 vs. 201.9; p=0.002) was observed. The low-density lipoprotein cholesterol (LDL-C) levels decreased in females and in males (107.4 vs. 99.9 mg/dL; p=0.001 and 121.5 vs. 115.1; p=0.002, respectively). The apoAI concentrations increased in smoking women and in men with BMI≥25 kg/m2 (p=0.032 and p=0.024, respectively). CONCLUSIONS: Low-dose FA supplementation has a beneficial effect on blood lipids through decreasing concentrations of total cholesterol and LDL-C and increasing concentrations of apoAI.

Does the progeny of premature ischemic stroke sufferers need intensive interest of physicians oriented toward primary prevention? A pilot study.

BACKGROUND: Few studies focus on the progeny of stroke patients with respect to the occurrence of other potential risk factors. METHODS: The study group covered 60 males and 62 females whose parents had suffered premature ischemic stroke (PIS); the control group comprised of 41 males and 47 females whose parents had no history of premature vascular event (mean age: 28.4 and 27.1 years, respectively). Examination of both the groups consisted of evaluation of their diet, measurement of arterial blood pressure and body mass index (BMI). Moreover, blood test was carried out and concentration of biochemical stroke risk factors was determined. RESULTS: The adult progeny of parents with a history of PIS followed a deficient, unbalanced, and nonvaried diet. Their average blood pressure and BMI reached higher values, compared with the results obtained in the control group (125.7±16.06 vs. 122.64±10.83 mmHg; 24.27±3.98 vs. 22.54±2.69 kg/m, respectively; P<0.05). The same applies to average concentrations of the triglycerides 1.22±0.76 vs. 1.06±0.54 mmol/l; total cholesterol (5.34±1.16 vs. 4.82±0.89 mmol/l), low-density lipoprotein-cholesterol (2.95±0.97 vs. 2.52±0.73 mmol/l), total homocysteine (11.22±4.22 vs. 10.18±2.45 µmol/l), and fibrinogen (2.91±0.68 vs. 2.78±0.6 g/l) (P<0.05). CONCLUSION: Adult children of PIS sufferers show different stroke risk factor profiles than the control group. It may indicate a need for preventive activities for this group in the future. Family occurrence of stroke requires further detailed studies on a larger cohort of patients from risk group.

Effects of fenofibrate treatment on prothrombotic state in patients with metabolic syndrome in relation to smoking and diabetes.

BACKGROUND: Patients with metabolic syndrome (MS) are characterized by enhanced procoagulant activity caused by an increased fibrinogen (Fb) level, impaired fibrinolysis, and platelet activation. Fibrate treatment usually normalizes these conditions. The aim was to determine the effect of fenofibrate treatment on Fb level, fibrinolysis, and platelet function in patients with MS with regard to smoking status and type 2 diabetes. MATERIAL/METHODS: Sixty-four patients with MS, including 20 active smokers, without clinical features of coronary heart disease were enrolled in the study. Before and during treatment with fenofibrate all patients took antihypertensive drugs and 25 patients with type 2 diabetes used oral antidiabetic drugs. Before and after the treatment the levels of lipids, fasting glucose insulin, Fb, PAI-1, t-PA, and platelet function expressed as closure time (CT, after Coll/Epi and Coll/ADP) were measured. RESULTS: Fenofibrate treatment resulted in normalization of abnormal lipid profiles and a reduction in Fb level. In smokers an increase in PAI-1 level and CT shortening after Coll/Epi and after Coll/ADP were found. In nonsmokers, CT was prolonged only after Coll/Epi. A slight reduction in PAI-1 and a reduction in fasting glucose were noted in the diabetics. CONCLUSIONS: Fenofibrate partially corrected procoagulant state in patients with MS, which was manifested by a significant reduction in Fb level in all patients and inhibition of platelet function exclusively in nonsmokers. Smoking neutralizes the effects of treatment with fenofibrate as absence of inhibition of platelet function and a lack of improvement of the fibrinolysis system were observed in them.

[Selected dietary atherosclerosis risk factors in offspring of patients with premature ischemic stroke]. / Wybrane zywieniowe czynniki ryzyka miazdzycy u potomstwa chorych z przebytym przedwczesnym niedokrwiennym udarem mózgu.

UNLABELLED: There are currently multiple reports which conclude that there is a correlation between cardiovascular risk factors, including wrong dietary habits, and occurrence of these factors in families. AIM OF THE STUDY: To evaluate daily intake of selected dietary items, which have influence on premature development of atherosclerosis, in adult offspring of patients who underwent premature ischemic stroke. MATERIAL AND METHODS: 54 patients were included in the study: 21 males, aged 21-38 years (average 25.8 yrs.) and 33 women aged 19-39 years (average 28.2 yrs.). All of them were examined including medical history, physical examination and fasting blood draw. Dietary habits were evaluated with the method of 24-hour history using a questionnaire developed by Institute of Food and Diet in Warsaw, Poland (Instytut Zywnosci i Zywienia). Intake of selected dietary components (dietary cholesterol, fiber, vitamins E, C, B6, B12 and folic acid) was assessed using a computer program "Dietician 2" ("Dietetyk 2") which had been developed by the Institute of Food and Diet. RESULTS: In males, compared to females, there was a significantly higher (p < 0.05) level of daily calorie intake (2400.8 +/- 716.2 vs 1583.1 +/- 584.3 kcal) as well as intake (expressed in percentage of daily allowance) of dietary cholesterol (106.8 +/- 46.2 vs 62.9 +/- 42.8), fiber (70.6 +/- 28.2 vs 52.0 +/- 22.2), vitamin E (98.4 +/- 49.8 vs 63.5 +/- 33.9), folate (53.9 +/- 23.1 vs 37.8 +/- 16.4) and vitamin B12 (99.0 +/- 58.3 vs 57.2 +/- 44.5). There were also significantly higher levels of the following parameters in 22 normal-weight females compared to 11 overweight/obese females: daily calorie intake (1735.2 +/- 613.2 vs 1278.9 +/- 387.7 kcal) as well as intake (expressed in percentage of daily allowance) of dietary cholesterol (73.9 +/- 44.8 vs 40.9 +/- 29.2), folate (42.3 +/- 17.0 vs 28.7 +/- 10.9) and vitamin B12 (68.2 +/- 48.0 vs 35.1 +/- 26.4). CONCLUSIONS: The examined offspring (especially daughters) of a parent with premature ischemic stroke ate insufficient, unbalanced and monotonous diet, which impaired their nutrition. This should motivate family physicians to put greater interest in primary prevention in this group of patients. Overweight and obese women were put at even greater risk because such diet was added to other atherosclerosis risk factors, i.e. family history of premature ischemic stroke and increased body mass.

[The assessment of the influence of natural coffee and its modified form on the level of homocysteine, vitamin B6 and folic acid in healthy volunteers]. / Ocena wplywu kawy naturalnej i jej formy zmodyfikowanej na stezenie homocysteiny oraz witaminy B6 i kwasu foliowego u zdrowych wolontariuszy.

UNLABELLED: The aim of our investigation was the assessment of the influence of natural coffee and that modified by water and pressure extraction (60% less of 2-methyl isoborneol) on the level of homocysteine, folic acid and vitamin B6 in healthy volunteers. MATERIAL AND METHODS: The study was conducted on 36 healthy volunteers. 20 women and 16 men; smokers constituted half of the group. The study was conducted as a double blind trial (coffee without labels) after randomization into two groups. Initially for 4 weeks, one group drank natural coffee and the other a modified one. After four weeks there was a 28-day break in drinking coffee, after which the groups swapped roles and another trial lasted for the subsequent 4 weeks. All people examined drank three servings of coffee a day brewed from 13 g of material in 180 ml of boiling water. Throughout the entire experiment the examined subjects did not change their diets and did not take any vitamin supplements. Blood for analysis was drawn four times and the following analyses were carried out. homocysteine, folic acid, vitamin B6 total, LDL and HDL-cholesterol, triglicerides, Lp(a) and fibrinogen. RESULTS: We found a significant increase level of plasma homocysteine from 9.6 to 11.4 micromol/l (p < 0.001) in persons drinking natural, unfiltered coffee. However drinking modified coffee free from irritants resulted in a tendency towards lowering the level of homocysteine (from 9.1 to 8.7 micromol/l). CONCLUSIONS: From the above study it may be concluded that lowering the content of irritants in coffee results in reducing its undesired influence on the homocysteine level. Reduction of natural coffee consumption or its change on coffee with lowering the content of irritants should be recommended to cardiovascular disease persons.

Does the type of hormone replacement therapy affect lipoprotein (a), homocysteine, and C-reactive protein levels in postmenopausal women?

BACKGROUND: The results of studies evaluating the effect of hormone replacement therapy (HRT) on the cardiovascular risk raise many controversies. This may be related to both the type of treatment used and the disregard of additional risk factors. OBJECTIVE: The objective of the study was to evaluate the effect of natural estrogens taken transdermally and synthetic estrogens taken orally on the concentrations of lipoprotein (a) [Lp(a)], homocysteine, and C-reactive protein (CRP) in healthy women in the early postmenopausal period. Material The study was conducted on 61 healthy women with average age of 52.3 +/- 4.1 years, in the postmenopausal period, who were randomly assigned to 3 groups depending on the type and route of administration of the products. Group I (n = 24) was administered transdermal estrogens (micronized 17beta-estradiol; Systen, Janssen-Cilag, Switzerland) and progesterone in the second phase of the cycle. Group II (n = 21) was administered oral hormones (Cyclo-Menorette). Group III (n = 16), serving as a control, included women taking placebo in the form of patches. In each group, therapeutic cycles took 22 days and were followed by a treatment-free interval of 7 to 10 days for a 3-month period. RESULTS: After 3 months of treatment, Lp(a) and homocysteine levels were not significantly different from the baseline, irrespective of the route of administration of estrogens or placebo. Both forms of HRT used indicate significant difference in changes of CRP concentration during 3 months of administration (analysis of variance P = .0356). CRP concentration values increased in the group of women using oral HRT from 1.22 to 2.68 mg/L. In the group of women using oral therapy, significantly more cases (61%) of increase in CRP concentration compared with 39% in the transdermal HRT group (chi(2) P = .015) were observed. CONCLUSIONS: On the basis of our observations, it appears that in women in the early postmenopausal stage with normal initial concentrations of Lp(a) and homocystein, the form of therapy used has no influence on values of these parameters. The 2 forms of HRT therapy differ in effect, which is expressed as a change in CRP concentration. A tendency to increase CRP values when using oral HRT is observed, while such an effect is not observed in case of transdermal therapy after 3 months.

[Effect of low doses of folic acid on selected biochemical atherosclerosis risk factors--preliminary study]. / Wplyw malych dawek kwasu foliowego na wybrane biochemiczne czynniki ryzyka miazdzycy--badanie wstepne.

UNLABELLED: The aim of the present paper was evaluation of the impact of the three-months' supplementation with low doses of folic acid on concentration of homocysteine and other biochemical atherosclerosis risk factors with patients endangered with ischemic stroke or other disease being atherosclerosis-derivative. MATERIAL AND METHODS: The examined group consisted of 34 adult children of parents of which at least one fell ill at a young age with ischemic stroke. There were examined 9 men and 25 women aged from 19 to 36 years (average age 24.8 years). The testing procedure consisted in three-months' supplementation with folic acid (a 0.4 mg a day) and in check-up of blood parameters. The tests were performed prior to and after 3 months of taking folic acid. There were following laboratory tests performed: lipid profile [triglycerides, total cholesterol as well as LDL-cholesterol and HDL-cholesterol fractions, apolipoprotein B and Al, lipoprotein(a)] and folic acid, homocysteine, fibrinogen, von Willebrand factor as well as blood cell count, thrombocytes, ESR and basic biochemical parameters. RESULTS: Increased average concentration levels were detected for folic acid by 5.4 ng/dl (increase by 62.8%), apolipoprotein Al by 2.3 mg/dl (1.5%) and for fibrinogen by 0.2 g/l (7.1%). Decreased average concentration levels were detected for: homocysteine by 2.1 micromol/ l (drop by 18.9%) and for LDL-cholesterol by 4.4 mg/dl (4.4%/1). Furthermore, a significant increase in average concentration level of uric acid was detected as well as drop in average hemoglobin value, erythrocytes, creatinine and urea. Other blood cell count elements, thrombocytes, ESR and biochemical parameters did not show, in a check test, any significant differences. CONCLUSIONS: Low doses of folic acid, owing to its reducing influence on some risk factors, may be recommended with precautions in the atherosclerosis prevention, e.g. for families with past premature cardiovascular episode. However, insufficient number of tested persons does not permit to draw more radical conclusions. The tests should be conducted on a bigger group of patients.

Effect of Lactobacillus plantarum 299v on cardiovascular disease risk factors in smokers.

BACKGROUND: The short-chain fatty acids formed in the human colon by the bacterial fermentation of fiber may have an antiinflammatory effect, may reduce insulin production, and may improve lipid metabolism. We previously showed in hypercholesterolemic patients that supplementation with the probiotic bacteria Lactobacillus plantarum 299v significantly lowers concentrations of LDL cholesterol and fibrinogen. OBJECTIVE: We determined the influence of a functional food product containing L. plantarum 299v on lipid profiles, inflammatory markers, and monocyte function in heavy smokers. DESIGN: Thirty-six healthy volunteers (18 women and 18 men) aged 35-45 y participated in a controlled, randomized, double-blind trial. The experimental group drank 400 mL/d of a rose-hip drink containing L. plantarum 299v (5 x 10(7) colony-forming units/mL); the control group consumed the same volume of product without bacteria. The experiment lasted 6 wk and entailed no changes in lifestyle. RESULTS: Significant decreases in systolic blood pressure (P < 0.000), leptin (P < 0.000), and fibrinogen (P < 0.001) were recorded in the experimental group. No such changes were observed in the control group. Decreases in F(2)-isoprostanes (37%) and interleukin 6 (42%) were also noted in the experimental group in comparison with baseline. Monocytes isolated from subjects treated with L. plantarum showed significantly reduced adhesion (P < 0.001) to native and stimulated human umbilical vein endothelial cells. CONCLUSION: L. plantarum administration leads to a reduction in cardiovascular disease risk factors and could be useful as a protective agent in the primary prevention of atherosclerosis in smokers.

A sensitive and specific HPLC method for the determination of total pentosidine concentration in plasma.

Pentosidine is an advanced glycation end-product (AGE) appearing when arginine and lysine residues in proteins are cross-linked with carbonyl derivatives. This paper presents an improved method for the synthesis of pentosidine and reversed-phase chromatography of this substance with fluorometric detection that enables sensitive (0.01 pmol/mg protein) and specific determination of pentosidine in plasma. Separation is done twice on the same C(18) Vydac 218TP54 column, first with trifluoroacetic acid and next with heptafluorobutyric acid as ion pair. The inter-day coefficient of variation is 6.4% at pentosidine concentration in plasma of 25 pmol/mg protein and 8% at 1.7 pmol/mg protein. Spectral properties of pentosidine exploited during identification of the substance with UV absorption and fluorescence detectors are described. Maximum of absorbance was observed at 325 nm, maximum fluorescence at lambda(ex)/lambda(em)=330/373 nm. The method may prove useful for the study of processes associated with generation and accumulation of pentosidine in the body as a marker of AGE production in healthy subjects and patients with chronic renal failure.

Homocysteine and metabolic risk factors in individuals with family history of premature ischemic stroke.

INTRODUCTION: Family history of stroke is an independent risk factor for cardiovascular disease (CVD). OBJECTIVES: The aim of this study was to evaluate selected metabolic risk factors and an association between the interaction of family history of premature ischemic stroke (PIS) and homocysteine (Hcy) levels with other risk factors in individuals with family histo ry of PIS. PATIENTS AND METHODS: The study involved 344 healthy individuals, including 143 with family history of PIS and 201 without family history of PIS (control group). RESULTS: In the group with family history of PIS, a significantly higher mean body mass index (BMI), systolic and diastolic blood pressure (SBP and DBP), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB), ApoB/ apolipoprotein A-I (ApoA-I), and glucose values were observed in women, while in men, significantly higher mean values of BMI, SBP and DBP, total cholesterol (TC), LDL-C, ApoB/ApoA-I, and lower ApoA-I. There was a significant interaction of family history of PIS × Hcy for TC/high-density lipoprotein cholesterol (HDL-C), HDL-C, and triglycerides (TG) in women, and for TC/HDL-C, TC, and TG in men. Higher Hcy levels were associated with significantly higher values of TC/HDL-C and TG both in men and women, and with lower HDL -C levels in women and higher T C and LDL-C levels in men. CONCLUSIONS: Men and women with family history of PIS are characterized by an unfavorable shift in the risk factor profile. This effect is additionally enhanced by higher Hcy levels, which might be an indication for primary prevention in these individuals.

Hyperhomocysteinemia in patients with symptomatic chronic heart failure: prevalence and prognostic importance--pilot study.

BACKGROUND: Patients with chronic heart failure (CHF) may be particularly susceptible to unfavorable effects of hyperhomocysteinemia (HHcy). The aim of this study was to assess the prevalence of HHcy (plasma homocysteine [Hcy]>or=14 micromol/L) in an unselected cohort of CHF patients, its clinical determinants, and prognostic implications. METHODS AND RESULTS: In 108 consecutive CHF patients (81 men, age: 66+/-11 years) with mean plasma Hcy level 12.5+/-5.5 micromol/L (range 2.3-28.3 micromol/L), 38 (35%) patients demonstrated HHcy. Among clinical and metabolic parameters, in multivariable regression models, advanced NYHA class (P<0.0001), plasma NT-proBNP (P<0.001), peak oxygen consumption (P<0.05), reduced glomerular filtration rate (P<0.0001) and elevated serum uric acid (P<0.05) predicted high plasma Hcy level. HHcy was related to increased mortality (HR=3.26, 95% CI: 1.78-5.98, P=0.0001), also when adjusted for conventional prognosticators in multivariable models (all P<0.01). In patients with HHcy, a 3-year survival was 37% (95% CI: 22-52%) as compared to 73% (95% CI: 63-83%) in those with normal Hcy levels (P<0.0001). CONCLUSIONS: HHcy is common in CHF, is related to the disease severity, depicts generalized metabolic imbalance (evidenced by hyperuricaemia), and independently predicts poor long-term prognosis.

[Assessment of metabolic atherosclerosis risk factors in progeny of patients with past ischemic stroke]. / Analiza metabolicznych czynników ryzyka miazdzycy u potomstwa chorych po przebytym niedokrwiennym udarze mózgu.

Early diagnosing and modification or elimination of atherosclerosis risk factors with the descendants of the ill with past ischemic stroke (IS) might reduce risk of subsequent stroke incidence in the family, or myocardial infarction or other disease being atherosclerosis - derivative. This subject seems to be essential because it concerns young people. The purpose of the present study is identification and assessment of metabolic atherosclerosis risk factors with adult progeny of the ill with past IS at young age. There were examined 43 adult children of the parents who fell ill at young age (between 39 and 55 years in case of men and 60 years in case of women) with IS. The test group included 21 men and 22 women aged from 19 to 39 years (average age - 26.3 years). The reference group consisted of 40 persons, including 18 men and 22 women aged from 22 to 39 years (average age - 26.8 years). The persons from reference group were corresponding (in respect of structural aspects, such as age and sex) to the test group, their parents had negative history towards atherosclerosis - derivative illnesses. None of the patients under examination was a cigarette smoker. Examination of both groups consisted in conducting anamnesis, measurement of body weighing and height, blood pressure as well as evaluation of biochemical atherosclerosis risk factors. Blood testing (blood serum or plasma) consisted of blood cell count and ESR as well as blood glucose level, creatinine, urea, transaminase and bilirubin levels as well as total cholesterol, LDL cholesterol and HDL cholesterol fractions, apolipoprotein B, apolipoprotein AI, lipoprotein (a), triglycerides, homocysteine, folate, fibrinogen, von Willebrand factor and C-reactive protein level. Among persons whose parents were affected, at young age, with IS higher average level of BMI (24.2 +/- 3.8 kg/m2) was detected as compared with that in the reference group (22.4 +/- 2.5 kg/m2), LDL cholesterol fraction (2.7 +/- 0.8 mmol/l vs 2.4 +/- 0.6 mmol/l) and triglycerides (1.1 +/- 0.4 mmol/l vs 0.8 +/- 0.4 mmol/l) as well as lower level of apolipoprotein Al (1.5 +/- 0.2 g/l vs 1.6 +/- 0.2 g/l). Average values of other factors in the blood serum were not significantly different in both with compared groups. In case of women, whose parents were affected with IS, higher levels of the following indicators were detected: BMI (24.3 +/- 3.9 kg/mz vs 21.5 +/- 2.3 kg/m2), total cholesterol (5.1 +/- 0.7 mmol/l vs 4.4 +/- 0.5 mmol/l, LDL cholesterol (2.7 +/- 0.6 mmol/l vs 2.1 +/- 0.4 mmol/l), apolipoprotein B (1.0 +/- 0.1 g/l vs 0.8 +/- 0.1 g/l), lipoprotein (a) (0.3 +/- 0.2 g/l vs 0.2 +/- 0.1 g/l) and triglycerides (1.0 +/- 0.4 mmol/l vs 0.7 +/- 0.2 mmol/l). In group of men whose parents were affected with IS lower levels of apolipoprotein Al (1.3 +/- 0.2 g/l vs 1.5 +/- 0.2 g/l) and of von Willebrand factor (71.4 +/- 23.9% vs 87.1% +/- 16,8%) were detected. Descendents of the ill with past IS should be treated as higher risk group especially when supranormative values of metabolic atherosclerosis risk factors are detected with them. In case of persons with positive family history of IS, having higher values of metabolic atherosclerosis risk factors, it is necessary to apply intensive actions towards change of their life styles, and if necessary - also to include pharmacological treatment.