The Prognostic Value of Neuregulin-1ß in Heart Failure Patients With Preserved Ejection Fraction.

Aim      To determine the neuregulin-1ß concentration in patients with chronic heart failure with preserved ejection fraction (HFpEF) and the association of this biomarker with the functional status of patients, echocardiographic parameters of the structural and functional condition of the heart, and the risk of unfavorable outcome.Material and methods  This observational, prospective study included 47 patients with HFpEF; 32 (68%) of them were females. Mean age was 70 [66-77] years, EF was 57 [56; 58] %. The group of healthy volunteers consisted of 40 people; 32 (55 %) of them were females; mean age was 56 [53-61] years. For all patients, the functional status was evaluated (6-min walk test, 6MWT); standard echocardiography (EchoCG) was performed; and concentrations of N-terminal pro-brain natriuretic peptide (NT-proBNP) and neuregulin-1ß were measured. The follow-up period was two years. Cases of cardiovascular (CV) death and hospitalizations for decompensated chronic heart failure (CHF) were recorded.Results Median concentration of neuregulin-1ß was 0.969 [0.348; 1.932] ng/ml in the HFpEF group, which was significantly higher than 0.379 [0.195; 0.861] ng/ml in the group of healthy volunteers (р=0.003). Significant correlations between the neuregulin-1ß concentration and the distance walked in 6MWT or with EchoCG parameters of left ventricular diastolic function were not found. Mean observation time was 456 [244; 730] days. 21 outcomes were observed, including 2 CV deaths and 19 hospitalizations for CHF. Patients with high concentrations of neuregulin-1ß (≥Me) had a greater frequency of hospitalizations for CHF (Log-rank, p=0.046) and a higher risk of this outcome (risk ratio, 1.30; 95 % confidence interval, 1.01-1.66; p=0.037).Conclusion      Patients with HFpEF had increased concentrations of neuregulin-1ß. High levels of neuregulin-1ß were associated with a higher risk of hospitalization for decompensated CHF.

To study the dynamics of serum levels of vascular remodeling in patients with hypertension, including in combination with type 2 diabetes mellitus during 12­month therapy with perindopril A.

Aim      To study the dynamics of serum markers for vascular remodeling in patients with arterial hypertension (AH), including AH associated with type 2 diabetes mellitus (DM2) during the 12-month treatment with the angiotensin-converting enzyme (ACE) inhibitor, perindopril A.Material and methods  The study included patients with grade 1-2 AH with or without type 2 DM (30 and 32, respectively). Perindopril A 10 mg/day was administered for the outpatient correction of previous, ineffective antihypertensive therapy. The following biomarkers were measured for all patients at baseline and at 12 months: matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1), E-selectin, endothelin 1, transforming growth factor ß-1 (TGF-ß1), and von Willebrand factor (WF). Laboratory tests were performed with enzyme immunoassay.Results After 12 months of the perindopril A (perindopril arginine) 10 mg/day treatment, both groups achieved the goal blood pressure. Evaluation of biomarker dynamics during the perindopril A treatment showed significant decreases in MMP-9, TIMP-1, and endothelin 1 in the AH group; then the level of TIMP-1 returned to normal values (р<0.05). In the AH+DM2 group, the MMP-9 concentration was significantly decreased (р<0.05); the other values did not show any significant differences. In both groups, MMP-9 was significantly decreased (28.6 % (р=0.01) in group 1 and 33.2 % (р=0.00) in group 2. Notably, in none of these groups, did this index reach normal values. Also, there were no significant differences in this index between the groups (р=0.66). It should be noted that the decreases in TIMP-1 were significantly different between the groups (р=0.001). Thus, this biomarker did not significantly decrease in patients with AH and DM2 (р=0.26) whereas in group 1 (AH without DM2), the level of TIMP-1 decreased by 39.3 % and reached the normal range (р=0.005).Conclusion      Concentrations of biomarkers were decreased in both groups. However, in the AH group, there were statistically significant decreases in the markers that reflect processes of fibrosis and vasoconstriction. At the same time in the AH+DM2 group, there was no significant dynamics of the biomarkers, which was most likely due to more pronounced damage of blood vessels. However, the decrease in MMP-9 may indicate an alleviation of fibrotic processes in arterial walls. These results allow a conclusion that the long-term treatment with the ACE inhibitor, perindopril A, may reverse remodeling of the vascular changes that are called "early vascular ageing".r aging".

Possible pathway for heart failure with preserved ejection fraction prevention and treatment: the angiotensin-converting enzyme inhibitor effect on endothelial function in comorbid patients.

Aim      To evaluate the effect of perindopril on the endothelial function and levels of endothelial dysfunction markers in groups of patients with heart failure with preserved (HFpEF) and mid-range (intermediate) left ventricular ejection fraction (HFmrEF).Material and methods  40 patients with HFpEF (n=20) and HFmrEF (n=20) were evaluated. At baseline, parameters of the morpho-functional state of large blood vessels and of microvessels were evaluated with photoplethysmography, and levels of E-selectin and endothelin-1 (ET-1) were measured. The patients were prescribed perindopril, and after 12 months of treatment, photoplethysmographic parameters and endothelial dysfunction markers were determined again.Results After 12 months of the perindopril treatment, improvements in the endothelial function of both large blood vessels and microvessels were noted. The phase shift increased from 10.1 to 10.9 ms in the HFpEF group (р=0.001) and from 8.35 to 9.65 ms in the HFmrEF group (р=0.002). Furthermore, the occlusion index increased from 1.45 to 1.75 in patients with HFpEF (р=0.004) and from 1.5 to 1.75 in patients with HFmrEF (р=0.010). The Е-selectin concentration decreased in both groups, from 57.25 to 42.4 ng/ml (р=0.00008) and from 40.5 to 35.7 ng/ml (р=0.010) in patients with HFpEF and HFmrEF, respectively. The ET-1 concentration decreased from pg/ml (р=0.010) in patients with HFpEF whereas in patients with HFmrEF, there was no significant change in the ET-1 concentration after 12 months of the perindopril treatment.Conclusion      At 12 months, the endothelial function improved and E-selectin and ET-1 levels decreased in patients with HFpEF and HFmrEF.

[Positive Effects of Perindopril on Microvascular Vessels in Patients With Chronic Heart Failure].

Aim      To evaluate the effect of 12-month perindopril treatment on structure and function of microvasculature (MV) in patients with chronic heart failure with preserved (HFpEF) and intermediate (HFiEF) left ventricular ejection fraction.Material and methods  30 patients with HFpEF and HFiEF were evaluated. Perindopril at a maximum tolerated dose was administered to all patients for 12 months. Changes in MV structure and function were assessed with photoplethysmography and capillaroscopy prior to the treatment onset and at 12 months, i.e., after completion of the perindopril treatment.Results The 12-month perindopril treatment was associated with improvement of the endothelial function evident as increases in the occlusion index (OI) and the phase shift (PS). OI increased from 1.45 [1.3; 1.6] to 1.8 [1.6; 2.2] (p=0.00004). PS increased from 7.1 ms [4.8; 10.2] to 9.2 ms [6.7; 13.2] (p=0.0003). Stiffness of muscular large blood vessels was decreased. Arterial stiffness index (aSI) decreased from 8.8 [6.6; 11.0] to 7.45 [6.5; 9.4] m /s (р=0.01). The perindopril treatment was associated with increased density of the capillary network at rest (р=0.008) and in tests with venous occlusion (р=0.003) and reactive hyperemia (р=0.0003).Conclusion      The study showed an improvement of endothelial function associated with the 12-month perindopril therapy in patients with HFpEF and HFiEF.

[Vasoprotective Effects of Prolonged Therapy With Perindopril A in Patients with Hypertension Including Concomitant Type 2 Diabetes Mellitus].

Objective Investigate the dynamics of morphological and functional markers of vascular remodeling in patients with arterial hypertension (AH), including those with concomitant type 2 diabetes mellitus (DM2), during 12-month administration of perindopril A.Material and Methods The study included patients with grade I-II AH, with and without DM2 (30 and 32 patients, respectively), who underwent outpatient correction of initially ineffective antihypertensive therapy and administration of perindopril A, 10 mg/day. Morphological and functional parameters of vascular remodeling were evaluated in all patients at baseline and at 12 months using photoplethysmography. Stiffness index (SI) and phase shift (PS) were measured in large vessels. Reflection index (RI) and occlusion index (OI) were measured in microvessels. Computed nailfold videocapillaroscopy was used to determine capillary density (CD) at rest (CDr), CD during venous occlusion test (CDvo), and CD during reactive hyperemia test (CDrh). Data are medians [interquartile range].Results After 12-month administration of perindopril A, the morphological and functional parameters of vascular remodeling in AH patients without DM2 significantly improved at all vascular levels. SI decreased to 9.25 [7.8; 10.93 ] m/s and PS increased to 7.4 [5.6; 9.05] ms. In microvasculature, a statistically significant reduction was observed in RI, 31 [27; 36.5]%, and an increase was observed in OI, which characterizes endothelium function, 1.75 [1.68; 1.9]. Capillary CDr significantly increased to 40.5 [34.93; 46] cap/mm2, as did CDvo and CDrh. At the same time, in the group of patients with AH and DM2, a significant improvement was observed for the large vessels. SI decreased to 9.8 [9.08; 10.58] m/s, and PS increased to 6.95 [5.13; 10.08]. The RI index, reflecting the structural condition of arterioles, significantly decreased to 34 [25.9; 45.53]%, and the OI index, characterizing endothelial function, did not change significantly, 1.4 [1.3; 1.6]. Capillary CDr significantly increased to 31.55 [27.68; 34.7 ] cap/mm2; however, CDvo and CDrh did not change significantly. Renal function improved in both groups.Conclusion Both groups demonstrated improvement of morphological parameters at all levels of the arterial bed. However, patients with AH and concomitant DM2 showed no improvement of the endothelial function of arterioles and capillaries compared to improvement in AH patients without DM2. This reflected the more severe endothelial dysfunction present in AH patients with DM2.

[Circulating Neuregulin-1 and Chronic Heart Failure with Preserved Ejection].

Chronic heart failure (CHF) with preserved ejection fraction (CHFpEF) is an unsolved, socially relevant challenge since it is associated with a high level of morbidity and mortality. Early markers for this pathology are unavailable, and therapeutic approaches are undeveloped. This necessitates extensive studying the mechanisms of CHFpEF to identify therapeutic targets. According to current notions, systemic inflammation and endothelial dysfunction play an important role in the pathogenesis of CHFpEF. These processes induce the development of myocardial fibrosis and impairment of cardiomyocyte relaxation, thereby resulting in diastolic dysfunction and increased left ventricular (LV) filling pressure. Neuregulin-1 (NRG-1) is a paracrine growth factor and a natural agonist of ErbB receptor family synthesized in the endothelium of coronary microvessels. The NRG-1 / ErbB4 system of the heart is activated at early stages of CHFpEF to enhance the cardiomyocyte resistance to oxidative stress. Preclinical and clinical (phases II and III) studies have shown that the recombinant NRG-1 therapy results in improvement of myocardial contractility and in LV reverse remodeling. Results of recent studies suggest possible anti-inflammatory and antifibrotic effects of NRG-1, which warrants studying the activity of this system in patients with CHFpEF.

[Effect of 12-Months Therapy With Perindopril A on Structural-Functional State of the Microcirculatory Vascular Bed in Patients With Chronic Heart Failure].

BACKGROUND: Experimental and clinical data confirm that endothelial dysfunction (ED) of microvessels is one of mechanisms of progression of chronic heart failure (CHF). PURPOSE: To assess the impact of 12-month treatment with perindopril A (5-10 mg/day) on structural and functional state of microcirculatory vascular bed in patients with CHF. MATERIAL AND METHODS: We included into this study 30 patients aged 45-70 years with NYHA class II-III CHF. All patients received perindopril A 5-10 mg/day for 12 months. For assessment of endothelial function we used test with reactive hyperemia. During this test we evaluated flow dependent vasodilation by photoplethysmography, and registered the state of skin capillary network by computer videocapillaroscopy. We also measured level of proinflammatory cytokines - von Willebrand factor, and -tumor necrosis factor (-TNF). RESULTS: After treatment with perindopril A 5 we observed improvement of microvascular endothelial function (occlusion index rose from 1.5 [1.2; 2.9] to 2.0 [1.7; 2.4], p=0.03), and of functional state of the finger skin capillary network (percentage of perfused capillaries rose from 88 [77; 95] to 95 [87; 97], p=0.05, percentage of recovered capillaries rose from 8 [4.5; 12.1] to 14.2 [9.3; 17.1], p=0.04). These effects were associated with significant lowering of (-TNF) level (from 6.58 [3.72, 10.3] to 3.35 [0.15; 6.33] g/L, p<0.01).

[Remodeling of vascular bed in patients with arterial hypertension: possibilities of diagnostics and correction].

Arterial hypertension determines the remodeling of the vascular bed at all levels, resulting in a high risk of developing cardiovascular complications. Recent studies performed on the basis of evidence-based medicine, demonstrated the high efficiency of the combination drug therapy with perindopril and amlodipine in preventing such complications. This may be due to the positive influence of a fixed combination of these drugs on the parameters of the state of the microcirculatory level of the vascular bed.

[Clinicogenetic aspects of carbohydrate metabolism disorders and efficacy of their correction with moxonidine and metformine in patients with arterial hypertension].

AIM: To study effects of monotherapy with moxonidine and metformine on metabolic parameters in hypertensive patients with carbohydrate dysbolism (CD) regarding polymorphic markers of genes PPARalpha, PPARgamma and IRS type 1 and 2. MATERIAL AND METHODS: A total of 83 patients (31 male and 52 female patients aged 40-75 years) with untreated arterial hypertension stage I, obesity and CD (by glucose tolerance test) entered the trial. The patients were randomized into two groups. Patients of group I (n=42) received moxonidin in a dose 0.4 mg/day, of group 2 (n=41)--metformin in a dose 1000 mg/day. Measurement of arterial pressure, blood count and biochemistry, oral test for glucose tolerance with glucose and insulin measurement before meal and 1, 2 and 3 hours later was made initially and on the treatment week 16 Genotypes of polymorphic markers of genes PPARA, PPARG2, IRS1 and IRS2 were defined in all the patients. RESULTS: Changes in basic hemodynamic and metabolic indices in therapy with moxonidine depending on polymorphic markers of genes PPARA, PPARG2, IRS1 and IRS2 in patients with AH and CD showed that G allele PPARG2 is associated with greater weight loss, G allele PPARA--with weight loss, C allele PPARA--with maximal fall of diastolic blood pressure. CONCLUSION: Genetic factors participate in development of metabolic disturbances in hypertensive patients, obesity and CD and determine treatment efficacy in each individual patient.

[Prospects of use of the combined preparation logimax in patients with essential hypertension]. / Perspektivy primeneniia kombinirovannogo preparata logimaks u bol'nykh éssentsial'noi arterial'noi gipertoniei.

AIM: To study the effectiveness and tolerance of a combined drug logimax in patients with essential hypertension (EH). MATERIAL AND METHODS: The antihypertensive activity and safety of logimax was evaluated in 15 EH patients at week 10 of therapy. RESULTS: Logimax has a good antihypertensive effect for 24 hours in 86.7% patients. This was evidenced by the lowered mean systolic and diastolic pressures shown during 24-hour monitoring. Logimax was well tolerated. There were no side effects in 73.3% of the patients. CONCLUSION: The combined drug logimax is indicated for patients with EH as an antihypertensive agent to treat and prevent cardiovascular events.

[Effects of perindopril and its combination with indapamide on risk stratification in patients with hypertension]. / Vliianie perindoprila i ego kombinatsii s indapamidom na stratifikatsiiu riska u bol'nykh gipertonicheskoi bolezn'iu.

AIM: To study effects of perindopril, indapamid and their combination on stratification of essential hypertension (EH) risk factors. MATERIAL AND METHODS: The 10-year risk to develop cardiovascular complications was assessed in 85 EH patients before and after 12 months of treatment with perindopril, indapamid and their combination. RESULTS: The high risk of cardiovascular complications in the above patients reduced by 21.5, 14.8 and 26.6% 12 months after treatment with perindopril, indapamid and their combination, respectively. CONCLUSION: Low risk of cardiovascular complications was related not only with a fall in systolic and diastolic blood pressure but also with positive effect on left ventricular hypertrophy, absence of negative influence on total cholesterol, glucose in blood plasma.

[Antihypertensive efficacy, tolerance and safety of lisinopril (sinopril) and captopril (capoten) in patients with mild and moderate arterial hypertension]. / Antigipertenzivnaia éffektivnost', perenosimost' i bezopasnost' lizinoprila (sinoprida) i kaptoprila (kapotena) u bol'nykh miagkoi i umerennoi arterial'noi gipertoniei.

AIM: To compare effectiveness, tolerance and safety of two inhibitors of angiotensin-converting enzyme--sinopril (lisinopril) and capoten (captopril)--in outpatient treatment of patients with mild and moderate hypertension. MATERIALS AND METHODS: The patients were randomly assigned to sinopril or capoten groups. Sinopril was given in daily dose 10-40 mg, capoten--in daily dose 25-100 mg for 8 weeks. In insufficient antihypertensive effect of monotherapy on day 21, hydrochlortiaside was added. The effect was judged by influence on arterial pressure, heart rate, tolerance (questionnaire), safety (blood count, urinalysis. ECG). RESULTS: Sinopril produced good antihypertensive effect in 73.3% of patients (monotherapy) and 88.9% (combined therapy). For capoten it was 68.9 and 82.2%, respectively. The time of the beginning of the antihypertensive effect (4-20 days after the start of the treatment) for sinopril and copoten differed insignificantly and depended on hypertension severity (mild or moderate). Tolerance of both drugs was good, serious side effects were absent. Discontinuation of the drugs was needed in 4% of patients, only. No negative action on bioelectric activity of the heart, clinical and biochemical blood indices were found. CONCLUSION: Sinopril and capoten demonstrate high antihypertensive activity.