Correlation between respiratory muscle weakness and frailty status as risk markers for poor outcomes in patients with cardiovascular disease

Abstract

Aims

Although the developmental mechanism of respiratory muscle weakness (RMW) and frailty are partly similar in patients with cardiovascular disease (CVD), their relationship remains unclear. This study aimed to investigate the correlation between RMW and frailty and its impact on clinical outcomes in patients with CVD.

Methods and results

In this retrospective observational study, consecutive 1217 patients who were hospitalized for CVD treatment were enrolled. We assessed frailty status by using the Fried criteria and respiratory muscle strength by measuring the maximal inspiratory pressure (PI_max) at hospital discharge, with RMW defined as PI_max <70% of the predicted value. The endpoint was a composite of all-cause death and/or readmission for heart failure. We examined the prevalence of RMW and frailty and their correlation. The relationships of RMW with the endpoint for each presence or absence of frailty were also investigated. Respiratory muscle weakness and frailty were observed in 456 (37.5%) and 295 (24.2%) patients, respectively, and 149 (12.2%) patients had both statuses. Frailty was detected as a significant indicator of RMW [odds ratio: 1.84, 95% confidence interval (CI): 1.39–2.44]. Composite events occurred in 282 patients (23.2%). Respiratory muscle weakness was independently associated with an increased incidence of events in patients with both non-frailty [hazard ratio (HR): 1.40, 95% CI: 1.04–1.88] and frailty (HR: 1.68, 95% CI: 1.07–2.63).

Conclusions

This is the first to demonstrate a correlation between RMW and frailty in patients with CVD, with 12.2% of patients showing overlap. RMW was significantly associated with an increased risk of poor outcomes in patients with CVD and frailty.

Graphical Abstract

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Introduction

Cardiovascular disease (CVD) is one of the leading causes of death worldwide.¹ An increase in patients with CVD is a progressive problem in Japan because of the increased proportion of the older population with cardiovascular risk factors.^2,3 Patients with CVD frequently suffer from breathlessness during exercise leading to exercise intolerance and decreased quality of life.^4,5 Exercise-related breathlessness partly results from respiratory muscle weakness (RMW) in approximately 30–50% of patients with CVD.^5,6 The RMW is caused by muscular atrophy and/or decreased actin-myosin cross-bridges, resulting from activation of neurohumoral factors due to ageing or disease conditions, especially in heart failure.⁶ Additionally, RMW is documented as a predictor for exercise intolerance and poor prognosis.^7,8 However, few studies have investigated the potential mechanism and correlated factors of RMW in patients with CVD.^9,10

In the last decade, frailty has been established as a syndrome characterized by an age-related decline in function and reserve of multiple physiological systems.¹¹ Frailty is commonly associated with disease conditions, including CVD, leading to increased risks of morbidity and mortality.¹² The proportion of older patients with CVD has been increasing resulting in a higher prevalence of frailty.¹³ The interaction between decreased metabolism, malnutrition and systemic inflammation, skeletal muscle abnormality, and decreased physical activity, namely the ‘frailty cycle’, is likely to be observed in older individuals or patients hospitalized with CVD.¹¹ Although the developmental mechanisms of RMW and frailty are partly similar, the relationship between these statuses remains unclear. The abnormalities of muscle function, exercise intolerance, and poor prognosis is frequently present in patients with heart failure as a progressive condition of CVD.⁵ We hypothesized that frailty is one of the leading causes of RMW and the correlation is a risk marker for the events of death and/or heart failure readmission in patients with CVD. This concept may reveal that respiratory muscles are potential treatment targets to improve frailty status in this population.

Therefore, this study aimed to investigate the correlation between RMW and frailty and its impact on clinical outcomes in patients with CVD.

Methods

Study design and population

This was a single-centre retrospective observational study. We reviewed a cohort of consecutive patients with CVD who were admitted to Kitasato University Hospital, Japan, from January 2015 to March 2020. The patients aged 20 years or older, who were admitted for treatment of CVD, including acute coronary syndrome, heart failure, and arrhythmia, and underwent cardiac rehabilitation during hospitalization, were included in this study. Patients who had received thoracic surgery within the last 3 months or had chronic respiratory diseases were excluded from the study. Comprehensive cardiac rehabilitation consisted of supervised exercise training and education on self-management and was based on the statement from the Japanese Circulation Society.¹⁴ Blood examinations and echocardiograms at hospital discharge were considered as baseline data. We also routinely measured pulmonary and respiratory muscle functions, physical function, functional capacity, and frailty status at discharge to assess the risk classification and to use them for prescription of exercise training. Events of all-cause mortality and/or readmission due to heart failure after the discharge were considered as the primary endpoint of this study. All variables were obtained from an electronic database. The study protocol was approved by the Kitasato Institute Clinical Research Review Board (KMEO B18-075) and was performed according to the ethical guidelines of the Declaration of Helsinki. We received verbal informed consent from all participants and information on the research was made public by opt-out.¹⁵

Patient characteristics

Data on age, sex, body mass index (BMI), causes of admission, medical history, smoking history, medications, and comorbidities, such as hypertension, diabetes mellitus, dyslipidaemia, chronic kidney disease, or atrial fibrillation, were obtained from medical records. Routine laboratory analysis included haemoglobin, serum albumin, C-reactive protein (CRP), and plasma brain natriuretic peptide (BNP). The estimated glomerular filtration rate (eGFR) was determined on the basis of serum creatinine levels. The left ventricular ejection fraction (LVEF) was also measured by 2D echocardiography.

Pulmonary and respiratory muscle functions

To assess pulmonary function, spirometry without a bronchodilator was performed to measure forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV₁) by using a spirometer (Autospiro AS-507, Minato Medical Science, Osaka, Japan), and their percentages were calculated relative to the predictive values issued by the Japanese Respiratory Society.¹⁶ To assess the respiratory muscle function, maximal inspiratory pressure (PI_max) was measured by using a pressure transducer (Autospiro AAM-377, Minato Medical Science, Osaka, Japan) connected to a spirometer according to the joint statement of the American Thoracic Society and European Respiratory Society.¹⁷ To measure PI_max, patients in a sitting position were asked to hold a 25-mm diameter mouthpiece in their mouth and perform a 3-s forced inspiration from the maximal expiratory level. Maximal inspiratory pressure was determined on the basis of the average value of the maximum inspiratory pressure over a 1-s period during the 3-s forced inspiration. Maximal inspiratory pressure was expressed as its absolute value in this study, although it shows negative pressure for atmospheric pressure. The respiratory pressure measurement was performed three times, and the maximum value in PI_max was accepted for analysis. Subsequently, we calculated the percentage PI_max (%PI_max) based on predictive values that were estimated by using age, sex, height, and body weight.¹⁸ Respiratory muscle weakness was defined as a %PI_max <70%.

Physical function, functional capacity, and frailty status

As physical function, we measured gait speed, handgrip strength, and the Short Physical Performance Battery (SPPB). In measuring the gait speed, patients were asked to walk at their usual pace and timed over the middle 10 m of a 16-m walkway. Handgrip strength was measured in the sitting position with the elbow joint at 90˚ flexion by using a digital dynamometer (TKK 5101 Grip-D; Takei, Tokyo, Japan). Two maximal isometric voluntary contractions of the hands for 3 s were collected for both hands, and the greatest strength in absolute value (kg) was used in the analyses. The SPPB consists of three components, standing balance, gait speed, and repeated chair stands, and was measured according to established methods. Each component is scored on a scale of 0 to 4; the sum of the scores ranged from 0 to 12, with lower scores indicating more severe physical dysfunction.¹⁹ The functional capacity was assessed by using the 6-min walk distance (6MWD) test based on the standard guidelines of the American Thoracic Society.²⁰

The frailty status was evaluated by using the Fried phenotype model proposed and validated by Fried et al. and is the most widely adopted model and generally regarded as the standard.¹² This model was assessed by evaluating five components, slowness (gait speed), weakness (handgrip), weight loss, exhaustion, and low physical activity. Physical frailty was defined as the presence of three or more components.

Endpoints

The endpoint of this study was a composite of all-cause death and/or readmission due to heart failure identified through a medical chart review. The time period for these events was calculated as the number of days from the date of hospital discharge to the date of the events.

Statistical analysis

Clinical variables, including patient characteristics, physical function, and respiratory function, were compared between the presence and absence of RMW in subgroups of frailty status by using the unpaired t-test or Mann–Whitney U-test for continuous variables and χ² or Fisher’s exact test for categorical variables, as appropriate. The association between RMW and clinical endpoints was analysed in all patients and in those stratified by frailty status using the Kaplan–Meier curve and log-rank test. We also analysed the univariate and multivariate Cox proportional hazard models to estimate the hazard ratio (HR) of RMW for the composite outcome. Subgroup analysis in stratification of frailty status was performed to assess the potential effect modification of frailty on the association of RMW with clinical events. Univariate and multivariate logistic regression models were used to determine if the frailty status was an independent relevant factor for RMW. The following clinical confounders at hospital discharge were used as covariates in multivariate analyses: age, sex, BMI, cause of admission, smoking history, comorbidities, medications, LVEF, and BNP. As a sensitivity analysis, multivariate Cox proportional hazard model of RMW for the composite outcome was examined with HR adjusted for propensity score that was estimated in the multivariate logistic regression model of RMW. For missing data on confounders, we performed multiple imputation using the chained equation method, assuming that analysed data were missing at random. Results from 20 imputed datasets were combined for analysis using Rubin’s formula. Continuous variables are reported as the mean ± standard deviation or median with interquartile range, and categorical variables are expressed as patient numbers and their percentages. A two-tailed P-value of <0.05 was considered to be indicative of statistical significance. Statistical analyses were performed by using SPSS 25.0 (IBM SPSS Statistics for Windows, IBM Corp., Armonk, NY, USA), Stata version 15.1 (Stata Corp., College Station, TX, USA), and R version 3.1.2 (R Foundation for Statistical Computing, Vienna, Austria).

Results

The potential study population consisted of 1685 consecutive patients with CVD who performed the assessment of respiratory muscle function and frailty status; those who had received thoracic surgery within the last 3 months (n = 445) or had chronic respiratory diseases (n = 23) were excluded from the study. Consequently, 1217 patients with CVD were included for analysis in this study.

Figure 1 shows the Venn diagram of the distribution and prevalence of RMW and frailty. Out of 1217 patients, RMW and frailty were observed in 456 (37.5%) and 295 (24.2%), respectively, and overlap status was observed in 149 (12.2%) patients.

Patient characteristics and physical and respiratory functions in the studied patients

Table 1 shows the baseline patient characteristics in the studied patients stratified by frailty status between patients with or without RMW. In the non-frail patients, RMW was associated with older age, higher prevalence of heart failure and comorbidities of atrial fibrillation and chronic kidney disease, higher prescription of loop diuretics, lower levels of haemoglobin, albumin, and eGFR, and higher levels of CRP and BNP. Conversely, in patients with frailty, there was no significant difference in baseline characteristics between patients with or without RMW.

Table 2 shows the physical function, functional capacity, and respiratory muscle functions stratified by frailty status. Respiratory muscle weakness was significantly associated with lower values of gait speed, handgrip strength, SPPB, 6MWD, and respiratory functions in both the frailty and non-frailty groups, but there was no significant difference in FEV₁/FVC in patients with frailty.

Association between respiratory muscle weakness and clinical endpoints with or without frailty status

A total of 282 composite events of all-cause death and/or heart failure readmission occurred during the median follow-up period of 1.5 years (interquartile range, 0.8–2.6), and the incidence rate of the events was 13.2/100 person-years. In unadjusted analyses, the prevalence of RMW, frailty, or both statuses were associated with higher incidences of clinical events (Figure 2).

Figure 3 shows the Kaplan–Meier survival curves stratified by RMW in all patients and subgroups of frailty status. The event-free survival rate was significantly lower in patients with RMW than in those without weakness regardless of frailty status. In the multivariate Cox proportional hazard model, RMW was significantly associated with lower event-free survival in all patients [adjusted HR (aHR), 1.44; 95% confidence interval (CI), 1.13–1.83; P = 0.003] and subgroup of non-frailty (aHR, 1.40; 95% CI, 1.04–1.88; P = 0.027) and frailty (aHR, 1.68; 95% CI, 1.07–2.63; P = 0.023) without statistical interaction (Figure 4). There was a consistent association between RMW and lower event-free survival in all patients and subgroups of frailty status in the Cox proportional hazard model adjusted for propensity score of the multivariate logistic regression analysis (Supplementary material online, Table S1).

Correlation between frailty status and respiratory muscle weakness

Table 3 shows the results of logistic regression models to determine if frailty status was an independent relevant marker of RMW. In univariate and multivariate logistic regression models after adjustment for clinical confounding factors, frailty was independently associated with RMW.

Discussion

The novel findings in this study were as follows. First, a higher prevalence of RMW was observed in patients with frailty, and overlap of RMW with frailty was observed in 12.6% of the patients with CVD. In addition, frailty was a significant and independent relevant factor associated with RMW. Second, RMW was consistently associated with poor outcome regardless of frailty in patients with CVD.

To the best of our knowledge, this is the first study to provide detailed information on the prevalence of frailty and RMW and show a strong correlation between these statuses in patients with CVD. In this study, RMW was observed in 37.5% of all (459/1217), 33.2% of non-frail (307/922), and 50.5% of frail (149/295) patients. In addition, frailty status was strongly correlated with RMW. The CVD condition is known to cause muscle atrophy due to activated reactive oxygen species levels and the ubiquitin proteasome system, resulting in impaired respiratory muscle function.⁶ Similarly, the interaction between age-related chronic diseases, oxidative stress, and inflammation leads to multisystem dysfunction and frailty phenotype.¹¹ Interestingly, we found that RMW was associated with baseline characteristics, such as older age and disease condition in non-frail patients, but this association was not observed in frail patients. A previous study with a large sample of community-living older persons reported that frailty and respiratory impairment were cross-sectionally and longitudinally associated with one another.²¹ Thus, our findings suggest that frailty status may be a major cause of RMW and that RMW may be one of the phenotypes of frailty in patients with CVD.

In the results of survival analyses, RMW was a significant relevant marker for lower event-free survival, even in frail patients. We previously reported respiratory muscle strength as a significant predictor of ventilatory inefficiency and poor prognosis in patients with heart failure,^7,8 In general, decreased respiratory muscle strength is associated with reduced pulmonary function,^7,22 a known risk factor for cardiovascular events.²³ We also showed that a combination of RMW and frailty status tended to be associated with a higher rate of composite events and lower values of physical function. Lower physical functions, such as muscle strength, gait speed, and 6MWD, have previously been established as indicators of worse prognosis in patients with CVD.^24–26 Therefore, it is considered that RMW is a useful risk indicator of lower physical fitness and poor prognosis even in CVD frail patients. Indeed, respiratory muscle function might be an important parameter for assessing frailty status in patients with CVD.

The present study finding of a strong correlation between frailty status and RMW has clinical implications because RMW is a relevant marker for decreased physical function and poor outcomes. In general, respiratory muscle strength is easily measured in clinical practice. Cardiovascular disease and frailty have been reported as risk markers of increased mortality in patients hospitalized with coronavirus disease-19 (COVID-19),²⁷ and respiratory muscle performance may contribute to outcomes related to acute respiratory distress syndrome from coronavirus infection.²⁸ Therefore, assessment of respiratory muscle strength might be crucial and useful for risk stratification in CVD patients with or without frailty, especially during the COVID-19 pandemic. Furthermore, respiratory muscle strength can be modified with exercise training, including inspiratory muscle training, in patients with CVD.^29,30 Several studies have indicated that increased respiratory muscle strength contributes to the improvement of respiratory muscle fatiguability, exercise tolerance, and quality of life.^30,31 Our previous study also demonstrated that positive change in respiratory muscle strength after cardiac rehabilitation was significantly associated with better prognosis in patients with heart failure.³² Additionally, an increase in respiratory muscle strength subsequently improves peripheral muscle blood flow with decreased peripheral vascular resistance.³³ The reason for this is that increased inspiratory muscle strength augments respiratory tidal volume and consequently improves input to the pulmonary stretch receptor and autonomic nervous activity.⁵ These results support the potential effectiveness of increased respiratory muscle strength for improving frailty status in patients with CVD.

However, there were some study limitations that should be considered. First, this was a single-centre study that only included Japanese patients and the sample size was relatively small, so external validity could have been reduced and the applicability of our findings to other patient groups must be demonstrated. Therefore, future multicentre studies are required to investigate the validity and reliability of RMW as a relevant factor of prognosis in patients with CVD and frailty. Second, respiratory muscle strength and frailty status were not assessed continuously, so it was impossible to identify a causal relationship between them. Hence, future longitudinal and interventional studies would be necessary to determine if increased respiratory muscle strength improves frailty status in patients with CVD. Third, the proportion of women, 31.2% of studied patients, were under-represented as in several clinical trials,^34,35 which may limit understanding the features of sex differences in RMW and frailty.

Conclusions

Our study showed that RMW was closely correlated with frailty in patients with CVD, and 12.2% of patients had overlap status. Moreover, RMW was significantly associated with an increased risk of poor outcomes in patients with CVD, even those with frailty. These findings suggest that RMW in patients with CVD might be one of the phenotypes of frailty and a potential intervention target for frailty.

Supplementary material

Supplementary material is available at European Journal of Cardiovascular Nursing online.

Funding

This work was supported by the Japan Society for the Promotion of Science Grant-in-Aid (JP19K19922).

Data availability

The data that support the findings of this study are available from the corresponding author, NH, upon reasonable request.

References

Author notes