Procollagen Type III N-terminal Propeptide Research Articles

Роль сывороточных маркеров в оценке состояния рубца на матке

Objective. To analyze the levels of serum fibrosis markers, procollagen type I N-terminal propeptide (PINP) and procollagen type III N-terminal propeptide (PIIINP), in relation to birth outcomes in patients with uterine scar after one previous cesarean section (CS). Patients and methods. This prospective study included 76 women with uterine scar after one previous CS. All patients had their PINP and PIIINP levels determined upon admission. Depending on birth outcomes, patients were divided into two groups: the study group consisted of 36 women who had spontaneous vaginal delivery without complications, and the comparison group was represented by 40 women who underwent unplanned cesarean delivery due to the development of complications. Results. Patients with successful birth outcomes in the presence of uterine scar had significantly lower levels of serum fibrosis markers: PINP reached 46.1 ng/mL and PIIINP – 2.6 μg/L, while in the comparison group, these values were 64.1 ng/mL and 4.2 μg/L, respectively. Such peculiarity of values may be associated with elevated expression of type I and III collagens. This mechanism provoked rapid fibrosis development, which was clinically manifested by uterine scar rupture during labor. Conclusion. Serum markers of fibrosis (PINP and PIIINP) are promising indicators for their further study as part of the problem of uterine scar assessment, but more observations are needed. For the conclusive evidence of their informativeness, it is important to perform immunohistochemical analysis of scar tissue samples with quantitative estimation of type I and III collagens and to compare these findings with peripheral blood values. Key words: uterine scar, connective tissue disorder, fibrosis, collagen, procollagen type I N-terminal propeptide, procollagen type III N-terminal propeptide

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 < 0.05), whereas serum PIIINP and galectin-3 were not (all p > 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.

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.

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.

Effects of spironolactone on serum markers of fibrosis in people at high risk of developing heart failure: rationale, design and baseline characteristics of a proof-of-concept, randomised, precision-medicine, prevention trial. The Heart OMics in AGing (HOMAGE) trial.

Asymptomatic patients with coronary artery disease (CAD), hypertension and/or type 2 diabetes mellitus (T2DM) are at greater risk of developing heart failure (HF). Fibrosis, leading to myocardial and vascular dysfunction, might be an important pathway of progression. The Heart OMics in AGing (HOMAGE) trial aims to investigate the effects of spironolactone on serum markers of collagen metabolism and on cardiovascular structure and function in people at risk of developing HF and potential interactions with a marker of fibrogenic activity, galectin-3. The HOMAGE trial is a prospective, randomised, open-label, blinded endpoint (PROBE) study comparing spironolactone (up to 50 mg/day) and standard care over 9 months in people with clinical risk factors for developing HF, including hypertension, CAD and T2DM, and elevated plasma concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP, 125 to 1000 ng/L) or B-type natriuretic peptide (BNP, 35 to 280 ng/L). Exclusion criteria included left ventricular ejection fraction < 45%, atrial fibrillation, severe renal dysfunction, or treatment with loop diuretics. The primary endpoint was the interaction between change in serum concentrations of procollagen type III N-terminal propeptide (PIIINP) and treatment with spironolactone according to median plasma concentrations of galectin-3 at baseline. For the 527 participants enrolled, median (interquartile range) age was 73 (69-79) years, 135 (26%) were women, 412 (78%) had hypertension, 377 (72%) CAD, and 212 (40%) T2DM. At baseline, medians (interquartile ranges) were for left ventricular ejection fraction 63 (58-67) %, for left atrial volume index 31 (26-37) mL/m2 , for plasma NT-proBNP 214 (137-356) ng/L, for serum PIIINP 3.9 (3.1-5.0) ng/mL, and for galectin-3 16.1 (13.5-19.7) ng/mL. The HOMAGE trial will provide insights on the effect of spironolactone on pathways that might drive progression to HF. ClinicalTrials.gov NCT02556450.

Collagen biomarkers are associated with decline in renal function independently of blood pressure and other cardiovascular risk factors: the Multi-Ethnic Study of Atherosclerosis Study.

We studied associations of circulating collagen type I carboxy-terminal telopeptide (ICTP) and procollagen type III N-terminal propeptide (PIIINP) with long-term renal function decline. In the Multi-Ethnic Study of Atherosclerosis, we included 2492 participants initially aged 45-84 years and free of clinical cardiovascular disease (CVD), excluding people with estimated glomerular filtration rate (eGFR) less than 60 ml/min per 1.73 m or urine albumin/creatinine (UAC) at least 30 mg/g. The primary outcome in median 9.4-year follow-up was renal function decline (≥30% decline in eGFR between any two exams or incident UAC ≥ 30 mg/g). The associations of baseline plasma ICTP and PIIINP with renal function decline were estimated using Poisson regression, adjusting for baseline variables race/ethnicity, sex, age, and continuous eGFR and UAC, with further adjustment for CVD risk factors and medications. Baseline serum ICTP was 3.27 ± 1.43 μg/l and PIIINP was 5.43 ± 1.85 μg/l. Mean baseline eGFR was 91.5 ± 18.4 ml/min per 1.73 m. Renal function decline occurred in 19.5% during 9.4-year follow-up. The renal function decline outcome was positively associated with serum ICTP and PIIINP: relative incidence density (95% confidence interval) per SD 1.22 (1.11-1.33) and 1.27 (1.16-1.40), respectively. Additional adjustment for other risk factors did not greatly alter findings. High collagen biomarker concentrations in serum were associated with future decline in renal function in people initially free of CVD and with normal eGFR, consistent with collagen production signaling renal decline. The continuous association observed for ICTP which, unlike PIIINP, is filtered by the kidney, may owe to its double status as a sensitive marker of glomerular function and collagen degradation.

Associations of Urine Biomarkers with Kidney Function Decline in HIV-Infected and Uninfected Men

Background: HIV-infected (HIV+) persons are at increased risk of chronic kidney disease, but serum creatinine does not detect early losses in kidney function. We hypothesized that urine biomarkers of kidney damage would be associated with subsequent changes in kidney function in a contemporary cohort of HIV+ and HIV-uninfected (HIV–) men. Methods: In the Multicenter AIDS Cohort Study, we measured baseline urine concentrations of 5 biomarkers from 2009 to 2011 in 860 HIV+ and 337 HIV– men: albumin, alpha-1-microglobulin (α1m), interleukin-18 (IL-18), kidney injury molecule-1 (KIM-1), and procollagen type III N-terminal propeptide (PIIINP). We evaluated associations of urine biomarker concentrations with annual changes in estimated glomerular filtration rate (eGFR) using multivariable linear mixed models adjusted for demographics, traditional kidney disease risk factors, HIV-related risk factors, and baseline eGFR. Results: Over a median follow-up of 4.8 years, the average annual eGFR decline was 1.42 mL/min/1.73 m²/year in HIV+ men and 1.22 mL/min/1.73 m²/year in HIV– men. Among HIV+ men, the highest vs. lowest tertiles of albumin (–1.78 mL/min/1.73 m²/year, 95% CI –3.47 to –0.09) and α1m (–2.43 mL/min/1.73 m²/year, 95% CI –4.14 to –0.73) were each associated with faster annual eGFR declines after multivariable adjustment. Among HIV– men, the highest vs. lowest tertile of α1m (–2.49 mL/min/1.73 m²/year, 95% CI –4.48 to –0.50) was independently associated with faster annual eGFR decline. Urine IL-18, KIM-1, and PIIINP showed no independent associations with eGFR decline, regardless of HIV serostatus. Conclusions: Among HIV+ men, higher urine albumin and α1m are associated with subsequent declines in kidney function, independent of eGFR.

Collagen biomarkers predict new onset of hypertension in normotensive participants: the Multi-Ethnic Study of Atherosclerosis.

Vascular remodeling associated with increased extracellular matrix (ECM) may precede hypertension. Procollagen type III N-terminal propeptide (PIIINP) and collagen type I carboxy-terminal telopeptide (ICTP) reflect collagen turnover and are important in ECM remodeling. PIIINP and ICTP are increased in cardiovascular diseases (CVD). We hypothesized that PIIINP and ICTP among normotensives predict incident hypertension. We included 1252 Multi-Ethnic Study of Atherosclerosis participants with mean age 58.1 ± 12.4 years, 48% men, free of overt CVD, having SBP and DBP less than 130/85 mmHg and not using any antihypertensive medication, and having plasma PIIINP and ICTP measurements, all assessed at baseline. We studied the association of baseline PIIINP and ICTP with the relative incidence density (RID) of incident hypertension, defined as SBP/DBP at least 140/90 mmHg, or antihypertensive therapy use during follow-up (four examinations over median 9.4 years). Baseline mean SBP/DBP was 110.9 ± 14.0/67.9 ± 10.4 mmHg. Mean concentration of PIIINP was 5.39 ± 1.95 μg/l and ICTP was 3.18 ± 1.39 μg/l. During follow-up visits, 35.9% of the participants developed hypertension. After adjustment for age, race, and sex there was a significant RID for new onset of hypertension of 1.16 (1.06, 1.28), P = 0.0017 for PIIINP and 1.20 (1.08,1.33) for ICTP, P = 0.0008. After additional adjustment for renal function, CVD risk factors and inflammatory variables, RID for new onset hypertension was 1.28 (1.15,1.42), P < 0.001 for PIIINP and 1.29 (1.15,1.44) for ICTP, P < 0.0001. Biomarkers of ECM remodeling predicted the development of hypertension in normotensive participants free of overt CVD.

The effect of anti-inflammatory and antifibrotic agents on fibroblasts obtained from arthrofibrotic tissue: An in vitro and in vivo study.

ObjectivesThe aims of this study were to determine whether the administration of anti-inflammatory and antifibrotic agents affect the proliferation, viability, and expression of markers involved in the fibrotic development of the fibroblasts obtained from arthrofibrotic tissue in vitro, and to evaluate the effect of the agents on arthrofibrosis prevention in vivo.MethodsDexamethasone, diclofenac, and decorin, in different concentrations, were employed to treat fibroblasts from arthrofibrotic tissue (AFib). Cell proliferation was measured by DNA quantitation, and viability was analyzed by Live/Dead staining. The levels of procollagen type I N-terminal propeptide (PINP) and procollagen type III N-terminal propeptide (PIIINP) were evaluated with enzyme-linked immunosorbent assay (ELISA) kits. In addition, the expressions of fibrotic markers were detected by real-time polymerase chain reaction (PCR). Fibroblasts isolated from healthy tissue (Fib) served as control. Further, a rabbit model of joint contracture was used to evaluate the antifibrotic effect of the three different agents.ResultsDexamethasone maintained the viability and promoted the proliferation of AFib. Diclofenac decreased the viability and inhibited the cell proliferation during the first week of cultivation. However, decorin inhibited AFib proliferation and downregulated the expressions of fibrotic markers. Additionally, decorin could improve the flexion contracture angle and inhibit the deposition of interstitial matrix components in the rabbit joint model.ConclusionDecorin decreased the expression of myofibroblast markers in AFib, inhibited the proliferation of AFib, and prevented the initial procedure of arthrofibrosis in vivo, suggesting that decorin could be a promising treatment to inhibit the development of arthrofibrosis.Cite this article: X. Tang, S. Teng, M. Petri, C. Krettek, C. Liu, M. Jagodzinski. The effect of anti-inflammatory and antifibrotic agents on fibroblasts obtained from arthrofibrotic tissue: An in vitro and in vivo study. Bone Joint Res 2018;7:213–222. DOI: 10.1302/2046-3758.73.BJR-2017-0219.R2.

Circulating matrix metalloproteinases and procollagen propeptides in inguinal hernia.

Degradation of collagen has been suggested involved in the pathogenesis of inguinal hernia. In this study, we aim to evaluate circulating biomarkers of procollagen type I N-terminal propeptide (PINP), procollagen type III N-terminal propeptide (PIIINP), matrix metalloproteinases (MMP)-2, MMP-9, copper and zinc in primary and recurrent inguinal hernia patients. This study included 110 inguinal hernia patients: 45 patients had primary indirect inguinal hernia, 40 patients had primary direct inguinal hernia, 15 patients had recurrent indirect inguinal hernia and 10 patients had recurrent direct inguinal hernia. Additional 45 patients operated for reasons other than hernia were included as a control group. All blood samples were obtained preoperatively. Circulating PINP, PIIINP, MMP-2 and MMP-9 were investigated using enzyme-linked immunoabsorbent assay (ELISA) methods, and copper and zinc were measured using an air acetylene flame atomic absorption spectrometer. Serum MMP-2 levels in patients with direct and recurrent inguinal hernias were significantly higher than controls. The ratios of PINP/PIIINP decreased more apparent in recurrent indirect or direct inguinal hernia group than primary indirect or direct inguinal hernia group. Based on receiver operating characteristic curve analysis, PINP/PIIINP can effectively diagnose recurrent inguinal hernia from primary inguinal hernia with area under the curve (AUC) of 0.919 for recurrent indirect inguinal hernia and 0.808 for recurrent direct inguinal hernia, respectively. The ratio of serum PINP/PIIINP was lower in patients with recurrent inguinal hernia, demonstrating more serious damage of collagen metabolism in these patients. Serologic ratio of PINP/PIIINP may be used to identify the presence of recurrent inguinal hernia in patients.

Valor pronóstico de los niveles de propéptido N-terminal del procolágeno tipos I y III asociados al remodelamiento ventricular en pacientes con insuficiencia cardiaca crónica

IntroductionHeart failure (HF) is the end-stage of many heart diseases. Although the changes in the composition of the extracellular matrix associated with the ventricular remodelling process have been described, neither the evolution nor the clinical impact of the myocardial fibrogenesis in patients with HF are completely understood. ObjectiveTo determine if the precursors of the synthesis and degradation of collagen are useful in the prediction of hospital admissions, death, or the need for a heart transplant in patients with chronic heart failure (CHF). MethodsA total of 204 patients with chronic heart failure were studied between the years 2015 and 2016, of whom 106 had ischaemic heart disease, and 98 had dilated cardiomyopathy. Measurements were made of the serum levels of noradrenaline, N-terminal pro–B-type natriuretic peptide, procollagen type I N-terminal propeptide, and procollagen type III N-terminal propeptide (PIIINP). The left ventricular volumes and ejection fraction were determined, as well a record made of the functional class and medical treatment. ResultsDuring follow-up, there were 55 hospital admissions, 7 deaths and 9 transplants. Age (p<0,001), PINP levels (p=0,04), PIIINP levels (p=0,016), and left ventricular volumes (p<0,05), were significantly higher in patients who achieved the primary outcome. In patients with severe dilation of the left ventricle (LV diastolic volume index, LVDVI > 110ml/m2, LV systolic volume index, LVTSVI > 50ml/m2), PIIINP levels > 6.2μg/L and a PINP > 40μg/L, were associated with a higher risk of hospital admission, death, or need of a transplant (event-free survival at 12 months: 45% versus 95%, p<0,0001). ConclusionsThe circulating levels of PINP and PIIINP are associated with left ventricular remodelling, and predict the outcomes in patients with chronic heart failure.

Effect of eplerenone on extracellular cardiac matrix biomarkers in patients with acute ST-elevation myocardial infarction without heart failure: insights from the randomized double-blind REMINDER Study.

Aldosterone stimulates cardiac collagen synthesis. Circulating biomarkers of collagen turnover provide a useful tool for the assessment of cardiac remodeling in patients with an acute myocardial infarction (MI). The REMINDER trial assessed the effect of eplerenone in patients with an acute ST-elevation Myocardial Infarction (STEMI) without known heart failure (HF), when initiated within 24h of symptom onset. The primary outcome was almost totally (>90%) driven by natriuretic peptide (NP) thresholds after 1-month post-MI (it also included a composite of cardiovascular death or re-hospitalization or new onset HF or sustained ventricular tachycardia or fibrillation or LVEF≤40% after 1-month post-MI). This secondary analysis aims to assess the extracellular matrix marker (ECMM) levels with regards to: (1) patients` characteristics; (2) determinants; (3) and eplerenone effect. Serum levels of ECMM were measured in 526 (52%) of the 1012 patients enrolled in the REMINDER trial. Patients with procollagen type III N-terminal propeptide (PIIINP) above the median were older and had worse renal function (p<0.05). Worse renal function was associated with increased levels of PIIINP (standardized β≈0.20, p<0.05). Eplerenone reduced PIIINP when the levels of this biomarker were above the median of 3.9ng/mL (0.13±1.48 vs. -0.37±1.56ng/mL, p=0.008). Higher levels of PIIINP were independently associated with higher proportion of NP above the prespecified thresholds (HR=1.95, 95% CI 1.16-3.29, p=0.012). Eplerenone effectively reduces PIIINP levels when baseline values were above the median. Eplerenone may limit ECMM formation in post-MI without HF.

Collagen Turnover Markers in Relation to Future Cardiovascular and Noncardiovascular Disease: The Multi-Ethnic Study of Atherosclerosis.

Sustained remodeling of extracellular matrix can compromise organs and tissues. Procollagen type III N-terminal propeptide (PIIINP) and collagen type I carboxy-terminal telopeptide (ICTP) reflect collagen synthesis and degradation. We studied their predictive value for future death and disease. A total of 3068 men and women in the Multi-Ethnic Study of Atherosclerosis who were free of cardiovascular disease (CVD) and in generally good health had a baseline blood sample taken for ICTP and PIIINP. Median follow-up was 13.0 years. Among 4 primary outcomes, CVD events (n = 697) were adjudicated, death (n = 571) was by death certificate, and chronic inflammatory-related severe hospitalization and death (ChrIRD, n = 726) and total cancer (n = 327) were classified using International Classification of Diseases codes. We used Poisson regression to study baseline ICTP and PIIINP relative to these outcomes. Mean (SD) PIIINP was 5.47 (1.95) μg/L and ICTP was 3.37 (1.70) μg/L. PIIINP and ICTP were highly correlated with each other and with estimated glomerular filtration rate (eGFR). Adjustment for age and eGFR attenuated relative risks, remaining 20%-30% per SD of both PIIINP and ICTP in prediction for total death and ChrIRD, and of PIIINP for cancer, with little additional attenuation by adjusting for risk factors and inflammatory biomarkers. CVD outcome was generally unrelated to PIIINP but became marginally inversely related to ICTP in the most adjusted model. The collagen biomarkers PIIINP and ICTP, in part through pathophysiologically parallel associations with renal function, predicted ChrIRD and total death. Moreover, PIIINP predicted future cancer. These collagen markers may help differentiate healthy from unhealthy aging.

Abstract 12899: Predictive Value of Markers of Collagen Turnover for Systolic and Diastolic Heart Failure: The MESA Study

Introduction: Markers of collagen turnover have prognostic value in heart failure (HF), but the predictive value of these markers for incident heart failure in asymptomatic subjects is unknown. Hypothesis: Collagen turnover markers (Procollagen Type III N-Terminal Propeptide (PIIINP) and Collagen Type I Carboxy-Terminal Telopeptide (ICTP)) may be associated with new onset of HF (total, systolic and diastolic HF) in subjects free of overt cardiovascular disease (CVD) at baseline. Methods: We used a nested case-control design in a multi-ethnic sample of 3147 subject initially aged 45-84 years and free of CVD. We assayed baseline serum PIIINP and ICTP concentrations using radio-immunoassay. Incident HF (n=196) was based on medical records through a median 12.1 years of follow-up. Systolic HF (HFrEF) was defined if ejection fraction (EF) &lt; 45 % and diastolic HF (HFpEF) if EF ≥ 45%. Poisson regressions were calculated using 2 models, adjusting for 1. Demographics (demog.) and estimated glomerular filtration (eGFrR) because ICTP is cleared by the kidney; 2. Model 1 + classical cardiovascular risk factors, and blood pressure and cholesterol lowering medication. Results: Mean (SD) ICTP was 3.38 ± 1.77 μg/L and Mean (SD) PIIINP was 5.48 ± 2.04 μg/L. Among 196 new HF cases, 95 were systolic HF (HFrEF) and 86 were diastolic HF (HFpEF); the 15 HF cases with no ejection fraction recorded were omitted from subtype analysis. In Poisson regression during 12.1 year follow-up (Table 1), Model 1 associations of ICTP and PIIINP with total HF and HFpEF were substantially attenuated in Model 2, although PIINP remained significantly associated with HFpEF. Conclusion: PIIINP as a marker of collagen turnover is predictive for incident HFpEF, in initially asymptomatic subjects free of overt cardiovascular disease, independently of classical cardiovascular risk factors.

Association of HIV infection with biomarkers of kidney injury and fibrosis in the Multicenter AIDS Cohort Study.

Chronic kidney disease (CKD) is common among HIV-infected individuals but serum creatinine is insensitive for detecting kidney damage at early stages. We hypothesized that HIV infection would be associated with elevations in subclinical markers of kidney injury and fibrosis in a contemporary cohort of men. In this cross-sectional study, we measured urine levels of interleukin-18 (IL-18), kidney injury molecule-1 (KIM-1), pro-collagen type III N-terminal pro-peptide (PIIINP) and albumin-creatinine ratio (ACR) in 813 HIV-infected and 331 uninfected men enrolled in the Multicenter AIDS Cohort Study. Median eGFR was 95 ml/min/1.73 m2 among African-Americans (n=376) and 87 ml/min/1.73 m2 among Caucasians (n=768). Among HIV-infected men, the median CD4 lymphocyte count was 572 cells/mm3 and 76% of men had undetectable HIV RNA levels. After multivariable adjustment for traditional CKD risk factors including eGFR, HIV infection was associated with 52% higher urine IL-18 (95% CI, 33%, 73%), 44% higher KIM-1 (27%, 64%), 30% higher PIIINP (15%, 47%) and 84% higher ACR (54%, 120%), with similar effect sizes among African-Americans and Caucasians (P>0.2 for tests of interaction by race). These associations remained statistically significant in analyses that excluded persons with detectable HIV RNA levels and in models that adjusted for cumulative exposure to tenofovir disoproxil fumarate. Compared with uninfected men, HIV-infected men had more extensive glomerular and tubulointerstitial damage, as assessed by urine biomarkers. Future studies should evaluate whether combinations of biomarkers can be used to monitor stages of kidney injury and to predict CKD risk in HIV-infected individuals.

Procollagen markers in microdialysate can predict patient outcome after Achilles tendon rupture

ObjectivePatients who sustain acute Achilles tendon rupture (ATR) exhibit variable and mostly impaired long-term functional, and patient-reported outcomes. However, there exists a lack of early predictive markers of long-term outcomes...

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.

Fibrosis markers, hip fracture risk, and bone density in older adults.

We examined whether blood levels of two markers of fibrosis (transforming growth factor beta one (TGF-β1) and procollagen type III N-terminal propeptide (PIIINP)) are related to hip fracture risk and to bone mineral density (BMD). TGF-β1 levels were associated with lower hip fracture risk in women and with lower BMD in men. PIIINP levels were not associated with either outcome. TGF-β1 serves several roles in bone formation and resorption. A consequence of TGF-β1 activation is the production of PIIINP, a marker of collagen III deposition. Here, we explore whether these two biomarkers are related to incident hip fracture and bone mineral density (BMD) and whether their associations are modified by systemic inflammation, as measured by C-reactive protein (CRP) levels. Participants were from the Cardiovascular Health Study (mean age 78years; mean follow-up 8.3years). We included 1681 persons with measured levels of TGF-β1 (149 hip fractures) and 3226 persons with measured levels of PIIINP (310 hip fractures). Among women, higher TGF-β1 levels were associated with lower hip fracture risk (HR, per doubling, 0.78 [95% CI 0.61, 0.91]). Among men, TGF-β1 levels were associated with hip fracture risk in a non-linear manner, but among those with elevated CRP levels, doubling was associated with increased risk of fracture (HR 2.22 [1.20, 4.08]) (p = 0.02, interaction between low and high CRP and TGF-β1 on fracture risk). TGF-β1 levels had no significant association with total hip or total body BMD in women but were significantly associated with lower BMD in men. There were no associations of PIIINP levels with hip fracture risk or BMD in men or women. TGF-β1 levels appear to be associated with bone-related phenotypes in a sex-specific manner. The reasons for these differences between men and women regarding TGF-β1 levels and hip fracture risk and bone density require further investigation.

Associations between metabolic dysregulation and circulating biomarkers of fibrosis: the Cardiovascular Health Study

AimFibrosis is one postulated pathway by which diabetes produces cardiac and other systemic complications. Our aim was to determine which metabolic parameters are associated with circulating fibrosis-related biomarkers transforming growth factor-β (TGF-β) and procollagen type III N-terminal propeptide (PIIINP). MethodsWe used linear regression to determine the cross-sectional associations of diverse metabolic parameters, including fasting glucose, fasting insulin, body mass index, fatty acid binding protein 4, and non-esterified fatty acids, with circulating levels of TGF-β (n = 1559) and PIIINP (n = 3024) among community-living older adults in the Cardiovascular Health Study. ResultsAmong the main metabolic parameters we examined, only fasting glucose was associated with TGF-β (P = 0.03). In contrast, multiple metabolic parameters were associated with PIIINP, including fasting insulin, body mass index, and non-esterified fatty acids (P<0.001, P<0.001, P=0.001, respectively). These associations remained statistically significant after mutual adjustment, except the association between BMI and PIIINP. ConclusionsIsolated hyperglycemia is associated with higher serum concentrations of TGF-β, while a broader phenotype of insulin resistance is associated with higher serum PIIINP. Whether simultaneous pharmacologic targeting of these two metabolic phenotypes can synergistically reduce the risk of cardiac and other manifestations of fibrosis remains to be determined.