[The role of hypotension as a factor of unfavorable prognosis in patients with chronic heart failure].

Despite obvious achievements during last decades in studies of pathogenesis and search for effective ways of treatment of chronic heart failure (CHF) it remains one of most severe and prognostically unfavorable diseases of the cardiovascular system. Thereby determination of predictors of death and detection of high risk patients for more active drug interventions on CHF progression appears to be actual. It has been shown in a number of epidemiological and cohort studies that low arterial pressure (AP) serves as an independent risk factor of prognosis in patients with CHF. In this paper we present short literature review on this theme, consideration of possible mechanisms of negative effect of arterial hypotension on function of vitally important organs in patients with CHF, and summation of data of studies which have demonstrated relationship between low level of AP and worsening of prognosis.

[Influence of chronic cardiac failure severity on the course of comorbid type 2 diabetes mellitus].

AIM: To assess relations between severity of chronic cardiac failure (CCF) and a course of comorbid type 2 diabetes mellitus (DM). MATERIAL AND METHODS: Time course changes of cerebral natriuretic peptide (CNUP) were used as a criterion of CCF severity in 81 patients with mild and moderate CCF (NYHA functional class II-III), left ventricular ejection fraction (LVEF) < 45% and type 2 DM. Of them, two groups of 19 patients each were compiled--with the highest and lowest CNUP levels. Also, patients with a rising CNUP level and CCF FC (n = 5) and those with decreasing CNUP and FC improvement (n = 33) were analysed. The following parameters were studied at baseline and 6 months later: clinicofunctional status, glomerular filtration rate (GFR), neurohormonal profile (CNUP), noradrenalin and angiotensin II, the level of HbA1c, baseline and postprandial plasma glucose, serum insulin and C-peptide. RESULTS: Insignificant changes in glycemia in low C-peptide were found in groups with mild CCF. In patients with high CNUP and CCF FC there was a positive correlation between high CNUP, noradrenalin and fasting glucose. With growing severity of CCF clinicofunctional status of the patients was deteriorating while levels of noradrenalin and angiotensin II tended to rise. CONCLUSION: Moderate decompensation of CCF had no effect on the course of associated DM. More severe and long-term decompensation may be accompanied with noticeable changes in glycemia.

[The study of peculiarities of immunotropic action of statins in chronic heart failure of various etiology].

AIM: To study features of statin therapy in patients with heart failure (HF) of different etiology on immune system. MATERIAL AND METHODS: The basic markers of immune activation in 43 patients with chronic heart disease (CHD) and HF in New York Heart Association (NYHA) class I to IV were studied. Mine age was 48 +/- 8 years (from 33 to 64 years). 43 patients with dilated cardiomyopathy (DCM) and HF were also observed. Mine age was 43 +/- 10 years (from 22 to 61 years). Parameters of systolic and diastolic left ventricle (LV) function were measured. Also non invasive methods for evaluation of endothelial function were used. Concentrations of hsCRP, IgG, IgA, IgM were measured using commercially available kits. IL 6, IL 8, sIL 2R, IL 18, IL 10, IFN Y, endothelin levels were measured using enzyme linked immunosorbent assay method. RESULTS: Statin therapy has immunomodulation effect in patients with heart failure any etiology. This effect depends on etiology of HF. In CHD patients the decreasing of IFN Y, IL 8, sIL 2R, hsCRP and increasing of IL 18, IL 6 levels were observed. In DCM patients the decreasing of IL 8, IL 18, sIL 2R and increasing of IL 10 were observed. There was significant clinical improving in patients with DCM and HF after statin therapy. But there were no changes of endothelial function in patients with CHD and DCM. There were no changes of LV function in patients with CHD. So statin therapy may reduce level of proinflammatory mediators but not fully control inflammation process in patients with HF of different etiology.

[Immune mechanisms of inflammation in dilated cardiomyopathy].

AIM: To study immune mechanisms of inflammation in dilated cardiomyopathy (DCM). MATERIALS AND METHODS: The study of main markers of immune activation was conducted in 44 patients with DCM with stage I - IIB and NYHA functional class (FC) I - IV chronic heart failure (CHF). Among them there were 42 men (95%) and 2 women (5%) in the age from 22 to 61 years. Mean age was 43(10) years. According to FC the patients were distributed in the following way: FC I--10 (23%), FC II--9 (20%), FC III--13 (30%), FC IV--12 (27%). EchoCG was carried out by standard recommendations with assessment of systolic and diastolic function of LV. Measurement of CRP, IgG, IgA, IgM was based on nephelometric method of detection. Content of Il-6, Il-18, Il-10, Il-10, sIl-2R, Il-8, IFN-gamma in blood serum was measured by the method of immunoenzyme analysis. RESULTS: Elevation of levels of CRP, sIl-2R, Il-8 was established in DCM, what evidenced for the presence of inflammatory process. In the group of patients with DCM with rhythm disturbances (predominantly of atrial fibrillation type) elevation of levels of IFN-gamma, CRP was noted what probably was related to Th-1 type of inflammatory reaction. It was revealed that disturbances of diastolic function of the heart had inflammatory genesis (IFN-gamma correlated with parameter of diastolic function DT; elevation of Il-6 level was found in restrictive type of diastolic function). CONCLUSION: Elevation of proinflammatory factors in DCM evidence for the presence of inflammatory process. there exist a link between elevated level of mediators of inflammation and complications of the disease--arrhythmia, worsening of heart failure class, deranged diastolic function of the heart.

[The role of inflammatory factors in pathogenesis of ischemic heart disease].

PURPOSE: To study mechanisms of immune derangements in coronary heart disease (CHD). MATERIAL AND METHODS: We measured basic markers of immune activation in 43 patients with CHD and NYHA I-IV class heart failure (HF). There were 41 men and 2 women aged 33 - 64 years (mean 48 +/- 8 years). Concentrations of hsCRP, IgA, IgM, IgG were measured using commercially available kits. IL-8, sIL-2R, IL-6, IL-18, IL-10, IFN-gamma endothelin levels were measured using enzyme-linked immunosorbent assay method. RESULTS: We found evidence of participation of proinflammatory factors in pathogenesis of HF and established associations of mediators of inflammation (CRP, IL-8) with severity of HF, endothelial dysfunction, and impairment of cardiac function.

[Effect of strict glycemic control on clinical state and course of the disease in patients with chronic heart failure and type II diabetes mellitus. Results of the REMBO "rational effective multicomponent therapy in the struggle against diabetes mellitus in patients with congestive heart failure" study].

With the aim to investigate influence of glycemic control on clinical state and course of disease, renal function, and neurohormonal profile of patients with chronic heart failure (CHF) and type 2 diabetes mellitus (DM) we studied 81 patients with NYHA functional class (FC) II - III CHF, left ventricular ejection fraction (LVEF) 45% and type 2 DM. As a result of randomization 2 groups were formed - active with achievement of target levels of glycemia (n=41) and usual treatment (n=40). Retrospective analysis in dependence of efficacy of sugar lowering therapy was also conducted. Group 1 (n=18) comprised patients with achieved 1% lowering of glycated hemoglobin (HbA1 ), group 2 (n=26) - patients with bA1c lowering < 1%, group 3 (n=31) - patients with increase of HbA1 . Total duration of the investigation for the first analysis was 12, for the second - 6 months. Control examination was carried out at baseline, after 6 and 12 months of investigation and included assessment of clinico-functional status, glomerular filtration rate, neurohormonal profile (brain natriuretic peptide, noradrenalin, and angiotensin II). The state of carbohydrate metabolism was assessed with the help of determination of the level of HbA1c and oral glucose tolerance test. Absence of dynamics of glycemia in active and nonactive groups, in the active group improvement of clinico-functional status, quality of life, and parameters of remodeling was noted. Complementary retrospective analysis revealed improvement of functional status, renal function, and lowering of RAAS activity at 1% lowering of HbA1 and achievement of its target values. With this it was shown that betterment of functional possibilities ensued at lowering of HbA1c level not less than by 0.8%. Thus necessity and efficacy of strict glycemic control of DM in patients with CHF was proved.

[Efficacy and safety of the use of metformin in patients with chronic heart failure and type 2 diabetes mellitus. results of the study "rational effective mulicomponent therapy in the battle against diabetes mellitus in patients with chronic heart failure"].

Aim of the investigation was to study safety of therapy with metformin and its effect on clinical, hemodynamic, functional and neurohumoral status in patients with chronic heart failure and type 2 diabetes mellitus DM). Eighty one patients with light and moderate NYHA functional class (FC) II-III CHF, left ventricular ejection fraction < 45%, and DM were examined. As a result of randomization 2 groups were formed: with active (n=41) and usual (n=40) treatment. In active group with achievement of target levels of glycemia 24 (59%) patients were on oral hypoglicemic drags, 17 (41) patients received. All patients were on basal therapy of CHF. Initially efficacy and safety of metformin was investigated in a cohort of active treatment (jn metformin n=29, control n=12), including patients who were prescribed metformin not for the whole period. In addition in active group analysis was carried out among patients, who continually were treated with metformin for 12 months (n=30) in comparison with patients never treated with metformin (n=8). Total duration of the period of treatment and supervision was 12 months. Control examination was conducted before randomization, after 6 months of treatment, at the end of the study and included assessment of clunico-functional status of patients, renal function (GFR), neurohumoral profile (MNUP, NA, AII). The state of carbohydrate metabolism was assessed with the help of determination of HBA1C level and test with nutritional load given as of common breakfast -- 2-3 in the course of which fasting and postprandial level (in 2 hours after breakfast) of glucose (GLC), and fasting insulin and C-peptide. Overall safety of metformin was confirmed -- throughout whole period of follow up with different variants of comparative analysis no cases of lactic acidosis were revealed. Practical lack of positive influence of metformin on glycemia at its initially not high level was accompanied with improvement of FC CHF, parameters of central hemodynamics, augmentation of functional capacities of patients, improvement of quality of life, lowering of number of decompensations of CHF and diminishment of degree of activation of SAS. It can be suggested that this dynamics is conditioned by the presence of cardioprotective properties in metformin what allows to recommend its application in patients with CHF and type 2 DM.

[Effect of long term therapy with spironolactone on parameters of 24-hour heart rhythm variability and ventricular arrhythmias in patients with heart failure receiving optimal therapy].

UNLABELLED: Aim of the investigation was the study of influence of spironolactone (25-75 mg/day) on clinico-functional and neurohormonal, 24-hour variability of cardiac rhythm, and ventricular disturbances of heart rhythm in patients with chronic heart failure (CHF) receiving optimal therapy. Forty nine patients were included in the study--44 men (89,8%) and 5 women (10.2%) in the age from 28 to 75 years with II-IV NYHA functional class (FC) CHF, LV ejection fraction (EF) 35%, plasma levels of creatinine 150 micromol/L and potassium 5 mmol/L. Main causes of development of CHF were dilated cardiomyopathy, ischemic heart disease (large focal postinfarction cardiosclerosis) and decompensated hypertensive heart [25/20/4 (51%/40.8%/8.2%), respectively]. As a result of randomization 2 groups of observation were formed: group 1-19 patients receiving spironolactone in a 24 hour dose 25-75 mg, group 2-control group-30 patients without therapy with spironolactone. Inhibitors of angiotensin converting enzyme (ACE) took 100%, beta-adrenoblockers--63.2% of patients. Control examination was conducted before randomization, in 6 and 12 months of follow up. During period of observation no changes of FC were noted in control group. In the spironolactone group after 6 months f treatment in 6 patients FC improved (p=0.028). By the end of follow up the given effect lost its significance, but in 5 (38.5%) patients by termination of the study FC II of CHF was noted, what was accompanied with moderate increase of distance walked during 6-minute walk test from 354 to 378 m. Addition of spironolactone to conducted therapy was followed by increase of concentration of aldosterone by 153 (84; 426) microg/ml, p=0.009, what discriminated (p=0.007) the given patients from control group and provoked increase of plasma rennin activity. Median concentration of angiotensin II changed not substantially [0.78 (-1.84; 2.66) mg/ml] after 12 months of treatment. Changes of noradrenalin, vasopressin, and endothelin were insignificant in both groups of observation. After 12 months of treatment median of changes of concentration of atrial natriuretic peptide was -51.9 ( -87; -43.9) microg/ml. At the same time in control group was observed gradual growth of concentrations of the given peptide from initial 107.3 to 168.5 microg/ml by the moment of termination of the study. Basic influence on spectral and temporal indexes of HRV spironolactone exerted in day time of 24 hours with increase of by 24.5 (10; 34) ms (p=0.042) after 6 months of treatment. Maximal lowering of number of ventricular extrasystoles from initial 75 (39; 477) to 12 (0; 15) (p=0.043) were achieved with administration of spironolactone in combination with ACE inhibitor and beta-adrenoblocker after 12 months of treatment what was followed with decrease of number of patients with episodes of of ventricular tachycardia from 50 to 18% (p=0.035). Addition of spironolactone in a dose of 75 mg/day to optimal therapy including ACE inhibitor and b-adrenoblocker is accompanied with betterment of clinical state and FC of patients with CHF. CONCLUSION: Neurohormonal markers of application of spironolactone in combination with ACE inhibitor appear elevation of activity of plasma renin and concentration of aldosterone in combination with lowering of concentration of atrial natriuretic peptide in plasma of patients with CHF. Long term block of aldosterone at receptor level is accompanied with betterment of parameters of HRV in patients with CHF during day time. Addition of spironolactone to therapy with ACE inhibitor and beta-adrenoblocker bisoprolol decreases quantity and severity of ventricular rhythm disturbances in patients with moderate and severe CHF.

[Is triple combination of different neurohormonal modulators recommended for treatment of mild-to-moderate congestive heart failure patients? (Results of Sadko-CHF study)].

AIM: To assess effects of different variants of neurohormonal (NH) modulation with angiotensin converting enzyme (ACE-I) quinapril (Q), angiotensin-receptor blocker (ARB) valsartan (V) and their combination in addition to beta-adrenergic blocker bisoprolol (B) on functional status, quality of life (QOL), parameters of left ventricular (LV) remodeling, main indices of 24-h heart rate variability (HRV) and NH profile in patients with stable mild-to-moderate congestive heart failure (CHF). MATERIAL AND METHODS: Sixty three patients with CHF (NYHA class II-III) as a result of ischemic heart disease and dilated cardiomyopathy with LV EF < 40% were randomly assigned to one of the treatment variants on 1:1:1 basis: B+Q (n = 22), B+V (n = 23) and combination of B+Q + V (n = 18). At baseline, all the patients in this study were on background B treatment and according to the study design Q or V were then added to B at randomization. NYHA FC, 6-min walking test (6MT), QOL, 2D-echocardiography, plasma renin activity (PRA), angiotensin II (AT-II), aldosterone (Ald), norepinephrine (NE), epinephrine (E), brain natriuretic peptide (BNP) concentrations and 24-hour HRV parameters were investigated at baseline, 3 and 6 months after randomization. RESULTS: During the study NYHA FC improvement was revealed in all three treatment groups with comparative significant changes in 6MT distance by 20.4%, 19.1% and 19.4% in B+Q, B+V and B+Q+V groups, respectively. QOL maximally decreased in B+V combination (from 45 to 21 points). LV volumes significantly decreased and LV ejection fraction (EF) increased in all groups to the end of the study. Triple combination had no additional effect on LV volumes and LVEF changes compared to B+Q and B+V groups. Plasma NE concentrations decreased maximally in B+Q group (from 650 to 430 pg/ml, p = 0.007). The lesser effect was observed in the combination of B+Q+V, with any NE changes in B+ V group. The E concentration increased significantly (from 215 to 295 pg/ml, p = 0.024) in the B+Q+V group at the end of the study. Plasma A-II concentration did not differ from the baseline during the study in B+Q group, but significantly increased in B+V group and maximally in B+Q+V group (from 11.4 to 23.5 pg/ml, p = 0.009). To the end of the study plasma Ald concentrations remain reduced significantly only in B+V group. The level of BNP significantly decreased in all 3 treatment groups. Significant changes in HRV indices, both in time and frequency domain, were revealed in the B+Q group at 3-month follow-up and SDNN increased on month 24 (p = 0.039). These changes became insignificant at the end of the study. The lesser effect was revealed in B+Q+V group, with insignificant trend toward an increase of SDNN to the end of the study. HRV indices did not improve in the B+V group. CONCLUSION: During long-term treatment the triple combination of B+Q+ V has no significant advantages over B+Q and B+V by the functional status, QOL and parameters of LV remodeling in patients with mild-to-moderate CHF. The combination of B+Q has more potent effect on 24-hour HRV parameters, sympatho-adrenal activity and renal function compared to B+V and B+Q+V groups in CHF patients in our study. The combination B+Q+V may have a negative effect on NH profile (excessive activation of ATII and E) in CHF patients. The triple combination is not recommended for therapy of stable mild-to-moderate CHF patients.

[Is triple combination of different neurohormonal modulators recommended for treatment of mild-to-moderate congestive heart failure patients? (Results of SADKO-CHF study). Part 2].

AIM: To assess different variants of neurohormonal (NH) modulation with angiotensin converting enzyme (ACE-I) quinapril (Q), angiotensin-receptor blocker (ARB) valsartan (V) and their combination in addition to beta-adrenergic blocker bisoprolol (B) on functional status, quality of life (QL), parameters of left ventricular (LP) remodeling, main indices of 24-h heart rate variability (HRV) and NH profile in patients with stable mild-to-moderate CHF. MATERIAL AND METHODS: 63 patients with CHF (NYHA class II-III) as a result of ischemic heart disease and dilated cardiomyopathy with LV EF < 40% were randomly assigned to one of the treatment variants on 1:1:1 basis: B+Q (n = 22; mean daily dose of B-5.5 mg; Q-15.4 mg), B+V (n = 23; mean daily dose of B = 4.8 mg; V = 128 mg) and combination of B+Q+V (n = 18; mean daily dose of B = 4.1 mg; Q = 12 mg; V = 82 mg). At baseline, all the patients in this study were on background B treatment and according to the study design Q or V were then added to B at randomization. NYHA FC, 6-min walking test (6MT), QL, 2D-echocardiography, plasma rennin activity (PRA), angiotensin II (AT-II), aldosterone (Ald), norepinephrine (NE), epinephrine (E), brain natriuretic peptide (BNP) concentrations and 24-hour HRV parameters were investigated at baseline, 3 and 6 months after randomization. RESULTS: During the study NYHA FC improvement was revealed in all 3 treatment groups with comparative significant changes in 6MT distance by 20.4%, 19.1% and 19.4% in B+Q, B+V and B+Q+V groups. QL maximally decreased in B+V combination (from 45 to 21 points). LV volumes significantly decreased and LV ejection fraction (EF) increased in all groups to the end of the study. Triple combination had no additional effect on LV volumes and LVEF changes compared to B+Q and B+V groups. Maximally plasma NE concentrations decreased in B+Q group (from 650 to 430 pg/ml, p = 0.007). A worse effect was observed in the combination of B+Q+V, with any NE changes in B+V group. The E concentration increased significantly (from 215 to 295 pg/ml, p = 0.024) in the B+Q+V group at the end of the study. Plasma A-H concentration did not differ from the baseline during the study in B+Q group, but significantly increased in B+V group and maximally in B+Q+V group (from 11.4 to 23.5 pg/ml, p = 0.009). To the end of the study plasma Ald concentrations remain reduced significantly only in B+V group. The level of BNP significantly decreased in all 3 treatment groups. Significant changes in HRV indices, both in time and frequency domain, were revealed in the B+Q group at 3-month follow-up and SDNN increased on month 24 (p = 0.039). These changes became insignificant at the end of the study. The lesser effect was revealed in B+Q+V group, with insignificant trend toward an increase of SDNN to the end of the study. HRV indices did not improve in the B+V group. CONCLUSION: During long-term treatment the triple combination of B+Q+V has no significant advantages over B+Q and B+V by the functional status, QL and parameters of LV remodeling in patients with mild-to-moderate CHF. The combination of B+Q has more potent effect on 24-hour HRV parameters, sympatho-adrenal activity and renal function compared to B+V and B+Q+V groups in CHF patients in our study. The combination B+Q+V may have a negative effect on NH profile (excessive activation of ATII and E) in CHF patients. The triple combination is not recommended for therapy of stable mild-to-moderate CHF patients.