Medical Therapy
Heart Failure Medication and Muscle Wasting
2024 Volume 88 Issue 1 Pages 20-21
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2024 Volume 88 Issue 1 Pages 20-21
Muscle wasting (MW) is a common comorbidity in individuals who have heart failure (HF), and it is a significant independent risk factor for death in these patients.1 Several factors are involved in MW in patients with HF; such as disuse, malnutrition, neurohumoral factor activation, and the HF medications themselves. The “fantastic four” (renin-angiotensin system [RAS] inhibitor or angiotensin-receptor neprilysin inhibitor [ARNI], β-adrenergic receptor blocker [BB], mineralocorticoid-receptor antagonist [MRA], and sodium-glucose cotransporter 2 [SGLT2] inhibitor) are recommended as guideline-directed medical therapy (GDMT) in patients with HF with reduced ejection fraction (HFrEF).2 Neurohumoral factors, especially activation of the RAS3 and sympathetic nervous system,4 play a central role not only in the development and deterioration of HF, but also in MW. Clinical studies suggest that angiotensin-converting enzyme inhibitors (ACEI)5 and/or BBs6 attenuate MW in patients with HF (Figure), but recent meta-analyses have shown that the use of SGLT2 inhibitors are linked to an increased risk of MW.7,8 It is important to take into account the effects on MW when using GDMT for patients with HF.
Muscle wasting (MW) is a common comorbidity in patients with heart failure (HF), and multiple factors are involved. Treatment with an angiotensin-converting enzyme (ACE) inhibitor5 and/or β-blocker6 are suggested to attenuate MW in these patients. Numazawa et al9 suggest that using a mineralocorticoid-receptor antagonist (MRA) without proper inhibition of the renin-angiotensin system (RAS) may potentially exacerbate MW.
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How do MRAs, another GDMT for HFrEF, affect MW? Because MRAs increase plasma renin activity (PRA) through a negative feedback mechanism, it potentially upregulates angiotensin II signaling and exacerbates MW. However, little is known about the effect of MRAs on MW in patients with HF. In this issue of the Journal, Numazawa et al9 provide an ambispective analysis showing the relationship between MRAs and MW in patients with HF. They analyzed the data of 329 patients with HF who were diagnosed according to the Japanese Circulation Society/Japanese Heart Failure Society Guidelines for Heart Failure.10 Appendicular skeletal muscle mass (ASM) was measured by dual-energy X-ray absorptiometry scan, and the ASM index (ASMI) was calculated as ASM/height2. MW was diagnosed on the basis of the criteria established by the Asian Working Group for Sarcopenia (AWGS) 2019 recommendation.11 Numazawa et al found that the use of MRAs was associated with lower ASMI and higher PRA in the non-RAS inhibitor group, but not the RAS inhibitor group. They concluded that an increase in PRA by the MRA without concurrent RAS inhibition, possibly contributing to upregulation of angiotensin II signaling, may potentiate MW.
Basic research in a mouse model of muscular atrophy has reported that inhibition of the mineralocorticoid receptor (MR) suppresses the expression of inflammatory cytokines and attenuates muscle atrophy.12 Aldosterone itself is reported to increase oxidative stress and suppress myogenesis; thus, inhibition of the MR suppresses these cellular responses.13 It has been also suggested that inhibition of the MR may suppress the progression of sarcopenia through mechanisms such as improving vascular endothelial function, suppressing apoptosis of skeletal muscle cells, improving metabolism within skeletal muscle cells, and fiber-type transformation of muscle fibers.14 However, those studies did not examine how concomitant RAS inhibitor use affects MW. According to the study by Numazawa et al, simultaneous use of RAS inhibitors and MRAs can affect MW.
There are several points that need to be clarified in a future study. First, patients’ characteristics, prognosis, and medications differ significantly based on the etiology of HF. Essentially, the GDMT differs between HFrEF and HF with preserved ejection fraction (HFpEF). Subanalysis depending on the HF phenotype is warranted. Second, the angiotensin II concentration is affected differently by ACEIs and angiotensin-receptor blockers (ARBs). The effect of MRAs on MW in patients receiving ACEIs or ARBs may be different. Third, the effects of different types of MRA on MW should also be investigated. Most studies to date that have examined the effects of MRAs on MW have focused on spironolactone. Because there are differences between spironolactone and other MRAs, such as selectivity for the MR and the presence or absence of a steroid nucleus, further studies are necessary to examine the effects of MRAs other than spironolactone on MW.
Despite these limitations, this is an important study showing that inhibition of the MR in the absence of appropriate RAS inhibition potentially exacerbates MW. Further evaluation is needed to determine the full effect of HF medications on MW.
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