The Effectiveness of Outpatient Treatment Under the Control of the Soluble ST2 Receptor Concentration in Patients With Heart Failure With Reduced Ejection Fraction After Acute Decompensation of Heart Failure.

Aim    To study the effectiveness of a treatment based on monitoring the soluble ST2 receptor (sST2) concentration in patients with chronic heart failure (CHF) with reduced left ventricular ejection fraction (LVEF) after acute decompensated heart failure (ADHF).Material and methods    The study included 37 patients hospitalized for ADHF with LVEF ≤40% and sST2 concentration ≥37.8 ng/ml at the time of discharge from the hospital. Patients were randomized into two groups: a sST2 monitoring (sST2M) group (19 patients) and a standard therapy (ST) group (18 patients). The follow-up period was 12 months. At baseline, the groups practically did not differ by clinical, functional, laboratory, and instrumental characteristics. For the sST2M group, the goal was reducing the sST2 concentration by >30% of baseline or to <30 ng/ml.Results    Therapy in both groups was comparable both in doses and in frequency of administration of basic drugs. However, the diuretic therapy was more frequently adjusted in the sST2M group (3.0 [1.0; 4.0] vs. 1.0 [0; 3.0] adjustments per patient, p = 0.047), which required more visits to the clinic (7.0 [6.0; 9.0] vs. 6.0 [6.0; 6.0] visits per patient, p=0.024). In the sST2M group at 6 months, the sST2 concentration was decreased by 43.3% (p=0.001), and 13 patients (72.2%) achieved the goal. In the ST group, the sST2 concentration was decreased by 38.5% (p=0.001), and 11 patients (68.8%) reached the target values. After 12 months, the downward trend continued in both groups. In both groups, the NT-proBNP concentration decreased: in the sST2M group by 27.7% (p=0.014), and in the ST group by 31.9% (p = 0.006). By the 12th month, the decrease remained only in the sST2M group. Only the sST2M group had an increase in LVEF (+28.5%, p=0.003), a decrease in left ventricular end-systolic volume (LVESV) (-12.0%, p=0.017), and a decrease in left atrial volume (-13.4%, p=0.045); at 12 months, LVEF remained increased (26%, p=0.006), and LA volume remained decreased (-14.3%, p=0.028). Quality of life and results of 6-minute walk test (6MWT) improved in both groups. For 6 months of treatment, the sST2M group had a significantly lower incidence of composite endpoints (CEP, cardiovascular death and decompensation/hospitalization due to HF), 26.3% (5 events) of the sST2M group compared to the ST group, 83.3% (15 events) (p=0.029), primarily due to a lower incidence of decompensated HF. For 12 months of follow-up, the incidence of CEP in the ST group was 122.2% (22 events), and 47.4% (9 events) in the sST2M group (p=0.035).Conclusions    The tactics of sST2 monitoring used in the treatment of "high-risk" HFrEF patients (with high sST2 concentrations) is associated with increased LVEF, improved functional status of patients, a beneficial effect on LV remodeling, and decreased incidence of CEP.

[Effects of sacubitril/valsartan in patients with cancer therapy-related heart failure].

AIM: To evaluate the effect of Sacubitril/Valsartan (S/V) on the functional status, systolic and diastolic function of the left ventricle (LV), tolerability of therapy and to determine predictors of its effectiveness in patients with cancer therapy-related heart failure (СTRHF). MATERIALS AND METHODS: Forty patients 58 [46; 65.5] years of age with HF associated with anthracycline-containing cancer therapy were enrolled. Clinical examination, echocardiography, and assessment of potassium and creatinine levels were performed at baseline and after 6 months of S/V therapy. RESULTS: NYHA functional class (FC) improvement was observed in 22 (64.7%) patients. Radiation therapy (RT) decreased (OR 0.091; 95% CI 0.01-0.83; p=0.03) while baseline low LV EF increased (OR 9.0; 95% CI 1.78-45.33; p=0.008) the odds of FC improvement. LV EF increased from 37.3 [30; 42.5] % to 45 [38; 48] % (p<0.0001) and exceeded 50% in 7 (20.6%) patients. The odds of LV EF recovery increased when S/V therapy was initiated ≤1 year after anthracycline therapy (OR 10.67; 95% CI 1.57-72.67; p=0.0016) and decreased in patients with the history of RT (OR 0.14; 95% CI 0.02-0.89; p=0.0037) and in patients over 58 years (OR 0.07; 95% CI 0.01-0.68; p=0.022). LV diastolic function improvement included E/e' descent from 13.6 [10; 18.3] to 8.9 [6.9; 13.7] (p=0.0005), and decrease in diastolic dysfunction grade in 18 (45%) patients (p=0.0001). No significant change in serum potassium (4.45 [4.2; 4.8] versus 4.5 [4.3; 4.8]; p=0.5) and creatinine (75.4 [67.6; 85.1] versus 75.5 [68.2; 98.3]; p=0.08) levels were observed. CONCLUSION: S/V therapy is associated with improvement of EF, systolic and diastolic LV function, demonstrates a favorable tolerability profile in patients with СTRHF. Lack of RT and low baseline LV EF increased the odds of LV EF improvement; lack of RT, early (≤1 year) start of treatment after discontinuation of anthracycline therapy, and age <58 years increased the odds of LV EF recovery.

Early diagnosis of acute renal injury in patients with acute decompensation of chronic heart failure.

AIM: To study the possibilities of previously diagnosing acute renal damage in patients with acute decompensation of chronic heart failure with reduced systolic function using biomarkers of acute renal injury. MATERIALS AND METHODS: The study included 60 patients (62.0±11.1 years) with HADS (BNP >500 pg/ml) and a reduced left ventricular ejection fraction (LV 27.05% [23.25; 32.75], c FC III-IV NYHA). The level of creatinine, urea, uric acid, albumin in serum was determined in all patients, as well as a number of biomarkers: lipocalin associated with neutrophil gelatinase (NGAL) and cystatin C (CysC) in serum; kidney damage molecule-1 (KIM-1) and angiotensinogen (AGT) in the urine. RESULTS: AKI is determined based on changes in serum creatinine concentration or diuresis value. The results obtained indicate a high specificity and sensitivity of the use of biomarkers for the diagnosis of AKI in patients with ADHF. NGAL AUC - 0.833 (p<0.001), Se - 82.8%, Sp - 4.2%. CysC AUC - 0.823 (p<0.001), Se - 79.3%, Sp - 74.2%. KIM-1 AUC - 0.782 (p<0.001), Se - 75.9%, Sp - 74.2%. AGT AUC - 0.829 (p<0.001), Se - 82.8%, Sp - 77.4%. In a multifactorial regression analysis, it was found that with NGAL greater than 157.35 ng/ml, the risk of AKI increases 13.1 times (95% CI 1.365-126.431), with an increase in KIM-1, the risk of the development of AKI increases 20.6 times (95% CI 1.802-235.524), and with an increase in AGT more than 14.31 leng/ml, the risk of AKI increases 32.8 times (95% CI 2.752-390.110). CONCLUSION: Acute kidney injury develops in 48.3% of patients hospitalized with acute decompensation of chronic heart failure. Patients with acute decompensation of chronic heart failure and AKI have significantly higher serum NGAL and CysC, KIM-1 and AGT values in the urine compared with patients without impairing renal function. These biomarkers can serve both for the early diagnosis of acute kidney damage and the prediction of AKI in patients with acute decompensation of chronic heart failure.

[Autoantibodies to M2-cholinoreceptors as a potential development factor of arrhythmia in patients with paroxysmal atrial fibrillation].

AIM: We aimed to assess autoantibodies to M2-cholinoceptors (M2-CR) in patients with paroxysmal lone atrial fibrillation (AF) and in patients with AF and arterial hypertension (AH). MATERIALS AND METHODS: 100 patients with lone AF and 84 patients with AF and AH were included. Patients underwent clinical blood and urinalysis, assessment of biochemistry blood panel, 12-lead ECG, 24-hour Holter monitoring, echocardiography and stress - testing (treadmill or stress - echocardiography). Assessment of IgM and IgG autoantibodies to M2-CR was performed by indirect immunoenzyme assay. The following peptide molecules were used as epitopes for detection of autoantibodies: M1 - amino acid sequence YTVIGYWPLGVVCDL (83-98) of the first extracellular loop of M2-CR; M2 - sequence VRTVEDGECYIQFFSNAAVTFGTAI (168-192) of the second extracellular loop of M2-CR; M3 - sequence NTFCAPCIPNTV (410-421) of the third extracellular loop of M2-CR; M4 - short sequence VEDGECYIQFFS (171-182) of the second extracellular loop of M2-CR; M1+M4 - chimeric molecule formed by sequences of the first and the second extracellular loops of M2-CR connected by disulfide bound YTVIGYWPLGVVCDL + VEDGECYIQFFS (83-98 + 171-182). RESULTS: Autoantibodies to M2-CR were found in 45% patients with lone AF and in 35% patients with AF and AH. In patients with lone AF prevalence of increased IgG to M2-CR were greater than in patients with AF and AH (32% vs 20%; p.

[Recent advances in diagnosis and management of atrial fibrillation].

Alterations of heart rhythm are a common clinical event. They can be caused by almost any kind of heart disorder. Atrial fibrillation (AF) is the most common type of abnormal heart rhythm. Prevalence of AF in the general population is 1-2%, and given that AF incidence rate continues to increase it can be predicted that the number of patients will be doubled within the next 50 years. This review provides the most recent diagnostic and treatment methods, including both unique domestic antiarrhythmic drugs and non - drug methods for AF treatment which were developed and implemented in clinical practice at NMRC of Cardiology of the Ministry of Health of the Russian Federation.

[Detection of Autoantibodies Against the 1-Adrenergic Receptor in the Sera of Patients via the Competitive cell-Based Enzyme Linked Immunosorbent Assay].

OBJECTIVE: This study aimed to assess the level of anti-1-adrenergic receptor autoantibodies in patients with ventricular arrhythmias with no signs of organic heart disease and with presence of cardiovascular pathology in comparison with a group of healthy volunteers. MATERIAL AND METHODS: The study included 44 patients with ventricular arrhythmias with no signs of organic heart disease ("idiopathic"), 34 patients with diagnosed dilated cardiomyopathy (DCM) of inflammatory origin, 35 patients with coronary heart disease and ventricular arrhythmias, 12patients with coronary heart disease with no ventricular arrhythmias, and 19 healthy volunteers (control group). The level of autoantibodies against the 1-adrenergic receptor was determined by the developed competitive cell-based enzyme-linked immunosorbent assay (ELISA) and by the standard ELISA using peptides corresponding to the second extracellular loop of the 1-adrenergic receptor. RESULTS: Elevated level of autoantibodies detected by a competitive cell-based ELISA was observed in 62% of patients with DCM compared to 21% of healthy volunteers (p=0.0006). In patients with "idiopathic" ventricular arrhythmias, the level of 1-adrenergic receptor autoantibodies was lower than in healthy subjects (p=0.003). Coronary heart disease patients with or without ventricular arrhythmias exhibited no differences from the control group. The number of significantly positive signals in peptide-based ELISA did not exceed 10% in any of the groups. No correlation between the data from competitive cell-based ELISA and peptide-based ELISA was found. CONCLUSIONS: This study demonstrated that competitive cell-based ELISA technique can be applied for detection of 1-adrenergic receptor autoantibodies. The results in DCM patients generally correspond to the expected. Decreased level of autoantibodies in patients with "idiopathic" ventricular arrhythmias indicates that this disease is related to changes in the immune system. Such relation is not observed in the case of coronary heart disease patients.

[Synthetic conformational antigen, simulating the extracellular part of M2-muscarinic receptor and its reactivity with sera from patients with idiopathic arrhythmias].

Linear peptides corresponding to fragment 83-98 of the first loop and fragments 168-192 and 171-182 of the second extracellular loops of M2-muscarinic receptor (marker of early cardiac disorders and arrhythmias) were synthesized by Fmoc-SPPS method. A new conformational antigen was synthesized by method of selective ligation of linear peptides by disulfide bond with native localization. Peptides were studied in reaction with sera from patients with idiopathic arrhythmias. A new conformational antigen was recognized by sera from patients with idiopathic arrhythmias with high reactivity.

[Novel conformational peptide antigen, which simulates an immunodominant epitope of the 2nd extracellular loop of ß1-adrenoceptor. Computer simulation, synthesis, spatial structure].

By means of computer simulation has been built polypeptide antigen conformational structure that imitates the immunodominant epitope of the 2nd extracellular loop of ß1-adrenoreceptor. A linear 25-membered peptide corresponding to calculated sequence was synthesized by means of solid-phase methoyd using Fmoc-technology, then directed by the closure ofdisulfide bridges was obtained original bicyclic polypeptide corresponding to the proposed structure of the conformational antigen. With the help of high-resolution NMR spectroscopy 3D structure of synthetic conformational antigen was investigated. It was shown that the structure of the bicyclic polypeptide similar to that of building computer model. Bicyclic conformational antigen was suitable for the detection of autoantibodies in the blood serum of patients with rhythm and conductivity violation without evidence of organic disease of the cardiovascular system.

[Modification of the FF neuropeptide enhances its hypertensive effect].

Neuropeptide FF (H-Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH2) injected intravenously temporarily enhanced the arterial pressure (AP) and the heart rate (HR). However, its role in the regulation of blood circulation is obscure. To study the properties of the molecule, its analogue was synthesized, in which proline in position 7 was substituted with glycine, and leucine in the position 2 with norleucine. Modified neuropeptide FF (FFm) also temporarily and in a dose-dependent manner increased the AP and HR; however, the equal degree of increase was reached at doses of FFm being 5-7 times lesser as compared with the natural peptide. The application of the FFm at hemorrhagic shock excluded mortality of animals during the experiment, considerably increased the degree of AP and HR restoration in the remaining experiments, and improved the survival of animals in 24 hours. It has been found that the level of antibodies to the fragment of hFF1 receptor in the serum is lower in spontaneously hypertensive rats SHR as compared with Wistar rats, but it is increased in patients of cardiological profile as compared with donors. The findings suggest involvement of neuropeptide FF in the regulation of blood circulation; however, the precise mechanisms remain to be determined.

[Effect of water soluble non-membrane proteins on the phospholipid structure]. / Vliianie vodorastvorimykh nemembrannykh belkov na strukturnuiu organizatsiiu fosfolipidov.

The interaction of water-soluble nonmembraneous proteins (trypsin and the basic pancreatic trypsin inhibitor (BPTI)) with soybean phospholipids was studied using multilamellar vesicles. Multilamellar vesicles were obtained from soybean lipid extracts and mixtures of individual phospholipids based on phosphatidylcholine. These mixtures contain different phospholipids: "bilayer", "nonbilayer", and negatively charged. It was shown that the content of both proteins in the complex depends on pH and the presence of negatively charged components. On the basis of this finding, the conclusion about the electrostatic nature of lipid-protein interaction was made. The structural organization of soybean phospholipids in multilamellar vesicles was studied in the presence and absence of the proteins using broad-line 31P-NMR spectroscopy. It was found that, in mixtures of phospholipids of complex composition, different types of phases coexist, and phospholipids of different classes can compensate the effects of each other. Trypsin and BPTI affect the structure of phospholipids in a similar way, inducing considerable structural changes in multilamellar vesicles of preparations containing negatively charged components in whose structure there coexisted primordially the bilayer and isotropic phases.

Complexing of basic pancreatic proteinase inhibitor with soybean phospholipid multilamellar vesicles.

The formation of complexes of basic pancreatic proteinase inhibitor (BPTI) with multilamellar vesicles (MLV) from six preparations of soybean phospholipids of various composition was studied. When BPTI, a non-membrane protein, interacts with MLV, the vesicles aggregate, forming a precipitate of protein-lipid complexes. The BPTI content in the protein-lipid complexes increases with decreasing pH of the medium and on addition of negatively charged components into the lipid mixture. The protein-induced aggregation of the phospholipid vesicles is suggested to be mainly determined by electrostatic forces. The antiproteinase activity of BPTI in the complexes was rather low but increased up to 70% of the initial activity on addition of an ionic detergent (sodium deoxycholate).