Features of The Dynamics of Profibrotic Markers and Regression of Left Ventricular Hypertrophy After Renal Denervation in Patients With Resistant Hypertension and Stenosing Atherosclerosis of the Coronary Arteries.

AIM: To compare the changes in serum concentrations of matrix metalloproteinases (MMPs) and their tissue inhibitor (TIMP) to the dynamics of blood pressure (BP) and parameters of left ventricular hypertrophy (LVH) 6 months after renal denervation (RD) in patients with resistant arterial hypertension (RAH) and complicated coronary atherosclerosis. MATERIAL AND METHODS: In 22 RAH patients with complicated coronary atherosclerosis (revascularization and/or history of myocardial infarction (MI)), 24-hour BP monitoring, echocardiography, and measurement of blood MMPs and TIMP were performed at baseline and six months after RD. The comparison group consisted of 48 RAH patients without a history of coronary revascularization or MI. RESULTS: In 6 months after RD, BP was decreased comparably in both groups. In the group of complicated atherosclerosis, there were no significant changes in profibrotic markers or LVH parameters. Thus, at baseline and after 6 months, the values of the studied indicators were the following: left ventricular myocardial mass (LVMM) 233.1±48.1 and 243.0±52.0 g, LVMM index 60.6±14.5 and 62.8±10 .9 g/m2.7, proMMP-1 4.9 [2.1; 7.7] and 3.6 [2.0; 9.4]  ng/ml, MMP-2 290.4 [233.1; 352.5] and 352.2 [277.4; 402.9] ng/ml, MMP-9 220.6 [126.9; 476.7] and 263.5 [82.9; 726.2] ng/ml, TIMP-1 395.7 [124.7; 591.4] and 424.2 [118.2; 572.0] ng/ml, respectively. In the comparison group, on the contrary, there was a significant decrease in LVMM from 273.6±83.3 g to 254.1±70.4 g, LVMM index from 67.1±12.3 to 64.0±14.4 g/m2.7, proMMP-1 from 7.2 [3.6; 11.7] to 5.9 [3.5; 10.9] ng/ml, MMP-2 from 328.9 [257.1; 378.1] to 272.8 [230.2; 343.2] ng/ml, MMP-9 from 277.9 [137.0; 524.0] to 85.5 [34.2; 225.9] ng/ml, and the MMP-9/TIMP-1 ratio from 0.80 [0.31; 1.30] to 0.24 [0.07; 0.76]. The BP dynamics in this group was inversely correlated with MMP-2 at 6 months (r=-0.38), and the MMP-9/TIMP-1 ratio was correlated with LVMM and the LVMM index at baseline (r=0.39 and r=0.39) and at 6 months (r=0.37 and r=0.32). The change in TIMP-1 from 543.9 [277.5; 674.1] to 469.8 [289.7; 643.6] ng/ml was not significant (p=0.060). CONCLUSION: In RAH patients with complicated coronary atherosclerosis, the dynamics of profibrotic biomarkers and LVH parameters after RD was absent despite the pronounced antihypertensive effect, probably due to the low reversibility of cardiovascular remodeling processes or more complex regulatory mechanisms of the MMP system.

Renal hemodynamics in patients with resistant hypertension and type 2 diabetes mellitus.

Aim    To study renal hemodynamics in patients with resistant arterial hypertension (RAH) in combination with type 2 diabetes mellitus (DM2) and to identify factors involved in the increase in intrarenal vascular resistance.Material and methods    This study included 59 patients (25 men) with RAH in combination with DM2. Mean age of patients was 60.3±7.9 years; 24-h blood pressure (24-BP) (systolic, diastolic, SBP/DBP) was 158.0±16.3 / 82.5±12.7 mm Hg during the treatment with 4.3 [4.0;5.0] antihypertensive drugs; glycated hemoglobin (HbA1c) was 7.5±1.5 %; estimated glomerular filtration rate (eGFR) was 73.1±21.8 ml/min / 1.73 m2 (CKD-EPI equation). Measurement of office BP, 24-h BP monitoring, renal artery (RA) Doppler, routine lab tests including determination of GFR (CKD-EPI), 24-h urine albumin excretion, and ELISA measurement of blood lipocalin-2, cystatin C, high-sensitive C-reactive protein (hsCRP), and asymmetric dimethylarginine (ADMA) were performed for all patients.Results    Incidence of increased RA resistive index (RI) was 39% despite the high rate of vasodilator treatment (93% for renin-angiotensin-aldosterone system inhibitors, 78% for calcium antagonists). According to a correlation and regression analysis, RA RI values were correlated with the kidney function (r=-0.46, p<0.001 for eGFR, r=0.56; p=0.006 for lipocalin-2), age (r=0.54, p<0.001), increases in concentrations of hsCRP (r=0.35, p<0.001) and ADMA (r=0.39, p=0.028), the increase in vascular stiffness (r=0.59, p<0.001 for pulse BP (PBP) as well as DM2 duration, and HbA1c (r=0.33, p<0.001 for both). The independent association of RA RI with the age, PBP, and duration of DM2 was confirmed by the results of multivariate regression analysis. According to the ROC analysis, the threshold level of RA RI corresponding to a decrease in GFR <60 ml / min / 1.73 m2 was ≥0.693 conv. units.Conclusion    In more than one third of patients with RAH in combination with DM2, increased renal vascular resistance was documented, which was closely associated with impaired kidney function, age, DM2 duration and severity, and markers of low-grade inflammation, endothelial dysfunction, and vascular stiffness. The value of RA RI ≥0.693 conv. units was a threshold for the development of chronic kidney disease (CKD).

[Systemic inflammatory response in cardiac surgery: possibilities of using colchicine].

AIM: To evaluate manifestations of systemic inflammatory response (SIR) and the effect of the colchicine therapy on SIR severity in patients with ischemic heart disease (IHD) after coronary artery bypass grafting (CABG) with extracorporeal circulation (EC). MATERIAL AND METHODS: This study included 100 patients aged 62+6.3 years with stable IHD and multivessel coronary atherosclerosis scheduled for CABG with EC. Patients of group 1 (n=50) were administered with a single dose of colchicine (Colchicum-Dispert) 500 µg 4 hours before surgery followed by 500 µg twice a day for 10 days after surgery. Patients of group 2 (n=50) received a standard treatment, including nonsteroid anti-inflammatory drugs after surgery. Severity of the inflammatory response was evaluated by measuring blood cytokines. RESULTS: In the postoperative period, patient of group 1 showed a tendency toward a lower incidence of pleurisy and heart rhythm disorders in the form of paroxysmal atrial fibrillation (AF) (p=0.18). Levels of the anti-inflammatory cytokines, interleukin-10 (IL-10) and interleukin-6 (IL-6), were significantly increased in both groups at 6 hours after surgery (p<0.05); at the same time, in group 1, IL-10 remained increased also at 10 days after surgery (р=0.0002). No significant time-related changes in the proinflammatory cytokines, tumor necrosis factor α (TNF-α) and interleukin 1ß (IL-1ß), were observed. At 3 days post-CABG, there were significant increases in tissue inhibitors of matrix metalloprotease 1 (TIMP-1) (р<0.0001) and matrix metalloproteinase 9 (MMP-9) (р<0.001); at the same time, patients of group 1 had lower MMP-9 concentrations than patients of group 2 (p<0.05). At 10 days of postoperative period, these values were comparable with the background values. Increases in neopterin compared to preoperative values were found in both groups on days 3 and 10 after surgery (р <0.0001). CONCLUSION: CABG with EC is associated with the activation of SIR. The colchicine therapy at a dose of 500 µg 4 hours prior to surgery and 500 µg twice a day for 10 days after surgery reduces manifestations of SIR, which is clinically evident as a tendency to reduced incidence of pleurisy and arrhythmias, and does not result in the development of serious complications. The dynamics of matrix metalloproteinases indicates that the colchicine treatment is promising for decreasing the risk of CHF progression and myocardial remodeling in patients with IHD.

Ex Vivo Analysis of an Association of Mechanical Strength of Dilated Ascending Aorta with Tissue Matrix Metalloproteinases and Cytokines.

We analyzed the associations of the mechanical strength of dilated ascending aorta wall (intraoperative samples from 30 patients with non-syndromic aneurysms) with tissue MMPs and the cytokine system. Some samples were stretched to break on an Instron 3343 testing machine and the tensile strength was calculated; others were homogenized and the concentrations of MMP-1, MMP-2, MMP-7, their inhibitors (TIMP-1 and TIMP-2), and pro- and anti-inflammatory cytokines were determined by ELISA. Direct correlations between aortic tensile strength and concentrations of IL-10 (r=0.46), TNFα (r=0.60), and vessel diameter (r=0.67) and an inverse correlation with patient's age (r=-0.59) were revealed. Compensatory mechanisms supporting the strength of the ascending aortic aneurysm are possible. No associations of MMP-1, MMP-7, TIMP-1, and TIMP-2 with tensile strength and aortic diameter were found.

Diastolic Dysfunction and Heart Failure With Preserved Ejection Fraction In Patients With Resistant Hypertension and Type 2 Diabetes Mellitus.

Aim      To study the incidence and clinical and pathophysiological features of diastolic dysfunction (DD) and chronic heart failure with preserved ejection fraction (HFpEF) in patients with resistant arterial hypertension (RAH) associated with type 2 diabetes mellitus (DM).Material and methods  A cross-sectional study that included 36 patients with RAH associated with type 2 DM (mean age, 61.4±6.4 years; 14 men) was performed. Measurement of office and 24-h blood pressure (BP), standard echocardiography with assessment of diastolic function (DF) and ventricular-arterial coupling, doppler ultrasound imaging of renal blood flow, and laboratory tests (blood glucose, glycated hemoglobin, blood creatinine, tumor necrosis factor α (TNF-α), brain natriuretic peptide (BNP), type 2 and type 9 matrix metalloproteinases (MMP-2 and MMP-9), tissue inhibitor of MMP 1 (TIMP-1), 24-h urine protein test, and 24-h urine volume test were performed for all patients. HFpEF was diagnosed according to criteria of the American Society of Echocardiography and the European Society of Cardiology 2019, and the Russian Clinical Guidelines on Diagnosis and Treatment of CHF 2017 and 2020.Results All patients had DD. Incidence of HFpEF detection according to the Russian Guidelines 2017 was 100%; according to the Russian Guidelines 2020, that included a required increase in BNP, and according to the criteria of the European Guidelines 2019, this incidence was 89 %. In 55.6 % of patients, DD corresponded to grade 2 (pseudonormal type). According to the correlation analysis, the DF impairment was associated with increases in pulse BP, myocardial mass, arterial and left ventricular elastance (arterial wall and left ventricular elasticity), basal glycemia and DM duration, MMP-2 level, proteinuria, blood creatinine, renal vascular resistance, and also with decreases in 24-h urine volume, MMP-9, TIMP-1, and TIMP-1/MMP-2. Significance of the relations of mean E / e' ratio with nighttime pulse BP, MMP-9, and 24-h urine volume were confirmed by results of multiple linear regression analysis. Increased myocardial and vascular wall stiffness, concentrations of MMP-2 and TNF-α and reduced 24-h urine volume were associated with progressive impairment of DF.Conclusion      The combination of RAH and DM-2 is characterized by an extremely high incidence of DD that determines a great prevalence of HFpEF. The development and progression of DD in such patients are closely related with a complex of metabolic, proinflammatory and profibrotic biomarkers, increased vascular wall stiffness, pronounced left ventricular hypertrophy, and with structural and functional alterations in kidneys.

[Refractory and resistant hypertension in patients with type 2 diabetes mellitus: differences in metabolic profile and endothelial function].

AIM: To determine the prevalence of refractory hypertension (RfH) in patients with and without type 2 diabetes mellitus (DM), as well as to evaluate whether diabetic patients with RfH significant differ from those with uncontrolled resistant hypertension (RH) in clinical phenotype, metabolic profile and endothelial function. MATERIALS AND METHODS: The study included 193 patients with RH: RH 74 patients with diabetes and 119 patients without DM. Uncontrolled RH and RfH were defined by the presence of uncontrolled blood pressure BP (140 and/or 90 mm Hg) despite the use of 3 but 5 antihypertensive drugs (for RH) and 5 antihypertensive drugs, including a mineralocorticoid receptor antagonist (for RfH). Clinical examination, lab tests were performed. Flow-mediated dilation (FMD) and vasoreactivity of middle cerebral artery (MCA) using both breath-holding and hyperventilation test were measured by high-resolution ultrasound. RESULTS: The prevalence of refractory hypertension in patients with and without DM was similar (30% vs 28%, respectively). No differences in BP levels, data of echocardiography and clinical phenotype were found between the diabetic groups, but value of HOMA index, plasma resistin level and postprandial glycaemia were higher in patients with RfH. FMD and MCA reactivity to the breath-holding test were worse in patients with RfH, and they had a more pronounced vasoconstrictor response of MCA to the hyperventilation test compared to patients with RH. CONCLUSION: The prevalence of RfH is the same in patients with and without diabetes. Diabetic patients with refractory hypertension have a more unfavorable metabolic profile and greater impairment of endothelial function than patients with uncontrolled resistant hypertension.

Bone Remodeling Markers in Assessing of Sternal Reparative Regeneration in Patients With Carbohydrate Metabolism Disorders After Coronary Bypass Surgery.

Aim      To study time-related changes in bone remodeling markers in patients with ischemic heart disease (IHD) associated with type 2 diabetes mellitus (DM) and disorders of carbohydrate metabolism (CM). Also, a possibility was studied of using these markers for evaluation of breast bone reparative regeneration in early and late postoperative periods following coronary bypass (CB).Materials and methods           This study included 28 patients with IHD and functional class II-III exertional angina after CB. Patients were divided into 2 groups based on the presence (group 1) and absence (group 2) of CM disorders. Contents of osteocalcin (OC), C-terminal telopeptide (CTTP) of type 1 collagen, deoxypyridinoline (DPD), and alkaline phosphatase bone isoenzyme (ALPBI) were measured by enzyme immunoassay on admission (Т1) and at early (Т2) and late (Т3) postoperative stages. Sternal scintigraphy with a radiopharmaceutical (RP) was performed at stage 3 following sternotomy.Results The content of OC and CTTP was reduced in group 1 compared to the values in the group without CM disorders (р<0.005) at stages Т1 and Т2. There were no significant intergroup differences in concentrations of ALPBI and DPD throughout the study. Time-related changes in OC, CTTP, and DPD had some intergroup differences: the increase in biomarkers was observed in group 1 considerably later, at stage Т3 (р<0.005), while in group 2, it was observed at stage T2 after sternotomy. Scintigraphy revealed significant intergroup differences in the intensity of RP accumulation in sternal tissue.Conclusion      The intergroup differences in the content of biomarkers evidenced a disbalance among processes of formation and resorption of bone tissue and delayed remodeling processes in patients with IHD associated with type 2 DM and CM disorders. The study confirmed significance of comprehensive evaluation of time-related changes in markers for bone tissue metabolism and sternal scintigraphy for diagnosis and evaluation of sternal reparative regeneration following sternotomy in patients with IHD associated with type 2 DM and disorders of CM metabolism.

Refractory and Resistant Hypertension in Patients with Type 2 Diabetes Mellitus: Different Response to Renal Denervation.

Aim      To compare the antihypertensive effectivity of renal denervation in patients with diabetes mellitus (DM) and associated refractory arterial hypertension (rfAH) (treated with 5 or more classes of antihypertensive drugs, including a thiazide diuretic and a mineralocorticoid receptor antagonist) and uncontrolled resistant AH (ucAH) (treated with 3-4 drugs).Material and methods  This interventional study with renal denervation included 18 DM patients with rfAH and 40 DM patients with ucAH; 16 and 36 of them, respectively, completed the study in 6 months. At baseline, patients were sex- and age-matched. Study methods included measurement of office blood pressure (BP; systolic/diastolic BP, SBP/DBP); outpatient BP monitoring; evaluation of kidney function (estimated glomerular filtration rate by the CKD-EPI formula); diurnal diuresis volume; diurnal urinary excretion of albumin, potassium and sodium; diurnal excretion of metanephrines and normetanephrines; and plasma levels of glucose and glycated hemoglobin, aldosterone, and active renin. Patients were instructed about maintaining compliance with their antihypertensive and hypoglycemic therapy throughout the study.Results At baseline, patients of both groups were comparable by BP and major clinical indexes, except for higher values of nocturnal SBP variability (p<0.05) in patients with rfAH. At 6 months following renal denervation, both groups displayed significant decreases in office and average daily SBP and also in the "load" with increased mean diurnal SBP. However, the decrease in average daily SBP was almost 4 times greater in the rfAH group than in the ucAH group ( -19.9 and -5.1 mm Hg, respectively, р=0.02). Moreover, 81 % of patients in the rfAH group responded to the intervention (average daily SBP decrease ≥10 mm Hg) while the number of responders in the ucAH group was considerably smaller (42 %; p=0.02). In patients with rfAH, renal denervation was associated with a significant decrease in pulse BP and nocturnal SBP variability and with the increase in diurnal diuresis. No other alterations were noted in laboratory test results in either group.Conclusion      DM patients with rfAH may be the best candidates for the procedure of renal denervation.

[Role of markers of inflammation and endothelial dysfunction in the prognosis of the development of cardiovascular complications in patients with coronary artery disease and metabolic syndrome after coronary stenting].

Aim To study the role of inflammation markers and endothelial dysfunction in predicting the risk of cardiovascular event following a percutaneous coronary intervention (PCI) in patients with ischemic heart disease (IHD) and metabolic syndrome (MS).Materials and methods 80 patients (72 men; median age, 56 (50;63) years) with IHD and PCI were evaluated. Based on the presence of MS according to NCEP-ATP III criteria, patients were divided into two groups, group 1 without MS (n=32) and group 2 with MS (n=48). The control age- and sex-matched group included 15 people without cardiovascular diseases. Serum concentrations of tumor necrosis factor α (TNFα), interleukin 6 (IL-6), IL-10, lipoprotein-associated phospholipase A2 (LP-PLA2), and endothelin 1 were measured by enzyme-linked immunosorbent assay (ELISA). Patients were followed up for 12 months after PCI with evaluation of the incidence of adverse cardiovascular events. Statistical analysis was performed with Statistica 10.0 and Medcalc 19.2.6 software. Differences between variables were considered statistically significant at р<0.05. Potential predictors were determined by the ROC analysis with construction of ROC curves, calculation of AUC (area under the curve), identification of COP (cut-off point by the Youden's index), and sensitivity (Se) and specificity corresponding to the COP.Results Patients with MS had statistically significantly higher serum levels of inflammatory markers than patients of the control group. Concentration of the intravascular inflammation marker, PL-PLA2, was 2.7 times higher in group 1 and 5.1 times higher in group 2 than in the control group (р<0.001). Concentrations of endothelin 1 were 1.9 times higher in group 1 and 3.7 times higher in the MS group compared to the control. At one year after PCI, the incidence of adverse outcomes in the form of cardiovascular events was higher for patients with MS: 10 (20.8 %) cases of stent restenosis and 13 (27.1 %) episodes of coronary atherosclerosis progression according to results of repeated coronarography vs. 2 (6.3%) restenosis cases (χ2-10.853; р=0.002) and 2 (6.3%) episodes of atherosclerosis progression (χ2-23.651; р=0.001) for patients without MS. The groups did not differ in rates of myocardial infarction and cardiac death. The most significant predictors of unfavorable prognosis were LP-PLA2 concentration >983.83 ng/ml (area under the ROC curve, 0.867; sensitivity, 80 %; specificity, 100%; р<0.001) and endothelin 1 overexpression >0.852 fmol/ml (area under the ROC curve, 0.885; sensitivity, 85.5 %; specificity, 83.6 %; р<0.001).Conclusion Patients with MS were characterized by more pronounced imbalance of pro- and anti-inflammatory factors. Concentrations of LP-PLA2 >983.83 ng/ml and endothelin 1 >0.852 fmol/ml were shown to be predictors of unfavorable prognosis for patients with IHD and MS after PCI with coronary stenting.

[Catheter treat-ment of patients with atrial fibrillation and myocardial inflammation].

The review presents current data on atrial fibrillation, therapeutic approaches, and possibilities of interventional treatment and addresses inflammatory heart damage and its interrelation with arrhythmia.The review presents current data on atrial fibrillation, therapeutic approaches, and possibilities of interventional treatment and addresses inflammatory heart damage and its interrelation with arrhythmia.

[Multiplex analysis on the luminex platform in complex estimation of cardiovascular biomarker dynamics in patients with acute myocardial infarction.]

The multimarker approach more accurately reflects the key mechanisms of pathogenesis and biochemical interactions, compared with the use of individual indicators. It is a reason of steadily growing interest in the development and use of various combinations of biomarkers in assessing the prognosis and stratification of cardiovascular risk in patients with a wide range of cardiological profiles. Multiplex analysis technology on the Luminex platform is the best tool for the simultaneous quantitative determination of a complex of different biomarkers in a single. Using the MILLIPLEX® MAP Human Cardiovascular Disease Panel, a multiplefold increase of FABP, Troponin I, CK-MB, BNP, Nt-proBNP, BNP in the first 24 hours after MI, decreasing in 6 months with a high degree of confidence, was shown. There were no differences in the content of LIGHT between the stages of observation, as well as in comparison with the reference range. The content of LIGHT on the first day of MI showed strong positive associations with markers of damage of myocardium and myocardial stress. On the first day of MI, a significant increase in the content of ESM-1, decreasing in 6 months after MI to the reference values was found. Strong positive associations of ESM-1 with Troponin I and BNP levels were established. A significant increase of proinflammatory cytokine OSM on the first day of MI, decreasing in the late post-infarction period to reference values was shown. Correlation analysis revealed direct relationships of OSM with Troponin I, CK-MB, Nt-proBNP and BNP. The use of the MILLIPLEX® MAP Human Cardiovascular Disease Panel 1 diagnostic multimarker panel allowed for the simultaneous quantitative analysis of 11 biochemical parameters, associated with inflammation, atherogenesis, endothelial dysfunction, ischemia and myocardial necrosis. The results can be used to improve the effectiveness of complex diagnostics in patients with primary myocardial infarction with ST segment elevation.