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.

Ultrasound Assessment of Kidney Volume in Patients with Acute Decompensated Heart Failure: A Predictor of Diuretic Resistance.

BACKGROUND: Diuretics are essential for treating acute decompensated heart failure (ADHF), but the response is inconsistent. This study aimed to clarify whether kidney volume as assessed by ultrasound (US) predicts diuretic resistance in patients with ADHF. METHODS: We enrolled 29 patients with ADHF and 32 controls. Height-adjusted kidney volume was assessed by US. We divided patients into two groups based on the median value of total daily use of furosemide (intravenous dose plus 0.5 × oral dose of furosemide equivalents) during 3 days from admission. RESULTS: Patients with ADHF had a significantly smaller left kidney volume than did control subjects (27.7 ± 10.0 vs. 32.8 ± 8.8 mL/m, P < 0.05). Patients in the high-dose furosemide group (≥ 51.7 mg/d) had a significantly lower estimated glomerular filtration rate (eGFR) and a significantly smaller kidney volume than did those in the low-dose furosemide group (eGFR: 43.9 ± 20.4 vs. 60.8 ± 21.6 mL/min/1.73 m2, left kidney volume: 23.2 ± 5.2 vs. 32.6 ± 11.0 mL/m, right kidney volume: 26.5 ± 7.5 vs. 32.6 ± 7.9 mL/m, all P < 0.05). Multivariate logistic analysis showed that left kidney volume, but not eGFR, was independently associated with the requirement of high-dose furosemide (odds ratio: 0.856, 95% confidence interval: 0.735-0.997, P < 0.05). CONCLUSION: Kidney volume as assessed by US is a useful predictor of diuretic resistance in patients with ADHF.

Inspiratory Muscle Weakness is Associated With Exercise Intolerance in Patients With Heart Failure With Preserved Ejection Fraction: A Preliminary Study.

BACKGROUND: The relationship between inspiratory muscle weakness (IMW) and exercise intolerance in patients with heart failure with preserved ejection fraction (HFpEF) remains unestablished. METHODS AND RESULTS: The present study enrolled 40 patients with HFpEF (EF ≥45%). IMW was defined as maximum inspiratory pressure <70% normal predicted values. The function of the diaphragm was assessed by means of ultrasound measurement of muscle thickening of the diaphragm. IMW was prevalent in 27.5% of patients. Patients with IMW had significantly lower vital capacity relative to normal predicted values (%VC), lower knee extensor muscle strength in relation to body weight (%KEMS), poorer nutritional status as assessed by means of the Geriatric Nutritional Risk Index, and shorter 6-minute walk distance (6MWD) compared with patients without IMW (all P < .05). Impaired diaphragm muscle thickening at end-inspiration (median value < 3.9 mm) was significantly associated with a high prevalence of IMW and reduced 6MWD (all P < .05). Subgroup analysis showed that IMW was accompanied by a further decrease in 6MWD in patients with restrictive pulmonary dysfunction (%VC <80%) or lower-limb muscle weakness (median %KEMS <30%; all P < .05). CONCLUSIONS: IMW is associated with exercise intolerance in patients with HFpEF.

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.

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

BACKGROUND: Heart 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. METHODS: An 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. RESULTS: Compared with patients in the usual care group, those in the intervention group more often received the optimal interventions such as discharge use of ß-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). CONCLUSIONS: Multidisciplinary 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.

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.

Geriatric nutritional risk index predicts functional dependency and mortality in patients with heart failure with preserved ejection fraction.

BACKGROUND: The clinical significance of nutritional risk assessment in patients with heart failure with preserved ejection fraction (HFpEF) remains undefined. Geriatric nutritional risk index (GNRI) is a simple nutritional assessment tool for elderly subjects. Its predictive value was evaluated in patients with HFpEF, a common HF phenotype in the elderly population. METHODS AND RESULTS: The present study enrolled 152 consecutive patients (mean age, 77 ± 11 years; male, 53.9%) who were hospitalized with HFpEF at the authors' institution. GNRI on admission was calculated as follows: 14.89 × serum albumin (g/dl)+41.7×body mass index/22. Characteristics and mortality (median follow-up of 2.1 years) were compared between 2 groups: low GNRI (<92) with moderate or severe nutritional risk; and high GNRI (≥ 92) with no or low nutritional risk. Patients in the low-GNRI group were more often female, and had lower serum hemoglobin and sodium, but higher serum blood urea nitrogen (BUN), C-reactive protein, and B-type natriuretic peptide (BNP) compared to those in the high-GNRI group (P<0.05, respectively). Physical activity at discharge measured by Barthel index was significantly lower in the low-GNRI group than the high-GNRI group (P<0.05). On Cox hazard analysis, lower GNRI predicted increased mortality independent of age, gender, prior HF hospitalization, and higher BUN and BNP (P<0.01). CONCLUSIONS: GNRI may be useful for predicting functional dependency and mortality in patients with HFpEF.

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.

Enhancing effects of salicylate on quinidine-induced block of human wild type and LQT3 related mutant cardiac Na+ channels.

It is unknown whether salicylate enhances the action of antiarrhythmic agents on human Na+ channels with state dependency and tissue specificity. We therefore investigated effects of salicylate on quinidine-induced block of human cardiac and skeletal muscle Na+ channels. Human cardiac wild-type (hH1), LQT3-related mutant (ΔKPQ), and skeletal muscle (hSkM1) Na+ channel α subunits were expressed in COS7 cells. Effects of salicylate on quinidine-induced tonic and use-dependent block of Na+ channel currents were examined by the whole-cell patch-clamp technique. Salicylate enhanced the quinidine-induced tonic and use-dependent block of both hH1 and hSkM1 currents at a holding potential (HP) of -100 mV but not at -140 mV. Salicylate decreased the IC50 value for the quinidine-induced tonic block of hH1 at an HP of -100 mV, and produced a negative shift in the steady-state inactivation curve of hH1 in the presence of quinidine. According to the modulated receptor theory, it is probable that salicylate decreases the dissociation constant for quinidine binding to inactivated-state channels. Furthermore, salicylate significantly enhanced the quinidine-induced tonic and use-dependent block of the peak and steady-state ΔKPQ channel currents. The results suggest that salicylate enhances quinidine-induced block of Na+ channels via increasing the affinity of quinidine to inactivated state channels.

Effect of losartan and benzbromarone on the level of human urate transporter 1 mRNA.

Both an angiotensin II receptor blocker, losartan (CAS 124750-99-8) and a serum urate lowering agent, benzbromarone (CAS 3562-84-3) exert a uricosuric action by inhibiting urate transporter 1 (URAT1). A recent clinical trial indicated that losartan could reduce the level of serum urate in hypertensive patients treated with urate lowering agents, suggesting the different mode of action of losartan from benzbromarone. In the present study, the effect of losartan and benzbromarone on the level of URAT1 mRNA was determined in transfected HEK293 cells. Losartan caused a significant reduction of its mRNA level, whereas it was not affected by benzbromarone. These results indicate that losartan decreases the level of human URAT1 mRNA, which may underlie the uricosuric action of losartan in hypertensive patients treated with serum urate lowering agents.

Effects of a low-dose antihypertensive diuretic in combination with losartan, telmisartan, or candesartan on serum urate levels in hypertensive patients.

BACKGROUND: A combination therapy of a low-dose antihypertensive diuretic with an angiotensin II receptor blocker (ARB) may have unfavorable effects on serum urate levels. METHODS: Forty-two hypertensive patients without hyperuricemia (18 men and 24 women, mean age 65 years) were randomly divided into three groups. Each of the group was allocated to a combination therapy with losartan (LOS; CAS 124750-99-8; 50 mg/day)/hydrochlorothiazide (HCTZ; CAS 58-93-5; 12.5 mg/day) (LOS/HCTZ group), telmisartan (TEL; CAS 144701-48-4; 40 mg/day)/HCTZ (12.5 mg/day) (TEL/HCTZ group), or candesartan (CND; CAS 145040-37-5; 8 mg/day)/HCTZ (12.5 mg/day) (CND/HCTZ group), respectively. Before and after the treatment, blood pressure and biochemical parameters of blood and urine were evaluated. RESULTS: Both systolic and diastolic blood pressures significantly decreased in all groups (p < 0.01) without any statistical differences. The LOS/HCTZ group showed no changes in serum urate levels (5.8 +/- 1.0 mg/dl to 5.8 +/- 1.4 mg/dl) and in % fractional excretion of urate (FEUA). In the TEL/HCTZ group, the serum urate level was significantly increased, from 5.5 +/- 0.9 mg/dl to 6.5 +/- 1.2 mg/dl (p < 0.01), whereas FEUA significantly decreased (p < 0.01). Similarly, the CND/HCTZ group showed a significant increase in the serum urate level from 5.4 +/- 0.9 mg/dl to 6.0 +/- 1.2 mg/dl (p < 0.01) and a significant decrease in FEUA (p < 0.01). No significant differences were found in fasting plasma glucose and electrolytes levels in any of the groups. CONCLUSIONS: A combination therapy with a low-dose HCTZ and ARBs resulted in reduced urate excretion and elevated serum urate levels. A combination therapy with the ARB losartan was not accompanied with these effects, likely because of its inhibitory action on urate transporter 1. The study limitations deserve mention in consideration of ethic restrictions, small size, short term examination and uncontrolled design.