Independent Link Between Use of Mineralocorticoid Receptor Antagonists and Muscle Wasting in Heart Failure Patients Not Receiving Renin-Angiotensin System Inhibitors

Abstract

Background: The renin-angiotensin system (RAS) activation is a proposed mechanism of muscle wasting (MW i.e., reduction in muscle mass). Although we reported that RAS inhibitors (RASIs) were associated with lower prevalence of MW in heart failure (HF) patients, the relationship between mineralocorticoid receptor (MR) signaling and MW has not been analyzed.

Methods and Results: We analyzed data from 320 consecutive Japanese HF patients who underwent dual-energy X-ray absorptiometry scanning for assessment of appendicular skeletal muscle mass index (ASMI). In multiple linear regression analyses, plasma renin activity (PRA) was negatively correlated with ASMI in patients not receiving RASIs, indicating an untoward role of the RAS in MW. Results of analysis of covariance in which risk factors of MW served as covariates showed that use of MR antagonists (MRAs) was associated with lower ASMI and higher PRA in the non-RASIs group. The close relationship between use of MRAs and lower ASMI or higher PRA in the non-RASIs group was confirmed in analyses in which the differences in baseline characteristics between users and non-users of MRAs were minimized by using an inverse probability of treatment weighting.

Conclusions: Increased PRA by MR inhibition without concurrent RAS inhibition, possibly contributing to upregulation of angiotensin II signaling, may be associated with reduction in muscle mass.

Heart failure (HF) is a major public health problem that affects >64 million people worldwide, and is a leading cause of poor quality of life and death.¹ Decline in physical function is a hallmark of HF, not only attributable to cardiac dysfunction, but also coexisting skeletal muscle abnormalities.² Sarcopenia, which is characterized by reduction in muscle mass and strength, was initially described as a geriatric syndrome,³ but results of recent studies have been shown that pathological conditions such as cardiovascular diseases including HF contribute to the development of sarcopenia.^4,5 Muscle wasting (MW, i.e., reduction in muscle mass) is highly prevalent in HF patients, though its complication rate varies depending on underlying diseases and the clinical stage of HF.^6,7 Importantly, the consequence of MW is not limited to decline in physical function: MW is an independent predictor for death in various HF cohorts.^6,8 Thus, diagnosis and treatment of MW are critical issues in HF patients, but there is no currently agreed treatment strategy targeting MW other than cardiac rehabilitation.⁵

Editorial p 20

The renin-angiotensin system (RAS) is a well-established regulator of body fluid volume, blood pressure, and tissue perfusion.⁹ Physiological activation of the RAS is necessary for maintenance of homeostasis through regulation of vascular tone, fluid volume, and electrolyte balance, and aberrant activation of the RAS plays a pivotal role in the development and exaggeration of HF through an increase in pre/afterload and maladaptive pathological remodeling. Indeed, inhibition of RAS by angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin-receptor blockers (ARBs) is a cornerstone in the treatment of HF with reduced ejection fraction (HFrEF), though its role in the treatment of HF with preserved EF (HFpEF) is limited.¹⁰ Furthermore, mineralocorticoid receptor antagonists (MRAs) exert additive favorable effects on outcomes in HFrEF patients receiving RAS inhibitors (RASIs).¹⁰ In addition to the detrimental role of RAS in the progression of HF, there are several lines of evidence showing untoward effects of RAS activation on muscle mass and strength.^11,12 The angiotensin II type 1 receptor (AT1R) is highly expressed in skeletal muscle and its activation by angiotensin II infusion reduced muscle mass through oxidative stress and imbalance of protein synthesis/degradation in mice.¹³ Furthermore, malnutrition is closely associated with the development of MW,¹⁴ and AT1R activation may contribute to malabsorption of nutrients through altered bowel perfusion by vasoconstriction and gut edema by volume retention, indirectly leading to the development of MW.¹⁵ These untoward effects of AT1R activation on skeletal muscle cells are theoretically reversed by RASIs. Results from experimental studies are supported by the findings of our recent retrospective study with propensity score (PS) matching: use of RASIs was associated with a lower prevalence of MW in HF patients independently of established risk factors.¹⁶

Thus, although a role of AT1R signaling in MW has been proposed, the relationship between mineralocorticoid receptor (MR) signaling and muscle mass has not been systematically analyzed. To obtain novel insights into the role of the RAS in MW, the relationships of muscle mass with plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were analyzed in the present study. Importantly, enhancement in PRA in patients receiving MRAs has been shown,^17–19 leading to the hypothesis that the use of MRAs without concurrent inhibition of angiotensin II receptor signaling potentiates MW. Therefore, the effect of the use of MRAs on muscle mass was separately examined in HF patients receiving RASIs and HF patients not receiving RASIs.

Methods

Study Design and Study Subjects

This study was a single-center, ambispective, and observational study. We enrolled consecutive Japanese patients who were admitted for diagnosis and management of HF during the period from August 1, 2015 to March 31, 2020. This period was selected because HF patients routinely underwent body composition analysis by a dual-energy X-ray absorptiometry (DEXA) scan for the diagnosis of sarcopenia and measurement of PRA and PAC. The retrospective study was carried out for the period from April 1, 2015 to April 10, 2019, and the prospective study continued until March 31, 2020. The inclusion criterion was diagnosis of HF according to the Japanese Circulation Society/Japanese Heart Failure Society Guidelines for Heart Failure.²⁰ Patients with pulmonary arterial hypertension, myocarditis, or valvular heart disease who were scheduled for surgical procedures were excluded. Patients at stage 5 of chronic kidney disease (CKD), defined by cystatin C-based estimated glomerular filtration rate (eGFR) <15 mL/min/1.73 m², and patients who were complicated by septic shock and underwent emergency coronary artery bypass grafting on the day of blood collection for measurements of PRA and PAC were also excluded.

Measurement of PRA and PAC

Data for blood samples, obtained within 7 days after DEXA measurements, were retrieved from the patients’ medical records. For assessment of PRA and PAC, blood samples were taken during the early morning fasting state after the patient had been resting supine for 30 min. PRA and PAC were measured using an immunoradiometric assay (Renin RIAbeads; TFB Factories Ltd., Tokyo, Japan) and a radioimmunoassay (Spec-S Aldosterone Kit; Fujirebio Inc., Tokyo, Japan), respectively. If the values of PRA and PAC were below the detection limit (i.e., PRA <0.2 pg/mL/h and PAC <7.0 pg/mL), they were considered missing values and were addressed by employing a multiple imputation technique as detailed in the statistical analysis section.

Body Composition Analysis and Assessment of Physical Function

Body composition analysis was performed using a DEXA scan (Horizon A DXA System; HOLOGIC, Waltham, MA, USA) as previously described.²¹ Appendicular skeletal muscle mass (ASM) was calculated as the sum of bone-free lean masses in the arms and legs. The ASM index (ASMI) and fat mass index (FMI) were defined as ASM/height² and FM/height², respectively. The definitions for MW are <7.00 and <5.40 kg/m² for males and females, respectively, on the basis of the criteria established by the Asian Working Group for Sarcopenia (AWGS) 2019 recommendation.²² As an index of functional fitness, usual gait speed was measured by timing patients walking at their usual pace over an intermediate 10 m of a 14-m distance, with walking aids permitted.

Collection of Data for Clinical Parameters

Additional clinical parameters were obtained from the patients’ medical records. Laboratory data for N-terminal pro B-type natriuretic peptide (NT-proBNP), serum albumin, hemoglobin, cystatin C, and cystatin C-based glomerular filtration rate (eGFR) were obtained within 7 days after DEXA measurements. Because the creatinine-based equation for eGFR is affected by muscle mass,²³ the cystatin-based equation, developed by the Japanese Society of Nephrology, eGFR (mL/min/1.73 m²) = 104 × cystatin C^−1.019 × 0.996^age (×0.929 if female) − 8, was used in the present study. CKD was defined as eGFR <60 mL/min/1.73 m². Transthoracic echocardiography was performed by standard protocol within 14 days after DEXA measurements, and the left ventricular EF (LVEF) was measured by the modified Simpson method. HF with reduced EF (HFrEF) was defined as LVEF <40%.²⁰

Sample Size Calculation

Considering the pharmacological effects on RAS activity, we stratified all analyses based on the usage of RASIs. The sample size for analyses was computed using G*power version 3.1.9.6 (Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany; http://www.gpower.hhu.de/). Setting a significance level of 0.05, a statistical power of 0.80, and an anticipated effect size of 0.15, the minimum required sample size was established to be 139 cases per group.

Statistical Analysis

Data are presented as mean±standard deviation or median (interquartile range [IQR]: 25–75^th percentile) based on the results of the Shapiro-Wilk test. Categorical variables are expressed as frequency and percentage. Continuous variables across 2 groups were compared using Student’s t-test or the Mann-Whitney U-test, and one-way analysis of variance or the Kruskal-Wallis test was used for comparisons across 3 groups. Differences in categorical variables between groups were examined using the chi-square test.

Missing data were handled using multiple imputation analysis, which incorporated the dependent variables and all exposures and adjustment variables. Assuming missing at random, we performed 100 imputations using chained equations and pooled the estimates to conducted multilinear regression analysis and analysis of covariance (ANCOVA).²⁴

To evaluate the potential association between RAS activity and ASMI in HF patients, a multilinear regression analysis was conducted. To further investigate the relationship between RAS activity and ASMI, we examined the association of usage of MRAs with ASMI using ANCOVA. We also investigated how administration of MRAs affected the PRA and PAC levels using ANCOVA. These multivariate models were adjusted for potential confounders including age, sex, gait speed, FMI, NT-proBNP, LVEF, New York Heart Association functional classification (NYHA-FC) III, albumin, eGFRcys, diabetes mellitus (DM), and use of loop diuretics, tolvaptan, and RASIs. To further verify the results obtained with ANCOVA, we calculated the inverse probability of treatment weighting (IPTW) using PS to minimize differences in potential confounding factors between the groups.²⁵ Covariates for the IPTW were selected based on the basis of the following baseline variables: age, sex, gait speed, FMI, NT-proBNP, LVEF, NYHA-FC III, albumin, eGFRcys, DM, and use of loop diuretics and tolvaptan in addition to use of RASIs. Logarithmic transformation was performed for variables without a normal distribution.

Two-tailed P values <0.05 were utilized to determine statistical significance in overall analyses. The interaction between usage of RASIs and usage of MRAs was considered statistically significant at P<0.10.²⁶ Analyses were performed using JMP Pro version 17.0.0 (SAS Institute Inc., Cary, NC, USA) and R version 4.3.0 (R Foundation for Statistical Computing, Vienna, Austria. https://www.r-project.org/).

Results

Of the 649 HF patients who met the inclusion criterion, 329 were excluded, so the data for 320 patients were used for analyses as shown in Figure 1.

Figure 1.

Flow chart of inclusion of patients. eGFRcys, cystatin C-based estimated glomerular filtration rate; HF, heart failure; PAC, plasma aldosterone concentration; PRA, plasma renin activity.

Baseline Characteristics

Baseline clinical characteristics of the patients are shown in Table 1. The median age was 70 years (IQR, 60 to 77 years) and 35% of the patients were women. Hypertension, DM, and CKD were present in 60%, 36%, and 51% of the patients, respectively. The most frequent etiology of HF was cardiomyopathy (37%), followed by ischemic heart disease (24%) and valvular heart disease (10%). In total, 50% of the patients were classified as having HFrEF.

Table 1.

Baseline Characteristics of the Study Patients

	Missing, n (%)	Overall (n=320)	RASIs (+) (n=172)	RASIs (−) (n=148)	P value
Age, years		70 (60, 77)	68 (57, 77)	72 (63, 78)	0.02
Female, n (%)		111 (35)	50 (29)	61 (41)	0.03
Height, cm		161.8±9.7	162.3±9.6	160.6±9.7	0.04
Body weight, kg		59.0 (50.7, 68.9)	61.0 (51.6, 71.8)	57.5 (48.9, 65.4)	<0.01
BMI, kg/m2		22.6 (19.9, 25.0)	23.3 (20.5, 25.6)	22.0 (19.5, 24.5)	0.01
NYHA functional class, n (%)					0.09
I		49 (15)	25 (15)	24 (16)
II		164 (51)	98 (57)	66 (45)
III		106 (33)	48 (28)	58 (39)
LVEF, %		40.0 (29.4, 55.0)	37.2 (28.7, 48.0)	43.3 (31.0, 58.3)	0.02
HFrEF, n (%)		159 (50)	92 (53)	67 (45)	0.15
History of HF hospitalization, n (%)		147 (46)	69 (40)	78 (53)	0.03
Etiology, n (%)					<0.01
Cardiomyopathy		117 (37)	73 (42)	44 (30)
Dilated cardiomyopathy		68 (21)	45 (26)	23 (16)
Hypertrophic cardiomyopathy		23 (7)	9 (5)	14 (9)
Other		26 (8)	19 (11)	7 (5)
Ischemic heart diseases		76 (24)	53 (31)	23 (16)
Valvular heart diseases		33 (10)	9 (5)	24 (16)
Comorbidity, n (%)
Hypertension		193 (60)	122 (71)	71 (48)	<0.01
Dyslipidemia		171 (53)	91 (53)	80 (54)	0.91
DM		115 (36)	66 (38)	49 (33)	0.35
Chronic kidney disease	22 (7)	151 (51)	78 (59)	73 (52)	0.64
Anemia		87 (27)	56 (33)	31 (21)	0.02
Atrial fibrillation		148 (46)	62 (36)	86 (58)	<0.01
Laboratory data
NT-proBNP, pg/mL		1,271 (644, 2,828)	1,193 (555, 2,505)	1,359 (703, 3,345)	0.20
Albumin, g/dL		3.6 (3.3, 4.0)	3.6 (3.3, 4.0)	3.7 (3.3, 3.9)	0.91
Hemoglobin, g/dL		12.8±2.2	12.8±2.2	12.8±2.2	0.81
Cystatin C, mg/L	22 (7)	1.12 (0.9, 1.6)	1.14 (0.91, 1.56)	1.11 (0.94, 1.56)	0.74
eGFRcys, mL/min/1.73 m2	22 (7)	60.0 (41.7, 74.9)	60.1 (41.6, 79.0)	59.6 (41.5, 71.9)	0.35
White blood cell, ×103/μL		5.6 (4.6, 6.8)	5.7 (4.6, 7.0)	5.5 (4.6, 6.7)	0.20
Neutrophils, ×103/μL		3.5 (2.7, 4.6)	3.4 (2.7, 4.7)	3.6 (2.7, 4.6)	0.86
Lymphocyte, ×103/μL		1.4 (1.0, 1.7)	1.4 (1.1, 1.8)	1.3 (1.0, 1.7)	0.01
Neutrophil-to-lymphocyte ratio		2.46 (1.78, 3.85)	1.37 (1.74, 3.67)	2.71 (1.81, 3.94)	0.17
PRA, ng/mL/h	42 (13)	2.5 (0.8, 7.8)	2.9 (0.8, 8.8)	2.3 (0.8, 7.1)	0.45
PAC, pg/mL	9 (3)	108.0 (70.0, 166.0)	100.0 (66.5, 155.3)	124.0 (73.5, 182.0)	0.02
Medications, n (%)
RASIs		172 (54)	172 (100)	0 (0)
ACEIs		65 (20)	65 (38)	0 (0)
ARBs		107 (33)	107 (62)	0 (0)
β-blockers		248 (78)	135 (78)	113 (76)	0.69
MRAs		144 (45)	83 (48)	61 (41)	0.22
Spironolactone		114 (36)	66 (38)	48 (32)
Eplerenone		30 (10)	17 (10)	13 (9)
SGLT2 inhibitor		23 (7)	16 (9)	7 (5)	0.13
Loop diuretics		196 (61)	96 (56)	100 (68)	0.04
Tolvaptan		67 (21)	24 (14)	43 (29)	<0.01
Statin		141 (44)	78 (45)	63 (43)	0.65
Proton pump inhbitor		195 (61)	110 (64)	85 (57)	0.25
Prednisolone		34 (11)	16 (9)	18 (12)	0.47
Functional fitness
Gait speed, m/s	56 (18)	0.91±0.26	0.94±0.24	0.88±0.26	0.09
Body composition
ASM, kg		16.2 (12.9, 20.0)	17.4 (13.2, 20.6)	15.0 (12.1, 19.1)	<0.01
ASMI, kg/m2		6.0 (5.2, 7.0)	6.3 (5.4, 7.2)	5.8 (5.1, 6.7)	<0.01
FM, kg		16.8 (12.6, 21.4)	17.1 (13.1, 22.5)	16.1 (12.0, 20.3)	0.048
FMI, kg/m2		6.3 (4.9, 8.2)	6.4 (5.1, 8.7)	6.2 (4.6, 8.0)	0.16

Data are presented as mean±standard deviation of the mean, median (interquartile range, 25^th, 75^th percentile), or number (with percentage). n, number of patients for whom the parameter was available. Of the entire patient cohort, 172 patients (54%) were prescribed RASIs, with 65 (38%) receiving angiotensin-converting enzyme inhibitors (enalapril, 56 patients, 2.7±2.1 mg; imidapril, 9 patients, 4.4±1.1 mg) and 107 (62%) receiving angiotensin II receptor blockers (losartan, 33 patients, 16.9±9.9 mg; candesartan, 20 patients, 6.3±5.0 mg; irbesartan, 5 patients, 100±0 mg; telmisartan, 14 patients, 33.6±22.1 mg; olmesartan, 20 patients, 21.5±10.4 mg; azilsartan, 5 patients, 23.0±6.7 mg; valsartan, 10 patients, 62.0±30.5 mg). ACEIs, angiotensin-converting enzyme inhibitors; ARBs, angiotensin II receptor blockers; ASM, appendicular skeletal muscle mass; ASMI, appendicular skeletal muscle mass index; BMI, body mass index; DM, diabetes mellitus; eGFRcys, cystatin C-based estimated glomerular filtration rate; FM, fat mass; FMI, fat mass index; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; LVEF, left ventricular ejection fraction; MRAs, mineralocorticoid receptor antagonists; NT-proBNP, N-terminal pro B-type natriuretic peptide; NYHA, New York Heart Association; PAC, plasma aldosterone concentration; PRA, plasma renin activity; RASIs, renin-angiotensin system inhibitors; SGLT2, sodium-glucose cotransporter 2.

Of the 320 HF patients, 172 (54%) were receiving RASIs at the time of DEXA measurement (Table 1). Patients receiving RASIs were younger than patients not receiving RASIs and included a larger proportion of men. Patients receiving RASIs had a lower LVEF than the patients not receiving RASIs. Patients on RASIs also had significantly reduced PAC levels. The use of loop diuretics and tolvaptan was less prevalent in patients administered RASIs, but the proportions of patients receiving β-blockers, MRAs, statins, proton pump inhibitors, and prednisolone were comparable between the 2 groups. Patients receiving RASIs had higher ASMI than patients not receiving RASIs, but the FMI did not show any significant difference.

Association Between Plasma RAS Status and ASMI in HF Patients

The relationships of ASMI with PRA and PAC were assessed by multiple linear regression analyses in which potential cofounders were included as adjusted variables as shown in the Methods. PRA was found to be independently associated with ASMI in patients who were not receiving RASIs (users of RASIs, P=0.06; non-users of RASIs, P=0.03, Table 2). An independent relationship between PRA and ASMI was also found when users of MRAs and non-users of MRAs were separately analyzed (users of MRAs, P=0.04; non-users of MRAs, P=0.01, Table 2). Conversely, there was no association between PAC and ASMI in any of the analyses (Table 2).

Table 2.

Association of Appendicular Skeletal Muscle Mass Index With PRA and PAC

	Univariate model			Multivariate model
	t	Estimate	P value	t	Estimate	P value
(A) The model stratified by the usage of RASIs
RASIs (+)
PRA	−0.08	−0.001 (−0.025 to 0.023)	0.94	−1.89	−0.016 (−0.032 to 0.001)	0.06
PAC	1.65	0.035 (−0.007 to 0.077)	0.10	0.02	0.0003 (−0.003 to 0.031)	0.98
RASIs (−)
PRA	−4.01	−0.051 (−0.076 to −0.026)	<0.01	−2.25	−0.025 (−0.046 to −0.003)	0.03
PAC	0.51	0.013 (−0.036 to 0.061)	0.61	1.88	0.034 (−0.001 to 0.068)	0.06
(B) The model stratified by the usage of MRAs
MRAs (+)
PRA	−1.21	−0.016 (−0.043 to 0.01)	0.23	−2.05	−0.020 (−0.039 to −0.001)	0.04
PAC	0.50	0.012 (−0.035 to 0.06)	0.62	0.49	0.008 (−0.024 to 0.04)	0.62
MRAs (−)
PRA	−0.99	−0.013 (−0.038 to 0.01)	0.33	−2.54	−0.023 (−0.040 to −0.005)	0.01
PAC	2.31	0.050 (0.008 to 0.10)	0.02	1.19	0.020 (−0.013 to 0.05)	0.23

Data are presented as t statistics and estimate. (A) Multivariate model was adjusted for age, sex, gait speed, FMI, NYHA-FC III, LVEF, NT-proBNP, albumin, eGFRcys, DM, and use of HF medications (loop diuretics, tolvaptan, and MRAs). (B) Multivariate model was adjusted for age, sex, gait speed, FMI, NYHA-FC III, LVEF, NT-proBNP, albumin, eGFRcys, DM, and use of HF medications (loop diuretics, tolvaptan, and RASIs). NYHA-FC, New York Heart Association functional classification. Other abbreviations as in Table 1.

Association Between Use of MRAs and ASMI in HF Patients

Of the entire patient cohort, 144 (45%) were prescribed MRAs, with 114 (36%) receiving spironolactone and 30 (10%) receiving eplerenone (Table 1). Considering the substantial differences in the baseline characteristics of HF patients receiving MRAs and those not receiving MRAs (Supplementary Table 1), 2 approaches were used to demonstrate the relationship between use of MRAs and ASMI.

First, ANCOVA into which potential cofounders were incorporated as covariates was performed to compare the differences in ASMI, PRA, and PAC between patients receiving MRAs and those not receiving MRAs. Use of MRAs was associated with lower ASMI and higher PRA and PAC than was non-use of MRAs in the analyses in which all patients were included (Figure 2A–C). There was a significant interaction on the effect of MRAs on ASMI, but not PRA and PAC, between use of RASIs and non-use of RASIs: use of MRAs was associated with lower ASMI in the non-RASIs group but not in the RASIs group (p for interaction=0.05, Figure 2). The post-hoc analyses after the exclusion of patients who were diagnosed as having amyloidosis and sarcoidosis (43 patients) yielded almost similar results to those in which all patients were included (Supplementary Figure 1). The clinical significance of these findings was confirmed by additional analysis showing that the prevalence of MW was higher in the MRAs group than in the non-MRAs group (Cochran-Mantel-Haenszel test adjusted for usage of RASIs, Figure 3). The effect of MRAs on the prevalence of MW was particularly pronounced in elderly HF patients (Supplementary Figure 2).

Figure 2.

Box plots showing results of analysis of covariance (ANCOVA) by which the relationships of use of MRAs with ASMI, PRA, and PAC were analyzed. Box plots and error bars represent least squares mean and 95% confidence interval of log ASMI (A), log PRA (B), and log PAC (C). Potential cofounders were incorporated into the ANCOVA as shown in the Methods. ASMI, appendicular skeletal muscle index; MRAs, mineralocorticoid receptor antagonists; PAC, plasma aldosterone concentration; PRA, plasma renin activity; RASIs, renin-angiotensin-aldosterone system inhibitors.

Figure 3.

Proportions of patients with muscle wasting among the patients receiving MRAs and those not receiving MRAs. The definition for muscle wasting was <7.00 and <5.40 kg/m² for males and females, respectively, on the basis of the criteria established by the Asian Working Group for Sarcopenia 2019 recommendation. Use of RASIs was adjusted by the Cochran-mantel-haenszel test. MRAs, mineralocorticoid receptor antagonists; RASIs, renin-angiotensin-aldosterone system inhibitors.

Next, to minimize differences in potential cofounders between patients receiving MRAs and those not receiving MRAs, IPTW was calculated using PS. After IPTW, the standardized mean differences of all covariates were <0.1, indicating that baseline differences in incorporated covariates were substantially improved (Figure 4A).

Figure 4.

The least squares mean of log ASMI and log PRA after inverse probability of treatment weighting (IPTW). (A) Distribution of standardized mean differences before and after IPTW. (B–E) Box plots and error bars represent least squares mean and 95% confidence interval of log ASMI (B–D) and log PRA (E–G), respectively. ASMI, appendicular skeletal muscle index; DM, diabetes mellitus; eGFRcys, cystatin C-based estimated glomerular filtration rate; FMI, fat mass index; HF, heart failure; LVEF, left ventricular ejection fraction; MRAs, mineralocorticoid receptor antagonists; NT-proBNP, N-terminal pro B-type natriuretic peptide; NYHA-FC, New York Heart Association functional classification; PRA, plasma renin activity; RASIs, renin-angiotensin-aldosterone system inhibitors.

Use of MRAs was associated with lower ASMI and higher PRA in the non-RASIs group, but such a relationship was not seen in the RASIs group (Figure 4B–G).

Discussion

Plasma renin is the rate-limiting step for angiotensin II synthesis from angiotensinogen, and PRA should correlate with plasma angiotensin II level in conditions devoid of RAS inhibition. Results of previous studies showing that angiotensin II promotes MW were supported by the results of the present study showing a close association between PRA and ASMI in patients not receiving RASIs (Table 2). Furthermore, use of MRAs was associated with lower ASMI and higher PRA in patients not receiving RASIs, but not in patients receiving RASIs, even when differences in the baseline clinical characteristics between the groups were minimized by using 2 approaches. This study is the first to show an independent association between MR inhibition and MW in HF patients not receiving RASIs, leading to the hypothesis that an increase in PRA by MR inhibition without concurrent RAS inhibition, leading to upregulation of angiotensin II signaling, may potentiate MW (Figure 5).

Figure 5.

Schematic of the working hypothesis. An increase in plasma renin activity by mineralocorticoid receptor (MR) inhibition without concurrent inhibition of the renin-angiotensin system (RAS), possibly contributing to upregulation of angiotensin II signaling, may potentiate muscle wasting.

A salient finding in the present study was the close association between use of MRAs and MW. The MR family is a family of nuclear steroid receptors including glucocorticoid receptor and androgen receptor, and these receptors have a high affinity for various steroid hormones such as aldosterone and cortisol.^27,28 The binding of aldosterone with MR in epithelial tissue (e.g., kidney) is a primary mechanism of sodium absorption and potassium excretion, but elevation in PAC is not the sole mechanism for pathological MR activation in non-epithelial tissue (e.g., heart and vessels); aldosterone-independent local MR activation by pathological stresses contributes to the pathogenesis of organ damage, which is inhibited by MRAs.^28,29 In addition, investigations over the past decade have revealed the presence of functional MR in skeletal muscle cells. A pioneering study by Chadwick et al showed that MR is expressed in both undifferentiated myoblasts and differentiated myotubes from mouse and human skeletal muscle cultures and that pharmacological MR inhibition modulated its downstream gene expression.²⁷ Treatment with MRAs improved skeletal muscle force and muscle membrane integrity in mouse models of Duchenne muscular dystrophy,³⁰ and pharmacological and genetic MR inhibition delayed muscle fiber growth in the repair process after acute skeletal muscle injury induced by barium chloride injections, indicating that MR activation plays a pivotal role in muscle repair.³¹ However, the role of MR signaling in the development of MW remains elusive. In the present study, use of MRAs with concurrent use of RASIs was not associated with lower ASMI and higher prevalence of MW, suggesting a limited effect of MR activation on muscle mass in HF patients, though this needs to be confirmed by a prospective study.

Androgens, mainly testosterone, are hormones with anabolic properties, and the reduction in testosterone levels caused by aging and various diseases is thought to be a mechanism of sarcopenia,³² though testosterone supplementation therapy for sarcopenic subjects has not necessarily yielded successful results.³³ Importantly, spironolactone has been shown to exert anti-androgenic actions that potentially mitigate muscle mass, although the effect of eplerenone on testosterone-induced androgenic receptor activation was found to be negligible.^34,35 Indeed, a post-hoc analysis of the present study showed that ASMI was lower in patients receiving spironolactone than in those receiving eplerenone among the HF patients receiving RASIs (Supplementary Figure 3), though the significance of this analysis is limited due to the small number of HF patients receiving eplerenone (21% of the patients receiving MRAs). Considering that the majority of HF patients on MRAs were receiving spironolactone, a close association between use of MRAs and MW may be explainable by the anti-androgenic action of spironolactone. In contrast, no differences in body composition, including muscle mass, between patients on spironolactone and patients on esaxerenone, a nonsteroidal MR antagonist, were found in the analyses for patients with primary aldosteronism, though blocking of androgen receptors by spironolactone was confirmed by a significantly higher testosterone level in patients receiving spironolactone.³⁴ A separate project is needed to demonstrate the role of the anti-androgenic actions of spironolactone in MW in HF patients.

There are several clinical implications of the findings in the present study. First, although treatment with RASIs did not indicate clinical benefits for patients with HFpEF, the results of the TOPCAT trial showed a significant reduction in the rate of HF hospitalization, which was a secondary outcome, in spironolactone-treated HFpEF patients.³⁶ Effects of long-term use of MRAs without proper RAS inhibition on skeletal muscle status should be analyzed. Next, although MRAs are often prescribed together with loop diuretics to maintain serum potassium and magnesium levels, use of loop diuretics has been shown to be associated with increased risks of sarcopenia in a dose-dependent manner in patients with CKD, liver cirrhosis, and HF.^37–39 In addition, there are some concerns about the pro-sarcopenic effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors, although conflicting results have been reported.⁴⁰ Therefore, muscle mass/strength and physical function should be carefully monitored when MR inhibition without concurrent RASIs treatment is given to HFpEF patients, and MRAs together with loop diuretics and/or SGLT2 inhibitors are prescribed especially in patients with pro-sarcopenic diseases.

Study Limitations

First, selection bias in the study subjects is possible because this study was observational in a single center. Second, although there are sex differences in the anti-androgenic actions of MRAs, males and females were not separately analyzed due to the small sample size. Third, the effects of MRAs in addition to RASIs on indexes of muscle strength, a criterion of sarcopenia, were not analyzed. Fourth, accurate information about duration of treatment with MRAs and/or RASIs was not available, although confounding factors including severity of HF, such as NT-proBNP and history of HF hospitalization, were adjusted by using 2 approaches. Fifth, the circulating angiotensin II concentration was not directly analyzed due to lack of stored serum/plasma samples. Sixth, effects of treatment with MRAs and/or RASIs on fat mass were not systematically analyzed, though adipose tissue is a pivotal source of pro-sarcopenic inflammatory cytokines. Finally, due to the small number of study subjects, statistical power may have been insufficient for detection of differences in the effects of MRAs on muscle mass among groups with different etiologies of HF (e.g., ischemic vs. non-ischemic HF or HFrEF vs. HFpEF), and differences in the effects on MW between patients receiving ACEIs and those receiving ARBs (Supplementary Figures 4,5).

Conclusions

Use of MRAs was associated with lower ASMI and higher PRA in the non-RASIs group but not in the RASIs group, indicating that an increase in PRA by MR inhibition without concurrent RAS inhibition, possibly contributing to upregulation of angiotensin II signaling, may potentiate MW. Caution is warranted when treatment with MRAs is prescribed for patients not receiving RASIs (e.g., HFpEF patients).

Funding

This study was supported by Grant JP20K19313 (R. Nagaoka) and JP22K11288 (S.K.) from the Japan Society for the Promotion of Science, Tokyo, Japan, the Hokkaido Heart Association Grant for Research, and the Kondou Kinen Medical Foundation.

The funding body played no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

Acknowledgments

We are very grateful to the participants in the study and to the staff in Sapporo Medical University Hospital.

Disclosures

T.Y. reports personal fees from Sumitomo Pharma and Bayer Yakuhin. M.F. reports personal fees from Kowa and Nippon Boehringer Ingelheim.

IRB Information

This study adhered to the Declaration of Helsinki and received approval from the Clinical Investigation Ethics Committee of Sapporo Medical University Hospital (no. 302-243). Given the retrospective and anonymized nature of this study, the Clinical Investigation Ethics Committee of Sapporo Medical University Hospital waived the need for informed consent from the patients who participated in this study from August 1, 2015 to April 10, 2019. An opt-out option on our website allowed patients to decline the inclusion of their data in this study. In addition, informed consent was obtained from patients who participated in this study from April 11, 2019 to March 31, 2020.

Data Availability

The deidentified participant data will not be shared.

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circj.CJ-23-0567

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