Outcome
Type |
Measure |
Description |
Time frame |
Safety issue |
Primary |
Change in peak oxygen uptake (VO2peak) due to training |
VO2peak will be measured by spiroergometry at the baseline and post-intervention visit: an incremental symptom-limited exercise test on an electronically operated bicycle ergometer (eBike, General Electric Company, Fairfield, Connecticut, USA) using a fixed ramp protocol (start at 10 watts, increase of 10 watts/minute) will be conducted. The test will be performed in an air-conditioned laboratory in the early afternoon under non-fasting conditions. After a 2-minute warm-up at 10 watts, patients will be instructed to pedal at a constant rate of 60 rpm to exhaustion or until signs of ischemia or serious cardiac arrhythmias appear. The exercise bout will be followed by a cool-down at 25 watts for 10 minutes or until HR is dropping down below 100 beats/minute. VO2peak will be defined as the highest value reached during exercise. |
Baseline and 12 weeks |
|
Secondary |
Change in disease-specific biomarkers |
Biomarkers such as NT-proBNP, Renin, AT-2, UCN-2, Osteopontin, sST2, Gal-3, GDF-15, Copeptin, Big-Endothelin-1, PlGF/sFlt-1, hs-CRP, IL-6 and IGF-BP7 will be measured. Furthermore, biomarkers for endothelial integrity, circulating mature endothelial cells and immature endothelial progenitor cells, systemic oxidative stress level and sarcopenia (irisin) will be assessed. Venous blood samples will be collected in serum or EDTA coated tubes (in total ~70ml). For serum isolation blood will be centrifuged and the serum will be frozen at -80°C and stored in the laboratory of the DSBG until the last participant will have completed the study procedures. Biomarkers except NT-proBNP will be analysed in external specialized laboratories or by trained personnel of the DSBG, if necessary. Whole blood will be immediately used to investigate circulating immature and mature endothelial progenitor cell numbers by flow cytometry - remaining mononuclear cells will be frozen at -80°C. |
Baseline and 12 weeks |
|
Secondary |
Change in echocardiographic parameters of the left ventricular systolic and diastolic function |
An echocardiography will be performed using a Full HD Color Doppler Ultrasound Scanner UF-890AG (Fukuda Denshi, Tokyo, Japan) by experienced echocardiographers blinded to the assignment of the patient to the intervention or control group, and independently analysed by trained study personal. |
Baseline and 12 weeks |
|
Secondary |
Change in arteriovenous oxygen difference (Da-vO2) |
Da-vO2 will be calculated using the Fick Principle: Peak Da-vO2 = VO2peak / peak cardiac output. VO2peak will be measured by spiroergometry, while peak cardiac output will be determined using the Full HD Color Doppler Ultrasound Scanner UF-890AG (Fukuda Denshi, Tokyo, Japan). |
Baseline and 12 weeks |
|
Secondary |
Change in pulse wave velocity (PWV) |
PWV will be measured at the same time as the echocardiographic parameters with the VaSera VS-2000 Vascular Screening System (Fukuda Denshi Co. Ltd, Tokyo, Japan) and evaluated by experienced blinded members of the study team. |
Baseline and 12 weeks |
|
Secondary |
Change in daily physical activity |
The number of daily steps, physical activity level and time spent at different walking speeds will be measured by the AiperMotion 440 PC (Aipermon GmbH, Munich, Germany), a three-axis accelerometer that is attached to the belt on the left hip, on 7 consecutive days for at least 12 hours a day with the exception of the time spent for showering, bathing and sleeping. For recording daily activities and non-wearing periods, patients will be asked to keep a diary. |
Baseline and 12 weeks |
|
Secondary |
Change in NYHA functional class |
NYHA functional class will be determined according to the New York Heart Association classification. |
Baseline and 12 weeks |
|
Secondary |
Change in quality of life (QoL): The 36-Item Short Form Health Survey (SF-36) |
The SF-36 consists of 36 items, which are formatted as binary questions or as semantic 6-point differential scales. It refers to the past 4 weeks and includes 9 content areas concerning vitality, general health perception, physical functioning, social functioning, role limitations (emotional/physical problems), pain, mental health and health change. |
Baseline and 12 weeks |
|
Secondary |
Change QoL: The Kansas City Cardiomyopathy Questionnaire (KCCQ) |
The KCCQ consists of 15 items concerning overall symptoms, emotional, social and mental status within the past 2 weeks. |
Baseline and 12 weeks |
|
Secondary |
Change in QoL: The Minnesota Living With Heart Failure Questionnaire (MLWHFQ) |
The MLWHFQ refers to the past 4 weeks and includes 21 questions on a 6-point scale with a maximum of 105 points (<24 good QoL, >45 poor QoL). |
Baseline and 12 weeks |
|
Secondary |
Change in body composition: Body Mass Index (BMI) |
BMI will be calculated from measured height in meters and weight in kilograms. Weight and height will be combined to report BMI in kg/m^2. |
Baseline and 12 weeks |
|
Secondary |
Change in body composition: Waist-to-Hip-Ratio (WHR) |
WHR will be calculated from measured waist circumference (WC) and hip circumference (HC) in centimetres. WC will be divided by HC to report WHR. |
Baseline and 12 weeks |
|
Secondary |
Change in macrovascular function: flow-mediated dilation (FMD) |
The flow mediated dilation (FMD) is a principle to measure the integrity of the endothelia. It refers to dilation of an artery when blood flow increases in that artery. The primary cause of FMD is release of nitric oxide by endothelial cells through shear stress. Flow-mediated dilatation (FMD) of the brachial arteries provides a non-invasive alternative to other measurement procedures. To determine FMD, brachial artery dilation following a transient period of forearm ischemia is measured using ultrasound (UNEFEX 38G 3.0, UNEX Co., Nagoya, Japan). The rationale behind the measurement is that endothelial cells are sentinels of cardiovascular health. Their function is reduced by the presence of cardiovascular risk factors, and is regained once pathological stimuli are removed |
Baseline and 12 weeks |
|
Secondary |
Change in microvascular function: retinal vessel analysis |
Static and dynamic retinal vessel analysis will be performed using the retinal vessel analysis system (RVA; IMEDOS Systems, Jena, Germany) and a fundus camera (450 FF; Carl Zeiss, Jena, Germany). We will take three valid images and two videos of the eye background to quantify retinal microvascular function. Conventional eye drops (Tropicamide 0.5%) will be used for pupil dilation of one eye, which is necessary for these measurements. All participants are asked to use public transport because of their dilated pupil. We recommend not to take part in road traffic for four hours after pupil dilatation. After this time, the vision should be normal again. In the first seconds after application of Tropicamide a light and temporary burning irritation or light headache are possible. |
Baseline and 12 weeks |
|
Secondary |
Change in macrovascular function: carotid artery reactivity |
Carotid artery reactivity (CAR) is a parameter, assessed noninvasively by transcutaneous ultrasound to examine endothelial function following sympathetic stimulation produced by the cold pressor test (CPT). Right carotid artery diameter is recorded before and during 90 seconds of immersion of the hand up to the wrist in ice water (4°C). Images will be obtained using a high-resolution ultrasound machine (UF-760AG, 5-12 MHz linear array transducer, Fukuda Denshi Co. Ltd., Tokyo, Japan). |
Baseline and 12 weeks |
|
Secondary |
Change in cardiovascular function: cardiac output |
The measurement of cardiac output will be performed with Cardioimpedanz (Physioflow, Manatec Biomedical, Poissy, France). |
Baseline and 12 weeks |
|
Secondary |
Change in muscular function: muscle oxygen saturation |
Muscle oxygen saturation is measured with Near infrared spectroscopy (NIRS, Portamon, Artinis Medical Systems, Elst, The Netherlands). NIRS relies mainly on two characteristics of human tissue. First, the relative transparency of tissue to light in the NIR range, and second, the oxygenation-dependent light absorbing characteristics of hemoglobin. By using a number of different wavelengths, the relative changes in hemoglobin concentration can be displayed continuously and saturation respectively absorption can be measured. If the absorption is known, the Lambert-Beer law can be used to calculate the chromophore's absorption. The technique on which NIRS relies is closely analogous to the technique of pulse oximetry and is in consequence not painful and not invasive. |
Baseline and 12 weeks |
|
Secondary |
Change in muscular function: muscle strength |
The strength test is a so-called Mid-Thigh-Pull Test. This isometric test is conceptualized in order to rate whole body force. The force of all extensors of the leg e.g. M. rectus femoris and of the back such as M. erector spinae as well as muscles of the hand. The test is comparable to elevate a table by hand. Two factors will be measured: the ability of a patient to generate maximum force ('Peak Force') and the second factor is measuring the increase of force over time (Rate of Force Development). |
Baseline and 12 weeks |
|