Procollagen Type I C-terminal Propeptide Research Articles

Proteomic profiles of left atrial volume and its influence on response to spironolactone: Findings from the HOMAGE trial and STANISLAS cohort.

High left ventricular filling pressure increases left atrial volume and causes myocardial fibrosis, which may decrease with spironolactone. We studied clinical and proteomic characteristics associated with left atrial volume indexed by body surface area (LAVi), and whether LAVi influences the response to spironolactone on biomarker expression and clinical variables. In the HOMAGE trial, where people at risk of heart failure were randomized to spironolactone or control, we analysed 421 participants with available LAVi and 276 proteomic measurements (Olink) at baseline, month 1 and 9 (mean age 73 ± 6 years; women 26%; LAVi 32 ± 9 ml/m2). Circulating proteins associated with LAVi were also assessed in asymptomatic individuals from a population-based cohort (STANISLAS; n = 1640; mean age 49 ± 14 years; women 51%; LAVi 23 ± 7 ml/m2). In both studies, greater LAVi was significantly associated with greater left ventricular masses and volumes. In HOMAGE, after adjustment and correction for multiple testing, greater LAVi was associated with higher concentrations of matrix metallopeptidase-2 (MMP-2), insulin-like growth factor binding protein-2 (IGFBP-2) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) (false discovery rates [FDR] <0.05). These associations were externally replicated in STANISLAS (all FDR <0.05). Among these biomarkers, spironolactone decreased concentrations of MMP-2 and NT-proBNP, regardless of baseline LAVi (pinteraction > 0.10). Spironolactone also significantly reduced LAVi, improved left ventricular ejection fraction, lowered E/e', blood pressure and serum procollagen type I C-terminal propeptide (PICP) concentration, a collagen synthesis marker, regardless of baseline LAVi (pinteraction > 0.10). In individuals without heart failure, LAVi was associated with MMP-2, IGFBP-2 and NT-proBNP. Spironolactone reduced these biomarker concentrations as well as LAVi and PICP, irrespective of left atrial size.

Correlation between Serum Myosin Light Chain 4 Levels and Recurrence after Radiofrequency Ablation in Patients with Atrial Fibrillation.

Atrial fibrillation (AF) is the most common arrhythmia that is harmful to human health. This study aims to explore the relationship between myosin light chain 4 (MYL4) and AF recurrence after radiofrequency ablation (RFA). Patients with AF (n = 85) were enrolled, and healthy subjects (n = 90) with normal sinus rhythm and no previous history of AF were selected as controls. The serum levels of MYL4, transforming growth factor (TGF) -β1, and procollagen type-I C-terminal propeptide (PICP) were determined. The correlation between MYL4 and atrial fibrosis remodeling indicators (TGF-β1/PICP) and left atrial diameter (LAD) was analyzed. The influence of MYL4 on AF recurrence after RFA was evaluated, and the independent correlation between them was assessed. Patients with AF and the controls showed no significant differences in age, gender, body mass index, systolic blood pressure, diastolic blood pressure, left ventricular ejection fraction, triglycerides, total cholesterol, high-density lipoprotein, low-density lipoprotein, white blood cell count, neutrophil/lymphocyte ratio, brain natriuretic peptide, and history of smoking, drinking, hypertension, and diabetes (P > 0.05), but with increased LAD in patients with AF (P < 0.01). Serum MYL4 level was reduced in patients with AF (0.6 ± 0.2) compared with that of controls (0.1 ± 0.6) (P < 0.01), and it was negatively correlated with TGF-β1, PICP, and LAD (r = -0.2389, P < 0.05; r = -0.5174, P < 0.01; r = -0.3191; P < 0.01). Low levels of MYL4 increased the risk of AF recurrence after RFA (χ2 = 16.64; P < 0.0001). A low MYL4 level in patients with AF showed a poorer prognosis. Serum MYL4 level and AF type were independent risk factors affecting AF recurrence after RFA.

Biomarkers for Prostate Cancer Bone Metastasis Detection and Prediction.

Prostate cancer (PCa) causes deaths worldwide, ranking second after lung cancer. Bone metastasis (BM) frequently results from advanced PCa, affecting approximately 90% of patients, and it also often results in severe skeletal-related events. Traditional diagnostic methods for bone metastases, such as tissue biopsies and imaging, have substantial drawbacks. This article summarizes the significance of biomarkers in PCa accompanied with BM, including (1) bone formation markers like osteopontin (OPN), pro-collagen type I C-terminal pro-peptide (PICP), osteoprotegerin (OPG), pro-collagen type I N-terminal pro-peptide (PINP), alkaline phosphatase (ALP), and osteocalcin (OC); (2) bone resorption markers, including C-telopeptide of type I collagen (CTx), N-telopeptide of type I collagen (NTx), bone sialoprotein (BSP), tartrate-resistant acid phosphatase (TRACP), deoxypyridinoline (D-PYD), pyridoxine (PYD), and C-terminal pyridinoline cross-linked telopeptide of type I collagen (ICTP); (3) prostate-specific antigen (PSA); (4) neuroendocrine markers, such as chromogranin A (CgA), neuron-specific enolase (NSE), and pro-gastrin releasing peptide (ProGRP); (5) liquid biopsy markers, such as circulating tumor cells (CTCs), microRNA (miRNA), circulating tumor DNA (ctDNA), and cell-free DNA (cfDNA) and exosomes. In summary, some of these markers are already in widespread clinical use, while others still require further laboratory or clinical studies to validate their value for clinical application.

Delayed inhibition of collagen deposition by targeting bone morphogenetic protein 1 promotes recovery after spinal cord injury.

Fibrotic scars appear after spinal cord injury (SCI) and are mainly composed of fibroblasts and excess extracellular matrix (ECM), including different types of collagen. The temporal and spatial distribution and role of excess collagens and ECM after SCI are not yet fully understood. Here, we identified that the procollagen type I C-terminal propeptide (PICP), a marker of collagen type I deposition, and bone morphogenetic protein 1 (BMP1), a secreted procollagen c-proteinase (PCP) for type I collagen maturation, were significantly elevatedin cerebrospinal fluid of patients with SCI compared with healthy controls, and were associated with spinal cord compression and neurological symptoms. We revealed the deposition of type I collagen in the area damaged by SCI in mice and confirmed that BMP1 was the only expressed PCP and induced collagen deposition. Furthermore, transforming growth factor-β (TGF-β), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) can activate the expression of BMP1. However, inhibition of BMP1 at the acute phase eliminated fibrotic scars in the damaged area and inhibited activation and enrichment of astrocytes, which made the damage difficult to repair and increased hematoma. Unexpectedly, knockdown of Bmp1 by adeno-associated virus or the inhibition of BMP1 biological function by specific inhibitors and monoclonal antibodies at different time points after injury led to distinct therapeutic effects. Only delayed inhibition of BMP1 improved axonal regeneration and myelin repair at the subacute stage post-injury, and led to the recovery of motor function, suggesting that scarring had a dual effect. Early inhibition of the scarring was not conducive to limiting inflammation, while excessive scar formation inhibited the growth of axons. After SCI, the collagen deposition indicators increased in both human cerebrospinal fluid and mouse spinal cord. Therefore, suppression of BMP1 during the subacute phase improves nerve function after SCI and is a potential target for scar reduction.

Serum biomarkers and left ventricular mechanics in the diagnosis of diastolic dysfunction in patients with epicardial obesity

Highlights. Patients with epicardial obesity develop myocardial fibrosis (the underlying mechanism of left ventricular diastolic dysfunction) the preclinical diagnosis of which is difficult to perform. In this regard, the search for non-invasive methods for diagnosing diastolic dysfunction at an early stage, including the methods of determining the serum level of biomarkers of heart failure and studying the parameters of left ventricular mechanics using speckle-tracking echocardiography, seems quite relevant.Background. Currently, the search for serum biomarkers and non-invasive methods for diagnosing diastolic dysfunction (DD) of the left ventricle (LV) at the preclinical stage in obese patients is relevant.Aim. To study the levels of heart failure biomarkers and their association with profibrotic factors and LV mechanics in patients depending on the presence of epicardial obesity (EO).Methods. Out of 143 men with general obesity, depending on the severity of EO, determined by the thickness of epicardial adipose tissue (tEАT), 2 groups of patients were identified: the EO (+) group with tEАT 7 mm or more (n = 70), and the EO (–) group with tEАT less than 7 mm (n = 40). The exclusion criteria from the study were: arterial hypertension, type 2 diabetes mellitus, coronary artery disease, and the presence of LVDD detected by echocardiography (echo). Levels of profibrotic factors (type I and type III collagen, procollagen type I C-terminal propeptide (PICP), matrix metalloproteinase-3 (MMP-3), transforming growth factor-β (TGF-β), vascular endothelial growth factor A (VEGF-A), sST2, and NT-proBNP were determined in all patients using enzyme immunoassay. With the help of speckle-tracking echocardiography, the mechanics of LV were analyzed.Results. The EO (+) group presented with increased sST2 level (22.11±7.36 ng/mL) compared to the EO (–) group (sST2 level 9.79±3.14 ng/mL (p&lt;0.0001). In the EO (+) group, a significant influence of tEAT on sST2 level was identified (F = 8.57; p = 0.005). In the EO (+) group, an increase in the level of MMP-3, type I collagen, type III collagen, PICP, transforming growth factor-β, and VEGF-A was revealed. Moreover, in the EO (+) group, a statistically significant relationship between sST2 and type III collagen was revealed (p = 0.01). When comparing the parameters of speckle-tracking echo, the EO group (+) presented with increased LV untwisting rate of –128.31 (–142.0; –118.0) deg/s-1 (p = 0.002), and increased time to LV peak untwisting rate of – 476.44 (510.0; 411.0) msec compared with the EO group (–) (p = 0.03). Moreover, a significant association between LV untwisting rate and sST2 level was revealed in the EO (+) group (r = 0.35; p = 0.02).&gt;˂0.0001). In the EO (+) group, a significant influence of tEAT on sST2 level was identified (F = 8.57; p = 0.005). In the EO (+) group, an increase in the level of MMP-3, type I collagen, type III collagen, PICP, transforming growth factor-β, and VEGF-A was revealed. Moreover, in the EO (+) group, a statistically significant relationship between sST2 and type III collagen was revealed (p = 0.01). When comparing the parameters of speckle-tracking echo, the EO group (+) presented with increased LV untwisting rate of –128.31 (–142.0; –118.0) deg/s-1 (p = 0.002), and increased time to LV peak untwisting rate of – 476.44 (510.0; 411.0) msec compared with the EO group (–) (p = 0.03). Moreover, a significant association between LV untwisting rate and sST2 level was revealed in the EO (+) group (r = 0.35; p = 0.02).Conclusion. The data obtained indicate that patients with EO have LVDD, which could not be detected using echo criteria for LVDD, and the determination of serum levels of the heart failure biomarker - sST2 can be used for the diagnosis of LVDD at the early stage.

Levels of Procollagen Type I C-Terminal Pro-Peptide and Galectin-3, Arterial Stiffness Measured By Pulse Wave Velocity, and Cardiovascular Morbidity and Mortality in 44 Patients 2 Years After Kidney Transplantation.

BACKGROUND Cardiovascular (CV) mortality remains high despite the improvement of kidney function after kidney transplantation. In heart failure (HF), high concentrations of biomarkers of fibrosis, related to cardiac and/or vascular impairment, are associated with CV outcomes, but their significance in kidney transplantation is still unclear. Our aim was to investigate the association of procollagen type I C-terminal pro-peptide (PICP) and galectin-3 (Gal-3), markers of fibrosis, with arterial stiffness measured by pulse wave velocity (PWV) and CV morbi-mortality in kidney transplantation recipients from the prospective monocenter TRANSARTE study (Transplantation and Arteries), which compared the evolution of arterial stiffness in transplanted patients and patients remained on dialysis. MATERIAL AND METHODS PICP and Gal-3 were measured at 2 years after transplantation in 44 kidney transplantation patients. Spearman's rank-order correlation analysis was conducted to assess the relationship between biomarkers and PWV. Association of biomarkers with CV morbi-mortality was evaluated using Cox regression analysis adjusted for age, renal function, and PWV. RESULTS There was no significant correlation between PWV and PICP (r=-0.16, P=0.3) or Gal-3 (r=0.03, P=0.85). Gal-3, after adjusting for key prognostic factors, including PWV, was significantly associated with CV morbi-mortality [HR (95% CI)=4.30 (1.01-18.22), P=0.048], whereas PICP was not significantly associated with outcome. CONCLUSIONS In multivariable adjusted analysis, elevated Gal-3 concentrations were associated with CV morbi-mortality in kidney transplantation patients, whereas PICP was not. As Gal-3 was not related to PWV, other sources of fibrosis (eg, cardiac fibrosis) may be underlying the prognostic value of Gal-3 in kidney transplantation.

The association between markers of type I collagen synthesis and echocardiographic response to spironolactone in patients at risk of heart failure: findings from the HOMAGE trial.

Procollagen type I C-terminal propeptide (PICP) and procollagen type III N-terminal propeptide (PIIINP) are markers reflecting collagen synthesis in cardiac fibrosis. However, they may be influenced by the presence of non-cardiac comorbidities (e.g. ageing, obesity, renal impairment). Understanding the associations between markers of collagen synthesis and abnormalities of cardiac structure and function is important to screen for myocardial fibrosis and monitor the antifibrotic effect of medications. The HOMAGE (Heart 'OMics' in AGEing) trial showed that spironolactone decreased serum PICP concentrations and improved cardiac remodelling over 9 months in a population at risk of developing heart failure (HF). We evaluated the associations between echocardiographic variables, PICP, PIIINP and galectin-3 at baseline and during the course of the trial. Among 527 individuals (74 ± 7 years, 26% women), median serum concentrations of PICP, PIIINP and galectin-3 were 80.6 μg/L (65.1-97.0), 3.9 μg/L (3.1-5.0), and 16.1 μg/L (13.5-19.7), respectively. After adjustment for potential confounders, higher serum PICP was significantly associated with left ventricular hypertrophy, left atrial enlargement, and greater ventricular stiffness (all p &lt; 0.05), whereas serum PIIINP and galectin-3 were not (all p &gt; 0.05). In patients treated with spironolactone, a reduction in serum PICP during the trial was associated with a decrease in E/e' (adjusted-beta = 0.93, 95% confidence interval 0.14-1.73; p = 0.022). In individuals at high risk of developing HF, serum PICP was associated with cardiac structural and functional abnormalities, and a decrease in PICP with spironolactone was correlated with improved diastolic dysfunction as assessed by E/e'. In contrast, no such associations were present for serum PIIINP and galectin-3.

Abstract 12139: Substance P Replacement Reduces Cardiac Fibrosis in Monkeys With Type 2 Diabetes

Introduction: Type 2 diabetes mellitus (T2DM)-associated cardiac fibrosis contributes to heart failure, especially in women. We have data showing that diabetic mice with cardiomyopathy, including cardiac fibrosis, exhibit low levels of the neuropeptide substance P (SP); and SP replacement reverses cardiac fibrosis, independent of body weight and blood glucose. To understand the potential translational significance of these findings, we sought to determine in a T2DM monkey model if replacement SP could reverse cardiac magnetic resonance (CMR) imaging and circulating markers of fibrosis, while also assessing safety of administration. Methods: Female T2DM African Green monkeys were randomized to receive SP (n=4, 0.5 mg/Kg/day S.Q. injection) or vehicle (n=3) for 10 weeks. We obtained CMR imaging and blood samples to assess left ventricular (LV) function and fibrosis by T1 map-derived extracellular volume (ECV) and circulating procollagen type I C-terminal propeptide (PICP). Hematological parameters for toxicities were also assessed. We performed a blinded paired analysis of all parameters. Results: Monkeys receiving replacement SP exhibited a decrease in ECV (Pre: 31.6 ± 5.53% vs. Post: 25.2 ± 3.3%, p=0.03), concomitant with decreased PICP levels (Pre: 5148.58 ± 1143.5 ng/mL vs. Post: 3851.1 ± 1377.5 ng/mL, p=0.01). Animals receiving vehicle showed no changes in ECV (p=0.32) or PICP (p=0.16). No changes in LV ejection fraction were observed (p=0.89). Complete blood counts, metabolic panel (ΔA1c, SP: -0.45 ± 0.59 % vs vehicle: -0.53 ± 0.61 %, p=0.43), lipids, liver and pancreatic enzymes, and inflammation markers were unchanged (p&gt;0.05 for all). Conclusion: Replacement SP reversed cardiac fibrosis in a large preclinical model of T2DM, independent of glycemic control. No organ-related toxicity was associated with replacement SP. These results strongly support a potential application for replacement SP as an antifibrotic therapy for diabetic cardiac fibrosis.

Attenuation of Myocardial Fibrosis Using Molecular Hydrogen by Inhibiting the TGF-β Signaling Pathway in Spontaneous Hypertensive Rats.

Previous studies have shown that hydrogen can antagonize the fibrosis of various organs. We investigated whether hydrogen-rich saline (HRS) can attenuate myocardial fibrosis in spontaneously hypertensive rats (SHRs) and clarified the mechanisms involved. We examined the effect of HRS and pirfenidone (PFD) on myocardial fibrosis in SHR. Systolic blood pressure, left ventricular mass index (LVMI), and heart weight index (HWI) were measured, Masson trichrome staining was performed. We assessed the role of superoxide dismutase (SOD), malondialdehyde (MDA), Alpha-smooth muscle actin (α-SMA), collagen I, collagen III, and tissue inhibitors of metalloproteinases (TIMPs) in myocardium. We detected the concentrations of procollagen type-I C-terminal propeptide (PICP), procollagen type-III N-terminal propeptide (PIIINP), and angiotensin II (Ang II) in rat serum. Furthermore, the relative protein levels of the transforming growth factor beta (TGF-β)/Smad pathway were tested. We discovered that HRS decreases LVMI (P < 0.05) and HWI (P < 0.05) in vivo. Compared with model group, HRS decreases the level of collagen volume fraction (P < 0.0001), collagen I (P < 0.001), and collagen III (P < 0.001) in myocardium, and Ang II (P < 0.05), PICP (P < 0.001), and PIIINP (P < 0.05) in serum. In addition, HRS downregulates the expression of MDA (P < 0.01), α-SMA (P < 0.05), and TIMPs (P < 0.05), and increased SOD (P < 0.05). Furthermore, HRS downregulated the expression levels of TGF-β1 (P < 0.0001), Smad3 (P < 0.0001), and Smad2/3 (P < 0.001), but had no effect on Smad7 expression (P > 0.05). PFD had similar effect compared with HRS and control group. HRS reduced oxidative stress and improved myocardial collagen content, which may be related to inhibition of the TGF-β signaling pathway. This suggests that HRS is an effective therapeutic strategy for myocardial fibrosis.

Serum markers of cardiac fibrosis suffering from heart failure with preserved left ventricular ejection fraction upon ST-segment elevation myocardial infarction

Aim. Currently, there is no method which accurately predicts an adverse outcome of heart failure with a preserved left ventricular ejection fraction (HFpEF) upon ST-segment elevation myocardial infarction (STEMI). Here we studied the prognostic significance of procollagen type I C-terminal propeptide (PICP) and procollagen type III N-terminal propeptide (PIIINP) in patients with post-STEMI HFpEF.Material and Methods. The study included 83 patients (60 men and 23 women) with post-STEMI HFpEF (left ventricular EF ≥ 50%) and 20 ageand gender-matched healthy controls. Serum concentrations of PICP and PIIINP were measured on the 1st day of hospitalization using enzyme-linked immunosorbent assay with the following calculation of PICP/PIIINP ratio.Results. Serum PICP and PIIINP on the 1st day of STEMI significantly (3.4-fold) exceeded the values of the control group and were as follows: PIIINP: 26.0 (18.9; 34.9) ng/mL (р = 0.047); PICP: 609.0 (583.0; 635.0) ng/mL (р = 0.049).Conclusion. Elevated values of procollagens indicate that cardiac fibrosis commences within the 24 hours after STEMI onset. The pivotal role of cardiac fibrosis in the formation of diastolic dysfunction suggests the usefulness of serum procollagens to predict the development of HFpEF in a long-term period upon STEMI.

Uncoupling of Bone Turnover may Compromise Skeletal Health of Young Patients With Haemophilia A

There is evidence that bone mass is decreased and bone metabolism is dysregulated in children with haemophilia (CWH). The objective of this study was to investigate the impact of haemophilia on skeletal health in children, with regards to bone mineral density (BMD) and metabolic bone profile. This study included 51 male CWH A. Dual-energy X-ray absorptiometry (DXA) was performed to assess BMD in lumbar spine (LS) and total body less head (TBLH) and Z-scores were calculated (low BMD Z-score<-2, low-normal BMD Z-score between -1 and -2). Serum levels of osteocalcin (OC), procollagen type I C-terminal propeptide (PICP), bone alkaline phosphatase (bALP), bone tartrate-resistant acid phosphatase 5b (TRAP5b), vitamin D, parathormone (PTH), urinary calcium/creatinine (uCa/uCr) and urine deoxypyridinoline/creatinine (uDPD/uCr) were measured. Mean BMD Z-scores were lower than predicted at both sites of measurement. More specifically, 10% of CWH A had low and 20% low-normal BMD Z-scores in LS, whereas 9.1% had low-normal TBLH BMD Z-scores and there were no patients with low BMD Z-scores at this site of measurement. 36.7% of CWH had low vitamin D levels and 19.6% had a history of fracture. Also, patients with haemophilia had lower OC and higher uDPD/uCr levels while OC positively correlated to BMD Z-scores and uDPD/uCr negatively correlated to BMD Z-scores at both sites. No statistically significant differences were observed with regards to mode of treatment, number of haemorrhages and the presence of target-joints. CWH A had decreased BMD Z-scores at both sites with an uncoupling of bone turnover LS BMD seemed to be more affected than TBLH BMD.

Serum markers of fibrosis, cardiovascular and all-cause mortality in hemodialysis patients: the AURORA trial

BackgroundBiomarkers of fibrosis are associated with outcome in several cardiovascular diseases. However, their relevance to chronic kidney disease and dialysis is uncertain, as it remains unclear how the kidneys and the dialysis procedure itself affect their elimination and degradation. We aimed to investigate the relationship of the blood levels of two markers associated with fibrosis: procollagen type I C-terminal pro-peptide (PICP) and galectin-3 (Gal-3) with mortality in dialysis patients.MethodsProcollagen type I C-terminal pro-peptide and galectin-3 were measured at baseline in 2773 patients enrolled in the AURORA trial, investigating the effect of rosuvastatin on cardiovascular outcomes, in patients on hemodialysis, and their interaction with CV death or all-cause mortality using survival models. The added prognostic value of these biomarkers was assessed by the net reclassification improvement (NRI).ResultsThe median follow-up period was 3.8 years. Blood concentrations of PICP and Gal-3 were significantly associated with CV death [adjusted HR per 1 SD = 1.11 (1.02–1.20) and SD = 1.20 (1.10–1.31), respectively] and all-cause mortality (all adjusted p < 0.001). PICP and Gal-3 had a synergistic effect with regard to CV death and all-cause mortality (interaction p = 0.04 and 0.01, respectively). Adding PICP, Gal-3 and their interaction on top of clinical and biological covariates, resulted in significantly improved prognostic accuracy NRI = 0.080 (0.019–0.143) for CV death.ConclusionIn dialysis patients, concomitant increase in PICP and Gal-3 concentrations are associated with higher rates of CV death. These results suggest that concomitantly raised PICP and Gal-3 may reflect an activated fibrogenesis relevant to risk stratification in dialysis, raising the hypothesis that anti-fibrotic therapy may be beneficial for cardiovascular protection in such patients.Graphic abstract

The effect of spironolactone on cardiovascular function and markers of fibrosis in people at increased risk of developing heart failure: the heart 'OMics' in AGEing (HOMAGE) randomized clinical trial.

Aims To investigate the effects of spironolactone on fibrosis and cardiac function in people at increased risk of developing heart failure.Methods and results Randomized, open-label, blinded-endpoint trial comparing spironolactone (50 mg/day) or control for up to 9 months in people with, or at high risk of, coronary disease and raised plasma B-type natriuretic peptides. The primary endpoint was the interaction between baseline serum galectin-3 and changes in serum procollagen type-III N-terminal pro-peptide (PIIINP) in participants assigned to spironolactone or control. Procollagen type-I C-terminal pro-peptide (PICP) and collagen type-1 C-terminal telopeptide (CITP), reflecting synthesis and degradation of type-I collagen, were also measured. In 527 participants (median age 73 years, 26% women), changes in PIIINP were similar for spironolactone and control [mean difference (mdiff): −0.15; 95% confidence interval (CI) −0.44 to 0.15 μg/L; P = 0.32] but those receiving spironolactone had greater reductions in PICP (mdiff: −8.1; 95% CI −11.9 to −4.3 μg/L; P < 0.0001) and PICP/CITP ratio (mdiff: −2.9; 95% CI −4.3 to −1.5; <0.0001). No interactions with serum galectin were observed. Systolic blood pressure (mdiff: −10; 95% CI −13 to −7 mmHg; P < 0.0001), left atrial volume (mdiff: −1; 95% CI −2 to 0 mL/m2; P = 0.010), and NT-proBNP (mdiff: −57; 95% CI −81 to −33 ng/L; P < 0.0001) were reduced in those assigned spironolactone.Conclusions Galectin-3 did not identify greater reductions in serum concentrations of collagen biomarkers in response to spironolactone. However, spironolactone may influence type-I collagen metabolism. Whether spironolactone can delay or prevent progression to symptomatic heart failure should be investigated.

Molecular biomarker profile of heart failure with mid-range and preserved ejection fraction in patients with type 2 diabetes

Aim. To study molecular biomarkers in patients with type 2 diabetes (T2D) in combination with heart failure with preserved (HFpEF) and mid-range ejection fraction (HFmrEF) and compare the data obtained with clinical characteristics of myocardial remodeling.Material and methods. The study included 42 patients with T2D (men — 53%, mean age — 60 years) with clinical manifestations of class II HF: 29 patients with HFpEF (group 1) and 13 patients with HFmrEF (group 2). The control group consisted of 13 healthy people, which were comparable in sex and age and had a normal body mass index (BMI). Patients received stable glucose-lowering and optimal drug therapy for HF for 3 months prior to enrollment in the study. Patients with HFpEF and HFmrEF were comparable in clinical and demographic parameters, had glycated hemoglobin (HbA ) of 8,5% and 8,8%, respectively (p&gt;0,05), increased BMI or grade I-II obesity.We studied following biomarkers: NT-proBNP, highly sensitive C-reactive protein (hsCRP), sST2, galectin-3, procollagen type I C-terminal propeptide (PICP), matrix metalloproteinase 9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1).Results. Volumetric parameters of the left ventricle (LV),LV mass indexed to growth and NT-proBNP were higher in the group of HFpEF patients (p&lt;0,05 for all). The concentrations of galectin-3, PICP were higher, and the MMP-9/TIMP-1 ratio decreased in patients with T2D compared with the control group (p&lt;0,05 for all). PICP values were higher in patients with HFmrEF compared with patients with HFpEF (106,4 (85,4; 140,4) ng/ml vs 46,8 (12,6; 98,6 ng/ml), respectively, p=0,043). In patients with T2D and HF, a relationship was found between TIMP-1 andLV end-diastolic volume (r=-0,68; p=0,042).Conclusion. Patients with HFmrEF and T2D have higherLV volume and mass, higher concentrations of NT-proBNP and PICP in comparison with patients with HFpEF. The direction of MMP-9/TIMP-1 changes may reflect a decrease in antifibrotic processes. Further prospective studies on large samples using a multiple biomarker model are required in T2D and various HF phenotypes.

High fibrosis indices in cerebrospinal fluid of patients with shunt-dependent post-traumatic chronic hydrocephalus.

ObjectiveA possible relationship between fibrosis along the route of cerebrospinal fluid (CSF) flow and the subsequent development of hydrocephalus has been indicated in previous studies. These changes in the fibrosis index may reflect the severity of hydrocephalus and could potentially become a diagnostic tool. The object of this study was to analyze the levels of procollagen type I C-terminal propeptide (PICP), procollagen type III N-terminal propeptide (PIIINP), hyaluronic acid (HA), and laminin (LN) in the CSF of patients with post-traumatic hydrocephalus and determine the significance of their presence.Subjects and methodsForty-four patients were included in the study: 24 patients with shunt-dependent post-traumatic hydrocephalus (group A - hydrocephalus group); ten brain trauma patients without any sign of hydrocephalus (group B - trauma group); ten patients without brain trauma and hydrocephalus (group C - normal control group). CSF levels of PICP, PIIINP, HA, LN and transforming growth factor-β1(TGF-β1) were detected using enzyme-linked immunosorbent assay (ELISA).ResultsLevels of PICP, PIIINP, HA, and LN in the group of hydrocephalus patients were significantly higher than those in the post-trauma patients without hydrocephalus (p < 0.05) and normal control patients (p < 0.05). Moreover, the increased levels of PICP, PIIINP, HA, and LN were positively correlated with the level of TGF-β1 (p < 0.05).ConclusionWe demonstrated an increase of fibrosis factors including PICP, PIIINP, HA, and LN, that was positively correlated with TGF-β1 levels. This indicates an important role for the process of fibrosis in the development of post-traumatic chronic hydrocephalus and shows the potential utility of PICP, PIIINP, HA, and LN as a diagnostic index in shunt-dependent post-traumatic chronic hydrocephalus.

Procollagen Type I C-terminal propeptide, procollagen Type III N-terminal propeptide, hyaluronic acid, and laminin in the cerebrospinal fluid of rats with communicating hydrocephalus

Fibrosis along the route of CSF flow is indicated by the development of hydrocephalus. The changes of fibrosis index might reflect the level of hydrocephalus and even become a diagnostic index of hydrocephalus. The object of this study was to analyze the levels of procollagen Type I C-terminal propeptide (PICP), procollagen Type III N-terminal propeptide (PIIINP), hyaluronic acid (HA), and laminin (LN) and their significance in the CSF of communicating hydrocephalus rat models. Thirty adult Sprague-Dawley rats were randomly divided into 3 groups: hydrocephalus group (20 rats) with intraventricular kaolin injections, sham control group (5 rats) with saline injections, and normal group (5 rats) without any processing. The levels of PICP, PIIINP, HA, and LN in the CSF were detected using ELISA. Levels of PICP, PIIINP, HA, and LN in the hydrocephalus group were significantly higher than those in the saline control group (p < 0.05). It was revealed by correlation analysis that the increase was positively correlated with the severity of ventricular dilation. Results indicated that PICP, PIIINP, HA, and LN continue to rise dramatically in experimental hydrocephalus and may serve as the diagnostic index of hydrocephalus.

Fibrosis and cardiac function in obesity: a randomised controlled trial of aldosterone blockade

ObjectivesAs myocardial fibrosis might be an important contributor to the association of obesity with left ventricular (LV) dysfunction and heart failure, we investigated the effects of spironolactone on LV function...

Abstract 17678: The Correlation Between Collagen Degradation and LV Function Following Induction of Beta-Blocker Therapy

Objectives: Beta-blocker therapy inhibits LV remodeling, and improves not only LV systolic function but also LV diastolic function, and improves prognosis of heart failure patients. But it is unknown why beta-blocker therapy improves LV function. Recently, serum collagen markers such as Procollagen type I C-terminal propeptide (PICP) and collagen type I C-terminal telopeptide (CITP), are useful as index of myocardium collagen synthesis and degradation. We investigate correlation between collagen turnover and LV function following induction of beta-blocker therapy with systolic heart failure patients. Methods: Study population consisted of 46 patients with systolic heart failure. Patients were clinically stable within 1 month and on stable medical therapy, including ACEI or ARB and diuretics, and no beta-blocker therapy. We started beta-blocker therapy, initiated at a target dose of from 5 to 10mg/day. Echocardiography was performed before, 2, 6, and 12 months after the initiation of beta-blocker therapy. LV systolic function was estimated using the LV ejection fraction by Simpson biplane method. Peak systolic strain in the radial direction was measured at the anterior and posterior walls in the short-axis view. We measured E- and A-wave peak velocities and deceleration time (DcT) form the mitral inflow profile, and tissue Doppler early diastolic mitral annular velocity (E'). Serum PICP and CITP were determined. Results (table): A total of 46 patients were enrolled. The median age of all patients was 56±14 years. 15 patients were women and 31 patients were men. EF, DcT and E' were improved after induction of beta-blocker therapy. PICP was not changed, but CITP was decreased from 8.9±7.8 to 6.1±1.7ng/ml at 12 months after treatment. The lower %changes in CITP was associated with the higher %changes in DcT (r=0.21, p&lt;0.05), EF (r=0.29, p&lt;0.01) and radial systolic strain (r=0.26, p&lt;0.05), but not E'. The %changes in PICP were not related %changes in DcT and E'. Conclusions: The improvement in LV systolic function as indexes in EF and radial systolic strain and LV diastolic stiffness as indexes in DcT, correlated with inhibition of collagen degradation in patients with LV systolic function.

Abstract 4890: Myocardial Fibrosis and Diastolic Dysfunction Following Calcium-Channel Blockers or Angiotensin II Receptor Blockers in Hypertensive Patients

Objectives : Myocardial fibrosis develops in the hypertensive heart, and brings about LV diastolic dysfunction. Myocardial fibrosis is regulated by collagen production and degradation. Collagen degradation is regulated by matrix metalloproteinases (MMPs), a family of zinc-dependent interstitial enzymes, and their tissue inhibitors (TIMPs). We investigated how long-term administration of calcium-channel blockers (CCB) or Angiotensin II receptor blockers (ARB) affects collagen production/degradation and LV diastolic dysfunction. Methods : Study population consisted of 44 untreated hypertensive patients (31 females, 13 males, mean age:57±11 years). They were randomly assigned to one of the 2 groups: CCB group in which Amlodipine of 5–10mg was given daily (n=22) and ARB group in which Losartan of 50–100mg was given daily (n=22). LV mass index (LVMI) and tissue Doppler early diastolic mitral annular velocity (E′) were echocardiographically assessed before and 6 and 12 months after treatment. Procollagen type I C-terminal propeptide (PICP) was determined with enzyme immunoassay as a serum marker of collagen production, while MMP-2 and TIMP-1 were determined with ELISA as makers of collagen degradation. Results (table ): E′ increased in the ARB group but not in the CCB group while reductions in blood pressure (BP) and LVMI were comparable between the group. PICP did not change after treatment in either group, but MMP-2 increased only in the ARB group. TIMP-1 did not change in either group. Conclusions : In spite of similar reduction of SBP and LVMI, ARB provided larger benefits on LV diastolic function than CCB. Collagen production was constant in both groups, but ARB facilitated more collagen degradation than CCB, and the difference should have contributed to the impact on LV diastolic function.

Changes in Biochemical Markers after Lower Limb Fractures

The bone remodeling sequence after bone fracture changes the concentrations of biochemical bone markers, but the relationships of fracture size and of healing time to changes in biomarkers are unclear. The present pilot study was undertaken to determine the changes found in serum bone markers after plate osteosynthesis of closed distal tibial and malleolar fractures during a study period of 24 weeks. We measured tatrate-resistant acid phosphatase (TRACP 5b), collagen type I C-terminal telopeptide (ICTP), bone-specific alkaline phosphatase (bone ALP), osteocalcin (OC), procollagen type I C-terminal propeptide (PICP), procollagen type III N-terminal propeptide (PIIINP), and human cartilage glycoprotein 39 (YKL-40) in 20 patients with lower limb fractures (10 malleolar, 10 tibia). A physical examination and radiographs were completed to assess evidence of union. All malleolar fractures healed within 6 weeks, whereas 2 tibial fractures did not show complete bone healing after 24 weeks. Changes were comparable but more pronounced in the tibia group, and marker concentrations remained increased at the end of study (bone ALP, 86 vs 74 U/L; OC, 14.9 vs 7.7 microg/L; ICTP: 5.6 vs 3.3 microg/L at day 84 after osteosynthesis, P <0.05 in tibia; 80 vs 70 U/L, 8 vs 5.2 microg/L, and 3.5 vs 3.2 microg/L, respectively, in the malleolar fracture group). In normal bone healing, changes in bone turnover markers were primarily dependent on the fracture size. Delayed tibia fracture healing may involve a disturbance in bone remodeling.