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.

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.

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.

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.

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.

Beta-erythropoietin effects on ventricular remodeling, left and right systolic function, pulmonary pressure, and hospitalizations in patients affected with heart failure and anemia.

Anemia in heart failure is related to advanced New York Heart Association classes, severe systolic dysfunction, and reduced exercise tolerance. Although anemia is frequently found in congestive heart failure (CHF), little is known about the effect of its' correction with erythropoietin (EPO) on cardiac structure and function. The present study examines, in patients with advanced CHF and anemia, the effects of beta-EPO on left ventricular volumes, left ventricular ejection fraction (LVEF), left and right longitudinal function mitral anular plane systolic excursion (MAPSE), tricuspid anular plane excursion (TAPSE), and pulmonary artery pressures in 58 patients during 1-year follow-up in a double-blind controlled study of correction of anemia with subcutaneous beta-EPO. Echocardiographic evaluation, B-Type natriuretic peptide (BNP) levels, and hematological parameters are reported at 4 and 12 months. The patients in group A after 4 months of follow-up period demonstrated an increase in LVEF and MAPSE (P < 0.05 and P < 0.01, respectively) with left ventricular systolic volume reduction (P < 0.02) with respect to baseline and controls. After 12 months, results regarding left ventricular systolic volume LVEF and MAPSE persisted (P < 0.001). In addition, TAPSE increased and pulmonary artery pressures fell significantly in group A (P < 0.01). All these changes occurred together with a significant BNP reduction and significant hemoglobin increase in the treated group. Therefore, we revealed a reduced hospitalization rate in treated patients with respect to the controls (25% in treated vs. 54% in controls). In patients with anemia and CHF, correction of anemia with beta-EPO and oral iron over 1 year leads to an improvement in left and right ventricular systolic function by reducing cardiac remodeling, BNP levels, and hospitalization rate.

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).

Osteoprotegerin and B-type natriuretic peptide in non-ST elevation acute coronary syndromes: relation to coronary artery narrowing and plaques number.

BACKGROUND: To analyse osteoprotegerin (OPG), and B-type natriuretic peptide (BNP) levels in patients with non-ST elevation acute coronary syndrome (NSTE-ACS), in relation to clinical presentation and to coronary atherosclerosis diffusion. OPG has been found in several tissues, including the cardiovascular system, BNP is selectively produced by myocardial cells. METHODS: 178 consecutive patients were classified in three groups: stable angina (SA), unstable angina/non-ST elevation myocardial infarction (NSTE-ACS) and control group, measuring OPG and BNP at hospital admission. We compared both biomarkers in relation to the number of coronary narrowed vessels (1-, 2- , 3- or 4- vessels disease), and to the stenoses degree by Duke Jeopardy score. RESULTS: OPG levels were higher in patients respect to controls (p<0.0001). Patients with SA showed more elevated levels than controls (2.6+/-1.2 vs 7.4+/-5.0 pmol/l p<0.01). However patients with NSTE-ACS had higher OPG level with respect to SA patients (11.8+/-7.1 pmol/l p<0.001). A positive relation was found between OPG levels and number of coronary plaques by Duke Jeopardy score (r=0.65). BNP levels were higher in patients with NSTE-ACS respect to controls and SA patients (p<0.001). Besides, BNP was significantly higher in multivessels vs 1-vessel disease (p<0.001). CONCLUSIONS: Patients with NSTE-ACS show high OPG levels. OPG increase seems related to the number of plaques in the coronary vessels, suggesting its involvement in the coronary disease progression. BNP is also increased during NSTE-ACS and more associated to coronary narrowing.

The effects of recombinant TSH on bone turnover markers and serum osteoprotegerin and RANKL levels.

OBJECTIVE: Recently it was found that thyrotropin (TSH) receptors are present both in osteoclast and osteoblast and that TSH can modulate bone remodeling independent of thyroid hormones. The aim of this study was, firstly, to evaluate the effects of acute administration of TSH on bone remodeling markers both in men and in women and, secondly, to evaluate if these effects are mediated by variations in serum osteoprotegerin (OPG) and receptor activator of nuclear factor-KB ligand (RANKL). DESIGN: We studied 30 thyroidectomized patients (10 premenopausal and 10 postmenopausal women, 10 men) affected by thyroid carcinoma on l-thyroxine therapy. Eighty age- and sex-matched subjects were used as controls. A blood sample was drawn from each patient at baseline and 3 and 5 days after recombinant human TSH (rhTSH) administration, in preparation for (131)I whole body scan, to assess serum bone markers and serum OPG and RANKL levels. MAIN OUTCOME: At baseline, postmenopausal women and men had significantly higher values of bone turnover markers and serum OPG compared to control subjects. In all thyroidectomized patients serum RANKL was lower than in controls. After rhTSH administration, serum N-terminal propeptide of type-I procollagen (PINP), a marker of bone formation, increased significantly in postmenopausal women, while serum RANKL significantly increased after 3 days in postmenopausal patients and men returning to baseline values at day 5. Serum OPG levels did not change significantly. CONCLUSIONS: The low serum TSH observed in thyroidectomized patients on l-thyroxine therapy is associated with an increase of bone turnover in postmenopausal women and men that is associated with an increase of OPG and a decrease of serum RANKL levels. The acute TSH administration results in an increase of PINP, an index of osteoblastic activity, associated with an increase of serum RANKL. The lack of this response in premenopausal women suggests an influence of estrogen status on bone reactivity to TSH.

Prevalence of risk factors, coronary and systemic atherosclerosis in abdominal aortic aneurysm: comparison with high cardiovascular risk population.

BACKGROUND: Abdominal aortic aneurysm (AAA) is considered a manifestation of atherosclerosis, however there are epidemiologic, biochemical, and structural differences between occlusive atherosclerosis and AAA. The pathogenesis of AAA involves several factors, first of all destruction of collagen and elastin in the aortic wall. Classical risk factors may influence the evolution and development of AAA, though no consistent association has been found. Aims of the study were to evaluate associations between risk factors and to establish the prevalence of carotid, peripheral vascular and coronary atherosclerosis in patients with AAA. METHODS: We studied 98 patients with AAA (Group 1) awaiting surgery compared with high cardiovascular risk population having two or more risk factors (n=82 Group 2). We evaluated traditional risk factors and we studied by eco-doppler and echocardiography the presence of carotid peripheral and coronaric atherosclerosis in two groups. RESULTS: We found a higher incidence of AAA in males (p < 0.01). The prevalence of infrarenal AAA was significantly higher than suprarenal AAA (81 vs. 17 p < 0.001). No differences in total cholesterol (199 +/- 20 vs. 197 +/- 25 mg/dl), low-density lipoprotein (142 +/- 16 vs. 140 +/- 18 mg/dl), triglycerides (138 +/- 45 vs. 144 +/- 56 mg/dl), glycemia (119 +/- 15 vs. 122 +/- 20 mg/dl), and fibrinogen (388 +/- 154 vs. 362 +/- 92 mg/dl) were found between groups. We demonstrated significant differences for cigarette smoking (p < 0.002), systolic and diastolic blood pressure (150 +/- 15 vs. 143 +/- 14 mmHg and 88 +/- 6 vs. 85 +/- 7 mmHg, p < 0.0001 and p < 0.05, respectively) and high sensititivity C reactive protein (2.8 +/- 1.3 vs. 1.3 +/- 0.7 mg/dl, p < 0.001). High-density lipoprotein (HDL) cholesterol levels were significant greater in Group 1 than Group 2 (p < 0.003). Subgroups of patients with AAA and luminal thrombus showed higher fibrinogen levels (564 +/- 235 vs. 341 +/- 83 mg/dl, p < 0.001) and lower HDL than in controls (46.6 +/- 6.5 vs. 52.1 +/- 7.8 mg/dl, p < 0.01). We did not find any difference in body mass index, or prevalence of coronary and peripheral atherosclerosis between groups. Conversely, we found higher prevalence of carotid atherosclerosis in Group 2 (9% vs. 25%, p < 0.004). CONCLUSION: Our AAA patients had fewer and different risk factors respect to patients with atherosclerosis. Only elevated blood pressure, C reactive protein, and smoking showed a significant association with AAA. Atherosclerosis in other arterial districts did not differ respect to subjects with high cardiovascular risk. Our results confirm the hypothesis that AAA and atherosclerosis are two different pathological entities with different risk profiles.

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.

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.

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.

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.

Longitudinal association between sex hormone levels, bone loss, and bone turnover in elderly men.

Male osteoporosis is an increasingly important health problem. It is known that sex steroid hormones play an important role in regulating bone turnover and bone mass in males as well as in females. However, the exact mechanism of bone loss in men remains unknown. In the present study, 200 elderly men (age range, 55-85 yr) were followed for 4 yr to evaluate the relationships between hormone levels, bone turnover markers, bone mineral density, and rates of bone loss. Femoral and lumbar bone mineral density, bone ultrasound parameters at the os calcis, serum testosterone (T), serum estradiol (E(2)), SHBG levels, and bone turnover markers (urinary crosslaps and bone alkaline phosphatase) were evaluated for each man at enrollment and 4 yr afterward. The free androgen index (FAI) and free estrogen index (FEI) as well as measures of the bioavailable sex hormones [calculated bioavailable E(2) (c-bioE(2)) and T (c-bioT)] were calculated from total hormone levels and SHBG. In the total population, T, c-bioT, c-bioE(2), FAI, and FEI, but not E(2), decreased significantly with age, whereas SHBG increased significantly. Subjects with FEI, c-bioE(2), and E(2) levels below the median showed higher rates of bone loss at the lumbar spine and the femoral neck as well as higher speed-of-sounds decrease at the calcaneus with respect to men with FEI, c-bioE(2), and E(2) levels above the median. Serum bone alkaline phosphatase and urinary crosslaps were significantly higher in men with FEI, c-bioE(2), and E(2) in the lower quartile than in men with FEI, c-bioE(2), and E(2) levels in the higher quartile. No statistically significant differences were observed in relation to T, c-bioT, or FAI levels. Finally, the ratio between E(2) and T, an indirect measure for aromatase activity, increased significantly with age and was higher in normal than in osteoporotic subjects. In conclusion, results from the present study indicate an important role of estrogens, and particularly of the ability to aromatize T to E(2), in the regulation of bone loss and bone metabolism in elderly men.

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.