CPET in heart failure
a Charité Medical School, Director Dep. Int. Medicine, ukb academic teaching hospital, Warenerstr. 7, D 12683 Berlin, Germany
b Dep. Int. Medicine, ukb academic teaching hospital, Warenerstr. 7, D 12683 Berlin, Germany
Received 3 May 2004; accepted 24 May 2004.
* F.X. Kleber, Charité Medical School, Director Dep. Int. Medicine, ukb academic teaching hospital, Warenerstr. 7, D 12683 Berlin, Germany. Tel.: +49-30-5681-3601; fax.: +49-30-5681-3603
FXKleber{at}ukb.de
Abstract
CPET has gained wide acceptance in CHF for evaluation and quantification of symptoms, for differential diagnosis of dyspnea, for judgement of prognosis, and as a guide to therapy. In this article technical as well as pathophysiological aspects are discussed and the clinical use of CPET in CHF is outlined. Aside from measurement of VO2 new parameters like VE/VCO2 and 
furnish the clinician with helpful information for diagnosis and treatment.
Key Words: Exercise testing (in) heart failure • Dyspnea • Prognosis • Symptoms
Exercise testing in heart failure
Exercise testing has been performed in clinical medicine for a very long period of time. Initially ventilation was studied, later on interpretation of exercise capacity and ECG alterations became the main interest. In the context of heart failure, the method to assess exercise capacity is primarily the evaluation of functional assessment by detailed patient history and the adjudication to a functional class according to the New York Heart Association (NYHA). Recently, the 6-min-walk-test has found considerable interest among investigators, however it does not correlate with other methods to assess exercise capacity like NYHA-class, VO2AT and VO2max1 and predicts survival less precise than NYHA-classification.2 Cardiopulmonary exercise testing (CPET) was initially used to measure peak oxygen consumption, e.g., in sports medicine. Today, it is much more sophisticated and a variety of parameters is used to derive physiological or pathophysiological information beyond the measurement of oxygen uptake.
Quantification of symptoms
In heart failure, the predominant symptoms are fatigue and dyspnea. Fatigue is largely caused by reduced exercise cardiac output, which correlates very closely to oxygen uptake, and by muscular training condition, which again closely correlates with muscular aerobic capacity. CPET measures overall oxygen uptake, in which uptake in the lungs, transport in the blood and metabolism in the peripheral musculature is involved. Thus, several reasons for fatigue like oxygen uptake deficiencies, low cardiac output and low peripheral metabolic capacity contribute to CPET findings in patients with fatigue.
Dyspnea is mainly felt if there is inadequate high ventilatory requirement for the amount of external work caused, e.g., by early anaerobiosis or by malperfusion of ventilated parts of the lung (see below). In addition breathing rate and breathing pattern have major influence on dyspnea.
Technical aspects
Measurement of gas exchange is done breath by breath and the result is almost simultaneously displayed on a computer screen by rapid computer processing and by correction for the time delay from expiration to measurement. Oxygen is usually measured either by the circonium diode or paramagnetically and CO2 by infrared spectroscopy.
The most widely used exercise protocol is the modified Naughton-protocol.3 This is an incremental exercise test on a treadmill with 2-min stages and increments in both gradient and velocity simulating increments of about one metabolic equivalent (approximately 3.5 ml O2xkg–1xmin–1). However in some relatively mild heart failure patients this protocol takes a long exercise time. An exercise test duration of 10–15 min is generally considered optimal and therefore in some cases a Bruce-protocol might be preferable. Moreover, instead of treadmill testing bicycle ergometry may be used, predominantly using a ramp protocol, with an exercise duration of 10–15 min. All tests are done as maximal exercise tests until exhaustion. However, submaximal parameters are at least as important. In addition percutaneous measurement of oxygen consumption is performed, usually via the ear-lobe.
Repeated daily calibrations and proof of tightness of face masks with no air leaking during maximal respiration as well as the familiarity of patients with the exercise situation are very important aspects of CPET.
Pathophysiological aspects
The peak VO2, which is achieved during maximal exercise is defined as VO2max. Though usually no real plateau exists at the end of a maximal effort there is a flattening of the oxygen uptake while VCO2 continues to rise. The last 30 seconds' average is the best averaging method to avoid noise in this measurement. Though there is considerable sex and age dependence of oxygen uptake the normalisation of oxygen uptake to percent of predicted oxygen uptake is not clearly better than the maximal oxygen uptake itself. This might be explained by a critical value of oxygen uptake that is necessary at any age and for both gender. VO2AT occurs at 55–75%4 of maximal oxygen uptake and the more severe heart failure is the closer it comes to the maximal uptake.
The best way to determine the VO2AT is the V-slope-method.5,6 To improve the validity of VO2AT-determination the sudden rise in VE/VO2 and in 
at this point is used. It signals, that additional CO2 is produced from buffering of lactate by bicarbonate. The additional drive of ventilation by this CO2 production renders ventilation less efficient as to O2 uptake and as to alveolar O2 disappearance.
VE/VCO2 nadir occurs around the anaerobic threshold, where the maximal ventilatory efficiency is reached. VE/VCO2 changes occur through uneven distribution of perfusion relative to ventilation (focal or areal alveolar hypoperfusion being the primary pathophysiology), by an increase in anatomical dead space through low tidal volumes, by a decreased 
set point, e.g., in acidosis, by disturbances of diffusion, by the activation of putative muscle ergoreceptors (alveolar hypoperfusion being a secondary phenomenon, a theory not clearly proven so far).7 The primary pathophysiology in CHF however is the uneven distribution of perfusion and ventilation.8,9 If the VE/VCO2-relationship is looked at as the steepness of the VE vs VCO2-slope, the final part of exercise, when acidotic drive further increases ventilation has to be excluded.9 In this case, the strict linear relationship of VE and VCO2 leaves linearity in the final part of exercise.
and 
are additional parameters to judge ventilatory efficiency. The alveolar partial pressure of CO2 represented by the endtidal partial pressure of CO2 is being compared to arterial 
. Usually the difference between arterial and entidal is very small. At rest, however, there might be a considerable difference of up to 7 mm caused by underperfusion of the apical parts of the lung due to the low pulmonary artery pressures. This is not the case in pulmonary arterial hypertension. In well-trained subjects and in patients with peripheral obstructive pulmonary disease might very well increase beyond , in athletes by the high CO2-inflow from venous blood, in chronic obstructive lung disease by trapping of air with large partial pressure.
Normal values
We refer to the normal values that have been published in the European Journal of Applied Physiology by Habedank et al.10 and normalise oxygen uptake for sex and age. In this paper, also the sex and age dependency of VE/VCO2 is described, as well as breathing reserve. While breathing reserve on average is 40% at the end of exercise (one standard deviation 10%), it is neither sex nor age dependent. Ventilatory efficiency is lower in women (VE vs. VCO2 is higher) and only to a small amount sex- and age-dependent. VO2 – as pointed out earlier – is very much sex and age dependent. For clinical use of cardiopulmonary exercise testing a normalization to sex and age adjusted values is not necessary, however, for determination whether heart failure is the reason of the patient's complain it might be useful (as well as for giving expert opinions in answering legal or insurance questions).
Parameters helpful for clinical assessment of heart failure
For clinical use, both VO2 max and VO2AT are used to assess symptomatic and prognostic status. As outlined above sex and age normalization has been shown to be of advantage in some reports,11 but this is not consistent in all publications. VE/VCO2 measures ventilatory efficiency while VE/VO2 measures ventilatory requirement in relation to oxygen uptake. Clinically, ventilatory efficiency as derived from VE/VCO2 is more important than VE/VO2, since it provides important information on pulmonary function. The expression of ventilatory efficiency either as the nadir of VE/VCO2 ratio or as the slope of the VE vs VCO2 relationship gives a similar information. Clinical useful upper normal values are 30 for the VE/VCO2 ratio and 35 for the VE/VCO2 slope.
and have to be included in any CPET for comparison of entidal gas pressures in the alveolar air versus arterial blood. Arterial gas is usually substituted with hyperemic capillary earlobe blood.
MVV is measured as FEV1x4112 and is important to be compared with achieved maximal ventilation. If more than 42% of MVV at AT or more than 80% at maximal exercise is used pulmonary mechanical limitation is likely.13
O2 pulse is calculated as VO2/HR and is used to see an early levelling off of the increase in stroke volume which is seen mainly in pulmonary hypertension and in ischemic left ventricular dysfunction.
Classification systems
Classification systems to categorize the patients have been proposed.3 However, since all the mentioned parameters are continuous variables it is not useful to use cut off points or categorizations instead of reporting just the measured values. A cut off for VO2 max of 12, 14 or 16 is similar useful to judge the prognosis of patients.14 On the bases of CPET results it is possible to compare the prognostic results of the proposed therapy (e.g., HTX with the natural history or other proposed therapeutic options).
Measurement of symptoms
As outlined before fatigue closely correlates to oxygen uptake. Therefore VO2AT and VO2 max represent in large the exercise capacity and the clinical symptom of fatigue in heart failure.
The measurement of dyspnea is more difficult, as dyspnea is a more complex sensation. Very important for correct judgement of pathogenesis of dyspnea is to consider breathing reserve in order to rule out contributions of mechanical pulmonary limitation, to judge whether arterial hypoxia occurs and of course to measure the absolute amount of ventilation and to normalize it to gas exchange, especially to VCO2. The almost unanimously found clinical symptom of dyspnea in pulmonary hypertension very closely correlates to the almost always reduced ventilatory efficiency.
Judgement of prognosis
VO2max as prognostic parameter has been proposed by a large number of investigators, the database of Myers14 being the largest one. The supplementation of VO2 max by hemodynamic parameters15 or by systolic blood pressure16 or simply by VO2 AT17 or by VE vs VO2slope18 improves prognostic information considerably and should be done in all cases. Recently additional prognostic information is derived from BNP measurements19 and the combination of BNP and VO2 (max or at AT) and VE/VCO2 (ratio or slope) is probably at least as good as any other prognostic multifactorial score to judge prognosis in heart failure.
Information about concomitant diseases
In heart failure patients lung disease and pulmonary embolism are often accompanying heart disease and are contributing to symptoms. CPET offers simple and easy parameters to judge the contribution of these diseases in giving information on pulmonary mechanical limitation, on hypoxia under exercise and on pulmonary ventilation perfusion mismatch. Thus it has been shown by our group,20 that similar increases in VE vs VCO2 slope in patients with acute and chronic pulmonary embolism and primary pulmonary hypertension have different pathophysiologies with a large difference in acute pulmonary embolism and hyperventilation with low and values in PPH, the patients with chronic pulmonary embolism showing findings in between these two (see Table 1). Thus not only the presence of pulmonary artery hypertension can be found in CPET, but also clues to the underlying pathophysiology are given.
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CPET as guide to therapy
Recently cardiac resynchronization therapy has been shown to be extremely useful for treatment of congestive heart failure. Its benefit is readily measured by CPET (see Table 2).
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Many drug therapies have shown less benefits in CPET and some investigators have questioned the likelihood to show benefit of medical therapy with CPET parameters. However, institution of medical therapy in decompensated heart failure also leads to massive improvement of oxygen uptake and ventilatory efficiency.8,9 Furthermore, in mild heart failure the improvement in exercise capacity is neither of great clinical importance nor is it as impressive as in severe heart failure.21
Unsolved questions
Controversies in exercise testing in heart failure still exist as to the type of exercise test (walk test, bicycle), the type of exercise protocol (Naughton, Bruce etc.), the parameters to measure and the usefulness of cut off points, furthermore as to normalization for bodyweight and sex. The usefulness of serial tests to further judge survival after improvement through medical therapy is not studied sufficiently. New parameters as O2 response time, O2 recovery time, the importance of periodic breathing and sleep apnea and the estimation of VO2max from submaximal parameters are fields that are being investigated currently.
Conclusion
Well adapted and recognised applications for measuring exercise ventilation and gas exchange in heart failure include the evaluation of prognosis, the objective assessment of exercise capacity, the indication for heart and heart lung transplantation, the differential diagnosis of dyspnea, the assessment of resynchronization therapy, the monitoring of therapy in severe heart failure. Measurement of VE/VCO2 is superior to VO2max measurement in patients limited by angina and motivation. Further useful fields include the diagnosis and differential diagnosis of heart failure and pulmonary hypertension, the judgement, which pathophysiology mostly contributes to dyspnea and/or to pulmonary hypertension and also the therapeutic monitoring in right heart failure.
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