Workpackage Leader: Wroclaw
Involved Partners: Charité, HULL, Hannover, Golnik, Zabrze
Objective 1: to establish a unified and validated protocol for cardiopulmonary exercise testing
We will prepare a protocol for cardiopulmonary exercise testing. All technical aspects/details will be presented to all other WP participants (CHAR, HULL, MHH, SCCS) who will be subsequently trained in WROC. All WP participants will perform a reproducibility study in their own laboratoriesThey will then send the crude values recorded during tests and all analyses will be performed in WROC using a unified approach. In spite of standard parameters (peak oxygen consumption, VE-VCO2 slope), we are planning to introduce other parameters, including an integrative response in VE, VO2, VCO2 and heart rate during exercise and during recovery.
Objective 2: to establish a unified and validated protocol for the assessment of heart rate and blood pressure control, baroreflex and chemoreflex sensitivity
We will prepare detailed protocols for a comprehensive assessment of cardiopulmonary reflex control. Technical details will be presented and discussed with all other participants of this work package. They will subsequently be trained in WROC.
Objective 3: To characterise a pattern of exercise intolerance in patients with heart failure with/without type 2 diabetes, along with a description of over-time changes in CPX-derived parameters
Patients will be assessed regarding exercise capacity in centres participating in this part (anticipated recruitment numbers: WROC 240 pts, HULL: 50 pts, SCCS: 120 pts, CHAR: 80 pts, RUSSIA (AC/CRC + MSU ): 300 pts, ROME 80 pts, Bolnisnica Golnik 50 pts HF and 20 pts DM. Data from exercise capacity will be integrated with clinical parameters, laboratory data (including biomarkers and anabolic/catabolic indices), assessment of body composition, assessment of exercising muscles (including local anabolic/catabolic status). A cardiopulmonary exercise capacity will be repeated after 4-6, 16-18 and at annual intervals thereafter (i.e. 28-30 months etc.). WROC will collect the data from participating centers and will prepare the final results regarding a magnitude of exercise intolerance, changes over time and its determinants.
Objective 4: To characterise a pattern of cardiorespiratory reflex control in patients with heart failure with/without type 2 diabetes, along with a description of over-time changes in cardiorespiratory reflex indices
Patients will be assessed regarding cardiopulmonary reflex control in centres participating in this part of a project (the total recruitment numbers: WROC (BARO+HRv+CHEMO): 100-110 pts, HULL (BRS+HRV): 50 pts + (CHEMO): 25 pts, CHAR (BRS+HRV): 30 pts, RUSSIA (AC/CRC+MSU, BRS+HRV): 100 pts), Bolnisnica Golnik 20 pts. Data describing cardiorespiratory reflex control will be integrated with clinical parameters, laboratory data (including biomarkers and anabolic/catabolic indices), cardiopulmonary exercise test. Comprehensive evaluation of cardiopulmonary reflex control will be repeated after 4-6, 16-18 and at annual intervals thereafter (i.e. 28-30 months etc.). WROC will collect data from participating centers and will prepare the final results regarding a description of an assessment of cardiopulmonary reflex control, changes over time and its determinants.
Objective 5: To establish diagnostic and prognostic applicability of CPX-derived parameters in patients with heart failure with/without type 2 diabetes
Patients with an assessment of cardiopulmonary exercise test will be clinically followed for a period of at least 28-30 months by investigators in participating centers. WROC will collect the data from participating centers and will prepare the final results regarding indices of cardiopulmonary exercise test as potential independent prognosticators.
Objective 6: To establish diagnostic and prognostic applicability of an assessment of cardiorespiratory reflex control in patients with heart failure with/without type 2 diabetes
Patients with an assessment of cardiorespiratory reflex control will be clinically followed for a period of at least 2 years by investigators in participating centers. WROC will collect the data from participating centers and will prepare the final results regarding indices of cardiopulmonary reflex control as potential independent prognosticators.
Objective 7: To evaluate the anabolic status (assessed in the blood and locally in exercising skeletal muscles) as determinants of exercise capacity in patients with heart failure with/without accompanying type 2 diabetes
We will include patients with an assessment of cardiopulmonary exercise test, assessment of cardiopulmonary reflex control and skeletal muscle biopsies (WROC: 40 pts + re-assessed after 6 and 12 months). Steroid hormones (including androgens, estrogens, aldosterone, cortisol, etc.) will be assessed in peripheral blood and muscle biopsies using very sensitive chromatography methods in WROC. WROC will collect the data from participating centers and will prepare the final results regarding steroid hormones in circulation and exercising muscles as potential determinants of exercise capacity.
The methodology applied in the project will be the following:
CARDIOPULMONARY EXERCISE TEST. After a period of 5-minute rest patients will undergo a symptom-limited treadmill exercise test (modified Bruce's protocol) with respiratory gas exchange analysis. Minute ventilation (VE), oxygen consumption (VO2) and carbon dioxide production (VCO2) will be assessed every 10 seconds. Peak oxygen consumption (peak VO2) will be measured as an average of the last 30 seconds of exercise, and will be expressed in mL/min/kg and as a percentage of predicted values of age- and weight-matched healthy men (according to the equations of Wassermann et al). Ventilatory response to exercise (expressed as a VE-VCO2 slope) will be calculated as the regression slope relating minute ventilation [VE] to carbon dioxide output [CO2] during the whole exercise). For the analyses of derived indices using the prepared formulas, the crude values of VE, VO2, VCO2 and heart rate (breath-by-breath) from a 5-minute rest before exercise, an exercise and an at least 6-minute rest after exercise will be required (Jankowska et al., 2007; Francis et al., 2002; Ponikowski et al., 2001).
HEART RATE VARIABILITY AND BLOOD PRESSURE VARIABILITY. Patient should be lying for at least 20 minutes in a silent and peaceful room without any disturbances. All recordings will be obtained with the subject in a laying position. The signals (digital recording of synchronized BP and R-R intervals) will be acquired continuously on a personal computer at 1000 samples per channel and stored on a dics. BP will be recorded continuously using a pulse wave. ECG with 3 leads will provide subsequent R-R intervals. The lenght of recording used for the analyses should be unified, so we suggest to perform an at least 20-minute resting recording to finally get a 10-minute recording of an acceptable quality (with no artefacts neither ectopic beats). (Ponikowski et al., 1998)
TIME DOMAIN INDICES OF HRV using the following statistical measures: (i) SDNN: standard deviation of NN intervals, (ii) SDANN: standard deviation of average NN intervals, (iii) ASDNN: average of the standard deviation of NN intervals, (iv) NN50: number of adjacent NN intervals which differ by at least 50ms during a 24 hour recording, (v) pNN50: percentage of adjacent NN intervals in a 24 hour recording which differ by at least 50 ms
- rMSSD: root mean square of successive differences. Geometric time domain measures include (i) HRV triangular index, (ii) TINN: trinangular nterplation of NN intervals, (iii) Lorenz (Poincare) plots,
FREQUENCY DOMAIN TECHNIQUES using the following parameters: VLF, LF, HF for BP and R-R intervals separately
BAROREFLEX SENSITIVITY USING A SEQUENCE METHOD (BRS-Seq). Analyses are performed from a 20-minute resting recording of continuous R-R intervals and BP. For the final analyses we select the 10-minute recording of an acceptable quality as described above. BRS-Seq is an index based on the regression slope relating the change in BP as a result of changes in R-R intervals in the most frequent sequences of particular range of changes. To assess BRS using BRS-Seq method particular sequences of BP recordings (changes with a difference of at least 1.0 mmHg) accompanied by changes in heart rate recordings (difference in R-R interval of at least 5.0 miliseconds) will selected, plotted and analysed using linear regressions relating observed variability of the second parameter to changes in BP. Three of all analysed slopes (characterized by the greatest number of sequences) for each examined individual will be calculated and averaged as one measure of BRS-Seq (Ponikowski et al., 1998).
BAROREFLEX SENSITIVITY USING A CONTROLLED BREATHING METHOD (BRS-CtrBr). Analyses are performed from a 5-minute recording of continuous R-R intervals and BP during controlled breathing (6 breaths/minute). For the final analyses we select the 3-minute recording of an acceptable quality. The frequency of breathing is presented to a patient as visual instructions on the computer screen. BRS-CtrBr is calculated as a ratio of the average amplitude of oscillations in R-R interval to the average amplitude of oscillations in systolic BP.(Ponokowski et al., 1997; Ponikowski et al., 1998; Davies et al., 2001; Ponikowski et al., 1999).
CENTRAL CHEMOSENSITIVITY. Central chemosensitivity will be assessed using a re-breathing method with a 5-L bag initially containing over 90% oxygen, and room air in the remaining volume. During the whole test, minute ventilation (VE), and end-tidal carbon dioxide concentration (PETCO2) will be measured breath by breath using a gas exchange system. The test is divided into three parts: i) resting recording (3 minutes); ii) re-breathing within a closed circuit (a 5-L bag); iii) recovery (3 minutes). During both resting and recovery stages subjects are breathing with room air. At the beginning of the second stage, subjects should be switched unnoticeably to breathing within a closed circuit using a previously mentioned 5-L bag filled mainly with oxygen (90%). During the re-breathing stage hypercapnia will be developing which in turn in a reflex manner will induce hyperventilation. This stage shoul be stopped when a patient will be breathless or when PETCO2 will exceed 10% (70 mmHg). Hypercapnic chemosensitivity is defined as the slope of the regression line relating VE to PETCO2 concentration measured during the stage of breathing within a closed circuit (Ponikowski et al., 1997; Chua et al., 1996; Chua et al., 1997)
PERIPHERAL CHEMOSENSITIVITY. Analyses are performed from a 10-minute resting recording of continuous R-R intervals and BP. At the end of this phase a blood sample from a cubital vein is taken and the partial oxygen pressure is determined in venous blood. The mean R-R interval is calculated. Then the patient is inhaling 100% pure oxygen via a nasal mask (at least 5-L/min flow) for next 10 minutes. At the end of this phase a blood sample from a cubital vein is taken and the partial oxygen pressure is determined in venous blood. The mean R-R interval is calculated again. The difference between the mean R-R interval before and after oxygen inhalation divided by the difference between venous partial oxygen pressure before and after oxygen inhalation is defined peripheral chemosensitivity. In a modification of this method, a recording of saturation during resting without and with oxygen is related to changes in R-R intervals (Marcus et al., 2002; Hennersdorf et al., 2001).
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