Liver fibrosis staging with combination of APRI and FIB-4 scoring systems in chronic hepatitis C as an alternative to transient elastography.

BACKGROUND: Liver disease severity must be determined before treatment of chronic hepatitis C (CHC). We evaluated the diagnostic performance of the APRI and FIB-4 scores compared to transient elastography liver stiffness (TE-LS) in detecting significant fibrosis (F3) or cirrhosis (F4). METHODS: We retrospectively enrolled 575 patients with CHC who underwent TE-LS between May 2014 and September 2018: 365 (63.5%) male, mean age 51.54±12.4 years. APRI and FIB-4 scores were compared to TE-LS. RESULTS: One hundred patients (17.5%) had TE-LS values between 9 and 11.9 kPa, and were classified as F3, while 265 (46%) were classified as F4 (TE-LS ≥12 kPa). APRI and FIB-4 scores predicted F4 patients adequately using cutoff values of 0.65 (sensitivity 85.5%, specificity 77%) and 1.63 (sensitivity 91%, specificity 77%), respectively. Cutoff values of 0.64 for APRI and 1.46 for FIB-4 predicted F3/F4 patients (sensitivity 72% and 81.5%; specificity 83% and 79%, respectively). The use of these cutoff values with APRI and FIB-4 in combination adequately predicted patients with significant fibrosis or cirrhosis (positive predictive value 91.5%), while cutoff values of 0.3 and 0.98, respectively, predicted F1/F2 patients with specificity 94.5% and sensitivity 26.5%, suggesting that in 58.5% of patients TE-LS could possibly be avoided. CONCLUSIONS: The APRI/FIB-4 combination performed well in predicting significant fibrosis, while FIB-4 performed well in predicting cirrhosis. These noninvasive biochemical markers could be used as screening tools instead of LS measurement, which is not widely available. Further prospective validation studies are required to confirm this finding.

Novel biomarkers assessing renal function in heart failure: relation to inflammatory status and cardiac remodelling.

BACKGROUND: Patients with heart failure (HF) have a significant decline of renal function. We investigate the association between novel biomarkers of renal dysfunction and indices of inflammatory status and cardiac remodeling in patients with HF. METHODS: We enrolled 79 consecutive patients with HF and 79 healthy subjects, adjusted for age and sex. Serum levels of neutrophil gelatinase-associated lipocalin (NGAL), cystatin-C, b-type natriuretic peptide (BNP), tumor necrosis factor alpha (TNFα) and matrix metalloproteinase-9 (MMP-9) were measured by ELISA. Creatinine clearance was estimated using Cockcroft-Gault formula (eCcl). Left ventricular ejection fraction was determined by echocardiography. RESULTS: Patients with HF, compared to healthy subjects, had significantly higher NGAL (p=0.007) and cystatin-C levels (p=0.005). In HF patients, NGAL levels were positively correlated with Creatinine levels (r=0.40, p<0.001), TNFa levels (r=0.43, p<0.001), BNP levels (r=0.36, p=0.003), MMP-9 levels (r=0.37, p=0.02) and inversely correlated with left ventricle ejection fraction (r=-0.23, p=0.045). Interestingly, the association between NGAL and MMP-9 levels was independent from confounders such as age, gender, left ventricle ejection fraction, body mass index, TNFα levels, and BNP levels. Moreover, in HF patients, cystatin-C levels were inversely correlated with eCcl (r=-0.21, p=0.04). Cystatin-C levels were not correlated with TNFa, BNP, MMP-9 levels and with left ventricle ejection fraction (p=NS for all). CONCLUSIONS: NGAL is associated with left ventricle ejection fraction, and biomarkers of inflammation and cardiac remodeling in patients with HF. These findings highlight a possible common pathogenetic mechanism of renal dysfunction, inflammatory process and cardiac dysfunction in HF.

Dose-dependent effects of short term atorvastatin treatment on arterial wall properties and on indices of left ventricular remodeling in ischemic heart failure.

OBJECTIVES: Statins, beyond their lipid lowering role, exert beneficial effect on endothelial function in patients with atherosclerosis. Aim of the present study was to examine the short term pleiotropic effects of different doses of atorvastatin treatment, on endothelial function, arterial stiffness and indices of left ventricular remodeling in heart failure (HF) patients. METHODS: We studied the effect of 4 weeks administration of atorvastatin in 22 patients with ischemic HF. The study was carried out on two separate arms, one with atorvastatin 40 mg/d and one with atorvastatin 10 mg/d (randomized, double-blind, cross-over design). Endothelial function was evaluated by flow mediated dilation (FMD) in the brachial artery and arterial stiffness by augmentation index (AIx). Serum levels of matrix metalloproteinase-9 (MMP-9) and intracellular adhesion molecule-1 (sICAM-1) were measured as biomarkers of left ventricular remodeling and endothelial function, respectively, while, b-type natriuretic peptide (BNP) was measured as a marker of left ventricular function. RESULTS: Compared to baseline, atorvastatin 40 mg/d significantly improved FMD values (3.18 ± 3.03% vs. 5.98 ± 2.49%, p = 0.001) and AIx values (25.98 ± 8.55% vs. 23.09 ± 8.87%, p = 0.046). In addition, compared to baseline measurements, treatment with atorvastatin 40 mg/d resulted in significantly decreased levels of serum logMMP-9 levels (2.47 ± 0.23 ng/ml vs. 2.39 ± 0.24 ng/ml, p = 0.04) and of logICAM-1 levels (2.46 ± 0.13 ng/ml vs. 2.37 ± 0.16 ng/ml, p < 0.001). No significant changes were found after treatment with atorvastatin 10 mg/d in the aforementioned parameters. CONCLUSIONS: Short term treatment with 40 mg/d of atorvastatin exerts beneficial impact on arterial wall properties and on indices of left ventricle remodeling in heart failure patients.

Serum osteoprotegerin and osteopontin levels are associated with arterial stiffness and the presence and severity of coronary artery disease.

BACKGROUND: Osteopontin (OPN) and osteoprotegerin (OPG) have recently emerged as key factors in both vascular remodeling and development of atherosclerosis. Arterial stiffness has an independent predictive value for cardiovascular events. We evaluate the relationship between OPG, OPN serum levels and vascular function in coronary artery disease (CAD) patients. METHODS: The study population was consisted of 409 subjects (280 with CAD and 129 without CAD). Carotid-femoral pulse wave velocity (PWV) was measured as an index of aortic stiffness. OPG and OPN levels were measured, as markers of vascular remodeling and calcification, by ELISA. Gensini score was used to evaluate the extent of CAD. RESULTS: CAD patients, compared to those without CAD, had higher OPG (3.91 ± 1.87 pmol/l vs. 2.88 ± 1.32 pmol/l, p<0.001) and logOPN levels (1.81 ± 0.18 ng/ml vs. 1.71 ± 0.24 ng/ml, p<0.001) and impaired PWV (8.94 ± 2.21 m/s vs. 8.28 ± 1.91 m/s, p=0.006). Furthermore, PWV was associated with serum OPG levels (r=0.19, p<0.001) and with serum logOPN levels (r=0.10, p=0.049). Multivariate linear regression analysis revealed that increased OPG (p=0.013) and logOPN (p=0.006) levels are associated with 3-vessel CAD and Gensini score (p=0.04 for OPG and p=0.09 for OPN), independently of other known cardiovascular risk factors. CONCLUSION: The present study revealed that serum OPG and OPN levels are positively associated with arterial stiffness, and with the extent of CAD. These preliminary results suggest that OPG and OPN levels are significantly correlated with vascular function contributing to the pathogenesis of atherosclerosis in CAD. Further studies are needed to explore the mechanisms of action of OPG and OPN in CAD.

Ultra-performance liquid chromatography/tandem mass spectrometry method for the determination of lercanidipine in human plasma.

A simple, sensitive and rapid ultra-performance liquid chromatography/positive electrospray ionization tandem mass spectrometry (UPLC/ESI-MS/MS) method has been developed and validated for the determination of lercanidipine in human plasma. Lercanidipine and the internal standard, nicardipine, were extracted from plasma by liquid-liquid extraction using tert-butyl methyl ether as the extraction solvent. UPLC analysis was performed isocratically on an AcQuity UPLC BEH C18 analytical column (2.1 x 50.0 mm i.d., particle size 1.7 microm). The mobile phase consisted of 70% acetonitrile in water containing 0.2% v/v formic acid and pumped at a flow rate of 0.30 mL/min. ESI in positive ion mode, with multiple reaction monitoring (MRM), was chosen for the detection of the analytes. The assay was linear over a concentration range of 0.05-30 ng/mL for lercanidipine with a limit of quantitation of 0.05 ng/mL. Quality control samples (0.05, 0.15, 15 and 25 ng/mL) in five replicates from five of analytical runs demonstrated intra-assay precision (% CV < or =7.3%), inter-assay precision (% CV < or =6.1%) and an overall accuracy (% relative error) of less than 6.2%. A run time of less than 1.0 min for each sample made it possible to analyze a large number of human plasma samples per day. The method can be used to quantify lercanidipine in human plasma covering a variety of pharmacokinetic or bioequivalence studies.