Interleukin 6 Signalling in Heart Failure With Preserved and Reduced Ejection Fraction.

AIM: Identification of interleukin-6 (IL-6) signaling pathways in patients with chronic heart failure (CHF). MATERIAL AND METHODS: The diversity of IL-6 effects is due to the presence of classical signaling and trans-signaling pathways. The study included 164 patients with CHF hospitalized for acute decompensated heart failure (ADHF), of which 129 had reduced left ventricular ejection fraction (HFrEF), and 35 had preserved ejection fraction (HFpEF). Blood concentrations of IL-6, soluble IL-6 receptor (sIL-6R), soluble transducer protein gp130 (sgp130), and high-sensitivity C-reactive protein (hsCRP) were measured. RESULTS: Patients with HFpEF had lower concentrations of IL-6 (6.15 [2.78, 10.65] pg/ml) and hsCRP (11.27 [5.84, 24.40] mg/ml) than patients with HFrEF (9.20 [4.70; 15.62] pg/ml and 17.23 [8.70; 34.51 mg/ml], respectively). In contrast, concentrations of rIL-6R were higher in HFpEF (59.06 [40.00; 75.85] ng/ml) than in HFrEF (49.15 [38.20; 64.89] ng/ml). Concentrations of sgp130 were not significantly different. In patients with HFrEF, positive correlations were found between the concentrations of IL-6 and hsCRP, IL-6 and rIL-6R, and IL-6 and sgp130, while in patients with HFpEF, there was a correlation only between IL-6 and hsCRP, which appeared stronger than in patients with HFrEF (r=0.698; p<0.001 and r=0.297; p<0.05, respectively). CONCLUSION: Classical IL-6 signaling and trans-signaling are expressed to different degrees in patients with HFrEF and HFpEF in ADHF. The results of the study supplement the existing knowledge about the pathogenesis of inflammation in CHF and may contribute to the development of new methods and approaches to the treatment of the disease.

[Possibilities of instrumental determination of volemic status in patients with acute decompensation of chronic heart failure].

AIM: To evaluate and compare the accuracy of volemic status determination by remote dielectric sensing with computed tomography (CT) in patients with acute decompensated heart failure. MATERIALS AND METHODS: In 28 patients volemic status was determined by ReDS (remote dielectric sensing), chest computed tomography (CCT), and chest X-ray twice during hospitalization (the day of admission and the day of discharge from the hospital). The ReDS measurements were then compared with CT data using software that allows the use of semi-automated tools to determine mean lung density (MLD). MLD results from Hounsfield Units [HU] were then converted to fluid levels (FU%), allowing them to be compared with ReDS values. In addition, to assess the effect of physical activity on the dynamics of pulmonary stasis there was performed 6-minute walk test (6MWT) followed by determination of volumic status by ReDS method. RESULTS: Correlation analysis revealed an average direct significant correlation (r=+0,5; p=0.001) between the CCT and ReDS data. Hypervolemia indexes according to the CCT revealed statistically significant decrease in the dynamics, which was also reflected in the ReDS index decrease. Lung fluid content according to ReDS averaged 38.2±4.6% on admission, and 34.5±3.9% on discharge (p=0.005). According to CT scan of the CCT, MLD at admission was 23.03±3.9%, at discharge 19.6±3.3% (p=0.003). The positive dynamics of the study methods was also reflected in the positive dynamics of NT-proBNP, which decreased by 46%. In the analysis of ReDS data before and after exercise, there was an increase in ReDS value after the performed 6MWT and it was 35.09±3.9% compared with the initial value of 34.5±3.9%. A strong direct significant correlation (r=+0.7; p=0.0001) was found between the ReDS before and after 6MWT at discharge.

[Difficulties in differential diagnosis of the AL- and ATTR-cardiac amyloidosis. Case report].

The article presents a clinical case describing a complex differential diagnosis of cardiac amyloidosis types and verification of the diagnosis of AL-amyloidosis.

[A rare variant in the TTR gene (p.E112K) is associated with systemic amyloidosis and a new symptom - skin hyperemia in response to ethanol intake: family segregation analysis, literature review, and a clinical case. Case report].

Transthyretin amyloidosis (ATTR-amyloidosis) is a systemic disorder associated with extracellular deposition in the tissues and organs of amyloid fibrils, transthyretin-containing insoluble protein-polysaccharide complexes. The change in transthyretin conformation, leading to its destabilization and amyloidogenicity, can be acquired (wild type, ATTRwt) and hereditary due to mutations in the TTR gene (variant, ATTRv) [1, 2]. Hereditary ATTR-amyloidosis has an earlier onset and greater phenotypic diversity. The age of the manifestation, the predominant phenotype, and the prognosis are often determined by the genetic variant. To date, more than 140 variants in the TTR gene have been identified; however, most of them are described in single patients and do not have clear evidence of pathogenicity. The prospects of a new pathogenetic treatment of ATTR-amyloidosis [3], especially effective in the early stages of the disease, increases the relevance of timely diagnosis, which is challenging due to physicians' lack of awareness. This article presents a clinical case of ATTRv-amyloidosis associated with a rare pathogenic variant in the TTR gene and a newly described skin symptom. This article is a literature review.

Dynamics of the Levels of Interleukin 6, Its Soluble Receptor, and Soluble Glycoprotein 130 in Patients with Chronic Heart Failure and Preserved or Reduced Ejection Fraction.

The features of IL-6 trans-signaling were studied in patients with heart failure with reduced (n=74) and preserved (n=31) ejection fraction (EF) during acute decompensation of HF (ADHF) and after 1 year. Patients with ADHF with reduced EF demonstrated higher levels of IL-6 and soluble glycoprotein 130 in comparison with those in patients with preserved EF: 10.18 (7.07; 16.14) pg/ml vs 6.35 (3.52; 11.00) pg/ml and 543.46 (455.37; 634.43) ng/ml vs 498.50 (408.16; 632.23) ng/ml, respectively. The levels of soluble IL-6 receptor little differed in these groups: 57.82 (47.55; 79.85) ng/ml vs 61.30 (44.97; 78.08) ng/ml. After 1 year, the levels of IL-6 in HF patients with reduced EF significantly decreased (5.36 (3.35; 8.35) pg/ml), while in patients with preserved EF, the decrease in this parameter was less pronounced (5.86 (4.05; 7.32) pg/ml), and the difference between groups disappeared. The levels of soluble glycoprotein 130 increased in both groups: 448.06 (357.74; 550.67) ng/ml vs 385.35 (344.29; 523.72) ng/ml. It should be noted that after 1 year (in stable patients), the levels of soluble IL-6 receptor increased in both groups: 65.75 (54.84; 75.39) ng/ml vs 70.81 (57.51; 82.25) ng/ml. Thus, despite the high levels of IL-6 in HF patients with reduced EF, the potential limiting IL-6 trans-signaling in these patients is higher than in patients with preserved EF.

[Acute decompensation of heart failure: state of the problem].

Are presented the key aspects of the management of patients with acute decompensation of heart failure leading to improved clinical outcomes. Are described the existing problems and possible solutions.

[Myocardial scintigraphy with 99mTc-pyrophosphate in the diagnosis of cardiac amyloidosis: place in the diagnostic algorithm, features of the implementation and interpretation of the study].

The article summarizes the current experience of the nuclear medicine department of the Chazov National Medical Research Center of Cardiology in the implementation of myocardium scintigraphy with 99mTc-pyrophosphate with the differential diagnosis of the types of cardiac amyloidosis. Causes of false-positive, equivocal and non-diagnostic results, are analyzed. Possible ways to eliminate mistakes, including by modifying protocols of planar and tomographic research and optimizing the whole diagnostic algorithm for amyloidosis of the heart, are discussed.

[SGLT2 inhibitors in acute decompensated heart failure, what do we know?]

The current worldwide prevalence of heart failure is growing, while its combination with cardiovascular and other conditions determines a poor prognosis in these patients. Furthermore, acute decompensated heart failure is associated with a low survival rate mostly caused by target organ damage. The effects of early administration of SGLT2 inhibitors on renal function in patients with acute decompensated heart failure are being studied to determine the possibility of improving response to treatment, as well as partial or complete recovery of renal function. The goal of the review was to synthesize currently available evidence for the use of SGLT2 inhibitors in patients with acute decompensated heart failure. A systematic search for studies published from 2018 to 2021 and their analysis was carried out in the following databases: Web of Science, Scopus, PubMed/MEDLINE.

[Practical guidelines for the diagnosis and treatment of transthyretin amyloid cardiomyopathy (ATTR-CM or transthyretin cardiac amyloidosis)].

This paper summarizes the data from updated international protocols and guidelines for diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CM). The invasive and non-invasive diagnosis techniques and their combinations are briefly reviewed; the evidentiary foundations for each diagnostic option and tool are analyzed. The paper describes a customized algorithm for sequential diagnosis and differential diagnosis of patients with suspected ATTR-CM with allowance for the combination of clinical signs and diagnostic findings. Along with the awareness of primary care providers about the red flags of the disease and visualization criteria, as well as providing information to the patients about the possibility of performing therapy of ATTR amyloidosis and the risks of delayed diagnosis, the proposed algorithm enables timely patient routing and prescribing specific treatment.

[Remote monitoring of patients with heart failure in real clinical practice].

Prevalence of chronic heart failure (CHF) is continuously growing and is associated with increased incidence of hospitalizations, morbidity and mortality. Furthermore, the increase in the number of rehospitalizations results in greater expenses and worsening of quality of life. In order to decrease the number of unscheduled hospitalizations and the death rate, the outpatient care should be improved, which can be achieved by using telemedical technologies. The aim of this review was collection and analysis of currently available information about the use of telemonitoring for patients with CHF. A systematic search and analysis of reports published from 2010 through 2020 in Web of Science, Scopus, and PubMed/MEDLINE databases was performed.

[Pro-inflammatory cytokines in chronic cardiac failure: state of problem].

Systemic inflammation is characterized by the induction of pro-inflammatory cytokines, the increased level of which in the blood of patients with chronic heart failure (CHF) correlates with unfavorable clinical outcomes. However, it is unclear whether pro-inflammatory cytokines are the cause or the consequence of the disease progression. CHF with preserved ejection fraction and CHF with reduced ejection fraction demonstrate different inflammatory features, which suggests different degrees of pro-inflammatory pathway activation. The review deals with participation of pro-inflammatory cytokines in pathophysiological processes of CHF development, emphasizing the role of interleukin-6 activation and the effects of accompanying diseases on the course of systemic inflammation. The search for new approaches to prevention and therapy of CHF remains actual. The review presents the results of clinical trials of targeted anti-cytokine therapy which have revealed difficulties in controlling inflammation under the conditions of CHF. Identification of specific pro-inflammatory pathways in CHF pathogenesis will allow one to control inflammatory cascades, thus providing a prospective therapeutic strategy.

[Prognostic impact of uric acid in patients with acute decompensated heart failure].

AIM: To evaluate the prognostic impact of serum uric acid (SUA) on clinical outcomes in patients with acute decompensated heart failure, as well as identify the correlation between hyperuricemia and renal function and diuretic resistance in these patients. MATERIALS AND METHODS: The study included 175 patients (125 men and 50 women) with NYHA class IIIV acute decompensated heart failure. Median age was 64 (5675) years. The Information regarding the survival was obtained 3 years after the admission by telephone calls. RESULTS: 57 patients reached the end point (death from all causes); therefore, all patients were divided into groups: "alive", "dead". The SUA levels did not differ in the groups. The only significant difference in the studied parameters was the estimated glomerular filtration rate (eGFR), which was significantly higher in the "alive" group [70.5 (52.894) and 56 (4079), respectively; p=0.006]. A moderate negative correlation was found between SUA levels and eGFR in the correlation analysis (r=-0.313, p0.001). A comparative analysis showed, that SUA level on admission was significantly higher in patients who subsequently received increased doses of diuretics than in patients with a satisfactory response to standard doses of diuretics [567.8 (479.6791.9) and 512 (422.4619.4), respectively; p=0.011]. Also, higher eGFR level on admission was observed in patients from the normal SUA level group than in patients from the hyperuricemia group [94 (74.5101.5) and 63 (48.881.3), respectively; p=0.002]. CONCLUSION: We found no significant differences in the uric acid level in patients who reached the end point and those who did not reach it during the three-year follow-up. However, the found correlation between uric acid levels and diuretic resistance calls for further research.

[Experience with tafamidis in a patient with transthyretin amyloidosis].

Transthyretin amyloidosis (ATTR) is a threatening and severe genetic disease characterized by damages to organs and systems caused by a pathological protein transthyretin produced in the liver. Clinical manifestations of this disease vary from injuries of the nervous system to injuries of the cardiovascular system. Prognosis for ATTR-amyloidosis remains unfavorable. The absence of pathognomonic symptoms complicates diagnostics of this disease, which tends to simulate other conditions. At present, medicines exist, which are pathogenetic in the treatment of ATTR-amyloidosis. The article describes a clinical case of ATTR-amyloidosis with primary heart injury complicated with functional class III chronic heart failure during the tafamidis treatment.

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.

[Full - transcriptome analysis of miRNA expression in mononuclear cells in patients with acute decompensation of chronic heart failure of various etiologies].

It is known that micro RNAs are an important regulatory element in the pathogenesis of many diseases, including cardiovascular diseases. Different levels of expression of these molecules in various pathologies makes miRNA a potential diagnostic and prognostic biomarker. AIM: Analysis of miRNA expression levels in mononuclear blood cells (MBC) of patients with acute decompensation f chronic heart failure (CHF) of various etiologies and evaluation of the possibility of their use as a biological marker. MATERIALS AND METHODS: 7 male patients with acute decompensation of CHF with a reduced ejection fraction (EF), NYHA functional class II-IV (FC) according to NYHA [mean (M) EF 29.2%, standard deviation (SD) 13.27%] in age 38 to 65 years old [median (Me) 58 years]. In 3 patients, heart failure developed as a result of dilated cardiomyopathy (DCMP), in 4 patients - against the background of post - infarction cardiosclerosis of the ischemic nature [group of patients with coronary heart disease (CHD)]. The control group - 5 age - matched (from 41 to 57 years old, Me 49 years old) healthy male volunteers. A complete transcript analysis of miRNA expression in MNCs was performed for all patients and healthy volunteers. RESULTS: Differentially expressed miRNAs were determined in patients with CHF (regardless of etiology) compared with healthy individuals: miR-182, miR-144, miR-183, miR-486-5p, miR-143 (log2FC >1, FDR p - value.

[Neutrophil gelatinase-associated lipocalin for early diagnosis of acute kidney injury in patients with acute decompensated heart failure].

BACKGROUND: the incidence of acute kidney injury (AKI) is high in patients with acute decompensated heart failure (ADHF) and is linked with increased morbidity and mortality rates. Predictive biomarkers of AKI could allow improve outcomes in AKI. PURPOSE: to evaluate the value of serum neutrophil gelatinase-associated lipocalin (NGAL) concentrations for early diagnosis of AKI in patients with ADHF with left ventricular (LV) systolic function. METHODS: we enrolled 60 men (average age was 62.0±11.1 years) hospitalized with ADHF with reduced LV systolic function (LV ejection fraction (LVEF).

[MicroRNAs as Biomarkers of Cardiovascular Diseases].

The fact that microRNAs play an important role in the development and pathogenesis of cardiovascular disease is beyond doubt. This article provides a brief overview of recent data that relate to microRNA expression in various cardiovascular diseases. Detecting significant changes in the level of expression of these molecules in various diseases means that microRNAs can be considered to be potential biomarkers of human pathologies including heart failure. Studying the relationship between the mechanisms of cardiovascular disease and the level of expression of a variety of microRNAs, as well as establishing their exact relationships with the genes is an urgent problem and requires further research.

[Soluble Suppression of Tumorogenicity 2 Increases Opportunities for Risk Stratification After Acute Heart Failure Decompensation].

PURPOSE: to evaluate the significance of soluble ST2-receptor (sST2) concentrations in patient (pts) risk stratification in with acute decompensated heart failure (ADHF) during long-term follow-up period. METHODS: In the prospective single-center study were included 159 pts with ADHF III-IV FC NYHA. Blood samples to determine NT-proBNP, sST2, hsTnT concentration were collected at the admission and at discharge from the hospital, and after 3, 6 and 12 months of follow-up. The combined primary end point of the trial included cardiovascular (CV) death, hospitalization due to HF, episodes of HF deterioration needed additional i/v diuretics and CV death with successful resuscitation. RESULTS: At admission all pts had elevated biomarker concentrations: NT-proBNP - 3615.5 (1578.0; 6289.3)pg/ml, sST2 - 60,49 (41.95; 92.87) ng/ml, hsTnT - 29.95 (21.85; 49.63) pg/ml; and at discharge: NT-proBNP - 2165.5 (982.7; 4221,2) pg/ml (%=-38,27 (-49.7; -24.34)%, p<0.0001), sST2 - 38.43 (24.67; 63.72) ng/ml (%=-30,13 (-42,07; -17,64)%, p<0,0001), and hsTnT - 28,37(21.29; 46.6) pg/ml. During 1-year follow-up 56 pts (35.2 %) had 78 (49.1%) cardiovascular events. Biomarker concentrations in low risk pts (without CV events) were significantly lower compared with high risk pts (who have CV events). At the discharge NT-proBNP and sST2 concentrations had the most predictive capacity relatively the primary end point during 1-year follow-up: AUC=0.727 (95% CI 0.637-0.816), <0,0001, and AUC=0,768 (95% CI 0.682-0.854), <0.0001, respectively. Maximally sST2 values were predictive for 180 days period of follow-up: AUC=0,809 (95% CI 0.726-0.921; <0,0001). Lack of NT-proBNP and sST2 concentrations decrease below 1696 pg/ml and 37.8 ng/ml respectively were associated with the highest risk of CV events (HR 4.41 [95% CI 1.41-9.624], p<0,0001 and HR 6.755 [95% CI 3.026- 15.082], p<0.0001, respectively). Changes of sST2 concentration during the period of pts hospitalization were also prognostically important, AUC=0.696 (0.596-0.796); p<0.0001. And pts with insufficient degree of sST2 concentrations reduction during the period of hospitalization (% <-28,3%) had the worst short-term and long-term prognosis [HR 3.68 (95% CI 2.05-6.64), p<0.0001]. Values of sST2 at the discharge were the most significant independent predictor of CV events in long-term follow-up (=0.519, p<0.0001). 91,8% of pts without CV events in the study had sST2 and NT-proBNP levels below 37.8 ng/ml and 1696 pg/ml respectively after 3, 6 and 12 months of follow-up. CONCLUSION: The values of soluble ST2-receptor over 37.8 ng/ml and NT-proBNP over 1696 pg/ml at the discharge from the hospital reflects the adverse prognosis in patients with ADHF. Serial determination of sST2 and NT-proBNP concentrations after discharge from the hospital indicates the necessity of reduction the levels of these biomarkers below the cut-off values (<37.8ng/mL and <1696pg/ml respectively) in pts with ADHF in long-term follow-up period.