High-Protein Dietary Interventions in Heart Failure: A Systematic Review of Clinical and Functional Outcomes.

The researchers examined whether increasing dietary protein intake above standard recommendations improves clinical outcomes, functional capacity, and body composition in adults with heart failure (HF). The intervention was a high-protein diet, defined as consuming at least 1.1 grams of protein per kilogram of body weight per day (g/kg/day), or roughly 25–30% of total daily calories from protein. This was achieved through whole-food meal modifications, oral nutritional supplements (protein shakes or powders), or amino acid supplements.

The comparator was usual care—either a standard-protein diet (typically <1.0 g/kg/day), a placebo supplement, or continuation of the patient's regular diet without additional protein.

Outcome measures fell into four categories:

**Clinical endpoints:** death from any cause, HF-related hospitalizations

**Functional capacity:** six-minute walk distance (6MWD, in meters), peak oxygen consumption (peak VO₂, in mL/kg/min), exercise tolerance

**Body composition:** lean body mass (kg), total body weight (kg), body fat percentage

**Muscle strength:** handgrip strength (kg), knee extension strength (kg), or other dynamometer measures

**Biochemical markers:** serum albumin (g/dL), natriuretic peptides (BNP or NT-proBNP, pg/mL)

**Quality of life:** disease-specific questionnaires (e.g., Minnesota Living with Heart Failure Questionnaire, MLHFQ, 0–105 scale, lower = better)

The review included 10 trials (9 randomized controlled trials and 1 controlled pilot study) with a total of approximately 1,080 participants. Individual trial sample sizes ranged from 21 to 652 patients, with a median of roughly 38 participants per study. The largest single trial contributed 652 patients; most studies had fewer than 50 participants.

Participants were adults aged 18 years and older with a confirmed diagnosis of heart failure, including both heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). Mean ages across studies ranged from approximately 60 to 70 years. The majority of participants were male, reflecting the typical demographics of HF in older clinical trials. Some trials specifically enrolled patients with signs of malnutrition or cardiac cachexia (unintentional weight loss ≥5% of body weight); others included stable outpatients or patients recently discharged from hospital after an acute HF exacerbation. Studies were conducted in hospital outpatient clinics, cardiac rehabilitation centers, and home-based settings across multiple countries (Sweden, USA, Japan, Italy, and others). No restrictions were placed on HF severity, but most participants had moderate-to-severe HF (New York Heart Association class II–IV).

Each trial used a combination of the following instruments and methods:

**Six-minute walk distance (6MWD):** Patients walked as far as possible on a flat, hard surface in 6 minutes; distance recorded in meters. Higher = better functional capacity.

**Peak oxygen consumption (peak VO₂):** Measured during a cardiopulmonary exercise test on a treadmill or cycle ergometer; expressed in mL/kg/min. Higher = better cardiorespiratory fitness.

**Lean body mass:** Assessed via dual-energy X-ray absorptiometry (DXA), bioelectrical impedance analysis (BIA), or air displacement plethysmography (Bod Pod). Measured in kilograms.

**Muscle strength:** Handgrip strength measured with a hand dynamometer (kg); knee extension or flexion strength measured with an isokinetic dynamometer (Nm or kg).

**Serum albumin:** Blood draw, measured in g/dL. Lower levels indicate malnutrition or inflammation.

**Natriuretic peptides (BNP or NT-proBNP):** Blood draw, measured in pg/mL. Higher levels indicate greater HF severity and fluid overload.

**Quality of life:** Minnesota Living with Heart Failure Questionnaire (MLHFQ, 0–105, lower = better) or Kansas City Cardiomyopathy Questionnaire (KCCQ, 0–100, higher = better).

**Hospital readmissions:** Count of HF-related hospitalizations during follow-up, extracted from medical records or patient self-report.

**Mortality:** All-cause death, confirmed by medical records or family report.

**Study design:** This is a systematic review, not a new experiment. The authors searched four electronic databases (PubMed, MEDLINE, Embase, Cochrane CENTRAL) from their inception through June 2025 for randomized controlled trials and controlled intervention studies of high-protein diets in heart failure. Two independent reviewers screened titles, abstracts, and full texts, extracted data, and assessed risk of bias using the Cochrane Risk of Bias tool (RoB 2) for RCTs. Disagreements were resolved by consensus.

**Inclusion criteria:** Studies had to enroll adults (≥18 years) with HF (any type or severity), implement a high-protein intervention (≥1.1 g/kg/day or ~25–30% of energy from protein), include a control group (usual care, standard protein, or placebo), and report at least one relevant outcome (functional capacity, body composition, muscle strength, clinical events, or biomarkers). Only English-language studies were included.

**Exclusion criteria:** Observational cohort studies, case reports, reviews, and studies without a control group were excluded from the primary analysis (though referenced for context).

**Data synthesis:** The authors initially planned a meta-analysis (quantitative pooling of results) but found substantial heterogeneity across studies—differences in protein dosing (1.1–1.5 g/kg/day), supplement types (oral formulas vs. whole-food modifications), patient subgroups (stable vs. post-discharge, HFrEF vs. HFpEF), outcome measures, and follow-up durations (2–12 months). Because of this variability, they performed a narrative synthesis, grouping studies by outcome domain and summarizing the direction and magnitude of effects. Where at least three trials reported comparable outcomes under similar conditions, they calculated mean changes and ranges.

**Risk of bias assessment:** Two reviewers independently assessed each trial using the Cochrane RoB 2 tool, which evaluates five domains: randomization process, deviations from intended interventions (performance bias), missing outcome data (attrition bias), measurement of the outcome (detection bias), and selective reporting. Each study was rated as "low risk," "some concerns" (moderate risk), or "high risk" of bias overall.

**What this design can and cannot prove:** A systematic review aggregates evidence from multiple studies, providing a broader picture than any single trial. However, because the authors could not perform a meta-analysis (due to heterogeneity), their conclusions are based on qualitative synthesis rather than pooled statistics. This means the review can identify patterns and trends across studies, but it cannot produce a single, precise estimate of effect size. The review can highlight consistent findings (e.g., improvements in walking distance and lean mass) and flag gaps (e.g., inconsistent muscle strength results). It cannot prove causality—that is established by the individual RCTs, not the review itself. The review also cannot control for publication bias (the tendency for positive results to be published more often than null or negative results), though the authors attempted to mitigate this by searching multiple databases and reference lists.

**Major methodological weaknesses:** The included trials had several limitations that the review authors acknowledge: small sample sizes (median ~38 participants), short follow-up durations (most 2–6 months, only one study followed patients for 12 months), varied protein dosing protocols, lack of blinding in some studies (patients and staff knew who was receiving the high-protein intervention), and outcome heterogeneity that prevented meta-analysis. Only two of the ten trials were rated as low risk of bias; three were moderate risk, and one was high risk. The largest trial (n=652) dominated the results for clinical outcomes (readmissions and mortality), meaning the overall conclusions are heavily influenced by a single study.

The review identified 10 eligible trials. Below are the key results, reported as mean changes or ranges across studies where applicable. Note that not all studies measured all outcomes.

**Primary outcomes (functional capacity):**

**Six-minute walk distance (6MWD):** Four trials reported improvements. The mean increase was +32 ± 14 meters (range: +18 to +46 meters) in the high-protein group compared to control. For context, the minimal clinically important difference (MCID) for 6MWD in HF is typically 30–50 meters, so this improvement is borderline clinically meaningful.

**Peak VO₂:** Two trials reported improvements of +1.2 to +2.1 mL/kg/min in the high-protein group. One trial found no significant change. The MCID for peak VO₂ in HF is approximately 1.0–1.5 mL/kg/min, so these gains are modest but potentially meaningful.

**Secondary outcomes (body composition):**

**Lean body mass:** Five trials reported changes. The mean gain was +1.6 ± 0.9 kg (range: +0.5 to +2.8 kg) in the high-protein group compared to control. This is a consistent finding across studies.

**Total body weight:** Results were mixed. Some trials showed weight gain (primarily lean mass), while others showed no change or slight weight loss. High-protein diets did not consistently cause weight gain or loss; the composition of weight change (lean vs. fat mass) was more important.

**Secondary outcomes (muscle strength):**

**Handgrip strength:** Three trials reported changes ranging from −2% to +11% in the high-protein group compared to control. The results were inconsistent and not statistically significant in most studies.

**Knee extension strength:** Two trials reported improvements of +5% to +8%, but neither reached statistical significance.

**Secondary outcomes (clinical endpoints):**

**HF-related hospital readmissions:** Two trials reported this outcome. One large trial (n=652) found an 18% relative reduction in HF readmissions over 6 months in the high-protein group (p < 0.05). The other trial (n=48) found a non-significant trend toward fewer readmissions.

**All-cause mortality:** Only one trial (n=652) reported mortality data. There was no significant difference between groups (high-protein: 8.2% vs. control: 9.1%, p = 0.68).

**Secondary outcomes (quality of life):**

**Quality-of-life scores:** Four trials reported improvements. The mean enhancement was 9 ± 4% (range: 5–14%) on the MLHFQ or KCCQ in the high-protein group compared to control. This corresponds to a 5–10 point improvement on the MLHFQ (0–105 scale), which is below the typical MCID of 10–15 points for that instrument.

**Biochemical markers:**

**Serum albumin:** Three trials reported small increases of +0.2 to +0.4 g/dL in the high-protein group. One trial found no change.

**Natriuretic peptides (BNP/NT-proBNP):** Two trials reported no significant changes. One trial found a small decrease in BNP (−15 pg/mL) that was not statistically significant.

**Risk of bias results:**

2 studies rated low risk of bias

3 studies rated moderate risk ("some concerns")

1 study rated high risk of bias

4 studies had insufficient information to assess (pilot or non-randomized)

To translate these results into plain English:

**Walking distance:** The average improvement of +32 meters in the six-minute walk test is roughly equivalent to walking an extra half-lap around a standard track (400 meters = 1 lap). For someone with HF who struggles to walk 300 meters in 6 minutes, this improvement could mean the difference between needing a rest break and completing a short errand without stopping. However, this gain is at the lower end of what clinicians consider "meaningful" (30–50 meters).

**Lean body mass:** The average gain of +1.6 kg (about 3.5 pounds) of muscle over 2–6 months is modest but biologically relevant. For context, healthy adults doing resistance training typically gain 1–2 kg of lean mass in 3–4 months. In HF patients who are losing muscle due to their disease, even maintaining lean mass is a positive outcome; gaining 1.6 kg represents a reversal of the catabolic process.

**Quality of life:** A 9% improvement on quality-of-life questionnaires is noticeable but not transformative. A patient might report feeling "somewhat better" rather than "much better." For example, they might have slightly less shortness of breath during daily activities or feel a bit more energetic.

**Hospital readmissions:** An 18% relative reduction means that if 100 patients in the control group were readmitted over 6 months, about 82 patients in the high-protein group would be readmitted. This is a clinically meaningful reduction, but it comes from a single large trial and needs replication.

**Muscle strength:** The inconsistent results (−2% to +11%) mean that for the average patient, high-protein diets alone (without resistance exercise) may not reliably increase how much weight they can lift or how hard they can grip. This suggests that protein supplementation may need to be combined with strength training to produce meaningful strength gains.

**What the authors acknowledge:**

Small sample sizes in most trials (median ~38 participants), limiting statistical power to detect differences

Short follow-up durations (2–6 months for most; only one study followed patients for 12 months), providing no data on long-term efficacy or safety

Substantial heterogeneity in protein dosing (1.1–1.5 g/kg/day), supplement types, patient populations, and outcome measures, which prevented meta-analysis

Lack of blinding in several studies (patients and staff knew group assignment), introducing potential performance and detection bias

Only two of ten trials were rated low risk of bias; one was high risk

Possible publication bias (studies with null or negative results may not have been published)

Limited generalizability: most participants were older, male, and had HFrEF; results may not apply to women, younger patients, or those with HFpEF

No data on renal safety beyond short-term follow-up, despite theoretical concerns that high-protein diets could worsen kidney function in patients with pre-existing kidney disease

**What a critical reader would add:**

The largest trial (n=652) dominated the clinical outcomes (readmissions and mortality), meaning the overall conclusions about these endpoints rest heavily on a single study. If that trial had methodological flaws or unique population characteristics, the conclusions could be misleading.

The review did not formally assess publication bias using a funnel plot or statistical test (e.g., Egger's test), which is standard practice in systematic reviews. This is a notable omission.

The definition of "high-protein" varied across studies (1.1–1.5 g/kg/day), and some studies used percentage of energy (25–30%) rather than grams per kilogram. This makes it difficult to determine the optimal protein dose.

Most studies did not control for total calorie intake. If the high-protein group also consumed more total calories (from the protein supplements), the benefits could be due to increased energy intake rather than protein specifically.

Compliance with the dietary intervention was poorly reported. If patients did not actually consume the prescribed protein, the results underestimate the true effect.

The review excluded non-English studies, which could introduce language bias.

Industry funding was not reported for all trials; some supplements may have been provided by manufacturers with a commercial interest in positive results.

For someone running their own n=1 experiment (with medical supervision, as HF is a serious condition):

### What to test

**Intervention:** Increase daily protein intake to 1.2–1.5 g per kilogram of your current body weight. For a 70 kg (154 lb) person, this means 84–105 grams of protein per day. This can be achieved through whole foods (chicken breast ~31g per 100g, Greek yogurt ~10g per