Role of Angiopoietic Coronary Endothelial Dysfunction in the Pathogenesis of Ischemic Cardiomyopathy.

BACKGROUND: The angiopoietic endothelial dysfunction in ischemic cardiomyopathy (ICMP) remains unexplored. AIM: The identification of the imbalance of endothelial dysfunction mediators and the number of endothelial progenitor (EPC) and desquamated (EDC) cells in patients with coronary heart disease (CHD) with and without ICMP. METHODS: A total of 87 patients (47 with ICMP and 40 without ICMP) were observed. The content of EPCs (CD14+CD34+VEGFR2+) in vein blood and EDCs (CD45-CD146+) in the blood from the coronary sinus and cubital vein was determined by flow cytometry. The contents of HIF-1α and HIF-2α in vein blood as well as that of ADMA and endothelin-1 in sinus plasma and angiopoietin-2, MMP-9 and galectin-3 in both samples were assessed using ELISA, and VEGF, PDGF, SDF-1 and MCP-1 contents using immunofluorescence. RESULTS: ADMA and endothelin-1 levels in the sinus blood were comparable between the patient groups; a deficiency of HIF-1α and excess of HIF-2α were detected in the vein blood of ICMP patients. The EDC content in the vein blood increased in CHD patients regardless of ICMP, and the concentrations of VEGF-A, VEGF-B, PDGF, MCP-1, angiopoietin-2, and MMP-9 were normal. In ICMP patients, vein blood was characterized by an excess of galectin-3 and sinus blood by an excess of EDCs, angiopoietin-2, MMP-9 and galectin-3. CONCLUSION: ICMP is accompanied by angiopoietic endothelial dysfunction.

Morphological and immunological markers of repeated heart remodeling after surgical reconstruction of the left ventricle in ischemic cardiomyopathy.

INTRODUCTION: Effective treatment of patients with ischemic cardiomyopathy (ICM) is one of the most challenging issues in modern cardiac surgery. The aim of this study was to assess the state of cardiomyocytes and myocardial extracellular matrix, as well as to identify informative markers of an unfavorable prognosis for surgical treatment of ICM. MATERIALS AND METHODS: We retrospectively reviewed patients who underwent surgical treatment of ICM between 2011 and 2018 at a single center. Patients were divided into groups depending on the presence of repeated left ventricle (LV) remodeling in one-year follow-up after surgical reconstruction of the LV in ICM patients. RESULTS: A total of 45 patients with ICM were reviewed. The mean age of the patients was 57.9 ± 7.8 years. According to the results of the study, the area of cardiomyocyte nuclei differed statistically significantly among the regions with varying degrees of impaired local contractility (p = 0.042). According to the results of the pairwise comparison in dyskinetic areas of the myocardium, the area of cardiomyocyte nuclei was higher than in normokinetic areas (p = 0.042). A moderate positive correlation was found between the LV ejection fraction measured in one-year follow-up period after surgery and the number of CD163-positive cells (p = 0.012). CONCLUSION: In the myocardium of patients with LV reverse remodeling in the long-term postoperative period, perivascular fibrosis occurs more frequently than in patients with progressive LV remodeling. The number of M2-anti-inflammatory macrophages prevails in the myocardium of the patients with reverse remodeling compared with patients with progressive remodeling.

Production of Reactive Oxygen Species by Epicardial Adipocytes Is Associated with an Increase in Postprandial Glycemia, Postprandial Insulin, and a Decrease in Serum Adiponectin in Patients with Severe Coronary Atherosclerosis.

Purpose. This work investigates the relations between the production of reactive oxygen species (ROS) by epicardial adipose tissue (EAT) adipocytes and parameters of glucose/insulin metabolism, circulating adipokines levels, and severity of coronary atherosclerosis in patients with coronary artery disease (CAD); establishing significant determinants describing changes in ROS EAT in this category of patients. Material and methods. This study included 19 patients (14 men and 5 women, 53−72 y.o., 6 patients with diabetes mellitus type 2; 5 patients with prediabetes), with CAD, who underwent coronary artery bypass graft surgery. EAT adipocytes were isolated by the enzymatic method from intraoperative explants obtained during coronary artery bypass grafting. The size of EAT adipocytes and ROS level were determined. Results. The production of ROS by EAT adipocytes demonstrated a direct correlation with the level of postprandial glycemia (rs = 0.62, p < 0.05), and an inverse correlation with serum adiponectin (rs = −0.50, p = 0.026), but not with general and abdominal obesity, EAT thickness, and dyslipidemia. Regression analysis demonstrated that the increase in ROS of EAT adipocytes occurs due to the interaction of the following factors: postprandial glycemia (ß = 0.95), postprandial insulin (ß = 0.24), and reduced serum adiponectin (ß = −0.20). EAT adipocytes in patients with diabetes and prediabetes manifested higher ROS production than in patients with normoglycemia. Although there was no correlation between the production of ROS by EAT adipocytes and Gensini score in the total group of patients, higher rates of oxidative stress were observed in EAT adipocytes from patients with a Gensini score greater than median Gensini score values (≥70.55 points, Gr.B), compared to patients with less severe coronary atherosclerosis (<70.55 points, Gr.A). Of note, the frequency of patients with diabetes and prediabetes was higher among the patients with the most severe coronary atherosclerosis (Gr.B) than in the Gr.A. Conclusions. Our data have demonstrated for the first time that systemic impairments of glucose/insulin metabolism and a decrease in serum adiponectin are significant independent determinants of oxidative stress intensity in EAT adipocytes in patients with severe coronary atherosclerosis. The possible input of the interplay between oxidative stress in EAT adipocytes and metabolic disturbances to the severity of coronary atherosclerosis requires further investigation.

Low-dose dobutamine stress gated blood pool SPECT assessment of left ventricular contractile reserve in ischemic cardiomyopathy: a feasibility study.

PURPOSE: The purpose of the present study was to evaluate the feasibility of gated blood pool single-photon emission computed tomography (GBPS) with low-dose dobutamine (LDD) stress test, performed on a single-photon emission computed tomography (SPECT) camera equipped with cadmium-zinc-telluride (CZT) solid-state detectors, in assessing of left ventricle (LV) contractile reserve in patients with ischemic cardiomyopathy (ICM). METHODS: A total of 52 patients (age 59 ± 7.2 years, 47 men and 5 women) with ICM and a control group of 10 patients without obstructive coronary artery lesion underwent GBPS and transthoracic echocardiography (TTE) at rest and during LDD stress test (5, 10, 15 µg/kg/min). The duration of each GBPS step was 5 min. Stress-induced changes in LV ejection fraction (ΔLVEF), peak ejection rate, LV volumes, and mechanical dyssynchrony (phase histogram standard deviation, phase histogram bandwidth and entropy) obtained with GBPS were estimated. RESULTS: All GBPS indices except end-diastolic volume showed significant dynamics during stress test in both groups. The majority of parameters in ICM patients showed significant changes at a dobutamine dose of 10 µg/kg/min as compared to the rest study. Seventeen percent of ICM patients, but none from the control group, showed a decrease in LVEF during stress, accompanied by a significant increase in entropy. The intra- and inter-observer reproducibility was excellent for both rest and stress studies. There was a moderate correlation (r = 0.5, p = 0.01) between GBPS and TTE, with a mean difference value of - 1.7 (95% confidence interval - 9.8; 6.4; p = 0.06) in ΔLVEF. CONCLUSION: Low-dose dobutamine stress GBPS performed with high-efficiency CZT-SPECT cameras can be performed for evaluating stress-induced changes in LV contractility and dyssynchrony with lower acquisition time. A dobutamine dose of 10 µg/kg/min can potentially suffice to detect stress-induced changes in patients with ICM during GBPS. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04508608 (August 7, 2020).

The diagnostic value of SPECT CZT quantitative myocardial blood flow in high-risk patients.

BACKGROUND: The objective of this study was to evaluate the accuracy of global MBF and MFR quantitation performed by myocardial perfusion scintigraphy (MPS) for the detection of multivessel coronary artery disease (CAD). METHODS: 52 CAD patients underwent CZT MPS, with the evaluation of MBF and MFR, followed by invasive coronary angiography (ICA). According to MPS and ICA results, all patients were divided into three groups: (1) non-obstructive CAD and normal MPS scan (control group) (n = 7), (2) one vessel disease (1VD) (n = 16), (3) multivessel disease (MVD) (n = 29). RESULTS: Global absolute MBF and MFR were significantly reduced in MVD patients as compared to those with 1VD [0.93 (IQR 0.76; 1.39) vs 1.94 (1.37; 2.21) mL·min-1·g-1, P = .00012] and [1.4 (IQR 1.02; 1.85) vs 2.3 (1.8; 2.67), P = . 0 004], respectively. The Syntax score correlated with global stress MBF (ρ = - 0.64; P < .0001) and MFR (ρ = - 0.53; P = .0003). ROC analysis showed higher sensitivity and specificity for stress MBF and MFR compared with semiquantitative MPS stress evaluation. Multivariate regression analysis showed that only stress MBF [OR (95% CI) 0.59 (0.42-0.82); P < .0003] was an independent predictor of MVD. CONCLUSIONS: Quantitative myocardial blood flow values assessed with the use of CZT camera may identify high-risk patients, such as those with multivessel disease.

Results of reconstructive interventions in patients with ischemic cardiomyopathy.

BACKGROUND: Effective treatment of patients with ischemic cardiomyopathy is one of the most difficult issues in contemporary cardiac surgery. The aim of this study was to evaluate the long-term effectiveness of reconstructive interventions on the left ventricle during chronic heart failure in patients with ischemic cardiomyopathy. METHODS: Between March 2013 and December 2017, 178 patients underwent surgical treatment for ischemic cardiomyopathy. Isolated coronary artery bypass grafting was compared with coronary artery bypass grafting with left ventricular reconstruction, using propensity score matching analysis. The primary endpoints of the study were hospital mortality and long-term survival. RESULTS: After propensity score matching, 29 pairs of patients were compared. The 30-day hospital mortality was comparable (6.8% versus 6.8%, p = 0.952), the average follow-up was 37.4 ± 12.6 months, with no statistically significant difference in mortality from all causes (p = 0.352). After coronary artery bypass in combination with left ventricular reconstruction, patients showed a statistically significant decrease in clinical and functional indicators of chronic heart failure compared to those who had coronary artery bypass grafting alone, in terms of peak oxygen consumption (15.3 versus 13.5 mL·kg-1·min-1, p = 0.043) and N-terminal pro-brain natriuretic peptide concentrations (298.6 versus 461.1 pg·mL-1, p = 0.032). CONCLUSIONS: Compared to isolated coronary artery bypass, coronary artery bypass in combination with left ventricular reconstruction for the treatment of ischemic cardiomyopathy leads to a significant decrease in the clinical and functional parameters of chronic heart failure in the long-term postoperative period.

How human IgGs against DNA recognize oligonucleotides and DNA.

In the literature, there are no available data on how anti-DNA antibodies recognize DNA. In the present work, to study the molecular mechanism of DNA recognition by antibodies, we have used anti-DNA IgGs from blood sera of patients with multiple sclerosis. A stepwise increase in ligand complexity approach was used to estimate the relative contributions of virtually every nucleotide unit of different single- (ss) and double-stranded (ds) oligonucleotides to their affinity for IgG fraction having high affinity to DNA-cellulose. DNA-binding site disposed on the heavy chain demonstrates higher affinity to different dNMPs (Kd  = 0.63µM-3.8µM) than the site located on the light chain (28µM-170µM). The heavy and light chains interact independently forming relatively strong contacts with 2 to 4 nucleotides of short homo- and hetero-d(pN)2-9 . Then the increase in the affinity of different d(pN)n became minimal, and at n ≥ 8 to 9, all dependencies reached plateaus: approximately 3.2nM to 20nM and approximately 200nM to 460nM for the heavy and light chains, respectively. A similar situation was observed for different ribooligonucleotides, in which their affinity is 6-fold to 100-fold lower than that for d(pN)n . Transition from ss to ds d(pN)n leads to a moderate increase in affinity of ligands to DNA-binding site of heavy chains, while light chains demonstrate the same affinity for ss and ds d(pN)n . Long supercoiled DNA interacts with both heavy and light chains with affinity of approximately 10-fold higher than that for short oligonucleotides. The thermodynamic models were constructed to describe the interactions of IgGs light and heavy chains with DNA.