Effects of Protein and Amino Acid Supplementation on Physical Performance in Patients With Chronic Heart Failure　― A Systematic Review and Meta-Analysis ―

Abstract

Background: This study aimed to evaluate the effects of protein and amino acid supplementation on physical performance in patients with chronic heart failure (CHF).

Methods and Results: Studies from PubMed, the Cochrane Library, CINAHL, Web of Science, and PEDro published up to August 2024 were identified using a comprehensive strategy with no limitations on publication date or language. The primary outcome was physical performance, assessed using the 6-min walk distance (6MWD) test. This study included 15 randomized controlled trials involving a total of 744 patients. Control groups received either a placebo or usual care, including standard heart failure treatment. The meta-analysis demonstrated a significant improvement in 6MWD in the supplementation group compared with controls (mean difference 35.25 m; 95% confidence interval 15.93–54.58; I²=38%). Subgroup analysis showed no significant difference between supplementation alone and supplementation combined with exercise, suggesting independent effects. Patients aged ≥65 years showed similar benefits.

Conclusions: Our meta-analysis indicated that physical performance in patients with CHF was improved by using protein and amino acid supplementation, particularly in older adults or those unable to engage in adequate exercise therapy. However, the overall quality of the evidence was very low.

Central Figure

Chronic heart failure (CHF) affects more than 26 million people around the world, and its prevalence continues to rise due to aging populations and improved survival from cardiovascular diseases.¹ CHF develops as a consequence of either structural damage or functional impairment in cardiac anatomy, ultimately compromising cardiac output and oxygen delivery to tissue. Older adults with CHF are particularly susceptible to malnutrition and muscle wasting due to a combination of age-related physiological changes and disease-specific factors. Intestinal edema may impair nutrient absorption, while CHF-related inflammation and neurohormonal activation contribute to loss of appetite and an imbalance between protein catabolism and anabolism.^2,3 These mechanisms, along with an age-associated decline in muscle protein synthesis, increase the risk of sarcopenia and frailty.⁴ These geriatric syndromes are associated with reduced physical performance, a decline in quality of life, and a heightened likelihood of hospital admission and death among individuals with CHF.^5,6 Exercise training plays a central role in CHF management and is endorsed as a Class I treatment for stable patients in clinical guidelines.^3,7 However, many patients with CHF are older adults with sarcopenia or frailty, which may limit their ability to participate in resistance or aerobic training at sufficient intensity.^8,9

Nutritional supplementation has emerged as a potential strategy to counteract muscle wasting and functional decline. Protein and amino acid (AA) supplementation stimulates skeletal muscle anabolism, potentially preserving muscle mass and enhancing physical performance.^10,11 Randomized controlled trials (RCTs) targeting older adults with sarcopenia have demonstrated that protein and AA supplementation can improve lean body mass, muscle strength, physical performance, and quality of life.^12–14 Similar benefits have been observed in some populations with CHF; however, the evidence remains limited and inconsistent, mainly due to methodological limitations of small, heterogeneous studies. While guidelines support comprehensive nutritional management in CHF, specific recommendations for protein or AA supplementation are lacking.^2,3 Thus, clarifying the effects of protein-based nutritional interventions is crucial for optimizing care in this vulnerable population.

Therefore, this study aimed to assess the effects of dietary protein and AA supplementation on physical performance in patients with CHF.

Methods

This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 statement.¹⁵ This study protocol was registered with PROSPERO (CRD42023403818).

Search Methods for Identifying Trials

We searched PubMed, the Cochrane Library, the Cumulative Index to Nursing and Allied Health (CINAHL), the Web of Science, and the Physiotherapy Evidence Database (PEDro) for trials published in these electronic databases up to August 2024. Moreover, ClinicalTrials.gov was searched to identify ongoing trials registered in the trials registry. To ensure thorough and relevant coverage, we conferred with specialists when creating the search strategies for each database. We used free-text terms, keywords from titles and abstracts, and medical subject headings (Supplementary File 1). Our search was limited to peer-reviewed trials involving human participants.

Inclusion and Exclusion Criteria

Only published RCTs that satisfied the following requirements were included: (1) RCTs involving participants aged ≥18 years diagnosed with either heart failure with reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF); and (2) RCTs on interventions involving oral supplementation of proteins and AA. We adopted an inclusive definition of ‘protein/AA-based supplementation’ that also encompassed AA-derived nitrogenous compounds (e.g., creatine, carnosine) investigated for their potential to improve skeletal muscle energetic capacity or fatigue resistance. Regarding the intervention period, trials that implemented interventions lasting at least 4 weeks were included based on previous research.¹⁰ The primary outcomes in this review were physical performance indicators, including the 6-min walk distance (6MWD) and gait speed. Furthermore, data on secondary outcomes were collected, including body composition (skeletal muscle and fat mass), muscle strength (grip strength and knee extension strength), adverse events, and changes in renal function.

Data Extraction

Study characteristics and outcome data were collected using a standardized data extraction form. Two independent reviewers (Y.K., Y.F.) independently extracted the data. Discrepancies were resolved through discussion or, if necessary, by consulting a third reviewer (H.M.), who also independently verified the accuracy and completeness of the extracted data.

The data extraction form included the following information: participant demographics (mean age, sex, body mass index [BMI]), clinical status (New York Heart Association Functional Classification [NYHA-FC], and left ventricular ejection fraction [LVEF]), intervention details (type, dosage, frequency, and duration), control group conditions, and outcome measures, including physical performance (e.g., 6MWD, walking speed), body composition, muscle strength, renal function, and adverse events.

Among these results, the primary outcome was physical performance. The secondary outcomes were body composition, muscle strength, adverse events, and changes in renal function. When outcome data were incomplete, the authors of the original studies were contacted for confirmation or to obtain missing data.

Assessment of the Risk of Bias in the Included Trials

Two reviewers (Y.K., H.M.) independently conducted risk of bias assessments. The evaluation was based on the Revised Cochrane RoB 2 tool designed for RCTs.¹⁶ Their assessment covered 5 domains: (1) bias arising from the randomization process; (2) bias due to deviations from the intended intervention; (3) bias due to missing outcome data; (4) bias in the measurement of outcomes; and (5) bias in the selection of reported outcomes.¹⁶ Disagreements were resolved through discussion. If a consensus could not be reached, a third reviewer (T.K.) was consulted to make the final decision.

Assessment of Evidence Certainty

The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system was used to assess the certainty of evidence for the predefined outcomes.¹⁷ GRADE rates the quality of evidence on a 4-point scale (very low, low, moderate, and high), considering the consistency of effects, non-linearity, imprecision, and the risk of publication bias. The evaluation was conducted using the GRADEpro GDT,¹⁸ and the Cochrane Handbook for Systematic Reviews of Interventions was followed to guide the review process and recommendations.¹⁹

Data Synthesis and Analysis

In the meta-analysis, participants were categorized into 2 groups: those who received supplementation (either alone or in combination with exercise therapy), and those who received usual care or placebo, typically consisting of standard pharmacological treatment for heart failure.

To take into consideration possible heterogeneity among the included trials, such as variations in demographics and intervention techniques, all analyses were conducted using a random-effects model. Risk ratios (RRs) with 95% confidence intervals (CIs) were used to integrate data on binary variables. Standardized mean differences (SMDs) were used for continuous variable data when measures and scales varied between trials and mean differences (MDs) when they were the same. The means for analysis were calculated when trials only provided medians.²⁰ Heterogeneity among the included trials was quantified using the I² statistic and the degree of heterogeneity was interpreted based on the following criteria: 0–40% (negligible); 30–60% (moderate); 50–90% (substantial); and 75–100% (considerable). Furthermore, the statistical significance of heterogeneity was evaluated using Cochran’s Q test (χ² test), where a P value of <0.10 is deemed statistically significant. When more than 10 trials were included in the meta-analysis, potential publication bias was assessed using funnel plots and visually checked for asymmetry.²¹ The following criteria were used to perform subgroup analyses for the primary outcomes: (1) age (≤65 years or >65 years); and (2) type of intervention (supplementation alone or supplementation with exercise treatment). To further assess the robustness of the findings, we conducted sensitivity analyses that (1) excluded trials investigating creatine or carnosine supplementation, and (2) eliminated trials with a high risk of bias. All analyses were performed using Review Manager software (RevMan 5.4).

Results

The database was searched, and 8,694 records were found. After removing duplicates, we looked at the abstract and title of 5,308 records to filter them. Forty-six of these records were eligible and went through full-text review. The reasons for study exclusion during full-text screening are summarized in the PRISMA flow diagram (Figure 1). In the end, 15 trials^22–36 with 744 patients satisfied the requirements for inclusion in this review.

Figure 1.

Preferred reporting items for systematic reviews and meta-analyses flow diagram. CINAHL, Cumulative Index to Nursing and Allied Health Literature; PEDro, Physiotherapy Evidence Database; RCT, randomized controlled trial.

Table 1 summarizes the characteristics of the trials included in this analysis. This review analyzed trials conducted between 2008 and 2023. Sample sizes ranged from 11 to 157 participants, with a mean age of participants between 51 and 80 years. Most studies enrolled outpatients, while only 1 study also included inpatients. The intervention periods span from 6 weeks to 6 months (median 12 weeks). Regarding intervention methods, 6 trials administered protein supplements, 8 provided AA, and 1 combined both. Additionally, 5 trials incorporated exercise therapy (Table 2). Notably, most participants were classified as NYHA-FC class II or III. Based on LVEF, 6 trials investigated only HFrEF, 1 focused on HFpEF, 3 included both classifications, and 5 did not report LVEF data. Adherence rates were reported in 5 trials, ranging from 71% to 95%, while the remaining 10 trials did not provide adherence information.

Table 1.

Characteristics of Included Trials

Author	Country	No. patients, n (intervention/ control) Age (years) Sex, % male	LVEF (%) NYHA-FC	Type of supplementation	Total daily intake (g/day) Frequency (times/day)	Comparisons	Intervention duration	Adherence (%) and assessment method
Carvalho et al. (2012)24	Brazil	33 (17/16) 60±10 100	NR II–IV	Creatine	5 1	Placebo	6 months	NR NR
Lombardi et al. (2015)25	Italy	50 (25/25) 62±10 88	<45 I–III	L-carnosine	0.5 1	Standard care	6 months	NR NR
Wu et al. (2015)26	United States	31 (17/14) 58±3 84	≤35 I–IV	L-alanyl – L-glutamine	8 NR	Placebo	3 months	NR NR
Azhar et al. (2020)30	United States	16 (8/8) 72±9 45	>50 II, III	Whey protein	50 NR	Standard care	12 weeks	90 Food diary review
Pineda- Juárez et al. (2016)28	Mexico	66 (34/32) 72±16 59	≤30 II–IV	BCAA	10 2	Resistance exercise therapy	12 weeks	NR NR
Hotta et al. (2021)31	Japan	20 (10/10) 73±8 50	NR II, III	Whey peptides BCAA	20 2	Cardiac rehabilitation	12 weeks	NR NR
Salmani et al. (2021)32	Italy	50 (25/25) 56±6 68	<40 II, III	L-arginine	9 3	Placebo	10 weeks	85 NR
George et al. (2017)29	United States	11 (6/5) 80±6 45	NR II, III	Whey protein	NR NR	Nutritional counseling and education	6 months	NR Logbooks
Deutz et al. (2016)27	United States	157 (79/78) 78±8 NR	NR I–IV	Protein Calcium-HMB	40 2	Placebo	Hospitalization and 90 days post-discharge	90 Self-report
Rozentryt et al. (2010)23	Germany	29 (23/6) 51±10 76	≤30 II–IV	Protein	40 2	Placebo	6 weeks	NR NR
Cornelissen et al. (2010)22	Belgium	80 (40/40) 57±8 83	NR NR	Creatine	9 1	Placebo and exercise training	3 months	NR Biomarker analysis
Aquilani et al. (2008)33	Italy	38 (21/17) 74±4 71	≤30 II, III	EAA	8 2	Placebo	2 months	NR Packet counts/ biomarker analysis
Dos Santos et al. (2023)34	Brazil	33 (17/16) 65±12 79	≤50 I, II	Whey protein isolate	30 NR	Placebo	12 weeks	NR NR
Azhar et al. (2021)35	United States	92 (60/32) 76±1 32	≤60 I–III	Whey protein isolate EAA	18 2	Education	12 weeks	95 NR
Herrera- Martínez et al. (2023)36	Spain	38 (19/19) 68±12 29	<50 I–III	Protein	20 2	Mediterranean diet	24 weeks	71 Self-report

BCAA, branched-chain amino acid; EAA, essential amino acid; HMB, β-hydroxy-β-methylbutyrate; LVEF, left ventricular ejection fraction; NR, not reported; NYHA-FC, New York Heart Association functional classification.

Table 2.

Characteristics of Exercise Programs in 5 Trials Combined With Exercise

Author	Follow up	Type of exercise	Frequency (times/week)	Time of exercise (min)	Comparisons
Azhar et al. (2020)30	12 weeks	Gym session, water-based exercise session	3	70	Standard care
Pineda-Juárez et al. (2016)28	12 weeks	Resistance exercise	2	60	Resistance exercise
Hotta et al. (2021)31	12 weeks	Endurance training, low resistance training, self-exercise	3	NR	Cardiac rehabilitation
George et al. (2017)29	6 months	Aerobic and resistance exercises	6	20	Nutritional counseling and education
Cornelissen et al. (2010)22	3 months	Endurance training, moderate resistance training	3	90	Placebo and exercise training

NR, not reported.

Quality and Bias Assessment in the Included Trials

Figure 2 summarizes the risk of bias associated with physical performance. The overall risk of bias was classified as ‘high’, based on several factors, including the randomization process, deviations from the intended interventions, missing outcome data, and outcome measurement. We did not use a funnel plot to evaluate publication bias because there were fewer than 10 trials in the study.

Figure 2.

Risk of bias summaries for physical performance. (A) Risk of bias summary. (B) Risk of bias graph.

Primary Outcomes

Physical Performance Nine trials involving a total of 324 participants assessed physical performance. All trials used the 6MWD test as the primary measurement. The results showed that the supplement group improved significantly compared with the control group (MD 35.25; 95% CI 15.93–54.58; I²=38%; Figure 3). Excluding the 2 trials investigating creatine or carnosine, the pooled effect remained significant (MD 33.68; 95% CI 10.47–56.88; I²=45%), supporting the robustness of the primary finding (Supplementary Figure 1). A subgroup analysis was conducted based on the intervention method: supplement only (MD 39.94; 95% CI 9.68–70.19; I²=56%) and supplementation combined with exercise therapy (MD 36.28; 95% CI 13.21–59.35; I²=0%). This analysis revealed no significant difference between the 2 groups (test for subgroup differences: P=0.85; Figure 4). Another subgroup analysis was performed based on participant age: ≥65 years (MD 43.14; 95% CI 22.46–63.83; I²=0%) and <65 years (MD 28.97; 95% CI −4.25 to 62.19; I²=59%). Participants aged ≥65 years showed a significant improvement in physical performance, and no significant difference was observed between the age-based subgroups (test for subgroup differences: P=0.48; Figure 5). According to the GRADE approach, the quality of evidence was rated as ‘very low’ due to the high risk of bias and severe imprecision (Table 3).

Figure 3.

Forest plot comparing physical performance (6-min walk distance; m) between the supplement and control groups. CI, confidence interval; SD, standard deviation.

Figure 4.

Forest plot comparing physical performance (6-min walk distance; m) between the supplement and control groups. Subgroup analysis based on the intervention method (supplement alone vs. combination with exercise therapy). CI, confidence interval; SD, standard deviation.

Figure 5.

Forest plot comparing physical performance (6-min walk distance; m) between the supplement and control groups. Subgroup analysis based on age (≥65 years vs. <65 years). CI, confidence interval; SD, standard deviation.

Table 3.

Summary of Findings in This Review

Outcomes	Anticipated absolute effects (95% CI)†		Relative effect (95% CI)	No. participants (trials)	Certainty of the evidence (grade)
	Risk with control	Risk with supplement
Physical performance	Mean physical performance ranged 310–522 m	MD 35.25 m higher (15.93 higher to 54.58 higher)	–	324 (9 RCTs)	⊕〇〇〇 Very low‡,§
Adverse event	65 per 1,000	77 per 1,000 (31 to 194)	RR 1.20 (0.48 to 3.00)	203 (4 RCTs)	⊕〇〇〇 Very low‡,¶
Muscle strength	Mean muscle strength ranged 24.3–28.7 kg	MD 0.66 kg higher (1.69 lower to 3.02 higher)	–	161 (6 RCTs)	⊕〇〇〇 Very low‡,¶
Body composition	–	SMD 0.06 higher (0.22 lower to 0.35 higher)	–	205 (5 RCTs)	⊕〇〇〇 Very low‡,¶
Renal function	Mean renal function ranged 1.17–1.20 mg/dL	MD 0.05 higher (0.05 lower to 0.16 higher)	–	113 (3 RCTs)	⊕⊕〇〇 Low¶

^†The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). ^‡Downgraded 1 level due to risk of bias. ^§Downgraded 1 level due to imprecision. ^¶Downgraded 2 levels due to imprecision. CI, confidence interval; MD, mean difference; RCTs, randomized controlled trials; RR, risk ratio; SMD, standardized mean difference.

Secondary Outcomes

Adverse Events Four trials involving 203 participants assessed adverse events, which were defined as any occurrence other than serious outcomes like death or rehospitalization (Supplementary Figures 2,3). The most frequently reported adverse events were gastrointestinal symptoms, including diarrhea, nausea, and abdominal pain. No significant difference was observed in the incidence of adverse events between the 2 groups (RR 1.05; 95% CI 0.35–3.10; I²=0%).

Body Composition Five trials involving 205 participants assessed body composition by measuring lean body mass, skeletal muscle index, body fat mass, and muscle cross-sectional area (Supplementary Figures 4,5). The analysis showed no significant difference in body composition between the 2 groups (SMD 0.06; 95% CI −0.22 to 0.35; I²=0%).

Muscle Strength Six trials involving 161 participants assessed muscle strength. All trials measured handgrip strength (Supplementary Figures 6,7). No significant difference was found between the 2 groups (MD 0.66; 95% CI −1.96 to 3.02; I²=44%).

Renal Function Three trials involving 113 participants examined renal function using creatinine levels as the primary measure (Supplementary Figures 8,9). No significant difference was observed in renal function between the 2 groups (MD 0.05; 95% CI −0.05 to 0.16; I²=0%).

Discussion

This review included 15 RCTs involving 744 participants. Notably, 50% of the participants were aged ≥65 years and most were male. The findings showed that protein and AA supplementation significantly improved physical performance, as measured using the 6MWD, in patients with CHF. However, supplementation had no significant impact on muscle strength, body composition, or renal function. These findings suggest that while protein and AA supplementation may enhance physical performance in patients with CHF, their role in skeletal muscle adaptation remains unclear.

Our findings are consistent with previous meta-analyses investigating nutritional supplementation in older adults with sarcopenia or chronic diseases.^37,38 This discrepancy may reflect the need for additional anabolic stimuli such as resistance exercise, as well as age-related anabolic resistance that impairs responsiveness to protein intake.

In our study, although no consistent changes in muscle mass or strength were observed, protein and AA supplementation improved the 6MWD, suggesting the involvement of non-hypertrophic mechanisms. These may include: (1) improved muscular energy efficiency; (2) reduced inflammation and enhanced muscle quality; and (3) better neuromuscular coordination. The 6MWD integrates cardiovascular, musculoskeletal, and psychological responses under submaximal conditions,³⁹ and therefore may be more sensitive to functional adaptations than to changes in maximal strength or body composition. Such non-hypertrophic mechanisms may be particularly relevant for older adults with CHF, whose physiological reserve and responsiveness to anabolic stimuli are often limited. Notably, our findings build on previous reviews by providing quantitative confirmation of a statistically significant effect across a larger number of trials.

Our subgroup analysis found no significant difference in effectiveness between supplementation alone and supplementation combined with exercise. This suggests that protein or AA supplementation may independently improve physical performance. These findings are particularly relevant in clinical settings where some older adults with heart failure are unable to engage in sufficient exercise therapy, highlighting that supplementation is a potentially practical and effective strategy. However, as it is commonly assumed that combining exercise with supplementation would yield greater benefits, the absence of an additive effect in our analysis requires further investigation. Possible explanations include the limited number of available studies, which may have restricted a more in-depth assessment of the effects or participant characteristics that influence responsiveness to exercise.

Furthermore, the observation that patients aged ≥65 years showed improvements comparable with those of younger patients supports the applicability of this approach to the typical heart failure population, which is predominantly older. These findings support the use of protein and AA supplementation as an adjunctive intervention to enhance physical performance in patients with CHF, particularly those who have difficulty engaging in exercise therapy. Current CHF guidelines emphasize the importance of nutritional support but do not offer specific recommendations regarding protein or AA supplementation.^2,3,7 However, supplementation alone may not be sufficient, and incorporating structured exercise programs could be essential for meaningful gains in muscle strength and physical performance.

Study Limitations

The present study has several limitations. First, the number of trials and participants included was relatively limited. Moreover, a considerable number of studies were judged to carry a high risk of bias. Methodological limitations such as small sample sizes, lack of blinding, and missing outcome data undermined the reliability of the findings. Second, the different supplementation protocols (e.g., whey, branched-chain AAs, essential AAs, β-hydroxy β-methylbutyrate), dosage, and duration may have influenced the results. Moreover, inconsistent reporting of adherence across studies further limits interpretability. Future research should adopt standardized adherence measures to improve comparability.

Furthermore, most trials were conducted in Western countries, where patients typically have a higher BMI. In contrast, patients with CHF in Asian countries such as Japan often present with lower BMI and a higher prevalence of sarcopenia.^6,40 These physiological differences suggest that nutritional interventions may yield different effects in these populations. Our findings have direct implications for aging populations in Asia, where access to exercise therapy may be limited by geographic or resource-related constraints. In particular, older Asian patients with HFpEF – who may be more vulnerable to sarcopenia – could represent a relevant subgroup for future research on nutritional strategies, although current evidence remains limited.^3,41

Conclusions

Protein and AA supplementation can improve physical performance in patients with CHF without increasing the risk of adverse events. This benefit is particularly relevant for older patients who cannot participate in adequate exercise therapy, suggesting that supplementation may be a practical alternative to support physical performance in this population.

Acknowledgments

This study was supported by the Public Interest Incorporated Foundation Kisshokai, Medical Research Grant, FY2024 (Reiwa 6). The sponsor had no role in the study design, data collection, analysis, interpretation, decision to submit the manuscript, or its preparation. English proofreading assistance was provided using ChatGPT (OpenAI) in accordance with the Journal’s policy on the use of AI tools. The authors thank all individuals who contributed to this review.

Disclosures

This work was supported by the Public Interest Incorporated Foundation Kisshokai, Medical Research Grant, FY2024 (Reiwa 6). The funder had no role in the design, conduct, analysis, or reporting of the study.

IRB Information

Not applicable. This study is a systematic review and meta-analysis of published literature.

Data Availability

The deidentified participant data extracted from the included studies will be shared upon reasonable request. Please contact the corresponding author for further information.

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circrep.CR-25-0100

References

• 1.   Savarese G, Lund LH. Global public health burden of heart failure. Card Fail Rev 2017; 3: 7–11, doi:10.15420/cfr.2016:25:2.
• 2.   Makita S, Yasu T, Akashi YJ, Adachi H, Izawa H, Ishihara S, et al. JCS/JACR 2021 Guideline on rehabilitation in patients with cardiovascular disease. Circ J 2022; 87: 155–235, doi:10.1253/circj.CJ-22-0234.
• 3.   McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2021; 42: 3599–3726, doi:10.1093/eurheartj/ehab368.
• 4.   Lena A, Anker MS, Springer J. Muscle wasting and sarcopenia in heart failure: The current state of science. Int J Mol Sci 2020; 21: 6549, doi:10.3390/ijms21186549.
• 5.   Yang X, Lupón J, Vidán MT, Ferguson C, Gastelurrutia P, Newton PJ, et al. Impact of frailty on mortality and hospitalization in chronic heart failure: A systematic review and meta-analysis. J Am Heart Assoc 2018; 7: e008251, doi:10.1161/JAHA.117.008251.
• 6.   Konishi M, Kagiyama N, Kamiya K, Saito H, Saito K, Ogasahara Y, et al. Impact of sarcopenia on prognosis in patients with heart failure with reduced and preserved ejection fraction. Eur J Prev Cardiol 2021; 28: 1022–1029, doi:10.1093/eurjpc/zwaa117.
• 7.   Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM, et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure: A report of the American College of Cardiology/American Heart Association joint committee on clinical practice guidelines. Circulation 2022; 145: e895–e1032, doi:10.1161/CIR.0000000000001063.
• 8.   Chen R, Xu J, Wang Y, Jiang B, Xu X, Lan Y, et al. Prevalence of sarcopenia and its association with clinical outcomes in heart failure: An updated meta-analysis and systematic review. Clin Cardiol 2023; 46: 260–268, doi:10.1002/clc.23970.
• 9.   Kono Y, Sakurada K, Iida Y, Iwata K, Kato M, Kamiya K, et al. Real-world evidence of feasible assessment and intervention in cardiovascular physical therapy for older patients with heart failure: Insight from the J-Proof HF of the Japanese Society of Cardiovascular Physical Therapy. Circ Rep 2024; 6: 441–447, doi:10.1253/circrep.CR-24-0058.
• 10.   Nichols S, McGregor G, Al-Mohammad A, Ali AN, Tew G, O’Doherty AF. The effect of protein and essential amino acid supplementation on muscle strength and performance in patients with chronic heart failure: A systematic review. Eur J Nutr 2020; 59: 1785–1801, doi:10.1007/s00394-019-02108-z.
• 11.   Kamei Y, Hatazawa Y, Uchitomi R, Yoshimura R, Miura S. Regulation of skeletal muscle function by amino acids. Nutrients 2020; 12: 261, doi:10.3390/nu12010261.
• 12.   Bauer J, Morley JE, Schols AMWJ, Ferrucci L, Cruz-Jentoft AJ, Dent E, et al. Sarcopenia: A time for action. An SCWD position paper. J Cachexia Sarcopenia Muscle 2019; 10: 956–961, doi:10.1002/jcsm.12483.
• 13.   Springer J, Springer JI, Anker SD. Muscle wasting and sarcopenia in heart failure and beyond: Update 2017. ESC Heart Fail 2017; 4: 492–498, doi:10.1002/ehf2.12237.
• 14.   Cheng H, Kong J, Underwood C, Petocz P, Hirani V, Dawson B, et al. Systematic review and meta-analysis of the effect of protein and amino acid supplements in older adults with acute or chronic conditions. Br J Nutr 2018; 119: 527–542, doi:10.1017/S0007114517003816.
• 15.   Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ 2021; 372: n71, doi:10.1136/bmj.n71.
• 16.   Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: A revised tool for assessing risk of bias in randomised trials. BMJ 2019; 366: l4898, doi:10.1136/bmj.l4898.
• 17.   Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, et al. GRADE guidelines: 1. Introduction: GRADE evidence profiles and summary of findings tables. J Clin Epidemiol 2011; 64: 383–394, doi:10.1016/j.jclinepi.2010.04.026.
• 18.   Basu A. A tutorial on how to use Gradepro GDT Tool for writing reviews. PeerJ Preprints 2016; 4: e2520v1, doi:10.7287/PEERJ.PREPRINTS.2520V1.
• 19.   Higgins JPT, Green S. Cochrane handbook for systematic reviews of interventions: Cochrane book series. Hoboken, NJ: Wiley-Blackwell; 2008, doi:10.1002/9780470712184.
• 20.   Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodol 2005; 5: 13, doi:10.1186/1471-2288-5-13.
• 21.   Sterne JAC, Sutton AJ, Ioannidis JPA, Terrin N, Jones DR, Lau J, et al. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ 2011; 343: d4002, doi:10.1136/bmj.d4002.
• 22.   Cornelissen VA, Defoor JGM, Stevens A, Schepers D, Hespel P, Decramer M, et al. Effect of creatine supplementation as a potential adjuvant therapy to exercise training in cardiac patients: A randomized controlled trial. Clin Rehabil 2010; 24: 988–999, doi:10.1177/0269215510367995.
• 23.   Rozentryt P, von Haehling S, Lainscak M, Nowak JU, Kalantar-Zadeh K, Polonski L, et al. The effects of a high-caloric protein-rich oral nutritional supplement in patients with chronic heart failure and cachexia on quality of life, body composition, and inflammation markers: A randomized, double-blind pilot study. J Cachexia Sarcopenia Muscle 2010; 1: 35–42, doi:10.1007/s13539-010-0008-0.
• 24.   Carvalho APPF, Rassi S, Fontana KE, Correa K de S, Feitosa RHF. Influence of creatine supplementation on the functional capacity of patients with heart failure. Arq Bras Cardiol 2012; 99: 623–629, doi:10.1590/s0066-782x2012005000056.
• 25.   Lombardi C, Carubelli V, Lazzarini V, Vizzardi E, Bordonali T, Ciccarese C, et al. Effects of oral administration of orodispersible levo-carnosine on quality of life and exercise performance in patients with chronic heart failure. Nutrition 2015; 31: 72–78, doi:10.1016/j.nut.2014.04.021.
• 26.   Wu C, Kato TS, Ji R, Zizola C, Brunjes DL, Deng Y, et al. Supplementation of l-alanyl-l-glutamine and fish oil improves body composition and quality of life in patients with chronic heart failure. Circ Heart Fail 2015; 8: 1077–1087, doi:10.1161/CIRCHEARTFAILURE.115.002073.
• 27.   Deutz NE, Matheson EM, Matarese LE, Luo M, Baggs GE, Nelson JL, et al. Readmission and mortality in malnourished, older, hospitalized adults treated with a specialized oral nutritional supplement: A randomized clinical trial. Clin Nutr 2016; 35: 18–26, doi:10.1016/j.clnu.2015.12.010.
• 28.   Pineda-Juárez JA, Sánchez-Ortiz NA, Castillo-Martínez L, Orea-Tejeda A, Cervantes-Gaytán R, Keirns-Davis C, et al. Changes in body composition in heart failure patients after a resistance exercise program and branched chain amino acid supplementation. Clin Nutr 2016; 35: 41–47, doi:10.1016/j.clnu.2015.02.004.
• 29.   George M, Azhar G, Pangle A, Peeler E, Dawson A, Coker R, et al. Feasibility of conducting a 6-month long home-based exercise program with protein supplementation in elderly community-dwelling individuals with heart failure. J Physiother Phys Rehabil 2017; 2: 137, doi:10.4172/2573-0312.1000137.
• 30.   Azhar G, Raza S, Pangle A, Coleman K, Dawson A, Schrader A, et al. Potential beneficial effects of dietary protein supplementation and exercise on functional capacity in a pilot study of individuals with heart failure with preserved ejection fraction. Gerontol Geriatr Med 2020; 6: 2333721420982808, doi:10.1177/2333721420982808.
• 31.   Hotta K, Taniguchi R, Nakayama H, Yamaguchi F, Sato Y. The effects of an oral nutritional supplement with whey peptides and branched-chain amino acids for cardiac rehabilitation of patients with chronic heart failure. Int Heart J 2021; 62: 1342–1347, doi:10.1536/ihj.21-102.
• 32.   Salmani M, Alipoor E, Navid H, Farahbakhsh P, Yaseri M, Imani H. Effect of l-arginine on cardiac reverse remodeling and quality of life in patients with heart failure. Clin Nutr 2021; 40: 3037–3044, doi:10.1016/j.clnu.2021.01.044.
• 33.   Aquilani R, Opasich C, Gualco A, Verri M, Testa A, Pasini E, et al. Adequate energy-protein intake is not enough to improve nutritional and metabolic status in muscle-depleted patients with chronic heart failure. Eur J Heart Fail 2008; 10: 1127–1135, doi:10.1016/j.ejheart.2008.09.002.
• 34.   Dos Santos EM, Moreira ASB, Huguenin GVB, Tibiriça E, De Lorenzo A. Effects of whey protein isolate on body composition, muscle mass, and strength of chronic heart failure patients: A randomized clinical trial. Nutrients 2023; 15: 2320, doi:10.3390/nu15102320.
• 35.   Azhar G, Wei JY, Schutzler SE, Coker K, Gibson RV, Kirby MF, et al. Daily consumption of a specially formulated essential amino acid-based dietary supplement improves physical performance in older adults with low physical functioning. J Gerontol A Biol Sci Med Sci 2021; 76: 1184–1191, doi:10.1093/gerona/glab019.
• 36.   Herrera-Martínez AD, Muñoz Jiménez C, López Aguilera J, Crespin MC, Manzano García G, Gálvez Moreno MÁ, et al. Mediterranean diet, vitamin D, and hypercaloric, hyperproteic oral supplements for treating sarcopenia in patients with heart failure: A randomized clinical trial. Nutrients 2023; 16: 110, doi:10.3390/nu16010110.
• 37.   Nasimi N, Sohrabi Z, Nunes EA, Sadeghi E, Jamshidi S, Gholami Z, et al. Whey protein supplementation with or without vitamin D on sarcopenia-related measures: A systematic review and meta-analysis. Adv Nutr 2023; 14: 762–773, doi:10.1016/j.advnut.2023.05.011.
• 38.   Chang MC, Choo YJ. Effects of whey protein, leucine, and vitamin D supplementation in patients with sarcopenia: A systematic review and meta-analysis. Nutrients 2023; 15: 521, doi:10.3390/nu15030521.
• 39.   ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS statement: Guidelines for the six-minute walk test: Guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002; 166: 111–117, doi:10.1164/ajrccm.166.1.at1102.
• 40.   Zhang Y, Zhang J, Ni W, Yuan X, Zhang H, Li P, et al. Sarcopenia in heart failure: A systematic review and meta-analysis. ESC Heart Fail 2021; 8: 1007–1017, doi:10.1002/ehf2.13255.
• 41.   Kitzman DW, Whellan DJ, Duncan P, Pastva AM, Mentz RJ, Reeves GR, et al. Physical rehabilitation for older patients hospitalized for heart failure. N Engl J Med 2021; 385: 203–216, doi:10.1056/NEJMoa2026141.