Introduction

The prognosis of chronic thromboembolic pulmonary hypertension (CTEPH) has significantly improved owing to advancements in pharmacological and non-pharmacological interventions1. However, despite achieving normalized resting mean pulmonary artery pressure and pulmonary vascular resistance after intervention in most patients, an abnormal pulmonary vascular response during exercise may be apparent, explaining the reduced exercise tolerance in many patients2,3. As improvements in exercise tolerance remain suboptimal, this area has become a key focus among researchers.

Exercise tolerance is derived from central (cardiac function and pulmonary circulation) and peripheral (skeletal muscle function) factors4. Currently, there is growing interest in the peripheral factors, since earlier treatment options have already addressed the central factors5. Interestingly, our previous study revealed that quadriceps muscle strength was involved in exercise tolerance, even in hemodynamically normalized patients with CTEPH6. Furthermore, muscle strength is influenced by both quantitative factors, such as muscle mass or cross-sectional area, and qualitative factors, including muscle contraction force and alterations in muscle fiber type7,8,9,10. Muscle strength can be easily measured using bioelectrical impedance analysis.

Notably, a decrease in muscle mass is associated with poor prognosis, decreased quality of life, and reduced exercise tolerance in community-dwelling older people and in patients with cardiovascular diseases, including heart failure11,12,13,14. Moreover, bioelectrical impedance analysis-derived-phase angles (PhA), a qualitative indicator of muscle function15,16, have been used as predictive indicators of mortality and clinical outcomes17,18,19. Understanding the muscle characteristics essential for exercise tolerance, from both quantitative and qualitative perspectives, is crucial for establishing interventions to address impaired exercise tolerance in patients with pulmonary hypertension. However, the number of relevant studies regarding CTEPH is currently limited. Therefore, this study aimed to investigate body composition outcomes, including both quantitative (i.e., muscle mass) and qualitative (i.e., PhA) indicators of muscle, in patients with CTEPH and to determine their association with exercise tolerance through the 6-min walk test.

Results

Patient characteristics

A total of 257 health assessments from 181 patients with CTEPH were analyzed. The patient characteristics are summarized in Table 1. Balloon pulmonary angioplasty and pulmonary endarterectomy were performed in 76% and 2% of patients, respectively. The hemodynamic parameters were as follows: mean pulmonary artery pressure was 20 mmHg (interquartile ranges [IQR]: 16–25), cardiac output was 4.2 L/min (IQR: 3.7–5.0), and pulmonary vascular resistance was 2.6 wood units (IQR: 1.9–3.7). The 6-min walk distance (6MWD) was 414 m (IQR: 354–490).

Table 1. Patient characteristics (n = 257)
Full size table

Body composition data

Body composition results are presented in Table 2. Among the female patients, body mass index was 22.8 kg/m2 (IQR: 20.9–26.1), skeletal muscle mass index (SMI) was 6.1 kg/m2 (IQR: 5.6–6.5), and PhA was 4.3° (IQR: 3.8–4.7). Among the male patients, body mass index was 24.3 kg/m2 (IQR: 22.4–26.0), SMI was 7.7 kg/m2 (IQR: 7.2–8.3), and PhA was 5.2° (IQR: 4.6–5.6). The frequency distributions of SMI and PhA in each sex are shown in Fig. 1. Overall, 59 (32%) females and eight (11%) males in our cohort had an SMI below the cut-off value for low skeletal muscle mass per the definition of the Asian Working Group (females: 5.7 kg/m2, males: 7.0 kg/m2)20 Overall, 90 (49%) females and 18 (24%) males had a PhA value below the cut-off value for sarcopenia, which was determined based on a previous study of patients with cardiovascular disease (females: 4.3°, males: 4.6°)21.

Table 2. Body composition indicators
Full size table
Fig. 1
Fig. 1
Full size image

Frequency distribution of SMI (A): females, (B): males) and PhA (C): females, (D): males). PhA, phase angle; SMI, skeletal muscle index.

Contributing factors of exercise tolerance

The 6MWD was significantly shorter in the low-SMI group (defined as < 5.7 kg/m2 for females and < 7.0 kg/m2 for males) compared to the high-SMI group (386 m [IQR: 342–439] vs. 427 m [IQR: 363–509], p = 0.001). Similarly, a significant difference in 6MWD was observed between the low-PhA group (defined as < 4.3° for females and < 4.6° for males) and the high-PhA group (376 m [IQR: 324–421] vs. 454 m [IQR: 389–531], p < 0.001).

In the univariate linear regression analysis, the 6MWD was significantly associated with age (β = –0.31; 95% CI: –0.43, –0.20; p < 0.001), male sex (β = 0.30; 95% CI: 0.23, 0.46; p < 0.001), mean pulmonary artery pressure (β = –0.37; 95% CI: –0.47, –0.24; p < 0.001), SMI (β = 0.32; 95% CI: 0.20, 0.44; p < 0.001), and PhA (β = 0.48; 95% CI: 0.37, 0.59; p < 0.001). In the linear multiple regression analysis incorporating SMI (model 1) (adjusted R2 = 0.31; p < 0.001), 6MWD was significantly associated with age (β = –0.29; 95% CI: –0.40, –0.18; p < 0.001), male sex (β = 0.28; 95% CI: 0.12, 0.43; p < 0.001), and mean pulmonary artery pressure (β = –0.37; 95% CI: –0.47, –0.26; p < 0.001), but not with SMI. Meanwhile, in the linear multiple regression analysis incorporating PhA (model 2) (adjusted R2 = 0.33; p < 0.001), 6MWD was significantly associated with age (β = –0.19; 95% CI: –0.32, –0.07; p = 0.003), male sex (β = 0.22; 95% CI: 0.10, 0.34; p < 0.001), mean pulmonary artery pressure (β = –0.32; 95% CI: –0.42, –0.21; p < 0.001), and PhA (β = 0.21; 95% CI: 0.06, 0.36; p = 0.005) (Table 3). Importantly, variance inflation factor values for all variables in both model 1 and model 2 were below 3, indicating minimal multicollinearity. In addition, a significant moderate correlation was found between PhA and 6MWD (overall: ρ = 0.50, p < 0.001), with similar results for both females (ρ = 0.40, p < 0.001) and males (ρ = 0.49, p < 0.001) (Fig. 2).

Table 3. Association between body composition and 6MWD
Full size table
Fig. 2
Fig. 2
Full size image

Correlation between 6MWD and PhA (A): females, (B): males). 6MWD, 6-min walk distance; PhA, phase angle.

Discussion

Main findings

This exploratory study demonstrated that SMI and PhA, common quantitative and qualitative indicators of muscle properties, respectively, were impaired in patients with CTEPH. Moreover, a significant association was observed between exercise tolerance and PhA.

Body composition in CTEPH

To the best of our knowledge, there are currently no reports on body composition in patients with CTEPH. In this study, 32% of females and 11% of males had SMI values below the reference value for sarcopenia, suggesting low muscle mass20. Similarly, in terms of PhA, 49% of females and 24% of males exhibited values below the cut-off for sarcopenia, established based on a previous study of hospitalized Japanese patients with cardiovascular disease21 These findings indicate that impairment of skeletal muscle function, including both muscle quantity and quality, is common among patients with CTEPH. With advancements in treatment leading to better disease prognosis and a growing population of elderly CTEPH patients22, the prevalence of individuals with reduced SMI and PhA may increase in the future.

Contributing factors of exercise tolerance in patients with CTEPH

Associations of reduced exercise tolerance with low SMI in patients with heart failure and coronary artery disease12,13,14 and those with low PhA in idiopathic pulmonary fibrosis23 have been previously reported. However, the nature of these associations in patients with CTEPH remains unknown. In this study, patients with CTEPH who had low SMI or PhA demonstrated significantly shorter 6MWD. However, after adjusting for hemodynamic parameters, age, and sex in the multiple regression analysis, PhA, but not SMI, remained independently associated with exercise tolerance. Although the mechanisms underlying our results are unclear, they may suggest several possibilities.

First, PhA may reflect changes in skeletal muscle function more sensitively than changes in muscle mass. In older adults, the decline in muscle strength occurs more rapidly than the loss of muscle mass, and preserving or increasing muscle mass does not prevent age-related muscle weakness24. Umehara et al.25 reported that upper and lower limb muscle strengths were significantly lower in older patients with heart failure than in healthy older individuals, independent of decreased skeletal muscle mass. This may have occurred due to reduced muscle quality. Second, in bioelectrical impedance analysis-derived estimations of muscle mass, equations based on water content can lead to an overestimation of muscle mass due to overhydration caused by conditions such as edema26. However, PhA reflects the state of the cell membrane separating intracellular and extracellular water compartments27, making it a more clinically useful indicator for assessing skeletal muscle function in patients with CTEPH experiencing body congestion due to hemodynamic changes.

PhA as a simple parameter for evaluating exercise tolerance

In the current clinical European Society of Cardiology guidelines for pulmonary hypertension, exercise training is strongly recommended, and the establishment of specialized rehabilitation programs for patients with pulmonary hypertension is urgently needed1,28. During the rehabilitation process, repeated measurement of exercise tolerance is important to confirm its efficacy. However, exercise tolerance tests used in patients with pulmonary hypertension, such as the 6-min walk test and cardiopulmonary exercise test, have disadvantages such as high patient burden and being limited to specialized hospitals. Souza et al.,29 reported the usefulness of PhA as a simple measure for detecting and measuring the effects of resistance training interventions and as a load criterion in older females. They found that body composition measurements, including PhA, could be safely and easily performed while maintaining consistent conditions. Based on our findings, given the moderate associations observed between PhA and 6MWD, we hypothesized that bioelectrical impedance analysis-derived PhA could be useful in assessing rehabilitation effects in patients with CTEPH who have difficulty performing exercise tests and in those followed-up at nonspecialized hospitals. However, further studies are required to confirm these findings.

Interventions for exercise tolerance in patients with CTEPH

There are several potential therapeutic targets associated with PhA that can be utilized to improve exercise tolerance. First, interventions targeting the skeletal muscle, such as cardiac rehabilitation, may assist in normalizing exercise capacity. Second, PhA was reported to be associated with sarcopenia in a systematic review30. Nakayama et al.,31 also recently reported an association between sarcopenia and exercise tolerance in patients with pulmonary hypertension, including those with CTEPH. Third, PhA has been reported to be associated with nutritional status (the Nutritional Risk Screening-2002 and the Subjective Global Assessment)32,33. The association between PhA and nutrition has also been reported in patients with cardiovascular disease21. Furthermore, while no consensus has been reached on the relationship between nutritional status and exercise tolerance in patients with CTEPH, increasing evidence supports their association with other settings of cardiovascular diseases34. Therefore, future studies should assess the association among PhA, sarcopenia, nutritional status, and exercise tolerance in patients with CTEPH and the impact of exercise and nutritional interventions on PhA and exercise tolerance.

Study limitations

This study had several limitations. First, we adopted a cross-sectional observational design and did not employ a control group. Second, the participants in this study had relatively mild hemodynamic conditions, with most patients with CTEPH having undergone balloon pulmonary angioplasty or pulmonary endarterectomy. Third, although there is a wealth of data on PhA in older adults, no clear standards have been established35. Fourthly, because our study lacks prognostic data and serial 6MWD measurements, future studies are needed to evaluate the prognostic impact of skeletal muscle mass, PhA, and 6MWD. Finally, it is important to note that the current findings are specific to a single Asian ethnicity. Hence, studies on different populations are required to confirm our findings.

Conclusions

PhA, a muscle quality index, is associated with exercise tolerance in patients with CTEPH, even after correcting for age, hemodynamics, and other factors. Therefore, bioelectrical impedance analysis-derived PhA may be used as a simple parameter to evaluate exercise tolerance in patients with CTEPH. However, further studies are required to determine whether this index could serve as a viable therapeutic target.

Methods

Study design and patients

This retrospective, cross-sectional study examined health status assessments in patients with CTEPH admitted for right heart catheterization between May 2018 and November 2021 at the Kyorin University Hospital. During the analysis period, 76 patients were examined twice within an interval of at least one year. This study was approved by the Committee for Clinical Studies and Ethics of the Kyorin University School of Medicine, Tokyo, Japan, and it was conducted in accordance with the Declaration of Helsinki. This retrospective study utilized de-identified data, and as such, the requirement for informed consent was waived by the Committee for Clinical Studies and Ethics of the Kyorin University School of Medicine. The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

Right heart catheterization

Right heart catheterization was performed using a 6-F double-lumen balloon-tipped flow-directed Swan–Ganz catheter (Harmac Medical Products Inc., Buffalo, NY, USA) via a transjugular approach. Baseline hemodynamic data were recorded, with the zero-reference level adjusted at the mid-chest for pressure measurement. Pulmonary artery wedge pressure was obtained as the mean value of the arterial trace during occlusion. Measurements were taken at the end of normal expiration, with patients placed in the supine position to assess right atrial pressure, mean pulmonary artery pressure, and pulmonary artery wedge pressure. Oxygen saturation levels in arterial blood sampled from the radial or femoral artery and pulmonary artery were measured. Cardiac output was determined using Fick’s method. The pulmonary vascular resistance (wood units) was calculated using the following formula: (mean pulmonary artery pressure – pulmonary artery wedge pressure) / cardiac output.

Six-minute walk test

The 6-min walk test was performed a day before right heart catheterization according to the guidelines published by the American Thoracic Society36. The participants were instructed to walk as fast as possible for 6 min. Each participant completed the 6-min walk test in a quiet hospital corridor with a 20 m marked track, and chairs were used to support turning instead of cones if needed. The total distance walked was recorded as the 6MWD measurement, rounded to the nearest meter. Participants were continuously monitored via electrocardiogram to ensure adequate risk management, and peripheral oxygen saturation was assessed using a finger pulse oximeter.

Bioelectrical impedance analysis

Body composition was assessed using a bioimpedance analyzer (InBody770; InBody Co., Ltd., Seoul, South Korea) before the 6-min walk test. The InBody770 employed a multifrequency, segmental measurement method and an eight-point tactile electrode37. Multifrequency measurements were conducted at 1, 5, 50, 250, 500, and 1,000 kHz for each selected body segment (arms, trunk, and legs). The analyzer automatically displayed measurements of soft lean mass, extracellular water, total body water, and PhA. The SMI was calculated as the appendicular skeletal muscle mass (sum of the lean soft tissue of the upper and lower limbs) divided by the square of the height20. PhA was calculated from the resistance (R) and reactance (Xc; measured at 50 kHz) using the following equation: PhA (◦) = arctangent (Xc/R) × (180/π). Furthermore, we calculated the proportion of patients with an SMI below the cutoff value for low skeletal muscle mass (females = 5.7 kg/m2, males = 7.0 kg/m2), as defined by the Asian Working Group for Sarcopenia20, and those with a PhA below the cutoff value for sarcopenia in patients with cardiovascular disease (females: 4.3° and males: 4.6°)21.

Statistical analyses

Data are presented as medians (IQR) for continuous variables and as absolute counts and percentages (%) for categorical variables. Difference between the two groups was assessed using the Mann–Whitney U test for continuous variables. Followed by, univariate linear regression analysis was used to explore the linear correlation of the 6MWD with body composition outcomes (SMI and PhA), sociodemographic variables (age and sex), and hemodynamic parameters (mean pulmonary artery pressure, pulmonary artery wedge pressure, and cardiac output). Multiple regression analysis was then performed to determine the standardized regression coefficients, incorporating variables of clinical importance, including age, sex, and hemodynamic parameters (mean pulmonary artery pressure and cardiac output), along with SMI (model 1) or PhA (model 2). Assumptions of normality, multicollinearity, constant variance, independence, and linearity of the model were checked for each model. Correlation analysis, employing Spearman’s correlation coefficient, was conducted to evaluate the relationship between PhA and 6MWD. Subgroup analysis was performed separately for males and females. Data were analyzed using Easy R version 1.5438 P < 0.05 was considered statistically significant.