Comparison of the Effect of Two Types of Physical Exercises in Patients With Heart Failure With Preserved Ejection Fraction

Study Overview
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Brief Summary
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Background: Heart failure (HF) is a chronic disease with a very important and increasingly severe social and health impact with a prevalence of 6.8% in Spain. HF with preserved ejection fraction (HFpEF) represents approximately 50% of all patients with HF. In the absence of pharmacological treatments that have succeeded in reducing mortality or morbidity in this pathology, it is recommended that interventions be directed at prevention, symptomatic treatment of HF and treatment of comorbidities to avoid exacerbations, thus physical exercise is recognized as an important adjunct in the treatment of HF and is recommended by the guidelines of the American College of Cardiology (ACC)/American Heart Association (AHA) and the European Society of Cardiology (ESC). Currently, aerobic exercise is the most studied physical exercise in this population, but in recent years high-intensity interval training (HIIT) and the combination of aerobic exercise with strength training (combined exercise) have emerged. Objectives: The overall objective of this study is to compare the effectiveness of combined training and HIIT on exercise capacity, diastolic function, endothelial function, and arterial stiffness in patients with HFpEF. The specific objectives of this study are: a) to compare the effectiveness of combined training and HIIT on quality of life in patients with HFpEF and b) to analyze the cost-effectiveness of combined training and HIIT versus conventional treatment in patients with HFpEF. Methodology: The ExIC-FEp study will be a single-blind randomized clinical trial with 3 arms (combined exercise, HIIT and a control group), conducted at the Health and Social Research Center of the University of Castilla-La Mancha, to analyze two types of supervised physical exercise in patients with HFpEF for 6 months. Patients with HFpEF will be randomly assigned (1:1:1) to the combined exercise, HIIT or control group. All participants will be examined, at baseline (prior to randomization), at three months (mid-intervention) and at six months (at the end of the intervention). Participants will undergo physical examination, echocardiography, maximal cardiopulmonary stress test, and measurement of endothelial function and arterial stiffness. In addition, sociodemographic variables, quality of life, physical activity, adherence to the Mediterranean diet, strength, spirometry and blood sampling will be measured. Expected scientific contributions: this randomized clinical trial will represent a a significant advance in the scientific evidence available on the efficacy of physical exercise in the treatment of HFpEF, through: (a) transfer of the results to physicians, nurses and patients; (b) dissemination of results through scientific articles, doctoral theses and participation in congresses; (c) press releases and press conferences with the aim of disseminating the research results to the population; (d) dissemination through social networks to improve the social impact; and (e) design and content development of a web page.

Official Title
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Comparison of the Effect of Two Types of Physical Exercise on the Improvement of Exercise Capacity, Diastolic Function, Endothelial Function, and Arterial Stiffness in Patients With Heart Failure With Preserved Ejection Fraction (ExIC-FEp Study)

Conditions
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Heart Failure, Physical Exercise, Exercise Capacity, Diastolic Function, Endothelial Function, Arterial Stiffness

Intervention / Treatment
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* Behavioral: Combined exercise
* Behavioral: High interval training


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Heart Failure with preserved ejection fraction picture (diagnosis according to ESC 2021 criteria) Signs and symptoms of Heart Failure A left ventricular ejection fraction of ≥50%. Objective evidence of cardiac structural and/or functional abnormalities consistent with the presence of left ventricular diastolic dysfunction/elevated left ventricular filling pressures, including elevated natriuretic peptides. Sedentary men and women (structured exercise <2 x 30 min/week). Age ≥40 years Written informed consent Clinically stable for 6 weeks Optimal medical treatment for ≥6 weeks Exclusion Criteria: Non-cardiac causes of heart failure symptoms: Significant valvular or coronary artery disease - Uncontrolled hypertension or arrhythmias. Primary cardiomyopathies Significant pulmonary disease (FEV1<50% predicted, GOLD III-IV) Inability to exercise or conditions that may interfere with exercise intervention. Myocardial infarction in the last 3 months Signs of ischaemia during maximal cardiopulmonary exercise test. Comorbidity that may influence one-year prognosis 7. Participation in another clinical trial.

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Combined exercise<br> | Behavioral: Combined exercise<br>* Patients will exercise for 40 minutes three times a week on an ergometric bicycle at 50-60% of VO2max, 60-70% of HRmax, 11-13 on the Borg scale, without ergometer at 50-60% of VO2max, 60-70% of HRmax, 11-13 on the Borg scale, without shortness of breathing difficulty. In addition, strength training will be performed (bench press, leg press, leg curl, leg machine, bench press, leg press, leg curl, leg curl, leg machine). leg curls, leg curls, rowing machine, triceps dips, pectoral pull-ups) twice a week. week. Strength training will be performed with 15 repetitions per exercise and per session, with a corresponding workload of 15 repetitions. session, with a workload corresponding to 60% to 65% of the 1-repetition maximum (1RM) measured at (1RM) measured at the beginning and at the end of the intervention.<br>|
| Experimental: High interval training<br> | Behavioral: High interval training<br>* Patients will perform three training sessions per week. Each training session begins with a 10-minute warm-up at moderate intensity (corresponding to 50-60% of VO2max, 60-70% of HRmax, 11-13 on the Borg scale, no shortness of breath) before cycling, four 4-minute intervals at high intensity (corresponding to 85-90% of VO2max, 90-95% of HRmax, 15-17 on the Borg scale, shortness of breath). Each interval will be separated by 3 minutes of active pauses, with a HRmax of 50-70%. The training session will end with 3 minutes of cool down at moderate intensity (corresponding to 50-60%). moderate intensity (corresponding to 50-60% of VO2max, 60-70% of HRmax, 11-13 on the Borg scale, without difficulty). Borg scale, no shortness of breath). The total exercise time will be 40 minutes for the HIIT group.<br>|
| No Intervention: Usual care<br> | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Exercise capacity | Maximal cardiopulmonary stress test with Ergoline600 ergometer bicycle. | Change from Baseline exercise capacity at 3 months | 
| E velocity | E velocity in m/s | Change from Baseline E velocity at 3 months | 
| Endothelial function | Carotid intima-media thickness: by ultrasound with the Sonosite SII device. | Change from Baseline endothelial function at 3 months | 
| Arterial stiffness | Pulse wave velocity and augmentation index | Change from Baseline arterial stiffness at 3 months | 
| A velocity | A velocity in m/s | Change from Baseline A velocity at 3 months | 
| E/A ratio | E/A ratio | Change from Baseline E/A ratio at 3 months | 
| e' velocity | e' velocity in m/s | Change from Baseline e' velocity in m/s at 3 months | 
| E/e' ratio | E/e' ratio | Change from Baseline E/e' ratio at 3 months | 
| ejection fraction | percentage of ejection fraction | Change from Baseline ejection fraction at 3 months | 
| left ventricular volume index | left ventricular volume index | Change from Baseline left ventricular volume index at 3 months | 
| end-diastolic volume | end-diastolic volume | Change from Baseline end-diastolic volume at 3 months | 
| left ventricular mass | left ventricular mass | Change from Baseline left ventricular mass at 3 months | 
| left atrial diameter | left atrial diameter | Change from Baseline left atrial diameter at 3 months | 
| isovolume relaxation time | isovolume relaxation time in seg | Change from Baseline isovolume relaxation time at 3 months | 
| deceleration time | deceleration time in m/s | Change from Baseline deceleration time at 3 months | 
| left atrial volume index | left atrial volume index | Change from Baseline left atrial volume index at 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sociodemographic variables | Age, sex and socioeconomic level | Baseline | 
| Patient's medical history | Comorbidities and medication | Baseline | 
| Weight | Weight in kilogram | Change from Baseline weight at 3 months | 
| Muscular strength | Handgrip force to be determined with TKK 5401 Grip-D dynamometer. | Change from Baseline Muscular strength at 3 months | 
| Spirometry | Forced vital capacity (FVC), forced expiratory volume in the first second (FEV1) and FEV1/FVC ratio. | Change from Baseline spirometry at 3 months | 
| Glucose | Glucose | Change from Baseline Glucose at 3 months | 
| Physical activity | Accelerometry. Time of physical activity | Change from Baseline phisical activity at 3 months | 
| HQoL | Validated 12-item health questionnaire (SF-12). From 0 to 12 (higher values better HQoL) | Change from Baseline HQoL at 3 months | 
| Adherence to the Mediterranean diet | Validated 14-item questionnaire on adherence to the Mediterranean diet (MEDAS-14). From 0 to 14 (higher values better Adherence) | Change from Baseline Adherence to the Mediterranean diet at 3 months | 
| height | height in centimeters | Change from Baseline height at 3 months | 
| BMI | BMI in kg/m2 | Change from Baseline BMI at 3 months | 
| waist circumference | waist circumference in cm | Change from Baseline waist circumference at 3 months | 
| body fat | percentage of body fat | Change from Baseline body fat at 3 months | 
| blood pressure | systolic and diastolic blood pressure in mmHg | Change from Baseline blood pressure at 3 months | 
| total cholesterol | total cholesterol | Change from Baseline total cholesterol at 6 months | 
| triglycerides | triglycerides | Change from Baseline triglycerides at 6 months | 
| HDL-cholesterol | HDL-cholesterol | Change from Baseline HDL-cholesterol at 6 months | 
| LDL-cholesterol | LDL-cholesterol | Change from Baseline LDL-cholesterol at 6 months | 
| apolipoproteins A1 and B | apolipoproteins A1 and B | Change from Baseline apolipoproteins A1 and B at 6 months | 
| insulin | insulin | Change from Baseline insulin at 6 months | 
| ultra-sensitive C-reactive protein | ultra-sensitive C-reactive protein | Change from Baseline ultra-sensitive C-reactive protein at 6 months | 
| N-terminal pro-B-type natriuretic peptide (NT-proBNP) | N-terminal pro-B-type natriuretic peptide (NT-proBNP) | Change from Baseline N-terminal pro-B-type natriuretic peptide (NT-proBNP) at 6 months | 
| HbA1c | HbA1c | Change from Baseline HbA1c at 6 months |