The Efficacy of Aerobic Exercise Training on ANS and Endothelial Function in Compensated Cirrhosis

NCT06288828 | Completed Results

• 1 other identifier: IRB0569/66
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this randomized controlled trial is to investigate whether a 16-week structured aerobic exercise program combined with nutritional consultation can improve autonomic and endothelial function in patients with compensated cirrhosis. Study Design: This assessor-blinded, parallel-group randomized controlled trial will be conducted at King Chulalongkorn Memorial Hospital, Bangkok, Thailand. Fifty adults with compensated (Child-Pugh class A) cirrhosis will be recruited during routine hepatology clinic visits. Eligible participants are aged 45-75 years, have a sedentary lifestyle (\<150 minutes of moderate or \<75 minutes of vigorous physical activity per week), and have abstained from alcohol for at least six months. Exclusion criteria include active or recently treated hepatocellular carcinoma (within three months), severe portal hypertension complications (untreated large varices, prior variceal bleeding, or severe gastropathy), transjugular intrahepatic portosystemic shunt (TIPS), unstable cardiac disease, orthopedic limitations, morbid obesity (BMI \>35 kg/m²), or current use of alpha- or beta-blockers that affect autonomic function. Intervention: Participants will be randomly assigned to either the intervention or control group. Both groups will receive nutritional consultation and individualized dietary guidance at baseline, week 8, and week 16. Nutritional goals are set at 35 kcal/kg/day and 1.2 g/kg/day of protein intake. If targets are unmet, the dietitian will provide individualized recommendations to support adequate intake. The intervention group will participate in a 16-week aerobic exercise program consisting of brisk walking at moderate intensity (50-70% of maximal heart rate), totaling 150 minutes per week. The program includes two phases:

• Phase 1 (Weeks 1-4): Combined hospital-based (1 session per week) and home-based exercise under physical therapist supervision, with gradual intensity titration.
• Phase 2 (Weeks 5-16): Fully home-based exercise following prescribed intensity and frequency, with weekly follow-up via telephone or messaging to monitor adherence, safety, and exercise log completion. The control group will maintain their usual physical activity levels while receiving the same schedule of nutritional consultations and weekly follow-up for monitoring compliance and adverse events. Outcomes: Primary outcomes include changes in autonomic and endothelial function after 16 weeks.
• Autonomic function will be assessed using the Ewing autonomic battery test (HR response to standing, deep breathing, and Valsalva maneuver; BP response to posture and sustained handgrip) and heart rate variability (HRV) indices (SDNN, RMSSD, LF/HF ratio).
• Endothelial function will be evaluated using flow-mediated dilation (FMD) of the brachial artery, analyzed via Cardiovascular Suite™ software to assess nitric oxide-dependent vasodilation. Secondary outcomes include:
• Splanchnic hemodynamics: Changes in celiac and superior mesenteric artery (SMA) blood flow measured via mesenteric Doppler ultrasound (Vivid IQ, GE Healthcare). Time-averaged mean velocity (TAMV), vessel diameter, and blood flow will be recorded at baseline and post-intervention.
• Sarcopenia-related measures: Muscle mass (DEXA, BIA), muscle strength (handgrip dynamometry), and physical performance (6-minute walk test).
• Laboratory outcomes: Serum ammonia, liver function tests, fasting glucose, albumin, renal function, and coagulation profile.
• Correlative analyses: Associations between (a) muscle mass and serum ammonia, and (b) muscle mass and autonomic parameters (e.g., HRV indices).

Conditions

Cirrhosis; Aerobic Exercises; Lifestyle Modification; Endothelial Function; Autonomic Nervous System; Autonomic Dysfunction; Heart Rate Variability; Flow Mediated Dilation; Sarcopenia; Physical Activity; Physical Functional Performance; Physical Inactivity

Keywords

Cirrhosis; Autonomic nervous system; Endothelial function; Aerobic exercise

Outcome Measures

Primary Outcomes (6)

• Time-domain Heart Rate Variability (HRV) Parameters: SDNN and RMSSD and SDANN

  Heart rate variability (HRV) was assessed using a 15-minute resting ECG recording. This table reports three time-domain measures: 1) SDNN (Standard deviation of all NN intervals), 2) RMSSD (Root mean square of successive differences), and 3) SDANN (Standard deviation of the average NN intervals). These parameters reflect autonomic nervous system activity and cardiac vagal tone. All data are reported in milliseconds. Higher values indicate better autonomic regulation. Only these three time-domain parameters are presented in this table.

  Change from Baseline (week 0) at Week 16

• Time Domain Outcome: pNN50

  A time-domain measure of heart rate variability (HRV) reflecting parasympathetic activity. It is calculated as the percentage of successive normal-to-normal (NN) intervals that differ by more than 50 milliseconds. Data were collected using 3-lead ECG during a 15-minute resting period."

  Change from Baseline (week 0) at week 16

• HRV Frequency Domain Measures: TP, HF, LF, VLF

  Assessment of frequency-domain components of heart rate variability, including Total Power (TF), High Frequency (HF), Low Frequency (LF), and Very Low Frequency (VLF). Analysis was performed using Adinstrument (tm) on a 15-minute ECG recording at rest. These parameters reflect the power distribution across different frequency bands and represent autonomic nervous system activity. Data presented in the table represent the change from baseline to Week 16.

  Change from Baseline (week 0) at Week 16

• Changes in Ewing Autonomic Battery Test Scores (Improved, No Change, Worsened)

  Categorical assessment of changes in autonomic function using the Ewing Autonomic Battery test. Participants are classified into three categories: 'Improved', 'No change', or 'Worsened' based on their composite score changes from baseline to Week 16. Results are reported as the number of participants in each category.

  Change from Baseline (week 0) and Week 16

• Endothelial Function Test: Change in Flow-mediated Dilation (FMD)

  Assessment of the change in brachial artery flow-mediated dilation (FMD) from baseline to Week 16. FMD was determined by ultrasound as the percentage increase in arterial diameter during reactive hyperemia compared to baseline diameter. Results are reported as the percentage change (%). Positive values indicate an improvement in endothelial-dependent vasodilation.

  Change from Baseline (week 0) at Week 16

• HRV Frequency Domain Measures: Low Frequency/High Frequency (LF/HF) Ratio

  The LF/HF ratio is calculated as the ratio between the absolute power of the Low Frequency (LF) and High Frequency (HF) bands. It is used as an index of sympathovagal balance. Results are reported as a ratio (unitless).

  Change from baseline (week 0) to week 16

Secondary Outcomes (5)

• Muscle Mass Change

  Change from Baseline (week 0) at week 16

• Physical Function

  Change from Baseline (week 0) at week 16

• Muscle Strength Change

  Change from Baseline (week 0) at week 16

• Splanchnic Volume Flow

  Baseline and after 16-week intervention

• The Association Between Changes in Muscle Mass and Changes in Serum Ammonia Levels

  Baseline and Week 16

Study Arms (2)

Exercise group

EXPERIMENTAL

Participants in the intervention group will undergo 150 minutes of moderate aerobic exercise per week for 16 weeks, accompanied by a personalized nutritional plan (1.2 grams of protein per kilogram of ideal body weight per day and a calorie intake of 35 kilocalories per kilogram of ideal body weight per day).

Behavioral: Aerobic exercise + Nutrition consultant; Behavioral: Nutrition consultant

Control group

OTHER

The control group will solely receive nutritional guidance and maintain their physical inactivity.

Behavioral: Nutrition consultant

Interventions

Aerobic exercise + Nutrition consultant BEHAVIORAL

Participants in the intervention group will engage in 150 minutes of moderate aerobic exercise weekly for 16 weeks, primarily brisk walking or jogging. For the initial four weeks, they will visit the hospital weekly for guidance and participate in home-based exercise following a protocol totaling 150 minutes of moderate aerobic exercise in the form of brisk walking or jogging. Healthcare professionals will help adjust exercise intensity based on heart rate (60-80% of maximum) and perceived exertion (RPE 12-15), while monitoring vital signs and adverse events. After, they will transition to a home exercise program for twelve weeks, recording exercise details in a logbook. Weekly follow-up calls will ensure adherence and monitor adverse events. They will be provided with nutritional recommendations by a dietitian, the same as the control group.

Also known as: Exercise group, Active group

Exercise group

Nutrition consultant BEHAVIORAL

Participants will maintain their physical activity at the same level as before enrolling in the study. However, they will be provided with nutritional recommendations by a dietitian, which include 1.2 grams of protein per kilogram of ideal body weight daily and a calorie intake of 35 kilocalories per kilogram of ideal body weight per day. To assess adherence and make necessary adjustments, participants will complete a 3-day food record at the beginning of the study, at week 8, and at the end of the study at week 16. If participants encounter difficulties adhering to the recommended nutritional intake, the dietitian will provide additional guidance to help them meet the requirements.

Also known as: diet

Control group; Exercise group

Eligibility Criteria

• Age: 45 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• The diagnosis of cirrhosis is confirmed either through liver biopsy ,and/or compatible features on ultrasonography/ computer tomography or magnetic resonance imaging.
• The age range is between 45 and 75 years.
• Participants are classified as Child Pugh score class A.
• Participants report a physical inactivity, defined as engaging in physical activity for less than 150 minutes of moderate-intensity physical activity per week, or less than 75 minutes of vigorous-intensity physical activity per week, or an equivalent combination of both.

You may not qualify if:

• Active hepatocellular carcinoma (HCC) or remission of HCC within the past 3 months.
• Untreated large esophageal varices (EV) greater than F2 or history of upper gastrointestinal bleeding from portal hypertension or gastric varices.
• Active or history of hepatic encephalopathy (HE).
• Inpatient hospitalization for any reason or discharge from the hospital within the past 3 months.
• Complete portal vein thrombosis.
• Transjugular intrahepatic portosystemic shunt.
• Contraindications to exercise, such as recent myocardial infarction, unstable angina, electrocardiography changes within the past 24 hours, complete heart block, acute congestive heart failure, uncontrolled hypertension, hemoglobin level less than 11 g/dL, platelet count less than 50,000 cells/mm 3 .
• End-stage renal disease without dialysis.
• Severe orthopedic problems that limit the ability to exercise.
• Inability to communicate with the research team via telemedicine system.
• Body mass index (BMI) exceeding 35 kg/m 2 .
• On alpha or beta-blocker

Sponsors & Collaborators

• King Chulalongkorn Memorial Hospital: lead
• Chulalongkorn University: collaborator

Study Sites (1)

Faculty of medicine, King Chulalongkorn Memorial Hospital

Bangkok, Bangkok, 10330, Thailand

Location

MeSH Terms

Conditions

Fibrosis; Primary Dysautonomias; Sarcopenia; Motor Activity; Sedentary Behavior

Interventions

Exercise; Diet

Condition Hierarchy (Ancestors)

Pathologic Processes; Pathological Conditions, Signs and Symptoms; Autonomic Nervous System Diseases; Nervous System Diseases; Muscular Atrophy; Neuromuscular Manifestations; Neurologic Manifestations; Atrophy; Pathological Conditions, Anatomical; Signs and Symptoms; Behavior

Intervention Hierarchy (Ancestors)

Motor Activity; Movement; Musculoskeletal Physiological Phenomena; Musculoskeletal and Neural Physiological Phenomena; Nutritional Physiological Phenomena; Diet, Food, and Nutrition; Physiological Phenomena

Limitations and Caveats

This study's limitations include a small sample size, which reduced statistical power, and inconsistent adherence to unmonitored home sessions. Variability in HRV and ultrasound data occurred due to uncontrollable factors like stress and sleep. Additionally, being a single-center study limits generalizability. Finally, the focus on compensated cirrhosis meant participants had only mild impairments, potentially masking more significant effects seen in advanced disease.

Results Point of Contact

• Title: Dr. Sirinda Kittiprachakul
• Organization: Department of Rehabilitation Medicine, Faculty of Medicine, Chulalongkorn University

sirinda.ning@gmail.com

+66-2-256-4000

Study Officials

• Sirinda Kittiprachakul

  King Chulalongkorn Memorial

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: February 22, 2024
• First Posted: March 1, 2024
• Study Start: March 12, 2024
• Primary Completion: August 15, 2025
• Study Completion: September 30, 2025
• Last Updated: May 22, 2026
• Results First Posted: May 22, 2026

Record last verified: 2026-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: The data will be begin 9 months and end 36 months following article publication.
• Access Criteria: Share via E-mail on request Contact: sirinda.ning@gmail.com

Locations

TH (1)