Prognostic value of cardio-hepatic-skeletal muscle syndrome in patients with heart failure

Although heart failure (HF) and liver dysfunction often coexist because of complex cardiohepatic interactions, the association between liver dysfunction and physical dysfunction, and between coexistence of both and prognosis in HF patients remains unclear. We reviewed 895 patients with HF (mean age, 69.4 ± 14.2 years) who underwent liver function test using model for end-stage liver disease excluding international normalized ratio (MELD-XI) score and physical function test (grip strength, leg strength, gait speed, and 6-min walking distance [6MWD]). In the multiple regression analysis, MELD-XI score was independently associated with lower grip strength, leg strength, gait speed, and 6MWD (all P < 0.001). One hundred thirty deaths occurred over a median follow-up period of 1.67 years (interquartile range: 0.62–3.04). For all-cause mortality, patients with high MELD-XI scores and reduced physical functions were found to have a significantly higher mortality risk even after adjusting for several covariates (grip strength, hazard ratio [HR]: 3.80, P < 0.001; leg strength, HR: 4.65, P < 0.001; gait speed, HR: 2.49, P = 0.001, and 6MWD, HR: 5.48, P < 0.001). Liver dysfunction was correlated with reduced physical function. Moreover, the coexistence of lower physical function and liver dysfunction considerably affected prognosis in patients with HF.


Results
Patient characteristics. A total of 895 HF patients, excluding hemodialysis patients and subjects with missing values, were analyzed of the 918 patients included (Fig. 1). The baseline characteristics of all patients and for groups stratified according to the median of model for end-stage liver disease excluding international normalized ratio (MELD-XI) score are presented in Table 1. The study population had a mean age of 69.4 ± 14.2 years and 60.9% were men. The mean left ventricular ejection fraction (LVEF) was 44.4% ± 17.3% and median B-type natriuretic peptide (BNP) was 665 pg/mL. In comparison to the low MELD-XI score group, participants in the high MELD-XI score group were older, had a higher proportion of males, and had greater HF severity (i.e., higher New York Heart Association [NYHA] classification and BNP) and higher creatinine (Cr), Total bilirubin (T-bil), and prothrombin time-international normalized ratio (PT-INR), and fewer subjects were current smokers.

Discussion
There were two major findings in the present study. First, liver dysfunction was shown to be associated with physical dysfunction in patients with HF, even after adjusting for severity of HF, such as NYHA classification, BNP, coronary risk factors, and LVEF. In addition, liver dysfunction was more closely related to physical dysfunction than BNP, an established biomarker of HF. Second, the coexistence of lower physical function and liver dysfunction had a greater impact on prognosis than either alone in patients with HF. These findings suggest the importance of the cardio-hepatic-muscle relation in the prognosis and quality of life of patients with HF.
Previous studies showed that liver dysfunction is the strongest prognostic factor in HF 10 . Moreover, recent reports have shown that the MELD score is correlated with cardiac dysfunction and is associated with prognosis 4,5 . However, little is known about the association between liver dysfunction and physical function in patients with HF. A number of previous studies in patients with cirrhosis and liver disease have reported that sarcopenia or loss of skeletal muscle mass is a common complication and a strong prognostic predictor. The liver plays a major role in carbohydrate, fat, protein, and vitamin metabolism, in addition to lipid transport and bile secretion and excretion, all of which are involved in muscle and protein metabolism and are crucial for nutritional Table 2. Associations of severity of liver damage with physical function. β, standardized regression coefficient. 6MWD 6-min walking distance, MELD-XI score model for end-stage liver disease excluding international normalized ratio score, BMI body mass index, BNP B-type natriuretic peptide, NYHA New York Heart Association, LVEF left ventricular ejection fraction. www.nature.com/scientificreports/ status 7 . Liver dysfunction has been reported to reduce clearance of toxic substances, such as ammonia 11 , and the presence of toxic substances increases skeletal muscle myostatin levels, leading to the progression of skeletal muscle wasting 12,13 . This results in muscle breakdown, and may lead to muscle wasting and reduced physical function [6][7][8] . These mechanisms may explain the relationships between the combination of liver dysfunction and physical dysfunction and prognosis observed in this study.
In addition, the mechanism of muscle breakdown due to inflammatory cytokines and increased metabolic abnormalities has been reported in patients with HF 14 . In fact, in the present study, BNP and NYHA, which are related to the severity of HF, were also shown to be related to physical dysfunction, similar to the MELD-XI score. These results suggest that the coexistence of liver dysfunction and high severity of HF has a strong impact on reduced physical function.
Our study demonstrated that the complications of liver and physical dysfunction exacerbate the prognosis of patients with HF. Although various possible mechanisms have been postulated to explain these observations, we propose the concept of "cardio-hepatic-skeletal muscle syndrome, " defined as a vicious cycle in patients with HF in which HF causes both hepatic and motor dysfunction 3,15 . Liver dysfunction is a risk factor that increases www.nature.com/scientificreports/ the severity of HF 10,16 , and it may cause a decrease in metabolism and an increase in utilization of calories from proteins, resulting in skeletal muscle breakdown 6,7 .
Endurance and resistance training have beneficial effects on the cardiovascular system. Myokines (e.g., IL-6 and IL-15), produced and secreted through muscle contraction, regulate the maturation and redistribution of natural killer cells and promote the release of antiinflammatory cytokines, and may therefore protect the cardiovascular system and hepatocytes 17,18 . These myokines are produced exponentially through sustained muscle contraction, such as physical activity 19 , and are involved in determining the lower limb muscle strength and walking speed 20,21 . Irisin, a recently discovered exercise-induced myokine, was shown to inhibit mitochondrial fission and promote biosynthesis, and to be involved in the reduction of oxidative stress thus protecting the heart and hepatocytes during ischemia in mice 22,23 . Furthermore, Akt1 and follistatin-like 1 (FSTL1) are upregulated by skeletal muscle hypertrophy in mice, although these myokines show protective effects on the blood vessels, heart, and cardiovascularization, and are therefore prognostic factors in patients with HF 24,25 . Skeletal muscle loss is correlated with myocardial loss in the presence or absence of heart disease, and may indicate a decrease in muscle cells in other important organs 26 .
Through these mechanisms, liver and motor dysfunction may exacerbate HF, which would thereby further exacerbate liver and motor dysfunction.
Liver dysfunction is associated with poor prognosis in patients with HF 4,16 . The results of the present study showed that severity of liver damage was associated with decreased physical function. MELD-XI scores are determined from biochemical data of T-bil and Cr, which are commonly used in clinical practice and are readily available 4,8 . Therefore, evaluation using the MELD-XI score may provide additional information related to physical function, such as sarcopenia and frailty, in addition to predicting mortality risk in patients with HF. In fact, some studies have suggested that serum bilirubin level is correlated with physical function parameters, such as hand grip strength and 6MWD, and also with quality of life 27,28 . Conventionally, liver function and physical function have been assessed separately in patients with HF. However, a comprehensive assessment may provide additional information to predict future prognosis. Studies in patients with liver disease have shown that the incorporation of sarcopenia into the MELD score provided added value in predicting mortality 29 . Therefore, our findings may extend the treatment and risk management of patients with HF with hepatic dysfunction to interventions addressing cardio-hepatic-skeletal muscle interactions.
This study had some limitations, first, this was a retrospective observational study performed in a single center with a limited follow-up. Second, because this study used only one point of laboratory examination values obtained at the time of hospital visits, the impact of changes in liver function on motor function and prognosis is unknown. In addition, limited information was available regarding drugs prescribed by the attending physician. Therefore, this study did not consider congestion or dehydration as possible confounding factors. However, it has been reported that the components of MELD-XI score (T-bil and Cr) are likely to change depending on the treatment of heart disease, and that the MELD-XI score is likely to change 4 . Therefore, laboratory examination values after acute treatment may include confounding factors due to the initial treatment. Previous studies indicated that acute changes in liver function at the onset of HF are associated with prognosis in patients with HF 30 . This study showed that acute changes at the onset of HF are useful for predicting physical decline and mortality risk. Finally, there was no additional information on echography or diagnostic imaging of the liver. Therefore, organ Table 3. Unadjusted hazard ratio and adjusted hazard ratio for all-cause mortality. Adjusted by age, sex, body mass index, B-Type natriuretic peptide, New York Heart Association classification, left ventricular ejection fraction, hypertension, dyslipidemia, diabetes mellitus, obesity and current smoking. HR hazard ratio, CI confidence interval, MELD-XI score model for end stage liver disease excluding international normalized ratio score, 6MWD 6-min walking distance. www.nature.com/scientificreports/ manifestations due to liver congestion are unclear. However, this was also a strength of our study indicating the utility of MELD-XI score, which can easily evaluate liver function in daily clinical practice.

Conclusions
The severity of liver damage determined using the MELD-XI score was correlated with reduced physical function. Furthermore, the MELD-XI score was a better predictor of grip strength, leg strength, gait speed, and 6MWD than BNP. Moreover, the coexistence of reduced physical function and liver dysfunction considerably affected prognosis in patients with HF. Taken together, the results of the present study suggested that assessment of liver function and physical function in patients with HF would be useful for guiding treatment and improving patient survival and quality of life.

Methods
Patients. The present study used data from the Kitasato University Cardiac Rehabilitation Database. We conducted a retrospective review of 895 consecutive patients with acute HF, defined by the Framingham Criteria 31 , admitted to the Kitasato University Hospital Cardiovascular Center and evaluated for the severity of liver damage, defined according to the MELD-XI score, and physical functions between August 1, 2010 and January 31, 2018. Patients on maintenance dialysis and those with missing data or without sufficient follow-up were excluded from the present study (Fig. 1). The study protocol was performed in accordance with the tenets of the Declaration of Helsinki and was approved by the Ethics Committee of Kitasato University Hospital (KMEO B18-075). Because this study was an observational study that did not involve invasive procedures or interventions, written informed consent was not required under the Japanese Ministry of Health, Labor and Welfare's "Ethical Guidelines for Medical and Health Research for Subjects". Therefore, informed consent was waived with Kitasato University Medical Ethics Organization approval by the institutional guidelines for retrospective observational studies. Participants were informed by opting out that they could refuse to participate because the study protocol was based on the retrospective review of medical records.
Data collection and assessment of severity of liver damage. The clinical characteristics of the patients, including age, sex, BMI, laboratory examination results, biochemical data, vital signs (blood pressure and heart rate), and echocardiographic data were collected from the electronic medical records at the time of hospitalization. The clinical details of presentation (comorbidities and medication use) were recorded during hospitalization. All-cause mortality was used as the study endpoint, and time to endpoint was calculated as the time from the date of physical function assessment to the occurrence of the event (in days). Follow-up was performed according to discharge and the last day of the period that could be tracked was recorded as the censoring date of the all-cause mortality.
The original MELD score cannot be used in patients taking vitamin K antagonists (oral anticoagulants) because it uses PT-INR values for risk stratification. Therefore, we assessed the severity of liver damage using the MELD-XI score, a model developed by Heuman et al. 32 that excludes PT-INR, using the equation: MELD-XI = 5.11 × Ln (T-bil) + 11.76 × Ln (Cr) + 9.44. Any variable with a value of < 1.0 was assigned a value of 1.0 to avoid negative scores. Thus, the minimum possible MELD-XI score was 9.44.
Physical function tests. We measured grip strength, leg strength, gait speed, and 6MWD before discharge from hospital.
A dynamometer was used to measure grip strength (TKK5101 Grip-D; Takei, Tokyo, Japan). Briefly, the patient performed two maximal isometric voluntary contractions of both hands for 3 s each while seated on a bench with the elbow fixed at 90° flexion. The width of the dynamometer handle was adjusted for each patient to match the hand size. The greatest strength measurement in kg was used in the analyses.
The maximal quadriceps isometric strength was measured using a handheld dynamometer to determine leg strength (μ-Tas; ANIMA, Tokyo, Japan). Briefly, with the patient seated in a chair with a non-extensible strap connecting the ankle to a strain gauge, 5-s maximal isometric voluntary contractions of the quadriceps were collected three times for both legs with the hip joint at approximately 90° flexion. Measurements were obtained for the right and left quadriceps consecutively. The greatest strength values on the right and left sides were averaged and expressed as absolute value (kg) and relative to body mass (%BM).
Usual gait speed was measured by timing the patients walking at their usual speed over the middle 10 m of a 16-m walkway. The usual gait speed of each participant was calculated by dividing the distance (in m) by the time (in s).
6MWD was determined according to the guidelines of the American Thoracic Society (ATS) under supervision by technicians 33 . The patients were instructed to walk at their own pace along a straight, flat hallway marked at 1-m intervals, and the distance (in m) was recorded after 6 min. Statistical analysis. Normally distributed continuous variables are expressed as the mean ± standard deviation, and non-normally distributed variables are presented as the median (IQR). Categorical variables are expressed as numbers and percentages. Subjects were divided into subcategories according to the median MELD-XI score: < 11.7 points; low group: ≥ 11.7 points; high group. Baseline characteristics were compared using Student's t test, Mann-Whitney U test, or Fisher's exact test as appropriate.
Independent associations between parameters of physical function (i.e., grip strength, leg strength, gait speed, and 6MWD) were examined by multiple linear regression analysis. The variables entered into the model were defined a priori. Multivariate linear regression analysis was performed to assess the associations of MELD-XI score and the following HF risk factors or severity factors (independent variables) with patient's predicted physical function (dependent variables): age, sex, BMI, BNP, NYHA classification, LVEF, hypertension, dyslipidemia, diabetes mellitus, obesity, and current smoking. In addition, hierarchical multiple linear regression analyses were performed to assess the contributions of BNP and MELD-XI score to explain continuous levels of physical function after adjusting for clinical model. The clinical model consisted of the variables used in multivariate linear regression excluding BNP and MELD-XI score.
Kaplan-Meier analysis was performed to assess survival, and the log-rank test was used to assess prognostic significance for patients divided into four groups according to the median MELD-XI score (11.7 points) as the cutoff for high and low MELD-XI score and median physical function level for high and low physical function. Parameters of physical function, i.e., grip strength, leg strength, gait speed, and 6MWD, were divided according to the median stratified by sex.

Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.