Biomarkers Of Collagen Metabolism Research Articles

Role of biomarkers of collagen metabolism and systemic inflammation in myocardial remodeling in patients with stable chronic coronary artery disease and obstructive sleep apnea

Aim. To study the relationship of biomarkers of collagen metabolism and systemic inflammation with left ventricular (LV) remodeling in patients with stable coronary artery disease (CAD) and obstructive sleep apnea (OSA).Material and methods. The study included 195 patients with stable CAD, of which 63 without OSA and 132 patients with combination of CAD and OSA. The mean age of patients was 63,4±3,7 years. Biomarkers of collagen metabolism and systemic inflammation were assessed by determining the concentration of matrix metalloproteinase (MMP)-9, tissue inhibitor of matrix metalloproteinase-1, monocyte chemoattractant protein-1 (MCP-1) and calculating the neutrophil-to-lymphocyte (NLR) and platelet-tolymphocyte ratio (PLR). Echocardiography was performed according to a standard protocol.Results. There were no significant differences in systemic inflammation parameters (MCP-1, NLR, PLR) between the group of patients with CAD and CAD with mild OSA and a significantly higher level of MCP-1, NLR, PLR in more severe OSA. In patients with CAD and severe OSA, the eccentric LV remodeling was diagnosed in 75% of individuals, while the concentric type was diagnosed in only 25%.Conclusion. In patients with stable CAD, the more severe the OSA, the more pronounced systemic inflammation (MCP-1, NLR, PLR), and there are higher proportion of eccentric LV hypertrophy, which may be associated with an imbalance of fibrosis markers (high concentration of MMP-9 with an almost unchanged level of tissue inhibitor of MMP-1).

Biomarkers of Collagen Metabolism Are Associated with Left Ventricular Function and Prognosis in Dilated Cardiomyopathy: A Multi-Modal Study.

Collagen cross-linking is a fundamental process in dilated cardiomyopathy (DCM) and occurs when collagen deposition exceeds degradation, leading to impaired prognosis. This study investigated the associations of collagen-metabolism biomarkers with left ventricular function and prognosis in DCM. DCM patients who underwent endomyocardial biopsy, blood sampling, and cardiac MRI were included. The primary endpoint included death, heart failure hospitalization, or life-threatening arrhythmias, with a follow-up of 6 years (5-8). In total, 209 DCM patients were included (aged 54 ± 13 years, 65% male). No associations were observed between collagen volume fraction, circulating carboxy-terminal propeptide of procollagen type-I (PICP), or collagen type I carboxy-terminal telopeptide [CITP] and matrix metalloproteinase [MMP]-1 ratio and cardiac function parameters. However, CITP:MMP-1 was significantly correlated with global longitudinal strain (GLS) in the total study sample (R = -0.40, p < 0.0001; lower CITP:MMP-1 ratio was associated with impaired GLS), with even stronger correlations in patients with LVEF > 40% (R = -0.70, p < 0.0001). Forty-seven (22%) patients reached the primary endpoint. Higher MMP-1 levels were associated with a worse outcome, even after adjustment for clinical and imaging predictors (1.026, 95% CI 1.002-1.051, p = 0.037), but CITP and CITP:MMP-1 were not. Combining MMP-1 and PICP improved the goodness-of-fit (LHR36.67, p = 0.004). The degree of myocardial cross-linking (CITP:MMP-1) is associated with myocardial longitudinal contraction, and MMP-1 is an independent predictor of outcome in DCM patients.

Xinyang Tablet inhibits MLK3-mediated pyroptosis to attenuate inflammation and cardiac dysfunction in pressure overload

Ethnopharmacological relevanceXinyang tablet (XYT) has been traditionally used in the treatment of cardiovascular diseases (CVDs). Our previous study indicated that XYT exhibited protective effects in heart failure (HF). Aim of the studyThe aim of the present study was to determine the protective effects of XYT in pressure overload induced HF and to elucidate its underlying mechanisms of action. Materials and methodsWe analyzed XYT content using high-performance liquid chromatography (HPLC.). Mice were subjected to transverse aortic constriction (TAC) to generate pressure overload–induced cardiac remodeling and were then orally administered XYT or URMC-099 for 1 week after the operation. HL1 mouse cardiomyoblasts were induced by lipopolysaccharides (LPS) to trigger pyroptosis and were then treated with XYT or URMC-099. We used echocardiography (ECG), hematoxylin and eosin (H&E) staining, Masson's trichrome staining and a terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay to evaluate the effects of XYT. Messenger ribonucleic acid (mRNA) levels of collagen metabolism biomarkers and inflammation-related factors were detected. We determined protein levels of inflammation- and pyroptosis-related signaling pathway members via Western blot (WB). Caspase-1 activity was measured in cell lysate using a Caspase-1 Activity Assay Kit. Subsequently, to define the candidate ingredients in XYT that regulate mixed-lineage kinase-3 (MLK3), we used molecular docking (MD) to predict and evaluate binding affinity with MLK3. Finally, we screened 24 active potential compounds that regulate MLK3 via MD. ResultsECG, H&E staining, Masson's trichrome staining and TUNEL assay results showed that XYT remarkably improved heart function, amelorated myocardial fibrosis and inhibited apoptosis in vivo. Moreover, it reduced expression of proteins or mRNAs related to collagen metabolism, including collagen type 1 (COL1), fibronectin (FN), alpha smooth-muscle actin (α-SMA), and matrix metalloproteinases-2 and -9 (MMP-2, MMP-9). XYT also inhibited inflammation and the induction of pyroptosis at an early stage, as well as attenuated inflammation and pyroptosis levels in vitro. ConclusionOur data indicated that XYT exerted protective effects against pressure overload induced myocardial fibrosis (MF), which might be associated with the induction of pyroptosis-mediated MLK3 signaling.

Proteomic and Mechanistic Analysis of Spironolactone in Patients at Risk for HF

ObjectivesThis study sought to further understand the mechanisms underlying effect of spironolactone and assessed its impact on multiple plasma protein biomarkers and their respective underlying biologic pathways. BackgroundIn addition to their beneficial effects in established heart failure (HF), mineralocorticoid receptor antagonists may act upstream on mechanisms, preventing incident HF. In people at risk for developing HF, the HOMAGE (Heart OMics in AGEing) trial showed that spironolactone treatment could provide antifibrotic and antiremodeling effects, potentially slowing the progression to HF. MethodsBaseline, 1-month, and 9-month (or last visit) plasma samples of HOMAGE participants were measured for protein biomarkers (n = 276) by using Olink Proseek-Multiplex cardiovascular and inflammation panels (Olink, Uppsala, Sweden). The effect of spironolactone on biomarkers was assessed by analysis of covariance and explored by knowledge-based network analysis. ResultsA total of 527 participants were enrolled; 265 were randomized to spironolactone (25 to 50 mg/day) and 262 to standard care (“control”). The median (interquartile range) age was 73 years (69 to 79 years), and 26% were female. Spironolactone reduced biomarkers of collagen metabolism (e.g., COL1A1, MMP-2); brain natriuretic peptide; and biomarkers related to metabolic processes (e.g., PAPPA), inflammation, and thrombosis (e.g., IL17A, VEGF, and urokinase). Spironolactone increased biomarkers that reflect the blockade of the mineralocorticoid receptor (e.g., renin) and increased the levels of adipokines involved in the anti-inflammatory response (e.g., RARRES2) and biomarkers of hemostasis maintenance (e.g., tPA, UPAR), myelosuppressive activity (e.g., CCL16), insulin suppression (e.g., RETN), and inflammatory regulation (e.g., IL-12B). ConclusionsProteomic analyses suggest that spironolactone exerts pleiotropic effects including reduction in fibrosis, inflammation, thrombosis, congestion, and vascular function improvement, all of which may mediate cardiovascular protective effects, potentially slowing progression toward heart failure. (HOMAGE [Bioprofiling Response to Mineralocorticoid Receptor Antagonists for the Prevention of Heart Failure]; NCT02556450)

Mechanistic Insight Into The Effect Of Spironolactone For Preventing Heart Failure: Proteomics And Knowledge-based Network Analysis From The Homage Trial

Background Further to their beneficial effects in established heart failure (HF), mineralocorticoid receptor antagonists may act upstream on mechanisms preventing incident HF. In people at risk for developing HF, the “Heart OMics in Aging” (HOMAGE) trial showed that spironolactone treatment could provide antifibrotic and anti-remodelling effects, potentially slowing the progression to HF. Aims To further understand the mechanisms underlying spironolactone effect, we assessed its impact on multiple plasma protein biomarkers and respective underlying biological pathways. Methods Baseline, 1-month and 9-months (or last visit), plasma samples of HOMAGE participants were measured for protein biomarkers (n=276) using Olink®Proseek-Multiplex cardiovascular and inflammation panels. Spironolactone effect on biomarkers was assessed by analysis of covariance (ANCOVA) and explored by knowledge-based network analysis. Results 527 participants were enrolled, 265 were randomized to spironolactone (25-50 mg/day) and 262 to standard care (“control”). The median (percentile25-75) age was 73 (69-79) years and 26% were female. Spironolactone reduced biomarkers of collagen metabolism (e.g., COL1A1, MMP2), BNP, biomarkers related to metabolic processes (e.g., PAPPA), inflammation and thrombosis (e.g., IL17A, VEGF and urokinase). Spironolactone increased biomarkers that reflect the blockade of the mineralocorticoid receptor (e.g., renin), increased the levels of adipokines involved in anti-inflammatory response (e.g., RARRES2), biomarkers of haemostasis maintenance (e.g., tPA, UPAR), myelosuppressive activity (e.g., CCL16), insulin suppression (e.g., RETN), and inflammatory regulation (e.g., IL12B). Conclusion Proteomic analyses suggest that spironolactone exerts pleiotropic effects including reduction in fibrosis, inflammation, thrombosis, congestion and vascular function improvement, all of which may mediate cardiovascular protective effects potentially slowing progression toward heart failure.

His bundle pacing preserves left ventricular ejection fraction in patients with conduction disease and high risk of development pacing induced cardiomyopathy

Abstract Background His bundle pacing (HBP), contrary to right ventricular myocardial pacing (RVP), offers the most physiological activation of both ventricles and may not lead to pacing induced cardiomyopathy. The change in myocardial structure in failing heart due to myocardial pacing should be reflected in plasmatic levels of collagen metabolism biomarkers and inflammation markers. Purpose To compare a difference in the left ventricular ejection fraction (LVEF) and levels of selected biomarkers between two groups: HBP and RVP (preferably septal). Methods Eighty-six patients with conduction disease indicated to permanent cardiac pacing were randomized to HBP or RVP. Only high-risk patients for pacing induced cardiomyopathy development were included. Blood sampling and echocardiography were performed on the consequent day and 180 days after the pacemaker implantation. The measured biomarkers were: matrix metalloproteinase 9 (MMP-9), tissue inhibitor of metalloproteinase 1 (TIMP-1), galectin-3 (GAL3), ST2/IL-33R (ST2/IL) and TGF-beta 1 (TGFβ1). Statistical analysis included Students t-test, Fishers exact test and Chi-squared test. The p&amp;lt;0.05 was considered to be statistically significant. Results First group included 39 patients with HBP (selective or non-selective His bundle capture) and 47 patients with RVP. Both groups were similar with respect to gender, LVEF, QRS duration and the baseline levels of evaluated biomarkers. In both groups, there was a high burden of ventricular pacing after 6 months (above 90%) (p = NS). The ejection fraction of the left ventricle did not change in the HBPgroup (60 vs 60%, p=0,3), but it decreased significantly in the RVP group (59 vs 56%, p=0,004). The decline in the LVEF of at least 5% occurred in 12 patients (26%) from RVP group, compared to 3 patients (8%) in HBP group (p=0,03). The blood levels of dMMP-9 (p=0,02), TIMP-1 (p=0,003), ST2/IL (p=0,003) and TGFβ1 (p=0,021) declined significantly after 180 days in the HBP group, decline of Galectin 3 was nonsignificant. In the RVP group, there was a significant decline in blood levels of MMP-9 (p=0,014), TIMP-1 (p=0,001) and ST2/IL (p= 0,04), decline of Galectin 3 and TGFβ1 was nonsignificant. The biomarker level difference was not statistically significant between the two groups. Conclusion His bundle pacing, contrary to right ventricular myocardial pacing, preserves LVEF in patients with high risk of pacing induced cardiomyopathy development. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Charles University research programme. Q38. UNCE/MED/002

Si-Miao-Yong-An decoction attenuates cardiac fibrosis via suppressing TGF-β1 pathway and interfering with MMP-TIMPs expression

BackgroundMyocardial fibrosis is an important pathological feature of pressure overload cardiac remodeling. Si-Miao-Yong-An decoction (SMYAD), a traditional Chinese formula, is now clinically used in the treatment of cardiovascular diseases in China. However, its mechanisms in the prevention of heart failure are not fully revealed. PurposeTo determine whether treatment with SMYAD for 4 weeks would lead to changes in collagen metabolism and ventricular remodeling in a mice model of heart failure. MethodsMice were subjected to transverse aorta constriction to generate pressure overload induced cardiac remodeling and then were administered SMYAD (14.85 g/kg/day) or captopril (16.5 mg/kg/day) intragastrically for 4 weeks after surgery. Echocardiography and immunohistochemical examination were used to evaluate the effects of SMYAD. The mRNA of collagen metabolism biomarkers were detected. Protein expression of TGF-β1/Smad and TGF-β1/TAK1/p38 pathway were assessed by Western blot. ResultsSMYAD significantly improved cardiac function, increased left ventricle ejection fraction, and decreased fibrosis area and αSMA expression. Moreover, SMYAD reduced proteins expression related to collagen metabolism, including Col1, Col3, TIMP2 and CTGF. The increased levels of TGF-β1, Smad2, and Smad3 phosphorylation were attenuated in SMYAD group. In addition, SMYAD reduced the levels of TGF-β1, p-TAK1 and p-p38 compared with TAC group. ConclusionsSMYAD improved cardiac fibrosis and heart failure by inhibition of TGF-β1/Smad and TGF-β1/TAK1/p38 pathway. SMYAD protected against cardiac fibrosis and maintained collagen metabolism balance by regulating MMP-TIMP expression. Taken together, these results indicate that SMYAD might be a promising therapeutic agent against cardiac fibrosis.

Assessment of myocardial fibrosis by late gadolinium enhancement imaging and biomarkers of collagen metabolism in chronic rheumatic mitral regurgitation.

SummaryBackgroundIn chronic rheumatic mitral regurgitation (CRMR), involvement of the myocardium in the rheumatic process has been controversial. Therefore, we sought to study the presence of fibrosis using late gadolinium enhancement cardiac magnetic resonance imaging (LGE–CMR) and biomarkers of collagen turnover in CRMR. MethodsTwenty–two patients with CRMR underwent CMR and echocardiography. Serum concentrations of matrix metalloproteinase– 1 (MMP–1), tissue inhibitor of MMP–1 (TIMP– 1), MMP–1–to–TIMP–1 ratio, procollagen III N–terminal pro–peptide (PIIINP) and procollagen type IC peptide (PIP) were measured. ResultsFour patients had fibrosis on LGE–CMR. PIP and PIIINP concentrations were similar to those of the controls, however MMP–1 concentration was increased compared to that of the controls (log MMP–1 3.5 ± 0.7 vs 2.7 ± 0.9, p = 0.02). There was increased MMP–1 activity as the MMP–1–to– TIMP–1 ratio was higher in CRMR patients compared to the controls (–1.2 ± 0.6 vs –2.1 ± 0.89, p = 0.002). ConclusionMyocardial fibrosis was rare in CRMR patients. CRMR is likely a disease characterised by the predominance of collagen degradation rather than increased synthesis and myocardial fibrosis.

Circulating Biomarkers of Collagen Metabolism and Prognosis of Heart Failure with Reduced or Mid-Range Ejection Fraction.

Change in the architecture and composition of cardiac extracellular matrix is a key element in adverse cardiac remodeling that occurs during heart failure. Most of the times, the result is the development of fibrosis, which has a huge impact on the pathophysiology and clinical outcomes of heart failure syndromes. Several molecules related to collagen metabolism detectable in the blood have been proposed as biomarkers of myocardial fibrosis. Despite concerns regarding the true ability of these biomarkers to reflect quantitative and qualitative changes in myocardial collagen, a growing body of evidence suggests that they may play a potential role in several aspects of heart failure management. This review aimed to summarize published data regarding the role of circulating biomarkers of collagen metabolism in the assessment of prognosis in patients with heart failure with reduced or mid-range LVEF ventricular ejection fraction (LVEF < 40% or LVEF 40-49%, respectively). Medline electronic database was searched to identify relevant studies published through October 2016. Most evidence regarding the prognostic value of collagen biomarkers in HF with reduced or mid-range LVEF lies on data concerning PIIINP and several MMPs and TIMP-1. Several prospective studies found that higher levels of PIIINP, several MMPs and TIMP-1 are associated with higher rates of mortality and/or HF hospital admissions in HF patients with LVEF < 50%. Circulating collagen biomarkers have been shown to play a role in prognostic stratification in heart failure patients with reduced or mid-range ejection fraction.

Effects of a physical activity program on the urinary collagen crosslinks in pre- and postmenopausal women.

This study analyzes the effects of physical exercise on urinary collagen crosslinks, pyridinoline (PYD) and deoxipyridinoline (DPD), in women. Thirty premenopausal (PRE) and 40 postmenopausal (PST) women took part in a six month randomized controlled trial of moderate physical exercise. Moreover, skinfold thickness, muscle strength and flexibility were evaluated. Basal values of urinary PYD and DPD were higher in postmenopausal women versus premenopausal women (P<0.01). Physical exercise increased in both groups urinary PYD levels (P<0.05) and urinary DPD levels in postmenopausal women (P<0.05). After the exercise program, no changes were observed in the levels of urinary DPD in premenopausal women. Significant improvements in flexibility, muscle strength and decrease in skinfolds thickness were observed in the exercise group. No changes were observed in non-exercise group. In conclusion, the physical activity program produced beneficial effects on muscle strength and flexibility and changes in the musculoskeletal system. Also, the physical activity program led to a non-pathological increase in the urinary elimination of bone reabsorption and collagen metabolism biomarkers.

Abstract 19260: Predictive Value of Circulating Biomarkers of Collagen Metabolism Following Catheter Ablation of Atrial Fibrillation

Introduction: Myocardial fibrosis plays an important role in the pathogenesis of atrial fibrillation (AF). However, catheter ablation may eliminate AF sources but also increases fibrosis. We aimed to assess the predictive value of circulating biomarkers of collagen metabolism following AF catheter ablation. Methods: Serum levels (ELISA) of biomarkers of collagen metabolism were analyzed in patients undergoing AF ablation (62 paroxysmal, 67 persistent) at baseline and 12 months after ablation. Biomarkers levels in 20 patients in sinus rhythm were also evaluated to establish the normal values. Results: Before ablation, there was a direct linear correlation between PICP (carboxy-terminal propeptide of procollagen type I) levels and left atrial diameter for the overall sample (p=0.006). PICP levels at baseline were lower in paroxysmal AF patients with vs. without AF recurrences following ablation (68.30 ± 9.66μg/l vs 90.72 ± 3.78μg/l; p=0.017). At 12 months following ablation of paroxysmal patients, PICP levels significantly increased only in patients with AF recurrences (21.74μg/l vs -0.12 μg/l, Figure). There were no significant changes in biomarkers levels in persistent AF patients at baseline or during follow-up. Conclusions: Progressive increase of PICP levels following catheter ablation of AF is related with arrhythmia recurrence in paroxysmal AF patients. This result suggests that ablation may increase collagen turnover in non-responders paroxysmal AF patients.

Abstract 15018: Idiopathic, Isolated, Fibrotic Atrial Cardiomyopathy: An Overlooked Type of Cardiomyopathy

Introduction Myocardium fibrosis is a hallmark of cardiomyopathy and a proposed substrate for cardiac arrhythmias. Nevertheless, fibrosis of atrial myocardium and fibrotic atrial cardiomyopathy has not been systemically addressed. Hypothesis We hypothesized that idiopathic, isolated, fibrotic atrial cardiomyopathy (IIF-ACM) is a specific cardiomyopathy, which is characterized by atrial fibrosis and related arrhythmias. Methods In the past 8 years, 34 patients (male 13, mean age 46.5±13.3 yrs) were diagnosed with IIF-ACM based on: 1) clinical evaluation; 2) cardiac image examination; and 3) electro-anatomic mapping detected atrial scarring. Serum biomarkers of collagen metabolism and cardiomyopathy-related genetic screening were performed. Tissue pathology and virus detections were done for two patients. Results During clinical evaluation, electric silent areas were detected in all patients by intra-cardiac electro-anatomical mapping. Among 34 patients, 26 presented with atrial tachycardia (AT), 5 with sick sinus syndrome (SSS) and 3 with atrial standstill. 5 AT patients further developed SSS during the correction of AT by radiofrequency ablation. Late gadolinium-enhancement cardiovascular magnet resonance showed mild to severely dilated atria, without bilateral ventricular scarring or functional impairment. Serum biomarkers of collagen screening demonstrated significant increased collagen synthesis than collagen degradation in IIF-ACM patients. Cardiomyopathy-related genetic screening depicted no clinically relevant mutation. Histological studies showed global fibrosis of atria (Fig. 1). Conclusions We systemically reported 34 patients with IIF-ACM, which is characterized by atrial scarring and relevant arrhythmias. Ventricular functions of note were preserved in all patients. However, the underlying etiology of IIF-ACM remains to be investigated.

Collagen Metabolism Biomarkers and Health Related Quality of Life in Pulmonary Arterial Hypertension.

The goal of this study was to investigate the association between collagen metabolism biomarkers and health related quality of life (HRQoL) in PAH patients. We prospectively enrolled 68 stable idiopathic, anorexigen-associated, and hereditary PAH subjects and 37 healthy controls. Serum samples were analyzed for N-terminal propeptide of type III procollagen (PIIINP), c-terminal telopeptide of collagen type I (CITP), matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinase 1 (TIMP-1). The Minnesota Living with Heart Failure (MLWHF), Euro QoL-5D (EQ-5D), Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) and Short Form (SF-36) general health survey were administered at the time of blood draw. General linear models, as well as logistic regression models were used to assess associations between variables. CITP, PIIINP, MMP9, and TIMP1 levels, and all HRQoL domains were significantly different between controls and PAH patients (p<0.001 for each). Interestingly, PIIINP levels were significantly associated with MLWHF physical (coef=1.63, and p=0.02), SF-36 physical (coef=-2.93, p=0.004), and EQ-5D aggregate (coef=0.34, p=0.001) scores. Several of the CAMPHOR scores strongly linearly associated with PIIINP. The odds of obtaining a walk distance ≥330 meters decrease by 38% per unit increase in PIIINP (OR=0.62; 95% CI=0.43, 0.90) and a PIIINP cutoff of 5.53 μg/L provided 81% sensitivity and 82% specificity. PIIINP is a good predictor of disease severity, and is strongly related to HRQoL scores in PAH patients. These relationships suggest PIIINP as a promising tool for PAH clinicians to determine or confirm the level of disease severity.

Circulating Collagen Biomarkers as Indicators of Disease Severity in Pulmonary Arterial Hypertension

ObjectivesThe goal of this study was to determine if biomarkers of collagen metabolism in PAH identify patients with worse disease and higher risk of death. BackgroundThe relationship between circulating markers of collagen metabolism, degree of disease severity, and outcome in pulmonary arterial hypertension (PAH) is unknown. MethodsPatients with stable idiopathic, anorexigen-associated, and hereditary PAH were prospectively enrolled. Levels of the following collagen biomarkers were measured: N-terminal pro-peptide of type III procollagen (PIIINP), C-terminal telopeptide of collagen type I (CITP), matrix metalloproteinase (MMP)-9, and tissue inhibitor of metalloproteinase (TIMP)-1. Patients were divided into mild, moderate, and severe PAH groups. Data were compared between tertiles of each biomarker. Pearson correlation and Spearman rank coefficient analyses were performed. Data on time to death or transplantation were examined by Kaplan-Meier survival curves. ResultsCirculating levels of PIIINP, CITP, MMP-9, and TIMP-1 were higher in the PAH group (n = 68) as compared with age- and sex-matched healthy controls (n = 37) (p < 0.001 for each). PIIINP levels increased with the severity of disease (p = 0.002). PIIINP tertile data indicated that with increasing levels, 6-min walk distance and cardiac index decreased, World Health Organization functional classification worsened, and resting heart rate increased. A significant correlation existed between PIIINP levels and worsening World Health Organization functional classification (rs = 0.320; p < 0.01), and there was a negative correlation between cardiac index and 6-min walk distance (r = −0.304 and r = −0.362, respectively; p < 0.05). PIIINP tertiles showed a trend toward worse outcome in patients with higher tertiles (lung transplant or death) (p = 0.07; log-rank test). ConclusionsMarkers of collagen metabolism were associated with worse disease in patients with PAH.

Relation of Burden of Myocardial Fibrosis to Malignant Ventricular Arrhythmias and Outcomes in Fabry Disease

The aim of this study was to investigate the impact of myocardial fibrosis in Fabry disease. Seventy-three patients with genetically confirmed Fabry disease were followed for 4.8 ± 2.4 years. In accordance with current guidelines, 57 patients received enzyme replacement therapy (ERT) after study inclusion, whereas 16 did not. At baseline and latest possible follow-up, myocardial fibrosis was assessed noninvasively by cardiac magnetic resonance, and biomarkers of collagen metabolism were determined. Holter electrocardiography and clinical follow-up at yearly intervals were used to monitor malignant ventricular arrhythmias (MVAs; nonsustained and sustained ventricular tachycardia and sudden cardiac death). In total, 48 patients (66%) showed fibrosis assessed by late enhancement (LE) at baseline, and 4 patients developed new LE during follow-up, 2 of them despite ERT. The 2 patients receiving ERT (1.4 ± 1.9% vs 2.5 ± 2.6%, p <0.001) and the patients not receiving ERT (0.5 ± 0.8% vs 0.7 ± 1.0%, p = 0.035) showed a progression of LE during follow-up. None of the patients displayed reductions of LE during follow-up. Collagen biomarkers were elevated in patients with and without LE but did not correlate with LE amount. Thirteen LE-positive patients at the baseline examination had documented MVAs (including 5 sudden cardiac deaths), whereas none of the patients without LE had MVAs. The yearly increase in fibrosis was 0.9 ± 0.6% in patients with MVAs and 0.2 ± 0.3% in patients without MVAs (p <0.001). Logistic multivariate regression analysis revealed that the annual increase in fibrosis during follow-up was the only independent predictor of MVAs. In conclusion, myocardial fibrosis in Fabry disease is progressive, apparently not modified by ERT, and a crucial outcome determinant.

Circulating biomarkers of collagen metabolism in arterial hypertension

Increasing experimental evidence indicates that alterations in the extracellular matrix are implicated in hypertension and its chronic complications. Selected markers of extracellular matrix metabolism were investigated as potential biomarkers for hypertensive remodelling and correlated with the severity and extent of target organ damage (TOD) in patients with essential hypertension. We studied 159 consecutive patients being treated for essential hypertension. An exhaustive evaluation of the heart, kidney and blood vessel damage was performed, and plasma levels of plasma procollagen type I (PICP), matrix metalloproteinase-1 (MMP-1) and its inhibitor (tissue inhibitor metalloproteinase-1, TIMP-1) were determined. Patients were categorized into four groups: no TOD (33 patients), level 1 TOD (52 patients), level 2 TOD (44 patients) and level 3 TOD (30 patients). The serum levels of MMP-1 and TIMP-1 were higher in patients with TOD than in hypertensive patients without TOD. Increasing levels of these molecules were progressively associated with an increase in the number of organs damaged, with highest levels of markers in patients with level 3 TOD (heart, kidney and blood vessels). There were no differences in PICP levels between groups. We found a slight but significant correlation between TIMP-1 and all hypertensive organ damage. Logistic regression analysis showed that age, smoking, diabetes mellitus, abdominal perimeter, MMP-1 and TIMP-1 were independently related to the level of TOD. Circulating concentration of MMP-1 and TIMP-1 is associated with an extended hypertensive disease, with more TOD. TIMP-1 may have a role as a biomarker of total remodelling burden in hypertensive patients.

FRI0403 How early starts increased collagen synthesis in systemic sclerosis?

BackgroundOne of the hallmarks of overt Systemic Sclerosis (SSc) is the interstitial and perivascular fibrosis resulting in functional impairment of affected organs. During the fibrotic process, the increased collagen synthesis...

Improvement in collagen metabolism after 12 weeks’ cardiac resynchronization therapy in patients with ischaemic cardiomyopathy

To investigate the effects of cardiac resynchronization therapy (CRT) on collagen metabolism biomarkers and their relationship to cardiac function, in patients with ischaemic cardiomyopathy (ICM). Serum levels of matrix metalloproteinase (MMP)-9, tissue inhibitor of MMP-9 (TIMP-1), carboxyterminal propeptide of type I procollagen (PICP) and carboxyterminal telopeptide of type I collagen (ICTP) were quantified before and after 12 weeks' treatment, in patients with ICM receiving CRT and standard medical therapy (CRT group) or standard medical therapy alone (non-CRT group), and in controls. Cardiac function was measured echocardiographically. MMP-9, TIMP-1, ICTP and the MMP-9/TIMP-1 ratio were significantly higher, and the PICP/ICTP ratio significantly lower, in patients with ICM (n = 27) compared with controls (n = 20). After 12 weeks' treatment, MMP-9, TIMP-1, ICTP and the MMP-9/TIMP-1 ratio were significantly higher, and the PICP/ICTP ratio significantly lower, in the non-CRT group (n = 15) compared with the CRT group (n = 12). The PICP/ICTP ratio correlated positively with TIMP-1 and negatively with MMP-9. The early/atrial ratio and left ventricular ejection fraction correlated positively and negatively, respectively, with the MMP-9/TIMP-1 ratio. Echocardiographic measurements of cardiac function were significantly worse in patients with ICM compared with controls and improved significantly after treatment in the CRT group. In ICM, collagen degradation biomarkers were elevated and correlated positively with cardiac function. CRT partially reversed the deterioration in collagen metabolism and enhanced cardiac function.

Circulating biomarkers of collagen type I metabolism mark the right ventricular fibrosis and adverse markers of clinical outcome in adults with repaired tetralogy of Fallot

BackgroundRight ventricular (RV) fibrosis is common in patients with repaired tetralogy of Fallot (rTOF). Although accumulating evidence indicates the role of circulating biomarkers of collagen metabolism in left ventricular fibrosis, rTOF data are lacking. This study examined the expression profile and clinical relevance of circulating biomarkers of collagen type I metabolism in rTOF patients. MethodsSerum biomarkers of collagen type I synthesis (carboxy-terminal propeptide of procollagen type I, PICP), degradation (carboxy-terminal telopeptide of collagen type I, CITP), and enzymes regulating collagen degradation (matrix metalloproteinases, and type I tissue inhibitor, TIMP-1) were measured in 70 rTOF and 91 control adults. All patients had complete clinical data and received cardiovascular magnetic resonance scans with late gadolinium enhancement (LGE). ResultsCompared to the controls, rTOF patients had higher PICP levels (p<0.001), PICP:CITP ratios (p<0.001), and TIMP-1 concentrations (p<0.001). Increasing PICP levels correlated with higher RV LGE scores (r=0.427, p<0.001), lower VO2max (r=−0.428, p=0.002), and larger RV volumes. Furthermore, stepwise multivariate linear regression analysis identified RV end-diastolic volume index >150mL/m2 (β=40.52, p=0.016), RV LGE score (β=3.94, p=0.008), and age (β=−1.77, p=0.011) as independent correlates of circulating PICP levels. ConclusionsPatients with rTOF exhibited a profibrotic state with excessive collagen type I synthesis and dysregulated degradation. Elevated circulating PICP levels might reflect RV fibrosis, and link to adverse markers of clinical outcome.

Cardiac microinjury measured by troponin T predicts collagen metabolism in adults aged >=65 years with heart failure.

Repeated myocardial microinjuries lead to collagen deposition and fibrosis, thereby increasing the risk of clinical heart failure. Little is known about the longitudinal association between increases in myocardial injury and the biology of collagen synthesis and deposition. Repeated measures of highly sensitive cardiac troponin T (cTnT) were obtained in participants of the Cardiovascular Health Study (N=353; mean age, 74±6 years; 52% women) at baseline and at 3 years follow-up. Biomarkers of collagen metabolism were obtained at follow-up and included carboxyterminal propeptide of procollagen type I, carboxyterminal telopeptide of type I collagen, and aminoterminal propeptide of procollagen III. Multivariable linear regression analyses were used to examine the association between baseline cTnT and changes in cTnT with collagen metabolism markers at follow-up adjusting for demographics, heart failure status, and cardiovascular risk factors. Results indicated that cTnT increases over 3-years were significantly associated with higher levels of carboxyterminal telopeptide of type I collagen (β=0.22, P<0.001) and aminoterminal propeptide of procollagen III (β=0.12, P=0.035) at follow-up when adjusting for demographic, clinical, and biochemical covariates including baseline cTnT. These associations were stronger in patients with heart failure than in control subjects. Conclusions- Increases in myocardial microinjury measured by changes in cTnT adversely affect markers of collagen metabolism. These findings are important to the biology of myocardial fibrosis and tissue repair. Serial evaluation of cTnT combined with collagen metabolism markers may further elucidate the pathophysiology of heart failure.