Carboxy-terminal Telopeptide Of Collagen Type Research Articles

The Role of Two Heart Biomarkers in IgA Nephropathy.

Cardiovascular mortality is a leading cause of death in chronic kidney disease (CKD), as is IgA nephropathy (IgAN). The purpose of this study is to find different biomarkers to estimate the outcome of the disease, which is significantly influenced by the changes in vessels (characterized by arterial stiffness) and the heart. In our cross-sectional study, 90 patients with IgAN were examined. The N-terminal prohormone of brain natriuretic peptide (NT-proBNP) was measured as a heart failure biomarker by an automated immonoassay method, while the carboxy-terminal telopeptide of collagen type I (CITP) as a fibrosis marker was determined using ELISA kits. Arterial stiffness was determined by measuring carotid-femoral pulse wave velocity (cfPWV). Renal function and routine echocardiography examinations were performed as well. Based on eGFR, patients were separated into two categories, CKD 1-2 and CKD 3-5. There were significantly higher NT-proBNP (p = 0.035), cfPWV (p = 0.004), and central aortic systolic pressure (p = 0.037), but not CITP, in the CKD 3-5 group. Both biomarker positivities were significantly higher in the CKD 3-5 group (p = 0.035) compared to the CKD 1-2 group. The central aortic systolic pressure was significantly higher in the diastolic dysfunction group (p = 0.034), while the systolic blood pressure was not. eGFR and hemoglobin levels showed a strong negative correlation, while left ventricular mass index (LVMI), aortic pulse pressure, central aortic systolic pressure, and cfPWV showed a positive correlation with NT-proBNP. cfPWV, aortic pulse pressure, and LVMI showed a strong positive correlation with CITP. Only eGFR was an independent predictor of NT-proBNP by linear regression analysis. NT-proBNP and CITP biomarkers may help to identify IgAN patients at high risk for subclinical heart failure and further atherosclerotic disease.

THE RELATIONSHIP BETWEEN ARTERIAL STIFFNESS, SUBCLINICAL HEART FAILURE, CARDIAC FIBROSIS AND RENAL FUNCTION IN CHRONIC KIDNEY DISEASE, IGA NEPHROPATHY

Objective: IgA nephropathy (IgAN) is the most common primary glomerular disease worldwide. Arterial stiffness may predict cardiovascular (CV) mortality and morbidity in chronic kidney disease (CKD). Heart failure is very common in advanced CKD stages. Onset of myocardial fibrosis may be a pathophysiological alteration in CKD patients with heart failure. Design and method: In our cross-sectional study, we examined 90 patients who cared for IgAN in our clinic. Arterial stiffness was determined by measuring carotis-femoral pulse wave velocity (cfPWV) using the ShygmoCor device. N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and carboxy-terminal telopeptide of collagen type I (CITP) were measured using ELISA kits. Renal function was detected by the estimated glomerular filtration rate (eGFR-CKD-EPI). Furthermore, a routine echocardiography examination was performed. Results: Of the 90 patients included in the study, 50 were male, with a mean age of 54.9 ± 14.4 years. Patients were divided into two groups based on eGFR (CKD 1-2 and CKD 3-5). There were significantly higher NT-proBNP (p = 0.035), cfPWV (p = 0.004), and central aortic systolic pressure (p = 0.037), but not CITP, in the CKD 3-5 group. The number of patients with combined biomarker positivity (NT-proBNP and CITP) was also significantly higher in the CKD3-5 group (p = 0.035) compared to the CKD 1-2 group. The central aortic systolic pressure was significantly higher in the diastolic dysfunction group (p = 0.034), but the systolic blood pressure was not. eGFR and hemoglobin level showed a strong negative correlation, while left ventricular mass index (LVMI), aortic pulse pressure, central aortic systolic pressure, and cfPWV showed a positive correlation with NT-proBNP. cfPWV, aortic pulse pressure, and LVMI showed a strong positive correlation with CITP by Spearman's correlation. Only eGFR was an independent predictor of NT-proBNP by linear regression analysis. Conclusions: A possible mechanism for the development of heart failure in CKD patients may be an elevation of central aortic systolic pressure. NT-proBNP and CITP biomarkers may help to identify IgAN patients at high risk for subclinical heart failure and further atherosclerotic disease.

Exploring the potential relationship between collagen cross-linking and impaired myocardial relaxation in Marfan syndrome: An observational study using serum biomarkers

BackgroundIncreased collagen cross-linking (CCL) has been described in hypertensive cardiomyopathy by means of reduced serum ratio of serum carboxyterminal telopeptide of collagen type I (CITP) to matrix metalloproteinase-1 (MMP1). Previous studies have demonstrated the existence of primary impaired diastole in patients with Marfan syndrome (MFS), but little is known about the pathophysiology of this condition. Methods60 MFS patients (without previous cardiovascular surgery or significant valvular regurgitation) and 24 healthy controls (age and sex-matched) were enrolled. All participants underwent a comprehensive transthoracic echocardiographic study, including left atrial and left ventricular speckle-tracking strain analysis. CITP and MMP1 were measured in peripheral blood. ResultsAll participants had normal diastolic function according to guidelines. Peak left atrial strain in the reservoir phase (LASr) was significantly reduced in the MFS cohort compared to controls (32.2 ± 9.4 vs 43.9 ± 7.0%; p < 0.001). Serum CITP and CITP:MMP1 ratio were lower among MFS patients, showing significant correlations with LASr (R = 0.311; p = 0.020 and R = 0.437; p = 0.001, respectively). The MFS cohort was divided into quartiles of LASr. MFS patients in the lowest quartile of LASr (<26%) had significantly lower values of CITP:MMP1 ratio compared to the other quartiles. ConclusionsThe analysis of serum biomarkers revealed the presence of increased CCL in association with reduced LASr in the MFS cohort. Our results suggest that excessive CCL may play a role in the development of primary myocardial impairment in these patients. Future studies are needed to confirm our findings and evaluate the prognostic role of CCL markers in the MFS population.

Biomarkers as predictors of recurrence of atrial fibrillation post ablation: an updated and expanded systematic review and meta-analysis

BackgroundA high proportion of patients undergoing catheter ablation (CA) for atrial fibrillation (AF) experience recurrence of arrhythmia. This meta-analysis aims to identify pre-ablation serum biomarker(s) associated with arrhythmia recurrence to improve patient selection before CA.MethodsA systematic approach following PRISMA reporting guidelines was utilised in libraries (Pubmed/Medline, Embase, Web of Science, Scopus) and supplemented by scanning through bibliographies of articles. Biomarker levels were compared using a random-effects model and presented as odds ratio (OR). Heterogeneity was examined by meta-regression and subgroup analysis.ResultsIn total, 73 studies were identified after inclusion and exclusion criteria were applied. Nine out of 22 biomarkers showed association with recurrence of AF after CA. High levels of N-Terminal-pro-B-type-Natriuretic Peptide [OR (95% CI), 3.11 (1.80–5.36)], B-type Natriuretic Peptide [BNP, 2.91 (1.74–4.88)], high-sensitivity C-Reactive Protein [2.04 (1.28–3.23)], Carboxy-terminal telopeptide of collagen type I [1.89 (1.16–3.08)] and Interleukin-6 [1.83 (1.18–2.84)] were strongly associated with identifying patients with AF recurrence. Meta-regression highlighted that AF type had a significant impact on BNP levels (heterogeneity R2 = 55%). Subgroup analysis showed that high BNP levels were more strongly associated with AF recurrence in paroxysmal AF (PAF) cohorts compared to the addition of non-PAF patients. Egger’s test ruled out the presence of publication bias from small-study effects.ConclusionRanking biomarkers based on the strength of association with outcome provides each biomarker relative capacity to predict AF recurrence. This will provide randomised controlled trials, a guide to choosing a priori tool for identifying patients likely to revert to AF, which are required to substantiate these findings.Graphical abstract

Circulating Cardiac Biomarkers in Diabetes Mellitus: A New Dawn for Risk Stratification-A Narrative Review.

The aim of this narrative review is to update the current knowledge on the differential choice of circulating cardiac biomarkers in patients with prediabetes and established type 2 diabetes mellitus (T2DM). There are numerous circulating biomarkers with unconfirmed abilities to predict clinical outcomes in pre-DM and DM individuals; the prognostication ability of the cardiac biomarkers reported here has been established, and they are still being studied. The conventional cardiac biomarkers, such as natriuretic peptides (NPs), soluble suppressor tumorigenisity-2, high-sensitivity circulating cardiac troponins and galectin-3, were useful to ascertain cardiovascular (CV) risk. Each cardiac biomarker has its strengths and weaknesses that affect the price of usage, specificity, sensitivity, predictive value and superiority in face-to-face comparisons. Additionally, there have been confusing reports regarding their abilities to be predictably relevant among patients without known CV disease. The large spectrum of promising cardiac biomarkers (growth/differential factor-15, heart-type fatty acid-binding protein, cardiotrophin-1, carboxy-terminal telopeptide of collagen type 1, apelin and non-coding RNAs) is discussed in the context of predicting CV diseases and events in patients with known prediabetes and T2DM. Various reasons have been critically discussed related to the variable findings regarding biomarker-based prediction of CV risk among patients with metabolic disease. It was found that NPs and hs-cTnT are still the most important tools that have an affordable price as well as high sensitivity and specificity to predict clinical outcomes among patients with pre-DM and DM in routine clinical practice, but other circulating biomarkers need to be carefully investigated in large trials in the future.

A panel of multibiomarkers of inflammation, fibrosis, and catabolism is normal in healthy centenarians but has high values in young patients with myocardial infarction

ObjectivesFrailty confers a poor prognosis as it portends an increased risk of disability, dependence, and mortality. Although frailty is generally associated with aging, a marked interindividual variability exists. We compared a range of serum biomarkers of inflammation, fibrosis, and catabolism in three distinct cohorts, consisting of young patients with myocardial infarction, age-matched healthy volunteers, and disease-free centenarians. Study designProspective observational registry study. Main outcome measuresSerum levels of five biomarkers were measured in the three study groups. ResultsDisease-free centenarians had significantly lower (all p < 0.01) serum biomarker levels than young patients with myocardial infarction (growth differentiation factor 15: 877 ± 299 vs. 1062 ± 358 pg/mL; matrix metalloproteinase (MMP)-1: 1.7 ± 0.9 vs. 3.2 ± 1.2 ng/mL; MMP-2 174 ± 38 vs. 214 ± 44 ng/mL; MMP-9 325 ± 73 vs. 407 ± 54 ng/mL; and carboxy-terminal telopeptide of collagen type I: 3.3 ± 1 vs. 4.2 ± 1.3 ng/mL). No significant differences in biomarker concentrations between healthy controls and centenarians were identified. ConclusionsDisease-free centenarians had significantly lower levels of inflammation, fibrosis, and catabolism biomarkers than young patients with myocardial infarction. Advanced aging per se is not invariably associated with these biomarkers.

Collagen biomarkers and subclinical interstitial lung disease: The Multi-Ethnic Study of Atherosclerosis.

Lung fibrosis is attributed to derangements in extracellular matrix remodeling, a process driven by collagen turnover. We examined the association of two collagen biomarkers, carboxy-terminal telopeptide of collagen type I (ICTP) and amino-terminal propeptide of type III procollagen (PIIINP), with subclinical interstitial lung disease (ILD) in adults. We performed a cross-sectional analysis of 3244 participants age 45-84 years in the Multi-Ethnic Study of Atherosclerosis. Serum ICTP and PIIINP levels were measured at baseline by radioimmunoassay. Subclinical ILD was defined as high attenuation areas (HAA) in the lung fields on baseline cardiac CT scans. Interstitial lung abnormalities (ILA) were measured in 1082 full-lung CT scans at 9.5 years median follow-up. We used generalized linear models to examine the associations of collagen biomarkers with HAA and ILA. Median (IQR) for ICTP was 3.2 μg/L (2.6-3.9 μg/L) and for PIIINP was 5.3 μg/L (4.5-6.2 μg/L). In fully adjusted models, each SD increment in ICTP was associated with a 1.3% increment in HAA (95% CI 0.2-2.4%, p = 0.02) and each SD increment in PIIINP was associated with a 0.96% increment in HAA (95% CI 0.06-1.9%, p = 0.04). There was no association between ICTP or PIIINP and ILA. There was no evidence of effect modification by gender, race, smoking status or eGFR. Higher levels of collagen biomarkers are associated with greater HAA independent of gender, race and smoking status. This suggests that extracellular matrix remodeling may accompany subclinical ILD prior to the onset of clinically evident disease.

Biomarker‐based phenotyping of myocardial fibrosis identifies patients with heart failure with preserved ejection fraction resistant to the beneficial effects of spironolactone: results from the Aldo‐DHF trial

Myocardial fibrosis is characterized by excessive cross-linking and deposition of collagen type I and is involved in left ventricular stiffening and left ventricular diastolic dysfunction (LVDD). We investigated whether the effect of spironolactone on LVDD in patients with heart failure with preserved ejection fraction (HFpEF) depends on its effects on collagen cross-linking and/or deposition. We investigated 381 HFpEF patients from the multicentre, randomized, placebo-controlled Aldo-DHF trial with measures of the E:e' ratio. The ratio of serum carboxy-terminal telopeptide of collagen type I to serum matrix metalloproteinase-1 (CITP:MMP-1, an inverse index of myocardial collagen cross-linking) and serum carboxy-terminal propeptide of procollagen type I (PICP, a direct index of myocardial collagen deposition) were determined at baseline and after 1-year treatment with spironolactone 25 mg once daily or placebo. Patients were classified by CITP:MMP-1 and PICP tertiles at baseline. While CITP:MMP-1 tertiles at baseline interacted (P < 0.05) with spironolactone effect on E:e', PICP tertiles did not. In fact, while spironolactone treatment did not modify E:e' in patients with lower CITP:MMP-1 levels, this ratio was significantly reduced in the remaining spironolactone-treated patients. In addition, PICP was unchanged in patients with lower CITP:MMP-1 levels but was reduced in the remaining spironolactone-treated patients. A biochemical phenotype of high collagen cross-linking identifies HFpEF patients resistant to the beneficial effects of spironolactone on LVDD. It is suggested that excessive collagen cross-linking, which stabilizes collagen type I fibres, diminishes the ability of spironolactone to reduce collagen deposition in these patients.

Bone metabolism markers and angiogenic cytokines as regulators of human hematopoietic stem cell mobilization.

Hematopoietic stem cell (HSC) mobilization involves cleavage of ligands between HSC and niche components. However, there are scarce data regarding the role of bone cells in human HSC mobilization. We studied biochemical markers of bone metabolism and angiogenic cytokines during HSC mobilization in 46 patients' sera with lymphoma and multiple myeloma, by ELISA. Significant changes between pre-mobilization and collection samples were found: (1) Bone alkaline phosphatase (BALP) increased, indicating augmentation of bone formation; (2) Receptor activator of Nf-κB ligand/osteoprotegerin ratio (RANKL/OPG) increased, showing osteoclastic differentiation and survival; however, there was no evidence of increased osteoclastic activity; and (3) Angiopoietin-1/Angiopoietin-2 ratio (ANGP-1/ANGP-2) decreased, consistent with vessel destabilization. Poor mobilizers had significantly higher carboxy-terminal telopeptide of collagen type I (CTX) and lower ANGP-1 at pre-mobilization samples, compared to good ones. CTX, amino-terminal telopeptide of collagen type I (NTX) and ANGP-1 pre-mobilization levels correlated significantly with circulating CD34+ peak cell counts. Our results indicate that bone formation and vessel destabilization are the two major events during human HSC mobilization. Osteoblasts seem to be the orchestrating cells, while osteoclasts are stimulated but not fully active. Moreover, ANGP-1, CTX and NTX may serve as predictors of poor mobilization.

Phenotyping of myocardial fibrosis in hypertensive patients with heart failure. Influence on clinical outcome.

Myocardial fibrosis is associated with alterations in the cross-linking and deposition of collagen type I (CCL and CD, respectively). We aimed to evaluate whether the combination of circulating biomarkers of CCL [the carboxy-terminal telopeptide of collagen type I to matrix metalloproteinase-1 ratio (CITP : MMP-1)] and CD [the carboxy-terminal propeptide of procollagen type I (PICP)] identifies myocardial fibrosis phenotypes with distinct clinical outcome in hypertensive patients with heart failure. Endomyocardial biopsies and blood samples from 38 patients (small cohort), and blood samples from 203 patients (large cohort) were analyzed. Myocardial CCL and CD were assessed by histological methods. Serum PICP, CITP, and MMP-1 were determined by ELISA. Small cohort: CITP : MMP-1 cutoff 1.968 or less and PICP cutoff at least 110.8 ng/ml were used for predicting high CCL and severe CD, respectively. Large cohort: as defined by the above thresholds, patients were categorized into four subgroups based on the presence (+) or absence (-) of high CCL and severe CD. Compared with CCL-CD-, the adjusted hazard ratios for a composite end point of heart failure hospitalization or cardiovascular death over 5 years in CCL-CD+, CCL+CD-, and CCL+CD+ were 1.11 (P = 0.79), 1.99 (P = 0.07), and 2.18 (P = 0.04), respectively (P for trend = 0.005). In addition, the categorization based on CCL and CD yielded integrated discrimination (P = 0.03) and net reclassification (P = 0.01) improvements for the mentioned outcome. The combination of low serum CITP : MMP-1 ratio and high serum PICP identifies hypertensive patients with heart failure presenting with a phenotype of myocardial fibrosis characterized by the concurrence of excessive CCL and CD and associated with poor outcome.

Bone mass and bone turnover in premenopausal women with fibromyalgia syndrome

In this study, we aimed to compare osteoporosis (OP)-related bone mineral density, and bone turnover (markers of formation, and resorption) between patients with Fibromyalgia Syndrome (FMS) and degenerative disc disease, and to determine the relationship of these parameters with clinical, functional and emotional evaluation outcomes in FMS. Fifty premenopausal women with FMS and 50 premenopausal female control patients with degenerative disc disease were enrolled. The patient and physician’s global assessment of disease were assessed on a visual analog scale (VAS). Disease severity was determined with the Fibromyalgia Impact Questionnaire (FIQ). For the evaluation of fatigue The Modified Fatigue Impact Scale (MFIS) and Fatigue Severity Scale (FSS) were used. The quality of life of all patients was evaluated using Nottingham Health Profile (NHP), Oswestry Disability Index (ODI), and QUALEFFO-41. The emotional state of all patients with chronic pain was evaluated with Hospital Anxiety and Depression Scale (HADS). Bone turnover markers [serum bone-specific alkaline phosphatase (bALP) and serum osteocalcin as markers of bone formation, serum â-isomerized Carboxy-terminal telopeptide of collagen type I (â-CTX) and urine hydroxyproline (OH-Pro) as markers of bone resorption], serum parathyroid hormone (PTH) and 25-hydroxyvitamin D [25(OH)D] levels, lumbar spine and left proximal femur bone mineral density (BMD) and T scores were measured in both groups. The FIQ, MFIS, FSS, NHP, ODI, QUALEFFO-41, HADS-A and HADS-D scores were statistically significantly higher in the FMS group relative to the patient control group. A significant difference between FMS and patient control group as for bone formation (bALP and osteocalcin) and resorption (â-CTX ve OH-Pro) markers was not detected. In the FMS group lumbar spine and left proximal femur BMD and T score values were significantly lower when compared with the patient control group. In the FMS group significant correlations were found between serum 25(OH)D and â-CTX values and VAS scores evaluated by the patient and physician, SS scale, FIQ, MFIS, ODI, QUALEFFO-41 and NHP scores. In conclusion many factors including depression and anxiety attacks, the presence of widespread pain and a decline in physical activity level and quality of life in FMS patients make them more prone to osteoporosis. In patients with FMS, osteoporosis is a major cause of morbidity and should not be neglected.

Effect of ramipril/hydrochlorothiazide and ramipril/canrenone combination on atrial fibrillation recurrence in hypertensive type 2 diabetic patients with and without cardiac autonomic neuropathy.

IntroductionThe aim of this study was to compare the effect of ramipril/canrenone versus ramipril/hydrochlorothiazide (HCTZ) combination on atrial fibrillation (AF) recurrence in type 2 diabetic hypertensives with and without cardiac autonomic neuropathy (CAN).Material and methodsA total of 289 hypertensive type 2 diabetic patients, 95 with CAN, in sinus rhythm but with at least two episodes of AF in the previous 6 months were randomized to ramipril 5 mg plus canrenone 50 mg (titrated to 10/100 mg) or to ramipril 5 mg plus HCTZ 12.5 mg (titrated to 10/25 mg) or to amlodipine 5 mg (titrated to 10 mg) for 1 year. Clinic blood pressure (BP) and a 24-h ECG were evaluated monthly. Patients were asked to report any episode of symptomatic AF and to perform an ECG as early as possible. Serum procollagen type I carboxy-terminal peptide (PIP) and carboxy-terminal telopeptide of collagen type I (CITP) were evaluated before and after each treatment period.ResultsBlood pressure was similarly and significantly reduced by all treatments. A total of 51% of patients with amlodipine had a recurrence of AF, as did 31% of patients with ramipril/HCTZ (p < 0.05 vs. amlodipine) and 13% of patients with ramipril/canrenone (p < 0.01 vs. amlodipine and p < 0.05 vs. ramipril/HCTZ). A similar trend was found in diabetic patients with CAN. Both combinations reduced PIP and increased CITP, but the effects of ramipril/canrenone were significantly more marked.ConclusionsThese findings suggest that in type 2 diabetic hypertensives, ramipril/canrenone treatment was more effective than ramipril/HCTZ in reducing AF recurrence. This could be related to the greater improvement in cardiac fibrosis.

Decreased bone mineral density and alteration in biochemical bone metabolism markers in children affected by bone tumors after completion of therapy.

The aim of this study was to assess bone mineral density (BMD) and biochemical bone metabolism markers in patients with bone tumors after anti-cancer treatment. The study included 27 patients (median age 15 years) with malignant bone tumors and 27 healthy children. In all subjects, BMD and body composition were measured by dual-energy x-ray absorptiometry. Serum bone markers were determined by immunoenzymatic assays. After completion of treatment, patients with bone tumors had significantly decreased total and lumbar spine BMD. We observed lower calcium and vitamin Dlevels in patients and comparable values of bone turnover markers (carboxyterminal telopeptide of collagen type I- CTX, bone alkaline phosphatase - BALP and osteocalcin - OC) in both groups of children. However, the level of carboxylated osteocalcin (cOC) was significantly lower (p<0.01) and undercarboxylated OC (ucOC) was higher (p<0.05) in patients than in controls. Additionally, we observed similar values of anthropometric parameters in the subgroups of patients treated with methotrexate (MTX) or without MTX. In patients treated without MTX we found lower (p<0.05) ratio of cOC/ucOC, lower vitamin Dlevel and higher CTX concentrations. Patients with bone tumors after anticancer treatment had decreased bone mineral density and alterations in bone metabolism markers with potential decrease in bone formation. bone cancer survivors, bone mineral density, bone formation markers, bone resorption markers, methotrexate.

Clinical outcome, echocardiographic assessment, neurohormonal and collagen turnover markers in low-fl ow severe aortic stenosis with high transvalvular gradient

Patients with severe aortic stenosis (AS), high mean gradient (HMG), and preserved left ventricular ejection fraction (LVEF) may present with paradoxical "low flow" (LF). The aim of the study was to assess the potential effect of cardiac collagen metabolism on the HMG/LF phenomenon in patients with severe AS and to determine a clinical and echocardiographic pattern of these patients. We assessed a clinical status of 89 patients, aged over 64 years, with severe AS, HMG, and preserved LVEF (≥50%). Cardiac structure and function as well as systemic arterial hemodynamics were assessed with echocardiography, conventional Doppler, and tissue Doppler imaging. Moreover, plasma levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP), procollagen III N-terminal propeptide (PIIINP), carboxyterminal telopeptide of collagen type I, matrix metallopeptidase 9, and inhibitor of matrix metalloproteinase type 1 were evaluated. We analyzed 2 groups of patients: with normal flow (stroke volume index [SVI], ≥35 ml/m²; n = 70) and with LF (SVI, <35 ml/m²; n = 19). Patients with LF were older, had a larger left atrium and left atrial volume index, smaller aortic valve area, lower energy loss index, stroke work, mitral flow E velocity, mitral annular E' and S' velocities and systemic arterial compliance, higher relative left ventricular wall thickness, E/E', systemic arterial resistance and valvulo-arterial impedance. We observed a correlation between SVI and NT-proBNP, PIIINP, and selected parameters of cardiac structure and function. In patients with severe AS, HMG and preserved LVEF, the LF is related to a more severe obstruction, altered aortic hemodynamics, cardiac dysfunction, and higher blood levels of NT-proBNP. An inverse association between PIIINP and SVI may indicate enhanced tissue fibrosis as an underlying pathology.

Cardiovascular Phenotype in HFpEF Patients With or Without Diabetes: A RELAX Trial Ancillary Study

BackgroundThe RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction) study was a multicenter, randomized trial of sildenafil versus placebo in heart failure with preserved ejection fraction (HFpEF) with rigorous entry criteria and extensive phenotypic characterization of participants. ObjectivesThe aim of this study was to characterize clinical features, exercise capacity, and outcomes in patients with HFpEF with or without diabetes and gain insight into contributing pathophysiological mechanisms. MethodsThe RELAX study enrolled 216 stable outpatients with heart failure, an ejection fraction ≥50%, increased natriuretic peptide or intracardiac pressures, and reduced exercise capacity. Prospectively collected data included echocardiography, cardiac magnetic resonance, a comprehensive biomarker panel, exercise testing, and clinical events over 6 months. ResultsCompared with nondiabetic patients (n = 123), diabetic HFpEF patients (n = 93) were younger, more obese, and more often male and had a higher prevalence of hypertension, renal dysfunction, pulmonary disease, and vascular disease (p < 0.05 for all). Uric acid, C-reactive protein, galectin-3, carboxy-terminal telopeptide of collagen type I, and endothelin-1 levels were higher in diabetic patients (p < 0.05 for all). Diabetic patients had more ventricular hypertrophy, but systolic and diastolic ventricular function parameters were similar in diabetic and nondiabetic patients except for a trend toward higher filling pressures (E/e′) in diabetic patients. Diabetic patients had worse maximal (peak oxygen uptake) and submaximal (6-min walk distance) exercise capacity (p < 0.01 for both). Diabetic patients were more likely to have been hospitalized for heart failure in the year before study entry (47% vs. 28%, p = 0.004) and had a higher incidence of cardiac or renal hospitalization at 6 months after enrollment (23.7% vs. 4.9%, p < 0.001). ConclusionsHFpEF patients with diabetes are at increased risk of hospitalization and have reduced exercise capacity. Multimorbidity, impaired chronotropic reserve, left ventricular hypertrophy, and activation of inflammatory, pro-oxidative, vasoconstrictor, and profibrotic pathways may contribute to adverse outcomes in HFpEF patients with diabetes. (Evaluating the Effectiveness of Sildenafil at Improving Health Outcomes and Exercise Ability in People With Diastolic Heart Failure [The RELAX Study]; NCT00763867)

Biomarkers of collagen type I metabolism are related to B-type natriuretic peptide, left ventricular size, and diastolic function in heart failure.

Myocardial collagen metabolism can be assessed indirectly by circulating biomarkers. We aimed to examine associations between myocardial collagen type I synthesis and degradation, and echocardiographic, clinical, and B-type natriuretic peptide (BNP) findings in heart failure. We studied 57 women and 75 men 60 years or older with systolic heart failure (New York Heart Association II-IV and an ejection fraction ≤ 45%). Mean age was 75 years, blood pressure 134/80 mmHg, ejection fraction 34%, and median BNP 210 ng/l. Analyses of the carboxy-terminal propeptide of procollagen type I (PICP, biomarker of collagen type I synthesis) and the serum carboxy-terminal telopeptide of collagen type I (CITP, biomarker of collagen type I degradation) were measured. Extensive echocardiographic examinations were performed, including variables of dyssynchrony. Increased collagen synthesis (PICP) was independently related to increased BNP levels (r = 0.24, P = 0.018). Furthermore, independent associations were found between PICP and left ventricular size, isovolumic relaxation time, and relative wall thickness. Increased collagen degradation (CITP) was independently related to increased BNP levels (r = 0.35, P < 0.001). Also, univariable, but not multivariable, associations were found between CITP and E/E' septal and QRS duration. Biomarkers of collagen type I synthesis and degradation are independently related to BNP and to indices of left ventricular size and diastolic function in systolic heart failure. It is proposed that BNP may contribute to alterations in collagen type I metabolism in systolic heart failure.

Riesgo de fractura osteoporótica mayor y de cadera en pacientes con accidente cerebrovascular en fase aguda: estudio prospectivo multicéntrico

Summary Objetives: Hemiplegic patients are considered to be a population at risk of suffering osteoporotic fractures. The aim of this work is to understand the absolute risk of fragility fracture in patients with cerebrovascular accident (CVA) and the osteometabolic state of patients with ictus in the acute phase, as well as confirming if there are baseline differences compared to a control group without cerebrovascular pathology. Patients and method: Multicentre prospective study carried out in five Spanish hospitals. Two groups were established: a) patients with ictus of less than three months development, and b) a control group from a population without cerebrovascular disease. History of fragility fractures, number of falls in the previous year, bone mineral density (BMD) in the hip, FRAX ® index, determinations of biochemistry and bone markers - calcium, phosphorus, alkaline phosphatase, vitamin D, parathormone (PTH), and carboxy-terminal telopeptide of collagen type I (CTX) - were analysed. Results: A total of 82 patients were studied: 50 patients with CVA and 32 controls. 12% of those patients with CVA had an increased risk of suffering a hip fracture, and 8% an increased risk of a major osteoporotic fracture. In the control group the risk was greater. The hemiplegic patients had BMD in the hip lower than those in the control group, although the differences in both variables were not statistically significant. The levels of CTX were higher in patients with CVA, this being the sole determination which showed a statistical difference between the two groups studied. Conclusions: The patients with CVA had values of markers for bone resorption (CTX) significantly higher and a BMD in the hip lower than those in the control group.

Esclerostina y Dkk-1 séricos en pacientes que inician tratamiento con glucocorticoides: resultados preliminares

Summary Background and objectives: The Wnt pathway and its inhibitors (sclerostin and Dkk-1) have a primary role in the regulation of bone mass and osteoblastogenesis. The objective of this study was to analyse the effect of treatment with glucocorticoids (GCC) on the inhibitors of the Wnt pathway and their relationship with bone mass and the parameters for bone turnover. Methods: A transverse study including 15 patients (9 women and 6 men) with an mean age of 51±21 years at the start of treatment with GCC (≥7.5 mg/day, ≤6 months). Levels of sclerostin, blood Dkk-1 and blood markers for bone turnover (procollagen 1 N-terminal propeptide [P1NP], osteocalcin [OC], and carboxyterminal telopeptide of collagen type 1 [CTX] ) were determined, and bone densitometry ( DXA) in the lumbar spine was carried out, in all patients. The results were compared with a control group. Results: The mean dose of glucocorticoids was 58±21 mg/day, in the majority of patients (73%) indicated by idiopathic thrombocytopenic purpura. The patients treated with glucocorticoids had a reduction in the parameters for bone formation compared with a control group (OC: 7.4±2.8 vs 24.4±6.2 ng/ml, p<0.01) and a reduction in blood Dkk-1 (29.6±23.6 vs 48.3±15.6 pmol/L, p=0.02). No significant differences were observed in values for blood sclerostin, although this correlated positively with the dose of GCC received and lumbar bone mineral density. Conclusion: Contrary to what is seen in experimental studies, the start of treatment with glucocorticoids is associated with a reduction in blood levels of Dkk-1. These results indicate the necessity of analysing these inhibitors and their relationship with remodelling and bone mass during this process over the long term.

Can markers of collagen turnover or other biomarkers contribute to the diagnostics of heart failure with normal left ventricular ejection fraction?

Plasma levels of some biomarkers and markers of collagen turnover may reflect myocardial structural abnormalities associated with diastolic dysfunction. The aim of this study was to determine whether these markers could contribute to the diagnostics of heart failure with normal ejection fraction (HFNEF). 91 patients with exertional dyspnea and normal left ventricular ejection fraction and 20 healthy controls underwent plasma analysis of markers of collagen turnover and other biomarkers, spirometry, and resting and exercise echocardiography. 38 patients with dyspnea had evidence of HFNEF, diagnosed at the early stage. Compared to the remaining patients, those with HFNEF had a significantly higher plasma levels of carboxy-terminal telopeptide of collagen type I (median 4.5 µg/L vs. 3.5 µg/L, P<0.05) and big endothelin (median 1.1 pmol/L vs 0.9 pmol/L, P<0.05). Univariate logistic regression analysis revealed a significant association between HFNEF and the following biomarkers: big endothelin, amino-terminal propeptide of type III procollagen (PIIINP), and matrix metalloproteinase-2 (MMP-2). However, none of these biomarkers independently contributed to the HFNEF diagnostics in a multivariate logistic regression analysis. Plasma levels of big endothelin, PIIINP, and MMP-2 were found to be associated with the presence of early diagnosed HFNEF. However, none of these biomarkers contributed independently to current noninvasive HFNEF diagnostics recommended by the European Society of Cardiology guidelines.

Circulating cathepsin K as a potential novel biomarker of coronary artery disease

BackgroundCathepsin K (CatK) is one of the most potent mammalian collagenases involved in atherosclerosis-based vascular disease. We investigated whether circulating CatK is associated with the prevalence of coronary artery disease (CAD). MethodsTwo-hundred fifty-two consecutive subjects were enrolled from among patients who underwent coronary angiography and intravascular ultrasound analyses. One-hundred thirty-two age-matched subjects served as controls. Plasma CatK, intact procollagen type I N-terminal propeptide (I-PINP), and linked carboxy-terminal telopeptide of collagen type I (ICTP) were measured. ResultsPatients with CAD had higher CatK levels (44.0 ± 31.2 versus 15.5 ± 8.3 ng/mL, P < 0.001) and ICTP/I-PINP ratios (0.2 ± 0.1 versus 0.04 ± 0.03, P < 0.001) than the controls. Patients with acute coronary syndrome had higher CatK levels than those with stable angina pectoris. Overall, linear regression analysis showed that the CatK levels correlated positively with ICTP/I-PINP ratios (r = 0.41, P < 0.001). Multiple logistic regression analysis showed that CatK levels were independent predictors of CAD (odds ratio, 1.15; 95% CI, 1.07 to 1.23; P < 0.01). Furthermore, CatK levels were also correlated positively with percent plaque volumes and inversely with percent fibrous volumes by intravascular ultrasound. ConclusionsThese data indicated that high levels of CatK are closely linked with the presence of CAD and that CatK serves as a novel biomarker for CAD.