Modern Instrumental Methods of Diagnostics and Risk Assessment of Developing Antitumor Therapy Cardiovasculotoxicity.

The most important component of cardio-oncology is the assessment of the risk of development and diagnosis of cardiovascular toxicity of the antitumor therapy, the detection of which is largely based on visualization of the cardiovascular system. The article addresses up-to-date methods of non-invasive visualization of the heart and blood vessels, according to the 2022 European Society of Cardiology Clinical Guidelines on cardio-oncology. Also, the article discusses promising cardiovascular imaging techniques that are not yet included in the guidelines: assessment of coronary calcium using multislice computed tomography and positron emission computed tomography with 18F-labeled 2-deoxy-2-fluoro-d-glucose.

Patient Adherence and Duration of Continuous Treatment With Various Arbs in Patients With Uncomplicated Arterial Hypertension in the USA Based on The Analysis of the Truven Health Analytics MarketScan Database.

AIM: To discuss two aspects that can be used to improve the adherence to therapy in patients with arterial hypertension (AH): 1) which of the angiotensin II receptor blockers (ARBs) provides the highest adherence rates; 2) how various factors influence adherence rates. MATERIAL AND METHODS: An analysis of one of the world's largest clinical practice databases, Truven Health Analytics MarketScan (currently Merative MarketScan), was performed. The analysis included data on patients of both sexes aged 30 to 65 years who had been diagnosed with uncomplicated AH (at least once between March 1, 2012 and January 1, 2018) and prescribed monotherapy with one of ARBs. The exclusion criteria were heart failure and the treatment with two or more ARBs (simultaneously or sequentially) during the treatment period. Ultimately, the study included 717,099 patients with uncomplicated AH, who were divided into four groups based on the prescribed drug: azilsartan (n=4276), candesartan (n=6023), losartan (n=586,857), and valsartan (n=119,943). Adherence to treatment was evaluated by two parameters: duration of continuous therapy and medication possession ratio (MPR). The individual effect of each factor (specific ARB used for therapy, patient gender, age, initial ARB dose, patient co-payment per day of treatment) on the adherence to treatment was assessed using a regression analysis. RESULTS: The adherence to the ARB therapy was generally high. The MPR was the lowest in the azilsartan group and the highest in the candesartan group. However, the parameters that potentially influenced both the MPR and the duration of continuous therapy (patient's gender and age, initial ARB dose, co-payment size) differed significantly between the groups receiving different ARBs. The regression analysis showed that both adherence parameters and the duration of continuous therapy were higher in patients receiving candesartan than in patients receiving azilsartan, losartan or valsartan, when the effect on the adherence of other factors available for study (age, gender, initial dose of the drug, and the absolute size of co-payment for a day of therapy) was excluded. The lowest adherence to therapy was observed in the azilsartan treatment group (p<0.01). CONCLUSION: The study provided data for comparing the adherence of patients with uncomplicated AH to the therapy with different ARBs. Further study of adherence to treatment will provide additional data that will allow an optimal selection of drugs for the treatment of AH in patients with potentially poor adherence.

[Cardiac Dysfunction and Arterial Hypertension as Manifestations of Cardiovasculotoxicity of iVEGF-Containing Chemotherapy. Clinical Case].

Significant advances in timely diagnosis and modern antitumor therapy have led to a considerable increase in the survival rate of cancer patients. On the other hand, the incidence of cardiovascular (CV) diseases and their complications is increasingly growing, including due to side effects of anticancer drugs. CV complications are the most common cause of non-oncological death of cancer patients. The development of polychemotherapy-induced arterial hypertension (AH) is closely associated with the use of certain groups of drugs, for example, inhibitors of vascular endothelial growth factor (iVEGF). Such AH is generally dose-dependent and reversible after interruption or termination of treatment. However, systemic AH, regardless of its genesis, is one of the key risk factors for many CV events (myocardial infarction, stroke, heart failure, arrhythmias) and kidney disease. Therefore, thorough blood pressure monitoring and its timely and adequate correction if needed are indicated when using certain groups of chemotherapy drugs. This article describes a clinical follow-up of a patient with induced AH associated with the iVEGF antitumor therapy for advanced uterine cancer with a rapid development of left ventricular myocardial dysfunction.

The EXCEL Study: Long-term Observation of the Effectiveness of Drug and Non-drug Rehabilitation in Patients with Ischemic Heart Failure.

AIM: To study the long-term effect of enhanced external counterpulsation (EECP) therapy on exercise tolerance, quality of life (QoL), and indicators of the structural and functional state of the cardiovascular system in patients with stable ischemic heart disease (IHD) complicated by chronic heart failure (CHF). MATERIAL AND METHODS: This open randomized EXCEL study included 120 patients with verified IHD complicated by NYHA II-III functional class CHF with reduced or mid-range left ventricular (LV) ejection fraction. Patients were randomized into group 1 (n=40), optimal drug therapy (ODT) and EECP (35 hours, 2 courses per year); group 2 (n=40), ODT and EECP (35 hours, 1 course per year); and group 3 (control; n=40), ODT and placebo counterpulsation (35 h, 1 course per year). All patients underwent a 6-minute walk test (6MWT), evaluation of clinical status, QoL with the MLHFQ and SF-36 questionnaires, structural and functional state of large blood vessels and microvasculature, measurement of brain natriuretic peptide precursor (NT-proBNP), and echocardiography at baseline and after 12 months. RESULTS: In groups 1 and 2 after 12 months, the 6MWT distance increased statistically significantly (44.5 and 24.9%, respectively) and the following indexes improved: QoL (SF-36, MLHFQ), the condition of large blood vessels (phase shift, radial augmentation index, central aortic systolic pressure (CASP)) and microvasculature (occlusion index, percentage of perfused capillaries, percentage of capillary recovery), and the LV systolic function (from 40.6±7.5 to 47.5±10.2% and from 41.3± 6.8 to 43.9±10.3%, respectively). The proportion of patients with a >20% increase in the 6MWT at 12 months was 97.5, 72.5, and 7.7%, respectively. A statistically significant decrease in NT-proBNP was observed in all groups. In group 3, the incidence of hospitalizations for CHF and the risk of the composite endpoint were significantly higher. CONCLUSION: For the 12-month study period, the effects of EECP in patients with IHD complicated by CHF included improvements in exercise tolerance, QoL, vascular and cardiac functional parameters, and a decrease in the incidence of adverse outcomes.

Assessment of the Level of Matrix Metalloproteinases, VEGF and MicroRNA-34a in Patients With Non-obstructive and Obstructive Lesions of the Coronary Arteries.

AIM: To assess the levels of matrix metalloproteinases (MMP), vascular endothelial growth factor (VEGF), and miRNA-34a expression in patients with ischemic heart disease (IHD) and obstructive and nonobstructive coronary artery (CA) disease. MATERIAL AND METHODS: This cross-sectional observational study included 64 patients with IHD (diagnosis verified by coronary angiography or multislice computed tomography coronary angiography), of which 33 (51.6%) were men aged 64.9±8.1 years. 20 patients had nonobstructive CA disease (stenosis <50%), and 44 had hemodynamically significant stenoses. The control group consisted of 30 healthy volunteers. MMP-1, -9, -13, and -14, miRNA-34a, and VEGF were measured in all patients. RESULTS: The concentration of MMP-1 was significantly higher in patients with ischemia and nonobstructive CA disease (INOCAD) (p=0.016), and the concentration of MMP-9 was the highest in the group with obstructive CA disease (p<0.001). The concentrations of MMP-13 and MMP-14 did not differ significantly between the groups. The highest VEGF concentrations were observed in the INOCAD group (p<0.001). The expression of miRNA-34a significantly differed between the IHD groups with different types of CA disease and controls (p <0.001). Patients with hemodynamically significant stenosis showed moderate relationships between the concentrations of MMP-14 and VEGF (ρ=0.418; p=0.024), as well as between VEGF and miRNA-34a (ρ=0.425; p=0.022). Patients with INOCAD had a significant negative correlation between the concentrations of MMP-13 and VEGF (ρ= -0.659; p=0.003). Correlation analysis showed in all IHD patients a moderate relationship of the concentrations of MMP-1 and MMP-14 with VEGF (ρ=0.449; p=0.002 and p=0.341; p=0.019, respectively). According to ROC analysis, a MMP-9 concentration above 4.83 ng/ml can be a predictor for the presence of hemodynamically significant CA obstruction in IHD patients; a VEGF concentration higher than 27.23 pg/ml suggests the absence of hemodynamically significant CA stenosis. CONCLUSION: IHD patients with INOCAD had the greatest increase in MMP-1, whereas patients with obstructive CA disease had the highest level of MMP-9. According to our data, concentrations of MMP-9 and VEGF can be used to predict the degree of CA obstruction. The expression of miRNA-34a was significantly higher in IHD patients with INOCAD and CA obstruction than in the control group, which suggested a miRNA-34a contribution to the development and progression of coronary atherosclerosis. In the future, it may be possible to use this miRNA as a diagnostic marker for IHD.

Assessment of Specific Biomarkers' Profile and Structural, Functional Parameters of the Left Ventricle in Patients With Lymphomas Undergoing Antitumor Therapy.

AIM: To evaluate the dynamics of specific biomarkers for cardiotoxicity, endothelial dysfunction, fibrosis, systemic inflammation, and morpho-functional alterations in the left ventricular (LV) myocardium in patients with newly diagnosed lymphomas during 6 courses of polychemotherapy (PCT). MATERIAL AND METHODS: The study included 30 patients with newly diagnosed lymphomas. All patients were evaluated for laboratory markers of cardiotoxicity at baseline and after 6 courses of chemotherapy (6 months), including N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity troponin I (hsTnI), endothelin-1 (ET-1), circulating cardiac biomarker ST-2, high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and LV structural and functional echocardiographic (EchoCG) parameters. RESULTS: The changes in NT-proBNP and hsTnI concentrations during 6 courses of PCT were not statistically significant. Comparison of the baseline values with those after 6 courses of PCT showed increases in the median concentrations of ET-1 (3.38 and 5.5 pg/ml, respectively; p=0.438) and ST-2 (12.21 and 26.75 ng/ml, respectively; p=0.687). Markers of systemic inflammation were significantly decreased after 6 courses of PCT: the median CRP decreased from 15.2 to 0.72 mg/ml (p=0.006), and the median IL-6 decreased from 12.2 to 5.1 pg/ml (p=0.034). EchoCG data revealed a statistically significant impairment of the LV diastolic function parameters (E/A; E/e' lateral; E/e' average; left atrial volume index; isovolumic relaxation time). A moderate direct correlation was found between the ET-1 concentration and the isovolumic relaxation time at baseline and after 6 courses of PCT, respectively (r1 = 0.387, p=0.047 and r2 = 0.391, p=0.035). No changes in the LV systolic function were observed. CONCLUSION: The study showed that patients with lymphoproliferative diseases had no signs of cardiotoxicity during PCT according to the accepted criteria. This study described and highlighted for the first time the interrelation of endothelial dysfunction, profibrotic status, and LV diastolic dysfunction as manifestations of cardiovascular toxicity in patients with lymphoproliferative diseases. It is advisable to supplement the integrated strategies for the prevention and monitoring of PCT cardiovascular toxicity with a thorough evaluation of instrumental parameters of diastolic dysfunction for timely initiation/correction of cardioprotective therapy.

WNT Signaling Cascade Proteins and LRP6 in the Formation of Various Types of Coronary Lesions in Patients With Coronary Artery Disease.

AIM: Assessment of WNT1, WNT3a, and LRP6 concentrations in patients with ischemic heart disease (IHD) and obstructive and non-obstructive coronary artery (CA) disease. MATERIAL AND METHODS: This cross-sectional observational study included 50 IHD patients (verified by coronary angiography, CAG), of which 25 (50%) were men, mean age 64.9±8.1 years; 20 patients had non-obstructive CA disease (stenosis <50%), and 30 patients had hemodynamically significant stenosis. Concentrations of WNT1, WNT3a and LRP6 were measured in all patients. RESULTS: The concentrations of WNT1 and WNT3a proteins were significantly higher in patients with IHD and obstructive CA disease (p < 0.001), while the concentration of LRP6 was higher in the group with non-obstructive CA disease (p = 0.016). Data analysis of the group with obstructive CA disease showed a moderate correlation between WNT1 and LRP6 (ρ=0.374; p=0.042). Correlation analysis of all groups of patients with CA disease revealed a moderate association between the concentrations of WNT1 and uric acid (ρ=0.416; p=0.007). Regression analysis showed that risk factors for the development of IHD, such as increased body mass index, age, smoking, dyslipidemia, and hypertension, did not significantly influence the type of CA disease in IHD patients. According to ROC analysis, the obstructive form of IHD was predicted by a WNT3a concentration higher than 0.155 ng/ml and a LRP6 concentration lower than 12.94 ng/ml. CONCLUSION: IHD patients with non-obstructive CA disease had the greatest increase in LRP6, while patients with obstructive CA disease had significantly higher concentrations of the canonical WNT cascade proteins, WNT1 and WNT3a. According to the ROC analysis, a WNT3a concentration >0.155 ng/ml can serve as a predictor for the presence of hemodynamically significant CA stenosis in IHD patients (sensitivity 96.7%; specificity 70%), whereas a LRP6 concentration >12.94 ng/ml can predict the development of non-obstructive CA disease (sensitivity 76.7%; specificity 65%).

[Evaluation of the Functional Reserve and Exercise Tolerance in Patients with CHF in Clinical Trials (Consent Document of the Editorial board of the Journal of Cardiology, the Board of the Society of Specialists in Heart Failure (SSHF) and Working Group "Non-drug treatment methods" of SSHF)].

Assessing the functional capacity and exercise tolerance is an important and widely used research tool in patients with heart failure. It is used not only in cardiac rehabilitation and physical therapy, but also for inclusion criteria and outcome measures in studies of drug interventions. This document outlines the scope, guidelines for the implementation and interpretation, and limitations of the methods for assessing the functional capacity and exercise tolerance in clinical trials in patients with heart failure.

[Soluble guanylate cyclase: restoration of the NO-sGC-cGMP signaling pathway activity. A new opportunity in the treatment of heart failure].

Studying the key mechanisms of cardiovascular diseases has opened new possibilities for the pharmacological impact on the pathophysiological mechanisms of heart failure (HF). The signaling pathway, nitric oxide - soluble guanylate cyclase - cyclic guanosine monophosphate (NJ-sGC-cGMP), provides normal functioning of the cardiovascular system in healthy people and serves as a potential target for medicines in HF with reduced ejection fraction (HFrEF). In HFrEF progression, the sGC activity decreases due to endothelial dysfunction and oxidative stress. The increased synthesis of cGMP resulting from sGC stimulation can restrict myocardial fibrosis, reduce stiffness of the vascular wall and induce vasodilation; in this process, the mechanism of action of sGC stimulators does not overlap with other therapeutic targets. According to the results of the international randomized clinical study VICTORIA, the use of the sGC stimulator, vericiguat, in patients with HF, ejection fraction <45%, and a recent episode of decompensation in their history reduced the risk of repeated hospitalization and cardiovascular death. Also, this treatment was characterized by a favorable safety profile when added to standard therapy.

Cardio-oncology today: digest of the first European clinical guidelines (2022).

Over the past few decades, due to the extensive implementation of cancer screening programs, up-to-date early diagnostic methods, and effective combinations of antitumor therapy, it has become possible to significantly improve survival of cancer patients. At the same time, despite the effective treatment of malignancies, most patient face adverse and often life-threatening effects of specific treatment on the heart and blood vessels. All this resulted in active development of a new field in cardiology, cardio-oncology. In recent years, based on the experience of leading experts, data from large studies, and meta-analyses, both international and Russian Consensuses, conciliation documents, have been formed and published. These documents regulate principal methodological approaches to management and control of the cardiovascular conditions in cancer patients. Finally, 2022 was marked by issuing the first official European Guidelines on Cardio-Oncology in the history of medicine. This article highlights the most relevant, in our opinion, positions of these guidelines as well as controversial and unresolved issues.

[Assessment of systemic inflammation activity, myocardial structure and functional features, their relationship in patients with multiple myeloma, receiving bortezomib therapy].

AIM: To study the dynamics of calculated indices [neutrophil-lymphocyte ratio (NLR); systemic inflammation index (SIV)] and biomarkers of systemic inflammation [interleukin-1ß (IL-1ß); high-sensitivity C-reactive protein (hsCRP)], parameters of the structure-and-function state of the myocardium and intracardiac hemodynamics, and their relationship in patients newly diagnosed with multiple myeloma (MM) at the onset of the disease and after 6 courses of chemotherapy (CT) containing the proteasome inhibitor bortezomib. MATERIAL AND METHODS: This prospective study included 30 patients aged 63.8±10.0 years diagnosed with MM; 17 (56.7 %) of them were men. The following tests were performed for all patients: measurement of IL-1ß and hsCRP, calculation of the inflammation indexes NLR and SIV, transthoracic echocardiography before and after 6 courses of bortezomib-containing CT. At the time of study completion, 9 patients dropped out due to reasons not related to cardiovascular complications of CT. RESULTS: The antitumor therapy was associated with increases of immune-inflammation indexes: NLR increased from 1.54 [1.02; 1.83] to 2.9 [1.9; 4.35] (p=0.009) and SIV increased from 402.95 [230.5; 534.0] to 1102.2 [453.1; 1307.9] (р=0.014). IL-1ß increased from 5.15 [4.05; 5.77] to 6.22 [5.66; 6.52] pg/ml remaining within the reference range (p=0.142) whereas hsCRP decreased from 1.02 [0.02; 2.71] to 0.02 [0.02; 0.82] IU/l (p=0.138). Statistically significant changes in parameters of heart remodeling and clinical picture of cardiovascular complications were not observed. A correlation analysis showed significant inverse correlations of hsCRP with left ventricular ejection fraction (LV EF) (r= -0.557; p=0.003), the number of plasma cells (PC) with LV EF (r= -0.443; p=0.023), and a direct correlation of the number of PC with hsCRP (r=0.433; p=0.022). CONCLUSION: During the study, the accepted criteria for cardiotoxicity of bortezomib-containing chemotherapy in patients with MM, were not met. The identified correlations between the level of markers for acute inflammation, indexes of intracardiac hemodynamics, and the immediate MM substrate may indicate the role of chronic low-intensity inflammation in the pathogenesis of myocardial remodeling in patients with MM. This necessitates further studies on larger samples of patients to assess the prognostic significance.

[Prospects for use of Vericiguat in HFrEF: Implications of VICTORIA Trial Results. Advisory Board Summary].

In September 2021, an online meeting of the Council of Experts was held. The proposed focus of discussion was publishing the results of an international prospective, randomized, double-blind, placebo-controlled study VICTORIA. The objective of the VICTORIA study was evaluation of the efficacy and safety of supplementing a standard therapy with vericiguat at a target dose of 10 mg twice a day as compared to placebo for prevention of cardiovascular death and hospitalization for heart failure (HF) in patients with clinical manifestations of chronic HF and left ventricular ejection fraction <45% who have recently had an episode of decompensated HF. The aim of the meeting was interpretation of the VICTORIA study results on efficacy and safety of vericiguat for a potential use in a Russian population of patients after a recent episode of decompensated chronic HF with reduced ejection fraction.

[Mobile health technologies in cardiology].

Digital medicine is becoming an essential part of the healthcare system. The intense development of mobile technologies, the global coverage of mobile networks, and the growing attachment in the society to mobile devices have prompted the creation of mobile healthcare (mHealth). At present, mobile healthcare technologies have been tested in various cardiovascular diseases. Among the main tasks set for telemedicine, it is necessary to note improvements of general medical care, monitoring of patients' condition, accuracy of clinical diagnoses, timely correction of therapy, and improvement of emergency care. Clinical studies are performed in parallel with active work in the field of informational technologies to provide safety of data storage and intellectual processing. Finally, despite the broad public support for the development of this area of medicine, the search continues for methods to improve patients' compliance with the prescribed therapy. This article presents current information about the use of mHealth in cardiology, study results, prospects of mobile healthcare, and major difficulties in implementing projects in this area.

Characteristic of cardiovascular status and intracardiac hemodynamics in patients with multiple myeloma before the start of antitumor therapy.

AIM: assessment of risk factors, cardiovascular status and intracardiac hemodynamics in patients with multiple myeloma before the start of specific antitumor therapy. Materials and methods: The study included 2 equal groups of patients: the first group - 25 patients with a newly diagnosed diagnosis of multiple myeloma (MM), the comparison group - 25 patients with proven cardiovascular diseases (CVD) (hypertension (HD) and coronary heart disease (CHD)). All patients included in the study underwent standard laboratory diagnostics, instrumental research methods (ECG, Echo-KG, 24-hour Holter monitoring); proven CVD risk factors were also evaluated. Results: When comparing the two groups, it was reliably shown that the state of CVD in patients with MM is comparable to that in patients with proven CVD. In patients from the main group, were revealed significant positive correlations of average strength between indicators of systemic inflammation, the lipid spectrum and intracardiac hemodynamics: between the levels of CRP and triglycerides (r=0,415, p<0,05); between the values of CRP and LDL (r=0,345, p=0,09); CRP and LA volume (r=0,434, p<0,05); CRP and final diastolic volume (r=0,30, p<0,05). At the beginning, a high risk of developing CV- events in patients with MM may be due to cardiac remodeling associated with the activity of systemic inflammation. CONCLUSION: in view the use of potentially cardiovasculartoxicity drugs for the treatment of multiple myeloma, the assessment of the CV status and consultation with a cardiologist/cardiologist with the selection of the necessary therapy should be obligatory step before starting specific treatment.

The Effect of COVID-19 on Long-Term Cardiac Function in Patients With Chronic Heart Failure.

Aim      To evaluate functional changes in the heart in the long-term following COVID-19 in patients with chronic heart failure (CHF).Material and methods  Case reports of 54 patients aged 69.1±9.7 years who had COVID-19 from January 2021 through January 2022 and had been previously diagnosed with NYHA functional class II-III CHF were studied. Two comparison groups were isolated: HF with LV EF >50 % (n=39) and <50 % (n=15). Echocardiography was used to evaluate changes in LV EF and pulmonary artery systolic pressure (PASP) 5-6 months following COVID-19.Results In all CHF patients after COVID-19 at 5.8 months on average, LV EF decreased (median difference, 2.5 %; 95 % confidence interval (CI): 6.99×10-5- 4.99) and PASP increased (median difference, 8 mm Hg; 95 % CI: 4.5-12.9). In the HF group with LV EF <50 %, the decrease in EF was greater than in the group with LV EF >50 % (6.9 and 0.7 %, respectively; p=0.037); furthermore, the CHF phenotype did not influence the change in PASP (p=0.4). The one-factor regression analysis showed that the dynamics of LV EF decrease was significantly influenced by the baseline decrease in LV EF, whereas the change in PASP was influenced by the dynamics of LV EF decrease, presence of dyslipidemia, and statin treatment. Furthermore, the multifactorial analysis showed that prognostically significant factors for long-term changes in LV EF following COVID-19 were male gender (odds ratio (OR), 5.92; 95 % CI: 1.31-26.75; p=0.014), LV EF at baseline <50 % (OR, 0.88; 95 % CI: 0.8-0.96; p<0.001); changes in PASP depended on the presence of dyslipidemia (OR, 0.08; 95 % CI: 0.01-0.84; p=0.018).Conclusion      This study showed that COVID-19 in the long term can influence the course of CHF; in this process, HF patients with EF <50 % have progression of systolic dysfunction and PASP, whereas patients with EF >50 % have an isolated increase in PASP.

Comparative analysis of tryptophan and downstream metabolites of the kynurenine and serotonin pathways in patients with arterial hypertension and coronary artery disease.

Aim    To compare serum concentrations of tryptophane (Trp) and its metabolites in subjects with no cardiovascular disease (CVD) and patients with СVD, including arterial hypertension (AH) and ischemic heart disease (IHD).Material and methods    This study included 131 participants; 58 participants (11 of them with documented peripheral atherosclerosis) were included into the AH group, 46 participants were included into the IHD group, and 27 participants with no signs of CVD were included into the control group. Plasma concentrations of Trp and its metabolites were measured by high-performance liquid chromatography in combination with a triple quadrupole analyzer.Results    Comparison of the three study groups revealed significant differences in concentrations of Trp (р=0.029), kynurenine (p<0.001), kynurenine/Trp ratio (p<0.001), quinolinic acid (р=0.007), kynurenic acid (р=0.003), serotonin (p<0.001), and 5­hydroxyindoleacetic acid (5­HIAA) (р=0.011). When the AH group was subdivided into subgroups without and with documented peripheral atherosclerosis, the intergroup differences remained for concentrations of kynurenine, kynurenine/Trp ratio, quinolinic acid, kynurenic acid, serotonin, and 5­HIAA. Also, correlations were found between concentrations of Trp metabolites and laboratory and instrumental data, primarily inflammatory markers. Conclusion    Analysis of serum concentrations of Trp and its metabolites in CVD patients showed increases in kynurenine, kynurenine/Trp ratio, quinolinic acid, kynurenic acid, and 5­HIAA along with decreases in concentrations of Trp and serotonin in the groups of AH, AH with documented peripheral atherosclerosis, and IHD.

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.

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.

Relationship Between Markers of the Acute Phase of Inflammation, Parameters of Blood Lipid Composition and Intracardiac Hemodynamics During Chemotherapy in Patients With Multiple Myeloma.

Aim      To evaluate in a pilot study time-related changes in the clinical state, indexes of the acute phase of inflammation, parameters of blood lipid profile, intracardiac hemodynamics, and disorders of cardiac rhythm/conduction in patients who are not candidates for autologous hemopoietic stem cell transplantation, during three bortezomib-containing chemotherapy courses (VCD) followed by a correlation analysis.Material and methods  This pilot study included 20 patients diagnosed with myeloma, who were not candidates for autologous hemopoietic stem cell transplantation and who had undergone three courses of VCD chemotherapy (bortezomib, cyclophosphamide and dexamethasone). In addition to mandatory examinations, measurement of blood lipid profile, transthoracic echocardiography (EchoCG), and 24-h Holter electrocardiogram (ECG) monitoring were performed for all participants before and after a specific therapy.Results Following three bortezomib-containing courses of chemotherapy, patients of the study group had significant increases in the neutrophil-lymphocyte ratio (NLR) (1.6±0.2 and 2.5±0.4; р=0.05), cholesterol concentration (4.8±1.1 and 5.6±1.1 mmol/l, р=0.05), and low-density lipoprotein concentration (2.8±0.4 and 3.5±0.8 mmol/l, р=0.02). In comparing the changes in parameters of intracardiac hemodynamics, criteria for genuine cardiotoxicity were not met, however, a tendency to emergence/progression of myocardial diastolic dysfunction was noted. No clinically significant disorders of cardiac rhythm/conduction were observed. The correlation analysis performed prior to the start of chemotherapy, showed significant strong, direct correlations between the C-protein concentration and left atrial (LA) volume (r=0.793; p=0.006), right atrial (RA) volume (r=0.857; p=0.002), left ventricular (LV) end-diastolic dimension (EDD) (r=0.589; p=0.043), and LV end-diastolic volume (EDV) (r=0.726; p=0.017). Following the specific treatment, significant, medium-power and strong correlations were found between NLR and EDV (r= -0.673; p=0.033), NLR and end systolic volume (ESV) (r= -0.710; p=0.021), respectively. Significant direct correlations were found between the bortezomib dose per one injection and the serum concentration of triglycerides following the treatment (r=0.78; p=0.05); a single bortezomib dose and parameters of intracardiac hemodynamics: LA (r=0.71; p=0.026), RA (r=0.74; p=0.014), EDD (r=0.837; p=0.003), EDV (r=0.749; p=0.013), ESV (r=0.553; p=0.049).Conclusion      For the first time, a comprehensive evaluation was performed in patients with multiple myeloma, including the dynamics of blood lipid profile, intracardiac hemodynamics and disorders of cardiac rhythm/conduction during bortezomib-containing antitumor therapy, with an analysis of correlation with levels of acute inflammation phase markers. Although in the observation window for genuine cardiotoxicity, clinically significant cardiovascular complications were not detected, the found correlations may evidence a potential role of systemic inflammation activity in myocardial remodeling in the studied patient cohort.