HE4 Serum Levels Are Associated with Heart Failure Severity in Patients With Chronic Heart Failure

AbstractBackgroundThe novel biomarker human epididymis protein 4 (HE4) shows prognostic value in acute heart failure (HF) patients. We measured HE4 levels in patients with chronic heart failure (CHF) and correlated them to HF severity, kidney function, and HF biomarkers, and determined its predictive value.MethodsSerum HE4 levels in patients (n = 101) with stable CHF with reduced left ventricular ejection fraction (LVEF <45%) from the Vitamin D CHF (VitD-CHF) study (NCT01092130) were compared with those in age- and sex-matched healthy control subjects (n = 58) from the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study.ResultsHE4 levels were higher in CHF compared with control subjects (69.2 pmol/L [interquartile range 55.6-93.8] vs 56.1 pmol/L [46.6-69.0]; P < .001) and were higher with increasing New York Heart Association functional class. Levels were associated with HF risk factors, including age, gender, diabetes, smoking and N-terminal prohormone of B-type natriuretic peptide (NT-proBNP). HE4 demonstrated strong associations with kidney function and HF fibrosis biomarkers. In a multivariable model, we identified creatinine, NT-proBNP, galectin-3, high-sensitive troponin T, and smoking as factors associated with HE4. Independently from these factors, HE4 levels predicted death and HF rehospitalization (5-year follow-up, hazard ratio 3.8; confidence interval 1.31–11.1; P = .014).ConclusionsHE4 levels are increased in CHF, correlate with HF severity and kidney function, and predict HF outcome

Renal Handling of Galectin-3 in the General Population, Chronic Heart Failure, and Hemodialysis

Background-Galectin-3 is a biomarker for prognostication and risk stratification of patients with heart failure (HF). It has been suggested that renal function strongly relates to galectin-3 levels. We aimed to describe galectin-3 renal handling in HF. Methods and Results-In Sprague-Dawley rats, we infused galectin-3 and studied distribution and renal clearance. Furthermore, galectin-3 was measured in urine and plasma of healthy controls, HF patients and hemodialysis patients. To mimic the human situation, we measured galectin-3 before and after the artificial kidney. Infusion in rats resulted in a clear increase in plasma and urine galectin-3. Plasma galectin-3 in HF patients (n=101; mean age 64 years; 93% male) was significantly higher compared to control subjects (n=20; mean age 58 years; 75% male) (16.6 ng/mL versus 9.7 ng/mL, P Conclusions-In this small cross-sectional study, we report that urine levels of galectin-3 are not increased in HF patients, despite substantially increased plasma galectin-3 levels. The impaired renal handling of galectin-3 in patients with HF may explain the described relation between renal function and galectin-3 and may account for the elevated plasma galectin-3 in HF

New roles for renin and prorenin in heart failure and cardiorenal crosstalk

The renin-angiotensin-aldosterone-system (RAAS) plays a central role in the pathophysiology of heart failure and cardiorenal interaction. Drugs interfering in the RAAS form the pillars in treatment of heart failure and cardiorenal syndrome. Although RAAS inhibitors improve prognosis, heart failure–associated morbidity and mortality remain high, especially in the presence of kidney disease. The effect of RAAS blockade may be limited due to the loss of an inhibitory feedback of angiotensin II on renin production. The subsequent increase in prorenin and renin may activate several alternative pathways. These include the recently discovered (pro-) renin receptor, angiotensin II escape via chymase and cathepsin, and the formation of various angiotensin subforms upstream from the blockade, including angiotensin 1–7, angiotensin III, and angiotensin IV. Recently, the direct renin inhibitor aliskiren has been proven effective in reducing plasma renin activity (PRA) and appears to provide additional (tissue) RAAS blockade on top of angiotensin-converting enzyme and angiotensin receptor blockers, underscoring the important role of renin, even (or more so) under adequate RAAS blockade. Reducing PRA however occurs at the expense of an increase plasma renin concentration (PRC). PRC may exert direct effects independent of PRA through the recently discovered (pro-) renin receptor. Additional novel possibilities to interfere in the RAAS, for instance using vitamin D receptor activation, as well as the increased knowledge on alternative pathways, have revived the question on how ideal RAAS-guided therapy should be implemented. Renin and prorenin are pivotal since these are at the base of all of these pathways

Vitamin D supplementation and testosterone concentrations in male human subjects

ObjectiveA possible association between serum 25-hydroxyvitamin D and testosterone levels has been reported; however, contradictory results have emerged. DesignTo investigate a causal link between vitamin D and testosterone status, we studied the effect of vitamin D supplementation on serum testosterone concentrations in three independent intervention studies including male patients with heart failure (study 1), male nursing home residents (study 2) and male non-Western immigrants in the Netherlands (study 3). MethodsIn study 1, 92 subjects were randomized to either vitamin D (2000IU cholecalciferol daily) or control. Blood was drawn at baseline, after 3 and 6weeks. In study 2, 49 vitamin D deficient subjects received either vitamin D (600IU daily) or placebo. Blood was drawn at baseline, after 8 and 16weeks. In study 3, 43 vitamin D deficient subjects received either vitamin D (1200IU daily) or placebo. Blood was drawn at baseline, after 8 and 16weeks. Serum 25-hydroxyvitamin D levels were measured using LC-MS/MS or radioimmunoassay. Testosterone levels were measured using a 2nd generation immunoassay. ResultsSerum 25-hydroxyvitamin D levels significantly increased in all treatment groups (median increase of 27, 30 and 36nmol/l in studies 1, 2 3, respectively) but not in the control groups. The documented increase in 25-hydroxyvitamin D levels, however, did not affect mean testosterone concentrations at the end of the study (median increase of 0, 05 and 0nmol/l in studies 1, 2 and 3, respectively). ConclusionsIn this post hoc analysis of three small clinical trials of limited duration in men with normal baseline testosterone concentrations, vitamin D supplementation was not associated with an increase in circulating testosterone concentration

Vitamin D supplementation and testosterone concentrations in male human subjects

ObjectiveA possible association between serum 25-hydroxyvitamin D and testosterone levels has been reported; however, contradictory results have emerged.DesignTo investigate a causal link between vitamin D and testosterone status, we studied the effect of vitamin D supplementation on serum testosterone concentrations in three independent intervention studies including male patients with heart failure (study 1), male nursing home residents (study 2) and male non-Western immigrants in the Netherlands (study 3).MethodsIn study 1, 92 subjects were randomized to either vitamin D (2000IU cholecalciferol daily) or control. Blood was drawn at baseline, after 3 and 6weeks. In study 2, 49 vitamin D deficient subjects received either vitamin D (600IU daily) or placebo. Blood was drawn at baseline, after 8 and 16weeks. In study 3, 43 vitamin D deficient subjects received either vitamin D (1200IU daily) or placebo. Blood was drawn at baseline, after 8 and 16weeks. Serum 25-hydroxyvitamin D levels were measured using LC-MS/MS or radioimmunoassay. Testosterone levels were measured using a 2nd generation immunoassay.ResultsSerum 25-hydroxyvitamin D levels significantly increased in all treatment groups (median increase of 27, 30 and 36nmol/l in studies 1, 2 3, respectively) but not in the control groups. The documented increase in 25-hydroxyvitamin D levels, however, did not affect mean testosterone concentrations at the end of the study (median increase of 0, 05 and 0nmol/l in studies 1, 2 and 3, respectively).ConclusionsIn this post hoc analysis of three small clinical trials of limited duration in men with normal baseline testosterone concentrations, vitamin D supplementation was not associated with an increase in circulating testosterone concentrations.</p

Vitamin D supplementation and testosterone concentrations in male human subjects

ObjectiveA possible association between serum 25-hydroxyvitamin D and testosterone levels has been reported; however, contradictory results have emerged. DesignTo investigate a causal link between vitamin D and testosterone status, we studied the effect of vitamin D supplementation on serum testosterone concentrations in three independent intervention studies including male patients with heart failure (study 1), male nursing home residents (study 2) and male non-Western immigrants in the Netherlands (study 3). MethodsIn study 1, 92 subjects were randomized to either vitamin D (2000IU cholecalciferol daily) or control. Blood was drawn at baseline, after 3 and 6weeks. In study 2, 49 vitamin D deficient subjects received either vitamin D (600IU daily) or placebo. Blood was drawn at baseline, after 8 and 16weeks. In study 3, 43 vitamin D deficient subjects received either vitamin D (1200IU daily) or placebo. Blood was drawn at baseline, after 8 and 16weeks. Serum 25-hydroxyvitamin D levels were measured using LC-MS/MS or radioimmunoassay. Testosterone levels were measured using a 2nd generation immunoassay. ResultsSerum 25-hydroxyvitamin D levels significantly increased in all treatment groups (median increase of 27, 30 and 36nmol/l in studies 1, 2 3, respectively) but not in the control groups. The documented increase in 25-hydroxyvitamin D levels, however, did not affect mean testosterone concentrations at the end of the study (median increase of 0, 05 and 0nmol/l in studies 1, 2 and 3, respectively). ConclusionsIn this post hoc analysis of three small clinical trials of limited duration in men with normal baseline testosterone concentrations, vitamin D supplementation was not associated with an increase in circulating testosterone concentrations

Long-term changes in renal function and perfusion in heart failure patients with reduced ejection fraction

Little is known about the natural course of renal function and renal hemodynamics in heart failure patients with reduced ejection fraction (HFREF).We prospectively studied effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) in 73 HFREF patients with I-125-iothalamate/I-131-hippuran clearances with a mean follow-up of 34.6 +/- A 4.4 months. Fifteen percent were female, with age 58 +/- A 12 years and left ventricular ejection fraction (LVEF) 29 +/- A 10 %. Baseline GFR was 81 +/- A 23 mL/min/1.73 m(2) and declined 0.6 +/- A 4.7 mL/min/1.73 m(2) per year. Baseline ERPF was 292 +/- A 83 mL/min/1.73 m(2) and declined 4.3 +/- A 19 mL/min/1.73 m(2) per year. Of the baseline variables, older age and high urinary kidney injury molecule-1 were the only variables associated with GFR decline (

Effect of additive renin inhibition with aliskiren on renal blood flow in patients with Chronic Heart Failure and Renal Dysfunction (Additive Renin Inhibition with Aliskiren on renal blood flow and Neurohormonal Activation in patients with Chronic Heart Failure and Renal Dysfunction)

AIMS: We examined the effect of the renin inhibitor, aliskiren, on renal blood flow (RBF) in patients with heart failure with reduced ejection fraction (HFREF) and decreased glomerular filtration rate (GFR). Renal blood flow is the main determinant of GFR in HFREF patients. Both reduced GFR and RBF are associated with increased mortality. Aliskiren can provide additional renin-angiotensin-aldosterone system inhibition and increases RBF in healthy individuals. METHODS AND RESULTS: Patients with left ventricular ejection fraction ≤45% and estimated GFR 30 to 75 mL/min per 1.73 m(2) on optimal medical therapy were randomized 2:1 to receive aliskiren 300 mg once daily or placebo. Renal blood flow and GFR were measured using radioactive-labeled (125)I-iothalamate and (131)I-hippuran at baseline and 26 weeks. After 41 patients were included, the trial was halted based on an interim safety analysis showing futility. Mean age was 68 ± 9 years, 82% male, GFR (49 ± 16 mL/min per 1.73 m(2)), RBF (294 ± 77 mL/min per 1.73 m(2)), and NT-proBNP 999 (435-2040) pg/mL. There was a nonsignificant change in RBF after 26 weeks in the aliskiren group compared with placebo (-7.1 ± 30 vs +14 ± 54 mL/min per 1.73 m(2); P = .16). However, GFR decreased significantly in the aliskiren group compared with placebo (-2.8 ± 6.0 vs +4.4 ± 9.6 mL/min per 1.73 m(2); P = .01) as did filtration fraction (-2.2 ± 3.3 vs +1.1 ± 3.1%; P = .01). There were no significant differences in plasma aldosterone, NT-proBNP, urinary tubular markers, or adverse events. Plasma renin activity was markedly reduced in the aliskiren group versus placebo throughout the treatment phase (P = .007). CONCLUSIONS: Adding aliskiren on top of optimal HFREF medical therapy did not improve RBF and was associated with a reduction of GFR and filtration fraction