Clinical practice guidelines (CPGs) consist of clinical questions (CQs) and corresponding recommendations. Considering the estimation of body of evidence, patients' opinions, and medical economics, ...recommendations can vary depending on the votes of the committee members of CPGs. Taking this into consideration, concerns have already been raised on how financial conflict of interest (COI) potentially influences recommendations. In this study, we developed the third edition of guideline for the management of hyperuricemia and gout. This CPG was composed of seven CQs and recommendations. The direction and strength of the recommendations were determined by votes. There are three CQs. Individual questions asked whether uric acid-lowering-agents (ULAs) could be applied to hyperuricemic patients with chronic kidney disease (CKD) (CQ A), hypertension (CQ B), or heart failure (CQ C) to prevent organ damage. We examined whether the absence (18 members) or presence (8 members) of COIs of committee members could influence the votes. In total, 26 committee members with and without COI have equally determined the direction and strength of recommendations. In CQ A, members without financial COIs and those with financial COI selected conditional recommendation for the use of ULAs in patients with CKD (without COI, 17/18; with COI, 7/8). In CQ B, members without financial COIs and those with financial COI selected conditional recommendation against the use of ULAs in hypertensive patients (without COI, 14/18; with COI, 5/8). In CQ C, members without financial COIs and those with financial COIs have selected conditional recommendation against the use of ULAs in patients suffering from heart failure (without COI, 15/18; with COI, 4/8).We found that members with financial COIs have determined their recommendations in the same direction and strength as those without financial COIs.
Hyperuricemia is often observed in patients with chronic heart failure (CHF), and it is predictive of poor exercise capacity, inflammation and increased mortality. The uric acid (UA)-generating ...enzyme xanthine oxidase (XO) is a major source of reactive oxygen species (ROS) generation, and increased ROS has been accounted for multiple adverse effects in CHF pathophysiology. Therapeutic inhibition of XO with allopurinol reduced serum UA (SUA) levels and showed a range of beneficial effects in CHF with left ventricular (LV) systolic dysfunction. However, it is unclear if UA-lowering therapy by XO inhibition is beneficial in patients with LV diastolic dysfunction. Therefore, we evaluated the effects of the specific XO inhibitor febuxostat on LV diastolic function compared with the uricosuric agent benzbromarone.
The effects of febuxostat and benzbromarone (24 weeks each) were tested in 20 hyperuricemic patients (SUA > 7.0mg/dL) with LV diastolic dysfunction in a double-blind, randomized crossover study design. Both febuxostat and benzbromarone significantly decreased SUA levels (-35% and -41%, respectively, both p<0.01). E/E’ ratio in tissue Doppler imaging improved significantly after febuxostat (-20%, p<0.01) but not after benzbromrone (-6%, ns). BNP decreased by 27% after febuxostat (p=0.07) and by 18% after benzbromarone p=0.26). Urine 8-hydroxydeoxyguanosine (8-OHdG) and serum oxidized LDL levels (both markers of oxidative stress) improved after febuxostat (-36%; p<0.05 and -16%, p<0.001) but not after benzbromarone (both ns). The decrease of E/E’ ratio after febuxostat was significantly correlated with SUA levels at baseline and changes of SUA levels with febuxostat (r=-0.54 and 0.47, respectively, p<0.05 each). It was also correlated with urine 8-OHdG at baseline and changes of serum TNF-α levels (r=-0.67 and 0.51, respectively, p<0.05 each).
XO inhibition with febuxostat might improve LV diastolic function, especially in patients with high SUA levels. This effect may be related to the decreased oxidative stress by febuxostat.
Background Both renal hypouricemia (RHU) and gout are associated with renal dysfunction and urolithiasis. The difference in renal complications associated with RHU and gout, however, has not been ...studied. We characterized the urate metabolism and complications of patients with RHU and compared them with patients with gout. Methods Eighteen patients with RHU who had a serum uric acid (SUA) level <2 mg/dL (10 men and 8 women), 44 patients with gout (44 men) and 16 normouricemic patients (4 men and 12 women) were included. The blood and urinary biochemical data were evaluated. A genetic analysis of uric acid transporter 1 (URAT1) was also conducted in 15 cases with RHU. Results The SUA level of RHU was 0.9±0.5/mg/dl, and the Uur/Ucr and Cur/Ccr were 0.56%±0.14% and 45.7%±18.0%, respectively. A genetic analysis of URAT1 in 15 RHU patients showed that 13 harbored a URAT1 gene mutation, whereas 2 harbored the wild-type gene. The SUA level was significantly lower in RHU patients (n=11) than in either gout patients (n=44) or normouricemic patients (n=16). This reduction was accompanied by the elevation of Cua/Ccr. Urinary beta 2-microglobulin levels were higher in RHU patients than in gout or normouricemia patients. Cua/Ccr correlated with normalized urinary beta 2-microglobulin levels. The prevalence of urolithiasis was 18.2% in RHU cases and 6.8% in gout cases. A homozygous URAT1 mutation was associated with urolithiasis. Conclusion Besides urolithiasis, RHU can be associated with tubular dysfunction, such as elevated urinary beta 2-microglobulin levels.
Hyperuricemia is common in chronic heart failure (CHF), and it is a strong independent marker of prognosis. Upregulated xanthine oxidase (XO) activity and impaired renal excretion have been shown to ...account for increased serum uric acid (UA) levels in CHF. Therapeutic interventions with allopurinol to reduce UA levels by XO inhibition have been shown to be beneficial. Discussions are ongoing whether UA itself is actively involved or it is a mere marker of upregulated XO activity within CHF pathophysiology. Therefore, the aim of this study was to test the effect of lowering UA by uricosuric treatment without XO inhibition on hemodynamic and metabolic characteristics of CHF. Impaired renal excretion of UA was taken into account.
Serum UA (SUA), urinary UA (uUA) excretion, and renal clearance test for UA (Cl(UA)) were measured in 82 patients with CHF. SUA was significantly increased compared with controls of similar age (control, 5.45+/-0.70 mg/dL; New York Heart Association I, 6.48+/-1.70 mg/dL; New York Heart Association II, 7.34+/-1.94 mg/dL; New York Heart Association III, 7.61+/-2.11 mg/dL; P<0.01). Patients with CHF showed lower uUA excretion and Cl(UA). On multivariate analysis, insulin, brain natriuretic peptide (P<0.01), and creatinine levels (P=0.05) showed independent correlation with SUA. The treatment effect of the uricosuric agent benzbromarone was tested in 14 patients with CHF with hyperuricemia in a double-blind, placebo-controlled, randomized crossover study design. Benzbromarone significantly decreased SUA (P<0.01). Brain natriuretic peptide, left ventricular ejection fraction, and dimensions in echocardiographic assessment did not change after benzbromarone therapy. In contrast, fasting insulin (placebo, 18.8+/-8.9 microU/mL; benzbromarone, 11.0+/-6.2 microU/mL; P<0.05), homeostasis model assessment of insulin resistance index (placebo, 5.4+/-2.6; benzbromarone, 3.0+/-1.7; P<0.05), and tumor necrosis factor-alpha (placebo, 2.59+/-0.63 pg/mL; benzbromarone, 2.14+/-0.51 pg/mL; P<0.05) improved after benzbromarone, and the changes in tumor necrosis factor-alpha levels were correlated with reduction of SUA (P<0.05).
These results show that UA lowering without XO inhibition may not have an effect on hemodynamic impairment in CHF pathophysiology. To the extent that these data are correct, this finding suggests that upregulated XO activity rather than UA itself is actively involved in hemodynamic impairment in CHF. Clinical Trial Registration- clinical trials.gov. Identifier: NCT00422318.
Hyperuricemia and lifestyle-related diseases are often comorbid in the same subjects.Therefore, nutrition education is usually included in the educational program for improvement of their life-style. ...In this study, we investigated retrospectively the effect of nutrition education for the patients of dyslipidemia on their serum uric acid level.Forty-three subjects of dyslipidemia were enrolled. We investigated the data of body weight, serum lipid profiles, serum uric acid level and so on for 1 year after the first education exposure. The average times of nutrition education was 2.5. In the analysis of the all subjects, body weight significantly decreased in 3 and 12 months after the first education compared to before. Serum LDL cholesterol level significantly decreased from 150.9±32.6mg/dl (before education) to 139.0±35.7mg/dl (3 months) and 132.1±31.9mg/dl (12months). Serum uric acid level did not decrease by education in all subjects. In the analysis of non-medicated hyperuricemia subjects, serum uric acid level decreased significantly after the education. In the group of body weight loss tends to decrease serum uric acid level compared with the group of body weight increase.In this study, nutrition education for dyslipidemia subjects may be useful for the improvements of the serum uric acid level. The body weight loss might be a good surrogate goal in the education for the improvement of the life style for the decrease of the serum uric acid level.
To evaluate the current status of the management of hypertensive patients in Japan, we investigated 907 treated hypertensive patients (486 females and 421 males; mean age, 66.7 years) followed by ...cardiologists. According to the guidelines for the management of hypertensive patients in Japan in 2000 (JSH-2000), only 41.5% of the subjects achieved the target blood pressure, with a mean systolic blood pressure of 140.0±14.9 mmHg and a mean diastolic blood pressure of 80.0±10.7 mmHg. There were no differences between patients with and without concurrent disease or among age groups (<60, 60-69, 70-79, and 80 years and over) in systolic blood pressure levels achieved. However, the diastolic blood pressure decreased with age, indicating an increase of the pulse pressure. Overall, the prescription rates were: calcium channel blockers (CCBs), 73.0%; angiotensin converting enzyme inhibitors (ACE-inhibitors), 31.3%; angiotensin receptor blockers (ARBs), 18.9%; β-blockers, 16.2%; and diuretics, 10.1%. Although some selection of antihypertensive drugs was based on evidence from previous trials on hypertensive patients with diabetes mellitus, chronic heart failure and renal insufficiency, overall, CCBs were selected in all age groups and in all comorbid conditions. In conclusion, Japanese cardiologists do not appear to consider age and comorbidity when choosing antihypertensive managements. Based on current evidence, the management of hypertension should be individualized, with the blood pressure target level and antihypertensive medications chosen on the basis of age and comorbidity. (Hypertens Res 2002; 25: 717-725)
The present study was designed to determine whether exercise plasma noradrenaline (NA) levels could predict cardiac death in patients with mild heart failure in whom the plasma NA levels were only ...minimally elevated. Treadmill exercise testing with serial measurement of plasma NA and plasma adrenaline were performed in 142 patients with heart failure (New York Heart Association class I-II; age, 58±12 years) and 26 age-matched normal subjects. During a median follow-up of 9.6 years, 27 cardiac deaths occurred among the patients. By univariate Cox proportional hazard analysis, left ventricular end-systolic dimension (p<0.001), age (p<0.01), peak exercise heart rate (p<0.01), exercise plasma NA level (p<0.01) and left ventricular ejection fraction (p<0.001) were identified as significant prognostic markers. In a multivariate analysis, exercise plasma NA level was identified as the most powerful prognostic marker (p<0.001), followed by left ventricular end-systolic dimension and peak exercise heart rate. In addition, from the Kaplan-Meier analysis, patients with a supramedian level of exercise plasma NA concentration (NA ≥840 pg/ml) had a significantly lower survival rate than those with an inframedian level (p<0.01). Exercise plasma NA levels can provide prognostic information in patients with mild heart failure, which suggests an important role of exercise-induced activation of sympathetic nervous system activity in the prognosis of patients with mild heart failure. (Circ J 2002; 66: 261 - 266)
We examined the effects of angiotensin II (Ang II) on inward rectifier K+ currents (IK1) in rat atrial myocytes. 125IAng II-binding assays revealed the presence of both Ang II type 1 (AT1) and type 2 ...(AT2) receptors in atrial membrane preparations. Ang II inhibited IK1 in isolated atrial myocytes with an IC50 of 46 nmol/l. This inhibition was abolished by the AT, antagonist RNH6270 but not at all by the AT2 antagonist PD123319. Treatment of cells with pertussis toxin or a synthetic decapeptide corresponding to the carboxyl-terminus of Gialpha-3 abolished the inhibition by Ang II, indicating the role of a Gi-dependent signaling pathway. Accordingly, Ang II failed to inhibit IK1 in the presence of forskolin, dibutyryl-cAMP or protein kinase A catalytic subunits. In spite of the increased binding capacities for 125IAng II, Ang II failed to affect IKI in cells from spontaneously hypertensive rats (SHR). AT, immunoprecipitation from atrial extracts revealed decreased amounts of Gialpha-2 and Gialpha-3 proteins associated with this receptor in SHR as compared with controls. The reduced coupling of AT, with Gialpha. proteins may underlie the unresponsiveness of atrial IK1 to Ang II in SHR cells.
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