Simple Score to Predict Treatment Response to Low-Dose Tolvaptan in Patients with Heart Failure.

The recommended starting dose of Tolvaptan for heart failure (HF) is 7.5 mg/day in Japan; the recommended dose is 3.75 mg/day for older patients to avoid excessive diuresis and hypernatremia. However, low-dose Tolvaptan may delay the release of congestion in some patients. We aimed to develop a score to predict treatment responders to 3.75 mg tolvaptan.We retrospectively analyzed 106 patients with HF who initially received 3.75 mg/day of Tolvaptan in the derivation cohort (April 2013-December 2017) and 63 patients receiving 3.75 mg/day of Tolvaptan in the validation cohort (January 2018-April 2021). Treatment responders to 3.75 mg tolvaptan did not require dose escalation of Tolvaptan for congestion relief. In multivariate analysis, blood urea nitrogen (BUN) < 39 mg/dL and hematocrit > 35% were selected as variables to predict treatment responders. These were assigned 1 point each, and patients were stratified into groups with 2 points (n = 32), 1 point (n = 39), and 0 points (n = 35). The frequency of treatment responders was 82.9% in the 2-point group, 61.5% in the 1-point group, and 34.4% in the 0-point group (P < 0.05). The predictive ability of the score was acceptable with an area under the receiving operator characteristic curve (AUC) 0.726 (P < 0.05); its performance was maintained in the validation cohort (AUC 0.733, P < 0.05).A simple score using BUN and hematocrit could identify treatment responders to 3.75 mg tolvaptan, which may help determine the appropriate starting dose of Tolvaptan, balancing efficiency with safety for older patients with HF.

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.

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.

Difficulty initiating sleep in patients with heart failure: Impact of left atrial pressure.

BACKGROUND: Patients with heart failure (HF) often complain of sleep discomfort. Previous reports described that difficulty initiating sleep increased the cardiovascular risk in the general population. However, the association between difficulty initiating sleep and cardiac function in patients with HF remains unclear. This study aimed to investigate the associations between difficulty initiating sleep and clinical characteristics and cardiac function in patients with HF. METHODS: Eighty-seven patients with HF who underwent overnight polysomnography for suspected sleep-disordered breathing were included. Patients were divided into two groups of the longer sleep latency (SL) group (SL ≥14 min, n = 44) and the shorter SL group (SL <14 min, n = 43). The median value of SL was defined as the time from lights-off to falling asleep. We compared the patients' characteristics, laboratory data, and polysomnographic and echocardiographic indices between the two groups. RESULTS: The patients' median age was 67 years, and 85.1 % were men. There was lower beta blocker use [25 (56.8 %) vs. 34 (79.1 %), p = 0.046] and a higher peak mitral early filling velocity to mitral annular velocity ratio (E/e') [16.5 (14.2-21.7) vs. 13.7 (10.9-16.2), p = 0.005] in the longer SL group than in the shorter SL group. In multivariate logistic analysis, E/e' (odds ratio: 1.10, 95 % confidence interval: 1.01 to 1.19; p = 0.032) and systolic blood pressure before sleeping (odds ratio: 1.05, 95 % confidence interval: 1.00 to 1.10; p = 0.033) were significantly associated with a longer SL in patients with HF. CONCLUSIONS: Increased left atrial pressure suggested by increased E/e' and increased systolic blood pressure before sleeping is independently associated with difficulty initiating sleep in patients with HF. Management of these hemodynamic imbalances is required to improve difficulty initiating sleep in patients with HF.

Left ventricular mass index-to-QRS-voltage ratio predicts outcomes in heart failure with preserved ejection fraction.

AIMS: Increased left ventricular mass index (LVMI) disproportionate to electrocardiographic QRS voltage has been reported to be associated with cardiac fibrosis and amyloid infiltration to myocardium. This study aimed to assess whether the LVMI-to-QRS-voltage ratio predicts clinical outcomes in heart failure with preserved ejection fraction (HFpEF). METHODS AND RESULTS: The Japanese Heart Failure Syndrome with Preserved Ejection Fraction (JASPER) registry is a nationwide, observational, and prospective registration of Japanese patients hospitalized with HFpEF (EF ≥ 50%). LVMI was assessed by echocardiography using the cube formula. QRS voltage was assessed by Sokolow-Lyon voltage criteria. We divided 290 patients in the registry who met inclusion criteria into five groups according to the quintile values of their LVMI-to-QRS-voltage ratio. In the highest quintile group (≥71.8 g/m2 /mV), approximately 50% of the patients had concentric hypertrophy and 30% had eccentric hypertrophy. These patients had the highest proportion of atrial fibrillation (61.4%) and history of pacemaker implantation (12.1%) among the five groups (P < 0.05). During the mean follow-up of 587 ± 300 days, 31.4% of all patients met the composite endpoint of all-cause death or rehospitalization for HF. Even after adjustment for demographic and baseline variables, the highest quintile group had a significantly higher incidence of the composite endpoints than the lowest quintile group (<30.7 g/m2 /mV) (hazard ratio: 2.205, 95% confidence interval: 1.106-4.395, P < 0.05). CONCLUSIONS: A high LVMI-to-QRS-voltage ratio is independently associated with poor outcomes in patients with HFpEF.

Diagnostic performance of nutritional indicators in patients with heart failure.

AIMS: The aim of this study was to compare the diagnostic performance of the nutritional indicators, the mini nutritional assessment-short form (MNA-SF), the geriatric nutritional risk index (GNRI), and the controlling nutritional status (CONUT), in heart failure (HF) patients. METHODS AND RESULTS: Nutritional status was prospectively assessed by the aforementioned three nutritional indicators in 150 outpatients with HF who were then followed for 1 year. The prevalence of patients with the nutritional risk as assessed by the MNA-SF, GNRI, and CONUT scores was 50.0%, 13.3%, and 54.0%, respectively. There was slight agreement of nutritional risk assessment between the MNA-SF and GNRI scores (κ coefficient = 0.16), as well as the GNRI and CONUT scores (κ = 0.11), but poor agreement between the MNA-SF and CONUT scores (κ = -0.09). The CONUT score had the lowest area under the curve (AUC) for the identification of low body weight, low muscle mass, and low physical function among the three indicators (all P < 0.05). Compared with the MNA-SF score, both the GNRI and CONUT scores had lower AUCs for the identification of reduced dietary intake and weight loss (all P < 0.05). There was no significant difference in predicting all-cause mortality or HF rehospitalization among the three indicators. The prescription of statins reduced the diagnostic performance of the CONUT score, as the CONUT score includes cholesterol level assessment. CONCLUSIONS: Of the three indicators, the diagnostic ability of the MNA-SF score was the highest, and that of the CONUT score was the lowest, for the assessment of HF patient nutritional status. The CONUT score may misrepresent nutritional status, particularly in patients receiving statins.

Trimethylamine N-oxide and outcomes in patients hospitalized with acute heart failure and preserved ejection fraction.

AIMS: Trimethylamine N-oxide (TMAO) is a metabolite derived from the gut microbiota. Elevated TMAO levels are associated with a poor prognosis in patients with heart failure with reduced ejection fraction. However, the prognostic effect of elevated TMAO levels on heart failure with preserved ejection fraction (HFpEF) remains unclear. METHODS AND RESULTS: We consecutively enrolled 146 patients who were hospitalized and discharged from Tottori University Hospital with the primary diagnosis of HFpEF (ejection fraction ≥ 50%). High TMAO levels were defined as those greater than the median value in the patients (20.37 µmol/L). Patients with high TMAO levels had a significantly higher prevalence of prior hospitalization for heart failure and severe renal dysfunction than those with low TMAO levels. They also had a significantly higher acylcarnitine to free carnitine ratio than those with low TMAO levels, which indicated abnormal fatty acid metabolism and relative carnitine deficiency. After adjustment for differences in the patients' background in multivariate analysis, high TMAO levels remained independently associated with a high incidence of the composite endpoints of death due to cardiac causes and hospitalization for heart failure (adjusted hazard ratio, 1.91; 95% confidence interval, 1.01 to 3.62; P < 0.05). There was a significant interaction between TMAO and nutritional status on the primary outcome, and the prognostic effect of TMAO was enhanced in patients with malnutrition. CONCLUSIONS: Elevated TMAO levels at discharge are associated with an increased risk of post-discharge cardiac events in patients with HFpEF, especially those with the complication of malnutrition.

Child ego state and self-care behavior change in heart failure patients.

BACKGROUND: The psychological characteristics of ego functions interfere with self-care behavior in several diseases. However, the effect of ego functions on self-care behavior after education in heart failure (HF) remains unclear. METHODS: Seventy-one HF patients were enrolled. Patients' scores on the Japanese version of the European Heart Failure Self-care Behaviour Scale (EHFScBS) were measured before and after the HF intervention, and the rate of change was used as an indicator of educational effectiveness. The Tokyo University Egogram New Ver. II was used to assess five types of ego state functions: Critical parent, Nurturing parent, Adult, Free Child, and Adapted Child (AC). RESULTS: A comparison of the five ego states showed that AC scores were significantly lower than those of the other ego states (p < 0.01). Total EHFScBS scores significantly decreased from 33 (26-39) to 16 (14-20) (p < 0.01) after the HF education, and the median rates of change in EHFScBS was -46.2%. Patients with a lower rate of change in EHFScBS were more likely to have low AC scores, as characterized by a lack of compliance and coordination, and were less likely to receive higher education (all p < 0.05). Even after adjustment for covariates, low AC scores were independently associated with low rate of change in EHFScBS (p < 0.01). CONCLUSIONS: Educational behavior change for self-care is less effective in HF patients with an ego state with low AC.

Addition of losartan to angiotensin-converting enzyme inhibitors improves insulin resistance in patients with chronic heart failure treated without ß-blockers.

BACKGROUND: Angiotensin II and insulin resistance (IR) have clinical implications in the pathophysiology of chronic heart failure (CHF). However, it is still unclear whether the combination of an angiotensin-receptor blocker and angiotensin-converting enzyme inhibitor (ACEI) improves IR in CHF patients who do not receive ß-blockers. Thus, the aim of the present study was to evaluate the effects of losartan on glucose metabolism and inflammatory cytokines in CHF patients treated with ACEI but not ß-blockers. METHODS AND RESULTS: The effect of losartan treatment for 16 weeks on IR was analyzed in 16 CHF patients in a randomized crossover trial. Insulin level and homeostasis model IR index (HOMA-IR) decreased significantly (P<0.05), but fasting plasma glucose did not change significantly. Serum tumor necrosis factor (TNF)-α, interleukin (IL)-6, and monocyte chemoattractant protein (MCP)-1 levels were significantly decreased with losartan (P<0.05). Furthermore, the changes in IL-6 and MCP-1 levels were significantly correlated with the reduction in HOMA-IR (P<0.05), but the change in TNF-α levels was not significantly correlated. CONCLUSIONS: The addition of losartan to ACEI therapy improved IR and decreased inflammatory cytokines in CHF patients who did not receive ß-blockers.

A simple risk score to predict in-hospital death of elderly patients with acute decompensated heart failure--hypoalbuminemia as an additional prognostic factor.

BACKGROUND: Risk stratification for elderly patients with acute decompensated heart failure (ADHF) may help clinicians to select the appropriate therapy and raise the quality of care. METHODS AND RESULTS: The present study enrolled 349 patients aged over 65 years who were hospitalized with ADHF from January 2004 to October 2008. Five independent prognostic factors were identified by multivariate logistic regression analysis, and each factor was assigned a number of points proportional to its regression coefficient: prior heart failure hospitalization (2 points), sodium or=35 mg/dl (2 points), albumin or=980 pg/ml (2 points); in particular, hypoalbuminemia was identified as the strongest prognostic factor. The patients were stratified into 3 groups: low risk (0-4 points), moderate risk (5-7 points), and high risk (8-11 points). The respective in-hospital mortality rates were 1.6%, 15.8%, and 42.1% (P<0.05). CONCLUSIONS: In addition to known prognostic factors, hypoalbuminemia may provide important information for elderly patients with ADHF. A simple risk score may help to stratify the risk of in-hospital mortality and contribute to better clinical management of these elderly patients.

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.

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

AIMS: 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. METHODS AND RESULTS: Among 934 patients admitted to our hospital for HF from January 2004 to December 2015, we retrospectively reviewed the medical records of consecutive 106 patients who died in hospital (mean age 73 ± 13 years; male, 52.6%). During hospitalization, attending physicians conducted an average of 2.1 ± 1.4 end-of-life conversations with patients and/or their families. Only 4.7% of patients participated in the conversations and declared their preferences; surrogates made medical care decisions in 95.3% of cases. Most decisions by surrogates (98.1%) were made without the patient's advance directive. During initial end-of-life conversations, 49.4% of surrogates requested cardiopulmonary resuscitation (CPR). However, 72.0% of CPR preferences were changed to do not attempt resuscitation (DNAR) orders in the final conversation. Female surrogates were more likely to change the preference from CPR to DNAR than were male surrogates (47.1% vs. 25.0%, P = 0.023). CONCLUSIONS: Compared with male surrogates, female surrogates wavered more often in their decisions regarding life-sustaining treatments of Japanese patients with end-stage HF.

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

AIMS: 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. METHODS AND RESULTS: The present study enrolled 40 HF outpatients with previous history of HF hospitalization and receiving self-care management. Patients' psychological characteristics were assessed by Patient Health Questionnaire (PHQ-9) for screening depressive symptoms, and the Tokyo University Egogram (TEG) New Version II for analysing human behaviour based on five functional ego states; critical parent, nurturing parent, adult, free child, and adapted child (AC). Twelve patients (30.0%) had previous history of repeated (two or more) HF hospitalization. Most of them (75%) had a history of at least one or more re-hospitalizations related to inadequate self-care. Patients with repeated HF hospitalization had significantly lower AC score, which represents uncooperative and uncompromising behaviours, compared with those without repeated HF hospitalization (P < 0.05). There were no significant differences in other parameters, including PHQ-9, between the two groups. CONCLUSIONS: Low AC ego state was associated with high prevalence of repeated hospitalization in patients with HF. Assessing ego functions may be helpful to tailor educational approaches in these patients.