Heart failure (HF) is a global health pandemic that affects 26 million people worldwide, and is increasing rapidly due to the aging population.1 In 2021, HF was defined as a clinical syndrome with symptoms (e.g. dyspnea, and fatigue) and/or signs (e.g. pulmonary crackles and peripheral edema) caused by a structural and/or functional cardiac abnormality and corroborated by elevated natriuretic peptide levels and/or objective evidence of pulmonary or systemic congestion.2,3 Exercise intolerance, dyspnea, and fatigue are hallmark features of HF. The pathophysiological mechanisms underlying diminished functional capacity in HF are multifactorial, including both central and peripheral mechanisms such as abnormal skeletal muscle metabolism, muscle atrophy and a switch from slow type I to fast type II myofibrils.4,5 Furthermore, sarcopenia, characterized by reduced muscle mass and strength, affects up to 30–50% of patients with HF and reduced ejection fraction (HFrEF),6 contributing to increased morbidity.7–9

Given the high prevalence of HF and its profound impact on both functional capacity and health related quality of life (HRQoL), comprehensive interventions aimed at alleviating symptoms are crucial. Emerging evidence suggests that creatine may offer potential benefits for patients with HF. Creatine is a natural molecule comprised of 3 amino acids (methionine, arginine and glycine) that is primarily stored in skeletal muscle but also exists in the myocardium.10 It plays a pivotal role in energy metabolism by enabling rapid adenosine triphosphate (ATP) resynthesis, thereby enhancing muscular performance (Fig. 1).11,12 Consequently, creatine stands as the most widely used and studied supplement in athletes, demonstrating a broad spectrum of benefits, such as enhanced muscle strength and recovery, muscle mass gain, improved glycogen synthesis, and increased endurance.13,14 Some studies also suggest potential benefits for bone structure, cognitive functions, and even mood.15

Fig. 1.

Metabolic pathway: creatine, phosphocreatine, and ATP cycling. ADP, adenosine diphosphate; ATP, adenosine triphosphate; CK, creatine kinase; Cr, creatine; PCr, phosphocreatine.

Creatine preparations range from 5g/day to 30g/day, with studies showing that doses can vary widely to achieve effective intramuscular concentrations. However, the most commonly used and well-researched form is creatine monohydrate (CM) at a dose of 5g/day.13,16 In addition to the benefits it provides, CM has demonstrated to be safe, with the most common side effect being a slight increase in weight, attributed to enhanced muscle glycogen storage.9,17,13 A mild increase in serum creatinine (Cr) levels is observed during supplementation, but this rise is transient and does not affect other renal function parameters.18,19

In recent years, the use of CM has extended beyond the realm of athletic performance and has been tested in neurological disorders such as Parkinson's disease, mitochondrial encephalomyopathies and amyotrophic lateral sclerosis, suggesting potential improvement in muscle endurance, strength, exercise capacity and HRQoL.20–23 This application has sparked interest in exploring CM supplementation in HF. The benefits are 2-fold. Firstly, it could improve cardiac function, and potentially slow myocardial deterioration by replenishing intramyocardial creatine, phosphocreatine, and ATP levels. Secondly, it could enhance skeletal muscle performance helping to prevent sarcopenia. Experimental studies have demonstrated increased myocardial performance with in vitro supplementation,24 but in vivo evidence remains limited. Previous research suggests CM in patients with HF improves functional capacity and muscle strength, while maintaining safety.25–28 Nonetheless, these studies have small sample sizes and heterogeneous protocols and dosages.

Therefore, the aim of the current study was to investigate the impact of oral CM on functional capacity measured by the 6-minute walk test (6MWT) and HRQoL assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ). Additionally, we sought to evaluate the safety of the intervention and its impact on blood analysis and echocardiographic parameters, as well as long-term outcomes, including HF decompensations and cardiovascular (CV) mortality at 1 year. We hypothesized that oral CM would enhance functional capacity and HRQoL in HF patients and have no effect on echocardiographic, blood analysis parameters, HF decompensations or CV mortality.

The current study aimed to investigate whether a short period of CM supplementation (5g/day for 3 months), enhances exercise capacity, HRQoL, echocardiographic and laboratory parameters, in patients with HF. We also sought to evaluate the safety of this intervention.

In accordance with our initial hypothesis, CM supplementation proved safe for HF patients. No adverse outcomes were reported during supplementation, and we did not observe any significant increase in HF decompensations during the intervention or at 1-year follow-up. The rate of HF decompensation was 16% at 1-year, comparable to the annual rate reported in the ESC-HF-LT registry for patients with HFrEF.30 Additionally, there was no deterioration in blood analysis markers. The transient increase in serum Cr levels observed at week 12 is attributed to the rapid breakdown of CM into Cr, subsequently excreted by the kidneys.31 The apparent decline in eGFR during supplementation is a consequence of using serum Cr in eGFR formulas.32 Both Cr and eGFR normalized upon cessation of CM at week 24. These findings do not indicate kidney toxicity but rather a normal consequence of CM supplementation. Numerous studies have consistently supported the renal safety profile of CM across both short- and long-term regimens.18,19,33 In studies estimating GFR with alternative methods like cystatin C, no changes in renal function were observed.18

Regarding the efficacy of the intervention, we found that CM improves exercise capacity, as measured by the distance covered in the 6MWT. This result was statistically significant and clinically relevant, exceeding the minimal clinically important difference (MCID) of 35–37m reported for HF patients.30 Compared to other treatments for patients with HFrEF, CM obtained higher improvements in the 6MWT (48.69±32.76m). For instance, the DETERMINE trial showed that Dapagliflozin 10mg/day during 4 months, improved the 6MWT by 20m (interquartile range (IQR), [−2 to 42]).34 Similarly, a pilot study of 58 patients with HFrEF treated with Sacubitril/Valsartan showed an improvement in the 6MWT of 41.8m (IQR, [33.4–50.2]; P<.001) compared to baseline.35 Conversely, a comprehensive review and meta-analysis revealed that cardiac rehabilitation programs enhanced the 6MWT by an average of 60.43m.36 These results are important because exercise capacity is an independent predictor of mortality and CV events in patients with HF.37,38 Notably, these gains were achieved with CM alone, without a structured exercise regimen. Previous evidence suggests that muscle creatine uptake is enhanced when submaximal exercise is performed during supplementation, implying that combining CM with exercise could yield even greater benefits.39,40 This contrasts with previous studies that found no differences in functional capacity with CM in patients with HF compared to placebo.25,26,28 Carvalho et al. studied the effect of 5g/day of CM during 6 months in 33 male patients with HF and found no significant differences in functional capacity as measured by the 6MWT and VO2 peak.25 They suggested that the absence of an exercise routing during CM supplementation might account for the lack of improvement. Similarly, Kuethe et al. found no significant improvements in the 6MWT, VO2 peak or VO2 at the anaerobic threshold with 20g/day of CM for 6 months in HF patients with reduced exercise capacity.28 Comparing these results with our own is challenging due to the lack of a control group, a limitation we acknowledge.

Besides improvements in the 6MWT, we also found a reduction in patients’ perceived exertion. Post-intervention, Borg scale scores decreased by a mean of 1.56% compared to baseline, a result considered clinically meaningful as it exceeds the 1-point threshold recognized as the MCID in patients with HF.41 There was also a significant reduction in HR increment during exercise by 2.43bpm, which could also indicate enhanced exercise tolerance. These findings show both objective and subjective improvements in exercise tolerance, a key goal in HF management.

Additionally, CM enhanced HRQoL in patients with HF, as measured by the KCCQ. The improvement we observed in the total score post-intervention (4.08±12.29 points) was statistically significant, but did not reach the MCID of 5 points necessary for clinical relevance.42 Regarding the different KCCQ domains, all of them increased post-intervention, although only 2 reached statistical significance. The improvement in KCCQ total symptom score in our study (3.64±14.77 points), which is calculated by combining the first and second domain, exceeded that of other interventions in HFrEF. The DETERMINE trial reported an increase in the KCCQ total symptoms score of 2.1 points (IQR, [−4.2 to 14.6], in the Dapagliflozin group after 4 months.34 Improving HRQoL is a major treatment goal for HF patients due to the condition's impact on morbidity.2 Individuals with HF suffer from substantial symptoms, physical limitations and impaired HRQoL compared to healthy individuals and patients with other chronic diseases.43 Furthermore, HRQoL has demonstrated to be a strong and independent predictor of mortality and HF hospitalisations.44 These results contrast with previous research. Kuethe et al. found no difference in HRQoL, measured with the Minnesota living with HF questionnaire, in patients with HF supplemented with 20g/day CM for 6 months compared to placebo.28 Similarly, Cornelissen et al. reported that 9g/day of CM for 3 months did not improve HRQoL, measured with the SF-36 and McNew Heart disease questionnaires.26

Regarding cardiac function parameters, previous evidence indicates that diseased hearts, both human and animal models, exhibit at least a 20% reduction in total creatine content compared to healthy myocardium.3,7 In fact, a lower phosphocreatine-to-ATP ratio is a stronger predictor of CV mortality in patients with dilated cardiomyopathy than LVEF.45 This suggests that CM might improve cardiac function. However, we found no changes in systolic function measured by echocardiography, aligning with previous studies.46 For instance, Kuethe et al. found no increase in LVEF or a decrease in left ventricular telediastolic diameter with 20g/day of CM during 6 months in HF patients.28 The need for a larger patient population to detect significant changes in LVEF could explain these findings due to substantial intra- and interobserver variability.4,5

In conclusion, our study highlights the safety of CM supplementation in patients with HFrEF, showcasing significant enhancements in both functional capacity and HRQoL. These results suggest that CM may serve as a valuable complementary therapy for patients with HF.

The authors declare that no funding was used in this study.

The protocol was approved by the hospital's Ethics Committee (Ref: E.O. 2021-69 SuplementacionCreatinaIC-FEVIR; date of approval: 26/10/2021). Informed written consent was obtained from all participants. We confirm that SAGER guidelines regarding potential sex/gender bias have been followed.

During the preparation of this work the authors acknowledge the use of ChatGPT as a supplementary tool to refine the manuscript's language, ensuring clarity and coherence while adhering to scientific writing standards. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.

J.C. López-Clemente: writing (review and editing, writing) original draft, visualization, validation, resources, project administration, methodology, investigation, formal analysis, data curation and conceptualization. L. Fuertes-Kenneally: writing (review and editing, writing) original draft, visualization, validation, project administration, formal analysis, data curation and conceptualization. J. Abellán Huerta: writing (review and editing), validation, investigation, data curation and conceptualization. F. Soria Arcos: writing (review and editing), validation, investigation, data curation and formal analysis. J. González-López: writing (review and editing), validation, investigation, data curation and methodology. R. Mármol Lozano: writing (review and editing), validation, investigation and data curation. J.A. Castillo Moreno: writing (review and editing), supervision, resources, project administration, methodology, investigation, formal analysis, data curation and conceptualization.