Collagen Turnover In Patients Research Articles

Effects of empagliflozin on collagen biomarkers in patients with heart failure: Findings from the EMPEROR trials.

Extracellular matrix remodelling is one of the key pathways involved in heart failure (HF) progression. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) may have a role in attenuating myocardial fibrosis. The impact of SGLT2i on blood markers of collagen turnover in humans is not fully elucidated. This study aimed to investigate the effect of empagliflozin on serum markers of collagen turnover in patients enrolled in the EMPEROR-Preserved and EMPEROR-Reduced trials. Overall, 1084 patients (545 in empagliflozin and 539 in placebo) were included in the analysis. Procollagen type I carboxy-terminal propeptide (PICP), a fragment of N-terminal type III collagen (PRO-C3), procollagen type I amino-terminal peptide (PINP), a fragment of C-terminal type VIa3 collagen (PRO-C6), a fragment of type I collagen (C1M), and a fragment of type III collagen (C3M) were measured in serum at baseline, 12 and 52 weeks. A mixed model repeated measurements model was used to evaluate the effect of empagliflozin versus placebo on the analysed biomarkers. Higher baseline PICP, PRO-C6 and PINP levels were associated with older age, a more severe HF presentation, higher levels of natriuretic peptides and high-sensitivity troponin T, and the presence of comorbid conditions such as chronic kidney disease and atrial fibrillation. Higher PICP levels were associated with the occurrence of the study primary endpoint (a composite of HF hospitalization or cardiovascular death), and PRO-C6 and PINP were associated with the occurrence of sustained worsening of kidney function. On the other hand, PRO-C3, C1M, and C3M were not associated with worse HF severity or study outcomes. Compared to placebo, empagliflozin reduced PICP at week 12 by 5% and at week 52 by 8% (week 12: geometric mean ratio = 0.95, 95% confidence interval [CI] 0.91-0.99, p = 0.012; week 52: geometric mean ratio = 0.92, 95% CI 0.88-0.97, p = 0.003). Additionally, empagliflozin reduced PRO-C3 at week 52 by 7% (week 12: geometric mean ratio = 0.98, 95% CI 0.95-1.02, p = 0.42; week 52: geometric mean ratio = 0.93, 95% CI 0.89-0.98, p = 0.003), without impact on other collagen markers. Our observations are consistent with experimental observations that empagliflozin down-regulates profibrotic signalling. The importance of such an effect for the clinical benefits of SGLT2i in HF remains to be elucidated.

FRI210 - Aldafermin rebalances collagen turnover in patients with NASH and liver fibrosis in the ALPINE 2/3 study

FRI210 - Aldafermin rebalances collagen turnover in patients with NASH and liver fibrosis in the ALPINE 2/3 study

Biomarkers of Inflammation, Thrombogenesis, and Collagen Turnover in Patients With Atrial Fibrillation.

The purpose of this study was to determine whether there are any differences in the levels of inflammatory, thrombotic, and collagen turnover biomarkers between individuals with atrial fibrillation (AF) and healthy volunteers. Circulating plasma levels of plasminogen activator inhibitor 1 (PAI-1), CD40-ligand (CD40-L), nucleosomes (which are indicators of cell death), C-reactive protein (CRP), procollagen III N-terminal propeptide (PIIINP), procollagen III C-terminal propeptide (PIIICP), procollagen I N-terminal propeptide, tissue plasminogen activator, and von Willebrand factor were analyzed as potential biomarkers of AF. Baseline plasma was collected from patients with AF prior to ablation surgery at Loyola University Medical Center. Individuals with AF had statistically significantly increased levels of PAI-1, CD40-L, and nucleosomes, when compared to the normal population (P < .0001). Additionally, there was a statistically significant increase in the CRP (P = .01), PIIINP (P = .04), and PIIICP (P = .0008) when compared to normal individuals. From this study, it is concluded that the prothrombotic, inflammatory, and collagen turnover biomarkers PAI-1, CD40-L, nucleosomes, CRP, PIIICP, and PIIINP are elevated in AF.

Abdominal wall hernias—A local manifestation of systemically impaired quality of the extracellular matrix

Throughout life, inguinal hernia develops in approximately every fourth man, some of whom develop multiple hernias. If patients at risk of developing multiple hernias could be identified by a serologic biomarker, treatment might be able to be tailored and improved. Evidence suggests that abdominal wall hernia formation is associated with altered collagen metabolism. The aim of this study was to evaluate biomarkers for type IV and V collagen turnover in patients with multiple hernias and control subjects without hernia. Venous blood was collected from 88 men (mean age, 62years) with a history of more than 3 hernia repairs and 86, age-matched men without hernias. Biomarkers for synthesis of collagen type IV (P4NP) and type V (P5CP) as well as breakdown (C4M and C5M) were measured in serum by validated, solid-phase, competitive assays. Collagen turnover was indicated by the ratio between the biomarker for synthesis and breakdown. Type IV collagen turnover was 1.4-fold increased in patients with multiple hernias compared to control subjects (P<.001), whereas type V collagen turnover was 1.7-fold decreased (P<.001). Diagnostic power of P5CP was 0.83 (95%C.I.:0.77-0.89), P<.001. Patients with multiple hernias exhibit increased turnover of type IV collagen and a decreased turnover of type V collagen, demonstrating systemically altered collagen turnover. Biomarkers for type V collagen turnover may be used to identify patients at risk for or with multiple hernias.

Assessment of the correlation between serum prolidase and alpha-fetoprotein levels in patients with hepatocellular carcinoma.

To determine the predictive value of increased prolidase activity that reflects increased collagen turnover in patients with hepatocellular carcinoma (HCC). Sixty-eight patients with HCC (mean age of 69.1 ± 10.1), 31 cirrhosis patients (mean age of 59.3 ± 6.3) and 33 healthy volunteers (mean age of 51.4 ± 12.6) were enrolled in this study. Univariate and multivariate analysis were used to evaluate the association of serum α-fetoprotein (AFP) values with HCC clinicopathological features, such as tumor size, number and presence of vascular and macrovascular invasion. The patients with HCC were divided into groups according to tumor size, number and presence of vascular invasion (diameters; ≤ 3 cm, 3-5 cm and ≥ 5 cm, number; 1, 2 and ≥ 3, macrovascular invasion; yes/no). Barcelona-clinic liver cancer (BCLC) criteria were used to stage HCC patients. Serum samples for measurement of prolidase and alpha-fetoprotein levels were kept at -80 °C until use. Prolidase levels were measured spectrophotometrically and AFP concentrations were determined by a chemiluminescence immunometric commercial diagnostic assay. In patients with HCC, prolidase and AFP values were evaluated according to tumor size, number, presence of macrovascular invasion and BCLC staging classification. Prolidase values were significantly higher in patients with HCC compared with controls (P < 0.001). Prolidase levels were significantly associated with tumor size and number (P < 0.001, P = 0.002, respectively). Prolidase levels also differed in patients in terms of BCLC staging classification (P < 0.001). Furthermore the prolidase levels in HCC patients showed a significant difference compared with patients with cirrhosis (P < 0.001). In HCC patients grouped according to tumor size, number and BCLC staging classification, AFP values differed separately (P = 0.032, P = 0.038, P = 0.015, respectively). In patients with HCC, there was a significant correlation (r = 0.616; P < 0.001) between prolidase and AFP values in terms of tumor size, number and BCLC staging classification, whereas the presence of macrovascular invasion did not show a positive association with serum prolidase and AFP levels. Considering the levels of both serum prolidase and AFP could contribute to the early diagnosing of hepatocellular carcinoma.

The N-terminal propeptide of type III procollagen in patients with acute coronary syndrome: a link between left ventricular end-diastolic pressure and cardiovascular events.

BackgroundDespite the usefulness of N-terminal propeptide of type III procollagen (PIIINP) in detecting enhanced collagen turnover in patients with congestive heart failure, the value added by PIIINP to the use of clinical variables and echocardiography in relation to directly measured left ventricular (LV) end-diastolic pressure (EDP) and the outcome of acute coronary syndrome (ACS) has not been clearly defined.Methods and ResultsThis study involved 168 adult patients with ACS, who underwent echocardiography, measurement of serum PIIINP levels, and cardiac catheterization. Pulsed wave tissue Doppler imaging (PWTDI), which revealed mean peak systolic (s′), early (e′), and late diastolic (a′) velocities, was carried out and the eas index of LV function was evaluated: e′/(a′×s′). The patients were divided into three study groups based on the degree of LVEDP – normal (<16 mmHg), intermediate (16–30 mmHg), and high (>30 mmHg) LVEDP. All patients were followed-up to determine cardiac-related death and revascularization. Patients with high LVEDP had significantly more PIIINP than those with intermediate or normal LVEDP (all post hoc p<0.05). The presence of coronary artery disease, the left atrial volume index (LAVI), the ratio of transmitral early and late diastolic flow velocities, a′, and the eas index were significantly correlated with LVEDP. According to multiple stepwise analysis, PIIINP, LAVI and the eas index were the three independent predictors of the level of LVEDP (PIIINP, p <0.001; LAVI, p = 0.007; eas index, p = 0.021). During follow-up (median, 24 months), 32 participants suffered from cardiac events, PIIINP and LAVI were significant predictors of cardiac mortality and hospitalization (PIIINP, hazard ratio (HR) 2.589, p = 0.002; LAVI, HR 1.040, p = 0.027).ConclusionsPIIINP is a highly effective means to evaluate LVEDP in patients with ACS. The PIIINP is also correlated with cardiac mortality and revascularization, providing an additional means of evaluating and managing patients with ACS.

POSTER PRESENTATIONS

POSTER PRESENTATIONS

The Impact of Catheter Ablation on Biochemical Markers of Collagen Turnover in Patients with Persistent Atrial Fibrillation

Background: Previous study reported that biochemical markers of collagen turnover, such as transforming growth factor beta 1 (TGFβ-1), matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), reflected the fibrosis of atrium in patients with atrial fibrillation (AF). Left atrium (LA) volume could be reduced by catheter ablation (CA) for AF, but the effect of CA on atrial fibrosis remains unknown. We investigated the impact of CA on LA volume and atrial fibrosis by assessing such biochemical markers. Methods and Results: Study population consisted of 16 patients underwent CA to persistent AF. We determined LA volumes by 64-row multidetector CT, and measured 3 biochemical markers (TGFβ-1, MMP-1 and TIMP)-1 before, 3 months, and >12 months after CA. At baseline, plasma TGFβ-1 level was significantly correlated with end-diastolic (LAEDV; r=0.762, ρ=0.0003) and end-systolic LA volumes (LAESV; γ=0.743, ρ=0.0006). CA significantly decreased LAEDV by 25±13% and LAESV by 41±15%. Though TGFβ-1 levels (17.8±10.4, 23.1±12.9, 21.9±14.7 ng/ml) and TIMP-1 levels (129.1±36.4, 161.3±50.4, 146.9±25.2 ng/ml) didn’t change significantly after CA, MMP-1 levels (6.2±5.6, 5.9±4.5, 7.9±6.8 ng/ml) significantly increased in chronic phase (ρ=0.015). Conclusions: The plasma TGFβ-1 level, which is a marker of inflammation, was significantly correlated with enlarged LA in patients with persistent AF. Sinus conversion by CA reduced LA volume, and increased serum MMP-1 level, suggesting recovery from atrial remodeling and fibrosis.

Insulin resistance due to statin therapy: A potential contributor to the negation of statin-induced beneficial effects on cardiac remodelling in heart failure?

In their recently published article (a sub-study of UNIVERSE), Ashton E et al. explored potential adverse effects of rosuvastatin including effects on plasma coenzym Q10 (CoQ) levels and collagen turnover in patients with chronic heart failure (CHF) [1], and tried to explain why high dose rosuvastatin failed to improve cardiac remodelling in CHF in the UNIVERSE study [2]. I agree with the authors that increased collagen turnover and decreased plasma CoQ levels due to rosuvastatin therapy might have negatively influenced cardiac remodelling [1].

Natural History of Markers of Collagen Turnover in Patients With Early Diastolic Dysfunction and Impact of Eplerenone

This study was designed to evaluate the impact of eplerenone on collagen turnover in preserved systolic function heart failure (HFPSF). Despite growing interest in abnormal collagen metabolism as a feature of HFPSF with diastolic dysfunction, the natural history of markers of collagen turnover and the impact of selective aldosterone antagonism on this natural history remains unknown. We evaluated 44 patients with HFPSF, randomly assigned to control (n = 20) or eplerenone 25 mg daily (n = 24) for 6 months, increased to 50 mg daily from 6 to 12 months. Serum markers of collagen turnover and inflammation were analyzed at baseline and at 6 and 12 months and included pro-collagen type-I and -III aminoterminal peptides, matrix metalloproteinase type-2, interleukin-6 and -8, and tumor necrosis factor-alpha. Doppler-echocardiographic assessment of diastolic filling indexes and tissue Doppler analyses were also obtained. The mean age of the patients was 80 +/- 7.8 years; 46% were male; 64% were receiving an angiotensin-converting enzyme inhibitor, 34% an angiotensin-II receptor blocker, and 68% were receiving beta-blocker therapy. Pro-collagen type-III and -I aminoterminal peptides, matrix metalloproteinase type-2, interleukin-6 and -8, and tumor necrosis factor-alpha increased with time in the control group. Eplerenone treatment had no significant impact on any biomarker at 6 months but attenuated the increase in pro-collagen type-III aminoterminal peptide at 12 months (p = 0.006). Eplerenone therapy was associated with modest effects on diastolic function without any impact on clinical variables or brain natriuretic peptide. This study demonstrates progressive increases in markers of collagen turnover and inflammation in HFPSF with diastolic dysfunction. Despite high background utilization of renin-angiotensin-aldosterone modulators, eplerenone therapy prevents a progressive increase in pro-collagen type-III aminoterminal peptide and may have a role in management of this disease. (The Effect of Eplerenone and Atorvastatin on Markers of Collagen Turnover in Diastolic Heart Failure; NCT00505336).

Different estrogen sensitivity of urogenital tissue from women with and without stress urinary incontinence

Oral hormone replacement therapy (HRT) based on estradiol-17beta (E2), E2 esters or conjugated equine estrogens gives rise to huge amounts of circulating estrone (E1) as a result of the first liver pass. E1 is an estrogen (ER) receptor agonist but has also been reported to act as a partial E2 antagonist in vitro. Our aim was to investigate the influence of circulating estrogens on estrogen sensitivity of urogenital tissue collagen turnover in patients with stress urinary incontinence (SUI) and in urologically healthy women, with and without HRT, in view of possible effects of E1 as a partial E2 antagonist. Markers of collagen turnover, the carboxy-terminal propeptide of type I procollagen (PICP), the carboxy-terminal telopeptide of type I collagen (ICTP) and the amino-terminal propeptide of procollagen III (PIIINP) were assayed in urogenital tissue homogenates and E1 and E2 were analyzed in serum from 54 patients with SUI and 29 urologically healthy women. In the total control group only a significant positive correlation was found between E2 and T-PICP. Lowering the upper serum E1 limit resulted in significant positive correlations also between E2 and T-PIIINP and finally also between E2 and T-ICTP. This pattern was found also in subgroups of post- and premenopausal controls. No association between serum E2 and collagen turnover markers and no effects of lowering the upper serum E1 limit was found in the total and postmenopausal SUI patients, while the correlation pattern in premenopausal SUI patients showed some resemblance to that in the controls. At physiological E1 levels E2 increases collagen turnover in urogenital tissue in urologically healthy women but not in women with SUI in general; however, there was a certain effect of E2 in premenopausal but not in postmenopausal SUI patients. Urogenital tissue in SUI patients and in urologically healthy women may differ in estrogen sensitivty and in SUI patients this difference may be related to menopause. Circulating E1, which is present in huge amounts during oral HRT, may act as an estrogen receptor agonist as well as a partial E2 antagonist also in humans in vivo.

Increased Myocardial Collagen Turnover in Patients with Progressive Cardiac Conduction Disease

Histopathologically, progressive cardiac conduction disease (PCCD) is characterized by progressive fibrosis and sclerodegenerative changes in the proximal and distal conduction system of the heart. Therefore, we sought to determine the serum levels of myocardial collagen turnover markers, extracellular matrix components, transforming growth factor beta(1) (TGFbeta(1)), and bone morphogenic protein-7 (BMP-7) in this population. Study population included 20 patients (6 M/14 F, mean age 76 +/- 8 years) with acquired, permanent 2:1, or complete atrioventricular block and compared with age- and sex-matched, asymptomatic, healthy control subjects (n = 18, 6 M/12 F, mean age 75 +/- 7 years). Serum myocardial collagen turnover markers:matrix metalloproteinases (MMP-1, 2, 9), tissue inhibitor of matrix metalloproteinase (TIMP-1), amino-terminal propeptide of procollagen type I (PINP) and type III (PIIINP), carboxy-terminal telopeptide of collagen type I (CITP), and carboxy-terminal propeptide of procollagen type I (PICP), serum extracellular matrix components (laminin and fibronectin), TGFbeta(1), and BMP-7 levels were measured in both groups. Serum PICP (849 +/- 396 vs 631 +/- 294 ng/mL, P = 0.04), PIIINP (3.7 +/- 1.3 vs 3 +/- 1 mug/L, P = 0.03), CITP (0.68 +/- 0.35 vs 0.48 +/- 0.25 ng/mL, P = 0.037), and plasma MMP-9 (58.8 +/- 56 vs 25.9 +/- 17.3 ng/mL, P = 0.006) levels were higher in patient population compared to control subjects. Serum MMP-1 (24.1 +/- 20.5 vs 13.6 +/- 7.5 ng/mL, P = 0.045) and MMP-2 (1310 +/- 139 vs 1186 +/- 163 ng/mL, P = 0.01) levels were higher in control subjects compared to patient population. There was no difference in serum TIMP-1, PINP, laminin, fibronectin, TGFbeta(1), and BMP-7 levels between two groups. Our findings demonstrate the presence of increased myocardial collagen turnover and active fibrotic process in patients with PCCD compared to control subjects.

Longitudinal Strain and Torsion Assessed by Two-Dimensional Speckle Tracking Correlate with the Serum Level of Tissue Inhibitor of Matrix Metalloproteinase-1, a Marker of Myocardial Fibrosis, in Patients with Hypertension

We hypothesized that the alterations of myocardial collagen turnover in patients with hypertension may be involved in the early changes of regional contractile function assessed by a new speckle tracking method. In 56 patients with untreated hypertension (48 +/- 11 years, ejection fraction > 55%) and 20 age-matched control subjects, the serum levels of aminoterminal propeptide of procollagen I/III and tissue inhibitor of matrix metalloproteinase (TIMP)-1 were measured by radioimmunoassay and enzyme immunoassay. To assess the regional contractile function, the average of negative longitudinal strain of 6 segments at apical 4-chamber view (longitudinal epsilon), the average of radial strain (radial epsilon) and the average of circumferential strain (circumferential epsilon) of 6 mid-left ventricular (LV) segments, and basal-to-apical torsion were obtained by 2-dimensional speckle tracking imaging. Compared with control group, longitudinal epsilon was significantly decreased (-20.4 +/- 3.0% vs -22.1 +/- 2.2%, P = .030) and basal-to-apical torsion was increased (20.5 +/- 5.7 degrees vs 17.4 +/- 3.7 degrees, P = .013) in patient group. The serum level of log TIMP-1 was higher in the patients (3.6 +/- 0.6 vs 3.0 +/- 0.5, P < .001). The serum log TIMP-1 significantly correlated with longitudinal epsilon (r = 0.405, P = .015), basal-to-apical torsion (r = 0.331, P = .017), and the LV mass (r = 0.266, P = .047). In multivariate analysis, longitudinal epsilon (beta = 0.326, P = .015) and basal-to-apical torsion (beta = 0.402, P = .003) independently correlated with the serum TIMP-1 level. In patients who are hypertensive with normal ejection fraction, impaired longitudinal epsilon and increased LV torsion correlated with serum TIMP-1, which suggests that the change in collagen turnover and the myocardial fibrotic process may affect the early contractile dysfunction of LV.

Effects of Surgery on Peripheral N-Terminal Propeptide of Type III Procollagen in Patients with Crohn’s Disease

AimThis study investigates the effects of surgery on collagen turnover in patients affected by Crohn’s disease (CD). MethodsFifteen patients affected by active CD, assessed according to the Crohn’s disease activity index, and confirmed by histology, with different pharmacological treatments, were enrolled in the study. N-Terminal propeptide of type III collagen was assessed on peripheral blood before and 6 months after surgery, as an index of collagen turnover. A control group of 15 healthy age- and sex-matched subjects was also studied. ResultsIn CD patients peripheral N-terminal propeptide of type III collagen serum levels were significantly higher than in controls before surgery (5.0±1.8 vs 2.7±0.7 μg/l, respectively; p = 0.0001). Six months after these values were significantly reduced (from 5.0±1.8 to 3.1±0.8 μg/l; p = 0.003). Independently on the pretreatment regimen and the duration of the disease, an improvement in the patients’ symptoms was observed. ConclusionsThe surgical resection of the affected intestinal segment in CD patients seems to be able to break down the collagen synthesis processes. Peripheral N-terminal propeptide of type III collagen could be seen as an additive marker to clinical and endoscopic observations after surgery.

Association of β‐Blocker Dose with Serum Procollagen Concentrations and Cardiac Response to Spironolactone in Patients with Heart Failure

To determine whether beta-blocker dose influences cardiac collagen turnover and the effects of spironolactone on cardiac collagen turnover in patients with heart failure. Prospective clinical study. Two heart failure centers. Eighty-eight spironolactone-naïve patients with heart failure who were taking beta-blockers. In a subset of 29 patients, spironolactone was started at 12.5 mg/day, with the dosage titrated to 25 mg/day if tolerated. Venous blood samples were collected from each patient. Serum procollagen type I and type III aminoterminal peptides (PINP and PIIINP) were determined by radioimmunoassay and compared between the 25 patients receiving low doses (< 50% of recommended target dose) and the 63 patients receiving high doses (> or = 50% of recommended target dose) of beta-blockers. Patients receiving low-dose beta-blockers had higher mean +/- SD PIIINP concentrations (6.6 +/- 3.5 vs 4.9 +/- 2.6 microg/L, p=0.03) and tended to have higher PINP concentrations (74.0 +/- 44.1 vs 57.1 +/- 28.6 microg/L, p=0.10) compared with those receiving high doses. A repeat blood sample was collected from the 29 patients who received spironolactone after 6 months of therapy. Changes in procollagen peptides also were compared in this subset between low-dose (9 patients) and high-dose (20 patients) beta-blocker groups. Low beta-blocker doses were associated with greater reductions in concentrations of PINP (median [intraquartile range] -14.3 microg/L [-9.8 to -19.3 microg/L] vs -2.5 microg/L [5.9 to -9.8 microg/L], p=0.02) and PIIINP (-1.4 microg/L [-0.9 to -2.4 microg/L] vs 0.1 microg/L [0.9 to -1.3 microg/L], p=0.045) with spironolactone therapy than high beta-blocker doses. In addition, 100% of the patients in this subset taking low-dose beta-blockers versus only 35% taking higher doses had reductions in both markers of cardiac fibrosis. Spironolactone may benefit patients with heart failure who cannot tolerate upward titration of beta-blocker dosages, at least in terms of its effects on cardiac remodeling.

Transient enhancement of oxidant stress and collagen turnover in patients with acute decompensated congestive heart failure

Myocardial remodeling is a crucial step for progression of heart failure. Free radical generation from failing myocardium has been proposed to be linked to myocardial remodeling. The aim of this study was to evaluate urinary excretion of 8-iso-prostaglandin F2á (8-iso-PGF2á), a reliable marker for oxidant stress in vivo, and collagen turnover in patients with acute worsening of congestive heart failure (CHF). Enrolled were 43 patients with acute worsening of CHF due to various etiologies. At their admission (acute phase) and after approximately 2 week-conventional treatment (chronic phase), we measured: (1) immunoreactive urinary 8-iso-PGF2á, (2) serum total anti-oxidant status (TAS); and (3) serum levels of procollagen type I carboxyterminal peptide (PIP) and carboxyterminal collagen type I telopeptide (CITP), biochemical markers for collagen synthesis and degradation, respectively. From acute phase to chronic phase these parameters were monitored: 335.1±245.4 to 205.3±107.4 pg/mg creatinine for urinary 8-iso-PGF2á (P<0.0001); 0.92±0.16 to 0.98±0.13 mM for TAS (P<0.01); 171.4±72.5 to 93.7±33.9 ng/ml for PIP (P<0.0001); and 7.2±3.6 to 12.6±8.4 ng/ml for CITP (P<0.0001). In conclusion, acute worsening of CHF promotes free radical generation and collagen synthesis.

WITHDRAWN: Transient enhancement of oxidant stress and collagen turnover in patients with acute decompensated congestive heart failure

WITHDRAWN: Transient enhancement of oxidant stress and collagen turnover in patients with acute decompensated congestive heart failure

Transient Enhancement of Oxidant Stress and Collagen Turnover in Patients With Acute Worsening of Congestive Heart Failure

Myocardial remodeling is a crucial step for progression of heart failure (HF). Free radical generation by the failing myocardium has been proposed as linked to myocardial remodeling. The aim of this study was to evaluate the urinary excretion of 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha), a reliable marker for oxidant stress in vivo, and collagen turnover in patients with acute worsening of congestive HF. Enrolled were 43 patients with acute worsening of congestive HF of various etiologies. On admission (acute phase) and after approximately 2 weeks of conventional treatment (chronic phase), the following were measured: (1) immunoreactive urinary 8-iso-PGF2alpha, (2) serum total antioxidant status (TAS); and (3) serum levels of procollagen type I carboxyterminal peptide (PIP) and carboxyterminal collagen type I telopeptide (CITP), biochemical markers for collagen synthesis and degradation, respectively. From the acute to the chronic phase the parameters changed as follows: 335.1+/-245.4 to 205.3+/-107.4 pg/mg creatinine for urinary 8-iso-PGF2alpha (p<0.0001); 0.92+/-0.16 to 0.98+/-0.13 mmol/L for TAS (p<0.01); 171.4+/-72.5 to 93.7+/-33.9 ng/ml for PIP (p<0.0001); and 7.2+/-3.6 to 12.6+/-8.4 ng/ml for CITP (p<0.0001). Acute worsening of congestive HF promotes free radical generation and collagen synthesis.

Anabolic and catabolic function of chondrocyte ex vivo is reflected by the metabolic processing of type II collagen

The aim of the present study was to investigate collagen metabolism after anabolic and catabolic stimulation of chondrocytes ex vivo. Metabolic activities in ex vivo bovine cartilage explants were stimulated with insulin-like growth factor I (IGF-I) or a combination of tumor necrosis factor alpha (TNFalpha) and oncostatin M (OSM). Supernatants were assessed for changes in biochemical markers, N-terminal propeptide of type II (PIINP) collagen and fragments of C-telopeptide of type II collagen (CTX-II). Matrix metalloproteinases (MMP) were added to metabolic inactivated cartilage and evaluated by the two biochemical markers for formation or degradation, respectively. Finally, urinary CTX-II and PIINP were evaluated for assessment of type II collagen turnover in patients with rheumatoid arthritis (RA). In the bovine articular cartilage explants, IGF-I induced an increase in PIINP level up to 4.8+/-1.1[ng/ml]/mg cartilage whereas CTX-II remained below 0.1+/-0.1[ng/ml]/mg cartilage. In the catabolic stimulated explants both PIINP and CTX-II were released to the supernatant, reaching concentrations of 9.0+/-1.4 and 9.1+/-2.2[ng/ml]/mg cartilage, respectively. RA patients had significantly lower serum concentrations of PIINP (3.4+/-3.7 ng/ml) compared with those healthy individuals (18.7+/-12.41 ng/ml, P<0.001). In contrast, RA patients had significantly higher urinary CTX-II (0.8+/-0.8 mg/mmol) compared to the healthy controls (0.1+/-0.08 mg/mmol, P=0.004). This study is the first to demonstrate that precursors and degradation products of type II collagen released into the supernatant can effectively reflect the anabolic and catabolic activities of stimulated cartilage explants.

Enhanced Oxidant Stress Under Acute Decompensated Congestive Heart Failure Exacerbates Left Ventricular Remodeling at its Stable Phase

Progression of left ventricular remodeling (LVR) is crucial for prognosis of congestive heart failure (CHF). We recently reported the enhancement of oxidant stress (OS) and collagen turnover in patients with acute decompensated CHF (AD-CHF). The aim of this study was to clarify the association between enhanced OS and LVR in such patients. Thirty-two patients were admitted into our hospital due to AD-CHF. After successful treatment, they were followed up with conventional medicines. LVR was monitored with echocardiography at admission, 2 weeks later, and 6 months later.