Associations between in-hospital daily protein intake and adverse clinical outcomes in older patients with heart failure.

AIMS: The adverse effects of low daily protein intake (DPI) on clinical outcomes in patients with heart failure (HF) are known; however, an optimal DPI to predict event adverse outcomes remains undetermined. Moreover, whether protein restriction therapy for chronic kidney disease is applicable in patients with HF and renal dysfunction remains unclear. METHODS AND RESULTS: In this single-centre, ambispective cohort study, we included 405 patients with HF aged ≥65 years (mean age, 78.6 ± 7.5 years; 50% women). DPI was estimated from consumption over three consecutive days before discharge and normalized relative to the ideal body weight [IBW, 22 kg/m2 × height (m)2]. The primary outcome was a composite of all-cause mortality and HF-related readmission within the 2 year post-discharge period. RESULTS: During an average follow-up period of 1.49 ± 0.74 years, 100 patients experienced composite events. Kaplan-Meier survival curves revealed a significantly lower composite event-free rate in patients within the lowest quartile of DPI than in the upper quartiles (log-rank test, P = 0.02). A multivariate Cox proportional hazards analysis after adjusting for established prognostic markers and non-proteogenic energy intake revealed that patients in the lowest DPI quartile faced a two-fold higher risk of composite events than those in the highest quartile [hazard ratio (HR), 2.03; 95% confidence interval (CI), 1.08-3.82; P = 0.03]. The composite event risk linearly increased as DPI decreased (P for nonlinearity = 0.90), with each standard deviation (0.26 g/kg IBW/day) decrease in DPI associated with a 32% increase in composite event risk (HR, 1.32; 95% CI, 1.10-1.71; P = 0.04). There was significant heterogeneity in the effect of DPI, with the possible disadvantage of lower DPI in patients with HF with cystatin C-based estimated glomerular filtration rate <30 mL/min/1.73 m2. The cutoff value of DPI for predicting the occurrence of composite events calculated from the Youden index was 1.12 g/kg IBW/day. Incorporating a DPI < 1.12 g/kg IBW/day into the baseline model significantly improved the prediction of post-discharge composite events (continuous net reclassification improvement, 0.294; 95% CI, 0.072-0.516; P = 0.01). CONCLUSIONS: Lower DPI during hospitalization is associated with an increased risk of mortality and HF readmission independent of non-proteogenic energy intake, and the possible optimal DPI for predicting adverse clinical outcomes is >1.12 g/kg IBW/day in older patients with HF. Caution is warranted when protein restriction therapy is administered to older patients with HF and renal dysfunction.

Optimal serum 25-hydroxyvitamin D level to prevent sarcopenia in patients with heart failure: Insights from a dose-response relationship.

BACKGROUND AND AIMS: Low serum 25-hydroxyvitamin D (25 [OH]D) levels have been associated with sarcopenia, frailty, and risk of cardiovascular disease, whereas high levels negatively impact clinical outcomes. We determined optimal serum 25(OH)D concentrations to minimise the probability of sarcopenia in patients with heart failure (HF) by examining the dose-dependent relationship between serum 25(OH)D levels and sarcopenia. METHODS AND RESULTS: We enrolled 461 consecutive patients with HF (mean age, 72 ± 15 years; 39% female) who underwent dual-energy X-ray absorptiometry. Serum 25(OH)D levels were measured using a chemiluminescence immunoassay. Sarcopenia was diagnosed according to the 2019 Asian Working Group for Sarcopenia criteria. Overall, 49% of enrolled patients were diagnosed with sarcopenia. Adjusted logistic regression with restricted cubic spline function revealed that the odds ratio (OR) of sarcopenia increased in patients with HF presenting serum 25(OH)D levels <14.6 ng/ml or > 31.4 ng/ml, reaching the lowest OR at ∼20 ng/ml. Multivariate logistic regression revealed that a serum 25(OH)D level below 14.6 ng/mL was independently associated with the presence of sarcopenia (adjusted OR: 2.16, 95% confidence interval [CI]: 1.24-3.78). Incorporating serum 25(OH)D levels <14.6 ng/ml, but not <20.0 ng/ml, in the baseline model improved continuous net reclassification (0.334, 95% CI: 0.122-0.546) in patients with HF. CONCLUSION: A U-shaped relationship exists between serum 25(OH)D levels and sarcopenia probability in patients with HF. Maintaining serum 25(OH)D levels between 14.6 and 31.4 ng/ml may help prevent sarcopenia in patients with HF.

Relationship between serum iron level and physical function in heart failure patients is lost by presence of diabetes.

AIMS: Iron deficiency (ID) is common in patients with heart failure (HF) and is reportedly associated with exercise intolerance and impaired quality of life. Iron supplementation therapy in HF patients with ID improves exercise capacity. Conversely, protective roles of iron depletion in the development of diabetes mellitus (DM) and its complications have been proposed. This study aimed to determine the impact of ID on physical function in HF patients with and without DM. METHODS AND RESULTS: We enrolled consecutive patients who were admitted to our institute for HF diagnosis and management. The short physical performance battery (SPPB) was used to evaluate physical function, and low physical function was defined as an SPPB score of <10 points as individuals with SPPB scores of <10 points are most likely to be classified as frail and are at high risk for disability and future adverse events, including death. ID was defined as serum ferritin < 100 or 100-299 ng/mL when transferrin saturation (TSAT) was <20% according to the HF guidelines. Among the 562 HF patients (72 ± 14 years old; 56% male), 329 patients (58%) and 191 patients (34%) had ID and low physical function, respectively. Multivariate logistic regression analysis showed that TSAT as a continuous variable, but not ID, was a predictor of low physical function (odds ratio: 0.980, P = 0.024). Subgroup analysis showed that a significant association between low TSAT and low physical function was lost in HF patients with DM (P for interaction < 0.001). A spline dose-response curve for the relationship between TSAT and risk of low physical function with adjustments for covariates associated with low physical function in non-DM patients was almost linear with an increase in the risk of low physical function as the TSAT increased, but such a relationship was not found in the analyses of DM patients. A lack of close TSAT-SPPB relationship in HF patients with DM was confirmed also in a propensity-score-matched cohort. CONCLUSIONS: TSAT as a continuous variable, but not ID, was independently associated with physical function in HF patients, and a significant association was lost in patients with HF and DM, suggesting a limited impact of iron supplementation therapy in HF patients with DM.

Coexistence of sarcopenia and self-reported weight loss is a powerful predictor of mortality in older patients with heart failure.

AIM: We examined whether the addition of self-reported weight loss improves the accuracy of prediction of mortality caused by sarcopenia in heart failure (HF) patients. METHODS: We enrolled 477 HF patients (mean age 77 years) who received combined assessment of sarcopenia and self-reported weight loss. Sarcopenia was diagnosed according to the criteria of the Asian Working Group for Sarcopenia. If the patients answered "yes" to the question "have you lost 2 kg or more in the past 6 months?", they were diagnosed as having self-reported weight loss. RESULTS: Sarcopenia and self-reported weight loss coexisted in 32% of patients. During a median follow-up period of 763 days, 65 patients (15%) died. Kaplan-Meier curves showed a significantly higher rate of mortality in HF patients with both sarcopenia and self-reported weight loss than in HF patients with sarcopenia alone. Multivariate Cox proportional hazards analysis showed that the coexistence of sarcopenia and self-reported weight loss is an independent predictor of mortality in HF patients. Inclusion of the coexistence of sarcopenia and self-reported weight loss in the baseline model consisting of established prognostic markers significantly improved both the net reclassification index and the integrated discrimination index. CONCLUSIONS: The coexistence of sarcopenia and self-reported weight loss is a powerful predictor of mortality in HF patients. Geriatr Gerontol Int 2024; 24: 95-101.

Circulating level of ß-aminoisobutyric acid (BAIBA), a novel myokine-like molecule, is inversely associated with fat mass in patients with heart failure.

Results of experimental studies have shown that ß-aminoisobutyric acid (BAIBA), an exercise-induced myokine-like molecule, is an endogenous negative regulator of fat mass in mice, but it remains unclear whether that is the case in humans, though an enhanced BAIBA concentration in patients receiving sodium-glucose cotransporter 2 inhibitors was found in our recent study. The objective of this study was to analyze the determinants of circulating BAIBA concentration in humans, with focus on the possible link between circulating BAIBA and body composition including fat mass. Data for 188 consecutive patients with heart failure (HF, 64 ± 13 years; 70% male) who received a dual energy X ray absorptiometry (DEXA) scan for assessment of body composition including fat mass index (FMI) and appendicular skeletal muscle mass index (ASMI) were used in this study. Plasma BAIBA concentration in a fasting state after stabilization of HF was determined using ultraperformance liquid chromatography. Plasma BAIBA was detected in 66% of the patients. In simple linear regression analyses of data from patients in whom plasma BAIBA was detected, plasma BAIBA concentration was positively correlated with uric acid and was negatively correlated with body mass index (BMI), estimated glomerular filtration rate (eGFR), FMI, and % body fat. There were no correlations between plasma BAIBA concentration and indexes of muscle mass and bone mass. The results of multiple linear regression analyses showed that FMI and % body fat in addition to BMI, but not ASMI, were independent explanatory factors for plasma BAIBA concentration. In conclusion, plasma BAIBA concentration is inversely correlated with indexes of fat mass, indicating that BAIBA may be a therapeutic target for excessive fat accumulation.

Independent Link Between Use of Mineralocorticoid Receptor Antagonists and Muscle Wasting in Heart Failure Patients Not Receiving Renin-Angiotensin System Inhibitors.

BACKGROUND: The renin-angiotensin system (RAS) activation is a proposed mechanism of muscle wasting (MW i.e., reduction in muscle mass). Although we reported that RAS inhibitors (RASIs) were associated with lower prevalence of MW in heart failure (HF) patients, the relationship between mineralocorticoid receptor (MR) signaling and MW has not been analyzed.Methods and Results: We analyzed data from 320 consecutive Japanese HF patients who underwent dual-energy X-ray absorptiometry scanning for assessment of appendicular skeletal muscle mass index (ASMI). In multiple linear regression analyses, plasma renin activity (PRA) was negatively correlated with ASMI in patients not receiving RASIs, indicating an untoward role of the RAS in MW. Results of analysis of covariance in which risk factors of MW served as covariates showed that use of MR antagonists (MRAs) was associated with lower ASMI and higher PRA in the non-RASIs group. The close relationship between use of MRAs and lower ASMI or higher PRA in the non-RASIs group was confirmed in analyses in which the differences in baseline characteristics between users and non-users of MRAs were minimized by using an inverse probability of treatment weighting. CONCLUSIONS: Increased PRA by MR inhibition without concurrent RAS inhibition, possibly contributing to upregulation of angiotensin II signaling, may be associated with reduction in muscle mass.

Development and validation of osteoporosis risk assessment score, ORAS, in heart failure patients: comparison with the Osteoporosis Self-Assessment Tool for Asians (OSTA).

AIM: Osteoporosis is prevalent and is associated with poor prognosis in heart failure (HF) patients. However, bone mineral density (BMD) measurement by a dual-energy X-ray absorptiometry (DEXA) scan is not always available in a daily clinical setting and large-scale population-based studies. METHODS: A single-center, cross-sectional observational study was conducted with 387 patients (median age: 77 years [interquartile range: 68 to 83 years]; 37% women). BMDs were measured by DEXA scans, and osteoporosis was diagnosed as ≤ -2.5 standard deviation of the BMDs in healthy young adults. Osteoporosis risk assessment score (ORAS) was developed using significant predictors from a logistic regression model for osteoporosis and was subsequently validated. RESULTS: Osteoporosis was found in 103 (27%) of the 387 HF patients. Multivariate logistic regression analyses yielded the ORAS based on sex, BMI, handgrip strength, and anti-coagulant therapy utilization. The C-index of ORAS in the developmental set (0.796, 95% confidence interval: 0.747 to 0.845) was similar to the bootstrap validation of the prediction model (0.784), and tended to be higher than that of the Osteoporosis Self-Assessment Tool for Asians (OSTA). A nomogram of ORAS, established on the basis of the final logistic regression model, demonstrated 100% sensitivity at the lowest score (35 points), with an optimal cutoff point of 127 points, yielding 85% sensitivity and 62% specificity. CONCLUSIONS: ORAS exhibits superior predictive performance to OSTA in predicting osteoporosis in HF patients, establishing itself as a valuable tool for early detection in both daily clinical practice and large-scale population-based studies.

Impact of Radar Chart-Based Information Sharing in a Multidisciplinary Team on In-Hospital Outcomes and Prognosis in Older Patients With Heart Failure.

Background: A multidisciplinary team (MDT) approach is crucial for managing older patients with heart failure (HF). We investigated the impact on clinical outcomes of implementation of a conference sheet (CS) with an 8-component radar chart for visualizing and sharing patient information. Methods and Results: We enrolled 395 older inpatients with HF (median age 79 years [interquartile range 72-85 years]; 47% women) and divided them into 2 groups according to CS implementation: a non-CS group (before CS implementation; n=145) and a CS group (after CS implementation; n=250). The clinical characteristics of patients in the CS group were assessed using 8 scales (physical function, functional status, comorbidities, nutritional status, medication adherence, cognitive function, HF knowledge level, and home care level). In-hospital outcomes (Short Physical Performance Battery, Barthel Index score, length of hospital stay, and hospital transfer rate) were significantly better in the CS than non-CS group. During the follow-up period, 112 patients experienced composite events (all-cause death or admission for HF). Inverse probabilities of treatment-weighted Cox proportional hazard analyses demonstrated a 39% reduction in risk of composite events in the CS group (adjusted hazard ratio 0.65; 95% confidence interval 0.43-0.97). Conclusions: Radar chart-based information sharing among MDT members is associated with superior in-hospital clinical outcomes and a favorable prognosis.

Independent Association Between Use of Proton Pump Inhibitors and Muscle Wasting in Patients with Heart Failure: A Single-Center, Ambispective, Observational Study.

BACKGROUND: Although proton pump inhibitors (PPIs) play a pivotal role in the prevention and treatment of gastric acid-related diseases and gastrointestinal adverse events caused by antiplatelet therapies, the safety of long-term use of PPIs has been questioned. OBJECTIVE: The aim of this study was to determine the effects of use of PPIs on muscle mass and bone mineral density in heart failure (HF) patients. METHODS: This was a single-center, ambispective (combined retrospective and prospective), observational study. HF patients (n = 747; 72 years of age; males, 54%) who received a dual-energy x-ray absorptiometry scan were enrolled. Muscle wasting was defined as appendicular skeletal muscle mass index (ASMI) < 7.0 kg/m2 in males and <5.4 kg/m2 in females. Propensity scores for the use of PPIs were calculated using a multivariate logistic regression model to minimize selection bias. RESULTS: Before propensity score matching, ASMI was significantly lower in patients receiving PPIs than in patients not receiving PPIs, resulting in a higher prevalence of muscle wasting in the PPI group. Such a relationship between use of PPIs and muscle wasting remained after propensity score matching. In multivariate Cox regression analyses, use of PPIs was independently associated with presence of muscle wasting (hazard ratio 1.68, 95% confidence interval 1.05-2.69) after adjustment for established risk factors of sarcopenia. On the other hand, there were no differences in bone mineral density between the PPI group and the no-PPI group. CONCLUSION: Use of PPIs is associated with a high risk of muscle wasting in HF patients. Caution is warranted when long-term PPI treatment is performed in sarcopenic HF patients and HF patients with several risk factors for muscle wasting.

Elevated circulating level of ß-aminoisobutyric acid (BAIBA) in heart failure patients with type 2 diabetes receiving sodium-glucose cotransporter 2 inhibitors.

AIMS: The mechanism by which a sodium-glucose cotransporter inhibitor (SGLT2i) induces favorable effects on diabetes and cardiovascular diseases including heart failure (HF) remains poorly understood. Metabolomics including amino acid profiling enables detection of alterations in whole body metabolism. The aim of this study was to determine whether plasma amino acid profiles are modulated by SGLT2i use in HF patients with type 2 diabetes mellitus (T2DM). METHODS: We retrospectively examined 81 HF patients with T2DM (68 ± 11 years old; 78% male). Plasma amino acid concentrations in a fasting state after stabilization of HF were determined using ultraperformance liquid chromatography. To minimize potential selection bias in the retrospective analyses, the differences in baseline characteristics between patients receiving an SGLT2i and patients not receiving an SGLT2i were controlled by using an inverse probability of treatment weighting (IPTW)-adjusted analysis. RESULTS: Of amino acids measurable in the present assay, plasma ß-aminoisobutyric acid (BAIBA), an exercise-induced myokine-like molecule also known as 3-aminoisobutyric acid or 3-amino-2-methyproponic acid, was detected in 77% of all patients and the proportion of patients in whom plasma BAIBA was detected was significantly higher in patients receiving an SGLT2i than in patients not receiving an SGLT2i (93% vs. 67%, p = 0.01). Analyses in patients in whom plasma BAIBA was detected showed that plasma BAIBA concentration was significantly higher in patients receiving an SGLT2i than in patients not receiving an SGLT2i (6.76 ± 4.72 vs. 4.56 ± 2.93 nmol/ml, p = 0.03). In multivariate logistic regression analyses that were adjusted for age and sex, SGLT2i use was independently associated with BAIBA detection. The independent association between BAIBA and SGLT2i use remained after inclusion of body mass index, HF with reduced ejection fraction, ischemic etiology, renal function, NT-proBNP, albumin, hemoglobin, and HbA1c into the Cox proportional hazards model. When the differences in baseline characteristics between patients receiving an SGLT2i and patients not receiving an SGLT2i were controlled by using an IPTW-adjusted analysis, least squares mean of plasma BAIBA concentration was significantly higher in patients receiving an SGLT2i than in patients not receiving an SGLT2i. CONCLUSION: SGLT2i use is closely associated with increased circulating BAIBA concentration in HF patients with T2DM.

Anthropometric parameters-derived estimation of muscle mass predicts all-cause mortality in heart failure patients.

AIMS: Reduction in appendicular skeletal muscle mass index (ASMI) assessed by dual-energy X-ray absorptiometry (DEXA) has been shown to be independently associated with a higher mortality rate in patients with heart failure (HF). However, DEXA is not suitable for measurement of muscle mass in a daily clinical setting and in large population-based studies. The aim of this study was to determine whether ASMI predicted from anthropometric indicators (predicted ASMI) serves as an alternative to DEXA-measured ASMI for predicting all-cause death in HF patients. METHODS AND RESULTS: Data for 539 HF patients who received a DEXA scan and measurements of calf circumferences (CC) and mid-arm circumferences (MAC) in our hospital were analysed. Predicted ASMI was calculated as we previously reported: predicted ASMI (kg/m2 ) = [0.214 × weight (kg) + 0.217 × CC (cm) - 0.189 × MAC (cm) + 1.098 (male = 1, female = -1) + 0.576]/height2 (m2 ). Low ASMI values were defined as <7.00 kg/m2 and <5.40 kg/m2 for men and women, respectively, according to the criteria of the Asian Working Group for Sarcopenia. The median follow-up period was 1.75 years (interquartile range, 0.96-2.37 years), and 79 patients (15%) died. Kaplan-Meier survival curves showed that patients with low DEXA-measured ASMI and patients with low predicted ASMI had significantly lower survival rates than those for patients with high ASMI. In multivariate Cox proportional hazard analyses adjusted for age, sex, logarithmic B-type natriuretic peptide, cystatin C based-estimated glomerular filtration rate, and gait speed, DEXA-measured ASMI [hazard ratio (HR), 0.982; 95% confidence interval (CI), 0.967-0.998; P = 0.026] and predicted ASMI (HR, 0.979; 95% CI, 0.962-0.996; P = 0.018) were independent predictors of all-cause mortality. Inclusion of predicted ASMI into the adjustment model significantly improved continuous net reclassification improvement (0.338; 95% CI, 0.103-0.572; P < 0.01) and integrated discrimination improvement (0.020; 95% CI, 0.004-0.035; P < 0.05) for predicting mortality after discharge. CONCLUSIONS: Predicted ASMI, as well as DEXA-measured ASMI, can predict all-cause death in HF patients, and calculation of predicted ASMI will be useful for detecting high-risk patients in a daily clinical setting and in large population-based studies.

Loss of perceived social role, an index of social frailty, is an independent predictor of future adverse events in hospitalized patients with heart failure.

Aims: Although the impact of physical frailty on prognosis and the effect of cardiac rehabilitation in HF patients has been well established, data for the prognostic impact of social frailty (SF) in HF patients are limited. In addition, the relative importance of each SF domain in clinical outcomes remains unclear. We aimed to get a new insight into the associations of SF with clinical outcomes in elderly hospitalized HF patients. Methods: A single-center, retrospective cohort study was conducted using data from 310 in-hospital HF patients aged ≥ 65 years (mean age of 78 ± 8 years; 49% women). Makizako's five questions, a self-reported questionnaire, were used to define SF. The primary outcome was composite events defined by all-cause death and cardiovascular events. Results: Of the 310 elderly HF patients, 188 patients (61%) had SF. Seventy-five patients (24%) had composite events during a mean follow-up period of 1.93 ± 0.91 years. Kaplan-Meier curves showed that patients with SF had a significantly higher composite event rate than patients without SF. In multivariate Cox regression analyses, SF was independently associated with a higher composite event rate after adjusting for prognostic markers [adjusted hazard ratio (HR), 2.01; 95% confidence interval (CI), 1.07-3.78; p = 0.04]. Of the 5 questions for defining SF, an answer of yes to the question about not feeling helpful toward friends or family, which indicates loss of perceived social role, was an independent predictor of composite events (adjusted HR, 2.28; 95% CI, 1.36-3.82; p < 0.01). Inclusion of loss of perceived social role into the baseline prognostic model improved both the continuous net reclassification improvement (0.562; 95% CI, 0.298-0.827; p < 0.01) and integrated discrimination improvement (0.031; 95% CI, 0.006-0.056; p = 0.02). Conclusion: Loss of perceived social role is associated with increased adverse event risk and provides additive prognostic information in elderly HF patients.