Visa-versa! Breaking Instead of Pushing the Pedals-A

Study Overview
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Brief Summary
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Eccentric muscle work is defined as lengthening of a muscle while applying force. It was shown that with eccentric work, muscles are able to perform four times as much power compared to usual concentric work, which results in huge training gain with a highly decreased oxygen demand and thus lower cardiovascular load. Pulmonary hypertension (PH) is a chronic condition associated with significant reduced exercise capacity and increased morbidity and mortality, resulting in reduced quality of life. Physical training has been shown to be beneficial in PH, even in severely limited patients. However, due to cardiopulmonary constraints in PH, training intensities may be very low, so that many patients are physically almost unable to perform exercise on a high enough level to maintain muscle mass. A low body muscle not only feeds the vicious cycle of decreasing exercise capacity, but also has many deleterious metabolic and immunological consequences which further increase disability and decrease quality of life in PH. Thus, eccentric training, which allows to gain muscle mass with a low stress to the cardiopulmonary unit may to be highly beneficial for patients with PH and allied cardiopulmonary disease, such as chronic obstructive pulmonary disease (COPD) and heart failure. Therefore, the objective of the trial is, to compare differences in oxygen uptake (peak VO2 [l/min]) and other physiological measures during similar cardiopulmonary exercise test protocols of eccentric- vs. concentric cycling in PH- patients and comparators with or without other cardiopulmonary diseases.

Detailed Description
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Eccentric muscle work is when a muscle lengthens while applying force. Although eccentric muscle work is part of everyday life, e.g. whilst descending, it is not integrated in modern training protocols and its underlying physiological mechanisms are still incompletely understood. It was shown that muscles are able to perform four times as much power eccentrically compared to common concentric muscle work with a comparably very low oxygen demand and thus cardiovascular load. Thus, eccentric training may be of special interest for patients with cardiopulmonary diseases. Since much higher training intensities are achieved eccentrically, the training increase after a few weeks of eccentric training is huge compared to ordinary concentric training. In addition, it has been observed that these high intensities applied eccentrically lead also to a concentric gain in strength and are therefore transferable to everyday activities. Physical training has been shown to be beneficial in almost every cardiovascular disease, even in severely limited patients. However, training intensities may be very low in some patients with advanced cardiopulmonary disease, so some patients are physically almost unable to perform exercise on a beneficial level. Thus, for this collective, eccentric training may to be a very intriguing option. Patients with pulmonary vascular diseases such as pulmonary arterial and chronic thromboembolic pulmonary hypertension (PH) per definition reveal an elevated pulmonary artery pressure (PAP) along with an increased pulmonary vascular resistance (PVR). However, also other common diseases, such as left heart disease (LHD) or chronic obstructive pulmonary disease (COPD) are often associated with PH. The cardinal symptoms of PH is dyspnea on exertion leading to limited exercise performance, daily activity and quality of life. PH-patients also benefit from structured exercise training, but training intensities might be limited in patients with advanced disease. A few studies have investigated eccentric exercising in cardiopulmonary patients but none in PH. Most of these studies are in patients with coronary heart disease- (CHD) or COPD, including only few participants and often studies did not followed sound methodologies, such as randomized-controlled trial (RCT) protocols However, even in the hitherto limited patients´ investigated, eccentric training was assessed beneficial, feasible and safe. The physiological cardiopulmonary response to eccentric exercising has not been investigated in patients with PH and the physiological basis to investigate such training opportunities is completely lacking. The aim of this project is to investigate the cardiopulmonary effects of eccentric exercise in using solid randomized-controlled research protocols in cardiopulmonary diseases with focus on PH in order to provide a basis to the question of whether this promising training method could become established in cardiopulmonary rehabilitation, especially in patients with advanced disease and pulmonary hypertension.

Official Title
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Visa-versa! Breaking Instead of Pushing the Pedals: Eccentric Exercise to Improve Training Performance in Patients With Pulmonary Hypertension. A Single-center Randomized Controlled Trial

Conditions
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Pulmonary Hypertension

Intervention / Treatment
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* Procedure: 15 minutes eccentric cycling
* Procedure: 15 minutes concentric (normal) cycling


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients in a stable condition on the same disease specific medication >4 weeks. Signed informed consent. Precapillary pulmonary hypertension (PH) diagnosed according to international guidelines: mean pulmonary artery pressure (mPAP) ≥25 mmHg and pulmonary artery wedge pressure (PAWP) ≤15 mmHg, pulmonary vascular resistance >2 WU, measured by right heart catherization and clinically diagnosed as Pulmonary arterial and chronic thromboembolic pulmonary hypertension, class 1 or class 4 Exclusion Criteria: Severe daytime hypoxemia (pO2 ≤7.3 kPa or <55 mmHg) Other clinically significant concomitant disease states (e.g., renal, hepatic dysfunction, etc.). Inability to follow the procedures of the study, e.g. due to language problems, psychological disorder, dementia or confusional state of the subject, neurological or orthopedic problems with inability to ride a bicycle. Woman with known pregnancy. Enrolment into another clinical trial with active treatment.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Sham Comparator: Start with: Concentric (normal) cycling<br> | Procedure: 15 minutes eccentric cycling<br>* The exposure to eccentric exercise will be individualized-intensity stepwise incremental cycle exercise starting at 50 Watt with individually tailored increments every 5 minutes.<br>Procedure: 15 minutes concentric (normal) cycling<br>* The exposure to concentric exercise will be individualized-intensity stepwise incremental cycle exercise starting at 50 Watt with individually tailored increments every 5 minutes.<br>|
| Experimental: Start with: Eccentric cycling<br> | Procedure: 15 minutes eccentric cycling<br>* The exposure to eccentric exercise will be individualized-intensity stepwise incremental cycle exercise starting at 50 Watt with individually tailored increments every 5 minutes.<br>Procedure: 15 minutes concentric (normal) cycling<br>* The exposure to concentric exercise will be individualized-intensity stepwise incremental cycle exercise starting at 50 Watt with individually tailored increments every 5 minutes.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Oxygen uptake (peak VO2 [l/min]) | Difference in oxygen uptake (peak VO2 [l/min]) of eccentric vs. concentric cycling exercise. | 1 Day | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Respiratory exchange ratio (RER) | Volume carbon dioxide devided by the volume of oxygen( VCO2/VO2) | 1 day | 
| Breathing equivalent for carbon dioxide | Minute ventilation divided by volume carbon dioxide (VE/VCO2) | 1 day | 
| Pulmonary end tidal carbon dioxide (PET CO2) | The level of carbon dioxide that is released at the end of an exhaled breath | 1 day | 
| Arterial oxygen saturation (SpO2) | Noninvasively measured oxygenation of the hemoglobin by pulse oximetry (Light Sensors) | 1 day | 
| Borg Scale for dyspnea | Patient reported level of dyspnea from 0 to 10 while 10 is the worst | 1 day | 
| Borg Scale for leg fatigue | Patient reported level of leg fatigue from 0 to 10 while 10 is the worst | 1 day | 
| Cardiac output | How many liters blood is the heart able to move in one minute. Assessed by echocardiography. | 1 day | 
| Pulmonary Artery Pressure | Right ventricle pressure divided by the right atrium pressure gradient (RV/RA pressure gradient) to assess the systolic pulmonary artery pressure by echocardiography | 1 day | 
| Blood pressure | Systolic and diastolic blood pressure assessed by arm cuff measurement | 1 day | 
| Brain tissue oxygenation | Oxygenation of the brain tissue assessed by light sensors on the forehead | 1 day | 
| Muscle tissue oxygenation | Oxygenation of the muscle tissue assessed by light sensors on the quadriceps muscle | 1 day | 
| Arterial blood gases: PH | Arterial blood gases: PH, assessed by arterial blood sample | 1 day | 
| Arterial blood gases: Partialpressure for oxygen (PaO2) | Arterial blood gases: Partialpressure for oxygen (PaO2), assessed by arterial blood sample | 1 day | 
| Arterial blood gases: Bicarbonate (HCO3) | Arterial blood gases: Bicarbonate (HCO3), assessed by arterial blood sample | 1 day | 
| Arterial blood gases: lactate | Arterial blood gases: lactate, assessed by arterial blood sample | 1 day |