Serum PIIINP Research Articles

Vitamin D Status and Bone and Connective Tissue Turnover in Brown Bears (Ursus arctos) during Hibernation and the Active State

BackgroundExtended physical inactivity causes disuse osteoporosis in humans. In contrast, brown bears (Ursus arctos) are highly immobilised for half of the year during hibernation without signs of bone loss and therefore may serve as a model for prevention of osteoporosis.AimTo study 25-hydroxy-vitamin D (25OHD) levels and bone turnover markers in brown bears during the hibernating state in winter and during the active state in summer. We measured vitamin D subtypes (D2 and D3), calcitropic hormones (parathyroid hormone [PTH], 1,25-dihydroxy-vitamin D [1,25(OH)2D]) and bone turnover parameters (osteocalcin, ICTP, CTX-I), PTH, serum calcium and PIIINP.Material and MethodsWe drew blood from seven immobilised wild brown bears during hibernation in February and in the same bears while active in June.ResultsSerum 25-hydroxy-cholecalciferol (25OHD3) was significantly higher in the summer than in the winter (22.8±4.6 vs. 8.8±2.1 nmol/l, two tailed p - 2p = 0.02), whereas 25-hydroxy-ergocalciferol (25OHD2) was higher in winter (54.2±8.3 vs. 18.7±1.7 nmol/l, 2p<0.01). Total serum calcium and PTH levels did not differ between winter and summer. Activated 1,25(OH)2D demonstrated a statistically insignificant trend towards higher summer levels. Osteocalcin levels were higher in summer than winter, whereas other markers of bone turnover (ICTP and CTX-I) were unchanged. Serum PIIINP, which is a marker of connective tissue and to some degree muscle turnover, was significantly higher during summer than during winter.ConclusionsDramatic changes were documented in the vitamin D3/D2 ratio and in markers of bone and connective tissue turnover in brown bears between hibernation and the active state. Because hibernating brown bears do not develop disuse osteoporosis, despite extensive physical inactivity we suggest that they may serve as a model for the prevention of this disease.

Association between markers of collagen turnover, arterial stiffness and left ventricular hypertrophy in chronic kidney disease (CKD): the Renal Research Institute (RRI)-CKD Study

Markers of collagen turnover have not been well studied in the context of cardiovascular disease in patients with chronic kidney disease (CKD). We investigated the associations between serum markers of collagen turnover [N-terminal procollagen type 3 propeptide (PIIINP) and carboxy-terminal telopeptide (C1TP)] and both pulse wave velocity (PWV) and left ventricular mass index (LVMI) in a CKD cohort. The study included 242 patients (mean age 60 ± 15 years, 53% males, 80% Caucasian, CKD Stages 3-5) from the Renal Research Institute (RRI)-CKD Study. Serum PIIINP and C1TP levels were analyzed by radioimmunoassay. PWV was obtained by applanation tonometry from carotid and femoral pressure wave contours. LVMI was measured by echocardiography. Statistical analyses included Pearson's correlations and multiple linear regression. Both PIIINP and C1TP values were significantly higher in more advanced stages of CKD (P < 0.05). A positive correlation was demonstrated between PWV and LVMI (r = 0.25, P = 0.0018), persisting after adjustment for potential confounders (partial r = 0.27, P = 0.0009). PIIINP correlated with PWV (r = 0.16, p = 0.029) and LVMI (r = 0.16, P = 0.0018), while C1TP correlated with LVMI (r = 0.18, P = 0.013) but not with PWV (r = 0.12, P = 0.09). In multivariable analysis adjusting for race, diabetes, estimated glomerular filtration rate (eGFR) and renin-angiotensin-aldosterone system inhibitors, only PWV (β = 0.45, P = 0.0017) but not LVMI (P = 0.09) remained significantly associated with serum PIIINP. Our results demonstrate the association of PIIINP (but not C1TP), a circulating biomarker of collagen synthesis with arterial stiffness (but not with LVMI) in a CKD cohort, independent of eGFR. This suggests that altered collagen turnover may play a role in the pathogenesis of arterial stiffness in CKD.

Effect of primary percutaneous coronary intervention on serum collagen biomarkers following acute myocardial infarction

Objective — The aim of this study was to investigate the effect of primary percutaneous coronary intervention (PCI) on serum collagen biomarkers following acute myocardial infarction (AMI).Methods and results — Thirty-eight patients were enrolled into a primary PCI (n = 16) and a control (n = 22) group. The PCI group received successful PCI within 6 h of MI, whereas the control group received no PCI or thrombolytic therapy. Serum type I procollagen (PICP) and type III procollagen (PIIINP) were measured by enzyme-linked immunosorbent assay (ELISA). The baseline characteristics were similar between the PCI and control groups. There was no significant difference in left ventricular end-systolic, end-diastolic volume or ejection fraction between the two groups 30 min after MI (P > 0.05). A significant increase in PICP and PIIINP was noted in both groups 3 days after MI (P < 0.01). PICP and PIIINP in the PCI group declined overtime to the pre-PCI level, whereas they remained high in the control group. In the PCI group, the mean serum PICP and PIIINP on day 7, 14 and 30 was lower than in the control group (P < 0.01).Conclusions — AMI is associated with an increase in serum biomarkers of collagen synthesis. Early and successful PCI is associated with a reduction in serum collagen biomarkers.

1248 Procollagen Type Iii Propeptide Levels Among Preterm Infants in Neonatal Intensive Care Unit

Aim: To determine levels of the procollagen III propeptide (PIIINP) among preterm neonates whether septic, mechanically ventilated or growers. Also, to evaluate the clinical usefulness of the marker in early detection of fibrosis associated with mentioned neonatal disorders and to correlate it with the ventilation duration and other sepsis markers. Patients and Methods: We prospectively studied 55 neonates born at Kasr Al Aini obstetric hospital. Within 48 hours of age, 35 preterm infants with gestational age ≤35 weeks were stratified into 3 groups: Group (1) Septic preterms (n=15); Group (2) Mechanically ventilated (n=11) and Group (3) Growers: Preterms whose weight< 1600 gms admitted for weight gain (n=9). Twenty healthy full term infants were enrolled as control group. Procollagen III propeptide (PIIINP) was measured by radioimmunoassay. Results: Serum PIIINP is significantly higher in cases than controls. The highest levels were in the ventilated group, followed by the septic one and lastly the Grower group. Serum (PIIINP) levels were significantly higher in males than females (in cases and controls) and in those who developed bronchopulmonary dysplasia (BPD). Serum procollagen III is significantly positively correlated with ventilation duration and negatively correlated with gestational age and anthropometric measurements. Conclusion: Serum PIIINP levels are higher in septic, ventilated especially those complicated with BPD and growing preterm which is implicated in the pathogenesis of these disorders. Further research is needed to evaluate the clinical usefulness of the serum PIIINP as a potential marker for neonatal sepsis and BPD.

The relationship between aminoterminal propeptide of type III procollagen and heart rate variability parameters in heart failure patients: a potential serum marker to evaluate cardiac autonomic control and sudden cardiac death

Cardiac extra-cellular matrix (ECM) fibrosis plays an important role in the pathophysiology of heart failure (HF). It may provide electrical heterogeneity and a substrate for arrhythmogenicity, which may cause sudden cardiac death (SCD). Twenty-one patients with manifestations of HF and a left ventricular ejection fraction (LVEF) ≤50% were enrolled. The median age was 62 years and median LVEF was 33%. Time- and frequency-domain analysis of heart rate variability (HRV) on 24 h ambulatory electrocardiography recording was assessed. Serum markers of ECM turnover including type I and III aminoterminal propeptide of procollagen (PINP and PIIINP), matrix metalloproteinase-2 and -9 (MMP-2 and MMP-9), and tissue inhibitor of metalloproteinase-1 (TIMP-1) were analyzed. The serum PIIINP concentration was correlated significantly with standard deviation of all normal to normal R-R intervals (SDNN) (r=-0.722, p=<0.001), percentage of adjacent NN interval differences >50 ms (pNN50) (r=-0.528, p=0.014), percentage of adjacent NN interval differences >20 ms (pNN20) (r=-0.545, p=0.002), very low frequency (VLF) (r=-0.490, p=0.024), low frequency (LF) (r=-0.491, p=0.024), and high frequency (HF) (r=-0.513, p=0.018). PINP, MMP-2, -9, TIMP-1 were not correlated with time- and frequency-domain analysis of HRV. PIIINP was significantly correlated with time- and frequency-domain analysis of HRV in HF patients. PIIINP is a potential serological marker to evaluate cardiac autonomic control and risk of SCD in HF patients.

Abstract 5532: Apoptosis, Interstitial Collagen and Diastolic Function in Essential Hypertension

Introduction: Sustained hypertension (HT) leads to left ventricular hypertrophy (LVH) and left ventricular dilatation, processes associated with loss of cardiac myocytes through apoptosis. Nevertheless, the relationship of apoptosis, myocardial fibrosis and diastolic function remains unknown. Therefore, the aims of the present study were to analyze the relationship between aminoterminal propeptide levels of type III procollagen (PIIINP), sFas, soluble TNF receptor 1 (sTNF-R1) and diastolic function in essential HT. Hypothesis: We assessed the hypothesis that increased cardiac collagen turnover would be associated with LVH, diastolic dysfunction and apoptosis even in asymptomatic HT. Methods: The asymptomatic hypertensive group consisted of 253 Caucasian patients (mean age 60±13 years, 139 males) from 11 hospitals. A routine physical examination, laboratory analyses, and echo-Doppler study were performed. Results: Serum concentrations of PIIINP were higher in hypertensive patients compared to control group [4.18 (3.55 – 5.04 μ g/L) vs. 3.54 (2.98 – 4.54 μ g/L), p=0.006] and also plasma levels of sFas and sTNF-R1 [1.40 (1.13 – 1.69 ng/mL) vs. 1.00 (0.84 – 1.27 ng/mL), p&lt;0.0001; 385 (291 – 545 pg/mL) vs. 236 (194 – 302 pg/mL), p&lt;0.0001]. Log-transformed concentrations of anti-apoptotic cytokines were correlated between them (r=0.404, p&lt;0.0001). Moreover, serum PIIINP concentrations were associated with log-transformed sFas (r=0.386, p&lt;0.0001) and sTNF-R1 (r=0.298, p&lt;0.001). Then, multivariate analyses included sFas (p&lt;0.0001) and sTNF-R1 (p&lt;0.0001) as independent factors of serum procollagen levels. Finally, marker concentrations were significantly correlated with diastolic parameters. Conclusions: This study showed increased circulating levels of PIIINP, sFas and sTNF-R1 in our group of asymptomatic hypertensive patients. Furthermore, sFas and sTNF-R1 are independent factors of serum type III procollagen, and diastolic parameters showed a highly significant relationship with myocardial fibrosis and anti-apoptotic cytokines.

Evaluation of procollagen III peptide as a marker of tissue hyperthyroidism in long-term treated women with TSH suppressive doses of thyroxine.

Increased serum concentrations of the aminoterminal propeptide of collagen III (PIIINP) are found in overt hyperthyroidism. Thus, measurement of serum PIIINP might be useful as an early marker of tissue hyperthyroidism in patients with TSH suppressive thyroxine treatment. In a prospective study we evaluated female patients followed in the thyroid outpatient clinic. Serum PIIINP concentrations were analysed in three groups: patients with TSH suppressive thyroxine treatment for more than 6 months (n = 33, TSH < 0.1 mU/l), patients with thyroxine substitution for hypothyroidism for more than 6 months (n = 20, TSH 0.2-4.0 mU/l) and spontaneous hyperthyroid patients (n = 8, TSH < 0.03 mU/l, increased freeT4 and/or T3). Beside TSH, thyroid hormones and serum PIIINP we measured serum SHBG and a clinical score. Hyperthyroid patients had clearly elevated serum PIIINP and SHBG values and a higher clinical score when compared with other study groups (p < 0.001). Patients with TSH suppressive thyroxine treatment had higher fT4 and T3 concentrations than the thyroxine substitution group (fT4 22 +/- 4.8 pmol/l vs. 17 +/- 2.6 pmol/l, T3 2.2 +/- 0.4 nmol/l vs. 1.8 +/- 0.3 nmol/l, p < 0.001) and also elevated serum SHBG values (77.6 +/- 27.5 nmol/l vs. 58.4 +/- 18 nmol/l, p < 0.01). However, serum PIIINP concentrations and the clinical score were very similar in both thyroxine treated groups (PIIINP in TSH suppression group 3.0 +/- 0.67 microg/l vs. 2.8 +/- 0.65 microg/l in the substitution group, clinical score 2 +/- 1.8 pts. vs. 1.7 +/- 1.5 pts. p = n.s.). In conclusion, serum PIIINP is not a reliable early marker for detection of tissue hyperthyroidism in long-term thyroxine treated women with suppressed TSH.

Markers of collagen synthesis and degradation are increased in serum in severe sepsis: a longitudinal study of 44 patients

IntroductionSepsis-related multiple organ dysfunction is a common cause of death in the intensive care unit. The effect of sepsis on markers of tissue repair is only partly understood. The aim of this study was to measure markers of collagen synthesis and degradation during sepsis and investigate the association with disease severity and outcome.MethodsForty-four patients with severe sepsis participated in the study and 15 volunteers acted as controls. Blood samples were collected for 10 days after the first sepsis-induced organ dysfunction and after three and six months. Procollagen type I and III aminoterminal propeptides (PINP and PIIINP) and cross-linked telopeptides of type I collagen (ICTP) were measured.ResultsThe PIIINP concentration was elevated in the septic patients (8.8 ug/L, 25th to 75th percentile = 6.8 to 26.0) when compared with controls (3.0 ug/L, 25th to 75th percentile = 2.7 to 3.3; P < 0.001) on day one. Maximum serum PIIINP concentrations during sepsis were higher in non-survivors compared with survivors (26.1 ug/L, 25th to 75th percentile = 18.7 to 84.3; vs. 15.1 ug/L, 25th to 75th percentile = 9.6 to 25.5; P = 0.033) and in multiple organ failure (MOF) compared with multiple organ dysfunction syndrome (MODS) (24.2 ug/L, 25th to 75th percentile = 13.4 to 48.2; vs. 8.9 ug/L, 25th to 75th percentile = 7.4 to 19.4; P = 0.002). Although the PINP values of the septic patients remained within the laboratory reference values, patients with MOF had higher values than patients with MODS (79.8, 25th to 75th percentile = 44.1 to 150.0; vs.40.4, 25th to 75th percentile = 23.6 to 99.3; P = 0.007). Day one ICTP levels were elevated in septic patients compared with the controls (19.4 ug/L, 25th to 75th percentile = 12.0 to 29.8; vs. 4.1 ug/L, 25th to 75th percentile = 3.4 to 5.0; P < 0.001).ConclusionsMarkers of collagen metabolism are increased in patients with severe sepsis and can be investigated further as markers of disease severity and outcome.

Hepatic extraction of the aminoterminal propeptide of type III procollagen before and after bile duct ligation in pigs

The aminoterminal propeptide of type III procollagen is extracted from the circulation by the liver, and PIIINP is found in bile. This study was performed in order to investigate whether biliary excretion contributes substantially to the hepatic extraction of circulating PIIINP. Hepatic extraction before and during a 4-h period after ligation of the common bile duct was assessed from serum PIIINP concentrations in a systemic artery, the portal vein and a hepatic vein of seven healthy anaesthetized pigs. Seven sham-operated anaesthetized pigs served as controls. Ligation of the bile duct did not cause a decrease in the hepatic extraction ratio of circulating PIIINP. The PIIINP serum levels of the cholestatic pigs and of the controls were similar throughout the investigation period. The PIIINP concentrations in bile were only 10% of the corresponding serum values. Gel filtration of sera showed that the lower PIIINP concentration in the hepatic vein, as compared to the artery and the portal vein was due to a selective decrease in the concentration of the intact propeptide. The study shows that biliary excretion does not contribute significantly to the hepatic extraction of circulating PIIINP in the normal liver. Furthermore, the hepatic extraction of circulating PIIINP preferentially affects the intact propeptide, rather than the somewhat larger PIIINP related molecule in serum.

Serum Fibrosis Marker Levels Decrease After Successful Antiviral Treatment in Chronic Hepatitis C Patients With Advanced Fibrosis

Serum fibrosis marker levels during the lead-in treatment phase of patients enrolled in the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) trial were determined. Week 0, 24, 48, and 72 serum samples were analyzed for YKL-40, tissue inhibitor of matrix metalloproteinase-1, amino-terminal peptide of type III procollagen (PIIINP), and hyaluronic acid (HA) levels. All 456 chronic hepatitis C (CHC) patients received peginterferon alfa 2a and ribavirin for 24 to 48 weeks. Mean age was 49.2 years, 71% were male, and 39% had cirrhosis. Lower pretreatment serum YKL-40, tissue inhibitor of matrix metalloproteinase-1, PIIINP, and HA levels were associated significantly with week-20 virologic response (P < .0001). In multivariate analysis, non-1 CHC genotype, non-black race, prior interferon monotherapy, and lower baseline serum aspartate aminotransferase/alanine aminotransferase levels and log(10)YKL-40 levels were associated independently with week-20 virologic response. Statistically significant declines in all marker levels were observed at week 72 compared with baseline in the 81 patients with a sustained virologic response, but not in the 72 patients with breakthrough or relapse. At weeks 24 and 48, significant increases were observed in serum PIIINP and HA levels compared with baseline in virologic responders and nonresponders (P < .0001). Pretreatment YKL-40 levels are an independent predictor of initial virologic response to peginterferon and ribavirin treatment. Levels of all 4 serum fibrosis markers decreased significantly in the SVR patients, consistent with reduced hepatic fibrogenesis. Measuring serum fibrosis marker levels before and after antiviral therapy may provide important prognostic information in CHC patients.

Abstract 2155: Plasma Adiponectin Levels in Patients with Atrial Fibrillation

The occurrence and development of atrial fibrillation (AF) are associated with changes in electrical properties and cardiac structure, known as electrical and structural atrial remodeling. AF characterized by atrial remodeling also occurs with obesity-related conditions. Adiponectin, an adipose tissue-derived hormone, exerts beneficial effects on the heart in various pathological conditions. These observations led us to speculate that adiponectin levels affect the development and prevalence of AF. Here, we investigated a potential association between circulating adiponectin levels and atrial remodeling in patients with AF. We measured plasma adiponectin levels, serum carboxy-terminal telopeptide of collagen type I (CITP) levels, as a collagen type I degradation marker, and serum type III procollagen-N-peptide (PIIINP) levels, as a collagen type III synthesis marker in consecutive 414 patients; 225 paroxysmal AF, 81 persistent AF and 108 paroxysmal supra-ventricular tachycardia without AF history (control) patients, who admitted for scheduled radiofrequency catheter ablation. Plasma adiponectin levels were significantly higher in patients with persistent AF compared to paroxysmal AF and control patients (p&lt;0.05). Serum CITP levels, but not serum PIIINP levels, were also higher in patients with persistent AF compared to paroxysmal AF and control patients (p&lt;0.05). In addition, a positive correlation was observed between adiponectin levels and CITP levels (r=0.39, p&lt;0.005) or the P wave duration (r=−0.31, p&lt;0.05) in patients with persistent AF. High plasma adiponectin levels are associated with the presence of persistent AF, which is accompanied by increased CITP levels. Hyperadiponectinemia might also attenuate atrial conduction disturbance. Thus, measurement of plasma adiponectin could be useful for assessment of AF.

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.

Myocardial collagen metabolism in failing hearts before and during cardiac resynchronization therapy

In patients with heart failure cardiac resynchronization therapy (CRT) leads to reverse ventricular remodelling. To evaluate whether myocardial collagen metabolism in patients with heart failure is implicated in adverse ventricular remodelling and response to CRT. Collagen synthesis and degradation were assessed from the concentrations of aminoterminal propeptides of type I and type III collagen (PINP and PIIINP) and carboxyterminal telopeptide of type I collagen (ICTP), respectively, in serum of 64 patients with heart failure before and after 6 months of CRT. Forty-six patients (72%) showed a > 10% reduction in LV end-systolic volume at follow-up and were classified as responders to CRT, the other 18 patients (28%) were classified as non-responders. Responders demonstrated a mean (+/-SEM) increase of serum PINP and PIIINP during follow-up, from 32.9+/-2.2 to 46.7+/-4.0 microg/L (p < 0.001) and from 4.59+/-0.24 to 5.13+/-0.36 microg/L (p < 0.05), respectively. In non-responders, serum PINP and PIIINP remained unchanged during follow-up. At baseline, responders had significantly lower serum PINP than non-responders (32.9+/-2.2 vs. 41.8+/-4.3 microg/L; p < 0.05). ICTP levels of responders at baseline tended to be higher than in non-responders (3.54+/-0.56 vs. 2.08+/-0.37 microg/L, p = ns), and in both groups ICTP levels did not change upon CRT. Reverse LV remodelling following CRT is associated with increased collagen synthesis rate in the first 6 months of follow-up.

Serological markers for monitoring disease progression in noncirrhotic primary biliary cirrhosis on ursodeoxycholic acid therapy

Liver biopsy has so far been the only method to accurately follow the progression of primary biliary cirrhosis (PBC). The stage and the severity of lymphocytic piecemeal necrosis (LPN) have been shown to be an independent factor for the development of cirrhosis. In this 3-year prospective study, we evaluated the diagnostic value of several liver function tests, surrogate markers of fibrogenesis, hyaluronic acid (HA), procollagen III N-terminal peptide (S-PIIINP), cholestanol and plant sterols in noncirrhotic PBC patients treated with ursodeoxycholic acid (UDCA) or with UDCA and budesonide to assess the stage, inflammation and fibrosis. Seventy-seven stage I-III PBC patients were included into the study, with control biopsy at 36 months. Serum liver enzymes, bile acids (BA), HA, PIIINP, immunoglobulins, lipids and cholesterol precursors and plant sterols were measured at baseline and at 36 months. Aspartate aminotransferase (AST), HA, BA and PIINP were significantly different between stages I to III and differentiated mild (F0F1) from moderate (F2F3) fibrosis. The combination of these variables (PBC score) exhibited best sensitivity and specificity, compared with AST/platelet ratio, Forns' score and fibrosis index. Using a cut-off value of 66 for the PBC score, the sensitivity was 81.4% and specificity was 65.2% for classifying the stage of PBC, regarding the stage the and fibrosis in noncirrhotic PBC. Serum HA, BA, PIIINP and AST may serve as valuable simple tools to monitor the treatment response to UDCA in early stages of PBC. Combinations of these biomarkers into a single index further potentiate the diagnostic value of such measurements.

Circulating Adiponectin Levels in Patients With Atrial Fibrillation

Atrial fibrillation (AF) characterized by atrial remodeling occurs with obesity-related conditions. Adiponectin, an adipose tissue-derived hormone exerts beneficial effects on ventricular remodeling, so in the present study the potential association between circulating adiponectin levels and atrial remodeling in patients with AF was investigated. The levels of plasma adiponectin, serum carboxy-terminal telopeptide of collagen type I (CITP), as a collagen type I degradation marker, and serum type III procollagen-N-peptide (PIIINP), as a collagen type III synthesis marker, were measured in 304 consecutive patients (162 paroxysmal AF, 46 persistent AF, 96 paroxysmal supra-ventricular tachycardia [controls]). Plasma adiponectin levels were significantly higher in patients with persistent AF than in those with paroxysmal AF or the control patients (p<0.05). Serum CITP levels, but not serum PIIINP levels, were higher in patients with persistent AF compared with the paroxysmal AF and control patients (p<0.05). In addition, there was a positive correlation between adiponectin levels and CITP levels in patients with persistent AF (r=0.39, p<0.005). High plasma adiponectin levels are associated with the presence of persistent AF, which is accompanied by increased CITP levels. Thus, measurement of plasma adiponectin could be useful for assessment of AF.

Abstract 3078: Myocardial Collagen Metabolism In Failing Hearts Before And During Cardiac Resynchronization Therapy

Objective Cardiac resynchronization therapy (CRT) has proven efficacy in improving left ventricular ejection fraction (LVEF), LV diastolic function, NYHA functional class and outcome in patients with congestive heart failure (CHF), although a substantial number of patients respond poorly to CRT. We investigated whether myocardial collagen metabolism of patients with CHF is implicated in good or poor response to CRT. Methods We analyzed collagen synthesis and degradation by measuring the concentrations of aminoterminal propeptides of type I and type III collagen (PINP and PIIINP, resp.) and carboxyterminal telopeptide of type I collagen (ICTP), respectively, in serum of 64 patients with CHF before and 6 months after start of CRT. Patients had NYHA class III–IV, LVEF ≤35%, and QRS duration &gt;120 ms. Results In 46 patients, CRT resulted in &gt;10% reduction of LV end-systolic volume (LVESV), referred to as responders, whereas in 18 patients LVESV did not change upon CRT or even increased, referred to as non-responders. Responders demonstrated an increase of serum PINP and PIIINP upon CRT, from 32.9±2.2 to 46.7±4.0 μg/L (p&lt;0.001) and from 4.59±0.24 to 5.13±0.36 μg/L (p&lt;0.05), respectively, whereas serum PINP and PIIINP of non-responders did not change upon CRT (from 41.8±4.3 to 43.8±6.2 μg/L and from 4.03±0.45 to 4.28±0.31 μg/L, resp.). Responders had higher serum levels of ICTP at baseline and at 6 months follow-up (from 3.38±0.54 to 3.12±0.48 μg/L) than non-responders at both time points (from 1.96±0.37 to 1.92±0.38 μg/L), although these differences were not statistically significant. Conclusion Compared to future non-responders to CRT, future responders demonstrate relatively low levels of markers of collagen synthesis and relatively high levels of markers of collagen degradation at baseline. Unlike non-responders, responders show an increase in collagen synthesis in the first 6 months of CRT.

An Inverse Relationship Between Markers of Fibrogenesis and Collagen Degradation in Patients With or Without Alcoholic Liver Disease

Excessive deposition of collagen leading to cirrhosis is a major complication of alcohol abuse. However, the mechanisms behind the accumulation of the extracellular matrix proteins are poorly understood. We measured serum markers of collagen degradation (beta-CTx), fibrogenesis (PINP, PIIINP), and pro- and anti-inflammatory cytokines from 84 male heavy drinkers, who were either with (N = 52) or without (N = 32) clinical or histological signs of alcoholic liver disease (ALD), and from 20 healthy nonalcoholic controls. Serum beta-CTx levels in ALD patients were significantly lower than in healthy controls or in the alcoholics without liver disease, while PINP and PIIINP, reflecting type I and type III collagen synthesis, respectively, were significantly increased. The alcoholics without liver disease showed values, that were not significantly different from those of healthy controls. Serum beta-CTx correlated negatively with serum PIIINP and proinflammatory cytokines (IL-2, IL-6, IL-8, TNF-alpha), and positively with anti-inflammatory cytokines (IL-1, TGF-beta), whereas serum PIIINP correlated positively with these proinflammatory cytokines and negatively with the anti-inflammatory cytokines. Calculation of PIIINP/beta-CTx ratio was found to yield an excellent sensitivity (94%) and specificity (98%) in differentiating the alcoholics with liver disease. The present findings indicate a positive relationship between markers of collagen biosynthesis and proinflammatory cytokines, and a negative relationship between these markers and a marker of collagen degradation and anti-inflammatory cytokines, suggesting that a disturbed balance in these cellular responses may facilitate fibrogenesis and play a pivotal role in the pathogenesis of ALD. These findings should also be implicated in the development of noninvasive tools for discriminating individuals at risk for fibrogenesis.

Association of amino-terminal propeptide of type III procollagen and acute myocardial rejection in male patients receiving heart transplantation

The amino-terminal propeptides of type I and III procollagens (PINP and PIIINP) are markers reflecting the status of collagen turnover. We hypothesized that measurement of these serum procollagen propeptides could be used to non-invasively assess acute rejection in heart transplant recipients. In heart transplant recipients, endomyocardial biopsy specimens taken at 6 and 12 months after surgery were used for study. PINP and PIIINP were measured postoperatively at 3, 6, and 12 months. A total of 20 male heart transplant patients and seven male control subjects were enrolled. Five patients showed rejection 6 months after transplantation (group 1), while 15 patients showed no rejection (group 2). In group 2 patients, serum PINP and PIIINP levels decreased significantly 6 months after transplantation. In contrast, elevation of serum PINP and PIIINP levels persisted in group 1 patients 6 months after transplantation. At 6 months after transplantation, group 1 patients had significantly higher PIIINP levels than group 2 patients (p=0.025) and controls (p=0.003). After immunosuppressive therapy, all group 1 patients were free of rejection 12 months after transplantation and serial serum PIIINP levels decreased significantly in these patients. Serum PIIINP levels represent a non-invasive method to reflect the occurrence and resolution of acute rejection.

The relation of amino-terminal propeptide of type III procollagen and severity of coronary artery disease in patients without myocardial infarction or hibernation

Objectives: The association of cardiac fibrosis and coronary artery disease (CAD) in patients without infarction or hibernation is unclear. We investigated the relationship between serum concentrations of procollagen propeptides and severity of CAD in such patients. Design and methods: Forty-six patients (32 men; mean age 64 years) with chest pain were enrolled. All patients received stress thallium-201 single photon emission computed tomography (SPECT) and analysis of the serum levels of the amino-terminal propeptide of type I and III procollagen (PINP and PIIINP). Results: In patients with thallium-201 perfusion defects, the number of diseased vessels was associated significantly with PIIINP ( p = 0.024) rather than PINP ( p = 0.613). Follow-up serum PINP and PIIINP levels after coronary intervention (mean 84 days) revealed no significant decrease. Conclusions: Serum PIIINP level is significantly associated with the severity of CAD in patients without myocardial infarction or hibernation.

Aortic stiffness correlates with an increased extracellular matrix turnover in patients with dilated cardiomyopathy

An increased extracellular matrix (ECM) turnover has been associated with poor survival in patients with chronic heart failure (CHF) due to dilated cardiomyopathy (DCM). However, the influence of the accelerated collagen turnover on the progressive large artery stiffening process characterizing CHF has not been clarified. This is relevant because aortic stiffening imposes an additional systolic load and impairs exercise tolerance in CHF patients. Therefore, we investigated whether the serum aminoterminal propeptide of type III collagen (PIIINP), an established marker of ECM turnover and tissue fibrosis in DCM, was associated with aortic stiffness in DCM patients. A total of 89 patients with clinical diagnosis of DCM (age 62 +/- 9 years, 80% men, mean ejection fraction 34% +/- 8%) were selected. Aortic pulse-wave velocity (PWV), a well-established marker of aortic stiffness, was measured by Doppler ultrasonography. Serum concentration of PIIINP was determined by radioimmunoassay. Mean aortic PWV was 5.7 +/- 2.3 m/s, and PIIINP was 5.0 +/- 1.3 microg/L. The variables correlated with aortic PWV were age (r = 0.33, P = .002), PIIINP (r = 0.30, P = .005), heart rate (r = 0.27, P = .02), stroke volume (r = -0.24, P = .03) and New York Heart Association class (r = 0.25, P = .02). In a multivariate analysis, age (P = .02) and PIIINP (P = .01) were independently related with aortic PWV, accounting for 27% of its variance. Higher serum PIIINP levels are independently associated with a stiffer aorta in DCM patients. This suggests that abnormalities in the ECM turnover might involve the proximal elastic vasculature and could partially explain the progressive large artery stiffening process characterizing CHF.