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NCT Number: NCT06788275

Aerobic Exercise-induced Effect on Endothelial Function in Patients With Ischaemic Heart Disease

Endothelial dysfunction is one of the aetiological factors in ischaemic heart disease (IHD). Aerobic exercise is effective in improving endothelial function, as measured by flow-mediated dilation (FMD), in patients with IHD. Within the aerobic exercise methods, there is evidence showing that high-intensity interval training (HIIT) increases FMD to a greater extent than moderate-intensity training (MIT) in these patients. Notably, in a recent review, our research group found that only studies performing long bouts of HIIT (long HIIT: higher than 1 min) found a greater effect on FMD, while no differences were found in those studies using short bouts of HIIT (short HIIT: ≤ 1 min) and MIT. However, no experimental studies comparing the effect of long HIIT, short HIIT, and MIT on endothelial function, as well as other predictors of mortality, such as cardiorespiratory fitness, brain-derived neurotrophic factor (BDNF) levels or parasympathetic branch activity, have been performed. Therefore, the main objective of this project will be to compare the effect of the three aerobic exercise methods on endothelial function, as measured by FMD, in patients with IHD. Complementarily, the effect of aerobic exercise, depending on the exercise method, on different mortality predictors will be compared. For this purpose, a multicentre randomised study will be carried out (2 hospitals in Elche and one in Alicante). Assessors will be blinded to the patients allocation. Participants will be aware about their allocation in the experimental groups due to the nature of the study. A total of 132 men and women with IHD (66 per sex), diagnosed between three and 12 months before the start of the intervention, aged between 45 and 75 years, and without limitations for the practice of exercise training, will be recruited. All patients will train 3 days a week for 12 weeks. Participants will be assessed before the intervention (i.e., pre), at 6 weeks of training (i.e., mid) and after the intervention (i.e., post). Physiological and psychological variables will be registered in the assessment periods. Training intensity will be individually prescribed based on the cardiopulmonary exercise test (CPET). Intensity exercise will be adapted after the first part of the intervention. Analysis of covariance will be used to compare the values of the three groups after the intervention for the continuous variables, including the pre-intervention value as a covariate, while a logistic regression model will be used for the categorical variables.

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Key information

Conditions

Percutaneous Coronary Intervention (PCI) Acute Myocardial Infarction Angina (Stable) Angina Pectoris Angina, Stable Angina, Unstable Arterial Occlusive Diseases Arteriosclerosis Cardiorespiratory Fitness Cardiovascular Diseases Chest Pain Coronary Artery Disease Coronary Disease Heart Diseases Ischaemic Heart Diseases Myocardial Ischemia Neurologic Manifestations Pain Pathological Conditions, Signs and Symptoms Signs and Symptoms Unstable Angina Pectoris Vascular Diseases

Age range

45 year–75 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Instituto de Investigación Sanitaria y Biomédica de Alicante, Alicante, Spain

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Men and women aged between 45 and 75 years.
  • Diagnosed with acute myocardial infarction, unstable or stable angina.
  • Treated with percutaneous coronary intervention, coronary artery bypass grafting, or conservative treatment.
  • Event or intervention within 3 to 12 months prior to participation in the study.
  • Fluency in speaking and reading Spanish.
  • Residing in Elche or surrounding areas and able to attend evaluations and the exercise programme (not planning to be absent for more than one week during the programme).
  • Functional Class I-II according to the New York Heart Association (NYHA) classification.
  • No physical limitations for exercise.
  • Stable optimal medical treatment.
  • Physically inactive, defined as 1) not meeting the World Health Organization recommendations for both aerobic and strength exercise, and 2) not participating in a structured exercise programme at least 3 days per week for more than 3 months. Both conditions must be met for inclusion. Note: Casual walking is not considered grounds for exclusion.

Exclusion criteria

  • Use of walking assistive devices.
  • Treatment with chemotherapy for any type of cancer in the past 2 years.
  • Hospitalisation in an intensive care unit in the past 6 months for reasons other than the ischaemic event.
  • Acute myocardial infarction group IV Killip-Kimball.
  • Obesity grade III (≥40.0 kg/m²).
  • Medical contraindication for inclusion in an exercise programme.
  • Diabetes with uncontrolled blood glucose levels.
  • Poorly controlled hypertension: resting blood pressure > 180/110 mmHg.
  • Chest pain with exertion or ST-segment changes suggestive of residual ischemia during ergometry. Residual ischemia.
  • Severely reduced functional capacity on initial ergometry (<5 metabolic equivalent of task).
  • Left ventricular ejection fraction less than 50%.
  • Severe stenosis of the left main coronary artery (>50% significant disease).
  • Severe aortic stenosis, left ventricular outflow tract obstruction (e.g., obstructive hypertrophic cardiomyopathy) or aortic dissection.
  • Severe valvulopathy.
  • Acute pulmonary embolism or deep vein thrombosis.
  • Severe pulmonary hypertension.
  • Acute heart failure.
  • Acute endocarditis, myocarditis, or pericarditis.
  • Acute or chronic renal insufficiency (estimated glomerular filtration rate <30 ml/min).
  • Pulmonary fibrosis or interstitial disease (severe respiratory insufficiency or confirmed chronic obstructive pulmonary disease).
  • Uncontrolled cardiac arrhythmias/hemodynamically unstable.
  • Permanent or persistent/paroxysmal atrial fibrillation with episodes in the past 6 months.
  • High-grade cardiac block.
  • Presence of implantable devices: cardiac resynchronization therapy pacemaker, implantable cardioverter defibrillators, or pacemaker.
  • Presence of ischaemic symptoms during the incremental exercise test performed before the intervention.
  • Severe autonomic or peripheral neuropathy.
  • Use of nitrates in pharmacological treatment.
  • Any planned surgical or medical intervention during the study period.
  • Plans to participate in or current participation in other studies that may interfere with this study.
  • Current pregnancy or intention to become pregnant during the study period.

Treatment and study plan

Aerobic exercise (MIT)

Behavioral

Patients allocated to the MIT group will train on a cycle ergometer three days a week for 12 weeks (36 sessions). They will cycle continuously between the first and second ventilatory thresholds. The duration of each exercise session will be set according to the estimated energy expenditure of the long HIIT and short HIIT groups for each training block (energy expenditure-adjusted exercise sessions). All sessions will be supervised, and patients will be asked to avoid additional exercise. They will be allowed to perform extra physical activity (e.g., light walking) according to medical recommendations.

Other names: MIT

Aerobic exercise (Short HIIT)

Behavioral

Patients allocated to the Short HIIT group will train on a cycle ergometer three days a week for 12 weeks (36 sessions). They will perform from two to four 4-repetition sets of 1-min above the second ventilatory threshold. Patients will perform 1- and 3-min active recovery periods below the first ventilatory threshold between repetitions and sets, respectively. The total time spent at high intensity will range from eight to 16 min. All sessions will be supervised, and patients will be asked to avoid additional exercise training. They will be allowed to perform extra physical activity (e.g., light walking) according to medical recommendations.

Other names: Short HIIT

Aerobic exercise (Long HIIT)

Behavioral

Patients allocated to the Long HIIT will train on a cycle ergometer three days a week for 12 weeks (36 sessions). They will perform from two to four 4-min high-intensity exercise bouts above the second ventilatory threshold separated by 4-min active recovery periods below the first ventilatory threshold. The total time spent at high intensity will range from eight to 16 min. All sessions will be supervised, and patients will be asked to avoid additional exercise training. They will be allowed to perform extra physical activity (e.g., light walking) according to medical recommendations.

Primary outcomes

  1. Change from baseline in endothelial function at 7 weeks

    Time frame: 7 weeks

    Endothelial function (i.e., endothelial-dependent dilation) will be assessed by brachial FMD.

  2. Change from baseline in endothelial function at 14 weeks

    Time frame: 14 weeks

    Endothelial function (i.e., endothelial-dependent dilation) will be assessed by brachial FMD.

  3. Change from baseline in endothelial-independent dilation at 7 weeks

    Time frame: 7 weeks

    Brachial NMD will be used to measure endothelial-independent dilation.

  4. Change from baseline in endothelial-independent dilation at 14 weeks

    Time frame: 14 weeks

    Brachial NMD will be used to measure endothelial-independent dilation.

  5. Change from baseline in peak cardiopulmonary parameters at 7 weeks

    Time frame: 7 weeks

    Participants will perform a symptom-limited CPET on a cycle ergometer.

  6. Change from baseline in peak cardiopulmonary parameters at 14 weeks

    Time frame: 14 weeks

    Participants will perform a symptom-limited CPET on a cycle ergometer.

  7. Change from baseline in aerobic efficiency at 7 weeks

    Time frame: 7 weeks

    Efficiency-related variables will be measured during the CPET.

  8. Change from baseline in aerobic efficiency at 14 weeks

    Time frame: 14 weeks

    Efficiency-related variables will be measured during the CPET.

  9. Change from baseline in resting serum BDNF concentration at 7 weeks

    Time frame: 7 weeks

    Blood samples will be obtained through an indwelling catheter placed in the antecubital vein before the CPET.

  10. Change from baseline in resting serum BDNF concentration at 14 weeks

    Time frame: 14 weeks

    Blood samples will be obtained through an indwelling catheter placed in the antecubital vein before the CPET.

  11. Change from baseline in exercise-induced effect on serum BDNF at 7 weeks

    Time frame: 7 weeks

    Blood samples will be obtained through an indwelling catheter placed in the antecubital vein before and after the CPET.

  12. Change from baseline in exercise-induced effect on serum BDNF at 14 weeks

    Time frame: 14 weeks

    Blood samples will be obtained through an indwelling catheter placed in the antecubital vein before and after the CPET.

Secondary outcomes

  1. Change from baseline in pulmonary function at 7 and 14 weeks

    Time frame: 7 and 14 weeks

    Pulmonary function will be measured by spirometry

  2. Change from baseline in resting cardiopulmonary parameters at 7 and 14 weeks

    Time frame: 7 and 14 weeks

    Patients will be asked to rest for 5 min before stating the CPET.

  3. Change from baseline in cardiopulmonary parameters at first and second ventilatory thresholds at 7 and 14 weeks

    Time frame: 7 and 14 weeks

    First and second ventilatory threshold during the CPET will be analysed blindly using the ventilatory equivalents method.

  4. Change from baseline in cardiopulmonary variables measured during the recovery at 7 and 14 weeks.

    Time frame: 7 and 14 weeks

    Cardiopulmonary variables will be measured during the 3-min recovery period of the CPET.

  5. Change from baseline in MacNew domains at 7 and 14 weeks

    Time frame: 7 and 14 weeks

    The MacNew heart disease health-related quality of life instrument will be used as a disease-specific quality of life questionnaire. The MacNew consists of 27 items that fall into three domains (a 13-item physical limitations domain scale, a 14-item emotional function domain scale, and a 13-item social function domain scale). Scoring of the MacNew is straightforward. The maximum possible score in any domain is 7 (high quality of life) and the minimum is 1 (poor quality of life).

  6. Change from baseline in body composition at 7 and 14 weeks

    Time frame: 7 and 14 weeks

    Bioimpedance assessment will be conducted in fasting state.

  7. Change from baseline in resting heart rate variability (HRV) at 7 and 14 weeks

    Time frame: 7 and 14 weeks

    HRV will be measured after an overnight fasting period at the same time of day

  8. Change from baseline in echocardiographic variables at 7 and 14 weeks

    Time frame: 7 and 14 weeks

    A resting echocardiographic assessment will be performed before starting the CPET. The echocardiographic variables measured will be left ventricular end-diastolic diameter, septal and posterior wall thickness, left atrium dimension and volume, left ventricular ejection fraction (four-chamber and biplane Simpson's method, tricuspid annular plane systolic excursion, S' wave velocity, peak E and A wave velocities (in sinus rhythm), lateral and medial e' velocities, peak tricuspid regurgitation gradient, and velocity and gradient across the aortic valve.

  9. Change from baseline in blood analysis variables at 14 weeks.

    Time frame: 14 weeks

    Blood samples will be obtained after at least a 10-hours period of fasting.

  10. Change from baseline in ability to inhibit cognitive interference at 7 and 14 weeks

    Time frame: 7 and 14 weeks

    The Stroop test will be used to assess the ability to inhibit cognitive interference.

  11. Change from baseline in verbal memory performance at 14 weeks

    Time frame: 14 weeks

    Verbal learning and memory are assessed using the Rey Auditory Verbal Learning Test (RAVLT) under standardized environmental conditions. The procedure begins with five consecutive learning trials of a 15-word list (List A). The primary measures focus on the recall performance of this list at three key points during the test:

    Immediate post-interference recall (A6): After presenting a new distractor list (List B), participants are asked to recall the original List A to assess resistance to interference.

    20-minute delayed recall (A7): Assesses short-term retention. During this interval, participants complete the Corsi Block-Tapping Test (a visuospatial task) to prevent mental rehearsal of the words.

    24-hour delayed recall (A8): Measures long-term memory consolidation via an unexpected telephone call where participants are asked to recall List A once again.

  12. Change from baseline in visuospatial working memory performance at 14 weeks

    Time frame: 14 weeks

    Visuospatial working memory is assessed using the Corsi Block-Tapping Test. Participants reproduce sequences of tapped blocks in both forward (same order) and backward (reverse order) conditions. Sequence lengths increase progressively until the participant fails two sequences of the same length. The reported outcome includes the Corsi span (defined as the maximum sequence length correctly reproduced) and the total number of correctly reproduced sequences. For both metrics, higher scores indicate better visuospatial working memory performance. This task is administered during the 20-minute interval of the RAVLT to prevent mental rehearsal of verbal material.

Study contacts

Contact information is provided by the study sponsor or research team.

Agustin Manresa Rocamora, PhD

CONTACT

[email protected]

626542131

Jose Manuel Sarabia, PhD

CONTACT

[email protected]

965222568

Sponsors and collaborators

Lead sponsor

Instituto de Investigación Sanitaria y Biomédica de Alicante

Network

Collaborators

  • Universidad Miguel Hernandez de Elche

Registry information

Official study title

Effect of Different Aerobic Exercise Methods in Cardiac Rehabilitation on Endothelial Function in Patients With Ischaemic Heart Disease and Study of the Associated Physiological Mechanisms (ENDO-R)

Acronym: ENDO-R

Important dates

Study start
2024
Primary completion
2027
Study completion
2027
First posted
Jan 23, 2025
Registry last updated
Feb 27, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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