PICP Levels Research Articles

#3011 Pathophysiological link between renal and cardiovascular disease in patients with type 2 diabetes mellitus: preliminary results from a proteomic study

Abstract Background and Aims Diabetic kidney disease (DKD) affects nearly 40% of people with diabetes and is the leading cause of chronic kidney disease (CKD). A high prevalence of cardiovascular disease (CVD) is known in this population. Indeed, DKD and CVD are often related and lead to worse outcomes in type 2 diabetes mellitus (T2D), i.e. cardiac fibrosis and CV events are frequently described in patients with DKD. However, specific associations and accurate prediction biomarkers for DKD and CVD progression in T2D are still lacking as various proteins may play a multi-mechanistic role. Lipocalin-2 (LCN2) is involved in several pathophysiological processes (inflammation, renal disease and cardiometabolic complications in CKD). Its leukocyte-chemoattractant effect has shown to reduce CVD in experimental models of cardiomyopathy when suppressed. Excess LCN2 in CKD is a determinant of disease progression, but also a potent mediator of cardiac injury in CKD. Insulin-like growth factor binding proteins (IGFBPs) also play an important role in cell homeostasis by regulating cell transcription, migration, and apoptosis. IGFBP-3 down-regulation has demonstrated to be a predictor of rapid renal progression in T2DM. On the other hand, IGFBP-6 increases when GFR drops, being involved in the pathophysiological process of CKD as an apoptosis-inducing protein In this context, a proteomic-based approach would optimise the clinical utility of multiple plasma biomarkers. The aim was to identify proteins associated with DKD, cardiac fibrosis (estimated by the PICP biomarker) and the presence of a new CV event. Method A prospective cohort of 91 T2D patients, with a minimum follow-up of 3 years (mean: 4 years) was analysed. We evaluated the association between rates of change in GFR and PICP during follow-up (fold-change: end/initial) and their interaction with the development of a composite of cardiovascular (CV) events: CV death, stroke, ischaemic heart disease, atrial fibrillation, valvular heart disease and CV-related hospitalisation. In addition, ninety-two proteins were quantified in serum samples using a multiplex proximity extension assay with high-throughput protein detection technology (Olink proteomics, Cardiometabolic panel). Associations between variations in these proteins and changes in PICP and eGFR (all expressed as fold change from baseline) were assessed using linear regression analyses adjusted for their respective baseline values. All analyses were adjusted by multiple testing (Benjamini-Hochberg, FDR = 0.05%) using R software. Results Sixty-eight (74.7%) men and 23 (25.3%) women were included in the analysis. The mean age at baseline was 65.8 years, and the mean follow-up was 4 years (minimum 3 years). Sixteen cardiovascular events were recorded. An inverse association was observed between GFR and PICP (p = 0.003). Interaction analysis showed that this correlation occurred only in patients with incident CV events (p for interaction <0.001) (Fig. 1). By proteomic analysis (Fig. 2) several proteins were found to be significantly related to one of the three parameters studied (change in GFR, change in PICP and change with cardiovascular event), of which 3 proteins presented an overlap for all the parameters analysed: Lipocalin 2 (LCN2) and Insulin-like growth factor binding proteins 3 and 6 (IGFBP3 and IGFBP6). Interestingly, LCN2 and IGFBP6 were more highly expressed in patients with CV events whereas IGFBP3 was downregulated in these patients. Conclusion In patients with DKD, worsening enal function is associated with elevated circulating levels of the collagen synthesis biomarker PICP, particularly in those who developed at least one CV event. The link shown with LCN2, IGFBP-6 and IGFBP-3 shed light on possible multi-mechanistic pathways involved in DKD and narrow the scope towards a common pathway involving an interaction between pro-apoptotic and local inflammatory factors.

Permanent Pacemaker Implantation: Early Post-Implantation Data

Abstract Introduction: Data on the development of left ventricular dysfunction after permanent pacemaker implantation are available. Myocardial collagen deposition is a well-known mechanism that occurs in left ventricular remodelling. This gave us reason to dynamically monitor the levels of the main molecules involved in collagen synthesis, PIPC (carboxy-terminal propeptide of type I procollagen) and PIIINP (amino-terminal propeptide of type III procollagen). Materials and Methods: PIPC and PIIINP levels were studied using enzyme-linked immunoassays in plasma from 45 patients (25 men, 20 women, 72.1 ± 9 years) and 46 controls (24 men, 22 women, 71.9 ± 8.7 years) without known cardiovascular diseases (except arterial hypertension, conduction disorder, indication for the procedure) at baseline (immediately before PPM implantation for patients), at 12 and 24 weeks. Results: There was no difference in baseline levels of PICP and PIIINP between patients and controls (p > 0.05, Table abstract). At week 12, PICP levels increased significantly in patients compared to baseline in controls (p < 0.05, Table abstract). At week 24, values continued to increase and were again significantly higher than baseline in the controls (p < 0.001, Table abstract). At the 12-week follow-up visit, PIIINP values in patients were significantly higher than those at baseline in controls (p < 0.001, Table abstract). At week 24, the values of the patients were still higher than those of the controls, but the difference was not significant (p > 0.05, Table abstract). Conclusion: This study showed early activation of collagen synthesis < 6 months after PPM (permanent pacemaker) implantation. Due to the selection of patients without concomitant cardiovascular pathology, we have reason to assume that it is a result of the procedure itself and a serious prerequisite for increased collagen deposition in the myocardium.

Effects of empaglifozin on collagen biomarkers in patients with heart failure. Results from the EMPEROR trials

Abstract Background Extracellular matrix remodeling is one of the key pathways in progression of Heart Failure (HF). Clinical trials demonstrated that SGLT-2 inhibitors improved cardiovascular outcomes in HF patients, which may be partly explained by an effect on cardiac remodeling. Supporting data from preclinical studies suggested effects of SGLT-2 inhibitors on collagen synthesis and attenuation of fibrosis. However, the effect of SGLT-2 inhibitors on collagen turnover in HF patients is not fully elucidated. Purpose In patients of the EMPEROR-Preserved and EMPEROR-Reduced trials, across a wide spectrum of ejection fraction and renal function, the effect of empagliflozin on serum markers of collagen turnover was investigated. Methods 1084 patients (545 in empagliflozin and 539 in placebo) were included in the analysis. Biomarkers measured from serum samples at baseline, 12 and 52 weeks included PICP (a collagen type I formation marker; ELISA), PRO-C3 (a collagen type III formation marker; ECLIA), PINP (a collagen type I formation marker; ECLIA, Roche Diagnostics), PRO-C6 (a collagen type VI formation marker; ECLIA), C1M and C3M (markers of collagen type I and III degradation CLIA). A mixed model repeated measurements model (MMRM) was used to evaluate the treatment effects on the analysed biomarkers. Results Treatment with empagliflozin vs. placebo reduced PICP levels at week 12 and week 52, and reduced PRO-C3 at week 52. In contrast, no significant effect was observed on PINP, PRO-C6, C1M or C3M levels (Table 1). Conclusion Among patients with chronic HF, across a wide range of EF and of renal function, treatment with empagliflozin reduced the serum levels of PICP, a collagen type I formation marker, both at weeks 12 and 52 and PRO-C3, a collagen type III formation marker, at week 52. These results add support for an anti-fibrotic effect of empagliflozin and may help to explain the clinical effect of SGLT-2 inhibitors on cardiac remodeling.

Effect of Dapagliflozin on Patients with Rheumatic Heart Disease Mitral Stenosis.

(1) Background: Mitral stenosis is the most common rheumatic heart disease (RHD). Inflammation and fibrosis are the primary pathophysiology, resulting in left atrial stress and dysfunction. Dapagliflozin is a new heart failure treatment with anti-inflammation and anti-fibrosis effects from previous studies. However, the specific role of dapagliflozin in RHD mitral stenosis is unknown. This study aims to investigate (i) the effect of dapagliflozin on biomarkers of fibrosis, NT-pro BNP levels and left atrial function; (ii) the relationship between the changes in fibrosis biomarkers with left atrial function and NT-pro BNP levels. (2) Methods: An open-label randomized study was conducted on 33 RHD mitral stenosis patients divided into a dapagliflozin group which received 10 mg dapagliflozin and standard therapy, and a control group which only received standard therapy. All patients were examined for levels of PICP, MMP-1/TIMP-1 ratio, TGF-β1, NT-proBNP, mitral valve mean pressure gradient (MPG), and net atrioventricular compliance (Cn) pre- and post-intervention. (3) Results: This study found a significant increase in PICP and TGF-β1 and a reduction in the MMP-1/TIMP-1 ratio in the dapagliflozin group and the control group (p < 0.05). In the dapagliflozin group, the levels of NT-pro BNP decreased significantly (p = 0.000), with a delta of decreased NT-pro BNP levels also significantly greater in the dapagliflozin group compared to the control (p = 0.034). There was a significant increase in Cn values in the dapagliflozin group (p = 0.017), whereas there was a decrease in the control group (p = 0.379). Delta of changes in Cn values between the dapagliflozin and control groups also showed a significant value (p = 0.049). The decreased MPG values of the mitral valve were found in both the dapagliflozin and control groups, with the decrease in MPG significantly greater in the dapagliflozin group (p = 0.031). There was no significant correlation between changes in the value of fibrosis biomarkers with Cn and NT-pro BNP (p > 0.05). (4) Conclusions: This study implies that the addition of dapagliflozin to standard therapy for RHD mitral stenosis patients provides benefits, as evidenced by an increase in net atrioventricular compliance and decreases in the MPG value of the mitral valve and NT-pro BNP levels (p < 0.05). This improvement was not directly related to changes in fibrosis biomarkers, as these biomarkers showed ongoing fibrosis even with dapagliflozin administration.

Abstract 245: Endothelin-1 And Procollagen Type-1 Carboxy-terminal Propeptide Are Associated With Functional Tolerance And Cardiac Structure And Function In Heart Failure With Preserved Ejection Fraction

Introduction: The role of emerging biomarkers such as endothelin-1 (ET-1) and collagen peptides in functional tolerance among patients with heart failure with preserved ejection fraction (HFpEF) is not well understood. Hypothesis: We hypothesize that plasma ET-1 and procollagen type-1 carboxy-terminal propeptide (PICP) are associated with 6-minute walk distance and parameters of cardiac structure and function. Methods: In a cross-sectional cohort study, we evaluated the association of ET-1 and PICP with 6-minute walk distance and parameters of cardiac structure and function on cardiac magnetic resonance (CMR) imaging in patients with HFpEF. In a subset of patients, we used a novel diffusion tensor imaging CMR technique to determine the myocardial fiber orientation in the septum as characterized by the helix angle transmurality (slope of the helix angle versus transmural depth from endocardium to epicardium) (Fig 1C). Results: A total of 36 patients (25 with HFpEF, 11 controls), mean age 70 ± 7.7 yrs, BMI 33 ± 8.5 kg/m 2 , 94% men, 53% had diabetes, and 75% had hypertension. Mean LVEF 58.7 ± 7.7%, RVEF 49.1 ± 10.4%, mean global myocardial mid- LV T1 1285ms, mean LV mass indexed to body surface area 65 ± 12 g/m 2 . Using univariate linear regression, we found that both plasma ET-1 levels and PICP levels were moderately inversely associated with 6-minute walk distance (R 2 -0.56, p&lt;0.001) and (R 2 -0.40, p=0.02) (Fig 1A) respectively, with a non-significant association with age (R 2 = 0.30, p=0.08) and indexed LV mass (R 2 =0.29, p=0.09). ET-1 was moderately associated with septal HAT, a marker of myocardial fiber orientation, (R 2 =0.58, p=0.02), measured in a subset of patients (Fig 1B, C). Conclusions: Plasma ET1 and PICP levels are moderately associated with lower 6-minute walk distance; ET-1 is associated with septal myocardial fiber orientation in this exploratory analysis. Future studies are needed to determine the prognostic value of these biomarkers in patients with HFpEF.

Bone turnover markers and bone mineral density in patients with type 2 diabetes

Background: This study was designed in order to evaluate bone and mineral metabolism in type 2 diabetic patients and its relationship with bone mineral density and diabetic microvascular complications. Methods: Forty two type 2 diabetic patients and 23 healthy cases were included in the study. Serum osteocalcin, procollagen type 1 – C peptide (PICP), total and bone specific alkaline phosphatase (bone ALP), urinary deoxypyridinoline (free DPD), parathormone (PTH), serum and urinary calcium and phosphorus levels were measured. Bone mineral densities of all subjects were studied in lumbar vertebra and femur region using dual X-ray absorptiometry (DXA). Results: Serum osteocalcin and bone ALP levels of the diabetics were found to be significantly lower and total alkaline phosphatase and calcium levels were higher in diabetic patients compared to healthy controls, but PICP and free DPD levels were not different between these two groups. There was a positive correlation between PTH levels and urinary DPD excretion. Among diabetics, serum osteocalcin levels increased with the impairment of renal functions. Bone mineral densities were lower in diabetics with worse renal functions. Conclusion: Bone turnover is slow in type 2 diabetes and there is no prominent bone loss related to this condition. PTH is an important factor determining the rate of bone resorption in diabetics. Renal functional impairment is the most important factor affecting the bone mass in type 2 diabetic patients.

Simple Predictors for Cardiac Fibrosis in Patients with Type 2 Diabetes Mellitus: The Role of Circulating Biomarkers and Pulse Wave Velocity.

Cardiac fibrosis is the basis of structural and functional disorders in patients with diabetes mellitus (T2DM). A wide range of laboratory and instrumental methods is used for its prediction. The study aimed to identify simple predictors of cardiac fibrosis in patients with T2DM based on the analysis of circulating fibrosis biomarkers and arterial stiffness. The study included patients with T2DM (n = 37) and cardiovascular risk factors (RF, n = 27) who underwent ECHO, cardiac magnetic resonance imaging (MRI), pulse wave analysis (PWV), reactive hyperemia (RH), peripheral arterial tonometry, carotid ultrasonography, and assessment of serum fibrosis biomarkers. As a control group, 15 healthy subjects were examined. Left ventricular concentric hypertrophy was accompanied by an increased serum galectin-3 level in T2DM patients. There was a relationship between the PICP and HbA1c levels in both main groups (R2 = 0.309; p = 0.014). A negative correlation between PICP level and the global longitudinal strain (GLS) was found (r = −0.467; p = 0.004). The RH index had a negative correlation with the duration of diabetes (r = −0.356; p = 0.03), the carotid-femoral PWV (r = −0.371; p = 0.024), and the carotid intima-media thickness (r = −0.622; p < 0.001). The late gadolinium-enhanced (LGE) cardiac MRI was detected in 22 (59.5%) T2DM and in 4 (14.85%) RF patients. Diabetes, its baseline treatment with metformin, HbA1c and serum TIMP-1 levels, and left ventricle hypertrophy had moderate positive correlations with LGE findings (p < 0.05). Using the multivariate regression analysis, increased TIMP-1 level was identified as an independent factor associated with cardiac fibrosis.

Effects of Sacubitril/Valsartan on biomarkers of fibrosis and inflammation in patients with heart failure with reduced ejection fraction

AimsTo evaluate the circulating levels of remodeling biomarkers procollagen type 1 C-terminal propeptide (PICP), human cartilage glycoprotein-39 (YKL-40), plasma renin activity (PRA), aldosterone (Aldo) as well as clinical and echocardiographic parameters in patients with heart failure with reduced ejection fraction (HFrEF), before and after treatment with Sacubitril/Valsartan (S/V).Methods and resultsA total of 26 consecutive patients with HFrEF on stable clinical conditions were studied. Clinical, echocardiographic parameters and circulating biomarkers were measured at baseline, after 30 and 60 days of S/V treatment. Both systolic blood pressure (SBP) and diastolic blood pressure (DBP) decreased, from 126 ± 15 to 113 ± 4 mmHg (p < 0.001) and from 77 ± 11 to 72 ± 9 mmHg (p = 0.005), respectively, at the end of study. Concomitantly, left ventricular ejection fraction (LVEF) increased by 22.8% from 29.5 ± 5% to 36.2 ± 5%, (p < 0.001) and indexed left ventricular end-systolic volume (LVESVi) decreased by 12% from 38.6 ± 8.7 ml/m2 to 34.0 ± 10.0 ml/m2. (p = 0.007). Circulating levels of PICP, YKL-40, PRA and Aldo decreased by − 42.2%, − 46.8%, − 79.1% and − 76.7%, respectively (p < 0.001 for all), the decrements being already maximal within 30 days of S/V treatment. No significant changes of plasma electrolytes and creatinine were observed during the study (all p > 0.05).ConclusionsA decrease of circulating markers of inflammation and fibrosis during chronic treatment with S/V is associated with an improvement of hemodynamic and echographic parameters in patients with HRrEF. These data are compatible with an anti-fibrotic and anti-inflammatory effect of S/V, that may contribute to the beneficial outcomes of the drug in this clinical setting.

Collagen Remodeling Proteins, Inflammatory Biomarkers and FABP Regulation in Understanding the Pathogenesis of Atrial Fibrillation

IntroductionAtrial Fibrillation (AF) is the most common sustained form of cardiac arrythmia across the world with around 3 million active cases. Atrial fibrosis is the process by which collagen is deposited within the atria. Atrial fibrosis is correlated with AF. PINP and PICP, the two collagen remodeling proteins focused on in this study, are procollagen type I remodeling proteins and effective biomarkers of collagen deposition and bone formation. PINP exhibits diurnal variation with higher values occurring at night resulting in variance within the data set for PINP in AF patients. Long chain fatty acids (LCFAs), in excess, can lead to lipotoxicity which increases the risk of a potential arrythmia. Fatty Acid Binding Proteins (FABPs) bind to LCFAs to create a lower level of these fatty acid chains in the cytoplasm. Increased LCFAs has a direct correlation with increased FABPs which can ultimately increase the risk of arrythmia.PurposeThe purpose of this study was to analyze levels of collagen remodeling proteins, specifically PINP and PICP, and L‐FABP in an AF cohort to determine whether they can serve as viable biomarkers in the management and diagnosis of AF.HypothesisIt is expected that there will be an upregulation of collagen remodeling proteins, inflammatory biomarkers and FABP in AF patients compared to the NHP.Materials and MethodsThe study was conducted with a sample of 50 normal healthy human plasma and were tested for PINP, PICP, and FABP levels. These normal samples were purchased from George King Biomedical. The blood of the AF patients was collected following IRB protocol, centrifuged, and aliquoted at –80 degrees Celsius. AF plasma samples were analyzed using sandwich ELISA Kits. Results were statistically analyzed by using the IBM SPSS software and PRISM Graphpad.ResultsThe results were collected as mean ± SEM with a percent change of mean (%) to demonstrate upregulation. All three biomarkers PINP, PICP, and FABP demonstrated an upregulation, respectively, of (422.32 ± 43.78, 164.47%), (1.395902 ± 0.178727, 104.86%), and (13186.7517 ± 4256.96265, 157.75% with the outlier and 77.69% without outlier). All three biomarkers were statistically significant with p‐values of &lt;0.0001, &lt;0.01, and &lt;0.0001 respectively for PINP, PICP, and FABP. There was a significant outlier in the FABP data at 295.778.86 pg/mL. This value created a skewness statistic of 7.502 which changed to 3.795 after the outlier was removed. There was a strong, positive correlation between the two collagen remodeling proteins, PICP and PINP, with an r‐value (correlation coefficient) value of 0.62.ConclusionThe results prove that increased structural remodeling, proven by higher levels of collagen remodeling proteins, can indicate AF. FABP had an evident upregulation in the AF patient, but the data was severely skewed right due to an outlier. Once the outlier was removed, the data still demonstrated an upregulation of 77.69%. Elevated levels of these biomarkers suggest that they can serve as surrogate endpoints in the management and diagnosis of AF.

QiShenYiQi pill for myocardial collagen metabolism and apoptosis in rats of autoimmune cardiomyopathy

Context QiShenYiQi pill (QSYQ) is a traditional Chinese medicine with a myocardial protective effect. Objective To explore the effect of QSYQ on myocardial collagen metabolism in rats with autoimmune cardiomyopathy and explore the underlying mechanism from the aspect of apoptosis. Materials and methods We established an autoimmune cardiomyopathy model using Lewis rats. The rats were then randomly divided into six groups (n = 8): control, model, 3-methyladenine (15 mg/kg, intraperitoneal injection), QSYQ low-dose (135 mg/kg, gavage), QSYQ medium dose (270 mg/kg, gavage), and QSYQ high-dose (540 mg/kg, gavage) for four weeks. Van Gieson staining was applied for myocardial pathological characteristics, TUNEL fluorescence for myocardial cell apoptosis, enzyme-linked immunosorbent assay (ELISA) for serum PICP, PIIINP, and CTX-I levels, and western blot analysis for type I/III myocardial collagen, Bcl-2, Bax, and caspase-3 proteins. Results Results showed that QSYQ (135, 270, or 540 mg/kg) significantly reduced the expression of myocardial type I/III collagen, and concentrations of serum PICP, PIIINP, and CTX-I in rats. Moreover, QSYQ could alleviate myocardial fibrosis more effectively at a higher dose. QSYQ could also inhibit myocardial apoptosis via downregulating Bcl-2 expression, and upregulating Bax and caspase-3 expression levels. Discussion and conclusions The QSYQ can improve myocardial collagen metabolism by inhibiting apoptosis, which provides a potential therapeutic approach for autoimmune cardiomyopathy.

Association between Markers of Fibrosis and Heart Failure Incidence in Patients with Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus (T2DM) and chronic heart failure (HF) have close association, and several biomarkers have been studied to better understand this association and improve prediction of HF in T2DM. Furthermore, in recent clinical trials, sodium glucose cotransporter 2 inhibitors (SGLT2i), glucose-lowering drugs, improved HF outcomes. The objective of the present study was to evaluate association between circulating biomarkers of fibrosis and incidence of HF with preserved ejection fraction (HFpEF) in patients with T2DM receiving sodium glucose cotransporter 2 inhibitors (SGLT2i). Materials and Methods. At baseline, transthoracic echocardiography and laboratory assessment of N-terminal fragment of the brain natriuretic peptide (Nt-proBNP), soluble suppression of tumorigenesis-2 (sST2), galectin-3 (Gal-3), C-terminal propeptide of procollagen type I (PICP), N-terminal propeptide of procollagen type III (PIIINP), matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of matrix proteinase-1 (TIMP-1) were done. After 3 years of follow-up, information about HF events (hospitalization for HF, established HF in outpatient department by a cardiologist) was obtained. Results. Seventy-two patients were included in the study. The mean age was 57 (49.7; 63.2) years; 44% were female. Most patients had T2DM for more than 4 years. All patients were overweight or had obesity, and 93% patients had arterial hypertension (AH). After 3 years of follow-up, HFpEF was established in 21% patients. Patients were divided into two groups according to the presence of HFpEF, and baseline characteristics were compared. Patients with HF were older and had longer diabetes and AH duration and higher Nt-proBNP, Gal-3, PIIINP, and PICP levels at baseline than patients without HF (all p < 0.05). Gal − 3 > 10 ng/ml (OR = 2.25; 95% CI, 1.88–5.66; p = 0.01) and NT − pro − BNP > 80 pg/ml (OR = 2.64; 95% CI, 1.56–4.44; p = 0.001) were associated with increased risk of HF incidence. Age > 60 years, diabetes duration > 10 years, and presence of abdominal obesity were independent predictors of HFpEF as well. Conclusions. T2DM patients treated with SLGT2i, who developed HFpEF after 3 years of follow-up, had higher PICP, PIIINP, Gal-3, and NT-proBNP serum concentrations at baseline, and Gal-3 level was an independent predictor of HFpEF.

Changes in Intestinal Flora Structure and Metabolites Are Associated With Myocardial Fibrosis in Patients With Persistent Atrial Fibrillation.

Background: The occurrence of atrial fibrillation is often accompanied by myocardial fibrosis. An increasing number of studies have shown that intestinal flora is involved in the occurrence and development of a variety of cardiovascular diseases. This study explores the relationship between changes in the structure and function of intestinal flora and the progression of myocardial fibrosis in patients with persistent atrial fibrillation.Methods: Serum and stool samples were collected from 10 healthy people and 10 patients with persistent atrial fibrillation (PeAF), and statistical analyses were performed on the subjects' clinical baseline conditions. ELISA was used to measure the levels of carboxy-terminal telopeptide of type I collagen (CTX-I), propeptide of type I procollagen (PICP), procollagen III N-terminal propeptide (PIIINP), fibroblast growth factor-23 (FGF-23), and transforming growth factor-beta 1 (TGF-β1) in serum. Through 16S rRNA sequencing technology, the structural composition of the intestinal flora was detected and analyzed. In addition, metabolomics data were analyzed to determine the differences in the metabolites produced by the intestinal flora of the subjects.Results: By comparing the baseline data of the subjects, it was found that compared with those of the control group, the levels of creatinine (CRE) and serum uric acid (SUA) in the serum of PeAF patients were significantly increased. In addition, we found that the levels of CTX-I, PICP, PIIINP, and TGF-β1 in the serum of PeAF patients were significantly higher than those of the control group subjects. Although the control and PeAF groups exhibited no significant differences in the α diversity index, there were significant differences in the β diversity indexes (Bray-Curtis, weighted UniFrac and Anosim). At the phylum, family and species levels, the community structure and composition of the intestinal flora of the control group and those of the PeAF group showed significant differences. In addition, the compositions of the intestinal metabolites in the two different groups of people were significantly different. They were correlated considerably with PIIINP and specific communities in the intestinal flora.Conclusion: Pathologically, PeAF patients may have a higher risk of myocardial fibrosis. Systematically, abnormal changes in the structure and composition of the intestinal flora in PeAF patients may lead to differences in intestinal metabolites, which are involved in the process of myocardial fibrosis through metabolite pathways.

The combination of carboxy-terminal propeptide of procollagen type I blood levels and late gadolinium enhancement at cardiac magnetic resonance provides additional prognostic information in idiopathic dilated cardiomyopathy-A multilevel assessment of myocardial fibrosis in dilated cardiomyopathy.

AimsTo determine the prognostic value of multilevel assessment of fibrosis in dilated cardiomyopathy (DCM) patients.Methods and resultsWe quantified fibrosis in 209 DCM patients at three levels: (i) non‐invasive late gadolinium enhancement (LGE) at cardiac magnetic resonance (CMR); (ii) blood biomarkers [amino‐terminal propeptide of procollagen type III (PIIINP) and carboxy‐terminal propeptide of procollagen type I (PICP)], (iii) invasive endomyocardial biopsy (EMB) (collagen volume fraction, CVF). Both LGE and elevated blood PICP levels, but neither PIIINP nor CVF predicted a worse outcome defined as death, heart transplantation, heart failure hospitalization, or life‐threatening arrhythmias, after adjusting for known clinical predictors [adjusted hazard ratios: LGE 3.54, 95% confidence interval (CI) 1.90–6.60; P < 0.001 and PICP 1.02, 95% CI 1.01–1.03; P = 0.001]. The combination of LGE and PICP provided the highest prognostic benefit in prediction (likelihood ratio test P = 0.007) and reclassification (net reclassification index: 0.28, P = 0.02; and integrated discrimination improvement index: 0.139, P = 0.01) when added to the clinical prediction model. Moreover, patients with a combination of LGE and elevated PICP (LGE+/PICP+) had the worst prognosis (log‐rank P < 0.001). RNA‐sequencing and gene enrichment analysis of EMB showed an increased expression of pro‐fibrotic and pro‐inflammatory pathways in patients with high levels of fibrosis (LGE+/PICP+) compared to patients with low levels of fibrosis (LGE‐/PICP‐). This would suggest the validity of myocardial fibrosis detection by LGE and PICP, as the subsequent generated fibrotic risk profiles are associated with distinct cardiac transcriptomic profiles.ConclusionThe combination of myocardial fibrosis at CMR and circulating PICP levels provides additive prognostic value accompanied by a pro‐fibrotic and pro‐inflammatory transcriptomic profile in DCM patients with LGE and elevated PICP.

Lower Serum Irisin Levels Are Associated with Increased Osteoporosis and Oxidative Stress in Postmenopausal.

Irisin as an exercise-induced myokine was proposed to improve bone health. This study investigated the role of serum irisin (s-irisin) in patients with osteoporosis (OP) through correlating to most biological bone markers and oxidative stress. A cross-sectional study recruited an eligible 175 postmenopausal women at Al-Hussien Teaching Hospital, Iraq. They were scanned by DEXA and stratified into two groups based on T-score; the first 95 patients as control group (GI) with -1 ≤ T-score and the second 80 patients as cases group (GII) with T-score ≤ -2.5. Demographic criteria were age, bone mineral density (BMD, g/cm2) and T-score. Serum irisin, total serum calcium (s-calcium), serum inorganic phosphate (s-phosphate), serum alkaline phosphatase (s-ALP), serum 25 [OH] vitamin D, the serum parathyroid hormone (s-PTH), serum Carboxy terminal collagen crosslinks (CTx), serum procollagen type I C-termidnal peptide (s-PICP), serum malondialdehyde (s-MDA) and serum superoxide dismutase (s-SOD) were collected from blood samples. Serum irisin were 31.84 ± 2.65 vs. 20.88 ± 2.71 ng/mL for control and trial groups, respectively. Lower levels of BMD, T-score, 25 [OH] vitamin D, and s-irisin along with a higher serum levels of PTH, CTx, PICP, MDA and SOD were observed in patients with osteoporosis. All parameters were statistically meaningful upon correlation (p< 0.0001), except age and s-calcium (p= 0.0088 and p= 0.187, respectively). The results showed that, a significantly lower serum irisin levels among osteoporosis women, was intimately correlated to most bone turnover markers and it can be considered as encouraging results for clinical application in prediction and treatment of osteoporosis.

Integrative characterization of asymptomatic vs. symptomatic patients with moderate-severe primary mitral regurgitation

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This work was supported by NHLBI and Specialized Centers of Clinically Oriented Research grant in cardiac dysfunction, by Department of Veteran Affairs for Merit Review and NIH Grant P01. Background Optimal timing for surgery in primary mitral regurgitation (PMR) is a subject of debate. Purpose Use a combination of imaging, circulating biomarkers and histology to define the transition from asymptomatic (asx) to symptomatic (sx) stage in moderate-severe PMR. Methods 57 controls, 82 sx and 47 asx patients with moderate to severe PMR underwent cardiac MR(CMR), plasma BNP, levels of xanthine oxidase (XO) activity, and circulating markers of collagen (Col) synthesis (propeptide of procollagen type I, PICP) and degradation (Col type I fibers, ICTP). Results A progressive worsening in the severity of adverse LV remodeling was noted based on CMR indices listed in Table 1. The 3D mid-wall LV endocardial curvature to wall thickness was lower in normal and similar in asx and sx patients.Plasma BNP was progressively higher in normal vs. asx vs sx (Figure 1A). The levels of XO activity were higher in sx vs. asx (Figure 1B,1C). Levels of PICP were similar among the three; levels of ICTP were significantly higher in the sx vs the asx (Figure 1D,1E). LV biopsies revealed large areas of patchy replacement fibrosis and areas devoid of interstitial Col (Figure 1F). From the subgroup of 56 patients who underwent CMR 6 months after surgery, 27% had LVEF &amp;lt; 50%. The preoperative LVEF, LVESV, LVESD and LA emptying fraction were predictors of postoperative drop in LVEF. Conclusion Increased COl breakdown coupled with markers of oxidative stress and CMR-based LV remodeling characterize the transition from asx to sx PMR. Longitudinal studies are needed to define cutoff"s for patient selection and optimal timing for MV surgery. CMR indices in normal, asx and sx PMR. Normal (57) Moderate/Severe MR Asymptomatic (56) Pre-Surgery MR Symptomatic (81) P-value Age 48 (34, 55) 54 (46, 62) * 57 (50, 67) * &amp;lt;0.0001 Female/Male 30(53%)/27(47%) 35(63%)/21(38%) 25(31%)/56(69%) LVEF (%) 64 (61, 67) 62 (59, 66) 63 (59, 67) 0.3482 LV EDV (mL/m2) 71 (61, 76) 89 (73, 103) * 100 (83, 123) *# &amp;lt;0.0001 LV ESV (mL/m2) 24 (21, 29) 32 (26, 38) * 36 (28, 47) * &amp;lt;0.0001 LVSV (mL/m2) 43 (37, 50) 54 (43, 66) * 60 (54, 77) *# &amp;lt;0.0001 LVED Mass/Volume 0.7 (0.6, 0.8) 0.6 (0.5, 0.7) * 0.6 (0.6, 0.7) * 0.0012 LVED Mass/Vol x SI 1.29 (1.05, 1.50) 0.97 (0.77, 1.15) * 0.94 (0.77, 1.14) * &amp;lt;0.0001 Regurgitant Volume (mL) ― 38 (26, 54) 57 (38, 83) # 0.001 Regurgitant Fraction (%) ― 39 (28, 50) 46 (36, 56) # 0.042 Table 1 shows the CMR indices of LV remodeling in normal, asymptomatic and symptomatic patients with moderate-severe PMR. p-values *vs. Normal; # vs. Asymptomatic. Kruskal-Wallis test or unpaired t-test Abstract Figure 1.

Влияние дапаглифлозина на маркеры фиброза и воспаления у пациентов с сахарным диабетом 2 типа и очень высоким риском сердечно-сосудистых событий

Background: several randomized clinical trials have demonstrated that dapagliflozin, like other inhibitors of sodium-glucose cotransporter 2 (SGLT2), significantly improves cardiovascular and renal outcomes in type 2 diabetes (T2D). However, underlying mechanisms remain unclear. Aim: to assess changes in the levels of serum markers associated with fibrosis and inflammation in patients with T2D receiving dapagliflozin. Patients and Methods: this prospective single-center study included 27 patients aged 40–65 years with T2D that lasts more than 1 year and without verified atherosclerosis but multiple cardiovascular risk factors (i.e., dyslipidemia, obesity, hypertension). In addition to basic treatment for T2D, all patients received dapagliflozin 10 mg daily for 6 months. Before and 6 months after treatment, the levels of the markers of fibrosis (including procollagen type I carboxy-terminal propeptide/PICP) and inflammation were measured. Results: the median age was 56 [49; 61] years and the median duration of T2D was 7 [4; 12] years. After 6-month treatment with dapagliflozin, significant reduction in the concentration of PICP from 136.8 [100,4; 200,6] ng/ml to 104.8 [79.7; 162.0] ng/ml (р = 0.019). The levels of galectin-3, matrix metalloproteinase (MMP) 9, tissue inhibitor of MMP-1, growth stimulating expressed gene 2, high-sensitivity C-reactive protein, and N-terminal pro-atrial natriuretic peptide were similar at baseline and after 6-month treatment. Conclusions: 6-month treatment with dapagliflozin reduced the levels of PICP. Together with other mechanisms, this phenomenon illustrates the positive effects of dapagliflozin on cardiovascular and renal outcomes in T2D. KEYWORDS: type 2 diabetes, fibrosis, chronic inflammation, dapagliflozin, cardiovascular diseases. FOR CITATION: Lebedev D.A., Babenko A.Yu. Effects of dapagliflozin of the markers of fibrosis and inflammation in type 2 diabetes and very high cardiovascular risk. Russian Medical Inquiry. 2021;5(4):185–188 (in Russ.). DOI: 10.32364/2587-6821-2021-5-4-185-188.

Kinetics of selected serum markers of fibrosis in patients with dilated cardiomyopathy and different grades of diastolic dysfunction of the left ventricle.

Fibrosis of the extracellular matrix (ECM) in dilated cardiomyopathy (DCM) is common and compromises both systolic and diastolic function. The aim of this study was to investigate the kinetics of ECM fibrosis markers over a 12 month follow-up in patients with DCM based on the severity of diastolic dysfunction (DD). Seventy consecutive DCM patients (48 ± 12.1 years, ejection fraction 24.4 ± 7.4%) were included in the study. The grade of DD was determined using the ASE/EACVI algorithm. Markers of ECM fibrosis were measured at baseline and at 3 and 12 month follow-ups: collagen type I and III (PICP, PINP, PIIICP, PIIINP), transforming growth factor beta-1 (TGF1-b), connective tissue growth factor (CTGF) and galectin-3 were measured. Patients were divided into three groups according to DD severity: 30 patients with grade I, 18 with grade II and 22 with grade III of DD. Levels of PICP, PINP were increased over a 12-month period, while PIIINP decreased and PIIICP unchanged. Levels of TGF1-b decreased from the 3 to the 12-month points in grade I and II DD, and in grade III they remained unchanged. Levels of CTGF decreased over 12 months in grade III DD but were unchanged in grades I and II. Galectin-3 levels remained the same over all observation periods, irrespective of DD grade. Regardless of the DD grade, markers of collagen type I synthesis increased, markers of collagen type III decreased. Levels of TGF and CTGF had a tendency to decrease. Galectin-3 was revealed not to be a marker discriminating the severity of DD.

Therapeutic effect of teriparatide combined with lowfrequency pulsed electromagnetic field on hip fracture

Purpose: To evaluate the therapeutic effect of teriparatide in combination with low-frequency pulsed electromagnetic field in the management of hip fracture.Methods: Patients with hip fracture internal fixation and under conventional postoperative basic adjuvant therapy were compared with those patients who received teriparatide combined with low frequency pulsed electromagnetic field after operation. The content of Bone-Specific AlkalinePhosphatase (BALP), type I Procollagen Carboxy Terminal Propeptide (PICP), serum bone glaprotein (BGP), Ca2+, hip function and degree of bone scab formation were evaluated using Harris score and Fernadez-esteve scoring system. Kaplan-Meier survival curve was plotted to analyze differences in short-term prognosis of different postoperative adjuvant treatment measures.Results: Harris score of the hip joint and the effect of bone formation in the experimental group were higher than that of the control group. The blood levels of BGP, BALP, PICP and serum Ca2+ in the experimental group were higher than that of the control group (p &lt; 0.05). The plotted Kaplan-Meier survival curve indicates that the prognosis of the experimental group was better than that of control group (p &lt; 0.05).Conclusion: The adjuvant therapy of teriparatide combined with low-frequency pulsed electromagnetic field can improve the recovery function and enhance the prognosis of patients who underwent hip fracture surgery.&#x0D; Keywords: Teriparatide; Low frequency pulsed electromagnetic field, hip fracture

The relationship between the key markers of myocardial fibrosis and gut microbiota composition in patients with heart failure and preserved ejection fraction

Abstract Background Increased myocardial fibrosis may play a key role in heart failure with preserved ejection fraction (HFpEF) pathophysiology. The current gold standard for the diagnosis and assessment of myocardial fibrosis is endomyocardial biopsy. A number of circulating biomarkers have been proposed for the assessment of myocardial fibrosis, however the most consistent results have been found for C-terminal propeptide of procollagen type I (PICP) and N-terminal propeptide of pro-collagen type III (PIIINP). Some evidence suggests the possible link between the gut microbiota composition and myocardioal fibrosis. Purpose The aim of the study was to investigate the association between the serum markers of myocardial fibrosis (PICP and PIIINP) with gut microbial genera in patients with HFpEF. Methods 42 patients with confirmed HF-pEF (mediana and interquartile range of age 67 [64; 72] years, 47% men, body mass index &amp;lt;35 kg/m2 with no history of myocardial infarction or diabetes mellitus) were enrolled in the study. The patients underwent transthoracic echocardiography with Doppler study, HF-pEF was confirmed according to the recent ESC guidelines (based on E/e' ratio, N-terminal pro-B type natriuretic peptide &amp;gt;125 pg/ml and symptoms of HF). The levels of PICP and PIIINP were evaluated in patients' serum using enzyme-linked immunosorbent assay. The intestinal microbiome was investigated using high-throughput sequencing of bacterial 16S rRNA gene. Results The mediana and interquartile range in PICP was 918 [700; 1044] pg/ml, in PIIINP it was 6.215 [3.99; 8.29] pg/ml. The analysis revealed significant correlations between PICP and the following bacterial genera of Firmicutes:Ruminococcus (r=−0,36); Gemmiger (r=−0,35), Allisonella (r=0,32) and Howardella (r=−0,30). PIIINP significantly correlated with 2 genera: Blautia which belongs to Firmicutes phylum (r=0,36) and Bilophila which belongs to Proteobacteria phylum (r=−0,33). All values with p&amp;lt;0,05. Conclusion Both PICP and PIIINP had negative significant correlations with beneficial bacterial genera and positive correlations with several potencially harmful gut bacterial genera. This type of relationship might become the novel field of research in the group of patients with HF-pEF due to myocardial fibrosis. Funding Acknowledgement Type of funding source: None

Role of Carboxy Terminal Propeptide of Type I and Type III Procollagen (PICP and PIIICP) Toward the Severity Degree of Mitral Valve Regurgitation in Children’s Rheumatic Heart Disease

BACKGROUND: Rheumatic heart disease (RHD) is recognized as a heart disease that occurs as a result of sequelae in acute rheumatic fever (ARF), characterized by the occurrence of defects in the heart valves. The most common manifestation of childhood RHD is mitral regurgitation (MR). The role of inflammation and oxidative stress in RHD also involves several components consisting of carboxy-terminal pro-peptide of Type I procollagen (PICP) and carboxy-terminal pro-peptide of Type III procollagen (PIIICP).&#x0D; AIM: The aim of this study was to know whether PICP and PIIICP can be used to measure the severity level of mitral valve regurgitation.&#x0D; METHODS: This research is considered as descriptive-analytic research, and using cross-sectional analysis. Forty RHD patients underwent echocardiographic examinations to measure Wilkin and effective regurgitant orifice area scores. Patients were classified into ARF without valve abnormalities, mild, moderate, and severe MR. PICP and PIIICP were with ARF through venous blood and ELISA was examined. Data were analyzed by employing SPSS 22 with p = 0.05). Wilkins scores and PICP levels have a regression coefficient of 0.296 with a p-value of 0.032.&#x0D; RESULTS: There was a significant difference in PICP level among the studied sample groups with a p = 0.012, (p &lt; 0.05), with insignificant difference in PIIICP level among sample groups with a p = 0.083, greater than α = 0.05 (p &gt; 0.05). Wilkins scores and PICP level have a regression coefficient of 0.296 with a p = 0.032 (p &lt; 0.05), while PIIICP level has a regression coefficient of 0.093 with a p = 0.568 (p &gt; 0.05).&#x0D; CONCLUSION: There is no significant increase indicated on PIIICP level, but PICP level indicates a significant increase in RHD group with severe mitral valve abnormalities. PICP can be used to measure the severity level of mitral valve regurgitation.&#x0D;