Yoshiharu Kinugasa

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.

Multidisciplinary intensive education in the hospital improves outcomes for hospitalized heart failure patients in a Japanese rural setting

BackgroundHeart failure (HF) patients living in rural areas have a lack of HF knowledge and poor self-care because of limited medical care access. Multidisciplinary education to improve self-care behavior is indispensable for such patients. The present study evaluated whether intensive inpatient education improved outcomes of hospitalized HF patients in a Japanese rural setting.MethodsAn inpatient HF management program based on multidisciplinary team intervention was applied to hospitalized HF patients in a Japanese rural area. We defined patients treated within the program from May 2009 to April 2011 as the intervention group (n = 144), and those treated with the usual care from May 2006 to April 2009 as the usual care group (n = 133). The composite endpoints of HF hospitalization and all-cause mortality were compared between the two groups.ResultsCompared with patients in the usual care group, those in the intervention group more often received the optimal interventions such as discharge use of β-blockers, cardiac rehabilitation, pre-discharge diagnostic tests, and multidisciplinary intensive education including nurse-led patient education, pharmacist’s medication teaching, and dietitian’s nutritional guidance (all P < 0.05). The incidence of the composite endpoints significantly decreased after introducing the program (P < 0.001). Among a number of interventions, multidisciplinary intensive education was the most effective intervention to improve the primary outcome (P < 0.001).ConclusionsMultidisciplinary intensive education is a key strategy for helping improve the outcome for Japanese HF patients in a rural setting. Our data may give a positive impact on the improvement of healthcare system in Japan.

Signaling pathway and chronotropic action of parathyroid hormone in isolated perfused rat heart.

Parathyroid hormone (PTH) activates both adenylyl cyclase and phospholipase C via the PTH-1 receptor. We previously reported that PTH increased heart rate and that this effect was mediated via the pacemaker current (I f ). However, it has been reported that PTH exerts its chronotropic effect via an interaction with adrenergic receptors or via L-type calcium channels. Thus, the objective of the study was to elucidate the exact mechanism of the chronotropic effect of PTH. We tested whether its chronotropic effects could be abolished by inhibitors of the following systems in isolated perfused rat hearts: &agr;-adrenergic (prazosin); &bgr;-adrenergic (propranolol); angiotensin II (CV11974); endothelin-1 (TAK044); calcium channel (verapamil); adenylyl cyclase (miconazole); phospholipase C (U73122) or I f (CsCl). In addition, we measured the cyclic adenosine monophosphate level of the heart after PTH administration. Whereas prazosin, propranolol, CV11974, TAK044, verapamil, and U73122 did not inhibit the chronotropic effect of PTH, CsCl or miconazole suppressed it significantly. PTH increased the cyclic adenosine monophosphate level of the atrium but not the left ventricle. These results indicate that the chronotropic actions of PTH are mediated via selective activation of adenylyl cyclase to increase the I f current.

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.

Home telemonitoring study for Japanese patients with heart failure (HOMES-HF): protocol for a multicentre randomised controlled trial.

Introduction Despite the encouraging results from several randomised controlled trials (RCTs) and meta-analyses, the ability of home telemonitoring for heart failure (HF) to improve patient outcomes remains controversial as a consequence of the two recent large-scale RCTs. However, it has been suggested that there is a subgroup of patients with HF who may benefit from telemonitoring. The aim of the present study was to investigate whether an HF management programme using telemonitoring could improve outcomes in patients with HF under the Japanese healthcare system. Methods and analysis The Home Telemonitoring Study for Japanese Patients with Heart Failure (HOMES-HF) study is a prospective, multicentre RCT to investigate the effectiveness of home telemonitoring on the primary composite endpoint of all-cause death and rehospitalisation due to worsening HF in recently admitted HF patients (aged 20 and older, New York Heart Association classes II–III). The telemonitoring system is an automated physiological monitoring system including body weight, blood pressure and pulse rate by full-time nurses 7 days a week. Additionally, the system was designed to make it a high priority to support patients self-care instead of an early detection of HF decompensation. A total sample size of 420 patients is planned according to the Schoenfeld and Richter method. Eligible patients are randomly assigned via a website to either the telemonitoring group or the usual care group by using a minimisation method with biased-coin assignment balancing on age, left ventricular ejection fraction and a history of ischaemic heart disease. Participants will be enrolled until August 2013 and followed until August 2014. Time to events will be estimated using the Kaplan-Meier method, and HRs and 95% CIs will be calculated using the Cox proportional hazards models with stratification factors. Trial Registration: The study is registered at UMIN Clinical Trials Registry (UMIN000006839).

Spironolactone, not furosemide, improved insulin resistance in patients with chronic heart failure

BACKGROUND/OBJECTIVES Insulin resistance plays an important role in the pathophysiology in chronic heart failure (CHF). Diuretics generally have harmful effects on glucose metabolism, however, the effect of mineral corticoid receptor blockers on insulin resistance in CHF is unclear. This study aimed to evaluate the effects of the aldosterone blocker spironolactone, in comparison with furosemide, on insulin resistance in CHF patients. METHODS The effect of spironolactone (25mg/day) and furosemide (20mg/day) on IR for 16 weeks each was analyzed in 16 CHF patients using a double-blind, placebo-controlled, randomized cross-over study design. RESULTS Plasma BNP and left ventricular ejection fraction were improved with both treatments (furosemide: p=0.02 and p=0.009, respectively, spironolactone: p=0.03 and p=0.007, respectively). Fasting plasma glucose was not changed; however, plasma insulin levels decreased and insulin sensitivity (by homeostasis model assessment: HOMA-IR) improved with spironolactone as compared to furosemide (p<0.0005). TNF-α, IL-6 and MCP-1 decreased with spironolactone (p=0.002, p=0.02 and p=0.02 vs. baseline, respectively), but not with furosemide. Matrix metalloproteinase (MMP)-2 and MMP-9 were decreased with spironolactone (p=0.003 and p=0.04 vs. baseline, respectively), but not furosemide. Changes in TNF-α, IL-6 and MCP-1 levels after spironolactone treatment were significantly correlated with changes in HOMA-IR (r=0.61, r=0.55 and r=0.65, respectively; p=0.01, p=0.03 and p=0.01, respectively). Furthermore, changes in MMP-2 and MMP-9 levels were significantly correlated with changes in HOMA-IR (r=0.58 and r=0.58, respectively; p=0.02 and p=0.02, respectively). CONCLUSIONS Spironolactone, not furosemide, improved insulin resistance in CHF patients probably by the inhibition of inflammatory cytokines and MMPs.

Clinical Scenario 1 Is Associated With Winter Onset of Acute Heart Failure

BACKGROUND Several reports have evaluated the association between seasonal variation and acute heart failure (AHF) onset. Cold weather may induce AHF, but the clinical characteristics of patients susceptible to AHF during winter have not been established. Clinical Scenario (CS) is used in the early clinical management of AHF, so we investigated the relationship between CS classification and winter onset of AHF in Japan. METHODS AND RESULTS We enrolled 582 patients hospitalized for AHF and compared the frequency of AHF among the 4 seasons in each CS group to clarify the clinical characteristics of the winter onset group. Significant increase of AHF during winter was seen in CS1 (systolic blood pressure [SBP] (>140 mmHg) (P=0.01) but not in CS2 (SBP ≥ 100 and ≤ 140 mmHg) or CS3 (SBP <100 mmHg). CS1 patients were divided into winter and other season admission groups. In multivariate analysis, only lack of loop diuretic use was associated with winter admission of CS1 patients (odds ratio 0.562, 95% confidence interval: 0.256-0.798, P=0.006). CONCLUSIONS Winter predominance of AHF was seen only in CS1, and lack of loop diuretic use was a risk factor for winter onset. Future studies are necessary to confirm whether loop diuretics are useful in preventing AHF with CS1 in winter.

The challenge of frailty and sarcopenia in heart failure with preserved ejection fraction.

Frailty is a clinical state in which there is an increase in an individuals vulnerability for developing increased dependency and/or mortality when exposed to stressors. Frailty is often accompanied by heart failure with preserved ejection fraction (HFpEF), and frailty is likely to affect its clinical features and outcomes. Frail patients with HFpEF are frequently associated with sarcopenia (ie, muscle loss and weakness), which is a major component of the pathophysiology of frailty. Sarcopenia is a systemic skeletal muscle disease that impairs the function of limb skeletal muscles, as well as respiratory muscles, and this results in further functional decline. In addition, sarcopenia may contribute to cardiovascular remodelling and dysfunction, leading to the development of HFpEF through several metabolic and endocrine abnormalities. Although there is no established strategy for frail patients with HFpEF, a multidisciplinary approach, including various types of muscular training and nutritional intervention, may provide beneficial effects for these patients.