Introduction

Sarcopenia is an age-related syndrome characterized by progressive and generalized loss of skeletal muscle mass and strength, leading to the risk of frailty and hence, poor health outcomes, including falls, incident disabilities, hospitalization and mortality (1). Sarcopenia can be considered ‘primary’ (or age-related) when no other cause apart from aging itself is evident, and ‘secondary’ (or disease-related) when one or more other causes are evident. Disease-related sarcopenia is associated with advanced organ failure, chronic inflammatory diseases, malignancy, and endocrine diseases that affect protein synthesis, proteolysis, neuromuscular integrity and muscle fat content (2). Thus, sarcopenia in elderly patients with cardiovascular diseases (CVD) can be considered to be not only age-related, but also disease-related sarcopenia associated with chronic heart failure (CHF). Despite the increased awareness of sarcopenia, there is currently no clinical information regarding sarcopenia in Japanese patients with CVD.

A previous report from the European Working Group on Sarcopenia in Older People (EWGSOP) proposed several theories related to sarcopenia, including the role of nutrition, the role of physical activity and effective medications for the prevention and treatment of sarcopenia (2). These interventional managements of sarcopenia are similar to the therapeutic strategy of comprehensive cardiac rehabilitation (CCR) in patients with CVD. The present study, therefore, attempted to clarify the characteristics of sarcopenia in Japanese patients with CVD and to investigate the effects of CCR on sarcopenia in CVD patients.

Methods

Study Patients

We retrospectively registered 322 consecutive inpatients (age, 72±12 years; 187 males and 135 females) with cardiovascular diseases and/or those who had undergone cardiovascular surgery and were enrolled in the CCR program at our hospital between April 2013 and December 2014. These patients were retrospectively divided into the following two groups: patients with sarcopenia (n=90) and patients without sarcopenia (n=232). Each group then underwent two types of subdivisions, the first based on whether or not they received exercise training and the second based on whether or not they were receiving statins. Skeletal muscle index (SMI) was measured both 116 patients without sarcopenia and 63 patients with sarcopenia. All patients received medical therapy and dietary treatment. (Figure 1) Patients who had coronary artery disease and atherosclerotic vascular disease or chronic heart failure, as well as those who had previously undergone cardiovascular surgery were included in the program based on the guidelines of the American Heart Association (AHA) and the American College of Cardiology (ACC) Foundation (3). Exclusion criteria were unstable angina, uncontrolled heart failure and serious arrhythmia. Patients with pacemaker implantation were excluded because bioelectric impedance assay could not be measured in them. All patients were classed into two groups of A+B or C+D according to the “Stages in the development of heart failure/recommended therapy by stage” in the ACC/AHA guidelines (4). Briefly, the stage A group includes those at a high risk for heart failure but with no structural heart disease, stage B patients have asymptomatic heart failure with structural heart disease, stage C includes patients with symptomatic heart failure and structural heart disease, and stage D those with refractory heart failure that requires intensive care. Informed consent was obtained from all patients, and the study was approved by the Human Study Committee of our institution.

Nutritional Assessments

For assessment of general nutritional condition, we chose the controlling nutritional status (CONUT) scoring system, which is determined by serum albumin, total cholesterol and total lymphocyte count (5). Further, the actual total daily calorie and nutrient intake, including proteins, lipids and carbohydrates, was calculated by measuring the uneaten meal portion during hospitalization. The average intake of total calories and nutrients before and after exercise training was calculated for one week before exercise training and before discharge, respectively.

Muscle Mass Measurements

Muscle mass was measured by bioelectrical impedance assay using the InBody S10 (Biospace, Tokyo, Japan). This system applies electricity at frequencies of 1, 5, 50, 250 and 500 kHz, and 1 MHz, through the body. Whole-body impedance was measured using an ipsilateral foot-hand electrical pathway, and body composition (extracellular fluid, intracellular fluid, fat, free fat mass, minerals, water, protein, etc.) of each part of the body (right and left arms, right and left legs and trunk) was analyzed. The recommended conditions during bioelectrical impedance assay measurement were (I) fasting for 4 hours, (II) bladder voided and (III) no exercise in the 8 hours prior to measurement (6). Bioelectrical impedance assay in edematous patients was performed after improvement of edema. Absolute appendicular muscle mass was calculated as the sum of the muscle mass of the arms and the legs, and was converted to the skeletal muscle mass index (SMI) by dividing the value by the square of height in meters (kg/m2) (7).

Muscle Strength Measurements

Muscle strength was assessed as handgrip strength, which was measured using a Smedley hand dynamometer MY-2080 (Matsumiya Ikaseiki Seisakusho Co. Ltd., Tokyo, Japan). One trial was performed for each hand, and the result from the stronger hand was used for sarcopenia diagnosis. Using a hand held dynamometer (μ-Tas F-1; Anima Corp., Tokyo, Japan), quadriceps muscle strength was measured as an estimate of muscle strength of the leg. The average value (kgf) of the three times measurements was divided by body weight, and this value (kgf/kg) was defined as leg weight bearing index.

Physical Performance Measurements

Physical performance was assessed as usual gait speed. We referenced and modified a previous technique reported by Tanimoto et al (8). Patients were asked to walk straight ahead for 12 meters at their usual speed for measurement of 10-meter walk time. The walking speed reached steady speed at first 2 meters. Gait speed (m/sec) was calculated by dividing the distance covered 10 meters (m) by the 10-meter walk time (sec).

Diagnosis of Sarcopenia

Sarcopenia was diagnosed based on measurements of muscle mass, muscle strength and physical performance, according to the recommended diagnostic algorithm of the Asian Working Group for Sarcopenia (AWGS) guidelines (9). Sarcopenia was defined by either a gait speed of <0.8m/s or a low handgrip strength (<26 kg in males and <18 kg in females), together with a decrease in SMI (<7.0 kg/m2 in males and <5.7 kg/m2 in females). Age criteria were ignored by considering not only age-related but also disease-related sarcopenia in this study.

Comprehensive Cardiac Rehabilitation Program

Comprehensive cardiac rehabilitation was started on admission to the hospital. Dietary treatment and medication were immediately started on admission and continued during hospitalization. Exercise training was started from an early stage of admission, except for patients in the acute stage of acute coronary syndrome, congestive heart failure, lifethreatening arrhythmia and cardiovascular surgery. Aerobic, resistance and balance trainings were included in the exercise training protocol and were performed for 20 to 40 minutes daily. Aerobic training was performed using a bicycle ergometer for patients who could receive cardiopulmonary exercise tesing, and a 200-meter walk coupled with active, assistive and passive pedal ergometry (THERA-trainer mobi, Medica Medizintechnik GMBH, Hochdorf, Germany) for patients who could not do so. Peak oxygen consumption or anaerobic threshold was assessed by performing cardiopulmonary exercise testing with Stress Test System ML-900 (Fukuda Denshi, Tokyo, Japan), Well bike BE-250 (Fukuda Denshi, Tokyo, Japan), and Aeromonitor AE-310s (Minato Ikagaku K.K., Osaka, Japan) before and after exercise training. Resistance training included weight training of the limbs with a load of 20% of one-repetition maximum testing (1RM) measured with a handheld dynamometer and squat training. Balance training was performed with the patient sitting on a balance ball or standing on one leg. The number of patients in whom physical training was indicated was 183, which included 61 patients with sarcopenia and 122 patients without sarcopenia. Of these patients, 24 patients with sarcopenia and 84 patients without sarcopenia were suitable for cardiopulmonary exercise training.

Table 1 Baseline characteristics of patients
Full size table

The patient group that was not eligible for exercise training included those with orthopedic diseases, sustained active inflammation, uncontrolled arrhythmia and symptomatic heart failure, or who refused exercise training. Although these patients did not receive exercise training, they received similar medication and dietary treatment as patients with exercise training.

Statistical Analysis

All data were statistically analyzed using the Ekuseru- Toukei 2012 software purchased from Social Survey Research Information Co., Ltd. (Tokyo, Japan). Unpaired and paired Student’s t-tests were used for 2-group comparisons. For 3-group comparisons, we used analysis of variance (ANOVA) with a post hoc Scheffe’s test. Comparisons of all proportions were performed with chi-square analysis or Fisher’s exact test. Receiver operating characteristic (ROC) curve analysis was performed to predict the cutoff value of protein intake for diagnosis of sarcopenia. Single regression analysis was used to investigate the relationship between 2 numerical variables. Analysis of covariance (ANCOVA) was used to investigate the difference in the slope of each line between two groups in single regression analysis. Multivariate regression analysis was performed to select positive correlations between SMI and nutrients or possible medications. Statistical significance was considered at the level of p <0.05.

Results

Baseline Characteristics of Patients

Patient characteristics at baseline are shown in Table 1. Sarcopenia was diagnosed in 28.0% of the study subjects. The prevalence of CHF stage C+D and symptomatic CHF was significantly higher in patients with than in those without sarcopenia (34% vs. 19%, p <0.005). Patients with sarcopenia were significantly older (78±8 years vs 69±13 years, p <0.0001) and included a higher proportion of females as compared to the group without sarcopenia (62% vs. 34%, p <0.0001). Although duration of hospitalization was significantly longer in patients with sarcopenia, no statistically significant difference in duration of exercise training was found between patients with and without sarcopenia. Body weight and body mass index in patients with sarcopenia were significantly lower than their respective values in patients without sarcopenia, as was SMI. Further, handgrip strength was significantly weaker and gait speed was significantly slower in patients with sarcopenia than in those without sarcopenia.

Table 2 Effects of comprehensive cardiac rehabilitation in the entire study cohort
Full size table

No statistically significant differences in prevalence of ischemic heart disease, hypertensive heart disease, idiopathic cardiomyopathy, valvular heart disease, arrhythmia, peripheral artery disease and cardiovascular surgery were found between patients with and without sarcopenia. The prevalence of chronic kidney disease (CKD) in patients with sarcopenia was significantly higher than that in patients without sarcopenia, while there was no statistically significant difference in the prevalence of stroke between patients with and without sarcopenia. The prevalence of life-style related diseases, including diabetes mellitus, dyslipidemia and obesity, in patients without sarcopenia was significantly higher than that in patients with sarcopenia.

No statistically significant difference was found in statin usage between patients with and without sarcopenia.

Effect of Comprehensive Cardiac Rehabilitation

Table 2 demonstrates the effects of CCR in the entire study cohort. Weight and body mass index decreased significantly after CCR, although CONUT, indicating general nutritional status, did not change. Although SMI decreased after CCR, gait speed and muscle strength, including handgrip and leg weight bearing index, improved significantly. Levels of fasting serum glucose and glycosylated hemoglobin A1c significantly improved with CCR, as did the indices of heart failure, including NT-ProBNP, end-diastolic diameter of the left ventricle, left ventricular ejection fraction and NYHA functional classification. Indices of physical performance, including the Barthel index of activities of daily living, anaerobic threshold VO2/Wt and peak VO2/Wt significantly improved with CCR in both patient groups.

Relationship between Protein Intake and Skeletal Muscle Index, Handgrip Strength and Gait Speed

Multivariate regression analysis of the association between daily average intake of nutrients, including total calories, proteins, lipids and carbohydrates, and SMI after exercise training indicated that protein was the most significant and independent nutrient associated with SMI (β=0.3701, F=5.0193, p <0.05). There was no significant association between intake of the other nutrients and SMI (data not shown). As shown in Figure 1, protein intake significantly correlated with SMI (Figure 2A), handgrip strength (Figure 2B) and gait speed (Figure 2C). In ROC curve analysis of protein intake for the detection of sarcopenia, the sensitivity and specificity of the diagnostic accuracy for protein intake were 68 and 61.5%, respectively (area under the curve=0.683, p <0.001). The cutoff value of daily protein intake for the diagnosis of sarcopenia was 64 g/day.

Figure 1
figure 1

Flow chart describing the process of enrollment of the subjects in this study. N = number of subjects; pN = paired number of subjects assessed before and after exercise training; SMI = skeletal muscle index measurement; WBI = weight bearing index

Full size image
Figure 2
figure 2

Daily protein intake significantly correlated with skeletal muscle index (A), handgrip strength (B) and gait speed (C) 3).

Full size image

Effect of Exercise Training on Nutrition

Daily average intake of total calories, proteins and lipids (Figure 3A, 3B and 3C, respectively) significantly increased after exercise training in patients both with and without sarcopenia, although the intake in patients with sarcopenia before exercise training was significantly lower than that in patients without sarcopenia. The daily average intake of carbohydrates showed a significant increase after exercise training only in patients with sarcopenia (Figure 3D). Importantly, no statistically significant differences in the average total caloric intake and the intake of nutrients were found between patients with sarcopenia after exercise training and patients without sarcopenia before exercise training (Figure 3).

The CONUT score in patients with sarcopenia before exercise training was significantly higher than that in patients without sarcopenia (2.6±1.7 vs. 1.9±1.9, p<0.01), the score remaining unchanged after exercise training in the two patient groups.

Figure 3
figure 3

Comparison of dietary intake of total calories (A), proteins (B), lipids (C) and carbohydrates (D) before and after exercise training in patients without and with sarcopenia

Full size image
Figure 4
figure 4

Comparison of dietary intake of total calories (A), proteins (B), lipids (C) and carbohydrates (D) before and after exercise training in patients without and with sarcopenia

Full size image

Effects of Exercise Training on Skeletal Muscle Index, Muscle Strength and Physical Performance

As shown in Table 3, SMI in patients without sarcopenia significantly decreased after exercise training. However, SMI in patients with sarcopenia did not change after exercise training. In terms of muscle strength, both handgrip strength and leg weight bearing index increased significantly after exercise training in patients both with and without sarcopenia. Although the pre-exercise training leg weight bearing index in patients without sarcopenia was significantly greater than that in patients with sarcopenia, leg weight bearing indices before exercise training in patients without sarcopenia were similar to those after exercise training in patients with sarcopenia. In terms of physical performance, gait speed significantly increased after exercise training in patients both with and without sarcopenia. Peak VO2/Wt in patients without sarcopenia significantly increased after exercise training. However, peak VO2/Wt in patients with sarcopenia did not change with exercise training.

Table 3 Effects of exercise training on skeletal muscle index, muscle strength and physical performance
Full size table

Medication and SMI

In this study, 31 types of drugs were used in patients with CVD. Stepwise multivariate regression analysis of the association between these drugs and SMI at discharge indicated that statin use was significantly and independently associated with SMI (β=0.1594, F=4.4602, p <0.05). The remaining drugs did not show any statistically significant association with SMI (data not shown). Although no significant difference in SMI was observed between patients with and without statin treatment among those without sarcopenia (Figure 4A), a significant difference in SMI was observed in terms of statin treatment in patients with sarcopenia (Figure 4B). In patients without and with statin treatment (including hydrophilic statins such as pravastatin and rosuvastatin, and lipophilic statins such as atorvastatin, pitavastatin, fluvastatin and simvastatin), the significantly highest SMI was found in patients treated with lipophilic statins as compared to those treated with hydrophilic statins and with no statin treatment (Figure 4C). Attempts to determine a relationship between SMI and 7 cardiovascular diseases and 5 comorbidities, as shown in Table 1, using stepwise multivariate regression analysis indicated significant and positive correlations between SMI and dyslipidemia (β=0.1205, F=4.5694, p <0.0334) and obesity (β=0.2226, F=15.6709, p <0.0001). The proportion of statin use in patients with dyslipidemia or obesity was significantly higher than that in patients without these comorbidities (53.2% vs. 26.0%, p <0.0001). These findings were compatible with the positive correlation between use of statins and SMI.

The relationship between SMI and peak VO2/Wt is shown in Figure 4D. Significant correlations were observed between these parameters in patients both with and without statin treatment. Furthermore, the ratio of peak VO2/Wt and SMI was significantly higher in patients with statin treatment than those without statin treatment.

Discussion

The most important findings of the present study are: 1) sarcopenia was identified in 28% of hospitalized patients with CVD and was noted in those with symptomatic CHF (stage C+D) and CKD; 2) protein was the most important nutrient for skeletal muscle mass; 3) increased muscle strength and gait speed in patients with sarcopenia were found after exercise training; and 4) increased skeletal muscle mass was found in the statin treatment group. Thus, the present findings suggest that comprehensive CCR, including nutrition, physical exercise and effective medication, may be effective in the prevention and treatment of sarcopenia in patients with CVD.

Clinical Characteristics of Patients With Sarcopenia

In the present study, sarcopenia was defined by muscle mass, muscle strength and physical performance, based on the AWGS guidelines (9). In our study, sarcopenia was identified in 28% of patients. These patients were older and included a greater percentage of females. The prevalence of sarcopenia in this study was higher than in a previous study, in which the prevalence of sarcopenia was 11% among communitydwelling elderly subjects in Japan (8). A possible reason for these different results may be the higher prevalence of patients with symptomatic CHF (stage C+D), and hence, disease-related sarcopenia, in this study. Since the prevalence of CKD was significantly higher in sarcopenic patients, CKD is considered to be a high risk condition for sarcopenia. No cardiovascular disease specific for sarcopenia was found in comparisons between patients with and without sarcopenia. Furthermore, clinical parameters, such as anthropometric parameters, nutrition, muscle mass, muscle strength and physical performance, showed a greater degree of deterioration in patients with sarcopenia. Thus, sarcopenia in our patients with CVD was frequently found in weak, lean, elderly patients with CHF or CKD, especially in females.

The Role of Nutrition in Sarcopenia

In this study, the general nutritional condition in patients with sarcopenia was lower than that in patients without sarcopenia. Of the major nutrients, including protein, lipids and carbohydrates, protein has been shown to be the most important nutrient for SMI. Indeed, a significant correlation was found between actual protein intake and SMI. ROC curve analysis in our patients showed that the risk of sarcopenia was much higher at the lower cutoff value of protein intake (64 g/day). These findings support those of a previous study showing the association between dietary protein intake and lean mass change in older adults (10). Thus, our data suggests that appropriate protein intake may play an important role in inhibiting the progression of sarcopenia in patients with CVD.

The Role of Exercise Training in Patients With Sarcopenia

The present study revealed that exercise training significantly improved dietary intake, muscle strength and physical performance in patients with and without sarcopenia. The positive relationship between exercise training and handgrip strength suggests that exercise training might be an important method for increasing muscle strength. To further examine these results, we calculated weight bearing index to indicate exercise capacity, such as speed of walking upstairs (11). We found that leg weight bearing index significantly increased with exercise regardless of the presence or absence of sarcopenia. Importantly, exercise training improved the weight bearing index in patients with sarcopenia to the level before exercise training in patients without sarcopenia. Thus, our data suggests that exercise training could augment muscle strength during the hospitalization period, leading to improvement of physical performance. Hence, it is important that exercise training should be recommended even in patients with sarcopenia. The fact that peak VO2/Wt in patients with sarcopenia did not increase after exercise training could indicate that improvement in exercise tolerance requires a longer duration of exercise training. In this study, skeletal muscle mass did not increase in spite of an increase in protein intake, suggesting that the duration of protein intake was not enough to increase muscle mass. Additionally, the observed decrease in skeletal muscle mass after exercise training in patients without sarcopenia was suggested as being a consequence of the weight loss in patients requiring caloric restriction for life-style related diseases. Furthermore, no significant association was found between change in protein intake and change in muscle strength. These findings suggest that increased muscle strength was derived from neural adaptations to physical exercise, since an increase in muscular strength without noticeable hypertrophy is the first line of evidence of neural involvement in the acquisition of muscular strength (12, 13).

Possible Medication for the Treatment of Sarcopenia

Although there was no patient who was on treatment with only statins and hence, we could not clarify the independent effect of statins on skeletal muscle, the present retrospective cross-sectional study showed that statin treatment was independently and significantly associated with muscle mass. Indeed, muscle mass was significantly greater in patients with sarcopenia treated with statins than in those not receiving statins. Moreover, lipophilic statin treatment had a significant influence on muscle mass. Importantly, exercise capacity in relation to muscle mass was significantly higher in patients on statin treatment. Thus, our data suggests that statins may be considered a candidate medication in the prevention and treatment of sarcopenia.

The possible mechanisms underlying the beneficial effects of statin treatment on muscle mass must be considered. A previous report revealed that the function of satellite cells, which play an important role in repair of limited muscle damage, are impaired in patients with sarcopenia (14). Since statins activate not only phosphatidylinositol 3-kinase (PI3K)-Akt-a mammalian target of rapamycin (mTOR) signaling that promotes skeletal muscle synthesis (15-17), but also AMP-activated protein kinase (AMPK) (18,19), a suppressor of mTOR (20, 21), statins may activate satellite cells by limiting the damage to skeletal muscles with AMPK activation, and coincidently encourage PI3K-Akt-mTOR signaling. Since lipophilic statins suppress glucose metabolism (22) and adipocyte differentiation in adipocyte cell lines (23), increased adipocytes in skeletal muscles with aging-associated reduced muscle strength (24) may be suppressed by statin treatment. Moreover, statin treatment increased muscle mass in patients with sarcopenia, but not in patients without sarcopenia. We speculate that this discrepancy was attributable to an age difference between them. Since PI3K-Akt-mTOR signaling and the protein synthesis response to resistance exercise are attenuated in elderly subjects but not in younger ones (25), the effect of statins on the diminished PI3K-Akt-mTOR signaling might be more obvious in elderly patients with sarcopenia. Interdisciplinary research is needed to further investigate these issues.

Study Limitations

Although this study suggests the possibility that statin therapy may be an effective method for increasing skeletal muscle mass, we could not evaluate the appropriate duration of statin administration required for this effect because of the retrospective cross-sectional nature of this analysis. Large scale, longitudinal, prospective randomized studies are necessary to verify whether statins and additional intake of protein or other nutrients could improve muscle mass, muscle strength and physical performance. Very recently, the association between plasma ghrelin levels and sarcopenia in elderly subjects has been reported (26). Future studies should address biomarkers, such as ghrelin, to evaluate the effects of CCR or sarcopenia in patients with cardiovascular diseases.

Conclusions

The present study suggests the possibility that CCR, including nutrition, physical exercise and effective medication, may be a useful strategy for the prevention and treatment of sarcopenia in patients with CVD. Thus, CCR has been suggested to be an alternative therapeutic means to delay the onset of sarcopenia.

Acknowledgements: We thank Hiroko Motomura for data collection, Misako Ando for measuring nutritional intake, Kanae Matsuzaki, Yuya Tsukada and Michiya Kishimoto for providing physical exercise, and Emiko Shiotani for secretarial assistance with this work.

Funding: This work was supported by a research grant from Bristol-Myers Squibb and Academic Contributions from Pfizer Japan Inc.

Conflict of Interest: HH, HK, HN, YN, AK, NY, YF and HI have no conflict of interest to declare.

Ethics Statement: Signed informed consent was obtained from all participants, and the study was approved by the Human Study Committee of our institution.