The clinical syndrome of heart failure has been investigated so extensively that it may now almost be regarded as a metabolic disorder. Although an initial insult reduces cardiac pump efficacy, the resultant physiological response culminates in complex neurohormonal dysfunction. This has created confusion and prevented the acceptance of a universal definition of cardiac failure. With much current research concentrating on the pharmacological modification of neuro-endocrine imbalance, it is easy to lose sight of the fundamental principles behind heart failure management, namely, to improve cardiac function. In attempting to achieve this, the issues of morbidity and mortality must be addressed jointly; they are not mutually exclusive entities. Discrepant results between mortality studies and changes in exercise capacity have undermined the value of exercise testing. Because a treatment enhances longevity we should not ignore its effect on symptomatic status, and likewise we should not discard a therapy, which improves function because adverse events result in occasional premature deaths. Informed patient choice must exist.
Historically, exercise testing has been quintessential in our understanding and evaluation of heart failure. Peak oxygen consumption remains the best overall indicator of symptomatic status, exercise capacity, prognosis and hospitalisation. Unfortunately, muddling of surrogate and true end-points has confused many of these issues. Improved comprehension may be gained by applying the concept of cardiac reserve which has been described in a variety of heart conditions and used in cardiac failure patients to provide an indication of prognosis and functional capacity.
- exercise testing
- heart failure
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Exercise testing is routinely performed to assess patients with chronic heart failure (CHF) in specialist centres.1-4Combined respiratory gas analysis ensures that physiological parameters are more thoroughly explored and improves test reproducibility. Resting haemodynamics, eg, ejection fraction, correlate poorly with exercise capacity in heart failure patients5 and subjective profiles such as the 6-minute walk test6 are relatively insensitive. Whilst exercise tests are readily available and non-invasive, they are not without limitations and must not be relied upon excessively in the evaluation of therapeutic interventions.
In order to maximise the information available from an exercise test it is necessary to consider both the patient response and the nature of the test undertaken. At present no single exercise test is able to provide complete evaluation of the patient with cardiac failure. The search for such an investigative tool intensifies with the increasing incidence of heart failure,7 despite advances in cardiac management. The objectives of exercise testing in patients with CHF are to improve our understanding of pathophysiological mechanisms, to confirm and quantify symptoms/severity, to predict prognosis and to assess therapeutic success (box FB1). We will discuss each of these points in broad context and more specifically with regard to cardiac reserve, which represents the pumping capability of the heart and measures the difference between cardiac function at rest and during maximal stimulation.
When interpreting the results from an exercise test it is essential to consider the variables illustrated in box FB2. Exercise tests are conducted either on a treadmill or bicycle ergometer. There are considerable variations in national and international opinion as to which is the most appropriate for patients with CHF. Treadmill testing produces a higher peak oxygen consumption in ml/kg/min (VO2), and ventilation threshold due to the greater mass of skeletal muscle used.8 9 However, superior correlation between exercise time and oxygen consumption exists for bicycle testing.8 Submaximal tests such as the 6-minute walk test more accurately reflect daily activity yet have inferior reproducibility and quantitative value. Some investigators support dual maximal and sub-maximal testing.10 Whichever test is adopted, standardisation of the procedure is essential with regard to ambient temperature, humidity, time of day, and time span from last meal. A preliminary test for familiarisation is also mandatory.11
Protocol selection affects the results obtained. Peak VO2varies considerably whilst VO2 at the anaerobic threshold remains reproducible when the same patients complete different protocols.12 Variations in metabolite levels, eg, catecholamines, have similarly been reported during interval exercise of differing intensity.13 It is generally accepted that patients with CHF should be investigated using gentle protocols with small increments in speed and incline.
In selecting an end-point achieved during exercise it is necessary to consider both the value of the information obtained and its reliability. Peak VO2 is recognised as the best criteria of exercise capacity in patients with CHF.14-16 As an objective measure of maximal exertion it is used in the selection of patients for cardiac transplantation,17 as a prognostic indicator,18 and as a marker of success of medical intervention.19 20 Motivational inconsistency and patient distress during maximal testing reduce the efficacy of VO2as an end-point during exercise. Anaerobic threshold has thus been considered as an alternative. The sub-maximal testing required is less stressful and independent of patient motivation. Good correlation with VO2 21 ensures that exercise capacity is still represented. Unfortunately, problems with validation and reproducibility have been elicited by several investigators.22-24 This is thought to be due to erratic respiration25 and delayed peripheral metabolic changes23 in patients with CHF. Poor inter-observer reproducibility and bias arise because of the multiple methods used to calculate the anaerobic threshold.22 Attempts to eradicate this problem using computerised techniques have proved unsuccessful. The combined use of peak VO2 and anaerobic threshold as end points would improve patient evaluation but would permit variable statistical interpretation of results.
Measurement of cardiac output at rest and during exercise enhances the haemodynamic evaluation of a patient with CHF.26 Invasive procedures are impractical for routine use and are not without risk.27 We have validated and described good reproducibility for the non-invasive measurement of cardiac output in a wide range of cardiac patients,28 employing the principles of carbon dioxide rebreathing described by Collier29 and Defares,30 at rest and during exercise, respectively. Good correlation with peak VO2 (r = 0.92, p < 0.001) permits the use of cardiac reserve as an index of functional capacity.28 Other techniques have been described for assessment of contractile reserve and these also correlate with the functional class of heart failure patients.31 32
Many factors are overlooked which can profoundly influence the results obtained from exercise tests. The symptoms reported for termination of a test vary considerably, yet to have achieved ‘true’ maximum, a patient with CHF should be limited by fatigue. A patient experiencing chest pain may in fact be stopping prematurely due to coronary ischaemia. Assessment of anti-failure treatment would thus be inappropriate. Likewise, to ensure that a patient is exercising to an appropriate level, the anaerobic threshold must be exceeded. Failure to achieve this may result from hyperventilation or coincidental pathology, eg, respiratory or musculoskeletal disease. In this respect exercise testing can be of diagnostic value in heart failure by excluding other causes of exertional dyspnoea. Premature test termination also occurs due to supervisor inexperience or poor patient motivation.33 Such errors are improved by repeat testing,10 11 which might account for the observed ‘placebo’ effect seen in large heart failure trials.34
The morbidity experienced by patients with CHF is due to a reduction in functional capacity. The pathophysiological basis for this has been investigated by observing their response to exercise. Alteration in central haemodynamics, ventilation, peripheral circulation, neurohormonal activity and skeletal muscle all contribute to the impaired clinical status. Heart failure has been variously defined in terms of such abnormalities and therefore eliciting them during exercise can be of diagnostic value. Despite our incomplete knowledge, it is the modification of physiological adaptations which forms the fundamental basis for symptomatic treatment in heart failure.
The contribution of central haemodynamics to the physical limitation of CHF patients remains a contentious subject. Although resting and exercise left ventricular ejection fraction (LVEF) do not correlate with peak VO2,5 35 36 it is naive to conclude that abnormalities in cardiac function are not important in determining exercise tolerance. Attenuation of stroke volume increments during exercise in patients with CHF15 without alteration in LVEF, leads to a relative reduction in exercise cardiac output, which is exaggerated by chronotropic incompetence37 and the effect of mitral regurgitation. Accordingly, significant ‘pump failure’ during exertion has been proposed as the basis for exercise intolerance in heart failure.38 39 Significant correlation between maximal exercise cardiac output and peak VO2 demonstrated by several investigators15 35 36 40 adds credence to such a theory. It also explains the increase in arteriovenous oxygen difference during exercise in patients with CHF,41 42 the reduced cardiac output being responsible for decreased perfusion of working skeletal muscle resulting in premature anaerobic metabolism.42 43 Structural and biochemical changes in skeletal muscle44 45 also occur independently from blood flow limitation.46 An alternative theory, whereby peak VO2 correlates with peripheral functional47and vascular responses, has thus been proposed.48 49 Such changes are not uniform throughout muscle groups49 or during different types of exercise47 and further evaluation is required before conclusions can be made.
During physical activity, patients with CHF often experience disproportionate dyspnoea.50 This phenomenon is mediated by a multitude of mechanisms. According to Wasserman and Casaberi these can be classified as shown in box FB3.51 In the context of reduced functional capacity in CHF, the relationship between abnormal respiratory physiological parameters is extremely complex. Ventilatory equivalents for oxygen (VE/VO2) and carbon dioxide (VE/VCO2) are consistently elevated during exercise.15 41 52 53 Reasons for this include an elevation in respiratory rate and a reduction in tidal volume resulting in a proportional increase in physiological and anatomical dead space.15 53 Such excessive ventilation may be attributable to decreased lung compliance,54 55 and the presence of ventilation perfusion mismatch.56 The contribution of lung congestion mediated by J-receptor stimulation,57 is undermined by the poor correlation of capillary wedge pressure and peak VO2.36 40 52 The maintenance of normal arterial oxygenation,40 41 and the fact that only 60–68% of maximal voluntary ventilation is achieved during exercise15 indicate that respiratory abnormalities are not the limiting factors during exertion in heart failure patients.
Classification of patients with CHF according to severity of illness is essential in order to formulate a management strategy. The success of therapeutic intervention must be objectively assessed and the progress of disease monitored. No system presently exists which adequately classifies patients; instead we rely on a combination of subjective and objective parameters. Problems arising from such practice were disclosed by Cowley et al,58 who concluded that “different methods of assessing exercise capability provided different measures of patients' incapacity.”
Subjective evaluation is quick, cost effective and relies on symptomatic information. Widespread use of the New York Heart Association59 (NYHA) system continues despite its poor sensitivity in determination of functional capacity1 2and prediction of prognosis.60 The introduction of detailed questionnaires such as the Minnesota Living with Heart Failure scale,61 and the Yale Dyspnoea Fatigue index,62 was aimed at representation of normal daily activity. Unfortunately, both correlate poorly with objective measures of haemodynamic and ventilatory dysfunction.63
Objective evaluation using exercise tests requires expensive equipment, trained technical staff, and necessitates patient familiarisation. Measurement of peak VO2 enables definitive categorisation of patients according to functional capacity and prognosis.64 Sub-maximal testing produces surrogates of peak VO2 such as anaerobic threshold,21 and the respiratory equivalent for carbon dioxide (VE/VCO2),65 which permit similar classification. Poor sensitivity means that such parameters can only be relied upon when a patient is unable to exercise maximally. Simpler tests measuring distance travelled by a patient in a given time, eg, the 6-minute walk test,6 represent typical symptom-limited activity, costs are low and the need for trained personnel negated. Preliminary testing is, however, still mandatory. Results are of short-term prognostic value66 and represent another surrogate of peak VO2.67 Inferior sensitivity again makes such results an adjunct to, rather than a replacement for peak VO2. It is therefore logical to conclude that maximal exercise testing provides the best form of classification for cardiac failure patients. Because of the good correlation with peak VO2, maximal cardiac output and the derived cardiac reserve have been proposed as alternative measures,39 though further evaluation of sensitivity and specificity are required.
Accurate classification of heart failure is most vital in the consideration of patients for cardiac transplantation. The disparity between referral rates and organ availability demands rigorous scrutinization prior to acceptance. Many criteria therefore require evaluation.68 The ability of a peak VO2 in excess of 14 ml/kg/min to safely permit deferral17 led to the acceptance of this value as a cut-off point. Calculation of per cent achieved of a predicted peak VO2 allows adjustment for age and gender.69 Unfortunately, dissociation between peak VO2 and haemodynamic dysfunction in transplant candidates has forced reconsideration.70 71 A more integrated approach incorporating measurement of exercise haemodynamics has thus been proposed.72
Because of the high mortality associated with CHF,73an indication of prognosis may be the most appropriate measure of disease severity. Assessment of the impact of numerous variables on mortality should help to establish the relative importance of these clinical markers. Since death in these patients can occur suddenly or from progressive heart failure, therapeutic approaches could potentially be targeted at specific mechanisms of death.
Independent prognostic indicators for patients with CHF have been determined from multivariate analysis (box FB4). This list is not exhaustive and it must be emphasised that some indicators are significantly predictive in one study but not in another. Despite the diverse choice, peak VO2 is one the most extensively studied and hence clinically applicable.18 74-76 Thus, patients with a peak VO2 > 20 ml/kg/min have a good prognosis and those with a peak VO2 < 10 ml/kg/min have a severe prognosis. For those patients with an intermediate peak VO2, other indices should be combined to provide a predictive profile. Monitoring of respiratory response to exercise77 and resting haemodynamics78 have been used in just this way.
Measurement of exercise haemodynamics is less frequently performed. In one study by Griffin et al,79peak exercise stroke work index actually proved superior to peak VO2 as a prognostic indicator in patients with ischaemic heart failure and idiopathic dilated cardiomyopathy. Exertional cardiac output response is also an independent predictor in the selection of transplant candidates and is currently being used in combination with peak VO2.72 Independent work showed cardiac reserve to be of significant prognostic value during pharmacological stress in ambulatory CHF patients,80 81 and patients with cardiogenic shock.82 This represents patients with end-stage cardiac failure in whom exercise testing is inappropriate.
The treatment of CHF has huge implications regarding cost and resources. Patients require frequent out-patient follow-up, occasional hospital admission, and complex drug prescriptions. Treatment is aimed at improving both mortality and morbidity. Unfortunately, the results from several large studies assessing the impact of angiotensin-converting enzyme (ACE) inhibitors have created discrepancy regarding these principles. Mortality has been significantly reduced without consistent enhancement of exertional capacity and morbidity.83-86 Swedberg thus questioned the value of exercise testing in assessing the changes that occur as a result of drug therapy.87 Clinical practice adopted from the V-HeFT II study highlighted this point, as the improved exercise capacity sustained due to the hydralazine–isosorbide dinitrate combination was overshadowed by the superior effect of enalapril on mortality.88 Studies purporting similar alterations in exercise capacity have actually been prematurely terminated due to excess deaths in the treatment groups.89-95 An ethical dilemma thus confronts clinicians treating CHF: should we solely aim to reduce mortality at the expense of patient quality of life? Preliminary data suggest that beta-blockers enhance survival in CHF patients,96 yet given in sufficient doses such drugs can actually impede exertional performance.
In order to resolve such issues it is essential to understand the pathophysiologic effects of intervention on the heart and to relate these to functional capability. The heart is a pump, which must impart sufficient hydraulic energy to maintain the requisite level of circulation demanded by the body. Intrinsic myocardial contractility and vascular tone are integral in this, as emphasised by the improvement in functional status brought about by the positive inotropic effect of digoxin in patients with CHF.97Myocardial fibrosis and ventricular dilation result in reduced pump efficacy and consequently clinical heart failure. Increased cardiac myocyte necrosis due to angiotensin II98 and catecholamines99 can thus explain the cardioprotective action of ACE inhibitors and the adverse effect on mortality exhibited by milrinone and enoximone (sympathomimetics). Conversely, the positive inotropic component of the latter two drugs augments the cardiac pump and increases functional capacity. The treatment of end-stage CHF and cardiogenic shock depend on such mechanisms and it is therefore inappropriate to disregard the effect on exercise capacity of drug therapies.
In the evaluation of individual therapies it is essential to standardise patient status prior to randomisation. The objective nature of exercise tests ensures that this is achieved and also allows monitoring of patient morbidity. The inclusion of exercise testing is thus mandatory when designing any study to evaluate treatment of CHF.100
Although treatment of CHF relies heavily on pharmacological therapy, the benefits of physical training should not be overlooked. Mortality studies are at present very sparse; however, the effects of physical training on functional and symptomatic status are well established. Exercise testing has been integral in eliciting the improvement in functional capacity with high-101-103 and low-intensity104 training programmes. Investigation of the pathophysiological basis for such clinical enhancement has relied almost entirely upon exercise testing. A combination of central haemodynamic,102 peripheral,101 and metabolic changes,102 104 105 act together to improve physical performance, whilst respiratory effort is also reduced at a given work load.103
Exercise testing plays an essential and integral role in the evaluation and treatment of chronic heart failure. The concept of cardiac reserve provides further insight into the pathological and clinical mechanisms involved. Non-invasive measurement of cardiac function at rest and during maximal exertion has permitted cardiac reserve assessment in a variety of conditions.