Prednisone lowers serum uric acid levels in patients with decompensated heart failure by increasing renal uric acid clearance.

Clinical studies have shown that large doses of prednisone could lower serum uric acid (SUA) in patients with decompensated heart failure (HF); however, the optimal dose of prednisone and underlying mechanisms are unknown. Thirty-eight patients with decompensated HF were randomized to receive standard HF care alone (n = 10) or with low-dose (15 mg/day, n = 8), medium-dose (30 mg/day, n = 10), or high-dose prednisone (60 mg/day, n = 10), for 10 days. At the end of the study, only high-dose prednisone significantly reduced SUA, whereas low- and medium-dose prednisone and standard HF care had no effect on SUA. The reduction in SUA in high-dose prednisone groups was associated with a significant increase in renal uric acid clearance. In conclusion, prednisone can reduce SUA levels by increasing renal uric acid clearance in patients with decompensated HF.

Spot urine sodium excretion as prognostic marker in acutely decompensated heart failure: the spironolactone effect.

INTRODUCTION: Loop diuretic resistance characterized by inefficient sodium excretion complicates many patients with acutely decompensated heart failure (ADHF). Mineralocorticoid receptor antagonists (MRAs) in natriuretic doses may improve spot urine sodium excretion and outcomes. OBJECTIVE: Our primary aim was to assess the association of high-dose spironolactone with short-term spot urine sodium excretion, and our secondary aim was to determine if this higher short-term spot urine sodium excretion is associated with reduction in the composite clinical outcome (of cardiovascular mortality and/or ADHF hospitalization) event rate at 180 days. METHODS: Single-centre, non-randomized, open-label study enrolling 100 patients with ADHF. Patients were treated with standard ADHF therapy alone (n = 50) or oral spironolactone 100 mg/day plus standard ADHF therapy (n = 50). Spot urine samples were collected at day 1 and day 3 of hospitalization. RESULTS: Spironolactone group had significantly higher spot urine sodium levels compared to standard care group at day 3 (84.13 ± 28.71 mmol/L vs 70.74 ± 34.43 mmol/L, p = 0.04). The proportion of patients with spot urinary sodium <60 mmol/L was lower in spironolactone group at day 3 (18.8 vs 45.7, p = 0.01). In multivariate analysis, spironolactone was independently associated with increased spot urinary sodium and urinary sodium/potassium ratio of >2 at day 3 (both, p < 0.05). Higher spot urine sodium levels were associated with a lower event rate [HR for urinary sodium >100 mmol/L = 0.16 (0.06-0.42), p < 0.01, compared to <60], and provided a significant prognostic gain measured by net reclassification indexes. CONCLUSION: Spot urinary sodium levels >60 mmol/L and urinary sodium/potassium ratio >2 measured at day 3 of hospitalization for ADHF are associated with improved mid-term outcomes. Spironolactone is associated with increased spot urinary sodium and sodium/potassium ratio >2.

Effect of Corticosteroid on Renal Water and Sodium Excretion in Symptomatic Heart Failure: Prednisone for Renal Function Improvement Evaluation Study.

BACKGROUND: Recent evidence indicates that prednisone can potentiate renal responsiveness to diuretics in heart failure (HF). However, the optimal dose of prednisone is not known. METHOD: Thirty-eight patients with symptomatic HF were randomized to receive standard HF care alone (n = 10) or with low-dose (15 mg/d, n = 8), medium-dose (30 mg/d, n = 10), or high-dose prednisone (60 mg/d, n = 10), for 10 days. During this time, we recorded the 24-hour urinary output and the 24-hour urinary sodium excretion, at baseline, on day 5 and day 10. We also monitored the change in the concentration of serum creatinine, angiotensin II, aldosterone, high-sensitive C-reactive protein, tumor necrosis factor-α, interleukin 1ß, and interleukin 6. RESULTS: Low-dose prednisone significantly enhanced urine output. However, the effects of medium- and high-dose prednisone on urine output were less obvious. As for renal sodium excretion, high-dose prednisone induced a more potent natriuresis than low-dose prednisone. Despite the potent diuresis and natriuresis induced by prednisone, serum creatinine, angiotensin II, and aldosterone levels were not elevated. These favorable effects were not associated with an inflammatory suppression by glucocorticoids. CONCLUSIONS: Only low-dose prednisone significantly enhanced urine output. However, high-dose prednisone induced a more potent renal sodium excretion than low-dose prednisone.

The role of albuminuria as a non-invasive marker for congestive acutely decompensated chronic heart failure and the spironolactone effect in elderly Portuguese: a non-randomized trial.

BACKGROUND/OBJECTIVES: Albuminuria is a robust, validated cardiovascular risk factor. It is a simple and widely available test that was shown to be a powerful and independent predictor of prognosis in chronic heart failure. Mineralocorticoid receptor antagonists may reduce the acute and chronic harmful effects of mineralocorticoid receptor activation on the kidney. The objectives of the trial were to compare the effect of spironolactone versus standard acutely decompensated heart failure (ADHF) therapy on albuminuria and to investigate the role of albuminuria as a prognostic marker in patients with ADHF. METHODS: Secondary analysis of a prospective, interventional study including 100 patients with ADHF. Fifty patients were non-randomly assigned to spironolactone 100 mg/day plus standard ADHF therapy (intervention group) or standard ADHF therapy alone (control group). RESULTS: Patients in control group were older, had higher creatinine and urea levels, and had higher proportion of microalbuminuria (all, P < 0.05). Paired comparison of baseline and day 3 log albuminuria within each group, showed a more pronounced decrease in the intervention group (1.79 ± 0.75 to 1.59 ± 0.67, P = 0.003 vs 1.89 ± 0.70 to 1.79 ± 0.74, P = 0.096). In addition, the proportion of patients with normoalbuminuria increased from baseline to day 3 in spironolactone group (20 (40%) to 27 (54%), P < 001), accordingly the number of patients in the micro and macroalbuminuria groups was reduced. Day 1 albuminuria was positively correlated with day 1 N-terminal pro-brain natriuretic peptide (0.260 [0.105-0.758], P = 0.009). CONCLUSIONS: High-dose spironolactone added to standard ADHF therapy is likely to induce a more pronounced albuminuria decrease and a significant reduction in the proportion of micro and macroalbuminuria.

Betaine and secondary events in an acute coronary syndrome cohort.

BACKGROUND: Betaine insufficiency is associated with unfavourable vascular risk profiles in metabolic syndrome patients. We investigated associations between betaine insufficiency and secondary events in acute coronary syndrome patients. METHODS: Plasma (531) and urine (415) samples were collected four months after discharge following an acute coronary event. Death (34), secondary acute myocardial infarction (MI) (70) and hospital admission for heart failure (45) events were recorded over a median follow-up of 832 days. PRINCIPAL FINDINGS: The highest and lowest quintiles of urinary betaine excretion associated with risk of heart failure (p = 0.0046, p = 0.013 compared with middle 60%) but not with subsequent acute MI. The lowest quintile of plasma betaine was associated with subsequent acute MI (p = 0.014), and the top quintile plasma betaine with heart failure (p = 0.043), especially in patients with diabetes (p<0.001). Top quintile plasma concentrations of dimethylglycine (betaine metabolite) and top quintile plasma homocysteine both associated with all three outcomes, acute MI (p = 0.004, <0.001), heart failure (p = 0.027, p<0.001) and survival (p<0.001, p<0.001). High homocysteine was associated with high or low betaine excretion in >60% of these subjects (p = 0.017). Median NT-proBNP concentrations were lowest in the middle quintile of plasma betaine concentration (p = 0.002). CONCLUSIONS: Betaine insufficiency indicates increased risk of secondary heart failure and acute MI. Its association with elevated homocysteine may partly explain the disappointing results of folate supplementation. In some patients, especially with diabetes, elevated plasma betaine also indicates increased risk.

Fadrozole reverses cardiac fibrosis in spontaneously hypertensive heart failure rats: discordant enantioselectivity versus reduction of plasma aldosterone.

Reversal of cardiac fibrosis is a major determinant of the salutary effects of mineralocorticoid receptor antagonists in heart failure. Recently, R-fadrozole was coined as an aldosterone biosynthesis inhibitor, offering an appealing alternative to mineralocorticoid receptor antagonists to block aldosterone action. The present study aimed to evaluate the effects of R- and S-fadrozole on plasma aldosterone and urinary aldosterone excretion rate and to compare their effectiveness vs. the mineralocorticoid receptor antagonist potassium canrenoate to reverse established cardiac fibrosis. Male lean spontaneously hypertensive heart failure (SHHF) rats (40 wk) were treated for 8 wk by sc infusions of low (0.24 mg/kg.d) or high (1.2 mg/kg.d) doses of R- or S-fadrozole or by potassium canrenoate via drinking water (7.5 mg/kg.d). At the high dose, plasma aldosterone levels were decreased similarly by R- and S-fadrozole, whereas urinary aldosterone excretion rate was reduced only by S-fadrozole. In contrast, whereas at the high dose, R-fadrozole effectively reversed preexistent left ventricular interstitial fibrosis by 50% (vs. 42% for canrenoate), S-fadrozole was devoid of an antifibrotic effect. The low doses of the fadrozole enantiomers did not change cardiac fibrosis or plasma aldosterone but similarly reduced urinary aldosterone excretion rate. In conclusion, R-fadrozole may possess considerable therapeutic merit because of its potent antifibrotic actions in the heart. However, the observed discordance between the aldosterone-lowering and antifibrotic effects of the fadrozole enantiomers raises some doubt about the mechanism by which R-fadrozole diminishes cardiac collagen and about the generality of the concept of lowering aldosterone levels to treat the diseased heart.

Effects of calcium supplementation on bone loss and fractures in congestive heart failure.

BACKGROUND: Cross-sectional studies have shown that more than 50% of patients with congestive heart failure (CHF) have decreased bone mineral density (BMD). There is limited knowledge about the longitudinal changes of BMD and how to treat bone loss in patients with CHF. METHODS: The present study was a prospective, longitudinal trial in which 33 male patients with CHF (ejection fraction (EF): 30+/-11%) were assigned to 1000 mg calcium supplementation or no supplementation. BMD was measured at the lumbar spine (LS) and the femoral neck (FN) by dual-energy X-ray absorptiometry at baseline and after 12 months. RESULTS: Osteopenia (LS 33% and FN 36%) and osteoporosis (LS 15% and FN 6%) were frequently seen in these patients; 70% showed impaired renal function, 42% secondary hyperparathyroidism, and 33% hypogonadism. Bone resorption markers were strongly elevated and correlated negatively with the EF. Patients without calcium supplementation revealed a reduction of BMD (LS 1.7% and FN 1.9%) within 12 months. The fracture incidence was 6%. Patients with calcium supplementation also demonstrated a 6% fracture incidence and a decrease in BMD (LS 1.2% and FN 1.6%), which was not significantly different from the untreated group. Loss of BMD at FN was only seen in patients with impaired renal function. CONCLUSIONS: Patients with CHF demonstrate a progressive decrease in BMD when compared with age-matched healthy individuals. Increased bone resorption due to renal insufficiency with consecutive secondary hyperparathyroidism is a main reason for BMD loss in CHF. Calcium supplementation alone cannot sufficiently prevent the decrease in BMD.

Preventing oxidative stress in rats with aldosteronism by calcitriol and dietary calcium and magnesium supplements.

BACKGROUND: Prominent features of the clinical syndrome of congestive heart failure (CHF) include aldosteronism and the presence of oxidative stress. Secondary hyperparathyroidism (SHPT) accompanies aldosteronism due to increased urinary and fecal excretion of Ca. SHPT accounts for intracellular Ca overloading of diverse cells, including peripheral blood mononuclear cells (PBMC), and the appearance of oxidative stress. Parathyroidectomy or a Ca channel blocker each prevent these responses. Herein, we hypothesized calcitriol, or 1,25(OH)2D3, plus a diet supplemented with Ca and Mg (CMD) would prevent SHPT and Ca overloading of PBMC and thereby oxidative stress in these cells in rats receiving aldosterone/salt treatment (ALDOST). METHODS AND RESULTS: In rats with ALDOST for 4 weeks, without or with CMD, we monitored plasma-ionized [Ca]o and parathyroid hormone (PTH), and PBMC cytosolic-free [Ca]i and H2O2 production. Untreated, age- and gender-matched rats served as controls. Compared to controls, ALDOST led to an expected fall in plasma [Ca]o level with accompanying rise in plasma PTH level and intracellular Ca overloading of PBMC and their increased production of H2O2. CMD prevented SHPT and abrogated intracellular Ca overloading of PBMC and their increased H2O2 production. CONCLUSIONS: The appearance of SHPT in aldosteronism, induced by fallen plasma [Ca]o, leads to PTH-mediated Ca overloading of PBMC and their increased production of H2O2. SHPT in rats with aldosteronism can be prevented by calcitriol and a diet supplemented with Ca and Mg. These findings raise the prospect that the SHPT found in CHF could be managed with macro- and micronutrients.

Effects of kaliuretic peptide on sodium and water excretion in persons with congestive heart failure.

Kaliuretic peptide, a 20-amino acid peptide hormone synthesized in the heart, enhances urine flow twofold, whereas atrial natriuretic peptide (ANP) enhances urine flow four- to 11-fold in healthy persons. The present investigation was designed to (1) determine whether kaliuretic peptide may have beneficial diuretic effects in persons with congestive heart failure (CHF), and (2) compare its beneficial effects with ANP in the treatment of CHF. Kaliuretic peptide (100 ng/kg body weight/min) given intravenously for 60 minutes to subjects with New York Heart Association class III CHF increased urine flow fourfold (p <0.001), which was maximal 212 hours after its infusion was stopped. Kaliuretic peptide enhanced sodium excretion threefold in subjects with CHF (p <0.01). Kaliuretic peptide increased the urinary excretion rate of potassium ion and fractional excretion of potassium 3.5- and twofold (p <0.05), respectively. ANP (same concentration) did not significantly enhance urine flow. ANP enhanced sodium excretion two- to sixfold in half of the CHF subjects, whereas it had no effect on sodium excretion in the other half. ANP did not significantly increase fractional excretion of sodium but did increase fractional excretion of potassium (p <0.05) during the first 20 minutes of its infusion. ANP-infused patients with CHF became hypotensive. None became hypotensive secondary to kaliuretic peptide. These data indicate that the diuretic properties of kaliuretic peptide in persons with CHF, as opposed to those of ANP, are not diminished (but rather are increased) compared with their effects in healthy persons. In patients with CHF, kaliuretic peptide causes a natriuresis-a feature not observed in those without sodium retention.

Vessel dilator enhances sodium and water excretion and has beneficial hemodynamic effects in persons with congestive heart failure.

BACKGROUND: Vessel dilator, a 37-amino acid peptide hormone synthesized in the heart, enhances urine flow 4- to 12-fold and sodium excretion 3- to 6-fold in healthy humans. The present investigation was designed to determine whether vessel dilator might have similar beneficial effects in persons with congestive heart failure (CHF). METHODS AND RESULTS: Vessel dilator (100 ng/kg body weight per minute) given intravenously for 60 minutes to NYHA class III CHF subjects increased urine flow 2- to 13-fold, which was still increased (P<0.001) 3 hours after its infusion was stopped. Vessel dilator enhanced sodium excretion 3- to 4-fold in CHF subjects (P<0.01), which was still significantly (P<0.01) elevated 3 hours after infusion. Vessel dilator decreased systemic vascular resistance 24%, pulmonary vascular resistance 25%, pulmonary capillary wedge pressure 33%, and central venous pressure 27% while increasing cardiac output 34%, cardiac index 35%, and stroke volume index 24% without significantly affecting heart rate or pulmonary artery pressure in the CHF subjects. The control CHF patients did not have any changes in the above parameters. CONCLUSIONS: These results indicate that vessel dilator has significant beneficial diuretic, natriuretic, and hemodynamic properties in humans with congestive heart failure.

Salutary effect of Terminalia Arjuna in patients with severe refractory heart failure.

Twelve patients with refractory chronic congestive heart failure (Class IV NYHA), related to idiopathic dilated cardiomyopathy (10 patients); previous myocardial infarction (one patient) and peripartum cardiomyopathy (one patient), received Terminalia Arjuna, an Indian medicinal plant, as bark extract (500 mg 8-hourly) or matching placebo for 2 weeks each, separated by 2 weeks washout period, in a double blind cross over design as an adjuvent to maximally tolerable conventional therapy (Phase I). The clinical, laboratory and echocardiographic evaluation was carried out at baseline and at the end of Terminalia Arjuna and placebo therapy and results were compared. Terminalia Arjuna, compared to placebo, was associated with improvement in symptoms and signs of heart failure, improvement in NYHA Class (Class III vs. Class IV), decrease in echo-left ventricular enddiastolic (125.28 +/- 27.91 vs. 134.56 +/- 29.71 ml/m2; P < 0.005) and endsystolic volume (81.06 +/- 24.60 vs. 94.10 +/- 26.42 ml/m2; P < 0.005) indices, increase in left ventricular stroke volume index (44.21 +/- 11.92 vs. 40.45 +/- 11.56 ml/m2; P < 0.05) and increase in left ventricular ejection fractions (35.33 +/- 7.85 vs. 30.24 +/- 7.13%; P < 0.005). On long term evaluation in an open design (Phase II), wherein Phase I participants continued Terminalia Arjuna in fixed dosage (500 mg 8-hourly) in addition to flexible diuretic, vasodilator and digitalis dosage for 20-28 months (mean 24 months) on outpatient basis, patients showed continued improvement in symptoms, signs, effort tolerance and NYHA Class, with improvement in quality of life.(ABSTRACT TRUNCATED AT 250 WORDS)

[Effects of potassium chloride and triamterene on kaliuresis, natriuresis and diuresis in congestive heart failure]. / Vliianie khloristogo kaliia i triamterena na kaliurez, natriiurez i diurez pri zastoinoi serdechnoi nedostatochnosti.

KCl and triamterene were given to 52 patients (27 males and 25 females with CHF) aged 21-82 years. Large-dose KCl (6 g daily) apparently stimulate kaliuresis, natriuresis and diuresis. As a rule, this is associated with a rise or a fall of plasma potassium concentrations. In the latter case potassium elimination runs more actively and may involve both introduced and body's potassium. As low and moderate doses of KCl (1-4 g daily) showed neither natriuretic nor diuretic effects while enhanced kaliuresis occurred in half of the patients only, did not lower potassium concentrations in plasma they are preferable. Daily treatment with triamterene is characterized by inhibition of its K-retaining action on administration day 2-3. Within first 2 days of triamterene discontinuation all the retained K eliminates from the body. Diuretics-induced metabolic alkalosis decreased intensification of natriuresis and diuresis resultant from large-dose KCl treatment.

Thiamine deficiency in patients with congestive heart failure receiving long-term furosemide therapy: a pilot study.

PURPOSE: To test the hypothesis that long-term furosemide therapy in patients with congestive heart failure (CHF) is associated with clinically significant thiamine deficiency via urinary loss. DESIGN: (1) Biochemical evaluation of thiamine status in hospitalized patients with CHF treated with long-term furosemide and in age-matched control patients. (2) Uncontrolled trial of the effect of intravenous thiamine on cardiac performance in a subset of six patients with CHF. SETTING: General medical ward of a teaching community hospital. PATIENTS: Twenty-three patients with chronic CHF receiving furosemide, and 16 age-matched control patients without heart failure and not taking diuretics. Daily furosemide doses were 80 to 240 mg, and duration of furosemide therapy was 3 to 14 months. Patients with identifiable causes of inadequate thiamine intake, absorption, or utilization or increased metabolic requirements were excluded. INTERVENTION: A 7-day course of intravenous thiamine, 100 mg twice daily, in six consenting patients with CHF. RESULTS: A high thiamine pyrophosphate effect (TPPE), indicating thiamine deficiency, was found in 21 of 23 furosemide-treated patients and in two of 16 controls (p less than 0.001). The mean (+/- SE) TPPE (normal: 0% to 15%) in furosemide-treated and control patients was 27.7 +/- 2.5% and 7.1 +/- 1.6%, respectively (p less than 0.001). Despite the high TPPE, the mean (+/- SE) urinary thiamine excretion in the furosemide-treated patients (n = 18) was inappropriately high (defined as greater than 130 micrograms/g creatinine), 410 +/- 95 micrograms/g creatinine, even in comparison with that in the controls (n = 14): 236 +/- 69 micrograms/g creatinine. In six patients treated with intravenous thiamine, the elevated TPPE decreased to normal, from a mean (+/- SE) of 27.0 +/- 3.8% to 4.5 +/- 1.3% (p less than 0.001), indicating normal thiamine utilization capacity. Left ventricular ejection fraction increased in four of five of these patients studied by echocardiography. CONCLUSIONS: These preliminary findings suggest that long-term furosemide therapy may be associated with clinically significant thiamine deficiency due to urinary loss and contribute to impaired cardiac performance in patients with CHF. This deficit may be prevented or corrected by appropriate thiamine supplements.

Comparative natriuretic and diuretic efficacy of theophylline ethylenediamine and of bendroflumethiazide during long-term treatment with the potent diuretic bumetanide. Permutation trial tests in patients with congestive heart failure.

The additive natriuretic and diuretic effects of theophylline ethylenediamine and of bendroflumethiazide have been compared in permutation trial tests in patients with advanced congestive heart failure receiving long-term treatment with the highly potent diuretic, bumetanide. Statistical analysis of renal water and electrolyte excretion revealed that theophylline ethylenediamine, 400 mg orally, and bendroflumethiazide, 5 mg orally, had very similar effects, both quantitatively and qualitatively. The mechanism of action of the supplementary diuretics is discussed. It is concluded that theophylline ethylenediamine represents a useful alternative to thiazide diuretics when supplementary natriuretic treatment is considered in patients with congestive heart failure during long-term treatment with potent diuretics. The significance of maintaining the potassium balance during such a combined regimen is stressed.

A clinical study of the effect of coenzyme Q on congestive heart failure.

Expecting activation of myocardial energy liberation, coenzyme Q was applied as a treatment to 55 patients suffering from congestive heart failure. Daily doses of 50 to 100 mg of coenzyme Q7 were injected intravenously in 21 cases for 3 to 35 days. Daily doses of 60 mg of coenzyme Q7 were administered perorally in 17 cases for 14 to 196 days. Daily doses of 30 mg of coenzyme Q10 were administered perorally in 17 cases for 7 to 182 days. Clinical effects were evaluated within 4 weeks by the criteria using a scoring method of severity of congestive heart failure which was devised by the authors. In summary a certain effect was found in 20 cases and a mild effect was observed in 29 cases. No significant changes were observed in heart rate and blood pressure. Exanthema appeared in 2 patients of the group of coenzyme Q7 intravenous injection. In conclusion the therapeutic effect of coenzyme Q was thought to be mild but stable in supplement to digitalis therapy in cases of congestive heart failure.