Pharmacokinetic profile and effect on bone markers and muscle strength of two daily dosage regimens of calcifediol in osteopenic/osteoporotic postmenopausal women.

BACKGROUND: At present, although cholecalciferol represents the form of vitamin D of choice for the treatment of vitamin D deficiency, there is a growing interest in calcifediol. AIMS: This study aimed to evaluate the efficacy and the safety of two different daily doses of calcifediol. METHODS: Fifty osteopenic/osteoporotic women with serum levels of 25-hydroxyvitamin D (25OHD) between 10 and 20 ng/ml were randomized to a 6-month treatment with oral calcifediol 20 µg/day (n = 25) or oral calcifediol 30 µg/day (n = 25). In all, we measured the time course of the levels of 25OHD and other biochemical parameters. Moreover, we evaluated handgrip strength and serum levels of myostatin. RESULTS: The peak increase in 25OHD levels was reached after 90 days of treatment in group 1 (59.3 ng/ml) and after only 60 days in group 2 (72.3 ng/ml); thereafter in both groups, the levels of 25OHD showed a tendency towards stabilization. After 30 days, all the patients treated with 30 µg/day had values of 25OHD > 30 ng/ml. Handgrip strength showed a modest but progressive increase which reached the statistical significance in the 30 µg/day group. This latter group also presented a modest and non-significant decrease in serum levels of myostatin. CONCLUSIONS: Calcifediol is able to rapidly normalize the vitamin D deficiency, and the 30 µg daily dosage could be suggested in those patients who need to rapidly reach optimal 25OHD levels. Moreover, the 6-month treatment with calcifediol at a dose of 30 µg results in a modest but significant increase in upper limb strength.

Ultrasound indices of congestion in patients with acute heart failure according to body mass index.

BACKGROUND: The inverse relationship between body mass index (BMI) and natriuretic peptide levels complicates the diagnosis of heart failure (HF) in obese patients. Assessment of congestion with ultrasound could facilitate HF diagnosis but it is unclear if any relationship exists amongst BMI, inferior vena cava (IVC) diameter and the number of B-lines. METHODS: We performed a comprehensive echocardiographic evaluation within 24 h from hospital admission in patients with HF, including lung B-lines and IVC diameter, and studied their relationship with BMI and outcome. RESULTS: 216 patients (median age 81 (77-86) years) were enrolled. Median number of B-lines was 31 (IQR 26-38), median IVC diameter was 23 (22-25) mm and median BNP 991 (727-1601) pg/mL. BMI was inversely correlated with B-lines (r = - 0.50, p < 0.001), but not with IVC diameter (r = - 0.04, p = 0.58). Compared to overweight patients (BMI 25-29.9 kg/m2; n = 100) or with a normal BMI (BMI < 25 kg/m2; n = 59), obese patients (BMI ≥ 30 kg/m2; n = 57) had lower B-lines [28 (24-33) vs 30 (26-35), and vs 38 (32-42), respectively; p < 0.001] but similar IVC diameter. During the first 60 days of follow-up, there were 53 primary events: 29 patients died and 24 had a HF-related hospitalisation. B-lines and IVC diameter were independently associated with an increased risk. However, B-lines were less likely to predict outcome in the subgroup of patients with a BMI ≥ 30 kg/m2. CONCLUSIONS: Assessment of IVC diameter or B-lines in patients admitted with AHF identifies those at greater risk of death or HF readmission. However, assessment of B-lines might be influenced by BMI.

Combination of ST2 and B-type natriuretic peptide in diabetic patients with acute heart failure: relation with ventricular stiffness and outcome.

BACKGROUND: Diabetes is a common disease in heart failure and its prevalence ranges from 10 to 30%. ST-2 is a novel biomarker of myocardial fibrosis and remodelling in heart failure and may be involved in the inflammatory process of diabetes mellitus. In this study, we sought: to evaluate levels of ST-2 and B-type natriuretic peptide (BNP) in groups with acute heart failure with and without diabetes; to analyse the prognostic impact of ST-2 over a 6-month follow-up period. METHODS: We performed an echocardiographic examination and measured ST-2 and BNP within 24 h of hospital admission. Patients were classified as heart failure with reduced ejection fraction {HFrEF [left ventricular ejection fraction (LVEF) <50%]} or heart failure with preserved ejection fraction (HFpEF, LVEF ≥50%). We defined diastolic function according to recent guidelines, and we calculated left ventricular stiffness was assessed by the ratio between E/e' (index of left ventricular filling pressure) and left ventricular diastolic diameter (LVEDD) (index of left ventricular volume). The sum of death and rehospitalization due to cardiovascular causes was considered in the composite outcome. RESULTS: Of 121 patients enrolled, 58 experienced diabetes and 63 had normal glucose levels. Sixty patients showed HFrEF and 61 HFpEF. Among patients with diabetes, we observed significantly increased levels of serum ST-2 with respect to patients without diabetes [89 (29-147) 72 ±â€Š42 vs. 48 (29-80) 59 ±â€Š33 ng/ml; P = 0.04]. No differences were found between the two groups in terms of BNP levels, risk factors, renal function and echocardiographic measurements. Conversely, BNP was significantly higher in HFrEF with respect to HFpEF [786 (344-1390) vs. 423 (195-796) pg/ml; P = 0.004]. A significant correlation between ST-2 and BNP in diabetic patients (r = 0.50; P < 0.001) compared with nondiabetic patients (r = 0.40; P = 0.001) was found. ST-2 showed a numerically greater correlation with left ventricular stiffness in patients with diabetes (r = 0.56; P < 0.001) than patients without (r = 0.29; P = 0.04). Moreover, in all patients, ST-2 demonstrated a significant correlation with glycated glycosylated haemoglobin HbA1c (r = 0.40; P < 0.001). Univariate analysis demonstrated that both ST-2 more than 54 ng/ml and BNP more than 567 pg/ml were related to adverse events occurrence within 6 months [hazard ratio (HR): 3.64 (1.90-6.94), P < 0.001; HR: 2.21 (1.20-4.07), P = 0.01, respectively]. After adjustment for potential confounding factors, the multivariable analysis showed that only ST-2 levels greater than 54 ng/ml were associated with poor prognosis [HR: 3.56 (1.66-7.62); P = 0.001]. CONCLUSION: ST-2 confirmed its prognostic power independently of diabetes and LVEF. Patients with diabetes showed higher levels of ST-2. However, the mechanism related to ST-2 increase needs to be better understood, although increased left ventricle stiffness and filling pressure seem to be the most important causative factors. CLINICAL TRIAL REGISTRATION: www.clinicaltrial.gov Diur-HF Trial (Trial ID: NCT01441245).

Vitamin D levels in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).

Besides its well known function on bone metabolism, vitamin D role in cerebrovascular pathologies including cerebral small vessel disease has been confirmed by recent meta-analysis. In this study, we measured vitamin D levels in 56 Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) patients (mean age 49.9) with no or minimal disability (modified Ranking Score, mRS ≤2) and in 56 age, sex and seasonality matched healthy controls. History of ischemic events was recorded and cognitive functions were assessed using the Mini-Mental State Examination. White matter hyperintensities on brain T2-weighted magnetic resonance images were classified according to a modified Fazekas scale. Comparison of vitamin D levels between patients and controls showed significant lower values (p < 0.05) in no-to-mild CADASIL patients and a higher number of subjects with severe deficiency [25(OH)D <10 ng/ml]. Vitamin D levels did not correlate with vascular risk factors, clinical data or Fazekas score. The role of vitamin D is worth to be further explored in prospective studies.

Different trajectories and significance of B-type natriuretic peptide, congestion and acute kidney injury in patients with heart failure.

The exact relationship existing among congestion status, brain natriuretic peptide (BNP) changes and acute kidney injury (AKI) has not been elucidated in patients with acute heart failure (AHF). The aims of this study are: to investigate the relation and prognostic role of BNP, AKI and clinical congestion after discharge; to define the exact BNP cut off value or a BNP in-hospital reduction to identify patients with higher risk during vulnerable post-discharge phase. We consecutively enrolled 157 patients with a diagnosis of AHF. BNP and creatinine were measured in all patients, and degree of failure was assessed. AKI was defined as a creatinine increase ≥0.3 mg/dL or eGFR reduction ≥20% during hospitalization. All patients were followed for 1 and 3 months. Of 146 included patients, 110 patients (75%) displayed effective decongestion, 116 (79%) showed a BNP decrease ≥30%, and 28 (19%) developed in-hospital AKI. BNP in-hospital decrease ≥30% was found more often in patients who showed good decongestion in comparison to patients in persistent failure (63 vs 22%; p < 0.001). The ROC curve analyses at 3 months show that both BNP reduction of 30% between admission and discharge and decongestion at discharge identifies patients with a reduced incidence of cardiovascular events (AUC = 0.79, confidence interval 0.68-0.90, sensibility 90%, sensitivity 50% p < 0.001). Kaplan-Meier survival plots show a better outcome in patients with a BNP decrease ≥30% and good decongestion at discharge (p = 0.03). BNP reduction in AHF is associated with decongestion. BNP reduction associated with decongestion at discharge is a favorable prognostic indicator at 90-day survival irrespective of the AKI occurrence.

Additional value of Galectin-3 to BNP in acute heart failure patients with preserved ejection fraction.

BACKGROUND: Almost half of patients with acute heart failure have preserved ejection fraction (HFpEF). HFpEF is a diagnostic challenge using traditional investigation tools; Galectin-3 (Gal-3) is an emerging biomarker useful in individuals at risk for HF. The aim of our study is to analyse the relation and prognostic value of Gal-3, BNP and renal dysfunction in patients with HFpEF compared to patients with reduced ejection fraction (HFrEF). METHODS: We enrolled 98 patients with acute heart failure (AHF) and measured Gal-3, BNP, and estimated glomerular filtration rate (eGFR) within 12h of hospital admission. On the basis of echocardiographic findings we divided our sample into two groups: patients with HFrHF (ejection fraction<50%) or HFpEF (ejection fraction>50%). Patients were followed up at 6months. RESULTS: No differences in Gal-3 levels were found in the two subgroups (HFrEF: 19.5±5.1ng/mL; HFpEF: 20.5±8.7, p=0.56). Gal-3 was inversely related to renal dysfunction (LogGal-3 vs eGFR: r=-0.30, p=0.01) but did not correlate with LogBNP levels (r=0.07, p=0.55). Gal-3 was associated with more advanced diastolic dysfunction in HFpEF (p=0.009). In addition LogGal-3 was related to diastolic LV stiffness (all patients: r=0.45, p<0.001; HFpEF: r=0.64, p<0.001). Cox regression analysis showed that LogGal-3>1.30 was related to poor outcome independently from renal dysfunction and other risk factors only in HFpEF (univariate HR 23.98 [3.03-89.45]; p<0.001). Adjusted for renal dysfunction (HR 16.32 [1.98-34.09]; p=0.009). CONCLUSIONS: Gal-3 is not able to distinguish between HFrEF and HFpEF patients. However it is related to diastolic dysfunction severity and LV stiffness in HFpEF. Gal-3 demonstrates a prognostic role independently from renal dysfunction in subjects with HFpEF.

Diagnostic utility of contemporary echo and BNP assessment in patients with acute heart failure during early hospitalization.

BACKGROUND: The use of B-type natriuretic peptide (BNP) and echocardiography in acute heart failure (AHF) diagnosis is poorly employed in the Emergency Department. The aim of the present study is to evaluate relation among BNP levels systolic and diastolic dysfunction during early phases of AHF hospitalization. METHODS: We performed contemporary echocardiographic and BNP assessment in 310 patients with AHF within 12h since hospital admission. We studied the correlation among BNP and degree of diastolic dysfunction evaluated by pulsed Doppler transmitral flow and Tissue Doppler flow. Finally we investigated the relation among BNP and the right systolic longitudinal ventricular function (TAPSE) and the systolic pulmonary arterial pressure (PAPs). RESULTS: BNP levels were 1417±1126, 1081±955, 894±901pg/mL, for patients with EF≤25%, EF 25-40% and EF 40-50% (p=0.005), respectively. "BNP levels linearly correlate with the degree of diastolic dysfunction: 582±406pg/mL in altered relaxation pattern, 712±557pg/mL in pseudonormal pattern and 1694±805 in restrictive filling pattern (p<0.001 for all patterns)." BNP levels were significantly increased in patients with right systolic ventricular dysfunction (TAPSE<18mm; p=0.006) and in patients with PAPs≥40mmHg (p=0.001). ROC curve and logistic regression analysis highlighted the power of BNP to detect severe systolic dysfunction, right ventricular (RV) overload and dysfunction and diastolic dysfunction patterns. CONCLUSIONS: BNP levels correlate linearly with LV systolic dysfunction as well as with impaired degree of diastolic dysfunction. Significant PAP increase is a further factor influencing BNP elevation in patients with AHF during early hospitalization phase.

The prognostic combined role of B-type natriuretic peptide, blood urea nitrogen and congestion signs persistence in patients with acute heart failure.

AIMS: B-type natriuretic peptide (BNP) decrease during hospitalization has been related to reduced risk of readmission and death in patients with acute heart failure (AHF). Conversely, the exact role of blood urea nitrogen (BUN) is still debated. Currently, no data have been published regarding the relation between these two biomarkers and the relation between them and clinical signs of congestion. METHODS: We consecutively studied 107 patients with diagnosis of AHF and systolic dysfunction. All patients were observed during a 6-month follow-up period. BUN and BNP were measured according to the decrease of BNP levels at discharge of greater than 30% with respect to basal values; the persistence of congestion signs at discharge and BUN increase at discharge to more than 20% with respect to baseline. RESULTS: In all patients mean BNP was 1014 ±â€Š767 pg/ml; in patients with severe systolic dysfunction BNP was higher (1382 ±â€Š1025 vs. 848 ±â€Š549; P = 0.002). Mean BUN in all patients was 93 ±â€Š42 mg/dl; BUN was higher in patients affected by chronic kidney disease compared with patients with preserved renal function (114 ±â€Š45 vs. 68 ±â€Š21 mg/dl; P < 0.001). Cox regression analysis demonstrated that BNP decrease of at least 30% together with congestion signs resolution was related to outcome improvement (univariate hazard ratio: 0.45 [0.19-0.97], P = 0.05; multivariate hazard ratio: 0.44 [0.20-0.98], P = 0.05). BUN increase of greater than 20% at discharge was associated with poor outcome independent of persistence of congestion signs (univariate hazard ratio: 2.72 [1.03-7.28], P = 0.04; multivariate hazard ratio: 3.00 [1.12-8.06], P = 0.03). Changes (Δ) of both BNP (univariate hazard ratio: 1.30 [1.04-1.61], P = 0.01) and BUN (univariate hazard ratio: 5.24 [1.72-15.95], P = 0.003) were associated with mortality, independently of congestion. CONCLUSIONS: In patients with AHF, BNP reduction of greater than 30% during hospitalization is associated with outcome improvement only if it occurs together with congestion resolution. Conversely, BUN increase of more than 20% was associated with poor outcome, independently of the persistence of congestion signs.

Comparison of Neutrophil Gelatinase-Associated Lipocalin Versus B-Type Natriuretic Peptide and Cystatin C to Predict Early Acute Kidney Injury and Outcome in Patients With Acute Heart Failure.

Neutrophil gelatinase-associated lipocalin (NGAL) has been described in chronic heart failure (HF) as marker of tubular damage and renal dysfunction; however, less data are available in patients with acute HF. Because of high rate of acute kidney injury (AKI) development, we aimed to investigate the role of NGAL in predicting early AKI development; second, we compared NGAL with respect to cystatin C, B-type natriuretic peptide (BNP), renal function, and blood urea nitrogen (BUN) for outcome prediction. We measured admission serum NGAL, cystatin C, and BNP in 231 patients affected to acute HF; all patients were submitted to daily creatinine, estimated glomerular filtration rate, and measurement to identify inhospital AKI defined by Risk, Injury, Failure, Loss, End-Stage Kidney Disease and Acute Kidney Injury Network criteria. We also measured admission and discharge estimated glomerular filtration rate, creatinine, and BUN to evaluate their prognostic role during a 6-month follow-up period; 78 patients developed AKI during hospitalization. In these subjects, NGAL levels were significantly increased respect to patients without AKI (295 ± 228 vs 129 ± 108 ng/ml, p <0.001). A cutoff of 134 ng/ml has been related to AKI with good sensibility and specificity (85% and 80%, respectively; area under the curve 0.81, p <0.001). BNP was also mildly increased (1,000 ± 906 vs 746 ± 580 pg/ml, p = 0.03) but not cystatin C. Patients with chronic kidney disease demonstrated higher NGAL levels compared with subjects with preserved renal function (258 ± 249 and 120 ± 77 ng/ml, p <0.001). The receiver-operating characteristic curve analysis demonstrated that increased NGAL values were associated with increased mortality (cutoff 170 ng/ml, sensibility 60%, specificity 82%, accuracy 71%, area under the curve 0.77, p <0.001). The same significant correlation was also found for BUN at discharge (cutoff 100 mg/dl, sensibility 65%, specificity 85%, accuracy 71%, area under the curve 0.77, p <0.001). Multivariable Cox regression analysis showed that cutoff 170 ng/ml was related with adverse outcome (hazard ratio 1.77, confidence interval 1.24 to 2.83, p = 0.01). In conclusion, NGAL measurement is a sensible tool to predict AKI during hospitalization. Elevated NGAL levels appear to be related to BUN increase and post-discharge outcome. This suggests a prognostic role of tubular damage beyond renal dysfunction.

Role of BNP and echo measurement for pulmonary hypertension recognition in patients with interstitial lung disease: An algorithm application model.

BACKGROUND: This study evaluated the role of echocardiography and BNP in patients with interstitial lung disease (ILD), to identify those with PH and RV dysfunction. The aims of this study were: 1-to evaluate the accuracy of an algorithm including BNP, DLCO and echocardiographic measurements to identify PH and RV dysfunction; 2- to evaluate BNP and Echo values concordance in relation to right catheterization measurement. METHODS: We analyzed 113 patients with diagnosis of ILD. Echo examination included: Pulmonary systolic, diastolic and mean Arterial Pressure (PAPs, PAPd, PAP mean), End-Diastolic and End-Systolic right ventricle diameters, Inferior Caval Vein diameter, and Tricuspid Annular Plane Systolic Excursion (TAPSE). Patients revealing increased PAPs at echocardiography underwent to catheterization. RESULTS: Patients with PAPs > 40 mm Hg (37 patients), PAPmean ≥ 25 mm Hg (23 patients) and PAPd ≥ 20 mm Hg showed BNP increased (157 ± 96 vs 16 ± 14 pg/ml p = 0.004; 201 ± 120 vs 28 ± 17 pg/mL; 124 ± 88 vs 23 ± 18 pg/ml p < 0.001) as patients with TAPSE ≤16 mm (25 patients) (145 ± 104 vs 26 ± 21 pg/ml p < 0.001). In catheterized patients (37 patients) BNP was increased in patients with invasive PAPs > 40 mm Hg (165 ± 112 vs 29 ± 14 pg/ml p < 0.02), as well as in patients with Wedge pressure > 14 mm Hg (199 + 153 vs 54 + 39 pg/mL; p = 0.01). ROC Curve analysis showed that elevated values of BNP, PAPs, PAP mean are able to assess PH. On the other hand, lower values of DLCO (<40%) and TAPSE (≤16 mm) detect PH. Logistic regression analysis of the previous parameters, confirmed their diagnostic role in PH detection. CONCLUSIONS: In patients with ILD, an algorithm including BNP, DLCO and echocardiography could be useful for non invasive screening of PH. CLINICAL TRIAL REGISTRATION NAME AND NUMBER: ARTEMIS-HP trial; ID number: NCT00879229.

Short and long-term effects of continuous versus intermittent loop diuretics treatment in acute heart failure with renal dysfunction.

Intravenous loop diuretics are still the cornerstone of therapy in acute decompensated heart failure, however, the optimal dosage and administration strategies remain poorly defined particularly in patients with an associated renal dysfunction. This is a single-center, pilot, randomized trial involving patients with acute HF and renal dysfunction. Patients were assigned to receive continuous furosemide infusion (cIV) or bolus injections of furosemide (iIV). Primary end points were the evaluation of urine output volumes, renal function, and b-type natriuretic peptide (BNP) levels during treatment time. Secondary end point included: weight loss, length of hospitalization, differences in plasma electrolytes, need for additional treatment, and evaluation of cardiac events during follow-up period. 57 patients were included in the study. The cIV group showed an increase in urine output (2,505 ± 796 vs 2140 ± 468 ml/day, p < 0.04) and a more significant decrease of BNP levels in respect to the iIV group (679.6 ± 397 vs 949 ± 548 pg/ml, p < 0.04). We observed a significant increase in creatinine levels (1.78 ± 0.5 vs 1.41 ± 0.3 mg/dl, p < 0.01), and a reduction of the estimated glomerular filtration rate in cIV (44.8 ± 6.1 vs 46.7 ± 6.1 ml/min, p < 0.05). We observed a significant difference in eGFR (p = 0.01), creatinine (p = 0.02) and BNP levels (p = 0.03) from baseline to the end of treatment in both groups. A significant increase of in-hospital additional treatment as well as length of hospitalization was observed in cIV. Finally, cIV revealed a higher rate of adverse events during the follow-up period (p < 0.03). cIV appears to provide a more efficient diuresis and BNP level reduction during hospitalization, however, it was associated with increased rate of worsening renal function during hospitalization. cIV also appears related to a longer hospitalization and an increased number of adverse events during follow-up. For all of these reasons, a larger multi-center study is required to determine whether high-dose diuretics are responsible for worsening renal function and to define the best modality of administration.

Continuous versus bolus intermittent loop diuretic infusion in acutely decompensated heart failure: a prospective randomized trial.

INTRODUCTION: Intravenous loop diuretics are a cornerstone of therapy in acutely decompensated heart failure (ADHF). We sought to determine if there are any differences in clinical outcomes between intravenous bolus and continuous infusion of loop diuretics. METHODS: Subjects with ADHF within 12 hours of hospital admission were randomly assigned to continuous infusion or twice daily bolus therapy with furosemide. There were three co-primary endpoints assessed from admission to discharge: the mean paired changes in serum creatinine, estimated glomerular filtration rate (eGFR), and reduction in B-type natriuretic peptide (BNP). Secondary endpoints included the rate of acute kidney injury (AKI), change in body weight and six months follow-up evaluation after discharge. RESULTS: A total of 43 received a continuous infusion and 39 were assigned to bolus treatment. At discharge, the mean change in serum creatinine was higher (+0.8 ± 0.4 versus -0.8 ± 0.3 mg/dl P <0.01), and eGFR was lower (-9 ± 7 versus +5 ± 6 ml/min/1.73 m(2) P <0.05) in the continuous arm. There was no significant difference in the degree of weight loss (-4.1 ± 1.9 versus -3.5 ± 2.4 kg P = 0.23). The continuous infusion arm had a greater reduction in BNP over the hospital course, (-576 ± 655 versus -181 ± 527 pg/ml P = 0.02). The rates of AKI were comparable (22% and 15% P = 0.3) between the two groups. There was more frequent use of hypertonic saline solutions for hyponatremia (33% versus 18% P <0.01), intravenous dopamine infusions (35% versus 23% P = 0.02), and the hospital length of stay was longer in the continuous infusion group (14. 3 ± 5 versus 11.5 ± 4 days, P <0.03). At 6 months there were higher rates of re-admission or death in the continuous infusion group, 58% versus 23%, (P = 0.001) and this mode of treatment independently associated with this outcome after adjusting for baseline and intermediate variables (adjusted hazard ratio = 2.57, 95% confidence interval, 1.01 to 6.58 P = 0.04). CONCLUSIONS: In the setting of ADHF, continuous infusion of loop diuretics resulted in greater reductions in BNP from admission to discharge. However, this appeared to occur at the consequence of worsened renal filtration function, use of additional treatment, and higher rates of rehospitalization or death at six months. TRIAL REGISTRATION: ClinicalTrials.gov NCT01441245. Registered 23 September 2011.

Admission plasma neutrophil gelatinase associated lipocalin (NGAL) predicts worsening renal function during hospitalization and post discharge outcome in patients with acute heart failure.

UNLABELLED: Abstract Background: The role of neutrophil gelatinase-associated lipocalin (NGAL) has been described in chronic heart failure (HF), however less data are available in patients admitted for acute HF. METHODS: We evaluated the role of NGAL in predicting in-hospital worsening renal function (WRF) and post-discharge follow-up during six months period in patients with acute HF. All patients were submitted to creatinine, estimated glomerular filtration rate (eGFR), blood urea nitrogen (BUN) and B-type natriuretic peptide (BNP) measurement during hospitalization and before discharge. RESULTS: Patients with chronic kidney dysfunction (CKD) demonstrated higher NGAL respect to subject with preserved renal function (241 ± 218 and 130 ± 80 ng/ml; P = 0.0001). In subgroup that developed WRF during hospitalization, NGAL levels were significantly increased respect to patients without WRF (272 ± 205 versus 136 ± 127 ng/ml; P = 0.0001). A cut off of 134 ng/ml has been related to WRF with good sensibility and specificity (92% and 71% AUC 0.83; P = 0.001). Multivariable Cox regression analysis showed that cut-off of 134 ng/ml was the only marker related to death (HR: 1.75; 95% CI: 1.24-2.45; P < 0.001). Follow-up analysis confirmed that NGAL > 130 ng/ml was associated with adverse events during a six-month period. CONCLUSION: Admission NGAL measurement appears a sensible tool for in-hospital WRF prediction as well as an early marker for adverse outcome during post discharge vulnerable phase.

Patients with cardiorenal syndrome revealed increased neurohormonal activity, tubular and myocardial damage compared to heart failure patients with preserved renal function.

BACKGROUND: Cardiorenal syndrome (CRS) is associated with increased cardiovascular morbidity and mortality; still, its biomarker pattern has been poorly evaluated so far. The aim of this study was to measure the inflammatory activation, neurohormonal status and kidney and myocardial damage in patients with CRS compared to patients with heart failure (HF) without renal impairment (RI). METHODS: We analyzed 246 patients on the basis of renal function (group 1: 120 HF patients without RI; group 2: 126 CRS patients). In each group, interleukin-6, tumor necrosis factor-α, B-type natriuretic peptide (BNP), neutrophil gelatinase-associated lipocalin (NGAL), troponin T (TnT), osteoprotegerin and blood urea nitrogen (BUN) were measured. The diagnostic power of all laboratory parameters to detect CRS was evaluated by the receiver operating characteristic (ROC) curve and logistic regression analysis. RESULTS: A significant increase in BNP [626.4 pg/ml, confidence interval (CI) 518-749 vs. 487.8 pg/ml, CI 411-578; p < 0.05], NGAL (156 ng/ml, CI 129-186 vs. 89.1 ng/ml, CI 72-109; p < 0.0001), BUN (108.9 mg/dl, CI 98-120 vs. 51 mg/dl, CI 46-55; p < 0,0001) and TnT (0.62 ng/ml, CI 0.51-0.75 vs. 0.21 ng/ml, CI 0.15-0.28; p < 0.001) was seen in CRS patients compared to HF patients without RI. ROC curve analysis showed that only NGAL, BUN, BUN/creatinine ratio and TnT can discriminate patients with CRS from patients without RI. CONCLUSIONS: In CRS patients, renal tubular damage and neurohormonal and cardiac injury activation are increased compared to patients without RI. The current biomarker pattern could be used for an early diagnosis of RI in acute and chronic HF.

Long-term bone density evaluation in cerebrotendinous xanthomatosis: evidence of improvement after chenodeoxycholic acid treatment.

Cerebrotendinous xanthomatosis (CTX) is known to be associated with osteoporosis and a higher incidence of bone fractures. However, the underlying pathogenesis is still unknown, and the effects of long-term replacement therapy with chenodeoxycholic acid (CDCA) on bone mineral density (BMD) have not been fully investigated. We studied 11 CTX patients aged 13-43 years. We performed dual-energy X-ray absorptiometry and assessed serum cholestanol and 25-hydroxyvitamin D (25-OHD) concentrations both at the time of diagnosis and after long-term treatment with CDCA. At baseline, we found low BMD in nine patients, cholestanol elevation in all subjects, and 25-OHD decrease in nine. After a mean follow-up time of 30 months (range 24-36), no substantial clinical changes including bone fractures occurred; and we detected a significant increase of both planar and volumetric BMD as well as normalization of plasma cholestanol levels and increase of serum 25-OHD. Densitometric improvement following CDCA introduction was not correlated to changes of biochemical parameters. Our study confirms the presence of low bone mass in CTX and demonstrates that long-term CDCA treatment increases bone mineral content. In this respect, improvement of vitamin D intestinal absorption secondary to bile acid restoration could play an important role. Moreover, our data strongly suggest the utility of periodic bone density evaluation in CTX patients.

B-type natriuretic peptide as an independent predictor of coronary disease extension in non-ST elevation coronary syndromes with preserved systolic function.

OBJECTIVE: B-type natriuretic peptide (BNP) has been employed as a risk marker in patients with coronary artery disease (CAD) with ST elevation and non-ST elevation. It is not yet established if early BNP measurements provide additional information to troponin and electrocardiographic analysis in patients without ventricular enlargement and systolic dysfunction. DESIGN: This study compared BNP levels in patients with stable angina (SA) and acute coronary syndromes with non-ST elevation in relation to angiographic lesions (NSTEMI-ACS). Moreover, the diagnostic utility of BNP was determined using the receiver operating characteristic curve. PATIENTS: 280 patients with CAD without ST elevation and preserved systolic function were studied. BNP samples were measured in all recruited patients within 24 hours of hospitalization. RESULTS: BNP values increased progressively with the severity of diagnosis: SA (n = 85; 50.4 ± 50 pg/ml) NSTEMI-ACS (n = 195; 283 ± 269 pg/ml; p < 0.0001). The analysis of BNP in relation to the number of involved vessels demonstrated significantly increased levels in patients with multivessel disease compared to patients with 1- or 2-vessel disease (p < 0.001 and p < 0.003). Values of BNP >80 pg/ml were shown to be able to predict CAD severity and coronary vessel involvement (AUC = 0.80; p = 0.0001) with a sensitivity of 78% and a specificity of 72%. In multivariate analysis, BNP levels >80 pg/ml, CAD history, and ST deviation >2 mm were confirmed as independent predictors of CAD severity. CONCLUSIONS: Circulating BNP levels appear elevated in NSTEMI-ACS, without left ventricular systolic dysfunction. A BNP cut-off value of 80 pg/ml is a good predictor of CAD extension.

Detection of obestatin in seminal plasma and its relationship with ghrelin and semen parameters.

OBJECTIVE: To investigate the occurrence of ghrelin and obestatin in human semen. DESIGN: Prospective study. SETTING: University, center for research and therapy of male infertility. PATIENT(S): 112 consecutively selected men. INTERVENTION(S): Family history, clinical and physical examination, radioimmunoassay for ghrelin and obestatin determinations, semen analysis, annexinV/propidium iodide assay. MAIN OUTCOME MEASURE(S): Ghrelin and obestatin detected in the semen and relationships with semen parameters and conditions influencing semen quality (smoking, varicocele, ex varicocele, leukocytospermia). RESULT(S): The levels of both peptides in semen were higher versus serum. Linear correlations between ghrelin and obestatin levels in serum and in semen were observed. Serum ghrelin levels were negatively correlated with the men's ages. Semen obestatin levels were positively correlated with sperm concentration and motility. Obestatin levels were decreased in the semen of smokers and in the presence of leukocytospermia. CONCLUSION(S): This is the first study on the presence of obestatin in human semen and its relationship with sperm concentration and motility, suggesting a possible role of the peptide in controlling cell proliferation and survival. Further investigations are required to explore the exact role of obestatin and ghrelin in human semen.

B-type natriuretic peptide levels predict extent and severity of coronary disease in non-ST elevation coronary syndromes and normal left ventricular systolic function.

BACKGROUND: B-type natriuretic peptide (BNP) has been used recently as a biological marker in patients with coronary artery disease (CAD) with ST-elevation, as well as without ST-elevation. BNP is able to predict systolic dysfunction, adding new prognostic information to existing traditional markers. However is not known if there is a relation between the quantity of BNP levels and the severity of coronary artery disease. METHODS: This study compared B-type natriuretic peptide (BNP) levels in patients with stable angina (SA) and acute coronary syndromes (ACS) without ST-elevation in relation to angiographic lesions using TIMI and Gensini Scores. We studied 282 patients with CAD without ST elevation and preserved systolic function. BNP samples were measured in all recruited patients within 24 hours of hospitalization. RESULTS: BNP values were progressively increased in relation to the severity of diagnosis: SA (52.6±49.4 pg/mL ) UA (243.3±212 pg/mL) NSTE-ACS (421.7±334 pg/mL) (p<0.0001 and p<0.007 respectively). No statistically significant difference was observed between patients with SA and controls (21.2±6.8 pg/mL). The analysis of BNP levels in relation to the number of involved vessels demonstrated significantly increased levels in patients with multivessel disease compared to patients with 1 or 2 vessel disease (1-86.2±46.3 pg/mL; 2-127±297 pg/mL; 3-295±318 pg/mL; 4-297±347 pg/mL p<0.001 and p<0.003). Evaluation of BNP using Gensini Score showed a strong relation between BNP and coronary disease extension (r=0.38 p<0.0001).This trend was maintained in all CAD groups (SA=r 0.54; UA r=0.36 NSTE-ACS r=0.28). CONCLUSIONS: Circulating BNP levels appear elevated in ACS with diffuse coronary involvement, even in the absence of systolic dysfunction. BNP is also associated with multi-vessel disease and the extension of coronary disease.

Comparison of intravenous and intramuscular neridronate regimens for the treatment of Paget disease of bone.

Aminobisphosphonates actually represent the most common treatment for Paget disease of bone (PDB). In a previous study we demonstrated that either zoledronic acid (4 mg) or neridronate (200 mg) given as a single intravenous infusion showed a similar short-term efficacy in achieving biochemical remission in up to 90% of patient nonresponders to pamidronate. In this study we compared the long-term (36 months) effects of a same neridronate dose (200 mg) given as an intravenous (100-mg infusion for 2 consecutive days) or intramuscular (25-mg injection weekly for 2 months) regimen in 56 patients with active PDB. All patients were advised to receive calcium plus vitamin D supplementation throughout the study period. At 6 months, 92.6% and 96.5% of patients receiving intravenous and intramuscular neridronate, respectively, achieved a therapeutic response [defined as normalization of alkaline phosphatase (ALP) levels or a reduction of at least 75% in total ALP excess]. The response to treatment was significantly correlated with baseline ALP and 25-hydroxyvitamin D [25(OH)D] levels at 6 months. The decrease in ALP levels was highest in patients with higher baseline total or bone-specific ALP levels and with higher 25(OH)D levels at 6 months. Response rates were maintained at 12 months but decreased progressively at 24 and 36 months without significant differences between the two neridronate regimens. Both regimens were well tolerated. The only relevant side effect was an acute-phase response occurring in 14% of the patients. In conclusion, these results indicate that a 200-mg intramuscular neridronate course has a similar efficacy as an intravenous infusion of the same dose for the treatment of PDB and might be of particular value for patients intolerant to oral bisphosphonates and unwilling or unable to undergo intravenous infusions.

Anemia correction by erythropoietin reduces BNP levels, hospitalization rate, and NYHA class in patients with cardio-renal anemia syndrome.

Little is known about the effect of anemia correction with erythropoietin (EPO) on B-type natriuretic peptide (BNP) levels, NYHA class, and hospitalization rate. The aim of the study was to investigate, in patients with cardio-renal anemia syndrome, the effects of EPO on hemochrome and renal function parameters and BNP levels. We also analyzed the effect of EPO therapy on hospitalization rate and NYHA class after 12 months in comparison with a population undergoing to standard therapy. We performed a randomized double-blind controlled study of correction of the anemia with subcutaneous α (group A n = 13) or ß (group B n = 14) EPO for 12 months in addition to standard therapy with oral iron in 27 subjects. Control group (n = 25 patients) received only oral iron. Significant increase in hemoglobin (Hb), hematocrit (Hct), and red blood cells (RBC) were revealed in EPO groups at 12 months; Hb, group A 12.3 ± 0.6; group B 11.7 ± 0.8; control group 10.6 ± 0.5 g/dl P < 0.0001; Hct group A 34.2 ± 2.3, group B 34 ± 2, control group 32.3 ± 1.8% P < 0.01; RBC, group A 3.9 ± 0.2, group B 3.8 ± 0.2, control group 3.3 ± 0.2, (P < 0.0001). Plasma BNP levels in EPO groups were significantly reduced after 12 months (group A: 335 ± 138 vs. group B: 449 ± 274 pg/ml control group 582 ± 209 pg/ml (P < 0.01). After 12 months of treatment, hospitalization rate and NYHA class were reduced in EPO groups with respect to control group (P < 0.05). Finally, an inverse correlation was observed between BNP and Hb levels in EPO Groups (r = -0.70 P < 0.001). EPO treatment reduces BNP levels and hospitalization rate in patients with cardio-renal anemia syndrome. The correction of anemia by EPO treatment appears able to improve clinical outcome in this subset of patients with heart failure.