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

The Efficacy Of Aerobic Exercise Training On Autonomic Nervous System And Endothelial Function In Patients With Compensated Cirrhosis: A Parallel, RCT Study

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:

1. 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.
2. Sarcopenia-related measures: Muscle mass (DEXA, BIA), muscle strength (handgrip dynamometry), and physical performance (6-minute walk test).
3. Laboratory outcomes: Serum ammonia, liver function tests, fasting glucose, albumin, renal function, and coagulation profile.
4. Correlative analyses: Associations between (a) muscle mass and serum ammonia, and (b) muscle mass and autonomic parameters (e.g., HRV indices).

An additional non-invasive assessment, Mesenteric Duplex Doppler Ultrasound, will be performed to evaluate mesenteric and portal blood flow as an exploratory parameter.

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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