Metabolic aestivation as a novel pathogenetic link in sarcopenia in heart failure: a systematic review and meta-analysis

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Abstract
Aim. To evaluate the effects of fluid deficit, diuretic therapy, and osmotic stress on changes in the plasma osmolyte profile (osmolarity, sodium, and urea concentrations) and their association with clinical outcomes, including muscle catabolism. Material and methods . This systematic review was conducted in accordance with PRISMA-2020. The search was conducted in October 2025 in SciSpace, PubMed, EMBASE, Google Scholar, the Cochrane Library, Web of Science, and the ClinicalTrials.gov, WHO ICTRP, and EU-CTR registries (1680 records + 124 registries + 45 additional sources). After removing duplicates (n=118) and a two-stage screening, 18 following studies (2017-2025) were included: 7 clinical studies, 6 experimental studies, 3 review studies, and 2 mixed studies. Adults aged 18 years or older with markers of dehydration or osmotic stress were included in the analysis. Key parameters included plasma osmolarity, the proportion of Na+ and urea in eOSM, copeptin/vasopressin levels, amino acid profile, muscle catabolism, hemodynamics, and renal function. Risk of bias was assessed using ROB 2.0 and ROBINS-I. Results . The systematic review included 18 studies, of which 6 clinical studies were included in the quantitative meta-analysis. A meta-analysis showed that fluid deficit, diuretic therapy, and SGLT2 inhibitor therapy were associated with an increase in plasma osmolarity (SMD 0,63 [0,19; 1,07], random-effects model; I2=93,8%). An increase in urea concentration (SMD 0,44 [0,12; 0,75]) and a decrease in sodium concentration (SMD -0,17 [-0,27; -0,06], p=0,0029) were observed. Analysis of the relative contribution of urea to plasma osmolarity, available in 2 studies, revealed an increase in its share (SMD 1,00 [0,64; 1,36]). Conclusion. Metabolic aestivation is a universal adaptive water-saving program in humans, activated by dehydration, high salt load, and diuretic therapy. Osmolyte redistribution in favor of urea is accompanied by muscle catabolism, increased blood pressure, myocardial remodeling, and may contribute to HF progression and sarcopenia. Systematic review indicates the need to monitor osmolarity, Na + and urea contribution, and vigilance when restricting fluid intake in patients recei­ving diuretics. Monitoring for metabolic aestivation signs can improve therapy safety and prognosis in cardiovascular and cardiorenal diseases.

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