| Masaryk University|
Faculty of Medicine
Department of Preventive Medicine
heart rate variability in patients with ischemic heart disease during rehabilitation
Brno, Juni 2011
Author‘s name and surname: Mgr. Ashref Ali Erajhi
Name of disseration thesis: Heart rate vyriability in patients with ischemic heart disease during rehabilitation
Working compartment: Masaryk University, Faculty of Medicine
Dept. of Preventive Medicine
Dissertation thesis supervisor: Prof. MUDr. Jarmila Siegelová, DrSc.
Year of dissertation thesis defense: 2011
Annotation: This disseration thesis deals with autonomic nervous system dysfunction studied using heard rate variability in patients with ischemic heart disease before and after cardiac rehabilitation. For determination heart rate variability the measurement of heart rate beat by beat was used to analyze of heart rate variability by means of spectral analysis. Cardiac exercise training decreased sympathetic tone in patients with ischemic heart disease.
I agree with archivation of dissertation thesis in library of Masaryk University Brno and publication with quoting according to valid norms.
I declare that this dissertation prepared under the direction of self under supervision of prof. MUDr. Jarmila Siegelová, DrSc. and that I stated in the list of bibliographic citations, which is part of this work, all the literary and technical resources
I would like to thank all my colleagues from the Department of Physiotherapy and Rehabilitation, Department of Functional Diagnostics and Rehabilitation and Department of Preventive Medicine, Medical Faculty, Masaryk University and professor MUDr. Jarmila Siegelová, DrSc. for the support.
1 Introduction 8
^ patients with cardiovascular disease
Cardiovascular exercise training is an important part of non-pharmacological therapy. European Society of Cardiology, namely Cardiovascular Rehabilitation Working Group leaded to development of working group of cardiovascular exercise training of Czech Society of Cardiology (Chaloupka et al. 2006). This working group makes a number of activities to ensure that the importance of rehabilitation in patients with cardiovascular disease came to public awareness of the general cardiology. It was professionally important that the physiotherapist lead cardiovascular training under the cardiologists. Medical rehabilitation implemented in practice as a necessary part of non-pharmacological treatment for our patients has a great effect in decreasing morbidity and mortality of cardiovascular diseases (Chaloupka et al. 2006).
We consider cardiovascular rehabilitation as the process by which patients with heart disease try to restore and maintain their optimal physical, mental, social, occupational and emotional state and the best quality of live. It is therefore a comprehensive approach to the patient, which includes not only physical activity, but which incorporates the principles of secondary prevention and lifestyle changes. It is beyond any doubt that physical inactivity is a major risk factor for coronary heart disease (CHD). Increasing levels of physical activity is an indirect relationship with cardiovascular and overall mortality (Ades 2001, Anderson et al. 2004, Andersen 2004, Giannuzzi et al. 2003).
Cardiovascular training is aimed to improve the physical activity of patients with cardiovascular disease. Physical activity is movement produced by skeletal muscles resulting in energy output. Exercise is physical activity that is planned, structured, periodic, which aims to improve and maintain physical fitness. Physical fitness, which is the goal of physical activity is defined as "the ability to perform moderate to intense level of physical activity without undue fatigue." Physical fitness can be achieved and maintained in patients of any age and physical condition (Balady et al. 2000, Fleg et al. 2000).Physical fitness includes cardiorespiratory efficiency, muscular strength and a set of
properties that relate to the ability to perform physical activity. Best be evaluated using the maximum or peak oxygen consumption, but also by metabolic equivalents.
The intensity of cardiovascular training
The intensity of physical exercise can be defined in relative or absolute sense. Absolute intensity reflects the rate of energy expenditure and is expressed in kilojoules, calories or metabolic equivalents (METs). Relative intensity refers to the percentage of maximum aerobic power and usually expressed as a percentage of maximum heart rate or the percentage of maximal oxygen consumption (Jensen et al. 1996, Chaloupka et al. 2005, Placheta et al. 2001, Morrison et al. 2001).
Physical activity can be divided into dynamic and static. Dynamic load is a regular alternation of contraction and relaxation, then the static load includes isometric muscle contractions against resistance. Dynamic load is walking or running. Static load is applied in various short-day activities especially when carrying loads (Kavanagh et al. 2002, Jensen et al. 1996). When talking about strength / resistance training, we mean strengthening the muscles of the upper and lower extremities and trunk loads on a fitness trainer. But even ride on an ergometer or oar, especially when it became more resistance is strength training. So in general, strengthening against the great resistance leads to increased muscle strength, medium resistance represents a balance between strength and endurance training and low resistance to the endurance training . The scientific literature, most often use the term "resistance training" or "strength training" (Beniamini et al. 1999, Chaloupka et al. 2000, Elbl et al. 2005).
Cardiac rehabilitation is usually based on endurance aerobic training, with a prolonged dynamic load at or below the anaerobic threshold of the individual patient.
Regular endurance and strength training brings characteristic changes that lead to improved physical fitness. These changes are called training effect and help to achieve higher physical load at a lower frequency response (King et al. 2005, Lakusic et al. 2005).
Interval training is defined as training, which is composed from short stretches of load alternating with stretches of minimal activity or rest, a recovery phase. It is especially suitable for patients with low exercise tolerance and high risk of cardiovascular morbidity (Rroiutman et al. 1998, Karlsdottir et al. 2002, Mayer et al. 1997).
In every patients we are obliged to determine maximum and peak oxygen consumption (VO2 max, maximal aerobic capacity). At rest the oxygen consumption of approximately 3.5 ml per kg per min. This value is called metabolic equivalent, or 1 MET. During the maximum load the value greatly increases. Maximum oxygen consumption corresponds to the maximum amount of oxygen that can be investigated person transported to the tissues during the maximum dynamic load, and despite the continuing burden already increased. Its value depends on age, sex, physical condition and can be positively influenced by physical training. In practice, however, this value could not be every time meet, because the patient sometimes ends up the work load with the load before reaching a plateau of O2 consumption. For this reason, often use the term peak oxygen uptake (peak VO2) must not be reached (Placheta et al. 2001, Mayers eta l. 2002).
Rehabilitation of patients with heart disease
Rehabilitation process is divided into four stages.
- Phase I - in-patient rehabilitation. The main objective is to prevent in-patient rehabilitation decondition, trombo-embolitic complications and prepare the patient to return to normal daily activities.
- Phase II - early ambulatory cardiac rehabilitation under supervision. It should start as soon as possible after the release patients from hospital. The phase II has the duration up to 3 months. It is considered to be crucial for inducing the necessary lifestyle changes and adherence to the principles of secondary prevention. Patients require more intensive medical supervision and monitoring of electrocardiogram (ECG), blood pressure control.
- Phase III - a period of stabilization. It begins during the stabilization of clinical findings, puts in her emphasis on regular endurance training and consolidation of lifestyle changes.
- Phase IV – maintenance of the physical activity and healthy living style. The patient continues to respect the principles of previous professional activities with minimal supervision under assuming a lasting stabilization of health status (Chaloupka et al. 2006).
Phase I cardiovascular exercise training in hospital
In recent years a new therapeutic approaches were introduce in patients with acute coronary disease. Changes in treatment of acute coronary syndrome were accompanied also with the new cardiac rehabilitation procedure. As a rule, already during the first 12-24 hours of the disease is unclear whether it will be a complicated or uncomplicated myocardial infarction, and accordingly to the development cardiac exercise depends on the way forward. Patients with uncomplicated infarctus of myocardium with a good left ventricular function, no sign of persistent or recurrent ischemia, and who are electrically stable could be indicated for cardiovascular exercise training. Of course, all the cardiovascular complications slow the medical rehabilitation process (Chaloupka et al. 2006).
Bed rest is usually needed only 12-24 hours. The patient can independently carry out the necessary hygiene and eating. After 12-24 hours we begin with an active exercise which involves the basic movements of the upper and lower limbs lying on the bed, respiratory physiotherapy and exercise which increase venous return from lower extremities. Start of rehabilitation and exercise regimen determined by your doctor. The content of exercise unit, intensity and frequency is given by the responsibility of knowledgeable physiotherapist.
In the acute phase of myocardial infarction rehabilitation helps to overcome the fear of physical activity and helps to manage the resulting stress. It improves blood flow and prevents the reduction of muscle strength. Active leg exercises are also an important component of prevention of thromboembolic complications, especially in patients with complicated course and prolonged stay in bed.
Tolerance of physical activity is evaluated by measuring heart rate (HR) before exercise, blood pressure repeatedly, during the exercise and at the end of exercise. We measure blood pressure (BP) at rest, initially the changes in position from horizontal to vertical and at the end of exercise. We follow the subjective feelings of the patient during exercise.
To determine the heart rate is best suited rule during exercise that can be increased by 20-30 beats per minute and systolic blood pressure can increase by 30 mmHg during exercise. These indicators are only instrumental, but if there are a critical clinical conditions like stenocardia or shortness of breath and fatique or subjective perception of exertion, we must stop the exercise training.
Asymptomatic patient may 3rd day walk around the room. Gradually, we start walking up the stairs in order to handle the release of 1-2 floors. Estimated time of hospitalization for uncomplicated myocardial infarction (MI) is 5-7 days, sometimes shorter (3-5 days). Patient with PTCA therapy without infarctus of myocardium could be discharged second day.
Prior to discharge the patient should be informed at least a basic strategy for reducing risk factors, dietary measures and recommended modes of motion. The control and management of further rehabilitation plan should provide the treating cardiologist (Otsuka et al. 2003).
Consideration should be given absolute and relative contraindications to physical training. The absolute is generally considered: unstable angina pectoris, overt heart failure, dissecting aortic aneurysm, ventricular tachycardia or other life-threatening arrhythmias, sinus tachycardia > 120/min., Severe aortic stenosis, suspected pulmonary embolism, acute infectious disease, systolic BP > 200 mmHg and diastolic blood pressure > 115 mmHg or symptomatic hypotension (Piňa et al. 2003, Chaloupka et al. 2006).
Phase II cardiac exercise training
Treatment of patients with myocardial infarction in recent years has changed dramatically. This applies to both invasive approach, a rational pharmacotherapy. The rational drug therapy in patients after MI is a beta-blocker therapy, which are treated with a few exceptions, all patients under secondary prevention (Cannistra et al. 1999, Chaloupka et al. 2004, Gordon et al. 1991, Hambrecht et al. 1997).
Beta-blockers are known for their hemodynamic effects, which mainly reflects the reduction in blood pressure and lower heart rate at rest and during exercise. In patients with angina pectoris or burden provoked ischemia improves exercise tolerance, in healthy patients without ischemia and exercise tolerance reduced (Chaloupka et al. 2002).
Phase II of cardiac rehabilitation is organized either as an outpatient procedure training, or individual home workout or spa treatment.
Outpatient procedure training
For an individual approach to patient rehabilitation after MI is stratification into risk groups (Domingues et al. 2001, DeKam et al. 2002). Based on clinical findings and assessment of the function of the left ventricle (LV) divided patients into three groups. The group of patients with ejection fraction of the left ventricle under 45% has low risk of cardiovascular complications, the group with ejection fraction between 44 to 31percent is of middle risk and the group with ejection fraction under 30 percent has a high risk of cardiovascular complications (Lee et al. 2002, Mark et al 2003).
Training program is determined by the risk. The basic indicators are the intensity, frequency, duration, and progression in the way of exercise training.
The intensity of exercise training
Determination of levels of exertion is essential. To achieve the effect of training intensity must be sufficient, but on the other side safe to discourage the patient from regular exercise. There is still a lack of uniformity of opinion as to whether prolonged low load intensity is comparable to the increased load. It is likely that the burden greater intensity gives patients greater prognostic effect.
The intensity of load can be close to anaerobic threshold (AP), but it should not be exceeded. The best way is to measure the anaerobic threshold in every patient using the examination of spiroergometry in every patients. Anaerobic threshold is defined as the load level at which aerobic metabolism is supplemented by anaerobic metabolism with the rise in plasma lactate concentration. The stress level of anaerobic threshold also occurs to activate the renin angiotensin system and catecholamines with a higher risk of arrhythmias and other complications. The determination of anaerobic threshold is based mostly of determination from the curves of consumption of O2 and CO2 during spiroergometry.
Level of exertion
In determining the levels of exertion is traditionally based on the relatively linear relationship between oxygen consumption and heart rate. Therefore, the most commonly used training heart rate (HR) (Borg 1982, Placheta et al. 2001).
There are several ways to determine the training heart rate.
- Percentage of maximum oxygen consumption
- Percent of heart rate reserve- Percentage of maximum heart rate or symptoms limited heart rate
Percentage of maximal oxygen consumption
Determination of maximum oxygen consumption using anaerobic threshold of spiroergometry is an optimal method for determining appropriate levels of exertion. If we know the heart rate at anaerobic threshold, we can determine the optimal intensity of physical training. We know the heart rate at the anaerobic threshold. Like heart percent reserve margin is calculated percentages of oxygen consumption (VO2R). The values are comparable with the calculations of the percentage heart rate reserve (Placheta et al. 2001, Tanasescu et al 2002, Chaloupka et al. 2006).
Percentage of heart rate reserve
Calculation of heart rate reserve according to the heart is given by training heart rate = (HR max – HR rest) x (0.7-0.8) + HR rest. Most patients treated with beta-blockers achieved at peak stress test (maximum) heart rate 120-130 beats per min. From the literature it is known that the anaerobic threshold in these patients ranges at around 70-80% heart rate reserve (Van der Werf et al. 2003, Chaloupka et al. 2006).
Percentage of maximum heart rate
Use - the maximum heart rate values, the calculation according to the percentage of maximum heart rate for 70% HR max: 125 x 0.7 = 88 beats / min for 80% HR max. 125 x 0.8 = 100 beats per min. The recommended frequency of training under this method ranges from 88 - 100 beats per minute. We see that the recommended value of training according to the percentage HR max are lower than in the HR reserve. Therefore, the first method is recommended in the early stages of training and higher risk individuals, then the second way in advanced stages of training.
Regardless of which method of calculating the heart rate is used, it is clear that there is only one of many physiological responses that need to be monitored. These are primarily changes in blood pressure and clinical symptoms (fatigue, skin color, way of breathing, sweating, etc.) (Placheta et al. 2001, Chaloupka et al. 2006).
Classification of perceived fatigue
Subjective perception of load can be used as indicative indices rather in the individual training program. Based on the patient's subjective feelings was described by Borg method of of perceived effort during work load performance and now the most frequently used scale by Borg from zero to twenty. In the initial stage of phase II of rehabilitation, recommended training level is in the range 11 to 13 of this scale, after 3 weeks, from 12 to 15 points of the scale (Borg 1982, Placheta et al. 2001, Anderson et al. 2004, Anderson et al. 2004).
To assess the levels of exertion, we can use a simple method, (test du parler) for guidance "to talk, sing, gasp" (talk, sing, gasp). If the patient can talk during exercise, the load is reasonable at the level of anaerobic threshold. Patient must be able to sing, if the patients could not sing and he has short of breath, then the load is too large (Chaloupka et al. 2006).
Frequency and length of training
The optimum frequency of training is considered regular physical activity of 3 times a week for at least 60 minutes. It depends on the intensity of training. Caloric expenditure, which should gradually be less than 1000 kcal per week, can be achieved either by intensive training over a shorter or less intensive training over a longer period. Possible options that could have a comparable caloric expenditure, and is in some patients more suitable, are repeated, short (10 - 15min) activities during the day. This method of training is called intermittent training.
Most cardiac exercise rehabilitation programs are organized 3 times a week for 3 months. Some physical activity is expected in other days. Start of rehabilitation should be followed as soon as possible, preferably within 2-3 weeks after release (Chaloupka et al. 1998, 2006).
Methods of physical load
Warm up period
It is important in cardiovascular exercise training to prevent musculoskeletal injury. Prior to aerobic training is the initial warm-up (warm-up) performed 10 to 15 minutes. The exercise with a load of less intensity is included in worm up period.
Warm up often facilitates the transition from rest to full load, improves blood circulation and tone of skeletal muscle and joints. Increase metabolism of resting values to the needs of aerobic training. Suitable as a dynamic warm-up exercises, stretching exercises, walk slower, running, some gymnastic exercises etc. (Placheta et al. 2001, Chaloupka et al. 2006).
Optimal musculoskeletal function also requires adequate range of motion of all joints. Especially in the elderly is often limited range of motion in key joints and prevents them from performing certain activities. The exercises, which supports the maintenance of joint flexibility are part of the warm up period but may constitute a separate part of the exercise units.
It represents a major part of the exercise units. It could last from 15 to 40 minutes. Probably the best way is to workout on an exercise bike or treadmill. Accurately dosed and control the load, as well as circulatory and clinical outcomes (hemodynamics blood pressure, heart rate, effort exertion, pain on chest, arrhythmyas ). Cardiovascular training can be provided continuously or in intervals (load, rest period) (Placheta et al. 2001, Chaloupka et al. 2006).
In addition to traditional endurance training on the exercise bike or treadmill, which can be perceived as dull, it is recommended circulating training. Circulating training includes exercises the muscles of the lower and upper limbs and trunk, and combining different types of trainers - a bicycle, treadmill, oars, and combined steper simulators. Symmetric reinforcement as many muscle groups to better reflect the needs of patients for work and leisure physical activity than is unilaterally focused training. The patient alternates after 10-15 minutes, different ways of loading. This method of training is an appropriate method to improve both strength and endurance (Placheta et al. 2001, Chaloupka et al. 2006).
It is appropriate to assign the elements of strength training, to prevent muscle atrophy, which is idle very rapidly. The inclusion of strength exercises should be at least 2x a week. Force elements are usually classified after 14 days of aerobic training. Exercise unit usually consists of 3 exercises, down to 1-RM (one repetition maximum), which is the maximum load, which is ill able to overcome without help 1. 1-RM set for each exercise separately. The patient exercises for 50% of 1-RM for 30 seconds followed by 30 seconds rest. Blood pressure and heart rate are measured on the upper arm during leg exercise (Pollock 2000, Chaloupka et al. 2006, Mífková et al. 2004, 2005, 2006, Jančík et al. 2003, 2004). Strength exercises are performed slowly and smoothly, about 2 exercises for 5 seconds. Patients may not perform this exercise during the Valsalva maneuver. When the patient has a good exercise tolerance and blood pressure values of less than 200 / 120 mmHg, he can increase the intensity of his work by adding load, prolongation or repetition of the basic training cycle. He can also include strengthening other muscle groups as a methodological guide booster simulator.
Contraindications of resistance (strength) exercises are equivalent contraindications which include the rehabilitation in general. Greater attention should be made to the values of blood pressure (Pollock 2000, Chaloupka et al. 2006, Mífková et al. 2004, 2005, 2006, Jančík et al. 2003, 2004 ).
Use of resistance training (force elements) was for a long time not allowed in cardiac patients. The medical doctors were worried to recommend it for a long time for fear of provocation of ischemia and the possible arrhythmogenic effect of the pronounced rise in blood pressure and more recently for possible adverse effects on left ventricular remodeling. In clinical trials, none of these concerns failed, while the percentage of provoked ischemia or arrhythmia during strength exercises is lower than the classical aerobic training (Pollock 2000, Chaloupka et al. 2006, Mífková et al. 2004, 2005, 2006, Jančík et al. 2003, 2004).
Total duration of exercise units is about 60-90 minutes. Before the start, you must determine the value of BP and HR and ask the patient's subjective complaints (stenocardia, shortness of breath). BP and pulse should be observed in the aerobic exercise and immediately after, in persons with a higher risk of arrhythmias and should be connected to a monitor.
The patient should be advised physical activity on days when not attending training management. A good way of training would be the home exercise bikes or biking.
Optimal load for home training could be a walk. In terms of skeletal involvement and the occurrence of arrhythmias is the safest. I can walk to train intensively. For home training could be used also a very popular way in Finland called Nordic walking. Nordic Walking is normal, most agile walking with special sticks. Walking technique is close to the classic technique cross country skiing. It is reported that caloric expenditure is compared with the normal pace for up to 40% higher (Chaloupka et al. 2006).
Many patients, however, prefers a more enjoyable physical activity. They are swimming, tennis, skiing, volleyball, basketball, football and more. In pursuit of these activities play a vital role to two factors. These are the technical sophistication and competitiveness. Technical maturity reduces the effort associated with activities (eg. alpine skiing) and it increases competition, including the risk of complications. Sick does not prohibit these sports, but we recommend that they take place with less emotional passion or used various modifications, such as playing tennis without counting, etc. (Placheta et al. 2001, Chaloupka et al. 2006).
Progression of physical loading is usually divided into an initial period, the improvement period and maintenance period. In the introductory part, the patient adapts to physical training intensity and lower frequencies. Duration depends on clinical findings and physical condition. In the improvement, lasting 4-6 months, the patient gradually increases the intensity and duration of training, so that daily caloric expenditure was 200-400 kcal and 1000 kcal weekly minimum.
The aim is not only regular exercise to improve fitness, but also maintaining it. This worsens after 2 weeks of inactivity with a return to values before the training after 10 weeks to 8 months. Maintaining the training effect is in inverse proportion to the length of training, but may be influenced by physical condition, age or associated diseases.
Of the three basic factors-the intensity, frequency and duration of training is crucial. In other words, limit the frequency and duration of effect is not as negative as the decrease in intensity.
Influence of rehabilitation on the patient's psychic state
Acute coronary events
Acute coronary events mean for most patients a significant psychological burden. Already in the period of hospitalization the patient must be calm and prepare for changes in lifestyle and habits that are related to the disease. Here is the irreplaceable role of the attending physician, expert in cardiology, a specialist physiotherapist and possibly psychological assistance (Chaloupka et al. 2006). Even during phases of cardiac rehabilitation is necessary psychological support for patient-oriented psychologist on this issue, or in rehabilitation programs managed by physiotherapists specialized in the field of cardiovascular exercise training. To reach the optimum effect of rehabilitation, it is necessary to cooperate with the closest family members. The patient who has or acquires a positive attitude towards physical activity, he could provide exercise training easy and follows other principles of secondary prevention.
Rehabilitation of heart failure
Intolerance exercise in patients with chronic heart failure is multifactorial. In addition to left ventricular involvement are particularly changes in the periphery, leading to the limitation of physical activity (Auricchio et al. 2002, Clark et al. 1997, DeKam et al. 2002, Drexler et al. 1992).
In inactive patient the physical fitness decreases and it leads to atrophy of skeletal muscles. These changes are exacerbated by reduced exercise tolerance and fatigue, shortness of breath. Physical load as part of a comprehensive rehabilitation improves exercise tolerance and is associated with improved oxidative capacity of exercising muscles. Indicators of autonomous vegetative nervous system sympathetic and parasympathetic balance (the vagus nerve) may improve and thus have a protective effect on disease progression (Giannuzi et al. 2003, Hambrecht et al 1997).
When compared to healthy individuals there is reduced in patients with heart failure markedly maximal oxygen uptake (peak VO2), as an indicator of exercise capacity. It has been repeatedly demonstrated in patients with stable disease in stage of NYHA II – III, where occurred during physical exercise to improve peak VO2 (Working Group on Cardiac Rehabilitation 2001, Toman et al. 2001, European Heart Failure Training group 1998, Tenenbaum et al 2004, Špinarová et al. 2001, Widimský et al. 2003).
Physical training improves endothelial function, reduces peripheral vascular resistance and increases the blood flow of skeletal muscles. Patients with heart failure have less slow type I muscle fibers and more type I muscle fibers, fast, glycolytic. Fibres of muscle type II have low aerobic potential, and quickly get tired. Decreased oxidative capacity is therefore reflected in an increase of muscle fiber II content. It is also present muscular atrophy. In muscle of patients with chronic heart failure found together with histological changes in the enzymatic reduction of oxidative capacity as well as other metabolic substrates - adenosine triphosphate (ATP) and phosphocreatinine (PCR). These histological and biochemical changes show that in muscle there is a shift from aerobic to anaerobic metabolism and reduced oxidative enzymes. When you load previously appeared with acidosis and lactate production occurs before the depletion of PCR. Training reduces the accumulation of lactate and reduced anaerobic metabolism, it increases the size of muscle fibers, and restores their disturbed relationship. Physical training improves peripheral muscle metabolism with reduced acidification and reduce the increased activity of muscle receptors. Ergoreceptors activation contributes to a reduction in sympathetic activation and vasoconstriction.
Physical training leads to improved quality of life in patients with chronic heart failure. Central hemodynamics, by contrast, is usually not significantly affected (Toman et al. 2001, Špinarová et al. 2001).
Physical training in patients with chronic heart failure is based on the same principles that are applied to other cardiovascular patients. Even for them, according to the high risk administer the program and recommended lower training intensity, frequency, duration and progression in the way of body burden with a greater emphasis on individual approach.
Most clinical studies so far known to classify patients fitness with stable heart failure disease in stage II - III NYHA. The benefits of physical training is dependent on the etiology of heart failure (Chaloupka et al. 2006).