PICP Levels Research Articles

Irbesartan ameliorates myocardial fibrosis in diabetic cardiomyopathy rats by inhibiting the TGFβ1/Smad2/3 pathway

Myocardial fibrosis (MF) is an important pathological change in diabetic cardiomyopathy. The aim of the present study was to investigate whether irbesartan serves a role in improving MF in a diabetic rat model. Fasting blood glucose (FBG), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) levels were measured in rats using biochemical methods. Heart weight index (HWI), left ventricular weight index (LVWI), left ventricular systolic pressure (LVSP) and left ventricular end-diastolic pressure (LVEDP) were also measured, whilst type I collagen and hydroxyproline content in myocardial tissue was quantified. Western blotting was used to measure the expression of transforming growth factor β1 (TGFβ1), phosphorylated (p)-Smad2/3 and collagen type I α 1 chain (COL1A1) inmyocardial tissues or rat cardiac fibroblast (RCF) cells. Cell proliferation was measured using EdU staining. Procollagen type III N-terminal peptide (PIIINP) content, FBG, TC, TG and LDL-C levels were found to be significantly higher, whilst HDL-C levels were found to be significantly lower in rats in the diabetic group. Those in the diabetic group also exhibited significantly elevated HWI, LVWI, LVEDP, myocardial tissue type I collagen content and hydroxyproline content values, but significantly reduced LVSP. Changes in the aforementioned indicators were reversed after treatment with irbesartan, where the protein expression levels of TGFβ1 and p-Smad2/3 in myocardial tissue were also significantly reduced. In RCF cells, irbesartan significantly reversed high glucose-induced upregulation of TGFβ1 expression, Smad2/3 phosphorylation and COL1A1 expression, as well as reducing cell proliferation and rat type I PICP and PIIINP levels. Application of pirfenidone produced additive effects on reducing the expression levels of the proteins aforementioned when combined with irbesartan. Therefore, the present results demonstrated that irbesartan reduced the activity of the TGFβ1/Smad2/3 pathway and ameliorated diabetic MF by downregulating the expression of TGFβ1.

A prospective randomized controlled trial of bone metabolism in patients with charcot foot

BACKGROUND: Diabetic neuroosteoarthropathy (DNOAP, Charcots foot) - is a progressive destructive inflammatory disease of the osteoarticular apparatus of the foot, untimely and inadequate treatment of which can lead to the formation of gross deformities. More often, DNOAP is unilateral, bilateral lesion is relatively rare. It is not always possible to trace the relationship between the debut of DNOAP with trauma and chronic hyperglycemia. There is data demonstrating the role of individual pro-inflammatory factors in the pathogenesis of DNOAP, however, studies combining the evaluation of various metabolic markers of Charcots foot formation are currently extremely poor.
 AIM: To evaluate the hormonal and metabolic markers of bone formation and resorption in patients with DNOAP and without this diabetic complication.
 METHODS: A prospective, controlled trial included 70 patients with type 2 diabetes mellitus (37 men and 43 women) who formed 2 groups: group 1 included patients with DNOAP, group 2 was formed by patients with diabetes without foot skeleton damage. All patients underwent a study of 1,25-OH-vitamin D, sclerostin, pro-MMP-1, C-terminal propeptide type 1 collagen (PICP), type 1 collagen, osteocalcin, PTH, 25-OH-vitamin D, beta-cross-slaps.
 RESULTS: The results of the studies confirmed the presence of vitamin D deficiency in all patients with diabetes mellitus included in the study, revealed the absence of statistically significant differences between the groups in the values of sclerostin, pro-MMP-1; 25-OH-vitamin D, type I collagen, and osteocalcin (p 0.05). However, significant differences were found in the 1.25-OH vitamin D levels: patients with DNOAP presented the lower rates of 1,25-OH-vitamin D in comparison to control group (p 0.05). Beta-cross and PICP levels were significantly higher in DNOAP patients as well (p 0.05). Those findings show the more severe collagen degradation in patients with DNOAP and can be the genetically predisposed cause of DNOAP development. Though further studies are needed.
 CONCLUSION: In patients with DNOAP a decrease in 1,25-OH-vitamin D levels was found, as well as the alteration of the synthesis and destruction of collagen (beta-cross-slaps and PICP) compared to patients with diabetes mellitus without osteoarticular disorders.

A prospective randomized controlled trial of bone metabolism in patients with charcot foot

BACKGROUND: Diabetic neuroosteoarthropathy (DNOAP, Charcot’s foot) - is a progressive destructive inflammatory disease of the osteoarticular apparatus of the foot, untimely and inadequate treatment of which can lead to the formation of gross deformities. More often, DNOAP is unilateral, bilateral lesion is relatively rare. It is not always possible to trace the relationship between the debut of DNOAP with trauma and chronic hyperglycemia. There is data demonstrating the role of individual pro-inflammatory factors in the pathogenesis of DNOAP, however, studies combining the evaluation of various metabolic markers of Charcot’s foot formation are currently extremely poor. AIM: To evaluate the hormonal and metabolic markers of bone formation and resorption in patients with DNOAP and without this diabetic complication. METHODS: A prospective, controlled trial included 70 patients with type 2 diabetes mellitus (37 men and 43 women) who formed 2 groups: group 1 included patients with DNOAP, group 2 was formed by patients with diabetes without foot skeleton damage. All patients underwent a study of 1,25-OH-vitamin D, sclerostin, pro-MMP-1, C-terminal propeptide type 1 collagen (PICP), type 1 collagen, osteocalcin, PTH, 25-OH-vitamin D, beta-cross-slaps. RESULTS: The results of the studies confirmed the presence of vitamin D deficiency in all patients with diabetes mellitus included in the study, revealed the absence of statistically significant differences between the groups in the values of sclerostin, pro-MMP-1; 25-OH-vitamin D, type I collagen, and osteocalcin (p > 0.05). However, significant differences were found in the 1.25-OH vitamin D levels: patients with DNOAP presented the lower rates of 1,25-OH-vitamin D in comparison to control group (p <0.05). Beta-cross and PICP levels were significantly higher in DNOAP patients as well (p <0.05). Those findings show the more severe collagen degradation in patients with DNOAP and can be the genetically predisposed cause of DNOAP development. Though further studies are needed. CONCLUSION: In patients with DNOAP a decrease in 1,25-OH-vitamin D levels was found, as well as the alteration of the synthesis and destruction of collagen (beta-cross-slaps and PICP) compared to patients with diabetes mellitus without osteoarticular disorders.

Homage Proof of Concept Trial of Spironolactone for the Prevention of Heart Failure

Introduction In patients at risk of developing heart failure (HF), targeting cardiac fibrosis might be a major determinant of slowing the progression HF. Hypothesis HOMAGE (Heart OMics in AGEing) investigated whether a 9-month exposure to spironolactone can favourably alter markers of progression to HF. Methods In this proof-of-concept, multi-centre, randomized, open-label with blinded evaluation design (PROBE) trial, we compared the effect of spironolactone 25-50 mg/day to standard care in patients aged 60 or more, at risk of developing HF (coronary artery disease and/or diabetes and/or hypertension, and NT-pro BNP 125 to 1,000 ng/L or BNP 35 to 280 ng/L, and no HF history, signs or symptoms. Patients were assessed at baseline, 1, 3 and 9 months for changes in peptides Procollagen Type III N-Terminal Peptide (PIIINP) and Carboxy-Terminal Propeptide of Type 1 Procollagen (P1CP) (primary endpoint). Secondary end-points include changes in cardiac dimensions and function, functional capacity, NTproBNP and multi-omics biomarker profiles (Olink proteomics, miRNA, MS metabolomics and transcriptomics). Whether the effect can be predicted by the baseline bioprofiles was assessed using interaction analysis. Results A total of 527 patients were randomised, 265 to spironolactone and 262 to usual care. The treatment groups were well balanced (aged 73 years, 26% female, 40% diabetes 71% history of myocardial infarction, blood pressure 140/78 mmHg, eGFR 72 ml/min, LVEF 63%, the left atrial volume (LAV) 60 ml, LV mass 180g, median PIIINP 4 (3-5) ng/mL, PICP 80 (65-97) ng/mL, and Galectin-3 16 (13-20) ng/mL. Spironolactone did not significantly affect the PIIINP levels: -0.15 (-0.44, 0.15), p=0.32 but PICP was significantly reduced by spironolactone: -8.1 (-11.9, -4.3), p=0.001, increased LVEF +1.2 (0.2, 2.2), p=0.022, reduced LAV -2.5 (-4.5, -0.6), p=0.010, and tended to reduce LVM -4.1 (-8.6, 0.4), p=0.076. Detailed analyses of the other endpoints, and of prediction of changes using baseline bioprofiles, will be presented at the time of the meeting. Conclusions In patients at risk of developing HF, mineralocorticoid receptor antagonist therapy produces changes in circulating levels of PICP and in echocardiographic parameters, potentially contributing to preventing progression to HF. Other results, including whether multi-omics bioprofiles may predict response and could help selecting patients in a future MRA HF-prevention trial will be presented. (NCT02556450, EUFP7 HOMAGE ID: 305507).

P5303Relationship of the dynamics of serum collagen and epicardial adipose tissue in patients with coronary heart disease and visceral obesity

Abstract Purpose Study of the effect of epicardial adipose tissue and in serum collagen in patients with myocardial infarction depending on the presence of visceral obesity. Methods 88 patients with CVD were assessed and divided into two groups based on the presence of visceral obesity (VO). Magnetic resonance imaging (MRI) was used to determine the area of the visceral (VAT) and subcutaneous adipose tissue (SAT) of the abdominal region, the thickness of epicardial adipose tissue, and the percentage of myocardial cardiac fibrosis a year after MI. VO was verified when the area of VAT &gt;130 cm2. We investigated changes in serum collagen: collagen protein type I (COL-1), N-terminal propeptide of procollagen type III (PIIINP) and C-terminal propeptide of procollagen type I (PICP). All study was carried out in compliance with the Helsinki Declaration, and its protocol was approved by the Ethical Committee of Research Institute. Statistical analysis was performed using Statistica 10.0. All patients gave written informed consent to participate in the study. Results With VO, the thickness of the left ventricular epicardial tissue (EATLv) was 1.75 times greater, and that of the right ventricle (EATrv), 1.43 times more than in patients without VO. In the group of patients with VO, the presence of a direct correlation was established between the magnitude of the area of VAT and EATLv (r=0.26, p=0.02), EATrv (r=0.26, p=0.01). the results indicate that myocardial damage on the background of an acute MI is characterized by higher concentrations of COL-1 (29065 pg/ml), PICP (638 ng/ml) and PIIINP (31431 pg/ml), in the presence of VO during the hospital period of MI, and exceeded the figures of patients without VO 2.15, 1.07 and 1.19 times, respectively. One year after MI, the COL 1 level in both groups decreased compared with the acute MI period (1.68 times in patients without VO and 2.75 times in patients with VO), it still remained higher in patients with VO in 1,4 times higher. And the level of PICP was not significantly different on the first day of MI and a year after suffering MI in the studied groups. PIIINP decreased only in the group of patients without VO. The data of the correlation analysis showed that EATLv was in direct connection with the level of serum collagen in patients with VO: EATLv - COL-1 (1 day (r=0.73; p=0.01), 1 year (r=−0, 84; p=0.00); EATLv - PICP (1 day (r=0.63; p=0.01), 1 year (r=0.57; p=0.03) and EATLv - PIIINP (1 day (r=0.61; p=0.03), 1 year (r=0.31; p=0.01). Conclusions Thus, the presence of VO in patients with MI is associated with higher concentrations of COL 1, PICP, PIIINP, both in the acute period of MI, and one year after a coronary catastrophe. The thickness of EAT is directly dependent on the degree of VO, and the concentration of COL-1, PICP and PIIINP on the value of EATLv.

Altered serum levels of type I collagen turnover indicators accompanied by IL-6 and IL-8 release in stable COPD.

BackgroundCOPD, characterized by chronic inflammation and airway remodeling, has significant pathological alterations in composition and deposition of the extracellular matrix. The expression of procollagen 1 C-terminal peptide (PICP) and collagen type 1 C-terminal telopeptide (ICTP), two major by-products in the synthesis and degradation of collagen, was shown to be positively correlated with inflammatory mediator levels in previous studies.PurposeIn this study, we investigated whether the serum concentrations of PICP and ICTP were associated with the inflammation level for patients with stable COPD.Patients and methodsWe collected serum samples from 25 control subjects and 20 patients with stable COPD from December 2011 to October 2012 in Shanghai Zhongshan Hospital and Shanghai Dahua Hospital. We determined concentrations of PICP, ICTP, C-reactive protein (CRP), IL-6, IL-8, and tumor necrosis factor (TNF)-α by using enzyme-linked immunosorbent assay methods.ResultsDemographic characteristics were comparable between the two groups. In patients with stable COPD, serum levels of CRP, IL-6, IL-8, and TNF-α were all elevated compared to control subjects, but only changes of IL-6 achieved statistical significance. Serum concentration of PICP was significantly elevated in patients with COPD, and level of ICTP was slightly decreased. Moreover, serum concentrations of PICP were positively correlated with the levels of both IL-6 and IL-8.ConclusionThe increased levels of serum PICP in COPD might indicate the condition of airway remodeling, and IL-6 and/or IL-8 might play an important role in stimulating collagen synthesis.

Abstract P321: Substance P is Associated with Hypertension-induced Cardiac Fibrosis

Myocardial remodelling such as fibrosis is a major contributor to heart failure with preserved ejection fraction. We sought to determine the relationship between substance P (SP), a sensory neuropeptide, and this adverse remodelling. Using the angiotensin II mouse model of pressure overload we determined that Tac1 -/- mice that are genetically deficient in SP were protected from developing cardiac fibrosis (WT + Ang II = 1.452±0.1523% (n=9) vs Tac1 -/- + Ang II = 0.5678±0.078% (n=10), p&lt;0.0001). We then investigated the association between SP and fibrosis in hypertensive individuals. Plasma from consented individuals showed significantly higher levels of SP in the hypertensive group in comparison to the control group (control = 78.3 ±11.54 ng/mL (n=22), hypertensive = 127±17.5 ng/mL (n=43), p=0.023) (Figure). Interestingly, hypertensive males showed significantly higher levels of plasma SP than the male control group (control = 74.94±14.54 ng/mL (n=17), hypertensive = 143.2±23.96 ng/mL (n=29), p&lt;0.002), while no significant difference existed between these groups in females. Plasma levels of procollagen type 1 C-terminal pro-peptide (PICP), a marker of fibrosis, indicated that hypertensive individuals with SP levels greater than one standard deviation from the mean, had significantly higher levels of PICP (below = 5.539±0.688 ng/mL (n=38), above = 10.52±3.75 ng/mL (n=5), p=0.035). These findings indicate that high levels of plasma SP are associated with increased levels of a marker of fibrosis in hypertensive individuals. The human studies combined with the genetically modified mouse studies indicate an important role for SP in hypertension-induced cardiac fibrosis.

Application of Bone Turnover Markers PICP and β-CTx in the Diagnosis and Treatment of Breast Cancer with Bone Metastases

This study is to investigate the application of the bone turnover markers type I procollagen carboxyterminal propeptide (PICP) and β-isomerized forms of type I collagen breakdown products (β-CTx) in the diagnosis and treatment of breast cancer with bone metastases. A total of 162 breast cancer patients were included in this study. There were 70 cases with bone metastasis (BM group) and 92 cases without bone metastasis (non-bone metastasis, NBM group). The levels of the bone turnover markers PICP and β-CTx were measured using Electro-Chemiluminescence Immunoassay to compare the difference between BM and NBM group, before and after treatments in the NBM group, and to analyse the relationship with therapeutic effects. The BM group had higher PICP and β-CTx levels than the NBM group and also higher in the non-luminal type group than the luminal type group, the differences were all statistically significant. However, no statistically significant differences were found among the pN0, pN1, pN2, and pN3 subgroups of the NBM group. Among the 70 cases of BM patient after 3 months of treatment, there were 48 cases that showed clinical benefits, with significantly reduced PICP and β-CTx levels (p = 0.02, p = 0.00, respectively), but 22 cases showed disease progression with elevated PICP and β-CTx levels (p = 0.01, p = 0.04, respectively). The bone turnover markers PICP and β-CTx have crucial value in the diagnosis and treatment efficacy evaluation for women of breast cancer with bone metastases.

Levels of C-terminal propeptide of type I procollagen and oxyproline in patients with systemic lupus erythematosus: The relationship between the course of the disease and the structural and functional state of bone tissue

The high prevalence of osteoporosis in patients with systemic lupus erythematosus (SLE) makes it necessary to study the abnormalities in bone metabolism, its relationship with reduced bone mineral density (BMD) and the impact of the disease on it. The aim of this study was to determine serum levels of C-terminal propeptide of type I procollagen (PICP) and oxyproline in patients with SLE, their comparison with the structural and functional state of the patients’ bone tissue and the course of the disease. We examined 58 female SLE patients. The mean age of the patients was 45.1 ± 1.0 years. The control group included 29 healthy individuals,corresponding in age and sex with the researched group. For every patient, data were recorded on age, body mass index (BMI), menstrual history, smoking, chronic SLE damage (SLICC/ACR DI) and disease activity score (SLEDAI), cumulative glucocorticoid dose, serum concentrations of interleukin-6 (IL-6) and C-reactive protein (CRP), bone formation marker (C-terminal propeptide of type I procollagen) and bone resorption marker (oxyproline). In all patients BMD was measured by DXA (Dual-energy X-ray absorptiometry) at two sites. To determine vertebral compression fractures, female SLE patients were examined with an x-ray of the thoracic and lumbar spine. We established that bone turnover markers showed a significant difference between the SLE patients and the control group, with lower levels of PICP and higher levels of oxyproline in the SLE patients. Alterations of bone metabolism were associated with the severity of the disease, active inflammation (high levels of CRP and IL-6), the age of the patients, and the high cumulative glucocorticoid dose but no correlation was found with disease duration, BMI and smoking. Patients with osteopenia, osteoporosis and fractures were significantly more frequently found among patients with reduced bone formation and increased bone resorption rate. Thus, our findings showed that female SLE patients have alterations of bone metabolism in the form of increasing serum oxyproline and reducing serum C-terminal propeptide of type I procollagen, the correction of which would slow the progression of adverse structural and functional changes in the bone tissue.

Effects of Yishengukang decoction on expression of bone-specific alkaline phosphatase, carboxyterminal propeptide of type I procollagen, and carboxyterminal cross-linked telepeptide of type I collagen in malignant tumor patients with bone metastasis

OBJECTIVETo investigate the effect of Yishengukang decoction on the expression of the metabolic bone markers, bone-specific alkaline phosphatase (BAP), carboxyterminal propeptide of type I procollagen (PICP), and carboxyterminal cross-linked telepeptide of type I collagen (ICTP), in cancer patients with bone metastasis. METHODSPatients (n = 180) were divided into three groups: (a) bone metastasis patients treated with Yishengukang and pamidronate disodium injection (treatment group, n = 60); (b) bone metastasis patients treated with pamidronate disodium injection alone (control group, n = 60); (c) cancer patients without metastatic bone lesion (non-bone metastasis group, n = 60). Serum levels of the metabolic markers BAP, PICP, and ICTP were detected by enzyme-linked immunosorbent assay pre- and post-therapy. RESULTSA significant decrease in serum BAP level was observed in the treatment group compared with the control group. However there were no significant differences in serum levels of PICP and ICTP before or after treatment compared with the control group. CONCLUSIONYishengukang decoction combined with pamidronate disodium injection reduced serum BAP level to a greater extent that pamidronate disodium injection alone. Furthermore, the combined therapy was more beneficial in regulating imbalanced bone metabolism after bone metastasis, and may represent the molecular mechanism underpinning the effects of Yishengukang decoction.

Pain Syndrome, Markers of Bone Metabolism in Patients with Osteoarthritis, Approaches to Drug Therapy and the Impact of Obesity

The objective: to assess the nature of pain in patients with osteoarthritis, the impact of obesity on the clinical efficacy of treatment of osteoarthritis (OA) and dynamics of bone metabolism markers. Patients and methods. The research included 150 patients with OA, who were divided into two groups, according to the receiving therapy. Patients of the main group – received diacerein (drug «Flexirin» PC «Kyiv Vitamin Factory») and patients of control group – received only nonsteroidal anti-inflammatory drugs (NSAIDs). Results. The prevalence of neuropathic pain component in patients with OA was 64,7%, among which 80,7% use NSAIDs as an analgesic therapy. Obesity in patients with OA was associated with significantly higher levels of pain from the side of knee joints and higher degree of stiffness according to WOMAC index. The results of the study demonstrated a direct moderate correlation (R = 0,49; p = 0,04) between PICP level and the severity of pain at physical load from the side of hands and hip joints. The therapy by diacerein within 3 months resulted in a reliable decrease of pain syndrome intensity from the side of all articular zones, unlike to isolated NSAIDs use, where a reliable analgesic effect was demonstrated only from the side of knee joints. Obesity in patients with OA led to a significant decrease in clinical efficacy of therapy in point of functional status of the joints. Conclusions. Neuropathic pain is quite common among patients with OA, which at the same time is associated with the lack of patient’s awareness about possible risks during NSAID’s use. Medical treatment by diacerein (drug “Flexirin”) causes stability of osteocalcin level, in contrast to the isolated NSAIDs use, where priority changes have been demonstrated against osteocalcin level decrease. The use of diacerein also resulted to additional positive effects from the side of zonal prevalence of analgesic effect and improving of functional ability of joints. Obesity in patients with OA was associated with a reliable increase of pain level intensity from the side of knee joints and the higher degree of functional limitation, causing at the same time, reduction of clinical efficacy of therapy in point of achieving analgesic effect and improving functional ability of joints.

The association between insulin-like growth factor 1 (IGF-1), IGF-binding proteins (IGFBPs), and the carboxyterminal propeptide of type I procollagen (PICP) in pre- and postmenopausal women with rheumatoid arthritis

Objectives: To assess the association between plasma levels of the insulin-like growth factor (IGF) system including IGF-1, IGF-binding proteins (IGFBPs) including IGFBP-1, total (t-)IGFBP-3 and functional (f-)IGFBP-3, and the carboxyterminal propeptide of type I procollagen (PICP) in pre- and postmenopausal women with rheumatoid arthritis (RA).Method: Plasma concentrations of IGF-1, IGFBP-1, t-IGFBP-3, f-IGFBP-3, and PICP were measured by immunoassay.Results: No significant difference was observed in plasma IGF-1 levels between pre- and postmenopausal subjects. Plasma levels of IGFBP-1 were elevated in RA. PICP and f-IGFBP-3 were greatly affected by menopausal status. Of the three IGFBPs tested, only f-IGFBP-3 plasma levels in RA women correlated negatively with age and disease duration. A positive correlation was demonstrated between PICP and erythrocyte sedimentation rate (ESR) in RA. Moreover, there was no correlation between PICP and IGF-1 and any of the IGFBPs in RA women.Conclusions: Considerable disruption of the IGF system in RA was found to be related to disease activity and duration. Changes in the IGF–IGFBP axis and PICP levels were different in pre- and postmenopausal women with RA. Elevated plasma PICP concentrations may indicate an increased rate of bone formation in postmenopausal RA women. Additionally, the observed changes in the IGF/IGFBP system did not affect bone formation during RA.

THE MARKERS OF BONE METABOLISM AND SYSTEM INFLAMMATION IN PATIENTS WITH OSTEOARTHRITIS DEPENDING ON BODY MASS, THE INFLUENCE OF SYMPTOMATIC SLOW ACTING DRUGS

Aim. To assess the levels of markers of the bone synthesis and system inflammation in patients with osteoarthritis (OA) in combination with obesity and their dynamic under the influence of basic treatment. Materials and methods. The research included 40 women with OA, 46–78 years old (mean age – 59,8±1,5 years). Duration of the disease varied from 3 to 36 years (mean duration – 10,0±1,1 years). Mean body mass index (BMI) among patients was 30,6±0,7 [22,3; 39,5]kg/m2, according to which patients were divided in 3 groups: patients with OA without obesity (n=17), patients with OA with 1 degree of obesity (n=14), patients with OA with 2 degree of obesity (n=9). The level of osteochondral metabolism was assessed using quantitative measuring of the levels of procollagen IC-terminal propeptide (РІСР), (Cloud-CloneCorp. “procollagen IC-Terminal Propeptide”, USA) and osteocalcin (Roche Diagnostics «N-MID Osteocalcin», Switzerland) on analyzer «ELECSYS 2010» by the method of immune-enzyme analysis; the level of the system inflammation was assessed by the level of C-reactive protein (CRP) by the method of immunoturbidimetry. The clinical efficacy was assessed by the dynamics of intensity levels of pain syndromes at physical load and at rest by the visual-analogue scale (VAS). The measuring of РІСР, osteocalcin and CRP levels and also the assessment of clinical efficacy as to the decrease of pain syndrome were carried out twice – at the beginning and at the end of observation. The period of observation is 2 months. Results. The presence of direct correlation between РІСР and BMI (r=0,62; р=0,008) among patients with OA in combination with the normal body weight was established at the research, whereas among patients with OA in combination with obesity the analogous correlation was demonstrated between SRP and BMI (r=0,43; р=0,04) on the background of correlation of PICP and OC levels (r=0,46; р=0,03). Obesity in patients with OA was associated with the reliably higher levels of pain at both rest and physical load from the side of knee joints, with maximal intensity of the pain syndrome among patients with OA and 1 degree of obesity. Statistical analysis did not reveal the reliable dependence of РІСР and OC in patients with OA from the initial CRP level on the background of tendency to the higher РІСР level and lower OC level among patients with initially increased CRP level comparing with ones with normal CRP level. The therapy with basic preparations at OA during 2 months among patients with OA with increased CRP level led to the reliable decrease of РІСР level (р=0,0076) and the tendency to increase of OC level (р˃0,05), without the reliably significant difference between the initial and final РІСР and OC levels among patients with OA and normal CRP level. At the end of observation period the maximal analgesic effect was demonstrated as to the articulate pain at rest from the side of knee joints (р˂0,001) among patients with OA, who received diacerein, with clinically comparable effect from the side of other aticulate zones (р˂0,05), that was associated with reliable decrease of CRP level (р=0,013). Discussion. The received results testify that the control of the system inflammation level at OA is a target not only relative to the decrease of pain syndrome but also conditions the stable state of subchondral bone (SCB), providing the compensation of processes of destruction and synthesis in bone tissue. The significance of procollagen IC-terminal propeptide (РІСР) and osteocalcin (OC) as the markers of bone synthesis that are able to reflect metabolic processes in SCB at OA, and also the discordant influence of CRP level on PICP level at the relative stability of OC level were demonstrated at the research. The received results allow consider the inflammatory process at OA as a target for preservance of the bone tissue, conditioning the expedience of taking into account the ability of OA basic preparations to realize the control influence on the level of system inflammation. Diacerein that in ESCEO recommendations (2014) is related to the preparations of the 1 step of treatment of patients with OA provides the control on inflammation and stability of osteocalcin level that testifies to the balance of catabolic processes in SCB. Conclusions. At OA the levels of procollagen IC-terminal propeptide (РІСР) and osteocalcin (OC) were not associated with obesity and did not depend on the initial CRP level at the presence of correlation between РІСР level and BMI among patients with OA with the normal body weight and BMI and CRP level among patients with OA in combination with obesity. The absence of reliable dynamics from РІСР side and maintenance of the stable OC level on the background of the reliable anti-inflammatory effect at using diacerein in patients with OA can testify to the compensatory adequacy of reparation processes in SCB.

Effect of High Thoracic Sympathetic Nerve Block on Serum Collagen Biomarkers in Patients with Chronic Heart Failure

Objectives: The impact of high thoracic sympathetic block (HTSB) on myocardial fibrosis in chronic heart failure (HF) is unclear. Myocardial collagen synthesis can be assessed by measuring circulating biomarkers. We observed the effect of HTSB on serum collagen biomarkers in HF. Methods: Forty-four patients were randomized to a control and a HTSB group. They received routine medications. Repeated epidural injections were given to the HTSB group for 4 weeks. Echocardiography and measurements of serum carboxy-terminal propeptide of procollagen type I (PICP) and amino-terminal propeptide of procollagen type III (PIIINP) were performed at baseline and 4 weeks later. Results: There were significant reductions in left atrial diameter, left ventricular (LV) diameter and volume, LV weight index (LVWI) and serum PICP and PIIINP levels in the HTSB group (p < 0.05). The changes in LV end-systolic volume and ejection fraction (LVEF) were greater in the HTSB group than in the control group (p < 0.05). In the HTSB group, the decreases in PICP and PIIINP were correlated with the decrease in LVWI (PICP: r = 0.695, p = 0.000; PIIINP: r = 0.642, p = 0.001), and the decrease in PICP was negatively associated with the rise in LVEF (r = -0.813, p = 0.000). Conclusion: HTSB reduces myocardial fibrosis in HF, which may accompany the improvement of LV hypertrophy and dysfunction.

Effect of montelukast on markers of airway remodeling in children with asthma.

Asthma is a pathology characterized by chronic inflammation and remodeling of the airways. To evaluate the effect of montelukast treatment on markers of airway inflammation and remodeling in children with mild asthma and to evaluate if the administration of montelukast to children with mild asthma could inhibit the release of matrix metallopeptidase 9, matrix metallopeptidase 12, tissue inhibitor of metalloproteinase 1, transforming growth factor beta 1, C-peptide terminal procollagen type (PICP), and eosinophils count, which are markers of inflammation and remodeling in induced sputum. Thirty children with mild asthma were recruited. They were randomized into two groups: group A received montelukast and as needed beta-2-agonist for 8 weeks (T0-T1), whereas group B received placebo and as needed beta-2-agonist for 8 weeks. After 2 weeks of washout (T1-T2), they were reallocated for treatment according a crossover design (T2-T3). Tests for lung function, oral exhaled nitric oxide, and hypertonic saline solution-induced sputum level were performed at T0-T1-T2-T3. In the placebo group, the PICP mean (standard deviation [SD]) value at baseline was 2279.42 ± 2530.77 pg/mL and 1916.00 ± 2178.75 pg/mL after treatment. Patients treated with montelukast, in contrast, showed a baseline mean (SD) value of 2439.29 ± 2834.51 pg/mL and 1406.72 ± 1508.65 pg/mL after treatment. The difference between the mean pre- and posttreatment decrease of PICP in the two groups was statistically significant (delta -690.21 pg/mL [95% confidence interval, -1220.83 to -159.5844 pg/mL]; p = 0.011). The mean (SD) percentage of the eosinophil count in the placebo group was 3.11 ± 4.03% at baseline and 4.86 ± 5.83% after treatment. Patients treated with montelukast, in contrast, showed a percentage mean (SD) value at baseline of 4.51 ± 5.48% and, after treatment, of 3.06 ± 3.29%. The difference between the mean pre- and posttreatment decrease of the percentage eosinophil count in the two groups was statistically significant (delta -2.76% [95% confidence interval, -4.65 to -0.87%]; p = 0.004). This study investigated in vivo effects of montelukast on remodeling markers. The reduction of PICP levels and eosinophil count supported the hypothesis that montelukast can modulate collagen deposition in airways and reduce eosinophilic airway inflammation. Clinical Trials database clinicaltrials.gov (NCT00875082).

BLOOD LEVEL OF COLLAGEN BIOMARKERS AND SULFATED GLYCOSAMINOGLYCANS IN ACUTE TRANSMURAL MYOCARDIAL INFARCTION

Aim. To study dynamics of blood levels of carboxyterminal propeptide of I type procollagen (PICP), carboxyterminal telopeptide of type I collagen (CITP) and sulfated glycosaminoglycans (sGAG) in the dynamics, in patients with transmural transmural myocardial infarction (MI) complicated with aneurysm. Material and methods. Totally, 46 patients included with acute transmural anterior MI, who underwent the assessment of PICP, CITP and sGAG in dynamics. Results. On the 1st to 3rd days of MI without aneurysm there was increase of PICP up to 61,4 ng/mL, on 10-12th and 18-22nd days its level did not change significantly, remaining high. In aneurysm MI the level of PICP increased just from the 10-12th days and in lower grade — comparing to patients without aneurysm. Level of CITP in patients without aneurysm was comparable to controls during the entire study. Level of sGAG in non-aneurysm patients increased from 10-12th days, and in MI with aneurysm — did not differ from healthy persons during the entire study. Conclusion. Increase of CITP and lower PICP and sGAG in MI patients with aneurysm witnesses’ probable predominance of degradation processes of connective tissue over its synthesis.

ROLE OF COLLAGEN SYNTHESIS AND DEGRADATION SEROMARKERS, STRUCTURAL-FUNCTIONAL HEART PARAMETERS IN PROGNOSIS OF ATRIAL FIBRILLATION AMONG PATIENTS WITH PREMATURE VENTRICULAR EXCITATION SYNDROMES

Aim. The aim of the study was to optimize the diagnosis and prognosis of developing arrhythmias in this cohort and to reveal the possible role of fibrous matrix disturbance in development of arrhythmia. Materials and methods. The main group included 43 patients with premature ventricular excitation syndromes (WPW phenomenon, WPW syndrome), the comparison group - 15 practically healthy persons of the similar age. The mean age of patients belonging to the main group was 25,3 ± 9,15 years. All the groups were comparable by gender distribution ( p = 0,45, Fisher criterion) and age ( p = 0,27, U-criterion). Results. The greatest matrix metalloproteinase-9 (MMP-9) indices were assessed in patients with WPW syndrome - 96,1 ± 33,2 ng/ml, with WPW phenomenon - 54,3 ± 21,8 ng/ml; p = 0,0003). Practically healthy persons had minimum MMP-9 values - 27,4 ± 10,9 ng/ml ( p = 0,00014; p = 0,000002). Maximum values of tissue inhibitor of matrix metalloproteinases (TI MP-1) are presented in WPW phenomenon group and practically healthy persons (418,5 ± 69,8 ng/ml and 461,7 ± 72,2 ng/ml; p = 0,27). In patients with WPW syndrome, TIMP-1 was reliably lower - 341,1 ± 90,1 ng/ml ( p = 0,002; p = 0,00012). Procollagen type 1 carboxyterminal propeptide (PICP) level in patients with WPW syndrome was 179,9 ± 76,2 ng/ml, with WPW phenomenon - 97,8 ± 31,7 ng/ml ( p = 0,00014). All patients, included into the study, significantly differed from practically healthy persons by PICP level - 69,4 ± 23,9 ng/ml ( p < 0,05, U -criterion). Statistical processing of material showed reliable differences between extracellular matrix status indices depending on WPW syndrome and phenomenon, as well as presence or absence of AF paroxysms against the background of ventricular preexcitation. Conclusions. Changes in fibrous matrix, namely, increase in MMP-9, PICP concentrations and decrease in TIMP-1was registered. WPW syndrome is characterized by significant dysbalance of collagen synthesis and degradation seromarkers than WPW phenomenon. The studied seromarkers of fibrosis, probably, participate in formation of rhythm disturbance of the heart with actual syndromes available.

Fragmented QRS complexes are a marker of myocardial fibrosis in hypertensive heart disease.

Carboxy-terminal propeptide of type 1 procollagen (PICP) is a marker of extracellular collagen synthesis. Fragmented QRS (fQRS) on a 12-lead electrocardiogram (ECG) has been demonstrated as a marker of myocardial fibrosis. The present objective was to investigate the association between serum PICP concentration and presence of fQRS on ECG in hypertensive patients. Consecutive patients with previously or newly diagnosed hypertension were included. fQRS was defined as the presence of additional R-wave (R'), or notching of R- or S-waves, or the presence of fragmentation in 2 contiguous ECG leads. Serum PICP levels were measured by ELISA method. The study group consisted of 90 hypertensive patients (74% females, with a mean age of 54.7±8.5 years). Of these patients, 47 (52.2%) had fQRS on ECG. Age (p=0.121) and gender distribution (p=0.625) were similar in patients with or without fQRS. Receiver operating characteristic curve analysis yielded a strong predictive ability of PICP levels for the presence of fQRS (area under the curve: 0.850; 95% CI: 0.772-0.929; p<0.0001). In multivariate logistic regression analysis, PICP levels were strongly and independently associated with the presence of fQRS (OR: 1.938; 95% CI: 1.398-2.688). Serum PICP level is a strong and independent predictor of fQRS. Discriminative performance of serum PICP levels for the presence of fQRS is high. The present results are the first to demonstrate that fQRS may indicate myocardial fibrosis in patients with hypertension.

Abstract 19260: Predictive Value of Circulating Biomarkers of Collagen Metabolism Following Catheter Ablation of Atrial Fibrillation

Introduction: Myocardial fibrosis plays an important role in the pathogenesis of atrial fibrillation (AF). However, catheter ablation may eliminate AF sources but also increases fibrosis. We aimed to assess the predictive value of circulating biomarkers of collagen metabolism following AF catheter ablation. Methods: Serum levels (ELISA) of biomarkers of collagen metabolism were analyzed in patients undergoing AF ablation (62 paroxysmal, 67 persistent) at baseline and 12 months after ablation. Biomarkers levels in 20 patients in sinus rhythm were also evaluated to establish the normal values. Results: Before ablation, there was a direct linear correlation between PICP (carboxy-terminal propeptide of procollagen type I) levels and left atrial diameter for the overall sample (p=0.006). PICP levels at baseline were lower in paroxysmal AF patients with vs. without AF recurrences following ablation (68.30 ± 9.66μg/l vs 90.72 ± 3.78μg/l; p=0.017). At 12 months following ablation of paroxysmal patients, PICP levels significantly increased only in patients with AF recurrences (21.74μg/l vs -0.12 μg/l, Figure). There were no significant changes in biomarkers levels in persistent AF patients at baseline or during follow-up. Conclusions: Progressive increase of PICP levels following catheter ablation of AF is related with arrhythmia recurrence in paroxysmal AF patients. This result suggests that ablation may increase collagen turnover in non-responders paroxysmal AF patients.

102 Myocardial Fibrosis in Stroke Survivors

Background Myocardial fibrosis (MF) is a substrate for sudden cardiac death. Cardiac death is the commonest cause of death in stroke survivors. We recently showed that MF in stroke survivors can be treated by spironolactone and amiloride in a randomised placebo-controlled cross-over study. Purpose To determine the prevalence of severe MF in stroke survivors, as evidenced by Procollagen carboxyl-terminal telopeptide (PICP) >127 µg/L (which is 78% specific and 75% sensitive at diagnosing severe fibrosis, as identified by histological assessment of myocardial biopsy). We also tested the hypothesis that PICP is associated with reversible cardiac pathologies in stroke survivors. Methods 186 stroke survivors were studied. Patients who were known to have liver or lung fibrosis or recent surgery (within last 6 months), or atrial fibrillation were excluded at recruitment because these conditions can affect PICP levels. The concentration of PICP was measured by radioimmunoassay using a kit from Orion Diagnostics, Finland (assay coefficient of variation; = 1.48%). Dipyridamole myocardial perfusion imaging was performed. Ejection fraction was determined using gated SPECT. Left ventricular mass index (LVMI) was determined by echocardiography. Results 186 stroke survivors (111 male, 75 female) were studied. Severe MF is prevalent amongst stroke survivors. 36% (67 out of 186) had PICP >127 µg/L. Stroke survivors with severe fibrosis were older [68 (8) vs 65 (10), p = 0.049], but had similar blood pressure (144/79 mmHg in severe fibrosis patients, vs 144/80 mmHg), history of angina or myocardial infarction and degree of inducible ischaemia (0, interquartile range (IQR) = 0–3, vs 0 (IQR 0–4), p = 0.79) when compared with those with lower PICP levels (Table 1). There was a very weak correlation between PICP and LVMI [r = 0.2, p = 0.011]. No correlation was found between PICP and ejection fraction or BNP levels at rest or QT dispersion (Table 2). Interestingly, stroke survivors taking ACE-inhibitors had less severe MF (Mantel-Haenszel OR = 0.3, 95% CI = 0.15–0.74; Fisher’s exact 2-sided p = 0.007). Conclusions Severe MF is common in stroke survivors. Whilst a statistically significant association was found between MF and LVMI, the correlation is very weak.