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    Neutrophil Gelatinase-Associated Lipocalin (NGAL) is Associated with Symptomatic Carotid Atherosclerosis and Drives Pro-inflammatory State In Vitro. Eilenberg W,Stojkovic S,Piechota-Polanczyk A,Kaun C,Rauscher S,Gröger M,Klinger M,Wojta J,Neumayer C,Huk I,Demyanets S European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery OBJECTIVE:Neutrophil gelatinase-associated lipocalin (NGAL), a protein found in activated neutrophils, is expressed in kidney tubule cells in response to noxious stimuli, and is thus recognized as a marker of acute kidney injury. Recent studies have suggested that NGAL could also have pathophysiological importance in cardiovascular diseases. The aim of the present study was to examine NGAL expression in human carotid endarterectomy tissues ex vivo as well as the effects of NGAL in the main cell types involved in atherogenesis, namely in human macrophages, endothelial cells, and smooth muscle cells in vitro. METHODS:NGAL protein was analyzed in human endarterectomy samples from patients with asymptomatic and symptomatic carotid stenosis by immunofluorescence, and NGAL mRNA expression was detected using RealTime-PCR. Human monocyte derived macrophages (MDM), human coronary artery smooth muscle cells (HCASMC), and human umbilical vein endothelial cells (HUVEC) were treated with recombinant human (rh) NGAL at different concentrations. Interleukin (IL)-6, IL-8, and monocyte chemo-attractant protein-1 (MCP-1) were determined by specific enzyme linked immunosorbent assays (ELISAs) in culture supernatants of such treated cells. RESULTS:Expression of NGAL protein was demonstrated by macrophages, smooth muscle cells, and endothelial cells in human carotid atherosclerotic tissue. NGAL mRNA expression was detected at a higher rate in atherosclerotic tissue of patients with symptomatic carotid stenosis (in 70%; n = 19) compared with asymptomatic patients (in 37%; n = 20, p < .001). Treatment of MDM, HCASMC, and HUVEC with rhNGAL led to a significant (p < 0.05) and concentration dependent increase of pro-inflammatory cytokines IL-6, IL-8, and MCP-1 in all cell types analyzed. CONCLUSION:By induction of pro-inflammatory mediators in human macrophages, smooth muscle cells and endothelial cells, NGAL, which is predominantly expressed in atherosclerotic plaques of symptomatic patients, could be involved in creating the local and systemic pro-inflammatory environment characteristic for atherosclerosis. 10.1016/j.ejvs.2016.01.009
    Plasma Neutrophil Gelatinase-Associated Lipocalin Reflects Both Inflammation and Kidney Function in Patients with Myocardial Infarction. Lindberg Søren,Jensen Jan S,Hoffmann Søren,Iversen Allan Z,Pedersen Sune H,Biering-Sørensen Tor,Galatius Søren,Flyvbjerg Allan,Mogelvang Rasmus,Magnusson Nils E Cardiorenal medicine BACKGROUND/AIMS:Neutrophil gelatinase-associated lipocalin (NGAL) has emerged as a marker for acute kidney injury and cardiovascular outcome. However, the relative importance of inflammation versus kidney function on plasma NGAL levels is uncertain, making the interpretation of plasma NGAL unclear. Accordingly, we investigated the relationship between plasma NGAL, inflammation and kidney function in patients with myocardial infarction (MI). METHODS:We prospectively included 584 patients with acute ST-segment elevation MI (STEMI) treated with primary percutaneous coronary intervention (PCI) from 2006 to 2008. Blood samples were drawn immediately before PCI. Additionally, we included 42 patients who had 4 blood samples drawn before and after PCI. Plasma NGAL was measured using a time-resolved immunofluorometric assay. Cross-sectional analyses were performed in these two single-center, prospective study cohorts. RESULTS:Estimated glomerular filtration rate (eGFR) was associated significantly more strongly with plasma NGAL when eGFR was abnormal compared to normal eGFR: a decrease in eGFR of 10 ml/min was associated with an increase in NGAL of 27% (18-36%) versus 4% (1-7%), respectively (p < 0.001). Leukocyte count and C-reactive protein were the main determinants of plasma NGAL in patients with normal eGFR, whereas eGFR was the main determinant at reduced kidney function. CONCLUSIONS:eGFR determines the association of NGAL with either inflammation or kidney function; in patients with normal eGFR, plasma NGAL reflects inflammation but when eGFR is reduced, plasma NGAL reflects kidney function, highlighting the dual perception of plasma NGAL. From a clinical perspective, eGFR may be used to guide the interpretation of elevated NGAL levels in patients with STEMI. 10.1159/000443846
    [Clinical and Prognostic Value of Serum Neutrophil Gelatinase-Associated Lipocalin in Patients With ST-Segment Elevation Myocardial Infarction]. Zykov M V,Kashtalap V V,Bykova I S,Hryachkova O N,Kalaeva V V,Shafranskaya K S,Karetnikova V N,Barbarash O L Kardiologiia PURPOSE:to study clinical and prognostic significance of serum neutrophil gelatinase-associated lipocalin (s-NGAL) in patients with ST-segment elevation myocardial infarction (STEMI). MATERIAL AND METHODS:Patients with STEMI (n=85) of less than 24 hours duration admitted to the Kemerovo Cardiology Dispensary were included in the study. s-NGAL levels (ng/ml) were measured on day 1 and 12 of hospital stay by ELISA using commercial kit. Reinfarction rate and mortality were assessed over 3-year follow-up. RESULTS:Median s-NGAL levels on day1 and 12 were 1.33 (0.36-1.90) and 1.63 (1.25-2.61) ng/ml, that corresponded to a 3.32- and 4.07-fold increase, respectively, compared to reference values. Between days 1 and 12 s-NGAL levels increased by 22.55 % (p=0.0009). Higher values of serum NGAL on day 12 of MI were associated with presence of renal structural lesions, three-vessel coronary artery disease and anterior MI. Patients who underwent percutaneous coronary intervention (PCI) demonstrated only a negligible increase of s-NGAL level by day 12 while in those not subjected to PCI 3-fold increase was observed. Patients with s-NGAL levels >2.6 ng/ml compared with other patients had higher mortality (9.52 vs 31.83%; odds ratio 4.42 [1.30-15.16], p=0.012). CONCLUSION:High values of serum NGAL in STEMI patients were associated with severe clinical status. s-NGAL level above 2.6 ng/ml on day 12 of hospital stay was associated with 4- fold increase of all-cause mortality during 3-year follow-up. 10.18565/cardio.2016.5.24-29
    Serum Neutrophil Gelatinase-Associated Lipocalin Levels In Early Detection Of Contrast-Induced Nephropathy. Muratoglu Murat,Kavalci Cemil,Kilicli Elif,Findik Meliha,Kayipmaz Afşin Emre,Durukan Polat Clinical and investigative medicine. Medecine clinique et experimentale PURPOSE:The purpose of this study was to investigate the role of serum neutrophil gelatinase-associated lipocalin (NGAL) levels in the early detection of contrast-induced nephropathy (CIN). METHODS:This prospective study enrolled 74 patients undergoing abdominal tomography with contrast (1 November 2014 - 28 February 2015). Demographic properties (age and sex), symptoms and CT examination results were analysed. Sodium, potassium, urea, creatinine and NGAL levels were measured at 0th, 6th, and 72nd hours. P value < 0.05 was considered statistically significant. RESULTS:CIN developed in 16.2% of the study patients. The mean age was significantly higher in the patients who developed CIN (p0.05). Urea levels did not differ significantly between the groups at 0th and 6th hours (p>0.05) but was significantly higher in the patients with CIN at 72nd hour (p0.05). Creatinine level was not significantly different between the groups (p>0.05) but increased significantly over time (p>0.05). There were no significant differences between the groups with respect to NGAL levels at 0th and 72nd hours (p>0.05) whereas the group with CIN had a significantly higher NGAL level at 6th hour (p. 10.25011/cim.v39i3.26797
    Neutrophil Gelatinase-Associated Lipocalin as an Early Marker of Contrast-Induced Nephropathy After Elective Invasive Cardiac Procedures. Kafkas Nikolaos,Liakos Charalampos,Zoubouloglou Filitsa,Dagadaki Ourania,Dragasis Stylianos,Makris Konstantinos Clinical cardiology BACKGROUND:Contrast-induced nephropathy (CIN) is an acute kidney injury (AKI) defined as serum creatinine (sCr) increase 48 to 72 hours after contrast administration. Because most subjects undergoing invasive cardiac procedures are discharged within 24 hours, sCr is unsuitable for CIN detection. HYPOTHESIS:In the present study we tested the hypothesis that neutrophil gelatinase-associated lipocalin (NGAL) is superior compared with sCr and other established nephropathy markers in early CIN diagnosis after elective invasive cardiac procedures. METHODS:Serum creatinine, urine creatinine, serum cystatin C, urine albumin, urine NGAL (uNGAL), and plasma NGAL were measured at 0, 6, 24, and 48 hours after contrast administration in 100 elective invasive cardiac procedures. Estimated glomerular filtration rate and albumin-to-creatinine ratio were calculated. Changes from baseline were considered statistically significant at P < 0.05 and clinically significant when > the biomarker's reference change value. Participants were divided into those with and without clinically significant uNGAL changes (uNGAL positive and negative for AKI, respectively). RESULTS:Thirty-three individuals were uNGAL positive for AKI. Serum cystatin C changes were statistically and clinically nonsignificant in both groups. Serum creatinine and plasma NGAL were statistically but not clinically elevated 48 hours postcatheterization in the AKI group. Except for contrast volume (higher in AKI group), groups were comparable at baseline (P not significant) regarding cardiovascular risk factors, coronary heart disease, coronary interventions performed, and renal biomarkers. Baseline uNGAL was significantly correlated to estimated glomerular filtration rate and albumin-to-creatinine ratio. CONCLUSIONS:Urine NGAL is potentially superior compared with conventional nephropathy markers in early CIN diagnosis after elective invasive cardiac procedures. Definition of clinically significant uNGAL changes with reference change value is probably a valuable supplement to statistically defined significant variations. 10.1002/clc.22551
    Plasma cystatin C and neutrophil gelatinase-associated lipocalin in relation to coronary atherosclerosis on intravascular ultrasound and cardiovascular outcome: Impact of kidney function (ATHEROREMO-IVUS study). Brankovic Milos,Akkerhuis K Martijn,Buljubasic Nermina,Cheng Jin M,Oemrawsingh Rohit M,Garcia-Garcia Hector M,Regar Evelyn,Serruys Patrick W,van Geuns Robert-Jan,Boersma Eric,Kardys Isabella Atherosclerosis BACKGROUND AND AIMS:We investigated whether plasma cystatin C (CysC) and neutrophil gelatinase-associated lipocalin (NGAL) are associated with intravascular ultrasound (IVUS)-derived characteristics of coronary atherosclerosis and 1-year adverse coronary events in patients with normal and mildly-to-moderately impaired kidney function. METHODS:Between 2008 and 2011, virtual histology (VH)-IVUS of a non-culprit coronary artery was performed in 581 patients undergoing coronary angiography. Creatinine, CysC and NGAL were measured in pre-procedural blood samples. Presence of VH-IVUS-derived thin-cap fibroatheroma (TCFA) lesions, lesions with plaque burden (PB)≥70% and lesions with minimal luminal area (MLA)≤4 mm was assessed. Major adverse coronary events (MACE) comprised the composite of all-cause mortality, acute coronary syndrome, or unplanned coronary revascularization. Analyses were stratified using eGFR of 90 ml/min/1.73 m as the cut-off. RESULTS:In patients with normal kidney function, those with higher CysC levels had fewer lesions with PB ≥ 70% and fewer VH-TCFA lesions (adjusted odds ratios (ORs) and 95% confidence intervals (CIs): 0.46 [0.30-0.69] and 0.59 [0.44-0.83], respectively, per standard deviation (SD) ln[ng/mL] CysC). Those with higher NGAL levels also had fewer lesions with PB ≥ 70% (adjusted OR [95% CI]:0.49 [0.29-0.82]) In patients with impaired kidneys, no differences in high-risk lesions were observed for CysC or NGAL. However, those with higher CysC had higher risk of MACE (hazard ratio (HR):1.4, 95% CI [1.03-1.92]). This was not the case in patients with normal kidney function. NGAL did not influence risk of MACE. CONCLUSIONS:Mild-to-moderate kidney dysfunction modifies the relationship between CysC and high-risk coronary lesions. This has not been established before, and offers an explanation for the difference in findings between experimental and epidemiologic studies. 10.1016/j.atherosclerosis.2016.09.016
    Associations Between Neutrophil Gelatinase Associated Lipocalin, Neutrophil-to-Lymphocyte Ratio, Atrial Fibrillation and Renal Dysfunction in Chronic Heart Failure. Argan Onur,Ural Dilek,Kozdag Guliz,Sahin Tayfun,Bozyel Serdar,Aktas Mujdat,Karauzum Kurtulus,Yilmaz Irem,Dervis Emir,Agir Aysen Medical science monitor : international medical journal of experimental and clinical research BACKGROUND Atrial fibrillation (AF) and renal dysfunction are two common comorbidities in patients with chronic heart failure with reduced ejection fraction (HFrEF). This study evaluated the effect of permanent AF on renal function in HFrEF and investigated the associations of atrial fibrillation, neutrophil gelatinase-associated lipocalin (NGAL), and neutrophil-to-lymphocyte ratio (NLR) with adverse clinical outcome. MATERIAL AND METHODS Serum NGAL levels measured by ELISA and NLR were compared between patients with sinus rhythm (HFrEF-SR, n=68), with permanent AF (HFrEF-AF, n=62), and a healthy control group (n=50). RESULTS Mean eGFR levels were significantly lower, and NLR and NGAL levels were significantly higher in the HFrEF patients than in the control patients but the difference between HFrEF-SR and HFrEF-AF was not statistically significant (NGAL: 95 ng/mL in HFrEF-SR, 113 ng/mL in HFrEF-AF and 84 ng/mL in the control group; p<0.001). Independent associates of baseline eGFR were age, hemoglobin, NLR, triiodothyronine, and pulmonary artery systolic pressure. In a mean 16 months follow-up, adverse clinical outcome defined as progression of kidney dysfunction and composite of all-cause mortality and re-hospitalization were not different between HFrEF-SR and HFrEF-AF patients. Although NGAL was associated with clinical endpoints in the univariate analysis, Cox regression analysis showed that independent predictors of increased events were the presence of signs right heart failure, C-reactive protein, NLR, triiodothyronine, and hemoglobin. In ROC analysis, a NLR >3 had a 68% sensitivity and 75% specificity to predict progression of kidney disease (AUC=0.72, 95% CI 0.58-0.85, p=0.001). CONCLUSIONS Presence of AF in patients with HFrEF was not an independent contributor of adverse clinical outcome (i.e., all-cause death, re-hospitalization) or progression of renal dysfunction. Renal dysfunction in HFrEF was associated with both NLR and NGAL levels, but systemic inflammation reflected by NLR seemed to be a more important determinant of progression of kidney dysfunction. 10.12659/msm.898608
    Prognostic Value of Urinary Neutrophil Gelatinase-Associated Lipocalin on the First Day of Admission for Adverse Events in Patients With Acute Decompensated Heart Failure. Nakada Yasuki,Kawakami Rika,Matsui Masaru,Ueda Tomoya,Nakano Tomoya,Takitsume Akihiro,Nakagawa Hitoshi,Nishida Taku,Onoue Kenji,Soeda Tsunenari,Okayama Satoshi,Watanabe Makoto,Kawata Hiroyuki,Okura Hiroyuki,Saito Yoshihiko Journal of the American Heart Association BACKGROUND:Urinary neutrophil gelatinase-associated lipocalin (U-NGAL) is an early predictor of acute kidney injury and adverse events in various diseases; however, in acute decompensated heart failure patients, its significance remains poorly understood. This study aimed to investigate the prognostic value of U-NGAL on the first day of admission for the occurrence of acute kidney injury and long-term outcomes in acute decompensated heart failure patients. METHODS AND RESULTS:We studied 260 acute decompensated heart failure patients admitted to our department between 2011 and 2014 by measuring U-NGAL in 24-hour urine samples collected on the first day of admission. Primary end points were all-cause death, cardiovascular death, and heart failure admission. Patients were divided into 2 groups according to their median U-NGAL levels (32.5 μg/gCr). The high-U-NGAL group had a significantly higher occurrence of acute kidney injury during hospitalization than the low-U-NGAL group (=0.0012). Kaplan-Meier analysis revealed that the high-U-NGAL group exhibited a worse prognosis than the low-U-NGAL group in all-cause death (hazard ratio 2.07; 95%CI 1.38-3.12, =0.0004), cardiovascular death (hazard ratio 2.29; 95%CI 1.28-4.24, =0.0052), and heart failure admission (hazard ratio 1.77; 95%CI 1.13-2.77, =0.0119). The addition of U-NGAL to the estimated glomerular filtration rate significantly improved the predictive accuracy of all-cause mortality (=0.0083). CONCLUSIONS:In acute decompensated heart failure patients, an elevated U-NGAL level on the first day of admission was related to the development of clinical acute kidney injury and independently associated with poor prognosis. 10.1161/JAHA.116.004582
    Cystatin C, but not urinary or serum NGAL, may be associated with contrast induced nephropathy after percutaneous coronary invasive procedures: A single center experience on a limited number of patients. Cecchi Emanuele,Avveduto Gianfranco,D'Alfonso Maria Grazia,Terreni Alessandro,Gelera Emma,Caldini Anna,Giglioli Cristina Acta medica academica OBJECTIVE:This study aimed to test the association of both the baseline values and post-procedural variations of urinary and serum Neutrophil Gelatinase-Associated Lipocalin (NGAL) and Cystatin C (CysC) with contrast induced nephropathy (CIN) occurrence in patients undergoing percutaneous coronary invasive procedures (PCIP), and compare them to serum creatinine and the estimated glomerular filtration rate (eGFR). METHODS:In 43 patients admitted to our Cardiac Step-Down Unit and submitted to PCIP, we measured serum creatinine and eGFR as the standard markers for CIN diagnosis, and compared them to both serum and urinary NGAL as well as serum CysC, assessed before and 4 hours after PCIP. RESULTS:Patients who developed CIN (16%) were older, with significantly higher discharge creatinine values, lower eGFR values at creatinine peak, and higher baseline and post-PCIP CysC values. We did not detect any significant association between baseline serum and urinary NGAL values and their 4 hour variations after contrast medium administration and CIN occurrence. Furthermore, we observed that the baseline values of both serum and urinary NGAL were significantly higher in patients with greater neutrophil count. CONCLUSION:In our population submitted to PCIP, neither baseline serum and urinary NGAL nor their variations after PCIP were related to CIN occurrence, while CysC results were associated with CIN development, earlier than creatinine and eGFR variations. 10.5644/ama2006-124.184
    Experimental and Human Evidence for Lipocalin-2 (Neutrophil Gelatinase-Associated Lipocalin [NGAL]) in the Development of Cardiac Hypertrophy and heart failure. Marques Francine Z,Prestes Priscilla R,Byars Sean G,Ritchie Scott C,Würtz Peter,Patel Sheila K,Booth Scott A,Rana Indrajeetsinh,Minoda Yosuke,Berzins Stuart P,Curl Claire L,Bell James R,Wai Bryan,Srivastava Piyush M,Kangas Antti J,Soininen Pasi,Ruohonen Saku,Kähönen Mika,Lehtimäki Terho,Raitoharju Emma,Havulinna Aki,Perola Markus,Raitakari Olli,Salomaa Veikko,Ala-Korpela Mika,Kettunen Johannes,McGlynn Maree,Kelly Jason,Wlodek Mary E,Lewandowski Paul A,Delbridge Lea M,Burrell Louise M,Inouye Michael,Harrap Stephen B,Charchar Fadi J Journal of the American Heart Association BACKGROUND:Cardiac hypertrophy increases the risk of developing heart failure and cardiovascular death. The neutrophil inflammatory protein, lipocalin-2 (LCN2/NGAL), is elevated in certain forms of cardiac hypertrophy and acute heart failure. However, a specific role for LCN2 in predisposition and etiology of hypertrophy and the relevant genetic determinants are unclear. Here, we defined the role of LCN2 in concentric cardiac hypertrophy in terms of pathophysiology, inflammatory expression networks, and genomic determinants. METHODS AND RESULTS:We used 3 experimental models: a polygenic model of cardiac hypertrophy and heart failure, a model of intrauterine growth restriction and -knockout mouse; cultured cardiomyocytes; and 2 human cohorts: 114 type 2 diabetes mellitus patients and 2064 healthy subjects of the YFS (Young Finns Study). In hypertrophic heart rats, cardiac and circulating was significantly overexpressed before, during, and after development of cardiac hypertrophy and heart failure. expression was increased in hypertrophic hearts in a model of intrauterine growth restriction, whereas -knockout mice had smaller hearts. In cultured cardiomyocytes, activated molecular hypertrophic pathways and increased cell size, but reduced proliferation and cell numbers. Increased LCN2 was associated with cardiac hypertrophy and diastolic dysfunction in diabetes mellitus. In the YFS, expression was associated with body mass index and cardiac mass and with levels of inflammatory markers. The single-nucleotide polymorphism, rs13297295, located near defined a significant -eQTL for expression. CONCLUSIONS:Direct effects of LCN2 on cardiomyocyte size and number and the consistent associations in experimental and human analyses reveal a central role for LCN2 in the ontogeny of cardiac hypertrophy and heart failure. 10.1161/JAHA.117.005971
    Plasma Neutrophil Gelatinase-Associated Lipocalin and Predicting Clinically Relevant Worsening Renal Function in Acute Heart Failure. Damman Kevin,Valente Mattia A E,van Veldhuisen Dirk J,Cleland John G F,O'Connor Christopher M,Metra Marco,Ponikowski Piotr,Cotter Gad,Davison Beth,Givertz Michael M,Bloomfield Daniel M,Hillege Hans L,Voors Adriaan A International journal of molecular sciences The aim of this study was to evaluate the ability of Neutrophil Gelatinase-Associated Lipocalin (NGAL) to predict clinically relevant worsening renal function (WRF) in acute heart failure (AHF). Plasma NGAL and serum creatinine changes during the first 4 days of admission were investigated in 1447 patients hospitalized for AHF and enrolled in the Placebo-Controlled Randomized Study of the Selective A₁Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function (PROTECT) study. WRF was defined as serum creatinine rise ≥ 0.3 mg/dL through day 4. Biomarker patterns were described using linear mixed models. WRF developed in 325 patients (22%). Plasma NGAL did not rise earlier than creatinine in patients with WRF. After multivariable adjustment, baseline plasma NGAL, but not creatinine, predicted WRF. AUCs for WRF prediction were modest (<0.60) for all models. NGAL did not independently predict death or rehospitalization ( = n.s.). Patients with WRF and high baseline plasma NGAL had a greater risk of death, and renal or cardiovascular rehospitalization by 60 days than patients with WRF and a low baseline plasma NGAL (p for interaction = 0.024). A rise in plasma NGAL after baseline was associated with a worse outcome in patients with WRF, but not in patients without WRF ( = 0.007). On the basis of these results, plasma NGAL does not provide additional, clinically relevant information about the occurrence of WRF in patients with AHF. 10.3390/ijms18071470
    Lipocalin-2 (NGAL) Attenuates Autophagy to Exacerbate Cardiac Apoptosis Induced by Myocardial Ischemia. Sung Hye Kyoung,Chan Yee Kwan,Han Meng,Jahng James Won Suk,Song Erfei,Danielson Eric,Berger Thorsten,Mak Tak W,Sweeney Gary Journal of cellular physiology Lipocalin-2 (Lcn2; also termed neutrophil gelatinase-associated lipocalin (NGAL)) levels correlate positively with heart failure (HF) yet mechanisms via which Lcn2 contributes to the pathogenesis of HF remain unclear. In this study, we used coronary artery ligation surgery to induce ischemia in wild-type (wt) mice and this induced a significant increase in myocardial Lcn2. We then compared wt and Lcn2 knockout (KO) mice and observed that wt mice showed greater ischemia-induced caspase-3 activation and DNA damage measured by TUNEL than Lcn2KO mice. Analysis of autophagy by LC3 and p62 Western blotting, LC3 immunohistochemistry and transmission electron microscopy (TEM) indicated that Lcn2 KO mice had a greater ischemia-induced increase in autophagy. Lcn2KO were protected against ischemia-induced cardiac functional abnormalities measured by echocardiography. Upon treating a cardiomyocyte cell line (h9c2) with Lcn2 and examining AMPK and ULK1 phosphorylation, LC3 and p62 by Western blot as well as tandem fluorescent RFP/GFP-LC3 puncta by immunofluorescence, MagicRed assay for lysosomal cathepsin activity and TEM we demonstrated that Lcn2 suppressed autophagic flux. Lcn2 also exacerbated hypoxia-induced cytochromc c release from mitochondria and caspase-3 activation. We generated an autophagy-deficient H9c2 cell model by overexpressing dominant-negative Atg5 and found significantly increased apoptosis after Lcn2 treatment. In summary, our data indicate that Lcn2 can suppress the beneficial cardiac autophagic response to ischemia and that this contributes to enhanced ischemia-induced cell death and cardiac dysfunction. J. Cell. Physiol. 232: 2125-2134, 2017. © 2016 Wiley Periodicals, Inc. 10.1002/jcp.25672
    [NGAL as a marker for some extrarenal complications in acute coronary syndrome]. Shalenkova M A,Mikhailova Z D,Klimkin P F Kardiologiia AIM:To study the role of neutrophil gelatinase-associated lipocalin (NGAL) as a marker for extrarenal complications in patients with acute coronary syndrome (ACS). MATERIALS AND METHODS:For 110 patients with ACS on days 1-3 of hospitalization, concentrations of NGAL, serum (s-NGAL) and urinary (u-NGAL) NGAL, and N-terminal fragment of pro-B natriuretic peptide (NT-proBNP) were measured, and transthoracic echocardiography was performed. Incidence of cardiovascular complications was determined during the stay in the hospital; hemodynamic parameters (systolic and diastolic blood pressure, heart rate) were measured on admission. RESULTS:Concentrations of u-NGAL were significantly higher in acute heart failure (AHF) [10.4 (2.7; 51.2) ng/ml] than in absence of AHF [3.8 (1.7; 8.6) ng/ml, р=0.03]. Concentrations of u-NGAL and NT-proBNP were higher in patients with [10.17 (4.87; 51.2 ng/ml) and 744.6 (368.7; 2034.9) pg/ml] than without signs of pulmonary hypertension [3.41 (1.72; 7.39) ng/ml; р=0.004 and 431.8 (99.6; 780.1) pg/ml; р=0.012]. The u-NGAL values >9.96 ng / ml were shown to be predictive for AHF, and values >5.81 ng/ml - for pulmonary hypertension. Levels of u-NGAL significantly, directly correlated with values of end-diastolic dimensions and end-systolic dimensions and inversely correlated with values of end-diastolic volume and ejection fraction; levels of s-NGAL positively correlated with cardiac output and heart index. Levels of u-NGAL significantly, directly correlated with NT-proBNP values. CONCLUSION:Urinary levels of NGAL were significantly higher in ACS patients with than without AHF or signs of pulmonary hypertension. NGAL values >9.96 ng/ml were associated with an increased probability of AHF during stay in the hospital, and NGAL values >5.81 ng/ml - with a higher incidence of ACS patients with signs of pulmonary hypertension. In ACS, direct correlations of blood and urinary levels of NGAL with some echocardiographic parameters reflecting the systolic function and the LV dimensions and geometry were identified. Levels of u-NGAL were found to be positively correlated with blood levels NT-proBNP. NGAL may be used as a supplementary marker not only for acute kidney injury and chronic kidney disease but also for severity of cardiovascular conditions and heart remodeling in patients after exacerbation of ischemic heart disease.
    NGAL and MMP-9/NGAL as biomarkers of plaque vulnerability and targets of statins in patients with carotid atherosclerosis. Eilenberg Wolf,Stojkovic Stefan,Kaider Alexandra,Kozakowski Nicolas,Domenig Christoph M,Burghuber Christopher,Nanobachvili Josif,Huber Kurt,Klinger Markus,Neumayer Christoph,Huk Ihor,Wojta Johann,Demyanets Svitlana Clinical chemistry and laboratory medicine BACKGROUND:Neutrophil gelatinase associated lipocalin (NGAL) is expressed in atherosclerotic lesions and was recently implicated in the pathogenesis of cardiovascular pathologies. Statins are known to exert stabilizing effects on atherosclerotic plaque. The aims of our study were (1) to investigate the association of serum NGAL and metalloproteinase (MMP)-9/NGAL complex with the vulnerability of the atherosclerotic plaque, and (2) to reveal the effects of statin treatment on circulating NGAL and MMP-9/NGAL levels in patients with carotid artery stenosis. METHODS:We examined the levels of NGAL and MMP-9/NGAL in blood samples from 136 patients with carotid artery stenosis by specific enzyme-linked immunosorbent assays. RESULTS:Patients with vulnerable plaques, as determined by ultrasound (plaques with decreased echogenicity) and histological analysis (type VI according to the classification of American Heart Association [AHA]), displayed the highest levels of NGAL (both p<0.0001) and MMP-9/NGAL complex (p=0.0004 and p=0.004, respectively). Moreover, patients with symptomatic carotid atherosclerosis had significantly higher NGAL levels compared to asymptomatic patients (p=0.0007). The statin-treated group (n=108) demonstrated lower NGAL (73.9 vs. 128.0 μg/L, p<0.0001) and MMP-9/NGAL (28.9 vs. 40.6 μg/L, p=0.046) as compared to the non-statin group (n=28). Furthermore, in multivariate regression analysis NGAL, but not MMP-9/NGAL levels, were independently associated with symptomatic carotid artery stenosis. In addition, statin treatment was independently associated with lower NGAL levels. CONCLUSIONS:Circulating NGAL and MMP-9/NGAL are associated with plaque vulnerability in patients with carotid artery stenosis. Statin treatment could contribute to plaque stabilization by reducing circulating NGAL and MMP-9/NGAL levels. 10.1515/cclm-2017-0156
    More than a simple biomarker: the role of NGAL in cardiovascular and renal diseases. Buonafine Mathieu,Martinez-Martinez Ernesto,Jaisser Frédéric Clinical science (London, England : 1979) Neutrophil gelatinase-associated lipocalin (NGAL) is a small circulating protein that is highly modulated in a wide variety of pathological situations, making it a useful biomarker of various disease states. It is one of the best markers of acute kidney injury, as it is rapidly released after tubular damage. However, a growing body of evidence highlights an important role for NGAL beyond that of a biomarker of renal dysfunction. Indeed, numerous studies have demonstrated a role for NGAL in both cardiovascular and renal diseases. In the present review, we summarize current knowledge concerning the involvement of NGAL in cardiovascular and renal diseases and discuss the various mechanisms underlying its pathological implications. 10.1042/CS20171592
    Serum neutrophil gelatinase-associated lipocalin and cystatin C are diagnostic markers of renal dysfunction in older patients with coronary artery disease. Zhu Hong,Qian Yuying The Journal of international medical research Objective This study aimed to assess the diagnostic value of serum neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C for renal dysfunction in older patients with coronary disease. Methods A total of 84 older patients with coronary artery disease were included in this study. Serum NGAL and cystatin C levels were analysed using commercially available kits. Medical data of all patients were recorded and analysed. Results NGAL and cystatin C levels were significantly positively correlated with N-terminal prohormone of brain natriuretic peptide levels and negatively correlated with the estimated glomerular filtration rate. The areas under the receiver operating characteristic curves of serum NGAL and cystatin C levels for diagnosing early renal dysfunction were 0.884 and 0.744, respectively. Conclusion Serum NGAL and cystatin C are potential early and sensitive markers of renal dysfunction in older patients with coronary artery disease. 10.1177/0300060517748842
    Serum neutrophil gelatinase-associated lipocalin (NGAL) concentration is independently associated with mortality in patients with acute coronary syndrome. Nymo Ståle H,Hartford Marianne,Ueland Thor,Yndestad Arne,Lorentzen Erik,Truvé Katarina,Karlsson Thomas,Ravn-Fischer Annica,Aukrust Pål,Caidahl Kenneth International journal of cardiology BACKGROUND:Circulating neutrophil gelatinase-associated lipocalin (NGAL) concentration increases in cardiovascular disease, but the long-term prognostic value of NGAL concentration has not been evaluated in acute coronary syndrome (ACS). We examined the association between NGAL concentration and prognosis in patients with ACS after non-ST-elevation myocardial infarction (NSTEMI) or STEMI. METHODS AND RESULTS:NGAL concentration was measured in blood from 1121 consecutive ACS patients (30% women, mean age 65 years) on the first morning after admission. After adjustment for 14 variables, NGAL concentration predicted long-term (median 167 months) mortality (hazard ratio [HR] 1.33, 95% confidence interval [CI] 1.10-1.61, P = 0.003) for quartile (q) 4 of NGAL concentration. NGAL concentrations also predicted long-term mortality (HR = 1.63, 95% CI 1.31-2.03, P < 0.001, N = 741) when adjusting for Global Registry of Acute Coronary Events (GRACE) score, left ventricular ejection fraction (LVEF), and pro-B-type natriuretic peptide (proBNP) and C-reactive protein (CRP) concentrations. With these adjustments, NGAL concentration predicted long-term mortality in NSTEMI patients (HR = 2.02, 95% CI 1.50-2.72, P < 0.001) but not in STEMI patients (HR = 1.32, 95% CI 0.95-1.83, P = 0.100). In all patients, the combination of NGAL concentration and GRACE score yielded an HR of 5.56 (95% CI 4.37-7.06, P < 0.001) for q4/q4 for both variables. CONCLUSION:NGAL concentration in ACS is associated with long-term prognosis after adjustment for clinical confounders. Measuring circulating NGAL concentration may help to identify patients-particularly those with NSTEMI-needing closer follow-up after ACS. 10.1016/j.ijcard.2018.03.028
    Plasma neutrophil gelatinase-associated lipocalin predicts major adverse cardiovascular events after cardiac care unit discharge. Ito Masamichi,Doi Kent,Takahashi Masao,Koyama Katsuhiro,Myojo Masahiro,Hosoya Yumiko,Kiyosue Arihiro,Ando Jiro,Noiri Eisei,Yahagi Naoki,Hirata Yasunobu,Komuro Issei Journal of cardiology BACKGROUND:Emerging acute kidney injury biomarkers, including neutrophil gelatinase-associated lipocalin (NGAL), have a high potential for predicting worsening renal function. Acute exacerbation of renal dysfunction has a great impact on the outcomes of cardiovascular patients in critical conditions. This study aimed to evaluate whether plasma NGAL can predict the mortality and major adverse cardiovascular events (MACEs) after discharge from the cardiac care unit (CCU). METHODS:Patients who were admitted to the CCU of the Tokyo University Hospital were prospectively enrolled (101 patients). Blood and urinary markers, including the blood NGAL, brain natriuretic peptide, creatinine, cystatin C, urinary albumin, N-acetyl-β-d-glucosaminidase, and L-type fatty acid-binding protein, were measured at CCU discharge. The primary outcome was MACEs until at least 6 months after CCU discharge. RESULTS:Thirty-five patients experienced MACEs (35%). Multivariate logistic analysis revealed that the plasma NGAL, length of CCU stay, and existence of diabetes and heart failure were independent predicting factors for MACEs. Patients with the highest NGAL at discharge (>75th percentile) showed a significantly higher risk of MACEs than those with the lowest NGAL (<25th percentile) (log-rank test; hazard ratio, 5.15; 95% confidence interval 1.84-18.20; p<0.01). CONCLUSION:Plasma NGAL at CCU discharge is a significant prognostic indicator of outcomes at 6 months in critically ill cardiac patients treated in a CCU. 10.1016/j.jjcc.2015.05.010
    Plasma levels of neutrophil gelatinase-associated lipocalin in children with heart failure. Tawfeek Mostafa S K,Raafat Doaa M,Saad Khaled,Idriss Naglaa K,Sayed Sherif,Fouad Doaa A,El-Houfey Amira A Therapeutic advances in cardiovascular disease INTRODUCTION:Data about plasma levels of neutrophil gelatinase-associated lipocalin (NGAL) in children with heart failure (HF) are very limited. NGAL is used widely as a biomarker for the diagnosis of renal injury in numerous clinical studies. The aim of this study is to investigate the plasma NGAL in children with HF caused by idiopathic dilated cardiomyopathy (IDCM) and its relation to the severity of HF. MATERIAL AND METHODS:In a case-control study, 30 nondiabetic children, aged -16 years (all have IDCM) recruited from the pediatric department of our institute together with 30 healthy children were prospectively enrolled in this study. Patients underwent a detailed history taking, clinical examination, New York Heart Association (NYHA) class assessment and echocardiographic evaluation. Plasma levels of NGAL were measured by enzyme-linked immunosorbent assay. RESULTS:Plasma levels of NGAL were significantly higher in children with HF compared with healthy controls (mean: 290.97 versus 144.33, p < 0.0001). The relationship between NGAL and the severity of HF was investigated. However, we did not find any statistically significant relationship between plasma NGAL levels and indices of myocardial function. CONCLUSIONS:NGAL levels were significantly increased in children with HF caused by IDCM. However, there was no significant relationship between plasma NGAL levels and indices of myocardial function. Future multicenter clinical studies in a large population addressing the natural course of NGAL in HF and its potential as a treatment target are needed in the near future. 10.1177/1753944715619116
    Effects of N-acetyl cysteine on renal functions evaluated by blood neutrophil gelatinase-associated lipocalin levels in geriatric patients undergoing coronary artery bypass grafting. Aldemir Mustafa,Koca Halit Buğra,Doğan Bakı Elif,Çarşanba Görkem,Öztürk Kavrut Nilgün,Kavaklı Ali Sait,Adalı Fahri,Emmiler Mustafa,Darçın Osman Tansel Anatolian journal of cardiology OBJECTIVE:Recent conflicting studies on the renal effects of N-acetyl cysteine (NAC) after cardiac surgery have been published. The aim of this study was to evaluate the renal effects of NAC using neutrophil gelatinase-associated lipocalin (NGAL) blood levels in elderly patients undergoing coronary artery bypass grafting (CABG). METHODS:This randomized, double-blinded, placebo-controlled study was conducted among geriatric patients (>65 years) scheduled to undergo CABG. A total of 60 consecutive patients were randomly assigned to 2 groups. The first group received I.V. NAC (n=30) and the second group received placebo (n=30) at induction of anesthesia and then for 20 h. NGAL values were determined and conventional renal function tests were performed. Statistical analysis was performed using SPSS 17.0 (IL, Chicago, USA). A p value of <0.05 was considered statistically significant. RESULTS:Plasma creatinine levels at 24 h postoperatively were significantly higher in the placebo group than in the NAC group (1.41±0.63 vs. 1.13±0.35; p<0.05). The mean serum NGAL levels at 3 h postoperatively were higher in the placebo group than in the NAC group (104.94±30.51 vs. 87.82±25.18; p<0.05). NGAL levels were similar between the groups at all other measurement time points. Plasma creatinine levels of ≥1.5 mg/dL or >25% of the baseline value at any time during the study period were observed in 27% of patients in the NAC group and 37% of patients in the placebo group; the difference was statistically significant (p<0.05). CONCLUSION:In the present study, we found that I.V. NAC infusion in elderly patients undergoing CABG reduced the incidence of acute kidney injury as determined by blood NGAL and creatinine levels. 10.5152/AnatolJCardiol.2015.6287
    Serum neutrophil gelatinase-associated lipocalin concentration reflects severity of coronary artery disease in patients without heart failure and chronic kidney disease. Katagiri Mikako,Takahashi Masao,Doi Kent,Myojo Masahiro,Kiyosue Arihiro,Ando Jiro,Hirata Yasunobu,Komuro Issei Heart and vessels Serum neutrophil gelatinase-associated lipocalin (NGAL) is recognized as a useful biomarker for acute kidney injury. Recently, elevated NGAL levels were reported in patients with heart failure and cardiac events, but the association between serum NGAL and severity of coronary artery disease (CAD) has not been investigated adequately. This study aimed to evaluate the association between serum NGAL concentration and CAD severity in patients without heart failure and chronic kidney disease. Two-hundred thirteen patients [mean age: 66.2 ± 9.2 (SD)] without heart failure and chronic kidney disease (estimated glomerular filtration rate >60 mL/min/1.73 m(2)) who underwent coronary angiography were retrospectively analyzed using the SYNTAX score. The mean concentration of serum NGAL was 134.3 ± 111.3 ng/mL. A statistically significant correlation was observed between serum NGAL levels and the SYNTAX score (R = 0.18, P = 0.0091). Multivariable analysis also showed elevated serum NGAL as an independent risk factor for a high SYNTAX score (P < 0.01). Moreover, we evaluated the association of serum NGAL and brain natriuretic peptide (BNP) with the SYNTAX score. Patients with high levels of serum NGAL (>100 ng/mL) and high levels of BNP (>25 pg/mL) had a higher SYNTAX score (low-low vs. high-high: 13.8 ± 13.4 vs. 20.8 ± 18.9, P < 0.05). Serum NGAL levels were positively and significantly associated with CAD severity, and the evaluation of both serum NGAL and BNP was useful for predicting CAD in patients without renal dysfunction and heart failure. Serum NGAL might be a biomarker for CAD severity. 10.1007/s00380-015-0776-8
    Serum cystatin C and neutrophil gelatinase-associated lipocalin in predicting the severity of coronary artery disease in diabetic patients. Okyay Kaan,Yıldırır Aylin,Çiçek Mutlu,Aydınalp Alp,Müderrisoğlu Haldun Anatolian journal of cardiology OBJECTIVE:Cystatin C and neutrophil gelatinase-associated lipocalin (NGAL) are biomarkers of renal functions. We evaluated their roles in predicting the severity of coronary artery disease (CAD). METHODS:Fifty-two consecutive type 2 diabetic patients (32 males, 65.7±8.6 years) who underwent coronary angiography (CAG) for stable CAD were included in this single-center, prospective, cross-sectional study. Patients with an estimated glomerular filtration rate <60 mL/min/1.73 m2 and with a history of by-pass surgery and/or coronary stent implantation were excluded. The vessel score and Gensini score were calculated to assess the presence and severity of CAD. Mann-Whitney U test, Spearman test, and multiple linear regression analysis were used for the main statistical analyses. RESULTS:Serum cystatin C levels were higher in patients with multivessel disease than in those with single vessel disease [1260 ng/mL (953-1640) vs. 977 ng/mL (599-1114), p=0.017]. According to the median Gensini score, the higher score group also had higher cystatin C levels than the lower score group [1114 ng/mL (948-1567) vs. 929 ng/mL (569-1156), p=0.009]. However, serum NGAL levels were similar between these subgroups. There was a positive correlation between cystatin C and Gensini score (r=0.334, p=0.016). Multiple linear regression analysis revealed serum cystatin C as an independent predictor of the Gensini score (ß=0.360, t=2.311, p=0.026). These results may aid in defining cystatin C as a surrogate marker of the extent of CAD in further clinical trials. CONCLUSION:Serum Cystatin C, but not NGAL levels, could predict the severity of CAD in diabetic patients. 10.5152/AnatolJCardiol.2015.6645
    Neutrophil gelatinase-associated lipocalin predicts myocardial dysfunction and mortality in severe sepsis and septic shock. Wang Biao,Chen Gang,Li Jia,Zeng Yuanying,Wu Yunfu,Yan Xiaoye International journal of cardiology BACKGROUND:This study examines the clinical utility of plasma neutrophil gelatinase-associated lipocalin (NGAL) as an indicator of myocardial dysfunction and mortality in severe sepsis and septic shock. METHODS:We designed a prospective cohort study in an intensive care unit, and 53 patients with severe sepsis or septic shock were included. Data were used to determine a relationship between NGAL and the development of myocardial dysfunction and mortality. These associations were determined by the Mann-Whitney test, multiple logistic regression, plotting the receiver operating characteristic (ROC) curve, Kaplan-Meier curves and Spearman test. RESULTS:The High NGAL group had higher need for inotropic/vasopressor support (92% vs. 52%, p=0.0186), higher incidence of regional wall motion abnormalities (46% vs. 13%, p=0.0093), higher B-type natriuretic peptide (BNP) level (p=0.0197), higher cardiac troponin I (cTnI) level (p=0.0016), lower ejection fraction (EF) (p<0.0001) and higher mortality (p=0.0262) compared to the Low NGAL group. Patients with High NGAL were more likely to manifest electrocardiogram (ECG) abnormalities (p=0.042) and demonstrate clinical myocardial dysfunction (p=0.0186) as evidenced by clinical or radiological evidence of pulmonary edema as compared to those with Low NGAL group. NGAL, BNP, Acute Physiology and Chronic Health Evaluation (APACHE) II score, cTnI, and PaO/FIO ratio were independent predictor of death by multiple logistic regression analysis. The area under the ROC curve showed that plasma NGAL as a predictor of death in septic shock was significant. CONCLUSIONS:High plasma NGAL correlates with high mortality and myocardial dysfunction in severe sepsis and septic shock. 10.1016/j.ijcard.2016.10.096
    Novel Biomarkers of Heart Failure. Savic-Radojevic A,Pljesa-Ercegovac M,Matic M,Simic D,Radovanovic S,Simic T Advances in clinical chemistry Although substantial improvements have been made in majority of cardiac disorders, heart failure (HF) remains a major health problem, with both increasing incidence and prevalence over the past decades. For that reason, the number of potential biomarkers that could contribute to diagnosis and treatment of HF patients is, almost exponentially, increasing over the recent years. The biomarkers that are, at the moment, more or less ready for use in everyday clinical practice, reflect different pathophysiological processes present in HF. In this review, seven groups of biomarkers associated to myocardial stretch (mid-regional proatrial natriuretic peptide, MR-proANP), myocyte injury (high-sensitive troponins, hs-cTn; heart-type fatty acid-binding protein, H-FABP; glutathione transferase P1, GSTP1), matrix remodeling (galectin-3; soluble isoform of suppression of tumorigenicity 2, sST2), inflammation (growth differentiation factor-15, GDF-15), renal dysfunction (neutrophil gelatinase-associated lipocalin, NGAL; kidney injury molecule-1, KIM-1), neurohumoral activation (adrenomedullin, MR-proADM; copeptin), and oxidative stress (ceruloplasmin; myeloperoxidase, MPO; 8-hydroxy-2'-deoxyguanosine, 8-OHdG; thioredoxin 1, Trx1) in HF will be overviewed. It is important to note that clinical value of individual biomarkers within the single time points in both diagnosis and outcome prediction in HF is limited. Hence, the future of biomarker application in HF lies in the multimarker panel strategy, which would include specific combination of biomarkers that reflect different pathophysiological processes underlying HF. 10.1016/bs.acc.2016.09.002
    Estimating the prevalence of elevated plasma neutrophil gelatinase associated lipocalin level in patients with acute coronary syndromes and its association with outcomes. Lahiri Anandaroop,Alex Anoop George,George Paul V Indian heart journal OBJECTIVES:The principal objective of this study was to estimate the plasma levels of neutrophil gelatinase associated lipocalin (NGAL) in a cohort of patients with acute coronary syndromes (ACS) across their entire spectrum, and to correlate them with outcomes. METHODS:87 patients with acute coronary syndromes were included in the study. Apart from the routine work up and management, all patients underwent determination of plasma NGAL and serum high sensitivity C reactive protein (HSCRP) levels at admission. The patients were followed up through the hospital stay as well as for one month after discharge for clinical outcomes, and echocardiographic parameters of left ventricular function. Plasma NGAL was studied for its predictive power for various defined outcomes. RESULTS:Plasma NGAL levels were detectably elevated in 67% of patients with ACS without any significant proportion with renal dysfunction, sepsis or overt infection. Plasma NGAL was the strongest independent predictor of all cause hospital mortality in Cox regression multivariate analysis with an odds ratio of 8.353, p=0.0237. Plasma NGAL did not correlate with HSCRP, or severity of coronary artery disease (CAD). CONCLUSION:This is a small study that shows that plasma NGAL in patients admitted with ACS can predict hospital mortality and forms the basis for consideration of this molecule as a possible new risk marker in ACS meriting further and more extensive investigation. 10.1016/j.ihj.2017.06.005
    Association of vascular indices with novel circulating biomarkers as prognostic factors for cardiovascular complications in patients with type 2 diabetes mellitus. Naka Katerina K,Papathanassiou Katerina,Bechlioulis Aris,Pappas Konstantinos,Tigas Stelios,Makriyiannis Dimitrios,Antoniou Sophia,Kazakos Nikolaos,Margeli Alexandra,Papassotiriou Ioannis,Tsatsoulis Agathocles,Michalis Lampros K Clinical biochemistry BACKGROUND:The pathophysiology of atherosclerosis in type 2 diabetes mellitus (T2DM) is multifactorial. The association of vascular indices with circulating biomarkers of inflammation and insulin resistance and their role in the long-term cardiovascular prognosis in T2DM patients were currently investigated. PATIENTS AND METHODS:Patients with T2DM and poor glycemic control without known cardiovascular diseases (n=119) at baseline were enrolled and followed for about 9years. The end-point was the occurrence of any cardiovascular event (coronary heart disease, stroke, peripheral artery disease or cardiovascular death). Aortic pulse wave velocity (PWV), augmentation index (AIx), brachial flow-mediated dilation (FMD), hsCRP, Chitinase-3-like protein 1 (YKL-40), Neutrophil Gelatinase-Associated Lipocalin (NGAL), Fatty Acid Binding Protein (FABP-4) were assessed. RESULTS:Higher YKL-40 and NGAL were associated with higher PWV, while higher YKL-40 and FABP-4 were related to higher AIx (p<0.05 for all). In univariate Cox regression analysis, PWV>10m/s, YKL-40>78ng/ml and NGAL>42ng/ml were associated with cardiovascular events (p<0.05 for all). In multivariate analysis, after adjusting for classical risk factors and glycemic control, increased NGAL, YKL-40 and PWV and decreased FMD (i.e. ≤2.2%) (p<0.05 for all) were independently associated with cardiovascular events. CONCLUSION:In T2DM patients without established cardiovascular disease, novel indices of vascular inflammation (NGAL and YKL-40) were associated with subclinical atherosclerosis (arterial stiffness) but also with adverse clinical prognosis. Arterial stiffness and endothelial dysfunction were also independently related to adverse prognosis. 10.1016/j.clinbiochem.2017.12.010
    Neutrophil gelatinase-associated lipocalin prior to cardiac surgery predicts acute kidney injury and mortality. Bulluck Heerajnarain,Maiti Raju,Chakraborty Bibhas,Candilio Luciano,Clayton Tim,Evans Richard,Jenkins David P,Kolvekar Shyam,Kunst Gudrun,Laing Christopher,Nicholas Jennifer,Pepper John,Yellon Derek M,Hausenloy Derek J Heart (British Cardiac Society) OBJECTIVE:We aimed to investigate whether preoperative serum neutrophil gelatinase-associated lipocalin (sNGAL) predicted postoperative acute kidney injury (AKI) during hospitalisation and 1-year cardiovascular and all-cause mortality following adult cardiac surgery. METHODS:This study was a post hoc analysis of the Effect of Remote Ischemic Preconditioning on Clinical Outcomes in Patient Undergoing Coronary Artery Bypass Graft Surgery trial involving adult patients undergoing coronary artery bypass graft. Postoperative AKI within 72 hours was defined using the International Kidney Disease: Improving Global Outcomes classification. RESULTS:1371 out of 1612 patients had data on sNGAL. The overall 1-year cardiovascular and all-cause mortality was 5.2% (71/1371) and 7.7% (105/1371), respectively. There was an observed increase in the incidence of AKI from the first to the third tertile of sNGAL (30.5%, 41.5% and 45.9%, respectively, p<0.001). There was also an increase in both cardiovascular and all-cause mortality from the first to the third tertile of sNGAL, linear trend test with adjusted p=0.018 and p=0.013, respectively. The adjusted HRs for those in the second and third tertiles of sNGAL compared with the first tertile were 1.60 (95% CI 0.78 to 3.25) and 2.22 (95% CI 1.13 to 4.35) for cardiovascular mortality, and 1.25 (95% CI 0.71 to 2.22) and 1.91 (95% CI 1.13 to 3.25) for all-cause mortality at 1 year. CONCLUSION:In a cohort of high-risk adult patients undergoing cardiac surgery, there was an increase in postoperative AKI and 1-year mortality from the first to the third tertile of preoperative serum NGAL. Those in the last tertile (>220 ng/L) had an estimated twofold increase risk of cardiovascular and all-cause mortality at 1 year. CLINICAL TRIAL REGISTRATION:NCT101247545; Post-results. 10.1136/heartjnl-2017-311760
    Porcine model of progressive cardiac hypertrophy and fibrosis with secondary postcapillary pulmonary hypertension. Gyöngyösi Mariann,Pavo Noemi,Lukovic Dominika,Zlabinger Katrin,Spannbauer Andreas,Traxler Denise,Goliasch Georg,Mandic Ljubica,Bergler-Klein Jutta,Gugerell Alfred,Jakab Andras,Szankai Zsuzsanna,Toth Levente,Garamvölgyi Rita,Maurer Gerald,Jaisser Frederic,Zannad Faiez,Thum Thomas,Bátkai Sándor,Winkler Johannes Journal of translational medicine BACKGROUND:Meaningful translational large animal models for cardiac diseases are indispensable for studying disease mechanisms, development of novel therapeutic strategies, and evaluation of potential drugs. METHODS:For induction of heart failure, cardiac hypertrophy and fibrosis, a bare metal stent was implanted in the descending aorta of growing pigs (n = 7), inducing pressure stress on the left ventricle (group HYPI). The constant stent size in growing pigs resulted in antegrade partial obstruction of the aortic flow with a gradual increase in afterload. Five pigs with sham intervention served as control. Serial haemodynamic, pressure-volume loop measurements and transthoracic echocardiography (TTE) were performed to detect developing pressure overload of the LV and cardiac MRI with late enhancement for measuring LV and RV mass and ejection fraction. RESULTS:At 5-month follow-up, CT and contrast aortography, and intraluminal echocardiography confirmed aortic isthmus stenosis with a mean trans-stenotic gradient of 64 ± 13.9 mmHg. Invasive haemodynamic measurements revealed a secondary increase in pulmonary artery pressure (44.6 ± 5.1 vs 25.9 ± 6.2 mmHg, HYPI vs control, p < 0.05). TTE and ex vivo analyses confirmed severe concentric LV hypertrophy (mean circumferential wall thickness, 19.4 ± 3.1, n = 7 vs 11.4 ± 1.0 mm, n = 5, HYPI vs controls, p < 0.05). The LV and RV mass increased significantly, paralleled by increased isovolumic relaxation constant (tau). Histological analyses confirmed substantial fibrosis and myocyte hypertrophy in both LV and RV. Expressions of ANP, BNP, and miRNA-29a were up-regulated, while SERCA2a and miRNA-1 were down-regulated. Plasma NGAL levels increased gradually, while the elevation of NT-proBNP was detected only at the 5-month FUP. CONCLUSION:These data prove that percutaneous artificial aortic stenosis in pigs is useful for inducing clinically relevant progredient heart failure based on myocardial hypertrophy and fibrosis. 10.1186/s12967-017-1299-0
    [Diagnostic and prognostic biomarkers in acute coronary syndrome]. Kuběna Petr,Špinar Jindřich,Dastych Milan,Lokaj Petr,Pařenica Jiří Vnitrni lekarstvi Acute myocardial infarction (AMI) is an important cause of mortality and morbidity worldwide. Early diagnostics of this disease helps in the appropriate treatment of patients. Great attention is paid to the diagnostic and risk stratification of patients according to circulating biomarkers. There are a lot of scientific publications describing this topic. The aim of this article is to provide a comprehensive overview of the most important and most examined biomarkers in acute coronary syndrome. Meanwhile troponin takes a fundamental place for AMI diagnostic (mostly the high-sensitive methods) in preference to MB-fraction of creatine kinase and myoglobin. The connection to a higher sudden death risk, reinfarcts and heart failure occurring was also proved by many other biomarkers. The most important of them are the natriuretic peptides, the C-reactive protein, the heart fatty acid binding protein, the pregnancy-associated plasma protein-A, CD146, cystatin C, NGAL, copeptin, MR-proadrenomedullin, and the growth differentiation factor-15. More prospective randomized studies are needed for the further use of these other biomarkers in clinical practice.Key words: acute coronary syndrome - biomarkers.
    Predicting long-term outcomes after cardiac arrest by using serum neutrophil gelatinase-associated lipocalin. Park Yu-Ri,Oh Joo Suk,Jeong Hyunho,Park Jungtaek,Oh Young Min,Choi Semin,Choi Kyoung Ho The American journal of emergency medicine OBJECTIVES:Neutrophil gelatinase-associated lipocalin (NGAL) is secreted by various tissues in pathologic states. Previous studies reported that post-cardiac arrest serum NGAL levels correlate with short-term neurologic outcomes and survival. The aim of this study was to examine the associations between NGAL levels post-cardiac arrest and long-term outcomes and survival. METHODS:This prospective observational study and retrospective review included adult out-of-hospital cardiac arrest survivors who were treated by hypothermia-targeted temperature management. Serum NGAL was assessed at 0, 24, 48, and 72h after return of spontaneous circulation. The primary outcome was poor outcome at six months after cardiac arrest, defined as cerebral performance category score of 3-5. The secondary outcome was six-month mortality. RESULTS:In total, 76 patients were analyzed. The patients with poor outcomes showed significantly higher NGAL levels at 24, 48 and 72h after cardiac arrest than the patients with good outcomes. Long-term survival rates were significantly lower in the high-NGAL group than in the low-NGAL group at each time point. Subgroup analysis of patients who survived 72h showed that only serum NGAL 72h after cardiac arrest had prognostic value for long-term outcomes (area under the receiver operating characteristic curve=0.72; p=0.02). CONCLUSIONS:Post-cardiac arrest serum NGAL is associated with long-term outcomes and survival; particularly, three days post-cardiac arrest is the optimal time point for predicting long-term outcomes. However, the predictive power of NGAL is unsatisfactory, and it should be regarded as an additional prognostic modality. 10.1016/j.ajem.2017.12.013
    Neutrophil gelatinase-associated lipocalin as a risk marker in cardiovascular disease. Sivalingam Zenthuja,Larsen Sanne Bøjet,Grove Erik Lerkevang,Hvas Anne-Mette,Kristensen Steen Dalby,Magnusson Nils Erik Clinical chemistry and laboratory medicine Neutrophil gelatinase-associated lipocalin (NGAL) is a promising diagnostic biomarker of early acute kidney injury. Increasing evidence suggests that NGAL may also be involved in inflammatory processes in cardiovascular disease. NGAL modulates the enzymatic activity of matrix metalloproteinase-9 (MMP-9), which is an important mediator of plaque instability in atherosclerosis. The complex formation between NGAL and MMP-9 therefore suggests that NGAL might play a role in progression of atherothrombotic disease. This review summarises current data on NGAL in atherosclerosis, acute myocardial infarction, and heart failure. 10.1515/cclm-2017-0120
    Neutrophil Gelatinase-Associated Lipocalin from immune cells is mandatory for aldosterone-induced cardiac remodeling and inflammation. Buonafine Mathieu,Martínez-Martínez Ernesto,Amador Cristian,Gravez Basile,Ibarrola Jaime,Fernández-Celis Amaya,El Moghrabi Soumaya,Rossignol Patrick,López-Andrés Natalia,Jaisser Frédéric Journal of molecular and cellular cardiology Immune system activation is involved in cardiovascular (CV) inflammation and fibrosis, following activation of the mineralocorticoid receptor (MR). We previously showed that Neutrophil Gelatinase-Associated Lipocalin (NGAL) is a novel target of MR signaling in CV tissue and plays a critical role in aldosterone/MR-dependent hypertension and fibrosis. We hypothesized that the production of NGAL by immune cells may play an important part in the mediation of these deleterious mineralocorticoid-induced effects. We analyzed the effect of aldosterone on immune cell recruitment and NGAL expression in vivo. We then studied the role of NGAL produced by immune cells in aldosterone-mediated cardiac inflammation and remodeling using mice depleted for NGAL in their immune cells by bone marrow transplantation and subjected to mineralocorticoid challenge NAS (Nephrectomy, Aldosterone 200μg/kg/day, Salt 1%). NAS treatment induced the recruitment of various immune cell populations to lymph nodes (granulocytes, B lymphocytes, activated CD8 T lymphocytes) and the induction of NGAL expression in macrophages, dendritic cells, and PBMCs. Mice depleted for NGAL in their immune cells were protected against NAS-induced cardiac remodeling and inflammation. We conclude that NGAL produced by immune cells plays a pivotal role in cardiac damage under mineralocorticoid excess. Our data further stressed a pathogenic role of NGAL in cardiac damages, besides its relevance as a biomarker of renal injury. 10.1016/j.yjmcc.2017.12.011
    Serial measurements of neutrophil gelatinase-associated lipocalin: prognostic value in patients with ST-segment elevation myocardial infarction treated with a primary percutaneous coronary intervention. Lim Yeong-Min,Moon Jae Youn,Min Daniel,Kim Sang-Hoon,Yang Woo-In,Kim Won-Jang,Sung Jung-Hoon,Kim In Jai,Lim Sang-Wook,Cha Dong-Hun Coronary artery disease BACKGROUND:There are no previous data on serial changes in neutrophil gelatinase-associated lipocalin (NGAL) levels in ST-segment elevation myocardial infarction (STEMI) patients before and after a primary percutaneous coronary intervention (pPCI). The aim of the present study was to evaluate the prognostic value of serial NGAL measurements in patients with STEMI treated by pPCI. MATERIALS AND METHODS:We identified 169 STEMI patients who underwent pPCI within 12 h of symptom onset and had plasma NGAL measurements before (pre-NGAL) and 6 h after (post-NGAL) pPCI. The primary endpoint was 30-day all-cause mortality, including cardiac death, whereas the secondary endpoint was the change in NGAL levels from before to after pPCI. RESULTS:The mean pre-NGAL and post-NGAL levels were 109.2±76.1 and 93.3±83.8 ng/ml, respectively. Thirty-day mortality occurred in 12 (7.1%) patients. In terms of changes in serial NGAL levels, post-NGAL levels were decreased in 132 (79%) patients. Patients with elevated post-NGAL levels showed increased mortality compared with patients with decreased post-NGAL levels (P=0.005). Multivariate analyses indicated that old age and high post-NGAL levels were independent risk factors for 30-day mortality. CONCLUSION:In a large percentage of STEMI patients, plasma post-pPCI NGAL levels were decreased compared with pre-pPCI NGAL levels, even with the administration of potentially nephrotoxic contrast medium. Post-NGAL levels seemed to be superior to pre-NGAL levels for the prediction of 30-day mortality outcome. 10.1097/MCA.0000000000000542
    Early prediction of contrast-induced acute kidney injury by a "bedside" assessment of Neutrophil Gelatinase-Associated Lipocalin during elective percutaneous coronary interventions. Nusca Annunziata,Miglionico Marco,Proscia Claudio,Ragni Laura,Carassiti Massimiliano,Lassandro Pepe Francesca,Di Sciascio Germano PloS one Contrast-induced acute kidney injury (CI-AKI) is a serious complication during percutaneous coronary interventions (PCI). Currently, the diagnosis of CI-AKI relies on serum creatinine (SCr) that is however affected by several limitations potentially leading to delayed or missed diagnoses. In this study we examined the diagnostic accuracy of a "bedside" measurement of plasma Neutrophil Gelatinase-Associated Lipocalin (NGAL) in the early detection of CI-AKI in 97 patients undergoing elective PCI. The overall incidence of CI-AKI was 3%. A significant positive correlation was observed between 6-hours NGAL and post-PCI SCr (r = 0.339, p = 0.004) and a significant negative correlation between 6-hours NGAL and post-PCI CrCl (r = -0.303, p = 0.010). In patients with post-PCI SCr increase > 0.24 mg/dl (median SCr absolute increase), delta NGAL 0-6 hours and 6-hours NGAL values were higher compared with patients with SCr elevation below the defined threshold (p = 0.049 and p = 0.056). The ROC analysis showed that a 6 hours NGAL value > 96 ng/ml significantly predicted an absolute SCr increase > 0.24 mg/dl after contrast exposure with sensitivity of 53% and specificity of 74% (AUC 0.819, 95% CI: 0.656 to 0.983, p = 0.005). The use of bedside NGAL assessment may significantly hasten diagnosis and treatment of CI-AKI, with remarkable clinical prognostic consequences. 10.1371/journal.pone.0197833
    Early Elevation of Systemic Plasma Clusterin after Reperfused Acute Myocardial Infarction in a Preclinical Porcine Model of Ischemic Heart Disease. Traxler Denise,Spannbauer Andreas,Einzinger Patrick,Mester-Tonczar Julia,Lukovic Dominika,Winkler Johannes,Zlabinger Katrin,Gugerell Alfred,Mandic LJubica,Gyöngyösi Mariann,Pavo Noemi International journal of molecular sciences Clusterin exerts anti-inflammatory, cytoprotective and anti-apoptotic effects. Both an increase and decrease of clusterin in acute myocardial infarction (AMI) has been reported. We aimed to clarify the role of clusterin as a systemic biomarker in AMI. AMI was induced by percutaneous left anterior artery (LAD) occlusion for 90 min followed by reperfusion in 24 pigs. Contrast ventriculography was performed after reperfusion to assess left ventricular ejection fraction (LVEF), left ventricular end diastolic volume (LVEDV) and left ventricular end systolic volume (LVESV) and additional cMRI + late enhancement to measure infarct size and LV functions at day 3 and week 6 post-MI. Blood samples were collected at prespecified timepoints. Plasma clusterin and other biomarkers (cTnT, NT-proBNP, neprilysin, NGAL, ET-1, osteopontin, miR21, miR29) were measured by ELISA and qPCR. Gene expression profiles of infarcted and remote region 3 h ( = 5) and 3 days ( = 5) after AMI onset were analysed by RNA-sequencing. AMI led to an increase in LVEDV and LVESV during 6-week, with concomitant elevation of NT-proBNP 3-weeks after AMI. Plasma clusterin levels were increased immediately after AMI and returned to normal levels until 3-weeks. Plasma NGAL, ET-1 and miR29 was significantly elevated at 3 weeks follow-up, miR21 increased after reperfusion and at 3 weeks post-AMI, while circulating neprilysin levels did not change. Elevated plasma clusterin levels 120 min after AMI onset suggest that clusterin might be an additional early biomarker of myocardial ischemia. 10.3390/ijms21134591
    Preoperative risk assessment improves biomarker detection for predicting acute kidney injury after cardiac surgery. Lee Cheng-Chia,Chang Chih-Hsiang,Chen Shao-Wei,Fan Pei-Chun,Chang Su-Wei,Chen Yi-Ting,Nan Yu-Yun,Lin Pyng-Jing,Tsai Feng-Chun PloS one BACKGROUND:Although urinary neutrophil gelatinase-associated lipocalin (NGAL) has emerged as a promising biomarker for the early detection of kidney injury, previous studies of adult patients who underwent cardiac surgery have reported only moderate discrimination. The age, creatinine, and ejection fraction (ACEF) score is a preoperative validated risk model with satisfactory accuracy for predicting AKI following cardiac surgery. It remains unknown whether combining preoperative risk assessment through ACEF scores followed by urinary NGAL test in a population of high-risk individuals is an optimal approach with improved predictive performance. MATERIAL AND METHODS:A total of 177 consecutive patients who underwent cardiac surgery were enrolled. Clinical characteristics, prognostic model scores, and outcomes were assessed. Urinary NGAL were examined within 6 hours after cardiac surgery. Patients were stratified according to preoperative ACEF scores, and comparisons were made using the area under the receiver operator characteristic curve (AUROC) for the prediction of AKI. RESULTS:A total of 45.8% (81/177) of the patients had AKI. As expected, patients with ACEF scores ≥ 1.1 were older and more likely to have class III or IV heart failure. They were also more likely to have diabetes mellitus, myocardial infarction, and peripheral arterial disease. Urinary NGAL alone moderately predicted AKI, with an AUROC of 0.732. Risk stratification by ACEF scores ≥ 1.1 substantially improved the AUROC of urinary NGAL to 0.873 (95% confidence interval, 0.784-0.961; P < .001). CONCLUSIONS:Risk stratification by preoperative ACEF scores ≥ 1.1, followed by postoperative urinary NGAL, provides more satisfactory risk discrimination than does urinary NGAL alone for the early detection of AKI after cardiac surgery. Future studies should investigate whether this strategy could improve the outcomes and cost-effectiveness of care in patients undergoing cardiac surgery. 10.1371/journal.pone.0203447
    Plasma neutrophil gelatinase-associated lipocalin and risk of cardiovascular disease: Findings from the PREVEND prospective cohort study. Kunutsor Setor K,Flores-Guerrero José L,Kieneker Lyanne M,Nilsen Tom,Hidden Clara,Sundrehagen Erling,Seidu Samuel,Dullaart Robin P F,Bakker Stephan J L Clinica chimica acta; international journal of clinical chemistry BACKGROUND:Neutrophil gelatinase-associated lipocalin (NGAL), a novel biomarker of acute kidney injury, might play a role in the development of atherosclerotic cardiovascular disease (CVD). We aimed to assess the association of circulating NGAL with CVD risk. MATERIALS AND METHODS:Plasma NGAL concentrations were measured at baseline in 5275 participants in the PREVEND prospective study. Hazard ratios (95% confidence intervals [CI]) for CVD were estimated. RESULTS:After a median follow-up of 8.3 years, 338 participants developed first CVD events. Plasma NGAL was weakly to moderately correlated with several CVD risk markers. There was a non-linear relationship between NGAL and CVD risk. In analyses adjusted for established risk factors, the hazard ratio (95% CI) for CVD in a comparison of the top quartile versus bottom quartiles 1-2 of NGAL values was 1.35 (1.05-1.75; P = 0.022), which was abrogated after additional adjustment for other potential confounders (mainly attributed to high sensitivity C-reactive protein) 1.20 (0.92-1.57; P = 0.176). The association was considerably attenuated following further adjustment for renal function 1.05 (0.79-1.40; P = 0.745). The association between NGAL and CVD risk did not vary importantly in relevant clinical subgroups. CONCLUSION:Evidence suggests a non-linear association between NGAL and CVD risk, which is dependent on inflammation and renal function. 10.1016/j.cca.2018.07.034
    Renal Functions and Prognosis Stratification in Chronic Heart Failure Patients and the Importance of Neutrophil Gelatinase-Associated Lipocalin. Lábr Karel,Špinar Jindřich,Pařenica Jiří,Špinarová Lenka,Málek Filip,Špinarová Monika,Ludka Ondřej,Jarkovský Jiří,Benešová Klára,Goldbergová-Pávková Monika,Lábrová Růžena Kidney & blood pressure research BACKGROUND/AIMS:The rate of incidence and prevalence of acute kidney injury is increasing due to an increased number of patients with heart failure. Therefore it is very pertinent to early detect the level of renal injuries and to make necessary heart failure predictions. Thus the aim of this study is to determine renal functions and prognosis stratification in chronic heart failure patients and importance of Neutrophil Gelatinase-Associated Lipocalin (NGAL), an early diagnostic marker of acute kidney injury, as well as stratification of cardiovascular risk in heart failure patients. METHODS:Data including age, gender, comorbidities and medical history of outpatients and hospitalized patients from Farmacology and NeuroHumoraL activation (FAR NHL) multicenter prospective registry comprising three Cardiological Centers in the Czech Republic were collected between 1st October 2014 and 30th November 2015. One-year follow-up data were collected in November 2016 in such a way that all patients had at least one-year data from the time of recruitment, but up to two years to the time of follow-up. One-year data were used for the whole set of patients while data up to 24 months were used with Kaplan-Meier's survival curves to analyse the patients' survival data. Blood samples were collected from the patients and basic parameters were evaluated in order to analyse Neutrophil gelatinase-associated lipocalin (NGAL) and plasma levels of N-terminal pro-brain natriuretic peptide (NT-ProBNP) using Lipocalin-2/NGAL Human ELISA kit (Bio Vendor, Czechia) and the Cobas E411 NT-proBNP Immunoassay kit (Roche Diagnostics, Indianapolis, IN, USA) respectively. Statistical analysis was further carried out to explain the level of significance of the evaluated parameters using Spearman Correlation, Mann Whitney or Kruskal-Wallis test and log-rank test. RESULTS:Out of 547 patients from Farmacology and NeuroHumoraL activation (FAR NHL) multicenter prospective registry with available data on hospitalizations, mortality, biomarkers and one-year follow-up that were recorded, there were 439 males (80.3%) with a median age of 66 years. At least one-month stable patients with left ventricle ejection fraction (LV EF) under 50% were recorded. The etiology of heart failure was ischemic heart disease in 54%, dilated cardiomyopathy in 40% and others in 6%. 69% patients were in New York Heart Association functional class II. There were 76 events (13.9%; all-cause mortality, acute heart failure hospitalization, left ventricle assist device implantation and orthotopic heart transplant) in the first 365 days of follow-up. The area under the receiver operating characteristic curve was higher for NT-proBNP (0.77) than the creatinine (0.57), NGAL (0.55) or creatinine clearance (0.54). In multivariable analyses, NT-proBNP (P= 0.001) and NGAL (P = 0.004) were significant predictors of events. Subjects with NT-proBNP and NGAL above the cut off value (NT-proBNP 1,121 pg/ml, NGAL 80 ng/ml) survived without any event in 55.7%, subjects with NT-proBNP and NGAL under the cut off value survived without any event in 90.5%, after two years (P = 0.001). CONCLUSION:The findings of the study showed that NGAL associated with NT-proBNP was a stronger predictor of the primary endpoint than NGAL or NT-proBNP alone. The level of NGAL was rising in hypertension, ischemia, anemia, hypoalbuminemia, diabetes or arrhythmias. 10.1159/000495819
    Early Renal-Protective Effects of Remote Ischemic Preconditioning in Elderly Patients with Non-ST-Elevation Myocardial Infarction (NSTEMI). Guo Suzhen,Jian Lian,Cheng Degang,Pan Li,Liu Shaoying,Lu Chengzhi Medical science monitor : international medical journal of experimental and clinical research <strong>BACKGROUND</strong> With the wide clinical application of angiography, contrast-enhanced nephropathy (CIN) has become the third-leading cause of acute kidney injury (AKI). Remote ischemic preconditioning (RIPC) is a non-fatal ischemia-reperfusion injury that can provide protection against lethal ischemia-reperfusion. This study aimed to assess the effect of RIPC on CIN in elderly patients with non-ST-elevation myocardial infarction (NSTEMI). <strong>MATERIAL AND METHODS</strong> Patients were randomly divided into 2 groups with 119 patients in each group treated with interventional therapy. Patients in the RIPC group received distal ischemic preconditioning 2 h before contrast exposure, while patients in the control group received a sham RIPC procedure. Incidence of CIN was the primary outcome. Changes in creatinine, NGAL, and KIM-1 after contrast administration were secondary outcomes. <strong>RESULTS</strong> CIN occurred in a total of 27 (12.3%) patients, including 12 (10.1%) in the RIPC group and 15 (15.1%) in the control group (<i>P</i>=0.329). RIPC treatment significantly reduced the levels of NGAL (<i>P</i>=0.024) and KIM-1 (<i>P</i>=0.007) at 12 h after contrast administration, suggesting RIPC treatment reduces sub-clinical renal damage. Subgroup analysis revealed that significant reduction of KIM-1 and NGAL by RIPC, mainly occurring in patients with a Mehran risk score of 6-10. <strong>CONCLUSIONS</strong> Although RIPC did not significantly reduce CIN incidence in elderly patients with NSTEMI, the application of more sensitive biomarkers - NGAL and KIM-1 - indicated a reduction of sub-clinical renal damage by RIPC, especially in the early stage of injury. As a simple and well-tolerated method, RIPC may be a potentially feasible option to prevent CIN. 10.12659/MSM.917442
    Acute kidney disease and acute kidney injury biomarkers in coronary care unit patients. Chen Yih-Ting,Jenq Chang-Chyi,Hsu Cheng-Kai,Yu Yi-Ching,Chang Chih-Hsiang,Fan Pei-Chun,Pan Heng-Chih,Wu I-Wen,Cherng Wen-Jin,Chen Yung-Chang BMC nephrology BACKGROUND:Acute kidney disease (AKD) describes acute or subacute damage and/or loss of kidney function for a duration of between 7 and 90 days after exposure to an acute kidney injury (AKI) initiating event. This study investigated the predictive ability of AKI biomarkers in predicting AKD in coronary care unit (CCU) patients. METHODS:A total of 269 (mean age: 64 years; 202 (75%) men and 67 (25%) women) patients admitted to the CCU of a tertiary care teaching hospital from November 2009 to September 2014 were enrolled. Information considered necessary to evaluate 31 demographic, clinical and laboratory variables (including AKI biomarkers) was prospectively recorded on the first day of CCU admission for post hoc analysis as predictors of AKD. Blood and urinary samples of the enrolled patients were tested for neutrophil gelatinase-associated lipocalin (NGAL), cystatin C (CysC) and interleukin-18 (IL-18). RESULTS:The overall hospital mortality rate was 4.8%. Of the 269 patients, 128 (47.6%) had AKD. Multivariate logistic regression analysis revealed that age, hemoglobin, ejection fraction and serum IL-18 were independent predictors of AKD. Cumulative survival rates at 5 years of follow-up after hospital discharge differed significantly (p < 0.001) between subgroups of patients diagnosed with AKD (stage 0A, 0C, 1, 2 and 3). The overall 5-year survival rate was 81.8% (220/269). Multivariate Cox proportional hazard analysis revealed that urine NGAL, body weight and hemoglobin level were independent risk factors for 5-year mortality. CONCLUSIONS:This investigation confirmed that AKI biomarkers can predict AKD in CCU patients. Age, hemoglobin, ejection fraction and serum IL-18 were independently associated with developing AKD in the CCU patients, and urine NGAL, body weight and hemoglobin level could predict 5-year survival in these patients. 10.1186/s12882-020-01872-z
    Plasma neutrophil gelatinase-associated lipocalin is independently associated with left ventricular hypertrophy and diastolic dysfunction in patients with chronic kidney disease. Kim Il Young,Kim June Hyun,Kim Min Jeong,Lee Dong Won,Hwang Cheol Gu,Han Miyeun,Rhee Harin,Song Sang Heon,Seong Eun Young,Lee Soo Bong PloS one BACKGROUND:Cardiovascular disease (CVD) is a leading cause of death in patients with chronic kidney disease (CKD). Left ventricular hypertrophy (LVH) and left ventricular diastolic dysfunction (LVDD) are known as predictors of CVD in these patients. Neutrophil gelatinase-associated lipocalin (NGAL) is a biomarker of acute kidney injury. Recently, elevated NGAL levels have been reported in patients with CVD. This study aimed to evaluate the association between plasma NGAL levels and LVH/LVDD in patients with CKD. METHODS:This study included 332 patients with pre-dialysis CKD (estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73m2). Two-dimensional echocardiography was performed to measure the left ventricular mass index (LVMI). Tissue Doppler imaging was used to measure early mitral inflow velocity (E) and the peak early mitral annular velocity (E'). Diastolic function was estimated using E' and the ratio of E to E' (E/E'). The associations of echocardiographic index with clinical and laboratory variables (age, sex, diabetes, hypertension, eGFR, albumin, uric acid, calcium, phosphate, total cholesterol, hemoglobin, C-reactive protein, intact parathyroid hormone (PTH), the inferior vena cava collapse index (IVCCI) < 50%, and plasma NGAL) were investigated using univariate and multivariate analyses. RESULTS:In multivariate logistic regression analysis, plasma NGAL was an independent predictor of LVH (OR: 1.02, 95% CI: 1.01-1.02), P < 0.001). In addition, hypertension, intact PTH, and IVCCI < 50% were independent predictors of LVH. Plasma NGAL (OR: 1.02, 95% CI: 1.01-1.02, P < 0.001) was also an independent factor of LVDD. Furthermore, hypertension, intact PTH, and IVCCI < 50% were independent predictors of LVDD. Receiver operating characteristic curve analysis (area under the curve: 0.835, 95% CI: 0.792-0.879) showed the best cutoff value of plasma NGAL for identifying LVDD was ≥ 258 ng/ml with an associated sensitivity of 77.6% and a specificity of 87.6%. CONCLUSION:Plasma NGAL levels were independent predictors of LVH and LVDD in patients with pre-dialysis CKD, suggesting that plasma NGAL could be a biomarker for LVH and LVDD in these patients. 10.1371/journal.pone.0205848
    Evaluation of neutrophil gelatinase-associated lipocalin and cystatin C as biomarkers of acute kidney injury after ST-segment elevation myocardial infarction treated by percutaneous coronary intervention. Nguyen Lee S,Spagnoli Vincent,Kerneis Mathieu,Hauguel-Moreau Marie,Barthélémy Olivier,Collet Jean-Philippe,Montalescot Gilles,Silvain Johanne Archives of cardiovascular diseases BACKGROUND:Two biomarkers of early acute kidney injury-plasmatic neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C-are not used in routine clinical practice in patients with ST-segment elevation myocardial infarction (STEMI) treated by percutaneous coronary intervention (PCI) because of a lack of supporting data. AIMS:To evaluate the predictive value of NGAL and cystatin C regarding the incidence of contrast-induced acute kidney injury (CI-AKI) and clinical outcomes after STEMI in patients treated by primary PCI. METHODS:Plasmatic NGAL and cystatin C were measured on admission, before any contrast exposure, in 701 unselected patients with STEMI. Associations between biomarker concentrations and incidence of CI-AKI (assessed at 48h), haemodialysis requirement at 1 year and all-cause mortality at 1 year were assessed by logistic regression analyses and receiver operating characteristic area under the curve analysis (c-statistic). Discrimination performance comparison was performed using the DeLong test. RESULTS:NGAL and cystatin C had mild discrimination regarding CI-AKI, with c-statistics of 0.60 (P=0.001) and 0.60 (P=0.002), respectively. Combining NGAL and cystatin C did not improve their discrimination (c-statistic 0.61; P=0.001). There was no significant difference in discrimination between NGAL, cystatin C and baseline creatinine (P=0.57). Regression analyses showed no independent association between NGAL and CI-AKI, haemodialysis or 1-year mortality. Similarly, cystatin C was not associated with these clinical outcomes. CONCLUSIONS:In this cohort of patients with STEMI treated by primary PCI, plasmatic NGAL and cystatin C did not provide additional value regarding CI-AKI prediction compared with known risk factors such as baseline creatinine. 10.1016/j.acvd.2018.11.006
    The clinical utility of remote ischemic preconditioning in protecting against cardiac surgery-associated acute kidney injury: A pilot randomized clinical trial. Stokfisz Karolina,Ledakowicz-Polak Anna,Zagórski Maciej,Jander Sławomir,Przybylak Katarzyna,Zielińska Marzenna Advances in clinical and experimental medicine : official organ Wroclaw Medical University BACKGROUND:Cardiac surgery-associated acute kidney injury (CSA-AKI) is a well-known, serious complication and a well-recognized independent risk factor for higher morbidity and mortality among patients undergoing cardiac surgery. OBJECTIVES:The aim of the study was to assess the efficacy of remote ischemic preconditioning (RIPC) in reducing the incidence of CSA-AKI, measured with the standard creatinine technique and using neutrophil gelatinase-associated lipocalin (NGAL) serum concentrations as a potential new biomarker of kidney damage. The ethics committee of the Medical University of Lodz prospectively approved the protocol (approval No. RNN/286/13/KE). The study was retrospectively registered with the U.S. National Institutes of Health - NIH (29 June 2017; ClinicalTrials.gov identifier: NCT03205410). MATERIAL AND METHODS:We conducted a prospective single-center double-blind randomized and controlled tudy. Data was collected from patients admitted to the Cardiosurgery Clinic at the Medical University of Lodz (Poland) between January and December 2014, scheduled for elective cardiac surgery (an off-pump coronary artery bypass). A total of 28 patients were randomized to receive either RIPC (n = 14) or sham RIPC (n = 14). After the induction of anesthesia, the patients assigned to the RIPC group underwent 3 cycles of five-minute inflation to 200 mm Hg and five-minute deflation of the upper-arm cuff. The control group had a deflated cuff placed on the upper arm for 30 min. The authors measured the patients' serum creatinine concentration to check for the occurrence of a CSA-AKI within 48 h after cardiac surgery, and NGAL serum concentration to check its level within 3 h after the operation. RESULTS:Fewer patients in RIPC group developed CSA-AKI within 48 h after cardiac surgery than in the control group (29% vs 93%; p = 0.003). Fewer patients in the RIPC group presented an increase in NGAL 3 h after surgery (medians: 124 vs 176.7; p = 0.0003). CONCLUSIONS:In patients undergoing an off-pump coronary artery bypass, RIPC significantly reduces the occurrence of CSA-AKI and protects against increased postoperative NGAL levels. 10.17219/acem/112610
    Association Between Plasma Neutrophil Gelatinase-Associated Lipocalin and Cardiac Disease Hospitalizations and Deaths in Older Women. Chong James J H,Prince Richard L,Thompson Peter L,Thavapalachandran Sujitha,Ooi Esther,Devine Amanda,Lim E E M,Byrnes Elizabeth,Wong Germaine,Lim Wai H,Lewis Joshua R Journal of the American Heart Association Background Neutrophil gelatinase-associated lipocalin ( NGAL ) or lipocalin 2 may promote atherosclerosis and plaque instability leading to increased risk of cardiac events. We investigated the relationships between plasma NGAL , cardiovascular disease biomarkers, and long-term cardiac events. Methods and Results The study population consisted of 1131 ambulant older white women (mean age 75 years) without clinical coronary heart disease ( CHD ) and measures of plasma NGAL in the Perth Longitudinal Study of Ageing Women with 14.5-year CHD and heart failure hospitalizations or death (events) captured using linked records. Over 14.5 years, 256 women had CHD events, while 118 had heart failure events. Per SD increase in log-transformed NGAL there was a 35% to 37% increase in relative hazards for CHD and heart failure events in unadjusted analyses, which remained significant after adjustment for conventional risk factors for CHD events (hazard ratio 1.29, 95% CI 1.13-1.48, P<0.001) but not heart failure ( P>0.05). Women in the highest 2 quartiles of NGAL had higher relative hazards for CHD events compared with women in the lowest quartile hazard ratio 1.61, 95% CI 1.08-2.39, P=0.019 and hazard ratio 1.97, 95% CI 1.33-3.93, P=0.001, respectively. These associations were independent of high-sensitivity cardiac troponin I, homocysteine, and estimated renal function. NGAL correctly reclassified 1 in 4 women who sustained a CHD event up in risk and 1 in 10 women without CHD events down in risk. Conclusions NGAL was associated with increased risk of long-term CHD events, independent of conventional risk factors and biomarkers. These findings provide mechanistic insight into the role of NGAL with cardiac events. 10.1161/JAHA.118.011028
    Hypoxia Stimulates Synthesis of Neutrophil Gelatinase-Associated Lipocalin in Aortic Valve Disease. Swaminathan Ganesh,Krishnamurthy Varun K,Sridhar Swetha,Robson Denise C,Ning Yao,Grande-Allen K Jane Frontiers in cardiovascular medicine Aortic valve disease is commonly found in the elderly population. It is characterized by dysregulated extracellular matrix remodeling followed by extensive microcalcification of the aortic valve and activation of valve interstitial cells. The mechanism behind these events are largely unknown. Studies have reported expression of hypoxia inducible factor-1 alpha (HIF1α) in calcific nodules in aortic valve disease, therefore we investigated the effect of hypoxia on extracellular matrix remodeling in aged aortic valves. Western blotting revealed elevated expression of HIF1α and the complex of matrix metalloprotease 9 (MMP9) and neutrophil gelatinase-associated lipocalin (NGAL) in aged porcine aortic valves cultured under hypoxic conditions. Consistently, immunofluorescence staining showed co-expression of MMP9 and NGAL in the fibrosa layer of these porcine hypoxic aortic valves. Gelatinase zymography demonstrated that the activity of MMP9-NGAL complex was significantly increased in aortic valves in 13% O compared to 20% O. Importantly, the presence of ectopic elastic fibers in the fibrosa of hypoxic aortic valves, also detected in human diseased aortic valves, suggests altered elastin homeostasis due to hypoxia. This study demonstrates that hypoxia stimulates pathological extracellular matrix remodeling via expression of NGAL and MMP9 by valve interstitial cells. 10.3389/fcvm.2019.00156
    Neutrophil gelatinase-associated lipocalin is a predictor of complications in the early phase of ST-elevation myocardial infarction. Šabanović-Bajramović Nirvana,Hodžić Enisa,Iglica Amer,Begić Edin,Resić Nerma,Aganović Kenana,Halilčević Mirela,Bajramović Senad Medicinski glasnik : official publication of the Medical Association of Zenica-Doboj Canton, Bosnia and Herzegovina Aim To evaluate a correlation of serum level of neutrophil gelatinase-associated lipocalin (NGAL) to the risk of the occurrence of complications in patients with the early phase of ST-segment elevation myocardical infarction (STEMI) treated with fibrinolytic therapy prior to percutaneous coronary intervention (PCI). Methods A total of 54 patients with the diagnosis of STEMI treated with fibrinolytic therapy (alteplase) prior to PCI were included. Patients were admitted to the Intensive Care Unit (ICU) of Clinic for Heart, Blood Vessel and Rheumatic Diseases in the period January to March 2018. All patients underwent coronary angiography and PCI within the maximum of 48 hours delay after fibrinolysis, according to the hemodynamic and electrical stability and PCI availability. Blood samples were taken immediately after admission prior to fibrinolytic administration. Patients were divided into two groups according to NGAL values (less or more than 134.05 ng/mL). Results Higher values of NGAL have effect on a higher mean systolic and diastolic pressure (p=0.001 and p=0.003, respectively). Patients with higher NGAL values also have higher values of brain natriuretic peptide (p=0.0001) and highly sensitive troponin I (p=0.002). In that group relative risk (RR) for lethal outcome was 6.4 times significantly higher (p=0.002), for the development of heart failure 2.88 times (p=0.0002), for post-myocardial infarction angina pectoris 2.24 times (p=0.0158), and for ventricular rhythm disturbances (ventricular tachycardia, ventricular fibrillation) 1.96 times higher (p=0.0108). Conclusion Increased NGAL value is related to an unfavourable outcome of patients in the early phase of STEMI treated with fibrinolytic therapy prior to PCI. 10.17392/1139-20
    Prognostic value of neutrophil gelatinase-associated lipocalin and glycosylated hemoglobin for non-ST-segment elevation myocardial infarction patients with single concomitant chronic total occlusion following primary percutaneous coronary intervention: A prospective observational study. Peng Wenhua,Zhang Channa,Wang Zhijun,Yang Wenqi,Luo He,Li Xiaofeng,Fu Dongliang,Yu Changan,Zhou Yifeng Medicine To investigate factors predicting the onset of major adverse cardiovascular and cerebrovascular events (MACCEs) after primary percutaneous coronary intervention (pPCI) for patients with non-ST-segment elevation infarction (NSTEMI) and single concomitant chronic total occlusion (CTO). Neutrophil gelatinase-associated lipocalin (NGAL) and glycosylated hemoglobin (HbA1c) both play essential role in cardiovascular and cerebrovascular homoeostasis. However, current knowledge of its predictive prognostic value is limited.422 patients with NSTEMI and CTO (59.7 ± 12.4 years, 74.2% men) who underwent successful pPCI were enrolled and followed for 2 years. Multivariate cox regression analysis and receiver operating characteristic (ROC) curve analysis were performed to determine the factors predicting MACCEs.140 patients (33.2%) experienced MACCEs in the follow-up period. Multivariate cox regression analysis found when we process the model with NGAL at admission, low left ventricular ejection fraction (LVEF, HR = 0.963, 95% CI 0.940 to 0.987, P = .003) and fasting blood glucose (HR = 1.078, 95% CI 1.002 to 1.159, P = .044), but not NGAL at admission, were independent predictors of 2 years MACCEs. While HbA1C (HR = 1.119, 95% CI 1.014 to 1.234, P = .025), LVEF (HR = 0.963, 95% CI 0.939 to 0.987, P = .003), estimated glomerular filtration rate (HR = 1.020, 95% CI 1.006 to 1.035, P = .006) and NGAL value 7 day (HR = 1.020, 95% CI 1.006 to 1.035, P = .006) showed their predictive value in another model. ROC analysis indicated NGAL 7 day (AUC = 0.680, P = .0054 and AUC = 0.622, P = .0005) and LVEF (AUC = 0.691, P = .0298 and AUC = 0.605, P = .0021) could predict both in-hospital and 2 years MACCEs, while higher NGAL at admission could only predict poorer in-hospital prognosis (AUC = 0.665, P = .0103). Further analysis showed the prognostic value of NGAL was particularly remarkable among those HbA1C<6.5%.Patients with NSTEMI and single concomitant CTO receiving pPCI with higher NGAL on 7 days during hospitalization are more likely to suffer 2 years MACCEs, particularly in those with lower HbA1C. 10.1097/MD.0000000000016982
    Predictive performance of plasma neutrophil gelatinase-associated lipocalin for neurologic outcomes in out-of-hospital cardiac arrest patients treated with targeted temperature management: A prospective observational study. Lee Ji Hwan,Park Incheol,You Je Sung,Kim Min Joung,Lee Hye Sun,Park Yoo Seok,Park Hyeong Cheon,Chung Sung Phil Medicine Few studies have demonstrated the prognostic potential of neutrophil gelatinase-associated lipocalin (NGAL) in post-cardiac arrest patients. This study evaluated the usefulness of plasma NGAL in predicting neurologic outcome and mortality in out-of-hospital cardiac arrest (OHCA) patients treated with targeted temperature management (TTM). A prospective observational study was conducted between October 2013 and April 2016 at a single tertiary hospital. We enrolled 75 patients treated with TTM and collected their demographic data, cardiopulmonary resuscitation-related information, data on plasma NGAL concentration, and prognostic test results. Plasma NGAL was measured at 4 hours after return of spontaneous circulation (ROSC). The primary endpoint was the neurologic outcome at discharge and the secondary outcome was 28-day mortality. Neurologic outcomes were analyzed using a stepwise multivariate logistic regression while 28-day mortality was analyzed using a stepwise Cox regression. The predictive performance of plasma NGAL for neurologic outcome was measured by the area under the receiver operating characteristic curve and the predictability of 28-day mortality was measured using Harrell C-index. We also compared the predictive performance of plasma NGAL to that of other traditional prognostic modalities for outcome variables. Thirty patients (40%) had good neurologic outcomes and 53 (70.7%) survived for more than 28 days. Plasma NGAL in patients with good neurologic outcomes was 122.7 ± 146.7 ng/ml, which was significantly lower than that in the poor neurologic outcome group (307.5 ± 269.6 ng/ml; P < .001). The probability of a poor neurologic outcome was more than 3.3-fold in the NGAL >124.3 ng/ml group (odds ratio, 3.321; 95% confidence interval [CI], 1.265-8.721]). Plasma NGAL in the survived group was significantly lower than that in the non-survived group (172.7 ± 191.6 vs 379.9 ± 297.8 ng/ml; P = .005). Plasma NGAL was significantly correlated with 28-day mortality (hazard ratio 1.003, 95% CI 1.001-1.004; P < .001). The predictive performance of plasma NGAL was not inferior to that of other prognostic modalities except electroencephalography. Plasma NGAL is valuable for predicting the neurologic outcome and 28-day mortality of patients with OHCA at an early stage after ROSC.This study was registered at ClinicalTrials.gov on November 19, 2013 (Identifier: NCT01987466). 10.1097/MD.0000000000016930
    The origin of plasma neutrophil gelatinase-associated lipocalin in cardiac surgery. Passov Arie,Petäjä Liisa,Pihlajoki Marjut,Salminen Ulla-Stina,Suojaranta Raili,Vento Antti,Andersson Sture,Pettilä Ville,Schramko Alexey,Pesonen Eero BMC nephrology BACKGROUND:Acute kidney injury (AKI) is common after heart surgery. Neutrophil gelatinase-associated lipocalin (NGAL) is produced in injured kidney. NGAL has been used as an early plasma biomarker for AKI in patients undergoing heart surgery. Neutrophils contain all isoforms (25-kDa, 45-kDa and 145-kDa) but the kidney produces almost exclusively the 25-kDa isoform of NGAL. We investigated first, whether there is association between NGAL and neutrophil activation, and second whether activated neutrophils are a significant source of circulating NGAL in plasma in patients undergoing cardiac surgery. METHODS:Two separate patient cohorts were studied: 1) the "kinetic cohort" (n = 29) and 2) the "FINNAKI cohort" (n = 306). As NGAL is strictly co-localized with lactoferrin in neutrophils, NGAL and lactoferrin were measured with enzyme-linked immunosorbent assay in all patients. In sixty-one patients of the "FINNAKI cohort" Western blot was used to separate NGAL isoforms according to their molecular size. Mann-Whitney U, Kruskal-Wallis H, Pearson's and Spearman's tests were used as appropriate. RESULTS:There was strong intraoperative association between NGAL and lactoferrin at all four time-points in the "kinetic cohort". In the "FINNAKI cohort", NGAL and lactoferrin concentrations correlated preoperatively (R = 0.59, p < 0.001) and at admission to the intensive care unit (R = 0.69, p < 0.001). At admission to intensive care unit, concentrations of NGAL and lactoferrin were higher in AKI than in non-AKI patients (NGAL: p < 0.001; lactoferrin: p < 0.029). In Western blot analyses, neutrophil specific 45-kDa isoform (median 41% [IQR 33.3-53.1]) and mostly neutrophil derived 145-kDa isoform (median 53.5% [IQR 44.0-64.9%]) together represented over 90% of total NGAL in plasma. Potentially kidney derived NGAL isoform (25-kDa) accounted for only 0.9% (IQR 0.3 - 3.0%) of total NGAL in plasma. There were no statistically significant differences in the distribution of NGAL isomers between AKI and non-AKI patients. CONCLUSIONS:Plasma NGAL during cardiac surgery is associated with neutrophil activation. Based on molecular size, the majority of circulating NGAL is derived from neutrophils. Neutrophil activation is a confounding factor when interpreting increased plasma NGAL in cardiac surgery. 10.1186/s12882-019-1380-4
    Neutrophil Gelatinase-Associated Lipocalin for the Early Prediction of Acute Kidney Injury in ST-Segment Elevation Myocardial Infarction Patients Treated with Primary Percutaneous Coronary Intervention. Merdler Ilan,Rozenfeld Keren-Lee,Zahler David,Shtark Moshe,Goldiner Ilana,Loewenstein Itamar Shimon,Fortis Lior,Hochstadt Aviram,Keren Gad,Banai Shmuel,Shacham Yacov Cardiorenal medicine INTRODUCTION AND OBJECTIVE:Neutrophil gelatinase-associated lipocalin (NGAL), a glycoprotein released by renal tubular cells, can be used as a marker of early tubular damage. We evaluated plasma NGAL level utilization for the identification of acute kidney injury (AKI) among ST-elevation myocardial infarction (STEMI) patients undergoing primary coronary intervention (PCI). METHODS:131 STEMI patients treated with PCI were prospectively included. Plasma NGAL levels were drawn prior to PCI (0 h) and 24 h afterwards. AKI was defined per KDIGO criteria of serum creatinine increase. Receiver-operating characteristic (ROC) methods were used to identify optimal sensitivity and specificity for the observed NGAL range. RESULTS:Overall AKI incidence was 14%. NGAL levels were significantly higher for patients with AKI at both 0 h (164 ± 42 vs. 95 ± 30; p < 0.001) and 24 h (142 ± 41 vs. 93 ± 36; p < 0.001). Per ROC curve analysis, an optimal cutoff value of NGAL (>120 ng/mL) predicted AKI with 80% sensitivity and specificity (AUC 0.881, 95%, CI 0.801-0.961, p < 0.001). In a multivariate logistic regression model, NGAL levels were independently associated with AKI at 0 h (OR 1.044, 95% CI 1.013-1.076; p = 0.005) and 24 h (OR 1.018, 95% CI 1.001-1.036; p = 0.04). CONCLUSIONS:Elevated NGAL levels, suggesting renal tubular damage, are independently associated with AKI in STEMI patients undergoing primary PCI. 10.1159/000506378
    Short-term prognostic implications of serum and urine neutrophil gelatinase-associated lipocalin in acute heart failure: findings from the AKINESIS study. Wettersten Nicholas,Horiuchi Yu,van Veldhuisen Dirk J,Mueller Christian,Filippatos Gerasimos,Nowak Richard,Hogan Christopher,Kontos Michael C,Cannon Chad M,Müeller Gerhard A,Birkhahn Robert,Taub Pam,Vilke Gary M,Barnett Olga,McDonald Kenneth,Mahon Niall,Nuñez Julio,Briguori Carlo,Passino Claudio,Maisel Alan,Murray Patrick T European journal of heart failure AIMS:Kidney impairment has been associated with worse outcomes in acute heart failure (AHF), although recent studies challenge this association. Neutrophil gelatinase-associated lipocalin (NGAL) is a novel biomarker of kidney tubular injury. Its prognostic role in AHF has not been evaluated in large cohorts. The present study aimed to determine if serum NGAL (sNGAL) or urine NGAL (uNGAL) is superior to creatinine for predicting short-term outcomes in AHF. METHODS AND RESULTS:The study was conducted in an international, multicentre, prospective cohort consisting of 927 patients with AHF. Admission and peak values of sNGAL, uNGAL and uNGAL/urine creatinine (uCr) ratio were compared to admission and peak serum creatinine (sCr). The composite endpoints were death, initiation of renal replacement therapy, heart failure (HF) readmission and any emergent HF-related outpatient visit within 30 and 60 days, respectively. The mean age of the cohort was 69 years and 62% were male. The median length of stay was 6 days. The composite endpoint occurred in 106 patients and 154 patients within 30 and 60 days, respectively. Serum NGAL was more predictive than uNGAL and the uNGAL/uCr ratio but was not superior to sCr [area under the curve: admission sNGAL 0.61, 95% confidence interval (CI) 0.55-0.67, and 0.59, 95% CI 0.54-0.65; peak sNGAL: 0.60, 95% CI 0.54-0.66, and 0.57, 95% CI 0.52-0.63; admission sCr: 0.60, 95% CI 0.54-0.64, and 0.59, 95% CI 0.53-0.64; peak sCr: 0.61, 95% CI 0.55-0.67, and 0.59, 95% CI 0.54-0.64, at 30 and 60 days, respectively]. NGAL was not predictive of the composite endpoint in multivariate analysis. CONCLUSIONS:Serum NGAL outperformed uNGAL but neither was superior to admission or peak sCr for predicting adverse events. 10.1002/ejhf.1642
    Elevated Neutrophil Gelatinase-Associated Lipocalin for the Assessment of Structural versus Functional Renal Damage among ST-Segment Elevation Myocardial Infarction Patients. Rozenfeld Keren-Lee,Zahler David,Shtark Moshe,Goldiner Ilana,Keren Gad,Banai Shmuel,Shacham Yacov Blood purification BACKGROUND:Neutrophil gelatinase-associated lipocalin (NGAL) is an early marker of renal tubular damage. We investigated the incidence and possible implications of elevated NGAL levels (suggesting renal damage) compared to both functional and damage markers (manifested as serum creatinine [sCr] elevation) and no NGAL/sCr change, among -ST-elevation myocardial infarction (STEMI) patients treated with primary percutaneous coronary intervention (PCI). METHODS:We included 131 patients with STEMI treated with PCI. Blood samples for plasma NGAL were drawn 24 h following PCI. We used the terms NGAL(-) or NGAL(+) with levels ≥100 ng/mL suggesting renal tubular damage and the terms. sCr(-) or sCr(+) to consensus diagnostic increases in sCr defining acute kidney injury. Patients were also assessed for in hospital-adverse outcomes. RESULTS:Of the study patients, 56 (42%) were NGAL(-)/sCr(-), 58 (44%) NGAL(+)/sCr(-), and 18 (14%) were both NGAL(+)/sCr(+). According to the 3 study groups, there was a stepwise increase in the proportion of left ventricular ejection fraction ≤45% (43 vs. 60. vs. 72%; p = 0.04), in-hospital adverse outcomes (9 vs. 14 vs. 56%; p < 0.001) and their combination. Specifically, more NGAL(+)/sCr(-) patients developed the composite endpoint when compared to NGAL(-)/sCr(-) patients (64 vs. 46%; OR 2.1, [95% CI 1.1-4.5], p = 0.05). A similar and consistent increase was observed in peak sCr, length of hospital stay, and C-reactive protein levels. CONCLUSIONS:Elevated NGAL levels suggesting renal tubular damage, increased inflammation, or both are common among STEMI patients and are associated with adverse outcomes even in the absence of diagnostic increase in sCr. 10.1159/000506175
    Aldosterone Target NGAL (Neutrophil Gelatinase-Associated Lipocalin) Is Involved in Cardiac Remodeling After Myocardial Infarction Through NFκB Pathway. Martínez-Martínez Ernesto,Buonafine Mathieu,Boukhalfa Ines,Ibarrola Jaime,Fernández-Celis Amaya,Kolkhof Peter,Rossignol Patrick,Girerd Nicolas,Mulder Paul,López-Andrés Natalia,Ouvrard-Pascaud Antoine,Jaisser Frédéric Hypertension (Dallas, Tex. : 1979) Myocardial infarction (MI) is accompanied by cardiac fibrosis, which contributes to cardiac dysfunction. Mineralocorticoid receptor (MR) antagonists have beneficial effects in patients with left ventricular (LV) dysfunction after MI. We herein investigated the role of the MR target NGAL (neutrophil gelatinase-associated lipocalin) in post-MI cardiac damages. Both higher baseline NGAL and a greater increase in serum NGAL levels during follow-up were significantly associated with lower 6-month LV ejection fraction recovery in a cohort of 119 post-MI patients, as assessed by cardiac magnetic resonance imaging. NGAL protein levels increased in the LV at 7 days post-MI in wild-type mice with MI. This effect was prevented by treatment with the nonsteroidal MR antagonist finerenone (1 mg/kg per day). NGAL knockout mice with MI had lower LV interstitial fibrosis and inflammation, better LV contractility and compliance, and greater stroke volume and cardiac output than wild-type mice with MI at 3 months post-MI. Aldosterone (10 mol/L) increased NGAL expression in cultured human cardiac fibroblasts. Cells treated with aldosterone or NGAL (500 ng/mL) showed increased production of collagen type I. The effects of aldosterone were abolished by finerenone (10 mol/L) or NGAL knockdown. This NGAL-mediated activity relied on NFκB (nuclear factor-κB) activation, confirmed by the use of the NFκB-specific inhibitor BAY11-7082, which prevented the effect of both aldosterone and NGAL on collagen type I production. In conclusion, NGAL, a downstream MR activation target, is a key mediator of post-MI cardiac damage. NGAL may be a potential therapeutic target in cardiovascular pathological situations in which MR is involved. 10.1161/HYPERTENSIONAHA.117.09791
    Neutrophil gelatinase-associated lipocalin (NGAL) and cardiovascular events in patients with stable coronary artery disease. Sivalingam Zenthuja,Erik Magnusson Nils,Grove Erik Lerkevang,Hvas Anne-Mette,Dalby Kristensen Steen,Bøjet Larsen Sanne Scandinavian journal of clinical and laboratory investigation Inflammation is an important mediator in the pathogenesis of atherosclerosis. Neutrophil gelatinase-associated lipocalin (NGAL) is a small glycoprotein secreted by neutrophils. NGAL regulates the activity of matrix metalloproteinase-9, which plays a role in plaque instability. It has therefore been hypothesised that NGAL may modulate inflammation and promote the development and progression of atherosclerosis. Our aim was to assess the predictive value of plasma NGAL in a prospective cohort study of 876 high-risk patients with stable coronary artery disease (CAD). NGAL levels were measured using the NGAL Test from BioPorto Diagnostics. Clinical follow-up was performed after a median of 3.1 years. The endpoint was a combination of non-fatal acute myocardial infarction (MI), cardiovascular death (CVD), or ischaemic stroke. The NGAL concentration was (median [25;75%]: 64.3 µg/L [51.3;81.4]). The area under the receiver operating characteristic curve (AUC) was 0.56 (95% confidence interval (CI): 0.49;0.64) for the diagnosis of the composite endpoint and 0.66 (95% CI: 0.56;0.75) after adding NGAL to high-sensitive C-reactive protein (hs-CRP), leucocyte count, interleukin-6 (IL-6), calprotectin, age, sex, body mass index (BMI), diabetes mellitus, smoking and creatinine. However, the AUC for hs-CRP, leucocyte count, IL-6, calprotectin, age, sex, BMI, diabetes mellitus, smoking and creatinine without NGAL was similar at 0.66 (95% CI: 0.56;0.76). NGAL alone had no predictive value with respect to the composite endpoint of non-fatal AMI, ischaemic stroke, or CVD in stable CAD patients. NGAL did not add any predictive value to the endpoint compared with existing inflammatory biomarkers and cardiovascular risk factors. 10.1080/00365513.2018.1499956
    Serum levels of neutrophil Gelatinase associated Lipocalin (NGAL) predicts hemodialysis after coronary angiography in high risk patients with acute coronary syndrome. Reyes Luis F,Severiche-Bueno Diego F,Bustamante Carlos A,Murillo Sixta,Soni Nilam J,Poveda Marcela,Gomez Efraín,Buitrago Ricardo,Rodriguez Alejandro BMC nephrology BACKGROUND:Contrast-induced nephropathy (CIN) following a percutaneous coronary intervention (PCI) is the third most common cause of acute kidney injury (AKI) worldwide. Patients who require hemodialysis secondary to CIN have an elevated mortality rate as high as 55%. The current definition of CIN is based on an elevation of creatinine and decrease in urinary output. Creatinine typically increases 48 h after the contrast exposure, which delays the diagnosis and treatment of CIN. The neutrophil gelatinase associated lipocalin (NGAL) has emerged as a sensitive and specific biomarker of renal injury. Limited data exists about the effectiveness of NGAL to predict CIN in high-risk patients with acute coronary syndrome (ACS) that underwent PCI. The primary aim of this study was to determine the association of serum NGAL levels and the need for hemodialysis after PCI. METHODS:This is a prospective, observational study. NGAL levels were measured using ELISA. Blood samples were obtained within the first 6 h of hospital admission, and 12 and 24 h after contrast exposure from angiography. The primary outcome was the requirement of hemodialysis. The non-parametric Mann-Whitney U test was used to test for differences in median serum levels of NGAL. A receiver operating characteristic (ROC) curve was developed to assess the accuracy of NGAL to predict the need for hemodialysis after PCI. RESULTS:A total of 2875 were screened; however, 45 patients with ACS that underwent PCI were included. All patients were at high risk of developing CIN defined by Mehran score > 11 points. The median (IQR) serum concentration of NGAL was significantly higher in patients that required versus did not require hemodialysis (340 [83-384] vs. 169 [100-210], p = 0.01). Elevated serum levels of NGAL with a cut-off at 6 h post PCI of 281 mg/dL predicted the need for hemodialysis with an area under the curve of 0.86 (95% CI, 0.66-1.00). CONCLUSIONS:In patients with ACS undergoing PCI; and high risk of developing CIN, an elevated serum level of NGAL 6 h after contrast exposure predicts the development of acute kidney injury requiring hemodialysis. 10.1186/s12882-020-01799-5
    Neutrophil Gelatinase Associated Lipocalin (NGAL) for Identification of Unstable Plaques in Patients with Asymptomatic Carotid Stenosis. Eilenberg Wolf,Stojkovic Stefan,Kaider Alexandra,Piechota-Polanczyk Aleksandra,Nanobachvili Josif,Domenig Christoph M,Wojta Johann,Huk Ihor,Demyanets Svitlana,Neumayer Christoph European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery OBJECTIVE:Neutrophil gelatinase associated lipocalin (NGAL) and matrix metalloproteinase (MMP)-9/NGAL complex were investigated in asymptomatic patients with carotid artery stenosis including gender specific differences aiming at vulnerable plaques prone to embolisation. METHODS:Serum NGAL and MMP-9/NGAL levels were analysed in 83 patients with asymptomatic carotid artery stenosis. Pre-operative ultrasound and post-endarterectomy histology of carotid atherosclerotic lesions were evaluated. RESULTS:Patients with vulnerable plaques, as determined by ultrasound (plaques with decreased echogenicity) and histological analysis (type VI according to the classification of the American Heart Association), displayed the highest levels of NGAL and MMP-9/NGAL complex (p = .0003 and p = .0078, respectively). Grade VI plaques were primarily detected in patients with "soft" plaques (12 type VI plaques in 25 patients), but also in patients with mixed (four of 19) and calcified (three of 39) plaques according to ultrasound. Higher grade carotid artery stenosis (≥90%) was not associated with elevated NGAL levels. The receiver operating characteristic curve analysis detecting grade VI lesions yields an area under the curve (AUC) = 0.85, with respect to soft plaque on ultrasound the AUC = 0.86. There were no gender specific differences in levels of NGAL 80.9 (37.7) ng/mL in women vs. 76.7 (36.3) ng/mL in men, p = .607) nor of MMP-9/NGAL 33.0 (18.2-55.5) ng/mL in women vs. 36.7 (20.2-54.0) ng/mL in men, p = .969. Likewise, there were no gender associated differences in vulnerable plaque characteristics: either for grade VI plaques (17.9% vs. 27.3%, p = .582) or for the presence of soft plaques as evaluated by ultrasound (35.9% vs. 25%, p = .503). CONCLUSION:Circulating NGAL and MMP-9/NGAL are significantly increased in asymptomatic patients with vulnerable carotid atherosclerotic plaques independent of gender. Accordingly, serum NGAL may be proposed as a valuable biomarker for the detection of unstable carotid plaques in asymptomatic patients, who can then be selected for early carotid endarterectomy or stenting. 10.1016/j.ejvs.2018.12.029