Vascular Remodeling In Patients Research Articles

#2224 Higher serum level of indoxyl sulfate is not associated with increased abdominal aorta calcification in patients on maintenance hemodialysis

Abstract Background and Aims Vascular calcification is strongly associated with an increase in all-cause and cardiovascular mortality, especially in patients with and stage renal disease. Results of numerous experimental studies have shown direct toxic effect of microbial-derived uremic toxins on vascular endothelial and smooth muscle cells which may contribute vascular calcification. Meanwhile, the effects of these metabolites on vascular remodeling in patients receiving dialysis treatment remains largely unclear. Here we aimed to investigate the relationship between serum level of the uremic toxin indoxyl sulfate and severity of abdominal aorta calcification (AAC) in patients on maintenance hemodialysis. Method This single-center, cross-sectional study included eighty (40 men, average age – 59,7±11,8 years) clinically stable patients receiving hemodialysis treatment for 52(21,3-120) months. 13(16,3%) participants had history of smoking, 27(33,8%) were diabetic, 63(78,8%) had high blood pressure, 17(21,3%) – previous history of ischemic heart disease, including 5(6,3%) suffered a myocardial infarction. Severity of AAC was determined by lateral lumbar radiography with Kauppila scoring. The total AAC score ranged from 0 to 24 points, and a higher AAC score indicated a more pronounced degree of calcification. Routine laboratory data were collected before hemodialysis session after fasting for 12 hours. Serum concentration of indoxyl sulfate was assessed by ELISA using commercially available kit (Cloud-Clone Corp., USA). Statistical analysis was performed with IBM SPSS Statistics 26 program. Non-parametric Spearman's rank correlation method was used to evaluate the associations between the studied parameters. Value of p <0.05 was considered statistically significant in all tests. Results Median serum indoxyl sulfate was 2,1(1,4-3,0) μmol/l (the same parameter in relatively healthy individuals without impaired renal function is 0,1(0-0,3) μmol/l, р˂0,001). Serum levels of calcium (Ca) was 2,27(2,1-2,5) mmol/l, ionized calcium (Ca++) – 1,15(1,1-1,3) mmol/l, phosphate (P) – 1,6(1,3-2,0) mmol/l, intact parathyroid hormone (iPTH) – 303(162,2-492,8) pg/ml, total cholesterol (TH) – 4,5(3,5-5,4) mmol/l, low-density lipoprotein (LDL) – 2,6(2,0-3,3) mmol/l. AAC score in hemodialysis participants was 4,5(0,0-9,0) and significantly correlated with age (r=0,693; р˂0,001), Ca (r=0,208; р=0,04) and iPTH (r=0,418; р=0,021) but not with other indicators, including indoxyl sulfate concentration (r=0,164; р=0,147). Conclusion Our preliminary results do not allow to consider the elevated level of indoxyl sulfate as a factor contributing to increased AAC in patients on maintenance hemodialysis. Further prospective studies in larger populations should clarify the true role of indoxyl sulfate in vascular remodeling in individuals with chronic kidney disease.

Vascular remodeling in patients with CKD as a risk factor for the development of vascular Parkinsonism

Vascular remodeling in patients with CKD as a risk factor for the development of vascular Parkinsonism

Evaluation of cardiac and vascular remodeling in patients with arterial hypertension in combination with atherosclerosis of the lower extremity arteries

Objective: to evaluate the features of cardiac and vascular remodeling in patients with arterial hypertension (AH) and atherosclerosis of the arteries of the lower extremities (LAA) of varying severity. Materials and methods: the study involved 120 patients with hypertension. Depending on the presence of AANC, all patients were divided into 3 groups: group 1 — 46 patients with hypertension and clinically manifested AANC, group 2 — 39 patients with hypertension and asymptomatic AANC, group 3 — 35 patients with hypertension without AANC. The characteristics of cardiac and vascular remodeling were assessed based on the results of 24-hour blood pressure monitoring (ABPM) using Vasotens technology, triplex ultrasound scanning (UTS) of the arteries of the lower extremities (LEA), and echocardiographic examination (EchoCG). Statistical data processing was carried out using Microsoft Office Excel 16 (2015, Microsoft, USA), Statistica 10.0 (StatSoft, USA) and IBM SPSS Statistica 26.0 (IBM, USA). Results: in the group of patients with severe circulatory disorders of the lower extremities, compared with patients with asymptomatic AANK, significantly lower values of the indicator — reflected wave propagation time (RWTT, ms) (p = 0.006) and significantly higher values of the indicator — augmentation index (AIX) were revealed) and augmentation index in the aorta (AIXao) (p<0.05). A direct statistically significant correlation of moderate strength was revealed between the degree of stenosis (%) of the ANC and the values of the AIX and AIXao indicators (r = 0.345, p = 0.001). Higher values of the dimensions of the walls of the left ventricle (LV) were determined: the thickness of the interventricular septum (IVS) and the posterior wall of the left ventricle (PLW) in patients of the 1st and 2nd groups in comparison with the indicators in patients of the 3rd group (p<0 .05). Patients of all three groups had thickening of the left ventricle and intraventricular septum (>11 mm) and an increase in LVMI. In patients with hypertension and severe AANC, the maximum values of LVMI were determined, which were significantly higher than the corresponding values in patients of the 2nd (p = 0.004) and 3rd (p = 0.0001) groups. LV systolic function in all patients included in the study was assessed as intact. However, the highest ejection fraction (EF) values were recorded in patients with hypertension without AANC, and were significantly higher than those in patients with hypertension and concomitant asymptomatic AANC (p = 0.02), as well as in patients with hypertension and clinically manifested AANC (p =0.001). Conclusions: the progression of AANK was associated with an increase in the stiffness of both peripheral and main arteries, which was accompanied by an increase in the load on the myocardium, which in 97.8% of cases led to more pronounced myocardial remodeling of the concentric hypertrophy type.

Violation of mineral metabolism and vascular remodeling in patients with CKD as a risk factor for the development of cerebral complications

Violation of mineral metabolism and vascular remodeling in patients with CKD as a risk factor for the development of cerebral complications

COPD: pulmonary vascular volume associated with cardiac structure and function

BackgroundEarly recognition of cardiac dysfunction in patients with chronic obstructive pulmonary disease (COPD) may prevent future cardiac impairment and improve prognosis. Quantitative assessment of subsegmental and segmental vessel volume by Computed Tomographic (CT) imaging can provide a surrogate of pulmonary vascular remodeling. We aimed to examine the relationship between lung segmental- and subsegmental vessel volume, and echocardiographic measures of cardiac structure and function in patients with COPD.MethodsWe studied 205 participants with COPD, included in a large cohort study of cardiovascular disease in COPD patients. Participants had an available CT scan and echocardiogram. Artificial intelligence (AI) algorithms calculated the subsegmental vessel fraction as the vascular volume in vessels below 10 mm2 in cross-sectional area, indexed to total intrapulmonary vessel volume. Linear regressions were conducted, and standardized ß-coefficients were calculated. Scatterplots were created to visualize the continuous correlations between the vessel fractions and echocardiographic parameters.ResultsWe found that lower subsegmental vessel fraction and higher segmental vessel volume were correlated with higher left ventricular (LV) mass, LV diastolic dysfunction, and inferior vena cava (IVC) dilatation. Subsegmental vessel fraction was correlated with right ventricular (RV) remodeling, while segmental vessel fraction was correlated with higher pulmonary pressure. Measures of LV mass and right atrial pressure displayed the strongest correlations with pulmonary vasculature measures.ConclusionPulmonary vascular remodeling in patients with COPD, may negatively affect cardiac structure and function. AI-identified remodeling in pulmonary vasculature may provide a tool for early identification of COPD patients at higher risk for cardiac impairment.

Blood Pressure Variability: Marker or Predictor of Cardiovascular Risk?

Background: Regardless of the mean blood pressure value, short-term and long-term BP variability (BPV) are associated with the development and progression of target organ damage and predictors of cardiovascular complications and mortality. The purpose of the present study was to evaluate the prognostic significance of increased BPV in patients with arterial hypertension (AH). Methods and Results: The study consisted of two stages. In the first stage, a retrospective analysis of 365 ABPM results was carried out. As a result of the analysis, 271 patients aged 56.1±10.0 years with uncontrolled AH Grades 1-3 (ESC/ESH, 2018) were included in this study. Depending on the values of BPV, AH patients were divided into two groups: Group 1 consisted of patients with normal BPV (n=145), and Group 2 consisted of patients with increased BPV (n=126). The second stage included 91 patients with uncontrolled hypertension without permanent antihypertensive therapy who had increased BPV. We found statistically significant differences in BP between the AH patients with normal BPV and increased BPV. Thus, in the group with normal BPV, compared with increased BPV, the parameters of the average 24-h systolic BP (SBP), daytime SBP, and nighttime SBP were statistically lower (141±14.6 vs. 147.2±20.2 mmHg, P<0.004; 142.8±15.1 vs. 148.4±20.7 mmHg, P<0.01; and 136.2±15.5 vs. 143.8±21.4 mmHg, P<0.001; respectively). A statistically significant moderate direct correlation was found between the average 24-h SBP and the average 24-h and daytime SBP variability (SBPV) (rs=0.49 and rs=0.40 respectively, P<0.001 in all cases). A statistically significant moderate to weak direct correlation also was found between the average daytime SBP, and the average 24-h and daytime SBPV (rs=0.45 and rs=0.37, respectively, P<0.001 in all cases). A moderate direct correlation was found between nighttime SBP and 24-hour SBPV (rs=0.52, P<0.001) and between nighttime SBP and daytime SBPV (rs=0.42, P<0.001). Weak direct correlations were found between the average 24-h SBPV and central SBP (SBPc) (rs=0.34, P<0.001), as well as between the average 24-h and daytime SBPV and central pulse pressure (PPc) (rs=0.33 and rs=0.32, respectively, P<0.001 in all cases). A weak direct correlation was found between carotid intima-media thickness (CIMT) and the average 24-h and daytime SBPV (rs=0.37 [P<0.001] and rs=0.3 [P=0.04]). Conclusion: The increased BPV is associated with impaired diurnal blood pressure profile (DBPP) and structural and functional changes in blood vessels, in particular, an increase in SBPc and PP in the aorta, and CIMT thickening, which characterizes increased BPV as a predictor of vascular remodeling in patients with uncontrolled AH.

#2887 ASSESSMENT OF EXTRA-BONE CALCIFICATION IN PATIENTS UNDERGOING PROGRAMMED HEMODIALYSIS

Abstract Background and Aims Chronic kidney disease is associated with the accumulation of so-called medium molecules in the blood, in particular parathyroid hormone, and the formation of secondary hyperparathyroidism with a tendency to extra-bone calcification. The most vulnerable organ in relation to calcification is the vascular wall. The ail of the study to study the features of vascular wall remodeling in patients with chronic kidney disease who are being treated with programmed hemodialysis. Method The study included 86 patients with CKD C5 (mean age 47.44±5.04 years) who had been on programmed hemodialysis for at least 6 months. All patients underwent examination, including multislice spiral computed tomography (MSCT) with an assessment of the calcium content in the coronary arteries (Agatston index), ultrasound examination of the carotid arteries with determination of the thickness of the intima-media complex, the degree of endothelium-dependent vasodilation in a sample with 5-minute compression of the brachial artery and determination of changes in the diameter of the brachial artery. The data obtained (presented in the form of an arithmetic mean and its standard error) were compared with normal values typical for a healthy population. Results There was an accumulation of calcium in the coronary vessels with an average Agatstone index of 146.83 ± 13.26 units. Also, during MSCT, calcifications were found in the aortic wall in 86 out of 57 patients. The intima-media complex in patients with CKD was significantly increased and averaged 1.21±0.06mm. The degree of endothelium-dependent vasodilation in patients with CKD was reduced and amounted to 5.48± 0.03% of the initial diameter of the brachial artery. Correlation analysis revealed significant positive associations of average strength between the value of the Agatson index, the thickness of the intima-media complex of the carotid arteries and the concentration of parathyroid hormone in peripheral blood (g = +0.58,P<0.05 with the Agatson index and P = 0.42, P<0.05 with the thickness of the intima-media complex), as well as a significant negative relationship between the product of the concentration of calcium and phosphorus in peripheral blood and the degree of endothelium-dependent vasodilation (g = -0.49, P<0.05). Conclusion In patients with CKD, against the background of programmed hemodialysis, there is a remodeling of the heart with an increase in the size of the heart cavities and LV myocardial mass, a violation of regional and general LV contractile function, LV diastolic dysfunction and an increase in pressure in the pulmonary artery system. The introduction of sevelamer hydrochloride into the therapy regimen is associated with the prevention of the progression of cardiac remodeling. Calcification of the aortic valve progresses, regardless of the therapy used. Vascular remodeling in patients with CKD on the background of programmed hemodialysis is manifested by an increase in the thickness of the intima-media complex of the carotid arteries and a violation of endothelium-dependent vasodilation in favor of paradoxical vasoconstriction. Against the background of calcium carbonate therapy, structural disorders of the vascular wall progress. The introduction of sevelamer phosphate binder into the therapy regimen allows to prevent the progression and improve the functional state of endothelial function.

THE ROLE OF CARDIOVASCULAR MAGNETIC RESONANCE IMAGING IN NONINVASIVE ASSESSMENT OF PULMONARY HYPERTENSION SEVERITY

Objective: Pulmonary hypertension characterized by structural and mechanical changes in pulmonary vascular bed. Invasively calculated pulmonary artery (PA) stiffness indeces are associated with mortality in pulmonary hypertension (PH). CMRI-derived pulmonary artery distensibility (PAD) index reflects vascular remodeling in patients with pulmonary PH. The aim of the study was to evaluate the relationship between noninvasive PAD index and invasive PA stiffness indeces and basic determinants of PH severity. Design and method: We included 48 pts with PH (mean age 42.8± 14.7 yrs, m:f = 13:35): 27 idiopathic pulmonary arterial hypertension pts, 5 pts scleroderma PAH, 6 corrected congenital heart disease and 10 with inoperable CTPEH. All pts underwent 6-min walk test (6MWT), right heart catheterization (RHC), ECHO, CMRI, cardiopulmonary exercise testing (CPX). PA stiffness index and elastic modulus were calculated using data from RHC and CMRI. Pulmonary artery distensibility index (%) were derived from cross-sectional images of the main PA on cardiac magnetic resonance imgaging. Results: We revealed increased PA stiffness index 6.1 (4.6–10.2) and elastic modulus 424 mm Hg (254-678), decreased PAD index in PH pts 10% (9 –16.5). There was a significant negative correlation between PAD index and PA stiffness index (r = –0.90; p < 0.0001), so we derived the formula to calculate the invasive PA stiffness using noninvasive PAD index: PA stiffness index = 102.4/ PAD index. There was also a negative correlation between PAD and elastic modulus (r = –0.91; p < 0,0001). Patients with decreased PAD index < 20 % had higher NT-proBNP level (1558 (738-4341) versus 306 (178-370); p<0.05), also ECHO signs of RV systolic dysfunction:lower TAPSE (1.7 ±0.4 cm versus 2.0±0.4 cm; p = 0,04), tricuspid annular systolic velocity (10±2 versus 12±1 cm/sec; p = 0,007), global RV myocardial deformation (13±4% versus 21±5%; p = 0,001) and RV fractional area change ( 24±7%; p = 0,02) and reduced cardiac output which were determined by RHC (4.0 ± 1.1 versus 4.9 ±1.2 l/min; p < 0,05). Conclusions: Noninvasive CMRI-derived PA distensibility index strongly correlated with PA stiffness indeces, and may be used for noninvasive assessment of PH severity.

THE ROLE OF NEUROHORMONAL FACTORS IN THE FORMATION OF A PATIENT’S CLINICAL PROFILE AND THE IMPACT ON STRUCTURAL CARDIAC AND VASCULAR REMODELING IN PATIENTS WITH MYOCARDIAL INFARCTION AFTER REPERFUSION THERAPY

The aim: To determine the dynamics of galectin-3 in the formation of the patient’s clinical profile and the impact on structural cardiac and vascular remodeling in patients with myocardial infarction after reperfusion therapy. Materials and methods: 140 patients with class II A CHF syndrome according to Vasilenko-Strazhesko FC II-III (NYHA), which occurred in patients with MI, and 22 patients with MI without signs of CHF were examined. Results: The average serum galectin-3 level of the studied patients was analyzed. The average concentration of galectin-3 in patients with stenting without signs of CHF was (10.87±1.65) ng/ml comparing to (6.57±0.21) ng/ml in healthy subjects (p<0.05). An increase in the concentration of this indicator was observed in the group of patients with CHF after MI with reperfusion - (35.2±1.76) ng/ml, which is significantly higher in comparison with practically healthy subjects, and in patients without revascularization it was (38.94±1.97) ng/ml (p<0.001). Positive correlations of medium strength were found between left ventricular end-systolic volume (ESV), left ventricular end-diastolic volume (LVEDV) and serum galectin-3 concentration in the examined patients. The correlation coefficient between the abovementioned indicators was 0.60 (p<0.01) and 0.53 (p<0.05), respectively. Conclusions: It has been determined that in patients with CHF with postinfarction cardiosclerosis there is a direct correlation of medium strength between the values of indicators of LV myocardial remodeling with plasma galectin-3 concentration, including ESV, EDV, in examined patients. The role of galectin-3 as a marker of postinfarction remodeling in patients with CHF for early diagnosis, prognosis, and risk stratification has been presented.

Mechanosensitive cation currents through TRPC6 and Piezo1 channels in human pulmonary arterial endothelial cells.

Mechanosensitive cation channels and Ca2+ influx through these channels play an important role in the regulation of endothelial cell functions. Transient receptor potential canonical channel 6 (TRPC6) is a diacylglycerol-sensitive nonselective cation channel that forms receptor-operated Ca2+ channels in a variety of cell types. Piezo1 is a mechanosensitive cation channel activated by membrane stretch and shear stress in lung endothelial cells. In this study, we report that TRPC6 and Piezo1 channels both contribute to membrane stretch-mediated cation currents and Ca2+ influx or increase in cytosolic-free Ca2+ concentration ([Ca2+]cyt) in human pulmonary arterial endothelial cells (PAECs). The membrane stretch-mediated cation currents and increase in [Ca2+]cyt in human PAECs were significantly decreased by GsMTX4, a blocker of Piezo1 channels, and by BI-749327, a selective blocker of TRPC6 channels. Extracellular application of 1-oleoyl-2-acetyl-sn-glycerol (OAG), a membrane permeable analog of diacylglycerol, rapidly induced whole cell cation currents and increased [Ca2+]cyt in human PAECs and human embryonic kidney (HEK)-cells transiently transfected with the human TRPC6 gene. Furthermore, membrane stretch with hypo-osmotic or hypotonic solution enhances the cation currents in TRPC6-transfected HEK cells. In HEK cells transfected with the Piezo1 gene, however, OAG had little effect on the cation currents, but membrane stretch significantly enhanced the cation currents. These data indicate that, while both TRPC6 and Piezo1 are involved in generating mechanosensitive cation currents and increases in [Ca2+]cyt in human PAECs undergoing mechanical stimulation, only TRPC6 (but not Piezo1) is sensitive to the second messenger diacylglycerol. Selective blockers of these channels may help develop novel therapies for mechanotransduction-associated pulmonary vascular remodeling in patients with pulmonary arterial hypertension.

SEMI-AUTOMATIC MEASUREMENT OF INTIMA-MEDIA THICKNESS OF BRACHIAL ARTERY IN PATIENTS WITH CONGESTIVE HEART FAILURE

Objective: Cardiovascular diseases are associated with an increase in intima-media thickness (IMT). However, the techniques used to measure IMT have limitations. A semi-automatic device called UNEX has been developed, which overcomes the limitation of classic systems (in particular the investigator-dependency of conventional, “hand-held’’ measurements). The purpose of this study was to measure the intima-media thickness of the brachial artery (bIMT) with the UNEX device in patients with and without congestive heart failure. Design and method: The UNEX device is comprised of a 7.5-MHz, H-shaped linear array transducer and a novel stereotactic probe-holding device (UNEX EF 18G; UNEX Co., Nagoya, Japan). Another advantage of this device is the continuous recording of B-mode images and A-mode waves of the brachial artery. Measurement of bIMT was automatically performed on A-mode images of the far wall of the brachial artery. The analysis system automatically detects the measurement point where an image was clearly obtained. The average of mean measurement values obtained from 10 cardiac cycles was defined as bIMT. In a first set of clinical studies, we measured bIMT in patients with reduced left ventricular ejection fraction (HFrEF) and in patients without heart failure. Results: Patients with HFrEF (n = 85, ejection fraction: 38.3 ± 8.4 %, NT-pro-BNP: 713 ± 714.7 pg/ml) compared to patients without heart failure (n = 63) were older (66.4 ± 9.2 vs. 53.8 ± 12.6 years, p < 0.001), with more male subjects (67 vs. 40, p = 0.039). bIMT was higher in patients with HFrEF compared to the other group (0.295 ± 0.083 vs. 0.249 ± 0.083 mm, p < 0.001). After adjustment for age, gender and other cardiovascular risk factors, the result remained significant (p = 0.032). Conclusions: Our study demonstrate that IMT of large muscular arteries can be automatically (investigator independently) measured. Our data indicate an increased vascular remodeling in patients with HFrEF independent of other confounders.

Evaluation of pulmonary arterial stiffness and comparison with right ventricular functions in patients with cirrhosis preparing for liver transplantation.

Pulmonary complications are common in patients with liver cirrhosis. Devolopment of pulmonary hypertension (PH) is associated with a poor prognosis in these patients. Pulmonary arterial stiffness (PAS) is considered an early sign of pulmonary vascular remodeling. The aim of this study is to investigate PAS and compare it with right ventricular (RV) functions in patients with cirrhosis who are scheduled for liver transplantation. The study included 52 cirrhosis patients (mean age 51.01 ± 12.18 years, male gender 76.9%) who were prepared for liver transplantation and 59 age and sex matched (mean age 51.28 ± 13.63 years, male gender 62.7%) healthy individuals. Patients with left ventricular ejection fraction (LVEF) less than 55%, ischemic heart disease, more than mild valvular heart disease, chronic pulmonary disease, congenital heart disease, rheumatic disease, moderate to high echocardiographic PH probability, rhythm or conduction disorders on electrocardiography were excluded from the study. In addition to conventional echocardiographic parameters, PAS value, pulmonary vascular resistance (PVR) and RV ejection efficiency was calculated by the related formulas with transthoracic echocardiography (TTE). Demographic characteristics and cardiovascular risk factors of the groups were similar. PAS, PVR, and sPAP values were found to be significantly higher in the patient group (20.52 ± 6.52 and 13.73 ± 2.05; 1.43 ± 0.15 and 1.27 ± 0.14; 27.69 ± 3.91 and 23.37 ± 3.81 p < 0.001, respectively). RV FAC and RV Ee were significantly lower and RV MPI was significantly higher in the patient group (45.31 ± 3.85 and 49.66 ± 3.62, p < 0.001; 1.69 ± 0.35 and 1.85 ± 0.23, p=0.005; 0.39 ± 0.07 and 0.33 ± 0.09, p=0.001, respectively). PAS was significantly correlated with RV FAC and MPI (r=-0.423, p < 0.001; r=0.301, p=0.001, respectively). Increased PAS in cirrhosis patients may be associated with early pulmonary vascular involvement. Evaluation of RV functions is important to determine the prognosis in these patients. FAC, MPI, and RV Ee measurements instead of TAPSE or RV S' may be more useful in demonstrating subclinical dysfunction. The correlation of PAS with RV FAC and MPI may indicate that RV subclinical dysfunction is associated with early pulmonary vascular remodeling in patients with liver cirrhosis.

To study the dynamics of serum levels of vascular remodeling in patients with hypertension, including in combination with type 2 diabetes mellitus during 12‑month 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 β-1 (TGF-β1), 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&lt;0.05). In the AH+DM2 group, the MMP-9 concentration was significantly decreased (р&lt;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".

Resistin-like molecule \u03b2 acts as a mitogenic factor in hypoxic pulmonary hypertension via the Ca2+-dependent PI3K/Akt/mTOR and PKC/MAPK signaling pathways

BackgroundPulmonary arterial smooth muscle cell (PASMC) proliferation plays a crucial role in hypoxia-induced pulmonary hypertension (HPH). Previous studies have found that resistin-like molecule β (RELM-β) is upregulated de novo in response to hypoxia in cultured human PASMCs (hPASMCs). RELM-β has been reported to promote hPASMC proliferation and is involved in pulmonary vascular remodeling in patients with PAH. However, the expression pattern, effects, and mechanisms of action of RELM-β in HPH remain unclear.MethodsWe assessed the expression pattern, mitogenetic effect, and mechanism of action of RELM-β in a rat HPH model and in hPASMCs.ResultsOverexpression of RELM-β caused hemodynamic changes in a rat model of HPH similar to those induced by chronic hypoxia, including increased mean right ventricular systolic pressure (mRVSP), right ventricular hypertrophy index (RVHI) and thickening of small pulmonary arterioles. Knockdown of RELM-β partially blocked the increases in mRVSP, RVHI, and vascular remodeling induced by hypoxia. The phosphorylation levels of the PI3K, Akt, mTOR, PKC, and MAPK proteins were significantly up- or downregulated by RELM-β gene overexpression or silencing, respectively. Recombinant RELM-β protein increased the intracellular Ca2+ concentration in primary cultured hPASMCs and promoted hPASMC proliferation. The mitogenic effects of RELM-β on hPASMCs and the phosphorylation of PI3K, Akt, mTOR, PKC, and MAPK were suppressed by a Ca2+ inhibitor.ConclusionsOur findings suggest that RELM-β acts as a cytokine-like growth factor in the development of HPH and that the effects of RELM-β are likely to be mediated by the Ca2+-dependent PI3K/Akt/mTOR and PKC/MAPK pathways.

Calcium-sensing receptor in the development and treatment of pulmonary hypertension.

Calcium-sensing receptor (CaSR) is widely involved in the cell proliferation, differentiation, migration, adhesion and apoptosis, which can affect the vascular remodeling in the humanbody. The main ligand of CaSR is extracellular Ca2+. CaSR has the physiological significance in Ca2+ homeostasis. Pulmonary vascular remodeling is one of the main histopathological changes of pulmonary hypertension (PH). The abnormal proliferation of pulmonary artery smooth muscle cells (PASMCs) results in the pulmonary vascular remodeling. CaSR is an important regulator of [Ca2+]i. [Ca2+]i is the main cause of the excessive pulmonary vascular remodeling in patients with PH. In this review, it was conclued that the structure of CaSR was prone to explore the devolopment or the treatment of PH. It was found that the regulation of CaSR with some miRNA could inhibit the proliferation of PASMCs, and that CaSR could affect the occurrence of autophagy in PH. Therefore, CaSR would become a new therapeutic target to PH.

Influence of the statin therapy on cardiovascular remodeling in arterial hypertension, combined with subclinical hypothyroidism

There is a proven relation between hypothyroidism and appearance of the pronounced structural and functional changes of the heart and blood vessels as well as atherosclerosis and its related diseases progress. At the same time, there is a lack of information regarding the influence of statins on indices of the structure and function of the heart and blood vessels in patients with arterial hypertension (AH) combined with subclinical hypothyroidism (SH).Aim. To study the effect of the long-term statin therapy on the cardiac structure and function, as well as on vascular remodeling in patients with arterial hypertension combined with subclinical hypothyroidism.Material and methods. The study involved 31 patients with arterial hypertension grade 1–3, stage II, of high and very high additional cardiovascular risk, with a concomitant SH. All patients received a combination of two or three first-line antihypertensive drugs at average therapeutic daily doses and atorvastatin at a dose of 20–30 mg per day.Prior to treatment and after one year of follow-up, all patients underwent an echocardiographic examination and a carotid artery scan on My Lab Seven (Italy) device as well as a 24h-blood pressure monitoring on a bifunctional device “Cardiotechnics-04” (Inkart, St. Petersburg, RF) with the simultaneous registration of BP and ECG.Results. Under the influence of therapy, the target level of systolic blood pressure was reached in 74 % (23/31) of patients during the daytime observation period, in 65 % (20/31) of patients during the nighttime observation period; target diastolic blood pressure for the daytime observation period – in 87 % (27/31) of patients, for the nighttime observation period – in 71 % (22/31) patients. However, there was no significant change in the size of cavities of the left atrium and both ventricles, ejection fraction (before treatment 68.84 ± 5.43 %, after 67.13 ± 5.45 %), thickness of the interventricular septum and posterior wall, relative wall thickness (before treatment 0.41 ± 0.07, after 0.41 ± 0.07, P = 0.871), LV mass index (before treatment 122.29 ± 37.36 g/m2, after 118.00 ± 31.00 g/m2, P = 0.849), indices of diastolic function of the left ventricle (LV). The specific gravity of patients with eccentric LV hypertrophy after a year of treatment increased from 32 % to 39 % (P = 0.5668), with concentric hypertrophy decreased from 42 % to 39 % (P = 0.8107), with normal LV geometry – from 19 % to 16 % (P = 0.7570). The number of patients with AH with a concomitant SH with signs of a concentric LV remodeling remained unchanged – before treatment 6 %, after 6 %. The influence of the statin therapy on vascular remodeling in patients with AH with a concomitant SH was characterized by a tendency towards a decrease in the thickness of the intima-media complex of the right (0.769 ± 0.276 mm vs. 0.701 ± 0.222 mm, P = 0.512) and left (0.759 ± 0.185 mm vs. 0.745 ± 0.179 mm, P = 0.988) common carotid arteries.Conclusion. In patients with AH with a concomitant SH, the antihypertensive therapy during the year with the first-line drugs with addition of statins was associated with achievement of the target SBP level in the active period in 74 %, in the passive period – in 65 % of patients (according to the 24h-BPM data), but was not accompanied by a significant decrease in the cavity size, wall thicknesses, LV mass, improvement of LV diastolic filling, reduction in thickness of the intima-media complex.

The Rho kinase 2 (ROCK2)-specific inhibitor KD025 ameliorates the development of pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a progressive and fatal disease that is characterized by the irreversible remodeling of the pulmonary artery. Although several PAH drugs have been developed, additional drugs are needed. Rho kinases (ROCKs) are involved in the pathogenesis of PAH, and thus, their inhibitors may prevent the development of PAH. However, the therapeutic benefits of ROCK isoform-specific inhibitors for PAH remain largely unknown. The in vitro and in vivo effects of the ROCK2-specific inhibitor, KD025, were examined herein using pulmonary arterial smooth muscle cells (PASMCs) from idiopathic pulmonary arterial hypertension (IPAH) patients and monocrotaline (MCT)-induced pulmonary hypertensive (PH) rats. The expression of ROCK1 was similar between normal- and IPAH-PASMCs, whereas that of ROCK2 was markedly higher in IPAH-PASMCs than in normal-PASMCs. KD025 inhibited the accelerated proliferation of IPAH-PASMCs in a concentration-dependent manner (IC50 = 289 nM). Accelerated proliferation was also reduced by the siRNA knockdown of ROCK2. In MCT-PH rats, the expression of ROCK2 was up-regulated in PASMCs. Elevated right ventricular systolic pressure in MCT-PH rats was attenuated by KD025 (1 mg/kg/day). These results strongly suggest that enhanced ROCK2 signaling is involved in the pathogenic mechanism underlying the development of PAH, including accelerated PASMC proliferation and vascular remodeling in patients with PAH. Therefore, ROCK2 may be a novel therapeutic target for the treatment of PAH.

Nerve growth factor receptor is involved in maintaining homeostasis of pulmonary arterial hypertension

Abstract Introduction Pulmonary arterial hypertension (PAH), characterized by vascular remodeling, is still disease with poor prognosis although many pulmonary vasodilators have been developed, and new mechanism of treatment for PAH is desired. Nerve growth factor receptor (Ngfr) is known to relate to inflammatory reaction and repair process in the damaged tissue. We have reported that Ngfr is associated to vascular remodeling in patients with acute coronary syndrome. However, it is unclear how Ngfr is involved in the pathogenesis of PAH. Purpose In this study, we investigated whether Ngfr relate to pathophysiology in PAH. Methods We estimated the frequency of Ngfr positive cells (% Ngfr+) in peripheral blood mononuclear cells obtained from PAH and non-PAH patients using flowcytometric analysis. In PAH patients, the hemodynamic parameters such as mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), and cardiac index (CI) were obtained by right heart catheterization, and evaluated for correlation with the % Ngfr+. Next, adult 8-week-old C57BL/6 (WT) mice and Ngfr knock out (KO) mice were exposed to chronic hypoxia (10% O2) or normoxia for 6 weeks. Then, mice were anesthetized and performed echocardiography and right heart catheterization. Then, mice were exsanguinated and blood sample was collected to evaluate the % Ngfr+ by flow cytometry. Right ventricular weight was measured and lung tissue was also collected for histological assessment and molecular pathway profiling. Results PAH (n=24) patients and non-PAH patients (n=17) were enrolled. The % Ngfr+ was significantly higher in PAH patients than that in non-PAH patients (0.056% versus 0.019%, p&amp;lt;0.0001). In PAH patients, the % Ngfr+ was correlated with severity of hemodynamic parameters such as mPAP (R=0.64 p&amp;lt;0.001), PVR (R=0.62 p&amp;lt;0.005), and CI (R=−0.48 p&amp;lt;0.05). In WT mice, chronic hypoxia significantly increased the right ventricular systolic pressure and induced vascular medial thickness and fibrosis around the pulmonary artery. Flow cytometry analysis revealed that the % Ngfr+ was significantly increased in the hypoxia compared to that in the normoxia. Under hypoxic conditions, the right ventricular systolic pressure was significantly increased in Ngfr KO mice compared to that in WT mice. In histological analysis, hypoxia-induced peripheral vascular fibrosis and medial thickness was more severe in Ngfr KO than that in WT mice. Conclusion Circulating Ngfr-positive cells are associated with severity of PAH in patients. In the hypoxia-induced PH model, gene deletion of Ngfr shows the progression of the pathogenesis of PAH. These results suggest that circulating Ngfr-positive cells have an important role in the pathogenesis of PAH and may be a novel target for PAH therapy. Funding Acknowledgement Type of funding source: None

Calcium-Binding Protein S100A4 Is Upregulated in Carotid Atherosclerotic Plaques and Contributes to Expansive Remodeling.

BackgroundCarotid plaques with expansive arterial remodeling are closely related to cerebral ischemic events. Although S100A4 (S100 calcium‐binding protein A4) is expressed in atherosclerotic lesions, its role in atherosclerotic plaque progression remains unknown. In this study, we examined the association between carotid arterial expansive remodeling and S100A4 expression.Methods and ResultsPreoperative high‐resolution magnetic resonance imaging was used to assess luminal stenosis and vascular remodeling in patients undergoing carotid endarterectomy. To examine murine carotid atherosclerosis, we induced experimental lesions by flow cessation in apolipoprotein E‐deficient mice fed a high‐fat diet. The role of S100A4 in plaque formation and smooth muscle cell proliferation was investigated in vivo and in vitro, respectively. Human carotid arterial expansive remodeling showed positive correlations with the expression of S100A4, MMP2, and MMP9. S100A4 mRNA levels were positively correlated with those of MMP2, MMP9, and MMP13. S100A4 was expressed in vascular smooth muscle cells (VSMCs) and VSMC‐derived foam cells in the plaque shoulder and marginal areas. S100A4 expression increased concomitantly with plaque formation in our animal model. Exogenous recombinant S100A4 protein enhanced the levels of Mmp2, Mmp9, and Mmp13 and the cell proliferation ability in VSMCs. A chemotaxis assay indicated that extracellular S100A4 functions as a chemoattractant for VSMCs.ConclusionsS100A4 expression was elevated in human carotid plaques and showed a positive correlation with the degree of expansive remodeling. S100A4‐positive VSMC‐derived cells are considered to play an important role in carotid expansive remodeling.

Caduet enhances connexin 43 phosphorylation in left ventricular and thoracic aorta of SH model rats.

Caduet, also known as amlodipine besylate and atorvastatin calcium (AM + AT) tablet, can improve cardiac and vascular remodeling in patients with spontaneous hypertension (SH), but the underlying mechanism remains unknown. The present study aimed to explore whether AM + AT improved hypertensive left ventricular and thoracic aortic remodeling by regulating connexin 43 (Cx43) phosphorylation. A total of 32 male spontaneous hypertension model rats (SHR) were randomly divided into four groups: SHR control group, amlodipine-alone group (SHR-AM), atorvastatin-alone (SHR-AT) and AM + AT group (SHR-AM + AT); 8 Wistar-Kyoto (WKY) rats with normal blood pressure were used as the normal control. Drugs were orally administered for 8 weeks; subsequently, body weight, heart rate (HR), left ventricular mass index (LVMI), blood pressure (BP), plasma lipid levels and morphological changes of myocardial tissue in each group were analyzed. The expression of total (T)-Cx43 and phosphorylated (P)-Cx43 protein in the left ventricular and thoracic aortic tissues was determined using western blotting and immunofluorescence double labeling. The results revealed that AM + AT significantly decreased LVMI and cardiomyocyte cross-sectional area compared with SHR-AM and SHR-AT group. The western blotting results demonstrated that AM + AT could inhibit the expression of T-Cx43 protein, but increased the expression of P-Cx43 in the left ventricular and thoracic aorta. Moreover, immunofluorescence results indicated AM + AT could also decrease the expression T-Cx43, and increase that of P-Cx43 in the left ventricular and thoracic aorta compared with AM and AT alone. Therefore, it was concluded that AM + AT may mitigate left ventricular and thoracic aorta remodeling in SH rats by enhancing Cx43 phosphorylation, and the efficacy of AM + AT was superior to that of AM and AT alone.