Katsunori Ishida

Uric Acid-Lowering Treatment With Benzbromarone in Patients With Heart Failure A Double-Blind Placebo-Controlled Crossover Preliminary Study

Background— 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. Methods and Results— Serum UA (SUA), urinary UA (uUA) excretion, and renal clearance test for UA (ClUA) 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 ClUA. 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 μU/mL; benzbromarone, 11.0±6.2 μU/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-α (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-α levels were correlated with reduction of SUA ( P <0.05). Conclusions— 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][1]. Received March 26, 2009; accepted November 3, 2009. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00422318&atom=%2Fcirchf%2F3%2F1%2F73.atomBackground—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. Methods and Results—Serum UA (SUA), urinary UA (uUA) excretion, and renal clearance test for UA (ClUA) 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 ClUA. 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 &mgr;U/mL; benzbromarone, 11.0±6.2 &mgr;U/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-&agr; (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-&agr; levels were correlated with reduction of SUA (P<0.05). Conclusions—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—clinicaltrials.gov. Identifier: NCT00422318.

Appropriate Use of Nasal Continuous Positive Airway Pressure Decreases Elevated C-Reactive Protein in Patients With Obstructive Sleep Apnea

BACKGROUND C-reactive protein (CRP) is an important risk factor for cardiovascular disease. Furthermore, it has been reported that levels of CRP are increased in patients with obstructive sleep apnea (OSA). The aim of this study was to examine the effects of long-term therapy with nasal continuous positive airway pressure (nCPAP) on CRP levels and to investigate whether compliance with nCPAP therapy more effectively attenuated markers of systemic inflammation in patients with OSA. METHODS AND RESULTS Fifty-five patients (mean [+/- SEM] age, 55 +/- 2 years; 44 male patients, 11 female patients) with newly diagnosed moderate-to-severe OSA (apnea-hypopnea index > 20 events/h) were studied before and after 6 months of nCPAP treatment. There was a significant reduction in CRP levels after nCPAP therapy (before nCPAP therapy, 0.23 +/- 0.03 mg/dL; after nCPAP therapy, 0.17 +/- 0.02 mg/dL; p < 0.01). Additionally, we divided these patients into two groups based on adherence to nCPAP therapy. A group of patients using nCPAP > 4 h/d and > 5 d/wk were designated as the good compliance group. The decrease in CRP concentration was significant (before nCPAP therapy, 0.23 +/- 0.04 mg/dL; after nCPAP therapy, 0.16 +/- 0.03 mg/dL; p < 0.05) in the good compliance group but not in the poor compliance group (before nCPAP therapy, 0.24 +/- 0.05 mg/dL; after nCPAP therapy, 0.20 +/- 0.05 mg/dL; p = 0.21). Furthermore, we divided those patients into a high CRP group (>/= 0.2 mg/dL) and a normal CRP group (< 0.2 mg/dL) before nCPAP therapy. The significant decrease in CRP levels in the good compliance group was evident only in those patients with an initially elevated CRP level (before nCPAP therapy, 0.48 +/- 0.08 mg/dL; after nCPAP therapy, 0.29 +/- 0.06 mg/dL; p < 0.05). CONCLUSION Appropriate use of nCPAP in patients with OSA may be required to decrease elevated CRP levels, with possible implications for cardiovascular morbidity and mortality.

Uric Acid-Lowering Treatment With Benzbromarone in Patients With Heart FailureCLINICAL PERSPECTIVE

Background— 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. Methods and Results— Serum UA (SUA), urinary UA (uUA) excretion, and renal clearance test for UA (ClUA) 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 ClUA. 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 μU/mL; benzbromarone, 11.0±6.2 μU/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-α (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-α levels were correlated with reduction of SUA ( P <0.05). Conclusions— 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][1]. Received March 26, 2009; accepted November 3, 2009. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00422318&atom=%2Fcirchf%2F3%2F1%2F73.atomBackground—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. Methods and Results—Serum UA (SUA), urinary UA (uUA) excretion, and renal clearance test for UA (ClUA) 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 ClUA. 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 &mgr;U/mL; benzbromarone, 11.0±6.2 &mgr;U/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-&agr; (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-&agr; levels were correlated with reduction of SUA (P<0.05). Conclusions—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—clinicaltrials.gov. Identifier: NCT00422318.

Analysis of lifestyle and behavioral characteristics in Meniere's disease patients and a control population.

A questionnaire was devised to quantify and measure four categories: the behavioral characteristics of Type A, self-restraint and escape; the causes of anxiety; means of relaxation; and symptoms incidental to anxiety. Questionnaire analysis was performed in patients (n=60) with Ménières disease and in a control population (nA questionnaire was devised to quantify and measure four categories: the behavioral characteristics of Type A, self-restraint and escape; the causes of anxiety; means of relaxation; and symptoms incidental to anxiety. Questionnaire analysis was performed in patients (n = 60) with Menieres disease and in a control population (n = 936). It was statistically proven that the patient group possessed a stress-causative tendency in behavioral characteristics, felt stronger anxiety and showed more severe symptoms owing to this anxiety. Since the level of anxiety highly correlates with the score of behavioral characteristics and also with severity of symptoms, it seems likely that behavioral characteristics produce the anxiety, which, in turn, results in various symptoms of autonomic nervous disorders. A tendency towards stress-causative behavioral characteristics in Menieres disease patients may be important in the genesis of endolymphatic hydrops.

Serum adiponectin levels and lifestyle factors in Japanese men

Adiponectin plays an important role in the development of various lifestyle-related diseases such as obesity, hypertension, type II diabetes mellitus, hyperlipidemia, and metabolic syndrome, leading to the development of heart and vascular diseases. However, the determinants that affect circulating adiponectin levels, including lifestyle factors, have still not been thoroughly investigated, in a general male population in particular. A total of 109 healthy Japanese male subjects (mean age, 55 ± 14 years) with constant lifestyles were enrolled. All were on no medication. Fasting serum adiponectin levels were measured with an enzyme-linked immunosorbent assay. Each subjects lifestyle was assessed by the self-administered Breslow Questionnaire (a well-established method to estimate various lifestyles) with minor modifications. Partial correlation analysis for serum adiponectin levels, after controlling age and all lifestyle factors, revealed a significant and independent negative correlation between serum adiponectin levels and body mass index (BMI) (r = −0.222, P = 0.025), and a significant and independent positive correlation between serum adiponectin levels and sleep duration (r = 0.252, P = 0.011). No significant correlations were observed between adiponectin and other lifestyle factors. These data suggest that increased BMI and shorter sleep duration may be significant independent risks for low serum adiponectin levels in healthy males. Therefore, these factors may be intervention targets to modulate adiponectin to its proper levels for the prevention of cardiovascular disorders.

Recurrent extrusion of cochlear implant at an interval of 5 years.

Objective To describe two different types of device extrusion occurring in the same patient 1 and 6 years after cochlear implantation and to discuss the relation between the two extrusions and problems of cochlear implantation in patients with chronic suppurative otitis media. Study Design Retrospective case review. Setting Tertiary referral center. Patient and Interventions The patient was a 52-year-old man with profound hearing loss in the right ear caused by chronic otitis media and deafness in the left ear caused by removal of an acoustic neuroma. Surgery for cleaning the tympanic cavity and reconstruction of the bony canal after previous radical mastoidectomy was performed in the right ear first. One year later, cochlear implantation was performed in this ear. Results One year after implantation, the anterior edge of the internal device of cochlear implant was exposed along the skin incision. This site was stable after corrective surgery. Five years after this operation, however, the posterior edge of the internal device extruded, accompanied by infection around the device. Conclusion The two extrusions occurred with a long interval in between and at two different sites. The first extrusion occurred along the skin incision, and the second extrusion occurred away from the skin incision with infection around the device. The authors assumed that the first and the second extrusion occurred independently; the first extrusion was caused by insufficient blood supply resulting from scar formation from repeated mastoid operations and by pressure on the skin from the internal and external devices, and the second extrusion was caused by proliferated tissue pushing the device upward and against the skin as a result of chronic middle ear infection. The clinical course indicates that sufficiently long follow-up periods are needed to determine the usefulness of the prevention techniques for cochlear implantation in patients with chronic suppurative otitis media.

Autoperipheral blood mononuclear cell transplantation improved giant ulcers due to chronic arteriosclerosis obliterans

We report the case of a 74-year-old man with Fontaine stage IV chronic arteriosclerosis obliterans who had been suffering from inveterate giant skin ulcers on the dorsum and heel of the right foot. As conventional medical treatments had not improved these ulcers and surgical treatment was considered unfeasible, amputation of the right lower limb below the knee appeared to represent the only option. The patient was admitted to Tottori University Hospital to attempt a new angiogenic therapy using auto-mononuclear cell transplantation to avoid amputation. On admission, neither right ankle blood pressure nor transcutaneous partial pressure of oxygen at the right toe were detectable. The patient had a history of multiple cerebral infarctions, and collection of mononuclear cells from bone marrow was considered too difficult, so collection of peripheral blood mononuclear cells was selected. Transcutaneous partial pressure of oxygen and skin temperature in the treated limb started to improve from 2 weeks after implantation. Ulcer size was recognizably reduced by 1 month after treatment. Partial auto-skin implantation on the right heel was performed 2 months after treatment, and the giant skin ulcer was finally completely covered. No adverse effects were noted during follow-up lasting 1 year. These results suggest that peripheral blood mononuclear cell implantation may offer a suitable alternative rescue therapy for patients with critical limb ischemia whose general condition is not good.

Discharge use of carvedilol is associated with higher survival in Japanese elderly patients with heart failure regardless of left ventricular ejection fraction.

Abstract: Previous clinical trials have proven beneficial effects of beta-blockers in patients with heart failure (HF) with reduced ejection fraction (EF). However, those studies excluded elderly patients from the subjects or included only a small number of them. We assessed whether beta-blocker treatment with carvedilol improves survival in elderly patients with HF regardless of left ventricular EF (LVEF). We retrospectively analyzed a total of 189 patients older than 75 years who were hospitalized with HF from January 2004 to December 2010. Of these, 84 patients (44%) had been treated with carvedilol at discharge. Patients treated with carvedilol were younger, were less likely to have chronic obstructive pulmonary disease, and had lower LVEF compared with those without carvedilol (all P < 0.05). During the median follow-up of 2.5 years after discharge, 92 patients died. Cox hazard analysis showed that, even after adjustment for covariates, carvedilol significantly decreased all-cause mortality in this cohort (P < 0.01). Furthermore, a beneficial effect on outcome was found in patients with reduced (LVEF ⩽ 40%) and preserved (LVEF > 40%) EF (all P < 0.05). In conclusion, Beta-blockers may provide beneficial effects on Japanese elderly patients with HF regardless of LVEF.

Tortuosity of the internal carotid artery — report of three cases and MR-angiography imaging

Three cases of a tortuous internal carotid artery bulging the lateral pharyngeal wall that caused a persistent throat abnormal sensation were presented. Magnetic resonance angiography was non-invasive and useful for establishing its diagnosis. Otolaryngologists should recognize this anomaly, because it may cause a fatal hemorrhage during surgical procedures on the pharynx.

Effects of Cilnidipine on Serum Uric Acid Level and Urinary Nitrogen Monoxide Excretion in Patients with Hypertension

The effects of cilnidipine on the serum uric acid level and urinary NO excretion in hypertensive patients were investigated. Blood and urine samples of 16 hypertensive outpatients were collected before and 2 months after cilnidipine therapy (10 mg). The serum uric acid level decreased significantly after cilnidipine treatment, while the uric acid–creatinine clearance ratio was unaffected. The cilnidipine medication produced a significant increase in urinary NO excretion, although amlodipine did not change it significantly. Therefore, cilnidipine has a profound antihypertensive effect and may reduce the serum uric acid level and increase NO production in the kidney.