Kiyotaka Yanagihara

Uricosuric Action of Losartan via the Inhibition of Urate Transporter 1 (URAT 1) in Hypertensive Patients

BACKGROUND The angiotensin receptor blocker losartan inhibited urate transporter 1 (URAT1) according to in vitro experiments. However, it is still unknown whether the inhibitory effect of losartan on URAT1 contributes to its uricosuric action in humans. METHODS Thirty-two patients with hypertension and nine patients with idiopathic renal hypouricemia (five with and four without hypertension) were enrolled for this study. Hypertensive patients were prescribed oral losartan (50 mg/day, n = 16) or candesartan (8 mg/day, n = 16). Before and after 1-month treatment, the serum concentration of urate (Sur) and creatinine (Scr), and the clearance value of urate (Cur) and creatinine (Ccr) were determined. Clearance studies using the URAT1 inhibitor benzbromarone (100 mg/day) or losartan (50 mg/day) loading test were also performed in these patients. RESULTS Blood pressure (BP) significantly decreased in the patients treated with either losartan or candesartan. Losartan significantly reduced Sur, which was associated with a concomitant increase in the Cur/Ccr ratio, whereas candesartan did not alter these parameters. In hypertensive patients with loss-of-function mutation of URAT1, losartan did not alter either Sur or Cur/Ccr, nor did benzbromarone. The lack of effect of URAT1 inhibitors on renal excretion of urate was independent of the renal function of hypouricemic patients. On the other hand, both losartan and benzbromarone increased Cur/Ccr ratio in hypertensive patients harboring the wild URAT1 gene, regardless of the presence of hypouricemia. CONCLUSIONS These findings suggested that losartan inhibited URAT1 and thereby it lowered Sur levels in hypertensive patients.

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.

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.

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.

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.

Diaphragm Muscle Dysfunction in Patients with Heart Failure

BACKGROUND Inspiratory muscle weakness is associated with the development of exercise intolerance in patients with heart failure (HF). Ultrasound assessment of the diaphragm is used to evaluate respiratory muscle function, but its application in patients with HF remains undefined. We examined the relationship of diaphragm function as assessed by ultrasonography with inspiratory muscle strength and exercise tolerance in HF. METHODS AND RESULTS Seventy-seven patients hospitalized with HF were enrolled. Impaired diaphragm muscle function was defined as a diaphragm thickness at end-inspiration of less than the median value of 4.0 mm, which represents diaphragm muscle loss and reduced contraction. Compared with patients with preserved diaphragm muscle function, those with impaired diaphragm muscle function were older; had significantly lower vital capacity, handgrip strength, and inspiratory muscle strength as assessed by the maximum inspiratory pressure; and had a significantly shorter 6-minute walk distance (6MWD; P < .05). Although low handgrip strength was also associated with a short 6MWD, the relationship between impaired diaphragm muscle function and short 6MWD was independent from age, vital capacity, and handgrip strength. CONCLUSION Diaphragm dysfunction as assessed by ultrasonography represents inspiratory muscle weakness and predicts exercise intolerance independently from comorbid pulmonary dysfunction and dynapenia in patients with HF.

Child ego state is associated with high prevalence of repeated hospitalizations in patients with heart failure

Inadequate self‐care management is a leading cause of re‐hospitalization in patients with heart failure (HF). Psychological factors such as some ego functions interfere with self‐care behaviour modification, leading to poor outcomes in patients with several chronic diseases. However, characteristics of ego states in patients with repeated hospitalization for HF remain undefined.

Dynapenia and diaphragm muscle dysfunction in patients with heart failure

Skeletal muscle dysfunction (dynapenia) is often present in patients with heart failure. However, the association of dynapenia with diaphragm muscle dysfunction remains undefined. Sixty-two patients hospitalized for heart failure were enrolled. Diaphragm muscle function was assessed by ultrasonography, and impaired diaphragm function was defined as diaphragm muscle thickness at the end of inspiration below the median value (i.e. <4.0mm) as previously described. Dynapenia was classified into two phenotypes: muscle weakness with low muscle mass (i.e. sarcopenia) and muscle weakness despite normal muscle mass. Muscle weakness and muscle loss were defined according to the criteria of the Asian working group for sarcopenia. Dynapenia with muscle loss and dynapenia with normal muscle mass were present in 32.3% and 40.3% of patients, respectively. Compared with patients without dynapenia, patients with either type of dynapenia were older, had significantly reduced knee extensor muscle strength, impaired diaphragm muscle function and a significantly shorter six-minute walk distance (6MWD) (Figure 1(a)). Reduced diaphragm muscle function was associated with a further decrease in the 6MWD of patients with either type of dynapenia (Figure 1(b) and (c)). In multivariate analysis, increased age, reduced diaphragm muscle function and decreased knee extensor muscle strength were independent determinants of short 6MWD in heart failure patients with dynapenia. The present study demonstrated that ultrasoundproven diaphragm muscle dysfunction was often present in heart failure patients with dynapenia and was a significant determinant of exercise intolerance regardless of the dynapenia phenotype. Independent effect of diaphragm muscle dysfunction on exercise intolerance in heart failure patients with dynapenia may be partly explained by the limb muscle dysfunction induced by the inspiratory metaboreflex. Diaphragm muscle fatigue during exercise is likely to induce sympathetic activation and peripheral vasoconstriction, resulting in fatigue of peripheral skeletal muscles and an impairment of their endurance. A previous study demonstrated the beneficial effects of inspiratory muscle training on exercise capacity along with improved diaphragm muscle function and attenuated inspiratory metaboreflex in patients with heart failure. Thus, in addition to conventional rehabilitation programs, inspiratory muscle training may be a therapeutic option for heart failure patients with dynapenia.

Sex differences in surrogate decision-maker preferences for life-sustaining treatments of Japanese patients with heart failure: Surrogate decision-maker preferences for life-sustaining treatments

Patients with end‐stage heart failure (HF) often require surrogate decision making for end‐of‐life care owing to a lack of decision‐making capacity. However, the clinical characteristics of surrogate decision making for life‐sustaining treatments in Japan remain to be investigated.