Shuichi Osaki

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.

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.

Interleukin-6 and tumor necrosis factor-α levels increase in response to maximal exercise in patients with chronic heart failure

Abstract Chronic heart failure (CHF) is characterized by the activation of neurohormones and cytokines. Strenuous exercise causes activation of both systems but the effect of acute bouts of exercise on cytokines is not known in patients with CHF. This study determined whether maximal exercise induces activation of cytokines in CHF. Plasma interleukin-6 (IL-6), tumor necrosis factor (TNF)-α, epinephrine, norepinephrine, and atrial and brain natriuretic peptides (ANP and BNP) were determined before and after symptom-limited cardiopulmonary exercise testing in 80 patients with CHF (LVEF=38±1%, peak V O 2 =18.8±0.5 ml/min/kg) and age-matched 33 controls. Resting IL-6 (Controls vs. CHF: 1.3±0.2 vs. 2.5±0.3 pg/ml, P P r =0.34 and r =0.35, respectively) with logplasma norepinephrine, and were negatively correlated ( r =−0.39 and r =−0.32, respectively) with peak V O 2 . Maximal exercise increased IL-6 and TNF-α both in controls and CHF (all P r =0.63, P r =0.57, P =0.0006) in controls, but not in CHF. ΔTNF-α correlated with ΔANP ( r =0.28, P =0.01) only in CHF. In summary, cytokine activation at rest was associated with high plasma norepinephrine and exercise intolerance. Maximal exercise caused increases in IL-6 and TNF-α concentrations. Sympathetic activation seems to be important for the IL-6 increase during exercise in controls. In CHF, changes in ANP during exercise were associated with the exercise-induced increase in TNF-α, but still unknown mechanisms are involved for the cytokine activation during exercise.

Augmented response in plasma brain natriuretic peptide to dynamic exercise in patients with left ventricular dysfunction and congestive heart failure

Abstract. Kato M, Kinugawa T, Ogino K, Endo A, Osaki S, Igawa O, Hisatome I, Shigemasa C (Tottori University Faculty of Medicine, Yonago, Japan). Augmented response in plasma brain natriuretic peptide to dynamic exercise in patients with left ventricular dysfunction and congestive heart failure. J Intern Med 2000; 248: 309–315.

Catecholamines, Renin-Angiotensin-Aldosterone System, and Atrial Natriuretic Peptide at Rest and During Submaximal Exercise in Patients With Congestive Heart Failure

The aim of this study was to determine the responses of plasma catecholamines, renin-angiotensin-aldosterone (RAA) activity, and plasma atrial natriuretic peptide (ANP) to exercise in patients with congestive heart failure (CHF). Cardiac and neurohormonal responses were assessed during submaximal treadmill exercise testing in 23 patients with CHF (New York Heart Association classes I-III) and 13 control subjects (without CHF). Plasma norepinephrine, epinephrine, renin activity (PRA), angiotensin II (ATII), aldosterone, and ANP were measured at rest and immediately after exercise. Exercise duration was shorter in patients with CHF (control, 10.4 +/- 0.9 minute; CHF, 6.2 +/- 0.7 minute; P < 0.01). Heart rate and blood pressure responses were similar except for the smaller peak heart rate (control, 145 +/- 5 beats per minute; CHF, 129 +/- 4 beats per minute; P < 0.05) and higher systolic blood pressure at recovery stage (control, 122 +/- 4 mm Hg; CHF, 142 +/- 4 mm Hg; P < 0.01) in patients with CHF. At rest, plasma norepinephrine levels were insignificantly higher in patients with CHF (control, 110 +/- 10 pg/mL; CHF, 170 +/- 26 pg/mL; P = 0.09), and ANP levels (control, 40 +/- 5 pg/mL; CHF, 94 +/- 17 pg/mL; P < 0.05) and PRA levels (control, 0.77 +/- 0.11 ng/mL/hr; CHF, 4.33 +/- 1.25 ng/mL/hr; P < 0.05) were significantly higher. There were no differences in peak norepinephrine, epinephrine, or ANP between the two groups. Angiotensin II and aldosterone levels were similar between the two groups, although, in patients with CHF, there was a trend toward higher levels of ATII while at rest (control, 12.4 +/- 1.4 pg/mL; CHF, 20.3 +/- 3.3 pg/mL; P = 0.08) and at peak (control, 20.5 +/- 1.8 pg/mL; CHF, 41.0 +/- 9.4 pg/mL; P = 0.10). Peak values of PRA, ATII, and aldosterone positively correlated with respective resting values of PRA (r = 0.88 ng/mL/hr, P < 0.01), ATII (r = 0.63 pg/mL, P < 0.01), and aldosterone (r = 0.99, P < 0.01). Peak norepinephrine and peak ANP also positively correlated with respective resting values of norepinephrine (r = 0.58 pg/mL, P < 0.05) and ANP (r = 0.94, P < 0.01). Analysis of these results showed that patients with CHF had significantly higher levels of PRA and ANP at rest, and a trend toward augmentation in RAA system activity during exercise with less exercise workload. Basal level of neurohormones seemed to be an important determinant for the degree of exercise-induced neurohormonal activation in patients with CHF.

Responses of plasma norepinephrine and renin-angiotensin-aldosterone system to dynamic exercise in patients with congestive heart failure

BACKGROUND Neurohormonal activation is present and neurohormonal responses to dynamic exercise are altered in congestive heart failure (CHF). Responses of plasma norepinephrine in various degrees of heart failure have been investigated, but the responses of the renin-angiotensin-aldosterone system have not been studied in relation to the severity of CHF. The aim of this study was to determine if the responses of the renin-angiotensin-aldosterone system to exercise are augmented according to the severity of CHF. METHODS AND RESULTS Ventilatory and neurohormonal responses were assessed in 38 patients with CHF (New York Heart Association class: I, 13 patients; II, 14 patients; III, 11 patients) and 11 normal subjects during symptom-limited cardiopulmonary exercise testing. Plasma norepinephrine, renin activity, angiotensin II, and aldosterone were measured at rest and at peak exercise. The increments in neurohormones were divided by peak oxygen consumption, and these ratios (norepinephrine exercise ratio, plasma renin activity-exercise ratio, angiotensin II-exercise ratio, aldosterone-exercise ratio) were compared among groups. Peak oxygen consumption and anaerobic threshold decreased progressively with the severity of CHF. Neurohormonal profiles at rest showed that plasma norepinephrine levels were significantly higher, and the renin-angiotensin-aldosterone system was augmented only in patients with class III CHF. Neurohormones increased during exercise both in patients with CHF and in normal subjects, but patients with class III CHF had significantly higher plasma renin activity (10.11 +/- 2.32 ng/mL/h), angiotensin II (73.9 +/- 14.2 pg/mL), and aldosterone (265.2 +/- 61.1 pg/mL) than did normal subjects. Plasma renin activity-exercise ratio, angiotensin II-exercise ratio, and aldosterone-exercise ratio in patients with class III CHF were significantly higher compared to normal subjects. This augmentation of the renin-angiotensin-aldosterone system was not observed in class I or II patients. Peak plasma norepinephrine levels were not different among normal subjects and subgroups of CHF patients, but the norepinephrine-exercise ratio was significantly higher in classes II and III CHF compared to normal subjects. CONCLUSIONS These data suggest that neurohormonal excitation during exercise increases along with the severity of CHF when normalized for peak exercise level.

Ammonia Response To Constant Exercise: Differences To The Lactate Response

1. We evaluated the plasma ammonia response to constant exercise at different intensities. Ten healthy male volunteers were asked to perform constant exercise for 15 min at five different intensities: 80, 90, 100, 110 and 120% of their ventilatory threshold (VT). Blood concentrations of lactate, ammonia and hypoxanthine were measured during and after exercise.

Effects of Spironolactone on Exercise Capacity and Neurohormonal Factors in Patients with Heart Failure Treated with Loop Diuretics and Angiotensin-Converting Enzyme Inhibitor

1. Treatment with spironolactone is reported to be useful when combined with loop diuretics and an angiotensin-converting enzyme (ACE) inhibitor in severe congestive heart failure (CHF). However, the effects of the addition of spironolactone on exercise capacity and neurohormonal variables have not been demonstrated. This study determined the effects of additive spironolactone on exercise capacity and neurohormonal factors in patients with mild CHF. 2. Oxygen uptake (VO2), plasma norepinephrine (NE), renin activity (PRA), angiotensin II (AII), aldosterone (ALD), and atrial natriuretic peptide (ANP) were measured at rest and after peak exercise in nine patients with CHF (six idiopathic and three ischemic cardiomyopathy; New York Heart Association (NYHA) classes II and III) who were already taking furosemide (mean 29 +/- 5 mg/day) and enalapril (mean 4.7 +/- 0.8 mg/day). Studies were repeated after 16 weeks of treatment with additive single daily dose of 25 mg of spironolactone. In four of nine patients, the exercise test was repeated after a 4-weeks washout of spironolactone. 3. Treatment with spironolactone caused natriuresis, decreased cardiothoracic ratio in chest X-ray (before vs. after treatment: 53.7 +/- 1.2 vs. 50.7 +/- 1.4%, P < 0.01), and improved NYHA functional class. Peak VO2 (17.1 +/- 1.6 vs. 17.5 +/- 2.2 ml/min/kg, NS) and heart rate and blood pressure responses to exercise were not altered. Resting NE (215 +/- 41 vs. 492 +/- 85 pg/ml, P < 0.01) and resting PRA (8.2 +/- 2.3 vs. 16.2 +/- 4.1 ng/ml/hr, P < 0.01) as well as peak NE (1618 +/- 313 vs. 2712 +/- 374 pg/ml, P < 0.01) and peak PRA (12.8 +/- 3.2 vs. 28.1 +/- 11.8 ng/ml/hr, P = 0.17) were augmented after additive spironolactone. ALD and AII were insignificantly increased, and ANP was insignificantly decreased at peak exercise after spironolactone treatment. Spironolactone washout was associated with a trend of the neurohormones to return toward pretreatment values. 4. In conclusion, chronic additive treatment with spironolactone was associated with neurohormonal activation both at rest and during exercise without changing the exercise capacity of patients with mild CHF who were already on loop diuretics and ACE inhibitor therapy.

Effects of the angiotensin-converting enzyme inhibitor alacepril on exercise capacity and neurohormonal factors in patients with mild-to-moderate heart failure.

1. Alacepril is a long‐acting, sulphydryl‐containing angiotensin‐converting enzyme inhibitor. Data are limited regarding the effects of alacepril on exercise tolerance in patients with chronic heart failure (CHF). The aim of the present study was to determine the effects of chronic alacepril treatment on exercise capacity and neurohormones in patients with CHF.

Cardiac and Plasma Catecholamine Responses to Exercise in Patients with Type 2 Diabetes: Prognostic Implications for Cardiac-Cerebrovascular Events

BACKGROUND Patients with diabetes mellitus have an altered exercise plasma catecholamine response, which may be related to the abnormal sympathoadrenal function and autonomic neuropathy. Presence of autonomic neuropathy is associated with poor prognosis, but relationship between exercise plasma catecholamine and prognosis has not been investigated. This study determined if altered plasma catecholamine response to exercise was associated with cardiac-cerebrovascular events. METHODS Forty patients with type 2 diabetes without apparent macrovascular complications and 30 control subjects performed treadmill exercise with serial measurements of plasma norepinephrine and epinephrine. Clinical, exercise, and catecholaminergic variables considered relevant to the cardiac-cerebrovascular events were examined by Cox regression model. Analysis of 24-hour heart rate variability was performed in a subgroup of patients. RESULTS During 7.2 years, 8 patients, but no control subjects, had events (3 myocardial and 5 cerebral infarctions). Compared with Event(-) patients, Event(+) patients had: (1) orthostatic hypotension; (2) lower peak exercise heart rate; (3) lower plasma norepinephrine immediately after exercise; and (4) lower plasma epinephrine at peak exercise. High frequency components in heart rate variability analysis were diminished in Event(+) patients. Multivariate analysis showed that peak heart rate (P = 0.04) and plasma epinephrine at peak exercise (P = 0.03) were independent predictors of subsequent events. CONCLUSIONS These data suggest that chronotropic incompetence and lower plasma epinephrine response to exercise are associated with high risk of cardiac-cerebrovascular events in patients with type 2 diabetes.