Biomarkers Of Myocardial Fibrosis Research Articles

Loss of Y Chromosome and Cardiovascular Events in Chronic Kidney Disease.

Chronic kidney disease represents one of the strongest risk factors for cardiovascular diseases, and particularly for heart failure. Despite improved pharmaceutical treatments, mortality remains high. Recently, experimental studies demonstrated that mosaic loss of Y chromosome (LOY) associates with cardiac fibrosis in male mice. Since diffuse cardiac fibrosis is the common denominator for progression of all forms of heart failure, we determined the association of LOY on mortality and cardiovascular disease outcomes in patients with chronic kidney disease. LOY was quantified in men with stable chronic kidney disease (CARE for HOMe study [XXX], n=279) and dialysis patients (4D study, n=544). The association between LOY and mortality, combined cardiovascular and heart failure-specific end points, and echocardiographic measures was assessed. In CARE for HOMe, the frequency of LOY increased with age. LOY >17% was associated with increased mortality (heart rate, 2.58 [95% CI, 1.33-5.03]) and risk for cardiac decompensation or death (heart rate, 2.30 [95% CI, 1.23-4.27]). Patients with LOY >17% showed a significant decline of ejection fraction and an increase of E/E' within 5 years. Consistently, in the 4D study, LOY >17% was significantly associated with increased mortality (heart rate, 2.76 [95% CI, 1.83-4.16]), higher risk of death due to heart failure and sudden cardiac death (heart rate, 4.11 [95% CI, 2.09-8.08]), but not atherosclerotic events. Patients with LOY >17% showed significantly higher plasma levels of soluble interleukin 1 receptor-like 1, a biomarker for myocardial fibrosis. Mechanistically, intermediate monocytes from patients with LOY >17% showed significantly higher C-C chemokine receptor type 2 expression and higher plasma levels of the C-C chemokine receptor type 2 chemokine (C-C motif) ligand 2, which may have contributed to increased heart failure events. LOY identifies male patients with chronic kidney disease at high risk for mortality and heart failure events.

Early signs of myocardial systolic dysfunction in patients with type 2 diabetes are strongly associated with myocardial microvascular dysfunction independent of myocardial fibrosis: a prospective cohort study

BackgroundPatients with diabetes demonstrate early left ventricular systolic dysfunction. Notably reduced global longitudinal strain (GLS) is related to poor outcomes, the underlying pathophysiology is however still not clearly understood. We hypothesized that pathophysiologic changes with microvascular dysfunction and interstitial fibrosis contribute to reduced strain.Methods211 patients with type 2 diabetes and 25 control subjects underwent comprehensive cardiovascular phenotyping by magnetic resonance imaging. Myocardial blood flow (MBF), perfusion reserve (MPR), extracellular volume (ECV), and 3D feature tracking GLS and global circumferential (GCS) and radial strain (GRS) were quantified.ResultsPatients (median age 57 [IQR 50, 67] years, 70% males) had a median diabetes duration of 12 [IQR 6, 18] years. Compared to control subjects GLS, GCS, and GRS were reduced in the total diabetes cohort, and GLS was also reduced in the sub-group of patients without diabetic complications compared to control subjects (controls − 13.9 ± 2.0%, total cohort − 11.6 ± 3.0%; subgroup − 12.3 ± 2.6%, all p < 0.05). Reduced GLS, but not GCS or GRS, was associated with classic diabetes complications of albuminuria (UACR ≥ 30 mg/g) [β (95% CI) 1.09 (0.22–1.96)] and autonomic neuropathy [β (95% CI) 1.43 (0.54–2.31)] but GLS was not associated with retinopathy or peripheral neuropathy. Independently of ECV, a 10% increase in MBF at stress and MPR was associated with higher GLS [multivariable regression adjusted for age, sex, hypertension, smoking, and ECV: MBF stress (β (95% CI) − 0.2 (− 0.3 to − 0.08), MPR (β (95% CI) − 0.5 (− 0.8 to − 0.3), p < 0.001 for both]. A 10% increase in ECV was associated with a decrease in GLS in univariable [β (95% CI) 0.6 (0.2 to 1.1)] and multivariable regression, but this was abolished when adjusted for MPR [multivariable regression adjusted for age, sex, hypertension, smoking, and MPR (β (95% CI) 0.1 (− 0.3 to 0.6)]. On the receiver operating characteristics curve, GLS showed a moderate ability to discriminate a significantly lowered stress MBF (AUC 0.72) and MPR (AUC 0.73).ConclusionsMyocardial microvascular dysfunction was independent of ECV, a biomarker of myocardial fibrosis, associated with GLS. Further, 3D GLS could be a potential screening tool for myocardial microvascular dysfunction. Future directions should focus on confirming these results in longitudinal and/or interventional studies.

The prognostic role of galectin-3 and endothelial function in patients with heart failure.

Heart failure (HF) is nowadays classified as HF with reduced ejection fraction (HFrEF), HF with mildly reduced EF (HFmrEF), and HF with preserved EF (HFpEF). Endothelial dysfunction (assessed by flow-mediated dilatation [FMD]), increased arterial stiffness (assessed by carotid-femoral pulse-wave velocity [PWV]), and galectin-3, a biomarker of myocardial fibrosis, have been linked to major adverse cardiovascular events (MACE) in patients with ischemic HF. In this study we prospectively enrolled 340 patients with stable ischemic HF. We assessed the brachial artery FMD, carotid-femoral PWV, and galectin-3 levels, and patients were followed up for MACE according to HF group. Interestingly, the FMD values exhibited a stepwise improvement according to left ventricular ejection fraction (LVEF) (HFrEF: 4.74 ± 2.35% vs. HFmrEF: 4.97 ± 2.81% vs. HFpEF: 5.94 ± ± 3.46%, p = 0.01), which remained significant after the evaluation of possible confounders including age, sex, cardiovascular risk factors, and number of significantly stenosed epicardial coronary arteries (b coefficient: 0.990, 95% confidence interval: 0.166-1.814, p = 0.019). Single-vessel coronary artery disease was more frequent in the group of HFpEF (HFrEF: 56% vs. HFmrEF: 64% vs. HFpEF: 73%, p = 0.049). PWV did not display any association with LVEF. Patients who presented MACE exhibited worse FMD values (4.51 ± 2.35% vs. 5.32 ± 2.67%, p = 0.02), and the highest tertile of galectin-3 was linked to more MACEs (36% vs. 5.9%, p = 0.01). Flow-mediated dilatation displayed a linear improvement with LVEF in patients with ischemic HF. Deteriorated values are associated with MACE. Higher levels of galectin-3 might be used for risk stratification of patients with ischemic HF.

Evaluation of right ventricular diastolic function, systolic function, and circulating galectin-3 concentrations in dogs with pulmonary stenosis.

Cardiovascular diseases with increased right ventricular (RV) afterload induce RV diastolic and systolic dysfunction, and myocardial fibrosis in humans. Studies in dogs with pulmonary stenosis (PS) evaluating RV diastolic function and markers of myocardial fibrosis are lacking. Dogs with PS have echocardiographic evidence of RV diastolic and systolic dysfunction and increased serum concentrations of galectin-3 (Gal-3), a surrogate biomarker for myocardial fibrosis. Forty client-owned dogs (10 controls, 30 with PS). Prospective study. All dogs had systemic blood pressure measurement, serum biochemical analysis, echocardiography, and measurement of serum Gal-3 concentration performed. Variables of RV diastolic function were obtained in 39/40 dogs. Trans-tricuspid flow velocity in early diastole to trans-tricuspid flow velocity in late diastole ratios (RV E/A) were lower (P < .001) in dogs with PS (median, 0.94; range, 0.62-2.04) compared to controls (1.78; 1.17-2.35). Trans-tricuspid flow velocity in early diastole to tricuspid annular myocardial velocity in early diastole ratios (RV E/e') were higher (P < .001) in dogs with PS (11.55; 4.69-28) compared to control (6.21; 5.16-7.21). Variables of RV systolic function were lower in dogs with PS (P = <.001). Serum Gal-3 concentration was higher (P = .002) in dogs with PS (285.1 pg/mL; 94.71-406.97) compared to control dogs (162.83 pg/mL; 52.3-232.82). Dogs with PS have RV diastolic and systolic dysfunction, and increased Gal-3 concentrations. These findings suggest the presence of RV myocardial fibrosis in dogs with PS, which could impact clinical management.

Biomarkers, Socioeconomic Factors, and Right Ventricular Function After Surgical Repair for Tetralogy of Fallot.

Right ventricular (RV) dysfunction early after tetralogy of Fallot (TOF) increases post-operative morbidity. We investigated associations of circulating biomarkers and socioeconomic factors with early post-operative RV systolic function. Single-center prospective cohort study of infants undergoing TOF repair. Six serologic biomarkers of myocardial fibrosis and wall stress collected at the time of surgery were measured with immunoassay. Geocoding was performed for socioeconomic factors. Multivariate adaptive regression splines (MARS) models identified factors associated with RV function parameters: fractional area change (FAC), global longitudinal strain and strain rate, andfree wall strain and strain rate. Seventy-one patients aged 3.5months (IQR 2.4, 5.2) were included. Galectin-3 was the highest ranked predictor for FAC, global longitudinal strain, and free wall strain, and procollagen type-I carboxy-terminal propeptide (PICP) was the highest ranked predictor for global longitudinal strain rate and free wall strain rate. Several neighborhood characteristics were also highly ranked. Models adjusted R2 ranged from 0.71 to 0.85 (FAC, global longitudinal strain/strain rate), and 0.55-0.57 (RV free wall strain/strain rate). A combination of serologic biomarkers, socioeconomic, and clinical variables explain a significant proportion of the variability in RV function after TOF repair. These factors may inform pre-operative risk-stratification for these patients.

The impact of myocardial fibrosis biomarkers in a heart failure population with atrial fibrillation—The HARVEST-Malmö study

Several studies suggest that circulating biomarkers of myocardial fibrosis are associated with worse prognosis in subjects with atrial fibrillation (AF). Here, we aimed to explore associations between fibrosis biomarkers, prevalent AF, and left atrial volume (LAV) enlargement in subjects with heart failure (HF). Additionally, we evaluated the prognostic impact of fibrotic biomarkers in HF with co-existing AF. Patients hospitalized for HF (n = 316, mean age 75 years; 30% women) were screened for AF. Seven proteins previously associated with myocardial fibrosis [metalloproteinase inhibitor 4 (TIMP-4), suppression of tumorigenicity 2 (ST-2), galectin-3 (GAL-3), growth/differentiation factor-15 (GDF-15), and matrix metalloproteinase 2, 3, and 9 (MMP-3, MMP-3, and MMP-9, respectively)] were analyzed using a proximity extension assay. Proteins with significant Bonferroni-corrected associations with mortality and re-hospitalization risk were taken forward to multivariable Cox regression analyses. Further, Bonferroni-corrected multivariable logistic regression models were used to study associations between protein plasma levels, prevalent AF, and severely enlarged left atrial volume index (LAVI ≥ 48 ml/m2). Prevalent AF was observed in 194 patients at the hospitalization of whom 178 (92%) were re-hospitalized and 111 (57%) died during the follow-up period. In multivariable logistic regression models, increased plasma levels of TIMP-4, GDF-15, and ST-2 were associated with the prevalence of AF, whereas none of the seven proteins showed any significant association with severely enlarged LAVI. Increased plasma levels of five proteins yielded significant associations with all-cause mortality in patients with co-existing AF; TIMP-4 (HR 1.33; CI95% 1.07-1.66; p = 0.010), GDF-15 (HR 1.30; CI95% 1.05-1.62; p = 0.017), GAL-3 (HR 1.29; CI95% 1.03-1.61; p = 0.029), ST-2 (HR 1.48; CI95% 1.18-1.85; p < 0.001), and MMP-3 (HR 1.33; CI95% 1.09-1.63; p = 0.006). None of the proteins showed any significant association with re-hospitalization risk. In this study, we were able to demonstrate that elevated levels of three plasma proteins previously linked to myocardial fibrosis are associated with prevalent AF in a HF population. Additionally, higher levels of five plasma proteins yielded an increased risk of mortality in the HF population with or without co-existing AF.

Dynamic right ventricular structural and functional changes in acute decompensated heart failure, new insights from serum sST2 and speckle-tracking echocardiography imaging

Abstract Background Right ventricular (RV) mechanics are affected by volume/pressure overload in acute decompensated heart failure (ADHF) which can be detected using biomarkers and echocardiography. ST2 (suppression of tumorigenicity 2) is a biomarker of myocardial fibrosis and remodeling, that has been studied in patients with ADHF. Although baseline serum soluble ST2 (sST2) values at ADHF admission have been proved to predict outcomes, serial measurements are even of greater value. Purpose To evaluate the right ventricular dynamic structural and functional changes in ADHF patients during hospitalization, using serum sST2 and speckle-tracking echocardiography imaging. Methods We prospectively enrolled 61 ADHF patients with LV ejection fraction less than 50% and serum NT-proBNP more than 900 pg/ml. All patients received intravenous diuretics and did not require inotropic support during hospital stay. Blood samples were collected to measure serum sST2 levels on hospital admission and discharge. All patients underwent serial conventional and speckle tracking echocardiography on admission, at 48 hours and on hospital discharge. RV speckle tracking echocardiography analysis was done using 2D Cardiac Performance Analysis version 4.6. Results Serum sST2 had significant strong positive correlation with serum NT-proBNP on admission (r=0.84, P&amp;lt;0.0001) and showed significant reduction from 2.47 (1.27–4.05) ng/ml on admission to 1.86 (1.06–3.24) ng/dl at hospital discharge (P&amp;lt;0.0001) denoting successful decongestion. There was significant decrease in inferior vena cava diameter (P&amp;lt;0.0001) and estimated pulmonary artery systolic pressure (EPASP) (P=0.002) throughout hospital stay, however this was not associated with significant change in RV dimensions (P&amp;gt;0.05) or contractility assessed by trans-annular plane systolic excursion (TAPSE) (P=0.09) and S-wave velocity at lateral tricuspid annulus (P=0.9). There was significant improvement in RV free wall strain (RVFWS) (P=0.005) assessed by speckle tracking echocardiography which was mainly noticed after the first 48 hours till discharge, but RV 4-chamber strain (RV4CS) did not change significantly (P=0.06). Conclusions RVFWS assessed by speckle tracking echocardiography can detect improvement in RV systolic function not detected by other conventional echocardiographic parameters in ADHF patients. Improvement in RVFWS together with decline in serum sST2 levels can be used as marker of improved cardiac mechanics and successful decongestion. Funding Acknowledgement Type of funding sources: None.

The prognostic role of galectin-3 and endothelial function in patients with heart failure according to left ventricular ejection fraction classification HF group

Abstract Background Heart failure (HF) is nowadays classified in HF with reduced ejection fraction (HFrEF), HF with mildly-reduced EF (HFmrEF) and HF with preserved EF (HFpEF). Endothelial dysfunction, increased arterial stiffness and galectin-3, a biomarker of myocardial fibrosis, have been linked to major adverse cardiovascular events (MACE) in patients with ischemic HF. Purpose The purpose of this prospective, follow-up study was to investigate in patients with stable ischemic HF the prognostic role of circulating galectin-3 levels, endothelial function and arterial stiffness according to left ventricular ejection fraction classification. Methods In this study we prospectively enrolled 340 patients with stable ischemic HF. Patients were categorized in HFrEF (when EF below or equal to 40%), HFmrEF (when EF is more than 40%&amp;lt;ef≤49%)&amp;gt; and below/equal to 49%) and HFpEF (when EF is more/equal to 50% along with the presence of structural or functional dysfunction and/or elevated natriuretic peptides) according to recent guidelines upon 2D echocardiographic assessment. We evaluated flow-mediated dilatation (FMD) of brachial artery as a marker of endothelial function, carotid-femoral pulse-wave velocity (PWV) as a marker of arterial stiffness and galectin-3 levels as a biomarker of fibrosis. Patients were followed-up for MACE and the primary endpoint was defined as cardiovascular death, myocardial infarction, coronary revascularization, stroke, and hospitalization due to HF. &amp;lt;ef≤49%)&amp;gt; Results Interestingly, FMD values exhibited a stepwise improvement according to LVEF (HFrEF: 4.74±2.35% vs. HFmrEF: 4.97±2.81% vs. HFpEF: 5.94±3.46%, p=0.01) which remained statistically significant after the evaluation of possible confounders including age, sex, cardiovascular risk factors and number of significantly stenosed epicardial coronary arteries (b coefficient: 0.990, 95% CI: 0.166–1.814, p=0.019). Multivessel coronary artery disease (CAD) was more frequent in the group of HFrEF (HFrEF: 56% vs. HFmrEF: 64% vs. HFpEF: 73%, p=0.049). Nevertheless, PWV did not display any association with LVEF. Patients who presented MACE exhibited worse FMD values (4.51±2.35% vs. 5.32±2.67%, p=0.02) and the highest tertile of galectin-3 was linked to more MACEs (36% vs. 5.9%, p=0.01). Conclusions FMD values have a linear improvement according to LVEF increase in patients with ischemic HF and worse values are linked to more MACEs. Higher levels of galectin-3 might be used for risk stratification of patients with ischemic HF. Funding Acknowledgement Type of funding sources: None.

DIABETIC STATUS AND NIGHT-TIME SYSTOLIC BLOOD PRESSURE PREDICT EARLY MYOCARDIAL DAMAGE IN NEWLY DIAGNOSED DIABETES MELLITUS TYPE 2 PATIENTS AS THIS IS DEPICTED BY GALECTIN-3 LEVELS

Objective: Long standing Diabetes Mellitus Type 2 (T2DM) shows a high frequency of cardiovascular events. However, it is not known if newly diagnosed patients with T2DM present early signs of cardiovascular dysfunction. On the other hand, galectin has been introduced as a novel biomarker of myocardial fibrosis. The aim of the study was to evaluate levels of galectin-3 in patients with a very recent diagnosis of T2DM without established cardiovascular disease. In addition, hemodynamic parameters as well as their possible correlation with galactin-3 levels were studied. Design and method: Patients with a recent diagnosis of T2DM (&lt;6 months) and non-T2DM volunteers were studied. A thorough medical history with emphasis on hypertension and relevant comorbidities, somatometric measurements and blood tests was obtained from all participants. Serum levels of galectin-3 were determined by ELISA. Myocardial function and hemodynamic profile were noninvasively assessed with impedance cardiography. Furthermore, Atherosclerotic Cardiovascular Disease Risk (ASCVD) was calculated. Results: We studied 135 subjects, 79 T2DM patients with a median disease duration of 1 month (IR: 5) and 56 controls matched by age, sex and hypertension. T2DM patients had significantly higher values of galectin-3 (90 ± 88ng/dl vs 32.92 ± 6.32ng/dl, p &lt; 0.001), Cardiac Output (CO), ASCVD Risk compared to controls. Galectin-3 was associated with T2DM (p &lt; 0.001), fasting glucose (p &lt; 0.001), glycosylated hemoglobin (p &lt; 0.001). Furthermore, galectin-3 was associated with CO (p = 0.023), nighttime systolic blood pressure (SBP) (p = 0.03) and ASCVD Risk (p = 0.001). In multiple linear regression analysis, T2DM (Beta: 0.406, p &lt; 0.001) and nighttime SBP (Beta: 0.196, p = 0.028), were identified as independent predictors of galectin-3, after adjustment for age, sex, Body Mass Index and CO. Conclusions: Galectin-3 is elevated in patients with early stage T2DM even in the absence of established cardiovascular disease, and is independently correlated with T2DM and nighttime SBP. In this group of patients galectin may be used as a biomarker of early myocardial damage. Nighttime SBP emerge as an important mediator in early target organ damage in cardiovascular diseases.

MO094: Intensive Blood Pressure Lowering and Myocardial Fibrosis Biomarkers in Individuals With and Without CKD: Results From the Systolic Blood Pressure Intervention Trial (Sprint)

Abstract BACKGROUND AND AIMS Circulating cardiac biomarkers implicated in the pathogenesis of heart disease may provide a non-invasive, more precise assessment of cardiovascular risk. In the Systolic Blood Pressure Intervention Trial (SPRINT), intensive blood pressure lowering was associated with a 25% reduction in cardiovascular events and a 27% reduction in all-cause mortality. We sought to assess whether the beneficial effect of lowering systolic blood pressure on clinical outcomes was accompanied by a reduction in serum biomarkers of myocardial fibrosis. METHOD SPRINT, a multicenter randomized controlled trial conducted in the United States, enrolled participants aged ≥ 50 years, at increased risk for cardiovascular disease and randomized them to intensive systolic blood pressure lowering (target &amp;lt; 120 mmHg) or standard blood pressure lowering (target &amp;lt; 140 mmHg). In a randomly selected subgroup of SPRINT participants, myocardial fibrosis was assessed by two collagen-derived serum peptides, C-terminal propeptide of procollagen type I (CICP) and N-terminal propeptide of procollagen type 3 (P3NP) and Galectin 3 measured at study baseline and at 24 months follow-up. Chronic kidney disease was defined as eGFR &amp;lt; 60 mL/min/1.73 m2. Analyses were based on linear mixed models including clinic site as a random effect, with adjustments for treatment group and baseline level of each respective biomarker. RESULTS A total of 742 SPRINT participants with and without CKD with available measurements of myocardial fibrosis biomarkers at study baseline and 24 months were included in the study. The median (IQR) Galectin 3, CICP and P3NP levels at study baseline and 24 months follow-up in the intensive versus standard group are presented in the Table 1. Intensive blood pressure lowering was not associated with longitudinal changes in CICP or P3NP (Table 1 and Figure 1). Intensive blood pressure lowering was associated with a statistically significant increase in Galectin 3 level [between group mean difference 0.47 (IQR: 0.03–0.92) ng/mL, P = 0.04]. All of the findings were generally consistent across participants with and without CKD (Table 1). CONCLUSION In a random sample of SPRINT participants, intensive versus standard blood pressure lowering was not associated with a reduction in circulating myocardial fibrosis biomarkers overtime in hypertensive individuals with and without CKD.

Comparison of serum biomarkers of myocardial fibrosis with cardiac magnetic resonance in patients operated for tetralogy of Fallot

BackgroundSerum biomarkers of myocardial fibrosis are considered markers of adverse outcome in adults with heart disease. Associations between biomarkers and clinical parameters in tetralogy of Fallot (TOF) has been understudied. We compared serum biomarker profiles with clinical and cardiac magnetic resonance (CMR) parameters of ventricular remodeling in patients with repaired TOF. MethodsSerum biomarkers [metalloproteinases MMP1 and MMP9, galectin-3, micro-RNA21 (miR21)), ST2, procollagen type I carboxy-terminal propeptide (PICP), and NTproBNP] were measured in TOF patients undergoing CMR. Associations between biomarkers and clinical and CMR variables were assessed using correlation coefficients, and linear and logistic regression. ResultsSixty patients were investigated, of which 47% were male. Age at CMR and TOF repair was 15 years [interquartile range (IQR) 9, 22] and 3.2 months (IQR 0.8, 6.2), respectively. Twelve (20%) had prior pulmonary valve replacement (PVR). MMP1 values were higher among those with prior PVR (16.7 (IQR 7.9, 25.5) vs 14.4 (IQR 9.9, 24.9), p = 0.02). When stratifying MMP1 into low and high groups, higher MMP1 was associated with higher indexed right (RV) and left ventricular (LV) mass and RV mass:volume ratios after adjusting for PVR. No other associations between biomarkers and CMR parameters were identified. ConclusionsOnly MMP1 was associated with markers of RV remodeling after TOF repair. As an enzyme involved in extracellular matrix degradation, MMP1 could be associated with fibrotic processes underlying RV remodeling, including dilation and hypertrophy. The additional biomarkers may not be specific towards cardiac remodeling. These findings merit further correlations with myocardial fibrosis measurements by CMR.

Extracellular Matrix in Heart Disease: Focus on Circulating Collagen Type I and III Derived Peptides as Biomarkers of Myocardial Fibrosis and Their Potential in the Prognosis of Heart Failure: A Concise Review.

Accumulating evidence indicates that two major proteins are responsible for the structural coherence of bounding cardiomyocytes. These biomolecules are known as myocardial fibrillar collagen type I (COL1) and type III (COL3). In addition, fibronectin, laminin, fibrillin, elastin, glycoproteins, and proteoglycans take part in the formation of cardiac extracellular matrix (ECM). In physiological conditions, collagen synthesis and degradation in human cardiac ECM are well-regulated processes, but they can be impaired in certain cardiovascular diseases, such as heart failure (HF). Myocardial remodeling is part of the central mechanism of HF and involves cardiomyocyte injury and cardiac fibrosis due to increased fibrillar collagen accumulation. COL1 and COL3 are predominantly involved in this process. Specific products identified as collagen-derived peptides are released in the circulation as a result of abnormal COL1 and COL3 turnover and myocardial remodeling in HF and can be detected in patients’ sera. The role of these products in the pathogenesis of cardiac fibrosis and the possible clinical implications are the focus of numerous investigations. This paper reviews recent studies on COL1- and COL3-derived peptides in patients with HF. Their potential application as indicators of myocardial fibrosis and prognostic markers of HF is also highlighted.

Association of plasma biomarkers and interstitial myocardial fibrosis in fontan population: A machine learning approach

BackgroundMyocardial fibrosis is a common final pathway in many myocardial diseases. Circulating biomarkers are recognized in heart failure management as potential treatment targets. The current study sought to evaluate the association between biomarkers of myocardial fibrosis and myocardial fibrosis using machine learning techniques. Methods and ResultsThe permutation-based feature importance and the cooperation network among important features in random forest algorithm were applied to evaluate the relationship of each biomarker to extracellular volume fraction (ECV). A total of 25 Fontan patients were included in the study with multiple serum biomarkers obtained at the time of CMR. The mean age at the time of assessment was 16.3 ± 6.8 years with the mean duration of Fontan circulation of 13.0 ± 6.3 years. Lateral tunnel was the most common Fontan type (52%), and the majority (72%) had a systemic left ventricle. The mean ECV was 28 ± 5%. Among different types of matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP), our study found that MMP-10, and TIMP-1 were the most strongly associated with cardiac fibrosis measured by ECV. ConclusionsTIMP-1 and MMP-10 are circulating biomarkers that may represent promising targets for the prevention and treatment of myocardial fibrosis in Fontan circulation.

Abstract 11416: The Prognostic Impact of Myocardial Fibrosis Biomarkers for Atrial Fibrillation in a Heart Failure Population

Introduction: Several studies suggest that circulating biomarkers of myocardial fibrosis are associated with worse prognosis of atrial fibrillation (AF). Hypothesis: Here, we aimed to evaluate the prognostic impact of myocardial fibrosis biomarkers for atrial fibrillation in a heart failure (HF) population Methods: Three-hundred-and-twenty-one patients hospitalized for HF (mean age 75 years; 32% women) were screened for co-existing AF and a proximity extension assay including estimation of 7 proteins associated with myocardial fibrosis; Metalloproteinase inhibitor 4 (TIMP-4), Soluble interleukin 1 receptor-like 1 (ST-2), Galectin 3 (Gal-3), Growth/differentiation factor 15 (GDF-15) and Matrix metalloproteinase 2, 3 and 9 (MMP-3, MMP-3 and MMP-9 respectively). Associations between AF and proteins were cross-sectionally studied in multivariable logistic regression models. Furthermore, associations between protein plasma levels, mortality and re-hospitalization risk were analyzed using multivariable Cox regression analysis adjusted for age sex, prevalent diabetes, smoking, body mass index (BMI), systolic blood pressure (SBP) and New York heart association classification (NYHA-class). Results: One-hundred-and-ninety-seven patients (61%) had prevalent AF at hospitalization. In multivariate logistic regression models, the prevalence of atrial fibrillation was significantly associated with increased plasma levels of TIMP-4, GDF-15, ST-2, MMP-2 and MMP-9. In the fully adjusted Cox regression model, increased plasma levels of 5 proteins yielded significant associations with mortality; TIMP4 (p=0,022 HR;1,46 CI95%1,06-2,01), GDF 15 (p=0,028; HR1,29; CI95% 1,03-1,63), Gal-3 (p=0,017; HR1,64;CI95% 1,09-2,47), ST2 (p=0,002; HR;1,43; CI95%1,14-1,80) and MMP3 (p=0,011; HR;1,29; CI95% 1,06-1,58). Further, increased levels of TIMP4 was significantly associated with rehospitalization (p=0,001; HR 1,58; C95% 1,19-2,08). Conclusions: We have demonstrated that increased plasma levels of plasma proteins related to myocardial fibrosis are associated with the risk of mortality in hospitalized HF patients, independently of traditional risk factors.

Identification of myocardial fibrosis by ATR-FTIR spectroscopy combined with chemometrics

Different degrees of myocardial fibrosis can often be observed in sudden cardiac death cases, so that the identification of myocardial fibrosis is an important step in forensics to identify cardiac death. Previous methods are restricted by complex algorithms, high cost, low sensitivity and high requirements. Attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy is an efficient and rapid method to identify tissue types, which has been used increasingly in forensics. This study aims to identify novel biophysical biomarkers of myocardial fibrosis and establish a prediction model by using ATR-FTIR analysis combined with chemometrics. A total of 129 tissue blocks taken from human hearts were cut into slices, and then ATR-FTIR spectroscopy and hematoxylin and eosin (HE) staining were performed. By using HE staining, the samples were divided into the experimental group (with myocardial fibrosis) and the control group (without myocardial fibrosis). The chemometrics classification results showed that the sensitivity and specificity of the training dataset were 0.91 and 1.0 respectively, and the sensitivity and specificity of the predictive dataset were 0.862 and 0.900. This study demonstrated that ATR-FTIR spectroscopy combined with chemometrics is a novel method for identifying myocardial fibrosis.

Triglyceride-Glucose Index and Extracellular Volume Fraction in Patients With Heart Failure.

Background: The triglyceride–glucose (TyG) index had been proposed as a reliable surrogate marker of insulin resistance. We aimed to evaluate the association between TyG index and myocardial fibrosis, which was quantified by extracellular volume (ECV) fraction using cardiovascular magnetic resonance (CMR) examination, and their prognostic value in patients with heart failure (HF).Methods: In this retrospective cohort study, 103 hospitalized HF patients were included. ECV fraction was calculated using CMR measurements and T1 mapping. TyG index was calculated using fasting triglyceride and blood glucose. The primary outcome events were defined as all-cause mortality and HF hospitalization during follow-up.Results: During the median follow-up of 12.3 months, 39 patients (37.9%) experienced primary outcome events and had higher levels of TyG index, N-terminal pro–B-type natriuretic peptide (NT-proBNP), and ECV fraction compared with those without events. Multivariate linear regression analysis showed that the TyG index was the significant factor determined for ECV fraction (rpartial = 0.36, P = 0.01). In multivariate Cox regression analysis, presence of diabetes [hazard ratio (HR) = 1.28, 95% confidence interval (CI) = 1.01–1.62], higher TyG index (HR = 2.01, 95% CI = 1.03–4.01), ECV fraction (HR = 1.73, 95% CI = 1.04–2.88), and NT-proBNP (HR = 2.13, 95% CI = 1.08–4.20) were independent risk factors for the primary outcome events.Conclusions: TyG index is a novel biomarker of myocardial fibrosis in HF patients and can be considered as a useful risk stratification metric in the management of HF.

Plasma Galectin-3 is associated with progression from paroxysmal to persistent atrial fibrillation

BackgroundGalectin-3 (Gal-3) is currently recognized as a promising biomarker for myocardial fibrosis. This study aimed to explore the potential association between plasma Gal-3 concentrations and atrial fibrillation (AF) progression in paroxysmal AF (PAF) patientsMethodsA total of 213 PAF patients were included for analysis in this study. All peripheral blood samples were prospectively collected and stored at -80℃ for subsequent Gal-3 quantification. The AF progression was defined as transformation from PAF to persistent AF (PsAF).ResultsA total of 51 PAF patients progressed to PsAF during a mean follow-up period of 674.44 ± 19.48 days. Patients with AF progression had significantly higher baseline plasma Gal-3 concentrations than those stayed in PAF status (13.52 ± 0.94 vs. 7.93 ± 0.37, p < 0.001). All PAF patients were divided into two subgroups based on the median value of plasma Gal-3 concentrations. Kaplan–Meier curve analysis showed a significantly higher AF progression rate in the higher plasma Gal-3 concentration group (log-rank test p < 0.001). In the Cox regression analysis, plasma Gal-3 concentration and left atrial diameter (LAD) were showed significantly associated with AF progression, even after adjustment of other potential confounding risk factors. Discrimination for AF progression with a simple model which consists of plasma Gal-3 concentration and LAD was modest with a C-statistic 0.72 (95%CI 0.64–0.80). Plasma Gal-3 concentration significantly improved the predictability by appropriately reclassifying several patients with progression (NRI = 28.3%, p = 0.003).ConclusionElevated plasma Gal-3 concentration is significantly associated with AF progression from PAF to PsAF. Plasma Gal-3 concentration could be used for PAF progression risk stratification and guiding management for PAF patients.

Combined corrected QT interval and growth differentiation factor-15 level has synergistic predictive value for long-term outcome of angiographically confirmed coronary artery disease.

The corrected QT interval (QTc) predicts prognosis for the general population and patients with coronary artery disease (CAD). Growth differentiation factor-15 (GDF-15) is a biomarker of myocardial fibrosis and left ventricular (LV) remodelling. The interaction between these two parameters is unknown. This study included 487 patients with angiographically confirmed CAD. QTc was calculated using the Bazett formula. Multiple biochemistries and GDF-15 levels were measured. The primary endpoint was total mortality, and the secondary endpoints comprised the combination of total mortality, myocardial infarction and hospitalisation for heart failure and stroke. The mean follow-up period was 1029±343days (5-1692days), during which 21 patients died and 47 had secondary endpoints. ROC curve analysis for the optimal cut-off value of primary endpoint is 1.12ng/mL for GDF-15 (AUC=0.787, P=9.0×10-6 ) and 438.5 msec for QTc (AUC=0.698, P=.002). Utilising linear regression, QTc has a positive correlation with Log-GDF-15 (r=.216, P=1.0×10-6 ). Utilising Kaplan-Meier analysis, both QTc interval and GDF-15 level are significant predictors for primary end point (P=.000194, P=2.0×10-6 , respectively) and secondary endpoint (P=.00028, P=6.15×10-8 , respectively). When combined these two parameters together, a significant synergistic predictive power was noted for primary and secondary endpoint (P=2.31×10-7 , P=1.26×10-8 , respectively). This combined strategy also showed significant correlation with the severity of CAD (P<.001). In Chinese patient with angiographically confirmed CAD, a combined strategy utilising an ECG parameter (QTc) and a circulating biomarker (GDF-15) has good correlation with the severity of CAD, and improves the predictive power for total mortality.

The consequence of biomarkers of myocardial fibrosis in the prediction of arrhythmias in patients with hypertension in combination with coronary heart disease (literature review)

The main morphological structural lesion substrate is myocardial fibrosis. The processes of fibrosis in a certain way are associated with the severity of a variety of cardiac arrhythmias. Myocardial fibrosis may be manifested by prolongation of the QRS complex, frequent ventricular arrhythmias and ventricular tachycardia on the electrocardiogram. Echocardiography is the main tool used to assess the structure and function of the heart, it reveals an increase in the left ventricle, and decrease in ejection fraction and diastolic dysfunction of the left ventricle and an increase in filling pressure. Biological markers are quantitatively defined biological parameters that, as indicators, determine the norm, pathology and result of medecinal correction of the disease (definition of experts from the Biomarkers Definitions Working Group, USA). Changes of biomarkers can be controlled to determine the individual risk of cardiovascular diseases development and measures to normalize them. Among the main causes of fibrosis activation, hyperactivation of the renin-angiotensin-aldosterone system and, as a consequence, the excessive formation of angiotensinogen and aldosterone are considered; increased levels of galectin-3, which contributes to the migration of macrophages, proliferation of fibroblasts and collagen synthesis in cardiomyocytes. Recently, much attention is paid to the study of biochemical markers such as aldosterone, galectin-3 and transforming growth factor- beta-1.Thus, these markers were determined in hypertension, metabolic syndrome, congestive heart failure, hypertrophic cardiomyopathy, myocardial infarction, atrial fibrillation. However, to date studies considering association between frequent ventricular premature beats, as a marker of electrical instability and plasma levels of biomarkers of fibrosis, such as aldosterone, galectin-3and transforming growth factor beta-1, in patients with essential hypertension without / or in combination with coronary heart disease are absent. Based on the aforesaid material,, further thorough study of this problem is promising.

Biomarkers of myocardial fibrosis and their genetic regulation in patients with heart failure

Currently, the development of chronic heart failure (CHF) is considered from the perspective of pathological structural remodeling of myocardium and fibrosis. Despite the widespread use of molecular genetic markers in clinical practice, only a small number of them are used to evaluate remodeling processes, as well as to predict potential complications associated with heart failure (HF). In addition, the relationship between many biomarkers with instrumental and histological confirmation of myocardial fibrosis has not yet been determined. Myocardial fibrosis remains quite debatable and controversial subject, which actualizes the further study of this direction. The discovery of pathogenetic and diagnostic markers of myocardial fibrosis could contribute to the development of targeted therapy. Of particular interest is the search for possible pathogenetic markers, since this is relevant for clinical practice.