Volker Adams
Professor. of Medicine
Head of Department of Internal Medicine/Cardiology
University of Leipzig - Heart Center
Leipzig, Germany

■シンポジウム：What is oxidative stress: Importance for the vasculature and its regulation by exercise training.

Oxidative stress is defined in the current literature as an imbalance between the production of reactive oxygen and a biological system´s ability to readily detoxify the reactive intermediates or easily repair the resulting damage. Meanwhile, several different reactive oxygen species (ROS) have been identified like hydroxyl radicals (OH^-), superoxideanions (O₂^-) or hydrogen peroxides (H₂O₂). Intracellular several sources for ROS generation could be identified during the last years. Inside the vascular wall the main ROS producer is the NAD(P)H oxidase, an enzyme complex localized at the cell membrane and composed of several subunits. Upon activation of the enzyme for example by angiotensin II one subunits gets phosphorylated and initiating the assembly of the subunits into the active enzyme complex. Beside the NAD(P)H oxidase also the mitochondrial respiratory chain and the endothelial nitric oxide synthase (ecNOS) in its uncoupled state are able to generate substantial amounts of ROS. One big problem in area of ROS research is the quantitative detection of ROS, because the half lifetime of an reactive oxygen species is very short. Therefore, several indirect methods like EPR (using spin traps to form a stable diamagnetic molecule which can be measured afterwards), DCFH and DHE fluorescence microscopy or the measurement of modified products like lipidperoxides or malondialdyhyde have been used.
What is the importance of ROS for the vasculature itself? On one hand, ROS have been shown to reduce the amount of bioavailable nitric oxide (NO), thereby influencing the vasodilation of the vasculature, but on the other hand NO is also an important signaling molecule for example in the generation of ecSOD and the angiotensin II induced hypertrophy of vascular smooth muscle cells.
Since we know that regular physical exercise training (ET) has a beneficial effect on the vasculature, in the last part of the talk, we will discuss the influence of ET on vascular ROS. As shown in cell culture experiments or animal experiments increased shear stress or ET has the potency to significantly induce the expression of ROS detoxifying enzymes like Cu/Zn-SOD or ecSOD. In addition as shown in human studies by our own group, exercise training can also reduce the expression and activity of the main produced of ROS in the vascular wall - the NAD(P)H oxidase. The reduction is probably due to a reduction of the angiotensin II receptor subtype 1. Last but not least we will discuss the influence of ET on the generation of ROS in an animal model of aortic valve sclerosis.

■教育セッション：Effects of exercise on muscle

Chronic heart failure (CHF) is a condition characterized by exercise intolerance. It has been frequently pointed out that the level of activity tolerated by individual could not be predicted by classical parameters of left ventricular performance. Therefore, in recent years considerable attention has been focused on the role of peripheral factors such as skeletal muscle a determinant of work capacity. In the last 10 to 20 years many alterations have been described in the current literature occurring in the skeletal muscle obtained from patients with chronic heart failure when compared to healthy controls. With this knowledge also the treatment of patients with CHF has changed dramatically. In former times patients were asked to avoid excessive strain and physical exercise. Now a days, exactly these patients are asked to participate in a supervised physical training program to increase exercise capacity and counteract the molecular changes in the skeletal muscle. Also the type of exercise training has changed over the last years. At the begin only endurance exercise training was performed, whereas recent studies also demonstrated a benefit from endurance and/or resistance training. This overview will describe several systems in the skeletal muscle demonstrating clear alterations upon exercise training. Topics covered during the talk are inflammatory cytokines, anabolic/catabolic factors, oxidative stress, stem cells and muscular capillarization.
Upon exercise training programs specific markers for inflammation such as tumor necrosis factor alpha and interleukin 6 are reduced in plasma but also in the skeletal muscle itself. This is the case for endurance and resistance training. In close relation to changes in the inflammatory activation changes in the anabolic/catabolic balance can be observed. Two specific systems will be discussed. First the specific ubiquitin proteasome E3 ligases Murf-1 and MafBx and second the anabolic factor insulin like growth factor 1 (IGF1).
Another system heavily influenced by exercise training is the generation and detoxification of reactive oxygen species (ROS). Especially a significant upregulation of superoxide dismutatase, catalase and glutathion peroxidase was evident after an exercise period. Last but not least exercise training also influences the amount of stem cells inside the musculature as well as the capillarization of the muscle.

Taken together, exercise training (endurance as well as resistance training) has the potency to positively influence several different systems in the skeletal muscle.

Philip A. Ades
Professor of Medicine
Director of Cardiac Rehabilitation and Prevention, University of Vermont College of Medicine, Vermont, USA

■プレナリーセッション：Importance of secondary prevention in cardiac rehabilitation

Cardiac Rehabilitation is standard of care for patients after a hospitalization for an acute coronary event such as myocardial infarction or coronary revascularization. Cardiac rehabilitation participation has been associated with a survival benefit and with an improved functional capacity that is reflected in improved fitness, diminished cardiac symptoms and improved physical functioning in the home and work setting. Preventive benefits, however, can be amplified if cardiac rehabilitation programs would also function as "secondary prevention centers". This involves:

• Baseline screening of all participating patients with measurement of cardiac risk factors
• Setting up individualized goals based upon cardiac prevention guideline statements
• Availability of lifestyle counseling to alter dietary and physical activity patterns
• Short- and longer term follow up assessments
• Active use of pharmacologic agents, as needed, to meet treatment goals.
• Transition of long-term preventive care to treating physician, and
• Measurement of program successes and challenges as grouped outcome measures (Performance Indicators) to guide programmatic quality improvement

Specific approaches to lipid management and weight reduction programs in CR will be described and these should be tailored to meet local needs in Japanese programs. An active stance to risk factor management needs to be taken with close communication of results to treating physicians. In summary, while exercise alone in Cardiac Rehabilitation provides a survival benefit and improvements in functional status, preventive benefits are amplified by administering cardiac rehabilitation as a secondary prevention program to improve long term outcomes.

■プレナリーセッション：Cardiac rehabilitation in the United States

Cardiac Rehabilitation (CR) was developed in the U.S. as an "exercise only" program for patients after acute myocardial infarction but has evolved into a secondary prevention program for cardiac patients with multiple cardiac diagnoses, after a cardiac hospitalization. While CR is supported in the U.S. as standard of care by multiple professional organizations (AHA, ACC, AACVPR, NIH) and health insurance companies consistently provide coverage, 15% of Americans have no health care coverage and others are "under-insured". Geographic availability of a CR program can also be problematic with a 10-fold variation in program density by state. In older cardiac patients, CR participation after myocardial infarction was measured at 19% (31% after CABG, 14% after MI). In younger patients participation varies from <10 to >50% with substantial geographic variation.

In the U.S. most programs start CR with a baseline stress test and baseline measures of cardiac risk factors including: lipid measures, glucose, blood pressure and obesity parameters. CR programming includes aerobic exercise and resistance exercise, particularly for older participants. Lifestyle counseling includes dietary and diabetic teaching, activity counseling and stress management programs. Specific modules for weight reduction and surveillance of diabetes and hypertension should be in place. In addition, the application of new or intensified pharmacologic therapy to attain risk factor treatment goals should be available. Strengths of the U.S. model include that it is recognized as standard of care, it is evolving towards the provision of individualized preventive care, it is staffed by caring, patient-oriented professionals and results in short-term exercise capacity and long-term improvements in survival. Challenges of the U.S. system include that there is relatively low overall participation rates (14-50+ %), many programs are "exercise-only" despite guideline recommendations, and that CR programs are fairly ineffective in the treatment of risk factors such as hyperlipidemia and obesity. Support by the physician community is improving but sub-optimal.

■シンポジウム：Predictors of exercise training response in CHD

The direct measurement of peak aerobic capacity (Peak VO₂) in Cardiac Rehabilitation (CR) is valuable as a powerful predictor of long-term prognosis. The measurement of the training response in CR is important as it not only correlates with improvements in physical function and decreases in cardiac symptoms but a greater training response also correlates with an improved prognosis. There is surprisingly little information on predictors of exercise training response in CR in the medical literature.

It appears that when training response is expressed as per cent improvement from baseline, one consistent independent predictor of training response is the baseline value of Peak VO₂ . The lower the value, the greater the relative training response. Thus, this explains why patients after bypass surgery appear to train to a greater degree than patients with a non surgical diagnosis. Age appears to have no effect on the relative training effect whereas female patients, despite a lower baseline Peak VO₂ than men, appear to have a lesser training response. In addition, patients with multiple medical co-morbidities and patients with exertional ischemia derive a lesser training response than individuals without these factors.

A recent study by Savage et al (JCRP 2009) found that 21% of patients in CR fail to improve Peak VO₂ whatsoever, in CR. "Non-improvers" were characterized by training at a lower relative exercise intensity despite a similar level of perceived exertion. Other independent predictors of training response include the presence of multiple medical co-morbidities (-), baseline Peak VO₂ (-), handgrip strength (+), and the presence of diabetes mellitus (-).

Identification of patients at a high risk of not training may allow for the design of specific interventions, such as interval training, to maximize training response.

Stefan D. Anker
Professor for Applied Cachexia Reserch
Cardiology & Cachexia Reserch Center for Cachexia Therapy,
Dept of Cardiology, Charité Berlin, Campus Virchow-Klinikum,
Berlin, Germany

■シンポジウム：Treatment of cachexia in CHF: Status 2009

Cachexia (i.e. wasting disease) in chronic heart failure is frequent and causes major morbidity and mortality. Many assume that there are common mechanisms for cachexia development in chronic illness, but published evidence for this suggestion is limited and often circumstantial.

Important pathophysiologic factors for cachexia in CHF and other chronic illness include:
- inflammation & cellular immune activation,
- neurohormonal activation,
- hormone resistance syndromes (like GH and insulin resistance),
- anabolic failure, i.e. lack or insufficiency of anabolic protection,
- activation of specific muscle wasting proteolytic processes, and
- activation of lipolysis pathways.

Together these pathophysiologic changes can be termed as a state of catabolic/anabolic imbalance [1].

For cachexia in CHF no treatment has been approved. Candidate developments include anti-inflammatory drugs, anabolics and growth factors as well has neurohormonal modulators.

ACE inhibitors prevent cachexia in CHF. Beta-blocker therapy can prevent and to some degree reverse cachexia in CHF. This findings may be a useful to apply in other cachexia illnesses.

Limited data exists for the application of ghrelin in cardiac cachexia that will be discussed.

In summary, I suggest that cachexia in different chronic illnesses similarly show a complex and multi-factorial pathophysiology resulting in a similar set of debeliating symptoms and adverse clinical outcomes. In conclusion: 1) treatments that are successful in one cachexia patient subgroup likely may also be useful in other cachexia indications,
2) more than one specific treatment approach will be necessary to optimally treat patients with cachexia, and 3) if one treatment is successful in one cachexia subgroup other treatment approaches still have a chance to be successful in that particular subgroup (even if used/tested on top of the first treatment).

[1] Anker SD et al. Circulation 1997.

■Meet the expert：Nutrition in CHF: Status 2009

The biggest nutritional problem of CHF is the development of muscle wasting and cachexia in chronic heart failure. Cardiac cachexia is frequent and causes major morbidity and mortality.

It is well known that the heart of patients with CHF can be considered as an "engine out of fuel". Micro- and macro-nutritional support may be a new way forward to improve outcome in CHF patients. Results of recent studies will be discussed in the presentation.

However, we suggest that nutritional support alone cannot significantly improve the long-term situation of patients, unless anti-catabolic therapies are actively used.

Bernard R. Chaitman
Professor of Medicine
Director, Cardiovascular resewrch
Director, The Core ECG/MKI Classification Laboratory, St Louis University School of Medicine,
Missouri, USA

■シンポジウム：Exercise ECG parameters as indexes for prognosis incardiac patients

Exercise testing is a major stress modality that is used to risk stratify cardiac patients recovering from an acute coronary syndrome or with chronic stable symptomatic or asymptomatic coronary disease. The post-test likelihood of having a cardiac event is dependent in part on the pretest risk that should be used along with the results of the exercise findings to optimize post-test prognostication. For example, age, prior history of heart failure, impaired left ventricular function, coronary disease extent if known, and serious comorbid conditions independently influence cardiac event rates regardless of the exercise test results and medical therapy with statins, ACEI/ARB, antiplatelet drugs and coronary revascularization reduce cardiac event rates such that post-test estimates of cardiac event rates are significantly less than earlier published data.
Exercise testing provides (1) an estimate of peak aerobic capacity, (2) an individual's hemodynamic response to various exercise workloads, (3) the potential to evoke myocardial ischemia as manifest by symptoms or new ECG findings, and (4) a threshold at which cardiac arrhythmias may be provoked in response to different loading conditions, autonomic tone, and increased circulating levels of catecholamines. When using exercise ECG parameters to estimate prognosis, the time to the onset of a myocardial ischemic response is more important than how many leads are involved, depth of ST segment response or the morphology of the ST segment (downsloping vs horizontal or slow-upsloping), since it indicates overall coronary vascular reserve. However, for any given level of work, more profound ST segment depression that involve more leads and downsloping ST segments carries more risk than lesser degrees of an ischemic response.
Measurement of exercise induced ST segment depression or elevation is optimized by recording 10 seconds of contiguous 12 lead ECG data rather than four consecutive 3-lead sets of 2.5 seconds since motion artifact may interfere with interpretation during the 2.5 second display. It is best to see at least 3 consecutive ECG complexes with the abnormality and a stable baseline to be sure the abnormality is a valid signal. Exercise-induced ST segment elevation in a non-infarct territory generally indicates severe ischemia and is relatively specific in predicting the artery causing the finding in contrast to ST segment depression. Heart-rate adjustment of the ST segment response improves the prognostic capability of the test and should be considered, as well as chronotropic response to exercise workload and heart-rate recovery.

■教育セッション：How to prevent and how to treat CAD in DM patients

Type 2 diabetes mellitus increases the risk of developing CAD and is associated with an increased risk of cardiovascular events. The BARI-1 trial, a randomized controlled trial of 1,829 stable patients with multivessel disease in the pre-stent era (1988-1991) compared PTCA to CABG and reported similar 10-year survival rates in nondiabetic patients but improved survival with CABG in diabetic patients. The BARI2D trial, conducted after the conclusion of BARI-1, screened 4,623 type II diabetic patients with stable CAD and randomized 2,368 (51%) to optimal medical therapy (OMT) or to OMT plus coronary revascularization from 2001 to 2005. The trial did not compare PCI to CABG but rather required the cardiologist to determine after coronary angiography if the patient was better suited for a PCI or CABG procedure. Once this decision was made, the patients were then randomized to (1) OMT or OMT+PCI, or (2) OMT or OMT+CABG. . Angiographic characteristics of the study population revealed more extensive CAD in the patients selected for CABG (as expected) (Am J Cardiol 2009;103:632-638). The study was a 2x2 factorial design and included randomization to a strategy of insulin sensitization (using metformin, a thiazolidinedione, or both) or a strategy of insulin provision (using a sulfonylurea, insulin, or both) to treat hyperglycemia (Am J Cardiol 2006;97[suppl]: 20G-30G). The primary end-point of BARI 2D was all-cause mortality and a major secondary end-point was the composite of death, myocardial infarction, or stroke. The study design has been reported (Am J Cardiol 2006;97[suppl]:9G-19G), as well as the cost-effectiveness parameters that will be evaluated (Am J Cardiol 2006;97[suppl]: 59G-65G). The baseline characteristics of the study population revealed an average age of 62 years with 70% men. Two and three vessel CAD were present in 36% and 31% of patients respectively. More than 80% of the study cohort had a history of hypertension, and 45% had the triad of smoking, hypertension, and hyperlipidemia. The average duration of diabetes was 10.4 years prior to randomization. At enrollment, average HbA1C was 7.7% and 1/3 of the patients had albuminuria (AHJ 2008; 156:528-536.e5.). Primary study results will be presented at the meeting.

Alain Cohen-Solal
Professor of Cardiology at the Faculty of Medicine (Paris 7),
Head of the Department of Heart Failure, Echocardiography and Cardiac Rehabilitation at the Hospital Lariboisière,
Paris, France

■プレナリーセッション：Effects of exercise on cardiac function

Long term exercise induces profound cardiac effects. These effects depend on many factors: duration, type of exercise, and the backgound state (normal or diseased) of the myocardium. Endurance training induces dose-dependent effects on cardiac systolic and diastolic functions, hemodynamics and remodelling. There is a increase in the expression of the genes of the contractile and the relaxation pathways. Contractility is increased, relaxation velocity and strength are also enhanced; compliance is improved. Maximal cardiac output is increased mainly due to an increase in stroke volume. Heart rate is decreased at rest and at any level of exercise and its recovery kinetics is also increased. Arterial elastance is increased and ventriculo-arterial coupling improved, explaining in part the slight increase in ejection fraction. Remodeling is also affected with an increased in both volume and thickness, with maintenance of a normal thickness/volume ratio.
These effects are much less marked in the diseased myocardium mainly because of the lower level of exercise. Progressive ventricular dilatation is slowed in case of heart failure whereas filling properties are improved as reflected by decrease in plasma BNP. There is however no major effect of ejection fraction or contractility and most of the clinical benefit seems to be related to improved peripheral vascular and muscle functions.

■シンポジウム：Recent advances in exercise therapy for chronic heart failure

Long contra-indicated, exercise has now been recognized as an effective treatment of chronic heart failure (CHF), adjunctive of medical therapy and devices. The effects of exercise are dependent on the duration, the level and the kind of exercise performed. In general, CHF patients are engaged in endurance training programmes. Various short scale studies have shown beneficial effects of exercise training on cardiac function, neurohormonal profile, inflammatory state, peripheral vasculature and muscle structure and function. These effects translate in a marked improvement of cardiac symptoms, quality of life and exercise capacity. Interval training seems to be more effective than continuous steady state training. Resistance training is now considered as a safe adjuvant to endurance training.
Various meta-analyses have suggested that exercise therapy may improve outcome in CHF patients. The ExtraMatch meta-analysis included more than 800 patients in 9 studies and suggested a 25% reduction both in mortality and in mortality or HF related hospitalizations. Recently, the large scale HF-ACTION, NHLBI sponsored, was conducted. This study included more than 2 500 CHF patients with left ventricular systolic dysfunction on optimal background therapy. Follow-up was 2.5 years. Patienst were asked to daily performed regular exercise on treadmill or bicycle. This study failed to show a significant effect on the primary endpoint of morbimortality but after adjustment on important baseline variables, there was a significant effect on outcome (11%) and the classical combined end-point of cardiovascular mortality or HF hospitalization was reduced by 15%. Post-hoc analysis showed a clear dose of exercise-effect relation, in this study where long term adherence to exercise was far lesser than expected. HF-ACTION leaves many question unanswered and points to the importance of exercise adherence as a key factor of physical training efficacy.

Stephan Gielen
Associate Professor of Medicine, Faculty of Medicine, University of Leipzig
Director, Heart Failure Clinic
Senior Physician, Dept. of Internal Medicine/Cardiology, Heart Center, University of Leipzig

■プレナリーセッション：Training effects on muscle and gene expression

It was a turning point in modern cardiovascular medicine when it was observed in the early 90's that no correlation could be found between exercise capacity and left ventricular ejection fraction in chronic heart failure (CHF). Systematic pathophysiological research revealed that secondary changes in peripheral muscle mass and function were much closer related to the exercise limitation in CHF. In addition to the skeletal muscle also ventilatory function and vascular endothelial function were severely affected by the CHF disease process.
Several molecular and biochemical alterations were found in peripheral skeletal muscle biopsies obtained from the vastus lateralis muscle in patients with CHF: (1) The aerobic energy metabolism was significantly reduced as a result of both a reduction in mitochondrial volume density and activity of key enzymes of oxidative phosporylation and energy transfer from the mitochondria to the cytosol. (2) Probably due to repetitive ischemia-reperfusion situations with increased local oxidative stress in the skeletal muscle a chronic inflammatory activation with five-to seven-fold overexpression of inflammatory cytokines (TNF-α, IL-1β, IL-6) occurs in CHF patients. (3) Inflammatory cytokines act as pro-catabolic factors and increase the degradation of structural proteins via the ubiquitin-proteasome system in CHF. (4) Because anabolic factors such as IGF-I are reduced in the skeletal muscle at the same time an anabolic-catabolic imbalance ensues with a net loss of skeletal muscle mass and force. CHF disease progression may therefore lead to a terminal state of cardiac cachexia with severe loss of muscle mass leading to disability and death. Epidemiological studies have clearly demonstrated the prognostic impact of weight-loss of >6% for survival in CHF.
These molecular changes can be positively affected by regular endurance-resistance exercise programmes: While the changes may not be completely reversible it is possible to decrease inflammatory activation by up to 50%, to decrease ubiquitine-proteasome mediated muscle catabolism by up to 40% and to increase IGF-I expression and mitochondrial volume density and aerobic energy generation in the skeletal muscle.
Training programmes aimed at improving skeletal muscle function and general exercise capacity are not mere symptomatic interventions. By interfering with the underlying disease process of peripheral organ involvement in the syndrome of heart failure and by the vascular training effects with reduced peripheral vascular resistance and afterload metaanalyses of training studies indicate a reduction of mortality and morbitidy as a prognostic impact of long-term training interventions.

■シンポジウム：Exercise therapy for a patient with peripheral artery disease: Training effects and molecular mechanisms

Peripheral artery occlusive disease (PAOD) is often regarded as that less dangerous manifestation of atherosclerosis as compared to coronary artery disease. However, but this perception may not be correct: The 5-year mortality rate of patients with PAOD is in the range of 28%, which places it above the mortality rate of breast cancer and Hodgkin's disease.
The principal goals of therapy in patients with PAOD are (1) the improvement of the patient's prognosis by treatment of the underlying general atherosclerosis to reduce a cardiovascular event rate, and (2) the improvement of the patient's symptoms by increasing pain-free walking distance and preventing limb loss.
Regular walking training provides the most effective way of increasing walking distance: In a metaanalysis Gardner calculated an average improvement in pain-free walking distance of 180% and of maximal walking distance of 130% after a supervised 3 to 6 months walking exercise program. These functional results are 3 to 4 times better than conventional pharmacological treatment with pentoxifylline or cilostazol. Although immediate pain relief is better after a percutaneous transluminal angioplasty (PTA) walking training surpasses PTA 6 months after the intervention with regard to walking distance.
Walking training in PAOD is the only example of ischaemic exercise training in vascular diseases: To achieve the maximum clinical benefit for the patient it is important that the patient does not stop walking training when claudication sets in. He must continue to until he reaches his maximal walking distance to activate the local mediating factors important for improvement of collateralisation and vascular function. Several molecular mechanisms contribute to the clinical benefit of walking training in patients with PAOD: (1) Regular exercise training improves vascular endothelium-dependent vasodilation, which is frequently attenuated in the presence of atherosclerosis. Repair mechanisms for the endothelium are activated and endothelial progenitor cells are liberated from the bone marrow to replace areas of disease endothelium. (2) Additionally, endothelial progenitor cells can also home to areas of limb ischaemia and induce a of process of vasculogenesis, which means the formation of entirely new blood vessels as opposed to angiogenesis, the sprouting of pre-existing capillary vessels. Training interventions have repeatedly shown to increase the number of circulating endothelial progenitor cells and their homing capacities in PAOD patients.

■シンポジウム：Benefits of exercise training: Molecular and genetic mechanisms

In recent years there has been a transition from exercise based post-MI rehabilitation to long-term exercise interventions aimed at modifying the underlying atherosclerotic disease process. The mechanisms responsible for mediating the beneficial effects of training in CAD can be found on different levels: (1) Modification of established risk factors, (2) neurohormonal effects, and (3) molecular vascular mechanisms of improved vasomotor function and regional perfusion.
(1) Modification of established risk factors:
In a meta-analysis of endurance training Fagard described training-induced significant net reductions of resting and day time ambulatory blood pressure of 3.0/2.4 mmHg and 3.3/3.5 mmHg, respectively. The reduction of resting blood pressure was more pronounced in the 30 hypertensive study groups (-6.9/-4.9) than in the others (-1.9/-1.6).
In this meta-analysis bodyweight decreased by 1.2 kg, waist circumference by 2.8 cm, percentage body fat by 1.4% and the Homeostatic Model Assessment (HOMA) index of insulin resistance by 0.31 units. High-density lipoprotein-cholesterol increased by 0.032 mmol/L.
(2) Neurohormonal effects:
Regular endurance training readjusts the balance between the sympathicoadrenergic and vagal system in favour of vagal tone. This leads to reduced myocardial oxygen demand, increased ventricular fibrillation threshold, and more economic cardiac work.
As an example of factors of the renin-angiotensin-aldosterone system plasma renin activity was reduced by 20%.
Improved vasomotor function:
Basically, regional myocardial hypoperfusion in CAD results from a combination of several pathogenetic components: Vascular stenosis, endothelial dysfunction, and microrheology/ hemostasis. All three components may be affected by exercise training in stable CAD.
Vascular Stenosis: Although training did not lead to a regression of coronary artery stenosis in the majority of patients it was effective in significantly retarding disease progression.
Endothelial Dysfunction: Invasive studies with measurement of coronary endothelial function have shown that aerobic exercise training improves coronary vasomotion in patients with stable CAD and leads to increased vascular expression and activity of the endothelial NO synthase.
Microvascular function: Long-term exercise training induces not only functional improvements with increased adenosine-dependent microvascular flow reserve but also morphologic changes of the microvasculature by increasing the total vascular bed cross sectional area. Exercise training also mobilizes endothelial progenitor cells from the bone marrow, which have the potential to home to areas of diseased endothelium (thereby improving endothelial function) or to form entirely new vessels in a process called angiogenesis.
Blood viscosity: Chronic endurance training has been shown to attenuate the post-exercise potentiation of platelet function, to increase platelet cGMP content and to suppress coagulability. Improvements of blood rheology by reduced viscosity add to these beneficial training effects.
The prognostic effect of these changes was confirmed in a Cochrane meta-analysis revealing a 27% reduction of total mortality and a 31% reduction in cardiac mortality.

■シンポジウム：Exercise training and left ventricular diastolic function

Left ventricular diastolic dysfunction occurs in different clinical settings: In patients with left ventricular hypertrophy, older individuals >60 years, and primary myocardial diseases (e.g. storage diseases like amyloidosis, or hypertrophic cardiomyopathy) diastolic left ventricular function is regularly diminished. In recent years it became evident that also primary left ventricular systolic dysfunction in chronic heart failure is regularly associated with echocardiographic signs of diastolic dysfunction.
So far, no specific pharmacological treatment of diastolic dysfunction is available: Studies of AT1 blockers (Charm preserved) suggested a clinical benefit, however, the endpoint-driven iPreserve study in diastolic heart failure did not show any clinical benefit. Studies for ACE-inhibition and digitalis were equally neutral.
In a single center study using pulsed wave Doppler Belardinelli measured E/A ratio before and after a six months aerobic training intervention in patients with CHF and was the first to describe a significant exercise-related improvement of left ventricular diastolic function in CHF. In a prospective randomised controlled study we used tissue-Doppler to assess left ventricular diastolic function before and after a four week supervised training intervention and were able to confirm a significant improvement of E/A ratio, E', E/E', isovolumetric relaxation time and mitral deceleration time in the training group. These findings were paralleled by a significant improvement of left ventricular systolic function. No age-associated decline of left ventricular diastolic dysfunction was measured in the CHF-group while there was a clear decrease in diastolic function among healthy individuals with aging.
The positive effects of training on diastolic function are now also being confirmed among patients with heart failure with normal ejection fraction (i.e. diastolic heart failure). Pieske confirmed a significant improvement in E/E' ratio following an aerobic training programme in diastolic heart failure.
These studies underline the importance of measuring parameters of diastolic function in patients with clinical symptoms and signs of heart failure - both diastolic and systolic. Training is the first clinical intervention to show a measurable and clinically relevant improvement of diastolic function. This novel aspect of training-based interventions in CHF adds to the solid evidence base in favour of systematic clinical application of training-based cardiac rehabilitation programmes in CHF patients.

Arto J. Hautala
Laboratory Manager, Dept. of Exercise and Medical Physiology, Verve Reserch
Adjunct Professor, Division of Cardiology, Dept of Medicine, University of Oulu
Oulu, Finland

■プレナリーセッション：Exercise and autonomic nervous system

Marked changes in heart rate (HR) occur during exercise and after exercise training interventions. The changes in HR are primarily due to alterations in autonomic nervous system (ANS) activity: parasympathetic (vagal) modulation slows down the HR, and sympathetic stimulation increases it. Assessment of ANS has played an important role in elucidating the centrally mediated neural mechanisms in diverse clinical and physiological settings. The most widely used methods involve measurement of an end-organ response to a physiological or pharmacological provocation. HR variability (HRV) and muscle sympathetic nerve activity (MSNA) are both objective and reliable tools for assessing ANS functioning.
Cross-sectional studies have revealed that cardiac vagal modulation, expressed as HRV, is higher in well-trained healthy subjects than in controls. In addition, in our latest study, we observed that subjects with high aerobic fitness level had lower sympathetic activity (MSNA) than did subjects with low aerobic fitness. These findings suggest that good aerobic fitness is related to high cardiac vagal modulation and low sympathetic outflow, providing evidence that good exercise capacity has beneficial effects on ANS regulation.
An obvious indicator of cardiovascular adaptation to regular endurance training is a lowering of HR at rest and during submaximal exercise. Furthermore, large body of data of intervention studies shows that regular endurance training alters ANS balance by increasing vagal modulation. It has also been reported that endurance training interventions changes ANS activity by decreasing sympathetic activity especially among patients with cardiac disease. Therefore, regular exercise training is recognized as integral to the comprehensive care of patients with cardiovascular disease also in terms of ANS function.

■教育セッション：Difference of physiological response to resistance and endurance training

Both endurance and resistance exercises have been recommended to include in exercise training programs in subjects with and without cardiovascular disease. The increased risk of cardiovascular complications related to blood pressure elevations are the primary concern with resistance training in patients with coronary artery disease (CAD). In our latest study we compared cardiovascular responses during acute resistance and endurance exercises. We found that cardiovascular responses did not differ between the exercises at low or moderate relative intensity levels of exercise. Peak cardiac work was even higher during endurance exercise compared to resistance exercise at the high intensity levels of exercise both in healthy subjects and in CAD patients. It appears that resistance training can be incorporated safely into rehabilitation programs for patients with CAD.
It is well recognized that regular exercise training reduces all-cause mortality and improves a number of health outcomes. However, a marked heterogeneity in the training-induced changes, e.g. in terms of cardiorespiratory fitness, has been observed in healthy subjects, even with highly standardized training programs. Mean improvements in fitness have been about 10 - 15 % of the baseline values, but the training-induced changes have ranged even from negative response to 40% increase.
Understanding the importance to study the mechanisms behind the individual exercise-training induced changes, the other important issue that will need to be considered is the practical implications. Do we have any tools or methods in the field of exercise science for low responders?
We tested the hypothesis that resistance training may increase cardiorespiratory fitness in healthy sedentary male and female subjects whose responsiveness to endurance training is low. The subjects performed both short-term endurance and resistance training programs including a break of two months between these programs. Endurance training consisted of cycling and resistance training was performed by using HUR training devices. Both training modes were performed according to current guidelines of American College of Sports Medicine.
The results of the study showed that if the training response is low after endurance training, cardiorespiratory fitness could be improved effectively by the resistance training. Those who are not able to improve their cardiorespiratory fitness by short-term endurance training should be advised to start resistance training programs in attempts to improve their cardiorespiratory fitness. These data suggest that training modes could be tailored individually by assessing first the responses to short-term exercise.

Georg Kojda
Professor of Medicine, Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum Düsseldorf, Düsseldorf, Germany

■プレナリーセッション：Molecular mechanisms of vascular adaptations to exercise

A lack of exercise training and/or regular physical activity is a known risk factor for cardiovascular disease. Exercise training induces marked vascular remodeling by increasing angiogenesis and arteriogenesis. These changes of the architecture of the vascular tree are likely associated with functional changes and improved organ blood flow. Physical forces such as shear stress, transmural pressure and cyclic stretch activate mechanotransduction mechanisms in endothelial and smooth muscle cells which are mediated by integrins and associated RhoA small GTPase. They stimulate various signal transduction pathways involving phosphorylation of kinases such as focal adhesion kinase, c-Src, Akt kinase, phosphatidylinositol 3-kinase, myosin light chain kinase, mitogen-activated protein kinase (MAPK) and extracellular signal related kinase (ERK). These mechanisms result in upregulation of genes mediating antiatherogenic effects by promoting antiapoptotic and antiproliferative signals, by increasing vascular NO-bioavailability and by changing calcium handling and the vascular myogenic response to pressure. Exercise-induced increase of vascular eNOS expression and of eNOS Ser-1177 phosphorylation is most likely an important and potentially vasoprotective effect of exercise training. The underlying mechanisms involve cell membrane proteins such as integrins and products of vascular oxidative stress such as hydrogen peroxide. Exercise-induced eNOS expression is transient and reversible and regulated by factors such as angiogenesis, arteriogenesis and antioxidative effects including upregulation of superoxide dismutases (SOD1, SOD3) and downregulation of NAD(P)H oxidase which likely blunts the effects of oxidative stress. Based on these observations it appears resonable to assume that exercise training can be viewed as an effective antioxidant and antiatherogenic therapy. (247 Words)

■シンポジウム：Effects of organic nitrate on endothelial function

Therapeutic activation of the vascular NO/cGMP pathway is induced by a variety of stimuli/mediators including physical activity, supplementation with the precursor L-arginine and organic nitrates which generate NO in the vasculature. The necessity of an enzymatic reduction for NO generation from these drugs as well as differences in the activity of the NO/cGMP pathway within the vascular tree determine the unique hemodynamic changes elicited by organic nitrates. These changes include preferential venodilation, vessel-size specific arterial dilation and improvement of the aortic distensibility and Windkessel-function. Some animal experiments and clinical investigations suggest that nitrates may also be endowed with cardioprotective and/or vasoprotective effects. "Early entry" therapy with nitrates do not significantly improve survial in myocardial infarction but increases the beneficial effects of the ACE-inhibitor enalapril by 50 %. Furthermore, nitrates have been shown to improve survival in heart failure, but prognostic effects in stable angina pectoris are unknown. Short-term experimental and clinical investigations suggest that nitrate tolerance induced by nitroglycerin is associated with toxic effects in the vasculature, but this is not true for pentaerythrityl tetranitrate and isosorbide mononitrate. The observed endothelial dysfunction induced by a continuous treatment with nitroglycerin may be an additional risk for patients who receive continuous nitroglycerin to treat conditions such as unstable angina and acute heart failure. In general, nitrates are remarkably safe drugs and are well tolerated. Appropriate clinical trials are needed to answer the question whether nitrates can do more than symptomatic relief in cardiovascular disease. (242 words)

Mats Manderbacka
Managing Director of R&D, HUR Oy Ab, Kokkola, Finland

■How to session：prescription for resistance training

■教育セッション：Exercise prescription for resistance training in cardiac patients

Prescribed and supervised resistance training has been accepted as a component of rehabilitation program for person with or without cardiac disease. Resistance training, which is properly implemented based on individual medical supervision, has been proved that it does not bring higher risks for the patient than aerobic endurance training. The appropriate resistance training method for the cardiac patients are dependent on each patient's clinical status and cardiac stress tolerance. Taking this into consideration, a number of guidelines and recommendations of resistance training method for cardiac patients has been published. The practical implication of the resistance training method has been put forward and recently training prescriptions and recommendations including major muscle groups, resistance adjustment and repetition setting for training has been tested and analyzed.
All the major muscle groups for cardiac rehabilitation are able to be trained with existing training equipments, which are designed for enhancing muscle performance and muscle mass. As the determinant for training intensity, heart rate monitor function should be contained in the equipment. Resistance is able to be set based on 1 repetition maximum (1RM); however, the primary concern in choosing the exercise, setting the resistance and repetition should always be the safety of the patient. The pain during and after the training possibly indicates that the patients have exceeded the individual limitation in terms of muscle capacity and cardiovascular stress tolerance.
In addition to medical supervision, equipment use for resistance training requires the knowledge of physiotherapy for posture and performance monitoring. Properly instructed resistance training enhances not only muscular strength and endurance but also functional capacity and quality of life.

Piotr Ponikowski
Professor of Medicine
Head of Dept. of Heart Disease, Faculty of Health Sciences, Medical University
Clinical Military Hospital,
Wroclaw, Poland

■プレナリーセッション：Effects of exercise on inflammation in patients with chronic heart failure

The current understanding of the natural history of chronic heart failure (CHF) recognizes it as clinical syndrome which originates from the diseased heart with subsequent involvement of several organs and systems. These non-cardiac abnormalities become an integral part of pathophysiology of CHF, and some of them may adversely affect cardiovascular system, playing a role in the progression of the disease. Over the recent years, it has become evident that immune activation with overexpression of proinflammtory cytokines characterises CHF. Deleterious biological effects of inflammatory mediators contribute to the central and peripheral manifestations of CHF. As a consequence, strategies specifically modifying inflammatory status in CHF have been proposed as novel therapeutic avenues for CHF patients. In this context there is a growing interest in the effects of regular exercise training in CHF. Active life style and regular physical activity are widely recommended as an element of self-care management for virtually all CHF patients. Regular, carefully-structured rehabilitation sessions constitute part of the complex management programs for of these patients. On the hand, it has been known for decades that physical activity can result in dysregulated inflammatory responses and some authors even raised concern whether exercise may be considered a foe of the aging immune system. In fact, there is an evidence that acute bouts of exercise, particularly strenuous, may elicit "danger" type of stress reaction and lead to robust inflammatory response characterized by mobilization of leucocytes, increase of proinflammtory mediators and oxidative stress with production of reactive oxygen species by the skeletal musculature and other tissues. Such effects of exercise in CHF patients with already compromised immune response and inflammatory activation may be potentially deleterious and contribute to the progression of the disease. However, the results of numerous studies reported in the recent years, have convincingly demonstrated this is not a feature of regular exercise in patients with CHF. Rather opposite findings have been reported - regular, long-lasting exercise training decreases proinflammatory mediators levels in the blood and peripheral tissues, reduces oxidative stress and normalizes immune response. All these favorable changes may translate into clinical benefit and explain overwhelming benefit of regular exercise activity in CHF patients.

■シンポジウム：Recent advances in pharmacological treatment for chronic heart failure

Recent developments in the understanding of the pathophysiology of chronic heart failure (CHF) have led to substantial improvement in the management of this clinical syndrome. Still though in the everyday, clinical practice mortality and morbidity in CHF are unacceptably high, and a choice of optimal therapy remains challenging. Life-saving treatments with four classes of drugs that target neuroendocrine activation i.e angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, beta-blockers and aldosterone antagonists are the cornerstones of current medical management of CHF with impaired left ventricular (LV) ejection fraction. There is compelling evidence that these drugs and only them reduce mortality and morbidity. However, it needs to be remembered that in clinical practice patients are often not optimally treated as life-saving therapies are underused or prescribed in not adequate, small doses. Other pharmacological options comprise digoxin, diuretics, and vasodilators but they are directed towards an improvement of CHF symptoms. From epidemiological perspective, CHF with preserved LV ejection is becoming equally important problem. Interestingly, no treatment has yet been shown, to reduce morbidity and mortality in these patients. Diuretics are used to control sodium and water retention and relieve symptoms. Adequate control of hypertension and treatment of myocardial ischaemia is also considered to be important. Recent years has brought rather disappointing results, as several studies with potentially promising therapeutic options for CHF (e.g. anti-cytokine therapies, endothelin antagonists, omapatrilat, statins, ivabradine) have failed to demonstrate their favourable effects on mortality and morbidity. Patients with CHF are often elderly people with multiple comorbid conditions which complicate clinical course of the disease, have an impact on therapeutic decisions and adversely affect the outcome. Recent registries clearly demonstrate that in Europe and in the US vast majority of HF patients present with several concomitant diseases, of which the most common are: arterial hypertension, diabetes mellitus, chronic pulmonary obstructive disease, renal insufficiency, atrial fibrillation and anaemia. In the next future some of them may become separate important therapeutic targets. There is still a need for further development and application of novel and better therapies for CHF patients. At the same time, already existing, life-saving therapies should be optimised. A individualized approach based on a better selection of patients who are more likely to benefit from a certain therapy is also warranted.

■シンポジウム：Chronic heart failure as an inflammatory disease

The clinical syndrome of chronic heart failure (CHF) has traditionally been linked to dysfunction of the heart with subsequent impairment of heamodynamics and peripheral circulation. In the recent years, however, there is growing evidence that complex pathophysiology of CHF although begins within the heart, also involves dysfunction of virtually all body organs, including the cardiovascular, musculoskeletal, renal, neuroendocrine, haemostatic, immune, and inflammatory systems. Elevated levels of circulating tumour necrosis factor alpha in patients with severe CHF were first reported in 1990 and generated a mounting interest in the effects that proinflammatory cytokines may exert on the myocardium and the peripheral circulation in CHF. Since then it has become evident that immune activation with proinflammatory cytokines overexpressed both in the systemic circulation and locally in the failing myocardium constitutes a typical feature of CHF syndrome. Sustained activation of inflammatory mediators results in numerous adverse biological effects including progressive left ventricular dysfunction, pulmonary edema, remodeling of the heart, reduced skeletal muscle blood flow, endothelial dysfunction, anorexia and cachexia, fetal gene expression. They all contribute to the development of both central and peripheral manifestations of the syndrome of CHF. Based on these observations the "cytokine CHF model" has been formulated which assumes that CHF progresses, at least in part, as a result of the toxic effects exerted by endogenous cytokines on the cardiovascular system. We and the others have recently proposed the hypothesis linking immune activation with autonomic imbalance - the other key abnormality in CHF. This hypothesis, put simply, is that damage to the heart triggers inflammatory processes in the central nervous system modifying function of the autonomic centers and causing central depletion of parasympathetic tone. Dysregulated cytokine network has been naturally considered as potential therapeutic target in CHF. As a result, a hypothesis of anti-cytokine therapy in CHF was developed and subsequently tested in several experimental and clinical studies. Despite promising results of the preliminary clinical studies, larger morbidity and mortality trials failed to demonstrate any favorable effect of such therapy in patients with CHF. There is no doubt that more studies are needed to investigate the complex cytokines network in CHF, comprising of numerous molecules, receptors, intra- and extracellular signals, in order to understand the role of inflammation in the pathophysiology of the CHF syndrome which eventually may help us to identify the optimal therapeutic approach.

■シンポジウム：Effects of exercise training on autonomic nervous system in heart failure patients

Carefully-designed exercise training programs are currently recommended as an important element of comprehensive management in patients with stable heart failure (HF). Numerous studies demonstrated beneficial effects of exercise rehabilitation in HF, namely improvement in exercise intolerance, functional class and quality of life. Only recently, it has been shown that long-term, home-based exercise-training is able to affect favorably patients' outcome by reducing mortality and morbidity. Although the mechanisms responsible for protective effects of exercise in HF are complex and still remain not clearly understood, it seems rather unquestionable that restoration of autonomic dysregulation in HF by regular exercise plays a key role here. An impaired autonomic balance with sympathetic predominance characterizes HF syndrome and has an impact on the progression of the disease and adversely affects prognosis. Exercise training results in readjustment of sympatho-vagal reflex control towards a reduction in sympathetic activity and enhancement of vagal control of the heart and circulation. As there is an evidence of a substantial decrease in the muscle sympathetic nerve activity in the response to training, central mechanisms may be involved here. Exercise training improves arterial baroreflex sensitivity which inhibits central sympathetic outflow. Additionally, it decreases excitatory inputs from the peripheral chemoreceptors and muscle ergoreceptors which further turns down sympathetic outflow at the central level. The overexpression of neuroendocrine systems and particularly sympathetic overactivity they constitute current therapeutic targets in HF. As exercise training has emerged as a potent non-pharmacological tool to normalize autonomic imbalance in HF it should be widely prescribed for all these patients.

Jorge P. Ribeiro
Associate Professor,
Faculty of Medicine, Federal University of Rio Grande do Sul;
Chief of Cardiology, Hospital Moinhos de Vento;
Chief of Interventional Cardiology, Hospital de Clínicas de Porto Alegre
Porto Alegre, Brazil

■シンポジウム：Respiration in heart failure

The traditional teaching in exercise physiology is that the respiratory system is overbuilt in healthy individuals and, therefore, should not limit performance; however, several experiments have shown that the respiratory system may indeed limit exercise performance. For instance, we have shown that inspiratory resistive loading after exercise reduces blood lactate concentration (Chiappa et al. Med Sci Sports Exerc 2008;40:111-6) and improves subsequent performance in healthy individuals (Chiappa et al. Eur J Appl Physiol 2009;106:297-303). Patients with chronic heart failure (CHF) may present exaggerated ventilatory response to exercise and exercise-induced oscillatory breathing (Ribeiro. Circulation 2006;113:9-10). These abnormal ventilatory responses require the progressive recruitment of inspiratory and expiratory muscles, but as a corollary to what was thought for healthy individuals, some clinicians may still believe that the respiratory system should not limit maximal exercise capacity in these patients. Several studies have demonstrated that a substantial number of patients with CHF may present inspiratory muscle weakness (IMW) and that this abnormality may have important implications not only for the exercise capacity but also for quality of life. The prevalence of IMW, defined as a maximal inspiratory pressure (PImax) less than 70 % of predicted, is 30 to 50 % in a heart failure outpatient clinic (Ribeiro et al. Curr Heart Fail Rep, in press, 2009). In patients with CHF, PImax is associated with NYHA functional capacity and correlates with resting cardiac index, but not with resting left ventricular ejection fraction. Peripheral chemoreflex response is a major determinant of ventilatory efficiency as well as in oscillatory gas exchange kinetics during exercise in CHF, and we have shown that IMW is associated with augmented peripheral chemoreflex response (Ribeiro et al. Eur J Cardiovasc Prev Rehabil 2008 [Abstract Supplement]:S113). Since respiratory muscle function is critical in the perception of dyspnea, PImax also correlates with the perception of dyspnea during submaximal exercise as well as with dyspnea during daily activities. Moreover, three cohort studies have clearly established the independent prognostic value of PImax in contemporary clinical practice. We have been following for 39 ± 26 months a cohort of 88 patients with CHF with IMW (Chiappa et al. Unpublished data, 2009). In this selected group of patients, peak oxygen uptake, inspiratory muscle endurance, and participation in training programs emerged as independent predictors of prognosis. These findings raise the hypothesis that inspiratory muscle training may improve prognosis in of patients with CHF and IMW.

■シンポジウム：Recent advances in exercise therapy forchronic heart failure

Inspiratory muscle weakness (IMW), defined as maximal inspiratory pressure (PImax) less than 70 % of predicted, is prevalent among patients with chronic heart failure (CHF) due to left ventricular systolic dysfunction, contributing to reduced exercise capacity and perception of dyspnea during daily activities. Inspiratory muscle training (IMT) using the threshold device is the most powerful intervention available to attenuate IMW. In our laboratory, we conducted a randomized, placebo-controlled trial, with blind evaluation of end-points on the effects of IMT in patients with CHF and IMW (Dall'Ago et al. J Am Coll Cardiol 2006;47:757-63). Following a protocol in which patients used the threshold device set at 30 % of PImax for 30 minutes, 7 sessions per week, for 12 weeks, PImax improved by 115 %, O2 peak increased by 17 %, and quality of life scores as well as 6-minute walk distance also improved. Moreover, variables with known prognostic impact in heart failure (Ribeiro et al. J Cardiopulm Rehabil 2006;26:63-71), such as ventilatory efficiency, oxygen uptake efficiency slope, and ventilatory oscillations during incremental exercise as well circulatory power and oxygen uptake kinetics during recovery also improved after IMT (Stein et al. J Cardiopulm Rehabil, in press, 2009). Recently, we have randomized patients with CHF and IMW to a 12-week program of whole-body aerobic training or to IMT plus aerobic training (Winkelmann et al. Submitted to publication, 2009). Both interventions improved PImax, but the addition of IMT to aerobic training resulted in significantly larger improvements in PImax, O2 peak, peak circulatory power, ventilatory efficiency, oxygen uptake efficiency slope, and recovery oxygen uptake kinetics, as well as in reduction of the relative size of ventilatory oscillations during exercise. We have also shown that, in patients with CHF and IMW, inspiratory muscle loading results in marked reduction of blood flow to resting and exercising muscles and that IMT improves blood flow under inspiratory loading in these patients (Chiappa et al. J Am Coll Cardiol 2008;51:1663-71). Moreover, the improvement in PImax strongly correlated with ultrasonographic-detected diaphragm hypertrophy. Therefore, patients with CHF and IMW have an abnormal activity of the inspiratory muscle metaboreflex and IMT may improve blood flow to exercising muscles, with possible consequences to exercise performance. Our findings suggest that routine screening for IMW may be performed in patients with CHF and that training programs may be recommended for those with IMW (Ribeiro et al. Curr Heart Fail Rep 2009, in press).

■パネルディスカッション：The difference between cardiac and respiratory rehabilitation

Outpatient, phase III cardiac rehabilitation has been extensively studied by randomized clinical trials (Moraes and Ribeiro. In Frontera, Dawson and Slovik. Exercise and rehabilitation medicine. Human Kinetics, 2006). In-hospital phase I cardiac and pulmonary rehabilitation are usually offered to patients submitted to coronary artery bypass surgery (CABG) in an attempt to reduce postoperative complications such as atelectasis, pleural effusion, pneumonia, and atrial fibrillation. However, a recent systematic review concluded that the usefulness of postoperative respiratory physical therapy for the prevention of complications after CABG remains unproved. Our group has recently evaluated the role of cardiopulmonary pre- and postoperative rehabilitation in patients submitted to CABG. The effect of postoperative incentive spirometry and expiratory positive airway pressure was evaluated by Haeffener et al (Am Heart J 2008;156:900.e1-8). In this randomized trial, the pulmonary physical therapy resulted in faster recovery of inspiratory muscle strength, lung function, and functional capacity after CABG. In another small randomized trial, we have shown that a 7-day postoperative cardiopulmonary rehabilitation attenuated the reduction in inspiratory muscle strength and also improved the recovery of functional capacity after CABG (Stein et al. Arch Phys Med Rehabil, in press, 2009). Our findings were compatible with the notion that inspiratory muscle strength is an important determinant of functional capacity after CABG. Finally, we randomized 56 patients who had to wait for CABG in-hospital to a program of pre- and postoperative cardiopulmonary rehabilitation or to no intervention (Herdy et al. Am J Phys Med Rehabil 2008;97:714-9). Patients who received the cardiopulmonary rehabilitation had shorter time to endotracheal extubation, a reduced incidence of pleural effusion, atelectasis, pneumonia, and atrial fibrillation. Length of in-hospital stay after surgery was also reduced. Therefore, the recent experience of our institution underscores the need for large randomized clinical trials with hard endpoints to evaluate the contribution of each of the components of phase I cardiopulmonary rehabilitation in patients submitted to CABG.

Hugo Saner
Professor of Medicine
Director of Cardiovascular Prevention and Rehabilitation, University Hospital of Bern, Bern, Switzerland

■プレナリーセッション：An overview of the situation of cardiac rehabilitation in Europe

The main challenge for prevention and rehabilitation in patients with cardiovascular disease in Europe is the fact that the number of patients with hospital discharge for cardiovascular disease is constantly increasing due to the growing number of the aging population. Another challenge is the fact that unhealthy lifestyle habits including lack of physical exercise, unhealthy nutrition and psychosocial stress lead to early manifestations of vascular damage even in young Europeans with the consequence of a growing number of patients with diabetes and vascular damage. In addition, we see a concealed levelling of mortality rates among young adults indicating that due to unhealthy lifestyle we have to expect an increasing number of younger participants in our rehabilitation programmes.

40 European national societies are member of the European Society of Cardiology and have been asked to fill in a questionnaire in regard to cardiac rehabilitation in their countries in 2008. The responsibility for cardiac rehabilitation is with national organisations in 36.8%, with working groups in 36.8% and there are no such organisations or working groups in 26.4% of the countries. One third of the countries have a national position paper available and in two thirds of the countries, national guidelines exist. In regard to the programmes offered, there is a wide variety. 80% indicate that they have a phase I in hospital programme, more than 90% indicate that they have phase II outpatient programmes and about 65% have phase II inpatient programmes. Home-based programmes are offered in 40% of the countries. A long-term phase III maintenance programme is offered in 87% of the countries. The typical duration of phase II is 3-12 weeks for outpatient programmes and 6-52 weeks for home-based programmes. The estimated percentage of eligible patients admitted for phase II and III cardiac rehabilitation programmes varies from 3% to 90%. In two thirds of the countries, the government or ministry of health is covering the costs for cardiac rehabilitation, in one third of the countries, there are private health insurance companies and in a few others some particular forms of financing the programmes. Most patients are after acute coronary syndrome, myocardial infarction or after coronary artery bypass surgery. Many other indications are also covered. In most countries, the overall responsibility for phase II cardiac rehabilitation is with the cardiologists, whereas in the UK it's with specialised nurses.

In conclusion, a wide spectrum of cardiac rehabilitation programmes is currently offered in Europe. Regular inventories and a process for continuous education, quality control and accreditation should improve the situation considerably within the next few years.

■シンポジウム：Rehabilitation after implantable cardioverter-defibrillator (ICD) implantation

Sudden cardiac death is the leading cause of cardiovascular death and can be prevented by ICD implantation in selected patients. Indications for ICD implantation include previous cardiac rest, left ventricular ejection fraction < 35%, severe heart failure, family history of sudden unexpected death and the presence of medically or invasively not controlled serious rhythm disturbances. Although, implantation relieves much of the fear of sudden death and is welcome by patients, it also imposes new fears and has its own set of negative consequences, so that the overall effect on psychological health is largely neutral.

Comprehensive cardiac rehabilitation improves the physical and psychical situation of the patient and cognitive behavioural therapy further improves the psychical situation. There is one randomised controlled trial with comprehensive cardiac rehabilitation for ICD patients published in HEART. Exercise tolerance improved with exercise training, whereas anxiety and depression decreased during a 12-week rehabilitation period. In particular, cognitive behavioural therapy has shown to be effective in decreasing anxiety and depression in these patients. There were no serious complications and in particular inappropriate shock delivery by the ICD was rare during exercise training. However, it has to be considered that peak heart rate during exercise has to be below the heart rate at onset of arrhythmias and below the intervention rate of the ICD. Special attention has to be given to young ICD recipients with high rate of device discharges and poor knowledge of cardiac condition or ICD and patients having a significant history of psychological problems, poor social support or increased medical severity or comorbidity.

The ultimate goals of support for ICD patients in the setting of cardiac rehabilitation are to provide patients and their families with education about heart disease, the ICD device, medications and routine hospital testing procedures; to offer emotional support to spouses or family members in a group setting; to provide an opportunity for sharing feelings, experiences and coping strategies; to reduce family member anxiety through clarifying misconception and answering questions and to serve as an adjunct to patient education provided by the cardiac arrhythmia service. If this service provision is combined with a careful exercise training knowing the underlying heart disease, the reason for ICD implantation and ICD programming, cardiac rehabilitation for ICD patients seems to be save and beneficial.

■パネルディスカッション：Challenges for cardiovascular prevention and rehabilitation in Europe

The true challenges in regard to cardiovascular disease in Europe are the following: increase of number of hospital discharges due to cardiovascular disease (CVD) in the aging population and increase in cardiovascular risk factors in childhood and young adults including physical inactivity, unhealthy eating habits, smoking and psychosocial stress with the consequence of a market increase in obesity and diabetes. Therefore, we have to expect an increasing number of elderly patients with particular problems in rehabilitation but also of younger patients with a need for lifestyle interventions. Furthermore, there is growing evidence that prevention should start early in the disease stage before the first event occurs. Screening in intermediate risk patients for subclinical disease will become another challenge for cardiovascular prevention and rehabilitation institutions. During the last 10 years, three surveys in the framework of EUROASPIRE have been performed to evaluate the quality of secondary prevention interventions in European patients. EUROASPIRE III including 76 centres from 22 countries in Europe with a total of 13'935 medical records has shown that large proportions of coronary patients do not achieve the lifestyle, risk factor and therapeutic targets for cardiovascular disease prevention. Cardiac rehabilitation programmes are not universally available and the number of patients included in such programmes after acute cardiac events varies from 3% to 90% between different regions and countries in Europe. To improve the situation, the following steps are planned by the European Association for Cardiovascular Prevention and Rehabilitation:

1. Integrate training in CVD prevention and rehabilitation into medical schools; 2. Integrate training in CVD prevention and rehabilitation into the CORE Curriculum of the European cardiologist; 3. Promote CVD prevention and rehabilitation programmes in all hospitals with acute cardiac care; 4. Promote the development from cardiovascular rehabilitation programmes into integrative modern prevention centres with the goal to have such prevention centres in 80% of European hospitals in 10 years. The modern prevention centre includes all subspecialties and programmes dealing with various forms of cardiovascular disease including patients with diabetes, with peripheral artery disease and with minor cerebrovascular disease, all of them being offered specific ambulatory cardiovascular rehabilitation programmes. Such a hospital-based prevention centre is highly effective because it just needs a coordinator for the various activities in the field of cardiovascular disease prevention already present in most hospitals. The development of such models of prevention centres is a primary goal of today's activities in this field in Europe.

■How to session：How to set up and run an ambulatory cardiac rehabilitation programme: the European way

The goals of cardiac rehabilitation and secondary prevention are to prevent disability resulting from coronary disease particularly in elderly persons and those with physical exertion involved in occupations and to prevent subsequent coronary event, subsequent hospitalisation and death from cardiac cause. There are three preconditions, which have to be fulfilled for an ambulatory cardiac rehabilitation programme: The programme has to be led by an expert cardiologist, the intervention has to be done by a multidisciplinary team, exercise should be a main component of the programme, all risk factors have to be addressed and the programme should have a minimum duration of 12 weeks in patients with cardiovascular disease. There should be structured reporting to the referring physician at the beginning and at the end of the programme with recommendations at the end of the programme in regard to working capabilities, social integration and medical treatment. There should also be a safety programme in case of medical emergencies including defibrillation for ventricular fibrillation. Beside the basic programme, larger centres specialised in cardiac rehabilitation have additional programmes for patients with heart failure, after ICD-implantation and for elderly patients. Many programmes are combined with intervention programmes for patients with diabetes and cardiovascular disease and for patients with peripheral artery disease.

Cardiac rehabilitation can easily be added to any existing cardiovascular department or a clinic for internal medicine in a state or private hospital as an outpatient programme. Several future partners such as colleagues, faculty members, hospital administrators and referring doctors have to be convinced that such a programme is needed. Organisational aspects include: team, location, programme, finances, promotion, evaluation, and quality control. Minimal staff includes cardiologist, physiotherapist, dietician and secretary as permanent members and access to a psychologist, a smoking cessation specialist and a social worker. Locations for the programme can be a gymnasium, a fitness centre, a heated pool or outdoor areas for hiking, walking and bicycling. The basic equipment should include the availability of a 12-lead-ECG, bicycle and/or treadmill ergometer, Doppler echocardiography, chest x-ray and emergency equipment including defibrillator.

Most programmes have a duration of 8-12 weeks and are attended 2-3 times per week followed by a long-term maintenance phase, which is offered once per week for an unlimited time period. Usually, there are at least two different training levels in regard to programme intensity. In some countries, there are position papers or guidelines and in a few European countries, there is also an auditing and quality control system.

Wang Le-min
Professor of Medicine
President, Tongji Hospital, Tongji University
Shanghai, P.R. Chaina

■プレナリーセッション：Cardiac Rehabilitation in Patients with Acute Myocardial Infarction of Infarct-Related Artery Patency----Shanghai Experience

Objective Cardiac rehabilitation program is an essential part of the contemporary care of the patient with cardiovascular disease （CVD）. Guidelines for prescribing aerobic exercise for patients with CVD are available elsewhere, except China. The purpose is to investigate the feasibility and safety of aerobic exercise prescription from the individually-based results of cardiopulmonary exercise test （CPET） and influence of aerobic exercise training for patients with acute myocardial infarction （AMI） after percutaneous coronary intervention （PCI）. Participants and Methods 120 patients with AMI after PCI were divided into exercise group and control group, who finished three times CPET and followed their rehabilitation program for 6 months. Patients in exercise group finished their aerobic exercise therapy from their individually-based aerobic exercise prescription. Results It was feasible and safe to proceed sub-maximal CPET and measure cardiac output（CO） when exercising in patients with AMI after PCI. The abnormal CO response at exercising was found in patients with AMI after PCI, which the CO was maxim when exercising at AT（AT：anaerobic threshold） load and was decreasing after the load was far exceeded the AT load. Oxygen uptake （VO2 ） at AT was the base of individually - based aerobic exercise prescription because VO2 at peak and VO2 at AT diminished progressively with age and the changes were obvious for aerobic exercise intensity. Aerobic exercise therapy increased exercise capacity and improved their function capacity and decreased the slope of VE/VCO2, which recovered normal exercise CO response and improved their life quality. Conclusions Exercise CO response is different in patients with AMI after PCI. AT exercise intensity is safe and scientific and effective, which can improve their exercise capacity and life quality. Aerobic exercise prescription must be individually made from their AT and may be adjusted at 3 months. Aerobic exercise therapy could correct abnormal exercise CO response, which is safe and effective and should be better recommended for patients with AMI after PCI. Key Words: Acute myocardial infarction；Cardiopulmonary exercise test；Cardiac rehabilitation；Anaerobic threshold；Cardiac output；Exercise prescription

Karlman Wasserman
Professor of Medicine, Emeritus, on Recall
Former Chief of Respiratory Physiology and Medicine, Harbor-UCLA Medical Center,
California, USA

■シンポジウム：Exercise Parameters and Prognosis in Left Ventricular Failure and COPD

For an accurate physiological diagnosis and measure of severity of heart and lung diseases, and for determining prognosis, the physiological data need to be optimally displayed. A 9 panel graphical array of 15 critical cardiopulmonary variables, simultaneously displayed on a single page, enables us to distinguish between cardiovascular and pulmonary disorders, and most types of each. In this presentation, I am going to focus on two common disorders that increase in frequency with aging, chronic heart failure (CHF) and chronic obstructive pulmonary disease (COPD). The 9 panels displaying cardiorespiratory variables in patients with CHF show a reduced peak VO₂, an abnormally slow increase in VO₂ relative to increase in work rate, a steepening heart rate-VO₂ relationship, if not receiving a heavy dose of beta-adrenergic blocking drugs, and a reduced and unchanging O₂ -pulse (VO₂ /HR) reflecting a reduced product of stroke volume X arteriovenous O₂ difference. In CHF, the anaerobic threshold is reduced, usually in proportion to the reduction in peak VO₂. This is reflected in an increased CO2 output due to release of CO₂ from bicarbonate buffering of lactic acid. The latter is formed in the cell during anaerobic glycolysis when O2 supply to the exercising muscle doesn't meet the requirement. With more severe CHF, the ventilation-perfusion relationships become uneven, primarily because of uneven reduced perfusion relative to ventilation. This can be quantified, non-invasively, by an increased VE/VCO₂ at the anaerobic threshold. Finally, an oscillatory breathing pattern develops in the more severely impaired heart failure patient. These six , non-invasively determined abnormalities (peak VO₂, peak O2 pulse, anaerobic threshold, VE/VCO₂ at the anaerobic threshold, falling VO₂ /work rate ratio, and oscillatory breathing pattern), characterize CHF. As prognosticators of 6-month survival, these parameters will be presented in the form of Kaplan-Meier plots and odds ratio of survival in a Cox analysis.
Similar CPET analysis will be presented for COPD. While, a reduced peak VO2 as well as abnormal ventilation-perfusion relationships are characteristic of COPD as well as CHF, the breathing reserve and pattern of breathing is abnormal in COPD but not CHF patients. These abnormalities are shown in panel 7 of the 9 panel plot. Other abnormal findings found in COPD during exercise will be discussed in the framework of the 9 panel plot. Data showing peak VO₂ as a good predictor of survival will be reviewed. Differences in exercise performance between CHF and COPD will be discussed.

■特別講演：History of Cardiopulmonary Exercise Testing - Past, Present and Future

The organizers of this conference have given me a very dangerous topic to discuss, "History of cardiopulmonary exercise testing - past, present and future". First the future is not history; it's future-telling. Foretelling the future is only guesswork based on current trends and my personal wishlist. In discussing past history, I am in danger of leaving out some of the major contributors to the current state of cardiopulmonary exercise testing (CPET or CPX). However, I will try to present historical landmarks and factors that led us to the present state of cardiopulmonary exercise testing. I will briefly describe what stimulated me to spend the last 49 years doing research in cardiopulmonary physiology during exercise. I was trained as a physiologist and physician, and was involved, as an investigator, in both circulatory and respiratory physiology. In 1960, I was doing research on the pulmonary circulation under a special NIH fellowship at the Cardiovascular Research Institute at the University of California in San Francisco. Dr. Julius H Comroe, Director of the Institute, invited me into his office and told me that we were undergoing an epidemic in heart disease. He asked me how we could detect heart disease at its earliest stages. I commented that the first evidence of heart malfunction should be during exercise, and the measurements should be to detect when the O₂ delivery by the cardiovascular system did not meet the O₂ requirement, i.e., the definition of heart failure. I thought that the VO₂ at the onset of heart failure was when muscle lactic acid and lactate/pyruvate started to accumulate from anaerobic glycolysis during exercise (Pasteur and Hill). I knew that the lactic acid would be totally dissociated at the pH of the cell and the H⁺ would be immediately buffered by the volatile buffer, bicarbonate (HCO₃). The resulting H₂CO₃ would immediately dissociate into CO₂ and H₂O. The increased CO₂ output, out of proportion to O₂ uptake could be detected in the breath. I was putting together, the scientific contributions of Lavoisier, Pasteur, Avogadro, Hill and the eminent cardiologists who discussed their understanding of heart failure at the American Physiology Society meeting in the early 1950s. Dr. Comroe then asked me to develop the method. I tooled up and obtained the help of WL Beaver, a very talented physicist who worked for Varian Associates in Central research. The first paper reporting exercise gas exchange, breath-by-breath was the outcome, followed by several other major conceptual and practical advances. To counter arguments that skeptics raised, we did many studies with arterial catheters in place to demonstrate that arterial lactate increase during exercise did fit a threshold model and that the accumulating lactic acid was buffered by HCO₃. We did an extensive number of studies on arterial acid-base regulation during exercise and regulation of blood gases in normal subjects and patients. An important event that led to the systematic use of CPET occurred in 1978 when the United States Department of Labor asked us to evaluate about 500 shipyard workers for disability evaluation. This got us extensively involved in clinical exercise testing. It taught us how to recognize the different causes of exercise limitation in patients and what was a normal response relative to age height and weight of the subject. In 1982, we started giving courses in cardiopulmonary exercise testing, twice a year. These courses (Practicums) were attended by cardiologists and pulmonologists and technical staff. Then cardiologists involved in selecting patients for heart transplantation demonstrated in the late 1980s and early 1990s the essential contribution of CPET to the selection process. Since then, there has been a growing application of CPET, reflected in an increased number of scientific reports. I'll conclude my lecture by briefly describing how cardiopulmonary exercise testing might develop in the future.

David A. Wood
Professor of Medicine
Cardiovascular Medicine, National Heart and Lung Institute, Imperial College London,
London, UK

■プレナリーセッション：An overview of the activities of the European Association for Cardiovascular Prevention and Rehabilitation

The mission of the European Association for Cardiovascular Prevention and Rehabilitation (EACPR) is "to promote excellence in research, practice, education and policy in cardiovascular prevention and rehabilitation in Europe" and to play a central role in the European policy agenda of the European Society of Cardiology (ESC). The Association was created over a period of two years and officially formed in 2006 in Athens at our first EuroPRevent Congress. Our membership has grown to over 1,600 (70% European Union) mainly cardiologists, scientists and nurses from university hospitals, and is open to all allied health professionals. EuroPRevent is our annual Congress - the meeting place in Europe for prevention - and following Athens was held in Madrid (2007), Paris (2008) and then Stockholm this year. It was attended by about 1,300 professionals in Stockholm. The next Congress will be held in Prague in May 2010. The journal of the Association, the European Journal of Cardiovascular Prevention and Rehabilitation, was first published in 2005. It is published 6 times a year and is now receiving over 400 papers per annum and has an impact factor which has risen from 1.979 in 2006 to 2.221 in 2007. Our Association provides the scientific, professional and educational leadership for all aspects of cardiovascular prevention and rehabilitation in clinical practice. The Joint European Societies Guidelines on Cardiovascular Disease Prevention, now in their 4th version with the next edition planned for 2011, is our main guideline which sets the priorities for prevention, thresholds for treatment and treatment targets. Position papers on secondary prevention and rehabilitation, and other specialist reports, support this European guideline. The communication, implementation and evaluation of these guidelines through National Coordinators for CVD Prevention is the sole responsibility of the Association and our strategy is based on a "Call for Action" to all National Societies of Cardiology aimed at promoting a heart healthy environment in Europe and the highest standards of preventive and rehabilitative care. The Association also runs education and training programmes on cardiac rehabilitation, preventive cardiology for nurses and allied health professionals, and scientific methods, and is developing a core curriculum and accreditation in preventive cardiology. Finally, the Association also has a political role in supporting the European Society of Cardiology in achieving European Union recognition for and action on cardiovascular prevention.

■パネルディスカッション：Importance of total risk assessment in priomary prevention:experience in Europe

The Joint European Societies Guidelines on cardiovascular disease (CVD) prevention updated in 2007 continue to advocate total vascular risk assessment and management. Asymptomatic individuals who are at high total risk of developing atherosclerotic disease because of (i) multiple risk factors resulting in a ten year risk of > 5% now (or if extrapolated to age 60) for developing a fatal CVD event (ii) markedly raised levels of single risk factors (iii) diabetes mellitus; are all priorities for prevention. The European risk estimation model called SCORE (Systematic Coronary Risk Estimation), based on prospective cohort studies in several European populations, is available for high and low risk countries, and country specific versions are being developed. The risk threshold for more intensive lifestyle intervention and, where appropriate, the use of drug therapies is now defined as > 5% risk of fatal CVD over 10 years. In addition to calculating the total SCORE for an individual the physician has also to take account of other risk factors such as diet, a sedentary lifestyle, central obesity and evidence of dysglycaemia - impaired fasting glycaemia or impaired glucose tolerance. All of these factors further increase total CVD risk. An electronic version of SCORE called HEARTSCORE (www.escardio.org/heartscore) is available on the European Society of Cardiology website and can be downloaded free of charge. The European challenge in CVD prevention is to manage risk factors such as blood pressure, lipids and glucose in the context of total cardiovascular risk. Using this total risk approach ensures treatments are given to those at highest risk and therefore those most likely to benefit. Setting a threshold of total CVD risk at which drug treatments should be considered is not just a function of scientific evidence, but the ability of medical services to deliver care to such patients and their cost.

■教育セッション：Diabetes mellitus and cardiovascular disease prevention in Europe

Diabetes mellitus and cardiovascular disease are seen as two sides of the same coin. People with diabetes have a clustering of risk factors which puts them at high risk of developing cardiovascular disease (CVD), and conversely people with coronary heart disease (CHD) often have diabetes, or other forms of dysglycaemia, either self reported or undetected, which puts them at high risk of recurrent vascular disease and death. The Task Force on Diabetes and Cardiovascular Disease of the European Society of Cardiology and the European Association of Diabetes provide evidence based guidance on diagnosis and management of diabetes and dysglycaemia (impaired fasting glycaemia {IFG} and impaired glucose tolerance {IGT}) in the context of total CVD risk. Diabetes mellitus is a major risk factor for the development of CVD and, for those who've developed CVD, diabetes is a major risk factor for recurrent vascular disease and death. An investigational algorithm is proposed starting with either the diagnosis of diabetes mellitus or CHD. If diabetes is diagnosed it's important to investigate for CHD, or other atherosclerotic vascular disease. ECG, echocardiography and an exercise test are proposed and, if any one of these investigations is abnormal, then referral for a cardiology opinion is advised. Conversely, if CHD is diagnosed an oral glucose tolerance test is proposed to diagnose diabetes mellitus, or IFG and/or IGT. If new diabetes or dysglycaemia is diagnosed then referral to a diabetologist is advised. Management of diabetes mellitus, with or without vascular disease, aims to reduce total CVD risk through lifestyle intervention and the management of other risk factors, principally blood pressure and lipids, not just glycaemic control. Lifestyle interventions through diet and physical activity will reduce the risk of dysglycaemic states progressing to frank diabetes, but once diabetes has developed the emphasis is on blood pressure and lipid management, in relation to cardiovascular outcomes, rather than reducing blood glucose alone. There is no randomized controlled trial evidence that reducing blood glucose will reduce total mortality.

■教育セッション：Hypertension and cardiovascular disease prevention in Europe

Prevention of cardiovascular disease (CVD) requires assessment of total cardiovascular risk and a treatment strategy to reduce all components of that risk including blood pressure. The Joint European Society of Hypertension and European Society of Cardiology guidelines on the management of arterial hypertension are based on this principle of total risk assessment and management. This concept is based on the fact that only a small fraction of the hypertensive population has an elevation of blood pressure alone, with the great majority having other CVD risk factors together with raised blood pressure. Cardiovascular treatment guidelines recognize that if patients have established CVD, or are at high total risk of developing CVD, lifestyle and pharmacological intervention should be given as appropriate to lower blood pressure. European treatment guidelines recommend that systolic and diastolic blood pressure goals for all high-risk patients should be below 140 and 90 mm Hg respectively, while in patients with established cardiovascular disease and diabetes, this target is lower still at < 130/80 mm Hg. The 4th Joint Task Force on European guidelines advocate the Systematic COronary Risk Evaluation (SCORE) system as the model to assess an individual's CVD risk, based on outcome data from large prospective European cohort studies. All CVD risk estimation models are based on the same principal; managing blood pressure in the context of total CVD risk. Initial blood pressure treatment strategies should address modifiable lifestyle characteristics that are known to contribute to raised blood pressure and increased CVD risk, e.g., an unhealthy diet high in saturated fat and salt, excessive alcohol consumption, and a sedentary lifestyle. It is important for the physician to encourage patients to be more committed to changing their lifestyle, and to monitor progress through regular follow-up sessions. Secondly, drug treatments to further lower blood pressure, and also modify lipids and glucose, to defined targets are required. Two or three anti-hypertensive drugs are usually required to achieve blood pressure targets and combination therapies will help to improve adherence to treatments over the longer term.