Procollagen I C-terminal Propeptide Research Articles

Cardiac remodeling in patients with heart failure with mildly reduced ejection fraction and metabolic disorders: association with biomarkers and autonomic nervous system parameters

Aim. The high prevalence of obesity in a cohort of patients with heart failure and mildly reduced ejection fraction (HFmrEF) determines the relevance of clarifying the role of biomarkers and autonomic imbalance in myocardial remodeling, taking into account metabolic risk factors.Material and methods. We examined 19 men with postinfarction cardiosclerosis and class II HFmrEF (median age 62 years), overweight/class I-II obesity, type 2 diabetes in 53/47%, 48% of cases, respectively, who received therapy. The biomarker panel included N-terminal pro-brain natriuretic peptide (NT-proBNP), galectin-3, pro-collagen I C-terminal propeptide (PICP), N-terminal propeptide of procollagen type III (PIIINP), C-terminal telopeptide of type I collagen, matrix metalloproteinase-9 (MMP-9), tissue inhibitor of matrix proteinase-1 (TIMP-1), leptin and adiponectin. Heart rate variability (HRV) and turbulence were obtained using 24-hour Holter monitoring. We assessed the time and frequency domains of HRV (24 h) and 5 min recordings of wakefulness at rest, calculated TO (turbulence onset) and TS (turbulence slope).Results. Significant positive associations of leptin and TIMP-1 levels with left ventricular hypertrophy markers were confirmed. Positive correlations of peak e' with following HRV indicators were revealed: SDNN (r=0,68; p=0,02) and RMSSD (r=0,69; p=0,003). Lower TS values were associated with higher index parameters of left ventricular mass (p<0,05 for all). Associations of biomarkers with autonomic nervous system (ANS) were observed: MMP-9 with RMSSD (r=0,54) and pNN50 (r=0,51); TIMP-1 with TO (r=0,46); PICP/PIIINP ratio with HFn (5 min) (r=-0,49); NT-proBNP/adiponectin ratio with SDNN (r=-0,49); leptin level with TS (r=-0,54) (p<0,05 for all).Conclusion. In patients with HFmrEF of ischemic origin and additional metabolic risks, serum biomarkers of fibrosis, adipokines, and ANS parameters are associated mainly with markers of increased left ventricular filling pressure. The study results predetermine the further search for potential risk-stratification markers of unfavorable myocardial remodeling and prognosis in large samples of patients with metabolic deviations and HF with EF >40% against the background of modern drug therapy.

Daily supplement of sesame oil prevents postmenopausal osteoporosis via maintaining serum estrogen and aromatase levels in rats

Estrogen deficiency is one of the main causes of postmenopausal osteoporosis in elderly women. Hormone replacement therapy has been employed to manage postmenopausal osteoporosis; however, it has raised concerns related to heart attacks and breast cancer. Sesame oil has been reported to affect sex hormone status. The aim of the present study is to evaluate the effect of sesame oil supplement on postmenopausal osteoporosis in rats. We used female Sprague Dawley rats that underwent bilaterally ovariectomy (OVX) as an experimental postmenopausal osteoporosis animal model. These rats were orally administrated sesame oil (0.25 or 0.5 mL/kg/day) for four months as the therapeutic group. We assessed bone mineral density (BMD) and the levels of osteocalcin, procollagen-I C-terminal propeptide (PICP), collagen cross-linked N-telopeptide (NTx), estradiol, and aromatase in the sera. The daily supplementation of sesame oil significantly increased BMD, serum osteocalcin levels, and trabecular areas in the OVX-treated rats. Sesame oil also elevated serum PICP levels and decreased NTx levels in these rats. Furthermore, sesame oil effectively maintained serum estradiol and aromatase levels in the OVX-induced osteoporosis rats. In conclusion, daily supplementation of sesame oil prevents postmenopausal osteoporosis by maintaining serum estrogen and aromatase levels, while also modulating the imbalance between bone formation and resorption in osteoporosis rats.

Dapagliflozin Treatment Improves Cardiac Remodeling and Dysfunction in Heart Failure Induced Rats

Background: Sodium-glucose cotransporter-2 (SGLT-2) inhibitor dapagliflozin is a novel antihyperglycemic drug that has cardioprotective effects. It has been shown to minimize the incidence of cardiovascular mortality and heart failure (HF) hospitalization. Furthermore, these benefits may remain regardless of the existence of diabetes. However, the mechanisms by which dapagliflozin mediates these effects in HF patient are unknown, and its efficacy and practical use are still debatable. Objectives: to assess the therapeutic effect of dapagliflozin on rat with experimentally induced HF and its possible underlying mechanism of action. Methods: The left anterior descending (LAD) coronary artery was ligated in rats to induce HF. Dapagliflozin (1 mg/kg/day) was given by gavage for four weeks. Heart weight (HW), Body weight (BW), blood pressure, heart rate (HR), fasting serum glucose, insulin, glycated hemoglobin A1C (HbA1c), cardiac injury markers [creatine kinase-MB (CK-MB), cardiac troponin I (cTnI), lactate dehydrogenase (LDH)], markers of fibrosis [transforming growth factor beta 1 (TGF-β1), procollagen I C-terminal propeptide (PICP), procollagen III N-terminal peptide (PIIINT)], mediators of inflamation [tumor necrosis factor-alpha (TNF-α)], markers of oxidative stress [super oxide dismutase (SOD) and malondialdehyde (MDA)] and mediators of apoptosis (caspase 3 and BCL-2) were assessed. Histopathological examinations were performed using hematoxylin and eosin (H & E) for the heart, lung, and liver, and masson trichrome for heart. Results: Dapagliflozin decreased HW, HW/BW, cardiac injury markers, markers of fibrosis, mediators of inflammation, MDA and cardiac level of Caspase 3, while increased levels of SOD and BCL-2 in HF-induced rats. Dapagliflozin also improved the histopathological picture of heart, liver and lung. Conclusion: Dapagliflozin attenuated fibrosis, inflammation, oxidative stress, and apoptosis in HF-induced rats, thereby alleviating myocardial remodeling and dysfunction. Dapagliflozin alleviated histopathological changes in the hearts, lungs, and livers.

Predicting the risk of left ventricular diastolic dysfunction in obesity

Obesity may develop heart failure with preserved ejection fraction, which is based on left ventricular diastolic dysfunction (LV DD). Currently, the search for effective predictors of LV DD is extremely relevant.Aim. To assess the prognostic value of key and additional metabolic risk factors (RFs), neurohumoral and profibrotic factors in the development of LV DD in obese patients.Material and methods. The study included 149 men with general obesity. The mean age was 49,7±7,9 years. The inclusion criteria was the presence of class I-III general obesity. The average body mass index was 32,9±3,6 kg/m2. The exclusion criteria were hypertension, coronary atherosclerosis, type 2 diabetes, as well as LV DD according to transthoracic echocardiography. Depending on the presence of epicardial adiposity, patients were divided into two groups: group 1 — epicardial adipose tissue (EAT) thickness ≥7 mm (n=70), group 2 — EAT <7 mm (n=31). In all patients, the following laboratory parameters were determined in blood serum using enzyme immunoassay: type I and III collagen, Procollagen I C-Terminal Propeptide (PICP), matrix metalloproteinase-3 (MMP-3), transforming growth factor β1, vascular endothelial growth factor, tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-10, C-reactive protein (CRP), adiponectin, soluble leptin receptor, leptin, lipid parameters and free fatty acids (FFA). After 4,7±0,3 years, echocardiography was repeated in order to assess LV diastolic function.Results. Comparative analysis of metabolic risk factors revealed a significant increase in the level of total cholesterol (p=0,001), low-density lipoprotein cholesterol (LDL-C) (p<0,0001), triglycerides (TGs) (p<0,0001). These groups had no differences in such parameters as high-density lipoprotein cholesterol (p=0,09) and glucose (p=0,12). An increase in the level of such pro-inflammatory cytokines as TNF-α (p<0,0001), CRP (p<0,0001), IL-6 (p<0,0001) in group 1 was revealed, while differences in IL-10 (p=0,34) levels were not significant. In group 1, there was a significant increase in leptin levels (p<0,0001), a decrease in levels of adiponectin (p<0,0001) and leptin receptor (p=0,001). In group 1, an increase in the level of all studied profibrotic factors was revealed. After 4,7±0,3 years, repeated echocardiography revealed that selected groups were comparable in such parameters as A, E, E/A, E/e’, e’, and the peak tricuspid regurgitation velocity. There was a significant difference in left atrial volume index (p=0,0003). LV DD was detected in 20 patients. Binary logistic regression revealed the following most significant predictors of LV DD in obese patients: glucose, LDL-C, triglycerides, leptin receptor, leptin, MMP-3, FFA, PICP, and EAT thickness.Conclusion. Thus, the following most significant predictors of LV DD in obese patients were identified glucose, LDL-C, triglycerides, leptin receptor, leptin, MMP-3, FFA, PICP, and EAT thickness.

Predicting the risk of left ventricular diastolic dysfunction in obesity

Obesity may develop heart failure with preserved ejection fraction, which is based on left ventricular diastolic dysfunction (LV DD). Currently, the search for effective predictors of LV DD is extremely relevant.Aim. To assess the prognostic value of key and additional metabolic risk factors (RFs), neurohumoral and profibrotic factors in the development of LV DD in obese patients.Material and methods. The study included 149 men with general obesity. The mean age was 49,7±7,9 years. The inclusion criteria was the presence of class I-III general obesity. The average body mass index was 32,9±3,6 kg/m2. The exclusion criteria were hypertension, coronary atherosclerosis, type 2 diabetes, as well as LV DD according to transthoracic echocardiography. Depending on the presence of epicardial adiposity, patients were divided into two groups: group 1 — epicardial adipose tissue (EAT) thickness ≥7 mm (n=70), group 2 — EAT <7 mm (n=31). In all patients, the following laboratory parameters were determined in blood serum using enzyme immunoassay: type I and III collagen, Procollagen I C-Terminal Propeptide (PICP), matrix metalloproteinase-3 (MMP-3), transforming growth factor β1, vascular endothelial growth factor, tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-10, C-reactive protein (CRP), adiponectin, soluble leptin receptor, leptin, lipid parameters and free fatty acids (FFA). After 4,7±0,3 years, echocardiography was repeated in order to assess LV diastolic function.Results. Comparative analysis of metabolic risk factors revealed a significant increase in the level of total cholesterol (p=0,001), low-density lipoprotein cholesterol (LDL-C) (p<0,0001), triglycerides (TGs) (p<0,0001). These groups had no differences in such parameters as high-density lipoprotein cholesterol (p=0,09) and glucose (p=0,12). An increase in the level of such pro-inflammatory cytokines as TNF-α (p<0,0001), CRP (p<0,0001), IL-6 (p<0,0001) in group 1 was revealed, while differences in IL-10 (p=0,34) levels were not significant. In group 1, there was a significant increase in leptin levels (p<0,0001), a decrease in levels of adiponectin (p<0,0001) and leptin receptor (p=0,001). In group 1, an increase in the level of all studied profibrotic factors was revealed. After 4,7±0,3 years, repeated echocardiography revealed that selected groups were comparable in such parameters as A, E, E/A, E/e’, e’, and the peak tricuspid regurgitation velocity. There was a significant difference in left atrial volume index (p=0,0003). LV DD was detected in 20 patients. Binary logistic regression revealed the following most significant predictors of LV DD in obese patients: glucose, LDL-C, triglycerides, leptin receptor, leptin, MMP-3, FFA, PICP, and EAT thickness.Conclusion. Thus, the following most significant predictors of LV DD in obese patients were identified glucose, LDL-C, triglycerides, leptin receptor, leptin, MMP-3, FFA, PICP, and EAT thickness.

Dual integrin αvβ3 and αvβ5 blockade attenuates cardiac dysfunction by reducing fibrosis in a rat model of doxorubicin-induced cardiomyopathy

Objective The present study aimed to evaluate the protective role of cilengitide (CGT), an integrin αvβ3 and αvβ5 inhibitor, on doxorubicin (DOX)-induced myocardial fibrosis and cardiac dysfunction in a rat model. Methods. Forty male rats were randomly divided into four groups: DOX (n = 12), intraperitoneal (i.p.) injection of DOX 0.8 ∼ 1.0 mg/kg three times a week for up to 6 weeks, then saline i.p. three times a week for another 3 weeks; CGT (n = 8), CGT 10 mg/kg, i.p. three times a week for 9 weeks; DOX + CGT (n = 12), DOX and CGT co-administration as above for 6 weeks, then CGT alone for another 3 weeks; Control (n = 8), saline i.p. three times a week for 9 weeks. Echocardiography, serum procollagen I C-terminal propeptide (PICP) procollagen III N-terminal propeptide (PIIINP) and C telopeptide type I (CTX-I) were evaluated at baseline and 3, 6 and 9 weeks after initial DOX administration for all surviving rats. The heart tissues were then harvested for myocardial hydroxyproline (HYP) evaluation, qRT-PCR, and western blotting. Results. CGT attenuated DOX-induced eccentric remodeling by improving relative wall thickness at the 9th week. CGT also improved systolic function at the 9th week and diastolic function at the 6th and 9th week. CGT reduced myocardial HYP and serum PICP, PIIINP, CTX-I, and the PICP/PIIINP ratio. RT-PCR and western blot showed that CGT blocked the TGF-β1/SMAD3 pathway and mitigating extracellular matrix turnover. Conclusions. CGT exerted a cardioprotective effect against doxorubicin-induced fibrosis and improved cardiac function.

Correlation between procollagen propeptides end echocardiography indices in patients with ST segment elevation myocardial infarction (STEMI)

Abstract Objective To investigate the correlation between Procollagen I C-Terminal Propeptide (PICP), Procollagen III N-Terminal Propeptide (PIIINP), indices of echocardiography and anamnestic data in patients with ST segment elevation myocardial infarction (STEMI) and preserved myocardial contractility. Materials and methods 60 men and 23 women diagnosed with STEMI were examined. Echocardiographic studies were performed using SONOS 2500 Cardiac – Vascular Ultrasound (Hewlett Packard, USA). Myocardial contractility was considered to be preserved with left ventricular ejection fraction (LVEF) ≥50%. In addition to standard indices of echocardiography, mitral flow propagation velocity (FPV) was evaluated to diagnose diastolic dysfunction. Coronary angiography was performed using INNOVA 3100 Cardiovascular Imaging System (USA). All patients, during the first twelve hours of the disease, underwent percutaneous coronary intervention (PCI) with stenting of the occluded culprit infarct-related artery. On the 1st and 12th days of hospitalization, the concentrations of PICP and PIIINP were determined for all patients by enzyme-linked immunosorbent assay (ELISA) using laboratory BCM Diagnostics kits (USA). All patients at the hospital received standard therapy. Results The following marker values were obtained: 1st day: PICP 609 (583; 635) ng/ml, PIIINP 26 (18.9; 34.9) ng/ml; 12th day: PICP 588 (580; 561) ng/ml, PIIINP 24.2 (18.6; 30.3) ng/ml. The following significant correlations were revealed: PICP 1st day / isovolumic contraction time – IVCT (m/s) 12th day, r=−0.68, p=0.042; PICP 1st day / Tei Index 12th day, r=−0.72, p=0.028; PICP 1st day / diastolic rigidity 12th day, r=−0.74, p=0.021; PIIINP 1st day/age, r=0.55, p=0.016; PIIINP 1st day/ body mass index (BMI), r=−0.59, p=0.009; PIIINP 1st day / E (cm/s) 1st day, r=0.72, p=0.018; PIIINP 1st day / Em /FPV 1st day, r=0.78, p=0.007; PIIINP 12th day / Em / FPV 1st day, r=0.65, p=0.041; PIIINP 12th day / E (cm/s) 1st day, r=0.67, p=0.033; PIIINP 12th day / E / Em) 12th day, r=0.70, p=0.023; PIIINP 12th day / Em/FPV 12th day, r=0.73, p=0.014. Conclusions The data obtained indicates the correlation between serum markers of myocardial fibrosis and the indices of echocardiography, as well as age. We conclude that, all the markers listed above, are able to represent myocardial remodeling in patients with STEMI. Funding Acknowledgement Type of funding source: None

Dynamics of Parameters of Transmitral Blood Flow and Markers of Myocardial Fibrosis in Patients with Myocardial Infarction

Aim To study possible correlations between echocardiography (EchoCG) indexes and markers of myocardial fibrosis, procollagen I C-terminal propeptide (PICP) and procollagen III N-terminal propeptide (PIIINP) during one year following ST-segment elevation myocardial infarction (STEMI).Material and methods 120 patients with STEMI were evaluated. EchoCG was used to assess dimensions and volumes of heart chambers, left ventricular (LV) systolic function, mean pulmonary arterial pressure (mPAP), and indexes of LV diastolic function (Em, early diastolic lateral mitral annular velocity; e', peak early diastolic septal mitral annular velocity; E / e', ratio of peak early diastolic transmitral inflow velocity and mitral annular velocity -, Е / А, ratio of peak early and late transmitral inflow velocities; DT, deceleration time of LV early diastolic filling). EchoCG indexes and serum concentrations of PICP and PIIINP were determined at 1 (point 1) and 12 (point 2) days of disease and one year after STEMI (point 3). The sample was divided into two groups: group 1 (n=86; 71.7 %) included patients with a LV ejection fraction (EF) ≥50 % and group 2 (n=34; 28.3 %) consisted of patients with LV EF ≤49 %.Results At one year, the number of patients with signs of diastolic dysfunction increased by 10% in group 1 whereas myocardial systolic dysfunction worsened in both groups. LV EF decreased in 15 (17.4%) patients of group 1 and in 4 (11.8%) patients of group 2. Concentrations of PIIINP were correlated with Em, E / e', mPAP, PICP, e', and LV EF.Conclusion Direct correlations between PIIINP concentrations and Em, E / e', and mPAP were found in the group with LV EF ≥50 %. In the group with LV EF <50 %, correlations were observed between PICP concentrations, LV EF, and e'. Also, in this group, the increase in PIIINP was statistically more significant. These results indicate continuing formation of myocardial fibrosis in a year following MI, which may underlie progression of chronic heart failure.

In-hospital changes of echocardiographic parameters and their relationship with the procollagen I C-terminal propeptide in patients with myocardial infarction and preserved left ventricle systolic function

Aim. To study the changes of echocardiographic parameters and their relationship with the procollagen I C-terminal propeptide (PICP) during hospitalization of patients with ST-segment elevation myocardial infarction (STEMI) and preserved left ventricular (LV) systolic function.Material and methods. A total of 120 (100%) patients hospitalized with STEMI were examined. Upon admission, all patients underwent standard examinations to verify myocardial infarction (MI), including coronary angiography and, if necessary, coronary stent implantation. The mean values of LV ejection fraction (LVEF) were 40-49% in 3 patients (2,5%), <40% — in 31 patients (26%), LVEF was. We also analyzed patients with LVEF ≥50%, n=86 (71,6%); mean age was 57,8 years. During the hospitalization, all patients received standard therapy; on the 1st and 12th day of MI, the PICP levels in venous blood serum was determined by enzyme-linked immunosorbent assay. In order to compare PICP values, a control group of healthy volunteers n=20 (100%) was formed, which were comparable by gender and age. In this group, the concentration of PICP was 179,2 [163.5; 194.9] ng/ml.Results. By the 12th day, a significant decrease in the following parameters of the transmitral flow was revealed: DT (p=0,049), dE (0,012), Em (0,029), Em/ Am (p=0,000), Em/PICP (p=0,001). This indicates diastolic function deterioration. At the same time, by the end of hospitalization, systolic function deterioration was recorded in 15,1% of cases. Initially, a higher PICP on the 1st day relative to the control group tended to decrease the concentration by the 12th day, but the differences did not reach statistical significance (p=0,466). Correlation analysis showed a relationship between PICP and echocardiography (Tei index, p=0,026, and mitral annulus velocity, p=0,049).Conclusion. At the hospital stage of treatment of patients with STEMI and preserved LVEF, a negative changes of echocardiography parameters characterizing diastolic dysfunction was revealed. Positive correlation was established between the concentration of PICP with mitral annulus velocity and the Tei index, indicating an association between the myocardial fibrosis and diastolic dysfunction.

Relations between markers of cardiac remodelling and left ventricular collagen in an isoproterenol-induced heart damage model.

There is a great urgency of detecting and monitoring myocardial fibrosis in clinical practice with the aim to improve and personalize therapy against cardiac remodelling. Hence, the aim of this study was to describe alterations in and show potential correlations between the structural characteristics and the molecular and biochemical markers of cardiac remodelling on a model of isoproterenol-induced heart failure. Two groups of 3-month-old male Wistar rats (n = 8 per group) were sacrificed after four weeks of treatment: control (placebo), ISO (5 mg/kg/day intraperitoneally). Chronic ISO treatment led to heart failure (HF) characterized by significant reduction of systolic blood pressure (SBP) accompanied by an increase in left ventricular weight (LVW) along with increased collagen content in the LV. The collagen content correlated negatively with SBP (R = -0.776, P < 0.001) and positively with LVW (R = 0.796, P < 0.001), with Col1a1 (0.83; P < 0.001) and Acta2 (0.73; P < 0.01). Moreover, the mRNA expression of fibrotic remodelling indicator, i.e. TGF-β1 tended to increase, while the level of fibrinolysis markers (MCP-1, TIMP-2, MMP) were unchanged. The plasma markers of collagen, procollagen I C-terminal propeptide (PICP) was 37.34 ± 7.10 pg/mL in control and was reduced by 42% (P < 0.05) in the ISO group and procollagen III N-terminal propeptide (PIIINP) was 1216.7 ± 191.0 pg/mL in control and was decreased by 66% (P < 0.05) in the ISO group. Surprisingly, there was no positive correlation between plasma markers of collagen, i.e. PICP and PIIINP and collagen content or molecular markers of collagen. However, both PICP and PIIINP correlated with BW (R = 0.712, resp. 0.803, P < 0.001), which was significantly reduced (by 25%, P < 0.05) in the ISO group. In conclusion, we assume that the collagen content of the left ventricle does not need unavoidably correlate with plasma markers of collagen, which might be affected by confounding factors in heart failure, such as loss of body weight, presumably associated with a catabolic condition.

Additional Diagnostic Value of Growth Differentiation Factor-15 (GDF-15) to N-Terminal B-Type Natriuretic Peptide (NT-proBNP) in Patients with Different Stages of Heart Failure.

BackgroundGrowth differentiation factor-15 (GDF-15) is a promising biomarker of cardiac remodeling. The purpose of this study was to explore the diagnostic value of plasma GDF-15 levels in different stages of heart failure (HF) and to assess the relationship with ventricular remodeling.Material/MethodsWe enrolled 219 HF patients from the Department of Cardiology in Tianjin Union Medical Center as the HF group and 32 healthy subjects as the control group. Circulating GDF-15, NT-proBNP, procollagen I C-terminal propeptide (PICP), and N-terminal procollagen III propeptide (PIIINP) levels were measured using ELISA. Associations between GDF-15 and clinical indicators in cardiac remodeling were assessed using receiver operating characteristic (ROC) curves and Spearman correlation. All the patients were followed up for 1 year.ResultsThe level of plasma GDF-15 in HF patients was higher than in the control group (P<0.05) and increased with higher ACCF/AHA and NYHA classification (P<0.05). Patients with HFrEF had higher GDF-15 levels compared to patients with HFmrEF (P<0.05). GDF-15 and left ventricular mass index (LVMI) were significantly increased as early as the pre-clinical HF stage. Also, GDF-15 levels were positively correlated to LVMI (r=0.433, P<0.05), PICP (r=0.378, P<0.001) and PIIINP (r=0.382, P<0.001). ROC curves were constructed and GDF-15 plus NT-proBNP (AUC=0.905, 95%CI: 0.868–0.942, P<0.001) was superior to NT-proBNP (AUC=0.869, 95%CI: 0.825–0.913, P<0.001) in identifying HF. GDF-15 levels did not predict prognosis after a 1-year follow-up period.ConclusionsGDF-15 combined with NT-proBNP significantly improves the accuracy of diagnosing HF. Plasma GDF-15 levels can indirectly reflect the degree of cardiac remodeling and fibrosis.

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.

Identification of a mutation causing deficient BMP1/mTLD proteolytic activity in autosomal recessive osteogenesis imperfecta

Herein, we have studied a consanguineous Egyptian family with two children diagnosed with severe autosomal recessive osteogenesis imperfecta (AR-OI) and a large umbilical hernia. Homozygosity mapping in this family showed lack of linkage to any of the previously known AR-OI genes, but revealed a 10.27 MB homozygous region on chromosome 8p in the two affected sibs, which comprised the procollagen I C-terminal propeptide (PICP) endopeptidase gene BMP1. Mutation analysis identified both patients with a Phe249Leu homozygous missense change within the BMP1 protease domain involving a residue, which is conserved in all members of the astacin group of metalloproteases. Type I procollagen analysis in supernatants from cultured fibroblasts demonstrated abnormal PICP processing in patient-derived cells consistent with the mutation causing decreased BMP1 function. This was further confirmed by overexpressing wild type and mutant BMP1 longer isoform (mammalian Tolloid protein [mTLD]) in NIH3T3 fibroblasts and human primary fibroblasts. While overproduction of normal mTLD resulted in a large proportion of proα1(I) in the culture media being C-terminally processed, proα1(I) cleavage was not enhanced by an excess of the mutant protein, proving that the Phe249Leu mutation leads to a BMP1/mTLD protein with deficient PICP proteolytic activity. We conclude that BMP1 is an additional gene mutated in AR-OI.

Early Changes in Biochemical Markers of Bone Formation Correlate with Improvements in Bone Structure during Teriparatide Therapy

Biochemical markers of bone turnover may reflect bone structure during anabolic treatment. The objective was to evaluate associations between changes in biochemical markers and structural and dynamic bone parameters during teriparatide treatment. This study was a randomized, multicenter, double-blind, placebo-controlled fracture prevention trial, with 20-month median treatment duration for biopsy subset. The trial was conducted at 11 clinical study sites. Sixty-one postmenopausal women with osteoporosis who had paired transiliac biopsy specimens participated in the study. Once-daily sc injections of either placebo or teriparatide (20 or 40 microg) were administered. The study measured: 1) serum and urinary biochemical markers of bone formation [bone alkaline phosphatase and procollagen I C-terminal propeptide (PICP)] and resorption (N-telopeptide and deoxypyridinoline); and 2) structural and dynamic analyses of bone biopsies, including two-dimensional (2D) histomorphometry and three-dimensional (3D) micro-computed tomography evaluations measured at baseline (n = 57) and 12 (n = 21) or 22 (n = 36) months. U-N-telopeptide/creatinine and serum-PICP correlated with bone structure and dynamic indices at baseline, respectively. Changes in bone alkaline phosphatase at 1 month correlated with changes at 22 months in 2D wall thickness (r = 0.73; P = 0.001), trabecular bone volume (trabecular bone volume per total volume, BV/TV) (r = 0.58; P < 0.05), marrow star volume (r = -0.51; P = 0.05); 3D trabecular thickness (r = 0.49; P < 0.05), and BV/TV (r = 0.54; P < 0.05). Changes in PICP at 1 month correlated with changes in wall thickness (r = 0.60; P = 0.01), and 2D BV/TV (r = 0.51; P < 0.05) at 22 months. Changes in markers at 6 or 12 months were not associated with changes in structural or dynamic parameters. Early (1-month) changes in biochemical markers of bone formation, but not resorption, correlated with improvements in bone structure after 22 months of teriparatide therapy.

High prevalence of impaired glucose metabolism in patients with idiopathic dilated cardiomyopathy

ABSTRACTS- Cardiac Function and Heart Failure 181A 11:00 a.m. 854-3 Myocardial Collagen Turnover in Hypertrophic Cardlomyopathy: Comparison to Healthy Subjects R~ffaalla Lombardi, Sandro Betocchi, Maria Angela Losi, Quidno Ciampi, Cado G. Tocchefti, EIpidio Pszzella, Filippo Finizio, Mariano Aversa, Marianna Miranda, Veronica De Crescanzo, Massimo Chiariello, Department of Clinical Medicine, Cardivascular and Immunological Science, University of Naples, Naples, Italy. BACKGROUND LV hypertrophy and fibrosis are characteristics of hypertrophic cardi- omyopathy (HCM). We assessed the impact of collagen turnover on LV anatomy and function in HCM. METHODS We studied 29 HCM patients (36±9 years) and 10 age and sex-matched controls. We assessed cardiac fibrosis by RIA measurement of serum con- centrations of: procollagsn III N-terminal propeptide (PtilNP), index of collagen III synthe- sis; procollagen I C-terminal propeptide (PICP) and collagen I C-terminal telopeptide (ICTP), indexes of collagen I synthesis and degradation. They were In-transformed. LV hypertrophy was quantified by the Wigle's score. Diastolic function was evaluated by the duration difference in antegrada (mitral) and retrograde (pulmonary vein) A wave (Adiff). RESULTS PIIINP and ICTP were higher in HCM than in controls (1.3(.4) vs .9(.3) ng/ml, p=.002; 1.0(.4) vs .8(.2) ng/ml, p=.048) and inversely related to age in HCM (r=-.424, p=.022; r=-.651, p<.001). PICP and ICTP were directly related to one another (r=.395, p=.013). PtlINP was inversely related to LV end-diastolic dimension, while ICTP was directly related to Wigle's score (Figure). PIIINP and ICTP were inversely related to Adiff (r=-.393, p=.035; and r=-.584, p<.001). CONCLUSIONS In HCM patients collagen metabolism is more active than in controls and it decreases with age. Collagen I degra- dation parallels synthesis (steady state). Collagen turnover influences degree of hyper- trophy, cavity size and passive diastolic properties.

Reconstituting telomerase activity using the telomerase catalytic subunit prevents the telomere shorting and replicative senescence in human osteoblasts.

The rate of bone formation is largely determined by the number of osteoblasts, which in turn is determined by the rate of replication of progenitors and the life span of mature cells, reflecting the timing of death by apoptosis. However, the exact age-dependent changes of the cellular activity, replicative potential, and life span of osteoblasts have not been investigated to date. Here, we present evidence that the cellular activity, telomere lengths, and replicative life span of osteoblastic cells obtained from juxta-articular bone marrow gradually decrease with the advance of donor age. Recently, telomerase reverse transcriptase (hTERT) has been identified as a human telomerase catalytic subunit. We transfected the gene encoding hTERT into telomerase-negative human osteoblastic cells from donors and osteoblastic cell strain NHOst 54881 cells and showed that expression of hTERT induces telomerase activity in these osteoblastic cells. In contrast to telomerase-negative control cells, which exhibited telomere shortening and senescence after 10-15 population doublings, telomerase-expressing osteoblastic cells had elongated telomere lengths and showed continued alkaline phosphatase activity and procollagen I C-terminal propeptide (PICP) secretion for more than 30 population doublings. These results indicate that osteoblasts with forced expression of hTERT may be used in cell-based therapies such as ex vivo gene therapy, tissue engineering, and transplantation of osteoblasts to correct bone loss or osteopenia in age-related osteoporotic diseases.

Thyroid hormone treatment aiming at reduced, but not suppressed, serum thyroid‐stimulating hormone levels in nontoxic goitre: effects on bone metabolism amongst premenopausal women

To study the effects of six months' treatment with either T4 or T3, aiming at reduced but not totally suppressed serum TSH levels, as measured by a third generation TSH assay, on biochemical bone turnover parameters as well as bone mass in patients with nontoxic goitre. Prospective randomized study with a matched control group, not blinded. Two University Hospital Clinics in Copenhagen. Twenty-four consecutive premenopausal women with moderate sized nontoxic goitre. Fourteen patients randomized to T4 or T3 treatment for six months with monthly titration of the dose, aiming at TSH values between 0.005 and 0.2 mUL(-1). Ten controls. Serum parathyroid hormone (PTH), serum procollagen I C-terminal propeptide (PICP), serum alkaline phosphatase, serum osteocalcin, u-pyridinoline, u-deoxypyridinoline, u-hydroxyproline. Bone mass (BMD) at the lumbar spine and at both femoral necks. Serum TSH was generally kept within the desired interval. There was no difference in any marker of bone metabolism between the effects of T4 and T3. Consequently, these groups were combined in order to evaluate the effect of thyroid hormones on the bone and mineral metabolism. Thyroid hormone treatment resulted in increased levels of serum ionized calcium (Ca) (P=0.02), serum alkaline phosphatase (P=0.007), serum-PICP (P=0.003), serum osteocalcin (P=0.02) and urinary excretion of deoxypridinoline (P=0.03) compared to untreated controls. Bone mass did not change. Six months treatment with either T4 or T3 of premenopausal women with nontoxic goitre, aiming at reduced but not totally suppressed TSH values, resulted in biochemical signs of increased bone turnover, whereas bone mass remained unaltered. No differences were found between the effects of T4 or T3 treatment.

Serum concentrations of procollagen I C-terminal propeptide, osteocalcin and insulin-like growth factor-I in patients with non-lethal osteogenesis imperfecta.

Serum concentrations of procollagen I C-terminal propeptide (PICP) were studied in 74 patients with various forms of non-lethal osteogenesis imperfecta and 27 unaffected family members. Using the standard deviation (SD) score, PICP concentrations were found to be > or = -1 SD in 16%, between -1 and -2 SD in 26% and < or = -2 SD in 58% of the patients with osteogenesis imperfecta compared to healthy controls. PICP values were lowest in osteogenesis imperfecta type I (-2.4 +/- 0.4 SD, n = 37) followed by type III (-1.9 +/- 0.5 SD, n = 13) and type IV (-1.3 +/- 0.7 SD, n = 20). Four patients with osteogenesis imperfecta with an atypical clinical course had normal or even elevated levels which may indicate heterogeneity in the underlying primary defects. In osteogenesis imperfecta type I, PICP concentrations proved to be a helpful serum marker for pedigree screening. Osteocalcin was high in 25 of 28 patients with osteogenesis imperfecta in the first decade but only in 1 of 18 older patients. Insulin-like growth factor-I was within the normal range in 53 cases of osteogenesis imperfecta, decreased in 2 and elevated in 3 patients. We conclude that PICP concentration is a useful parameter in the clinical management of osteogenesis imperfecta, including the assessment of future therapeutic interventions.