Aims: The aim of the present study was to investigate the inhibition of classically activated macrophages in myocardial infarction (MI) under the influence of the chemokine (C-C motif) receptor 2 (CCR2) antagonist propagermanium (PPG). Methods and Results: Mice (C57BL/6; n = 121) were subjected to occlusion of the left anterior descending artery and were randomized to the following groups: (a) MI with daily oral administration of 0.9% sodium chloride ("MI"), (b) MI with oral administration of 8 mg/kg PPG ("MI + PPG"), and (c) sham-operated mice served as control. Mice were euthanized 2, 5, 10, or 21 days after MI for isolation of total RNA, protein, and immunofluorescence measurements. Flow cytometry was performed to investigate peripheral blood leucocytes. Scar size and cardiac function were determined by MRI on Day 7 after surgery and by trichrome staining on Day 21. PPG administration led to a significantly improved ejection fraction (MI + PPG: 38.5% ± 3.4% vs. MI: 23.8% ± 3.0%; p < 0.05) after MI. MRI also revealed improved wall thickness (34.7% ± 3.2% vs. 21.8% ± 2.9%; p < 0.05) associated with a diminished akinetic area (13.8% ± 4.0% vs. 37.3% ± 5.6%; p < 0.01). Trichrome staining confirmed less collagen scar formation in the PPG-treated group (12.7% ± 1.4% vs. 21.9% ± 3.9%; p < 0.05). Flow cytometry showed fewer peripheral blood monocytes in MI + PPG than in MI 2 days after treatment (4.0% ± 0.7% vs. 12.7% ± 1.2% of total leucocytes; p < 0.05). Immunostaining and western blotting using activation type-specific markers CCR2 and MRC1 demonstrated that the number of alternatively activated macrophages within the infarct zone increased, whereas the overall number was reduced after PPG treatment. PPG led to increased expression of VEGF-α and VEGF-β in THP-1 cells in vitro and increased capillary density in vivo 2 days after MI (MI-PPG: 1071 ± 81/mm2 vs. MI: 648 ± 79/mm2 (p < 0.05)). Conclusion: Our results suggest that altering the activation type and distribution of invading macrophages in favor of alternative activation improves cardiac remodeling and function following MI.

Risk prediction in patients with severe, symptomatic aortic stenosis (AS) undergoing transcatheter aortic valve implantation (TAVI) remains an unsolved issue. In addition to classical risk scoring systems, novel circulating biomarkers like mid-regional pro-adrenomedullin (MR-proADM) and growth differentiation factor 15 (GDF-15) may be of value in assessing risk. Consecutive patients undergoing elective transfemoral TAVI were included in this prospective observational study. Baseline information, imaging findings, blood samples, and clinical outcomes were collected. Blood levels of the classical biomarkers interleukin-6 (IL-6) and high-sensitivity C-reactive peptide (hsCRP) and of the novel biomarkers MR-proADM and GDF-15 were measured and their predictive utility for mortality assessed. The study cohort consisted of 92 patients undergoing TAVI. The median age was 80.7 years [IQR 77.2;83.3], and 48 (52.2

Background: Currently available risk scores fail to accurately predict morbidity and mortality in patients with severe symptomatic aortic stenosis who undergo transcatheter aortic valve implantation (TAVI). In this context, biomarkers like matrix metalloproteinase-2 (MMP-2) and Galectin-3 (Gal-3) may provide additional prognostic information. Methods: Patients with severe aortic stenosis undergoing consecutive, elective, transfemoral TAVI were included. Baseline demographic data, functional status, echocardiographic findings, clinical outcomes and biomarker levels were collected and analysed. Results: The study cohort consisted of 89 patients (age 80.4 +/- 5.1 years, EuroScore II 7.1 +/- 5.8%). During a median follow-up period of 526 d, 28 patients (31.4%) died. Among those who died, median baseline MMP-2 (alive: 221.6 [170.4; 263] pg/mL vs. deceased: 272.1 [225; 308.8] pg/mL, p < 0.001) and Gal-3 levels (alive: 19.1 [13.5; 24.6] pg/mL vs. deceased: 25 [17.6; 29.5] pg/mL, p = 0.006) were higher than in survivors. In ROC analysis, MMP-2 reached an acceptable level of discrimination to predict mortality (AUC 0.733, 95% CI [0.62; 0.83], p < 0.001), but the predictive value of Gal-3 was poor (AUC 0.677, 95% CI [0.56; 0.79], p = 0.002). Kaplan-Meier and Cox regression analyses showed that patients with MMP-2 and Gal-3 concentrations above the median at baseline had significantly impaired long-term survival (p = 0.004 and p = 0.02, respectively). Conclusions: In patients with severe aortic stenosis undergoing transfemoral TAVI, MMP-2 and to a lesser extent Gal-3, seem to have additive value in optimizing risk prediction and streamlining decision-making.

AIMS:SPARCL1 was recently identified as a biomarker of right ventricular (RV) maladaptation in patients with pulmonary hypertension (PH), and N-terminal pro-brain natriuretic protein (NT-proBNP) is an established biomarker of RV failure in PH. The present study investigated whether NT-proBNP and SPARCL1 concentrations are associated with load-independent parameters of RV function and RV-to-pulmonary artery (RV-PA) coupling as measured using invasive pressure-volume (PV) loops in the RV. METHODS:SPARCL1 and NT-proBNP were measured in the plasma of patients with idiopathic pulmonary artery hypertension (IPAH, n = 73). Participants without LV or RV abnormalities served as controls (n = 28). All patients underwent echocardiography and right heart catheterization with invasive PV loop measurements. RESULTS:Our cohort had more females with IPAH than the control group (64% vs. 35%; P = 0.01) and was older [69 (interquartile range, IQR 57-76) vs. 51 (IQR 35-62) years; P < 0.001]. SPARCL1 and NT-proBNP levels were significantly higher in patients with IPAH as compared with controls (P < 0.0001). Patients with IPAH and maladaptive RV remodelling had higher SPARCL1 and NT-proBNP concentrations than those with adaptive RV remodelling (P < 0.01). Both SPARCL1 and NT-proBNP were good predictors of maladaptive RV remodelling in receiver operating characteristic analysis [area under the curve (AUC) (AUCSPARCL1 = 0.75, AUCNT-proBNP = 0.72, P = 0.36 for AUCSPARCL1 vs. AUCNT-proBNP]. The combined predictive value of SPARCL1 and NT-proBNP (AUC 0.78, P < 0.001) for maladaptive RV was numerically higher than that of either SPARCL1 or NT-proBNP alone (P = 0.16 for AUCSPARCL1 + NT-proBNP vs. AUCNT-proBNP and P = 0.18 for AUCSPARCL1 + NT-proBNP vs. AUCSPARC1). SPARCL1 showed numerically a tendency for a better predictive power than NT-proBNP for parameters of early maladaptive RV remodelling such as RV ejection fraction < 50% (AUCSPARCL1 = 0.77, AUCNT-proBNP = 0.67, P = 0.06 for AUCSPARCL1 vs. AUCNT-proBNP), RV end-diastolic diameter > 42 mm (AUCSPARCL1 = 0.72, AUCNT-proBNP = 0.65, P = 0.19 for AUCSPARCL1 vs. AUCNT-proBNP) and RV end-systolic volume index RVESVI > 31 mL/m2 (AUCSPARCL1 = 0.78, AUCNT-proBNP = 0.71, PP = 0.10 for AUCSPARCL1 vs. AUCNT-proBNP). CONCLUSIONS:SPARCL1 and NT-proBNP are good predictors of maladaptive RV remodelling and RV-PA uncoupling in IPAH patients. SPARCL1 may be a better predictor of early maladaptive RV remodelling than NT-proBNP.

Background: This study analyzed the utility of soluble ST2 (sST2) and GDF-15 as biomarkers of right ventricular (RV) function in patients with pulmonary hypertension (PH). Methods: GDF-15 and sST2 serum concentrations were measured in patients with PH (n = 628), dilated cardiomyopathy (n = 31) and left ventricular hypertrophy (n = 47), and in healthy controls (n = 61). Results: Median sST2 and GDF-15 levels in patients with left ventricular hypertrophy were higher than in patients with PH and dilated cardiomyopathy. In tertile analysis GDF-15 >1363 pg/ml and sST2 >38 ng/ml were associated with higher N-terminal pro-brain natriuretic peptide, RV systolic dysfunction, RV-pulmonary arterial uncoupling and hemodynamic impairment. Conclusion: GDF-15 and sST2 are potential biomarkers of RV dysfunction in patients with PH.

Fibroblast growth factor 23 (FGF-23) has been associated with left ventricular hypertrophy (LVH) and heart failure. However, its role in right ventricular (RV) remodeling and RV failure is unknown. This study analyzed the utility of FGF-23 as a biomarker of RV function in patients with pulmonary hypertension (PH). In this observational study, FGF-23 was measured in the plasma of patients with PH (n = 627), dilated cardiomyopathy (DCM, n = 59), or LVH with severe aortic stenosis (n = 35). Participants without LV or RV abnormalities served as controls (n = 36). Median FGF-23 plasma levels were higher in PH patients than in healthy controls (p < 0.001). There were no significant differences between PH, DCM, and LVH patients. Analysis across tertiles of FGF-23 levels in PH patients revealed an association between higher FGF-23 levels and higher levels of NT-proBNP and worse renal function. Furthermore, patients in the high-FGF-23 tertile had a higher pulmonary vascular resistance (PVR), mean pulmonary artery pressure, and right atrial pressure and a lower cardiac index (CI) than patients in the low tertile (p < 0.001 for all comparisons). Higher FGF-23 levels were associated with higher RV end-diastolic diameter and lower tricuspid annular plane systolic excursions (TAPSE) and TAPSE/PASP. Receiver operating characteristic analysis revealed FGF-23 as a good predictor of RV maladaptation, defined as TAPSE < 17 mm and CI < 2.5 L/min/m2. Association of FGF-23 with parameters of RV function was independent of the glomerular filtration rate in regression analysis. FGF-23 may serve as a biomarker for maladaptive RV remodeling in patients with PH.

Abstract Background Cardiac myosin binding protein-C is a protein expressed in the myosin thick filament backbone that was recently described as a novel cardiac biomarker. Its N-terminal region, C0-C1f, is released within the first minutes of ischemia and plays a crucial role in the initiation of inflammation in bone marrow-derived macrophages. Long-term C0-C1f exposure induces cardiac fibrosis in transgenic mice; however, the mechanism by which C0-C1f causes fibrosis is unclear. The aim of the study was to investigate the effects of C0-C1f on fibroblasts, which are the main contributor to cardiac fibrosis, in vitro. We determined whether C0-C1f directly activates fibroblasts and causes a transdifferentiation to myofibroblasts or induces inflammatory responses. Moreover, we clarify whether other cell types could be involved in inducing fibrosis, i.e. by the release of pro-inflammatory cytokines upon C0-C1f interaction. Methods A novel human fibroblast cell line (huFib) was treated with C0-C1f, C0-Linker, TGF-β, or LPS for different time periods. Inflammatory and fibrotic responses were evaluated at the RNA and protein level using different techniques including microarray, qRT-PCR, and immunofluorescence imaging. For signalling pathway analysis, TLR4 and NFκB were inhibited using chemical compounds TAK-242 or Bay11–0785 respectively. Results C0-C1f treatment induced an increase in mRNA corresponding to pro-inflammatory genes in huFib cells (i.a. CXL1 upon 24 hours treatment: 29 fold, p<0.001 and CCL2 4-fold, p<0.001). The mRNA expression levels of pro-fibrotic genes such as ACTA2 or COL1A1, which were upregulated by TGF-β, were not reduced by C0-C1f (ACTA2 induced by TGF-β: 3,8 fold, p<0.001, co-stimulation with C0-C1f: 1,8 fold, p=0.11 compared to control; COL1A1 induced by TGF-β: 2,94 fold, p<0.001, co-stimulation with C0-C1f: 2.09 fold (p<0.01) compared to control. Interestingly, co-stimulation of fibroblasts with C0-C1f and TGF-β led also to markedly lower inflammatory response compared to C0-C1f treatment alone (CXCL1 induction upon co-stimulation: 2,0 fold, p<0.001, CCL2: 1,9 fold, p=0.001, which is a reduction by 27 fold, p<0.001 or 2 fold, p=0.002, respectively). Inhibition of TLR4 or NFκB signaling diminished C0-C1f-mediated inflammatory responses. Conclusion C0-C1f induces inflammation in fibroblasts via TLR4/NFκB signalling pathway. Downregulation of C0-C1f mediated inflammatory responses upon co-stimulation with TGF-β suggests crosstalk between the two signaling pathways. Contrary, C0-C1f reduced TGF-β mediated pro-fibrotic responses reflected by conversion of fibroblasts into myofibroblasts was not observed. Taken together, these data are consistent with the idea that C0-C1f might play a key role in the early initiation of inflammation upon myocardial infarction, also in fibroblasts, and that TGF-β acts as a counterpart at later stages of cardiac remodeling. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): William G. Kerckhoff Stiftung für wissenschaftliche Forschung und Fortbildung

Aim: This study assessed the utility of osteopontin (OPN) and galectin-3 (Gal-3) as biomarkers of maladaptive right ventricular remodeling in pulmonary hypertension (PH). Materials & methods: We examined plasma levels of OPN and Gal-3 in patients with PH (n = 62), dilated cardiomyopathy (n = 34), left ventricular hypertrophy (LVH; n = 47), and controls without right ventricle (RV) or LV abnormalities (n = 38). Results: OPN and Gal-3 levels were higher in PH, dilated cardiomyopathy and LVH than in the controls. OPN concentrations in PH patients with maladaptive RV were significantly higher than in those with adaptive RV. Gal-3 did not differentiate between adaptive and maladaptive RV remodeling in PH. OPN and Gal-3 levels did not correlate with parameters of LV remodeling. Conclusion: OPN is a potential biomarker of RV maladaptation.

Inflammation is a hallmark of the period after a myocardial infarction (MI) that is either promoted or resolved by distinct subtypes of circulating inflammatory cells. The three main monocyte subpopulations play different roles inflammation. This study examined whether the type of MI (type 1 or type 2) or the extent of myocardial injury is associated with differences in monocyte subpopulations. For this purpose, peripheral whole blood from patients with a suspected MI was used for flow cytometric measurements of the monocyte subpopulations, and myocardial injury was classified by cardiac troponin levels in serum. In patients with acute coronary syndrome (n = 82, 62.2% male) similar proportions of the monocyte subsets were associated with the two types of MI, whereas total monocyte counts were increased in patients with substantial myocardial injury vs. those with minor injury (p = 0.045). This was accompanied by a higher proportion of intermediate (p = 0.045) and classical monocytes (p = 0.059); no difference was found for non-classical monocytes (p = 0.772). In patients with chronic coronary syndrome (n = 144, 66.5% male), an independent association with myocardial injury was also observed for classical monocytes (p = 0.01) and intermediate monocytes (p = 0.08). In conclusion, changes in monocyte subpopulation counts, particularly for classical and intermediate monocytes, were related to the extent of myocardial injury in acute and stable coronary artery disease but not to the type of MI.

Abstract Background Severe aortic stenosis (AS) is associated with left ventricular (LV) pressure overload that leads to myocardial remodelling and inflammatory processes. Interleukin 6 (IL6) is secreted by leukocytes as an early response to infection and tissue damage as well as high senisitve C-reactive Protein (hsCRP), which is subsequent in the same pathway. Several studies have suggested an association of elevated serum levels with a higher risk of cardiovascular events. GDF-15 and MR-proADM are also associated with inflammatory processes in cardiovascular diseases and are predictors for adverse events and mortality in patients with AS. The aim of the present study was to evaluate their potential prognostic value regarding the patients all-cause mortality. Methods A total of 92 consecutive patients (mean age: 80,8 [±5,3] years) undergoing TAVI were included in this study. TAVI was performed according to standard clinical practice. Venous blood samples for biomarker analysis were collected prior to and 6 months after TAVI, these were processed immediately and frozen at −80°C until the assay was performed. Safety events, physiological- and echocardiographical parameters, were assessed at the baseline and the 6-month follow-up. Furthermore, we compiled the all-cause mortality of our patients after two years. Results TAVI was performed successfully in all patients. During the two-year follow-up period 24 patients met the endpoint of all-cause mortality. At baseline, serum levels of the inflammatory biomarkers were significantly higher in patients who died within the follow-up period, when compared to survivors (IL6:14,450pg/ml [IQR:7,550; 42,150] vs. 4,200pg/ml [IQR:2,515; 13,875],p=0,0004; hsCRP:5,360 mg/l [IQR:2,248; 26,790] vs. 2,900mg/l [IQR:1,208; 8,210],p=0,022); MR-proADM:1,347nmol/l [IQR:1,038–1,678] vs. 0,922nmol/l [IQR:0,706; 1,202],p=0,0003 and GDF-15:2770,0pg/ml [IQR:2401,0; 3701,0] vs. 1675,2pg/ml [IQR:1141,6; 2524,4],p=0,001). The area under the curve was 0,767 for IL-6, 0,665 for hsCRP, 0,735 for MR-proADM and 0,735 for GDF-15. In addition, there was a significant decrease of IL-6 (baseline: 4,200pg/ml [IQR:2,525; 13,875] vs. 6FU:2,600pg/ml [IQR:1,500; 7,000],p<0,0001), hsCRP (baseline:2,900mg/l [IQR:1,208; 8,210] vs. FU: 2,101 mg/l [IQR: 0,980; 4,540],p=0,002) and MR-proADM (baseline:0,922nmol/l [IQR:0,706–1,202] vs. FU: 0,828nmol/l [IQR:0,642–1,132],p=0,01) serum levels in survivors after a follow-up of 6 months after TAVI, when compared to baseline values. While the median serum levels of GDF-15 (baseline:1675,2pg/ml [IQR:1141,6; 2524,4] vs. FU: 1663,8pg/ml [IQR:1176,5; 2538,1],p=0,563) remained stable. Conclusions In the present study there was a significant decrease of inflammatory biomarkers after TAVI in high risk patients with severe aortic stenosis and good clinical outcome. In this regard, IL-6, hsCRP, MR-proADM and GDF-15 were predictors of all-cause mortality in patients, who underwent TAVI. Funding Acknowledgement Type of funding sources: None.

The aim of our study was to analyse the protein expression of cartilage intermediate layer protein (CILP)1 in a mouse model of right ventricular (RV) pressure overload and to evaluate CILP1 as a biomarker of cardiac remodelling and maladaptive RV function in patients with pulmonary hypertension (PH).Pulmonary artery banding was performed in 14 mice; another nine mice underwent sham surgery. CILP1 protein expression was analysed in all hearts using Western blotting and immunostaining. CILP1 serum concentrations were measured in 161 patients (97 with adaptive and maladaptive RV pressure overload caused by PH; 25 with left ventricular (LV) hypertrophy; 20 with dilative cardiomyopathy (DCM); 19 controls without LV or RV abnormalities)In mice, the amount of RV CILP1 was markedly higher after banding than after sham. Control patients had lower CILP1 serum levels than all other groups (p<0.001). CILP1 concentrations were higher in PH patients with maladaptive RV function than those with adaptive RV function (p<0.001), LV pressure overload (p<0.001) and DCM (p=0.003). CILP1 showed good predictive power for maladaptive RV in receiver operating characteristic analysis (area under the curve (AUC) 0.79). There was no significant difference between the AUCs of CILP1 and N-terminal pro-brain natriuretic peptide (NT-proBNP) (AUC 0.82). High CILP1 (cut-off value for maladaptive RV of ≥4373 pg·mL−1) was associated with lower tricuspid annular plane excursion/pulmonary artery systolic pressure ratios (p<0.001) and higher NT-proBNP levels (p<0.001).CILP1 is a novel biomarker of RV and LV pathological remodelling that is associated with RV maladaptation and ventriculoarterial uncoupling in patients with PH.

OBJECTIVE:Blood monocyte subsets are emerging as biomarkers of cardiovascular inflammation. However, our understanding of human monocyte heterogeneity and their immunophenotypic features under healthy and inflammatory conditions is still evolving.RATIONALE:In this study, we sought to investigate the immunophenome of circulating human monocyte subsets.METHODS:Multiplexed, high-throughput flow cytometry screening arrays and computational data analysis were used to analyze the expression and hierarchical relationships of 242 specific surface markers on circulating classical (CD14++CD16-), intermediate (CD14++CD16+), and nonclassical (CD14+CD16++) monocytes in healthy adults.RESULTS:Using generalized linear models and hierarchical cluster analysis, we selected and clustered epitopes that most reliably differentiate between monocyte subsets. We validated existing transcriptional profiling data and revealed potential new surface markers that uniquely define the classical (e.g., BLTR1, CD35, CD38, CD49e, CD89, CD96), intermediate (e.g., CD39, CD275, CD305, CDw328), and nonclassical (e.g., CD29, CD132) subsets. In addition, our analysis revealed phenotypic cell clusters, identified by dendritic markers CMRF-44 and CMRF-56, independent of the traditional monocyte classification.CONCLUSION:These results reveal an advancement of the clinically applicable multiplexed screening arrays that may facilitate monocyte subset characterization and cytometry-based biomarker selection in various inflammatory disorders.

BackgroundSpecific matrix metalloproteinases (MMP‐2, MMP‐9) and inflammatory biomarkers (hsCRP, IL‐6) were found to be consistently up‐regulated in severe mitral valve regurgitation (MR) and are associated with mortality in heart failure patients. The aim of the present study was to examine the prognostic value of biomarkers of cardiac inflammation and remodeling processes in predicting mortality in patients with MR undergoing percutaneous mitral valve repair (PMVR).HypothesisWe hypothesize that increased cardiac inflammation and extracellular matrix turnover is predictive for mortality in patients with severe mitral regurgitation undergoing MitraClip.MethodsA total of 210 consecutive patients undergoing PMVR were included. PMVR was performed according to standard clinical practice. Venous blood samples for biomarker analyses were collected prior to and 6 months after PMVR. Physiological parameters, medication use, safety events, and all‐cause mortality were followed over 12 months.ResultsPMVR was performed successfully in all patients. Twelve months after PMVR there was an effective reduction in the severity of MR (P < 0.001), and an improvement in New York Heart Association class (P < 0.01) was documented. Elevated inflammatory biomarkers (AUChsCRP: 0.738 [IQR, 0.626–0.849], P = 0.001; AUCIL‐6: 0.811 [IQR, 0.724–0.899], P = 0.001) and biomarkers reflecting cardiac remodeling processes (AUCMMP‐2: 0.723 [IQR, 0.641–0.804], P = 0.001; AUCMMP‐9: 0.618 [IQR, 0.534–0.701], P = 0.01) were predictors of adverse cardiac events and mortality in patients with congestive heart failure undergoing PMVR.ConclusionsThe present study is the first to identify biomarkers reflecting inflammation (hsCRP, IL‐6) and cardiac remodeling processes (MMP‐2, MMP‐9) as predictors of mortality in high‐risk patients undergoing PMVR.

Background: Lipoprotein(a) (Lp(a)) is a major carrier of oxidized phospholipids (OxPL) and is associated with aortic stenosis incidence.However, it remains unclear whether elevated Lp(a) is associated with faster disease progression once the disease is established.Purpose: This study investigated whether Lp(a) and OxPL levels are associated with aortic valve disease activity, progression of aortic stenosis and clinical events in aortic stenosis patients.In vitro experiments will be performed to explore whether Lp(a) directed therapy may mitigate aortic valve calcification.Methods: We combined two prospective cohorts and measured Lp(a) and OxPL levels in 145 aortic stenosis patients (Vmax>2.0m/s), who underwent 18F-NaF PET/CT (valve calcification activity), CT calcium scoring (valve calcium burden) and echocardiography (haemodynamic progression).In vitro studies will be performed to investigate the effects of Lp(a) and OxPL on valvular interstitial cells.Results: Patients in the top tertile of Lp(a) had increased calcification activity at baseline compared with middle and bottom tertiles (18F-NaF TBR[MDSmean]: 2.16 vs. 1.97; p=0.043) despite similar disease severity and calcium burden.During follow-up, patients in the top tertile of Lp(a) had faster progression in both CT calcium score (309 (142-483) AU/yr vs. 93 (56-296) AU/yr; p=0.015) and valve hemodynamics (0.23±0.20 m/s/yr vs. 0.14±0.20 m/s/yr; p=0.019), as well as an increased risk for aortic valve replacement and cardiovascular death (hazard ratio 1.81; 95% CI, 1.07 to 3.07; p=0.027), compared with lower tertiles.We will report on the proposed in vitro studies.Conclusions: In patients with aortic stenosis, elevated Lp(a) is associated with increased valve calcification activity, faster disease progression and increased clinical events.

BACKGROUND:Compromised renal function is a major risk factor that is strongly associated with poor outcome in patients with mitral regurgitation (MR) and heart failure. Cystatin C, a cysteine protease inhibitor, has been used as a specific and sensitive biomarker of renal function. Neutrophil gelatinase-associated lipocalin (NGAL) is another sensitive biomarker that specifically indicates functional and structural kidney damage. The aim of the present study was to determine the predictive value of serum cystatin C and urinary NGAL as indicators of mortality in patients undergoing percutaneous mitral valve repair (PMVR).METHODS:A total of 120 consecutive patients (age: 77.3 years [±11.2]) undergoing PMVR using the MitraClip system were included in this study. Venous blood and urinary samples were collected for biomarker analysis prior to PMVR. Physiological parameters, medication use, safety events, and all-cause mortality were assessed 12 months after the procedure.RESULTS:Twelve months after PMVR, there was a significant reduction in the severity of MR (P < 0.001), and an improvement in the New York Heart Association class (P < 0.01) was documented. Baseline levels of serum cystatin C (nonsurvivors: 2.4 mg/L [interquartile, IQR: 1.7;3.1] vs survivors: 1.7 mg/L [IQR: 1,3;2.1], P < 0.001) and urinary NGAL (nonsurvivors: 242.0 ng/mL [IQR: 154.5;281.5] vs survivors: 132.0 ng/mL [IQR:107.0;177.3], P < 0.001) were significantly higher in patients who died during the 12-month follow-up period.CONCLUSION:Cystatin C and urinary NGAL were found to be predictors of long-term mortality in high-risk patients undergoing PMVR. Thus, cystatin C and NGAL assessment may be helpful in risk stratification in patients undergoing PMVR.

Background Percutaneous mitral valve repair (PMVR) is an interventional treatment option in patients with severe mitral regurgitation (MR) and at high risk for open‐heart surgery. Currently, limited information exists about predictors of procedural success after PMVR. Galectin‐3 (Gal‐3) and suppression of tumorigenicity 2 (ST2) induce fibrotic alterations in severe MR and heart failure. We sought to examine the predictive value of Gal‐3 and ST2 as specific indicators of therapeutic success in high‐risk patients undergoing PMVR. Hypothesis We hypothesize that extended cardiac fibrotic alterations might have impact on successful MR reduction after the MitraClip procedure. Methods A total of 210 consecutive patients undergoing PMVR using the MitraClip system were included in this study. Procedural success was defined as an immediate reduction of MR by ≥2 grades, assessed by echocardiography. Venous blood samples were collected prior to PMVR and at 6 months follow‐up for biomarker analysis. Results After PMVR there was a significant reduction in the severity of MR (MR grade: 3 ±0.3 vs 1.6 ±0.6, P <0.001). Low baseline Gal‐3 levels (PMVR success : 22.0 ng/mL [IQR, 17.3‐30.9] vs PMVR failure : 30.6 ng/mL [IQR, 24.8‐42.3], P <0.001) and ST2 levels (PMVR success : 900.0 pg/mL [IQR, 619.5‐1114.5] vs PMVR failure : 1728.0 pg/mL [IQR, 1051.March 1, 1930], P < 0.001) were associated with successful MR reduction after PMVR. Also, ROC analysis identified low baseline Gal‐3 and ST2 levels as predictors of therapeutic success after PMVR (AUC Gal‐3 :0.721 [IQR, 0.64‐0.803], P < 0.001; AUC ST2 : 0.807 [IQR, 0.741‐0.872], P < 0.001). Conclusions There was an association between low Gal‐3 and ST2 plasma levels and successful MR reduction in patients with severe MR undergoing PMVR using the MitraClip system.