INTRODUCTION — The purpose of this review is to discuss the physiologic basis for functional exercise testing, methodologic considerations, and clinical applications for cardiovascular medicine. Cardiologists have used this technique most often in the evaluation and management of patients with heart failure. (See "Exercise capacity and VO2 in heart failure".)
PHYSIOLOGIC ASPECTS OF EXERCISE — An understanding of exercise physiology and the Fick equation is a prerequisite for appreciating the utility of functional exercise testing. (See "Exercise physiology".)
Aerobic parameters — The Fick equation states that oxygen uptake equals cardiac output times the arterial-mixed venous oxygen content difference. This is usually expressed as follows:
VO2 = (SV x HR) x (CaO2 - CvO2)
where VO2 is the oxygen (O2) uptake, SV is the stroke volume, HR is heart rate, CaO2 is arterial oxygen content, and CvO2 is the mixed venous oxygen content. Oxygen uptake is often normalized for body weight and expressed in units of mL O2/kg per min. One metabolic equivalent (MET) is the resting oxygen uptake in a sitting position and equals 3.5 mL/kg per min.
At maximal exercise, the Fick equation is expressed as follows:
VO2max = (SVmax x HRmax) x (CaO2max - CvO2min)
The VO2max reflects the maximal ability of a person to take in, transport, and use oxygen, and it defines that person's functional aerobic capacity. VO2max has become the "gold standard" laboratory measure of cardiorespiratory fitness and is the most important parameter measured during functional exercise testing. Although some investigators insist that a VO2 plateau occurs at near maximal exercise, this is not always seen. It has been suggested that the term "peak VO2" be used instead of VO2max to define this situation .
●The VO2max response to exercise is linear until maximal VO2 is achieved. In many individuals, there is a plateau at near maximal exercise beyond which the VO2 does not change. Exercise training enables the person to achieve a greater maximal workload and a higher VO2max.
●The heart rate response is linear up to a maximal heart rate that approximately equals "220 beats/min - age." After training, the heart rate is lower at rest and at each stage of exercise, but the maximal heart rate does not change.
●The stroke volume response is curvilinear, increasing early in exercise with little change thereafter. The training effect increases the resting stroke volume and the stroke volume at each workload.
●The a-v O2 content difference widens as the mixed venous O2 content falls since arterial O2 content does not change in normal subjects. The maximal a-v O2 content difference increases after training.
Functional aerobic impairment (ie, exercise intolerance) is defined as an abnormally low VO2max. This can occur with any factor that affects one or more of the four parameters of the Fick equation that determine VO2max: a reduction in maximal heart rate, maximal stroke volume, or maximal CaO2; or an increase in minimal CvO2 (figure 2). As an example, the major factor limiting VO2max in patients with heart failure (HF) is the marked reduction in stroke volume response to exercise with smaller reductions in maximal heart rate and maximal a-v O2 content difference [3-5].
Other conditions that can compromise stroke volume are segmental wall motion abnormalities and valvular stenosis or regurgitation. On the other hand, diseases of the lungs, skeletal muscles, and hematologic system often have a profound effect on VO2max by affecting arterial or mixed venous oxygen content.
Anaerobic parameters — Although there is still considerable debate in the literature concerning the validity of the ventilatory anaerobic threshold (VAT), functional exercise testing often includes such measurements because it is clinically useful in assessing functional impairment in patients with HF [1,4,6,7].
During the initial (aerobic) phase of a progressive exercise test, which lasts until 50 to 60 percent of VO2max is reached, expired ventilation (VE) increases linearly with VO2 and reflects aerobically produced CO2 in the muscles (figure 3). Blood lactate levels do not change substantially during this phase, since muscle lactic acid production is minimal.
During the latter half of exercise, anaerobic metabolism occurs because oxygen supply cannot keep up with the increasing metabolic requirements of exercising muscle. At this time, there is a significant increase in lactic acid production in the muscles and in the blood lactate concentration. The VO2 at the onset of blood lactate accumulation is called the lactate threshold or anaerobic threshold.
In the peripheral blood, almost all the lactic acid is buffered by sodium bicarbonate according to the following reactions:
Lactic acid + NaHCO3 = Na lactate + CO2 + H2O
The excess CO2 produced during the buffering process is added to the aerobically produced CO2, causing expired ventilation to increase more steeply during the later stages of exercise. It is during this phase that exercising subjects begin to experience dyspnea.
Because the change in expired ventilation at the onset of anaerobic metabolism is reasonably well defined, noninvasive methods have been developed to detect this transition . The VO2 at the onset of this ventilatory change is appropriately called the ventilatory threshold (VAT) (figure 3). However, the validity of these noninvasive measures and whether or not a true threshold exists remain controversial.
METHODS OF FUNCTIONAL EXERCISE TESTING — Several different methods exist for measuring ventilation and respiratory gas parameters during exercise. Most clinical systems rely on breath-by-breath analysis techniques because they provide the best measures of the metabolic response to exercise. Functional exercise testing procedures and interpretation are reviewed in a 2010 American Heart Association guide to cardiopulmonary exercise testing .
Gas analysis techniques — Three basic parameters are continuously monitored at the mouthpiece during a breath-by-breath exercise study:
A nonrebreathing valve is connected to the mouthpiece to prevent mixing of inspired and expired air. Oxygen and carbon dioxide gas analyzers are usually incorporated in a "metabolic cart" designed specifically for functional testing. Respiratory volumes are computed by integrating the air flow signals over the time of inspiration and expiration. Breath-by-breath volumes of O2 intake, CO2 output, and expired ventilation are obtained by integrating the continuous variables over the time course of inspiration (for O2), and expiration (for CO2 and expired ventilation [VE]). Average minute volumes are derived from the breath-by-breath data multiplied by the respiratory rate. The gas volumes obtained under ambient conditions are then converted to STPD (standard temperature and pressure, dry) conditions using the appropriate conversion equations.
Exercise test protocols — Many different protocols are used for functional testing (see "Exercise ECG testing: Performing the test and interpreting the ECG results"). The purpose of the test and the functional capabilities of the patient determine the choice of protocol. In evaluating patients with heart failure (HF), both bicycle and treadmill protocols have been used (figure 4).
The rate of workload progression is somewhat arbitrary, although it has been suggested that optimal exercise duration for functional assessment on the bicycle is between 8 and 17 minutes . Bicycle work is quantified in watts or in kilopond meters per min (kpm/min; 1 watt equals approximately 6 kpm/min). The initial workload for patients with HF patients is usually 20 to 25 watts and increased by 15 to 25 watts every two minutes until maximal exertion is reached. Alternatively, the workload can be computer controlled for electronically-braked bicycle ergometers, and a ramp protocol (eg, increasing by 10 watts/min) is often used.
The modified Naughton protocol is recommended for treadmill exercise testing in patients with HF . This protocol is designed to increase the workload by approximately 1 metabolic equivalent (MET) (3.5 mL O2/kg/min) for each two-minute stage.
Patients with heart disease require continuous electrocardiogram monitoring and frequent blood pressure measurements during exercise testing. Hand signals (eg, one to five fingers for perceived intensity and thumbs down to stop) are used by the patient during exercise, since verbal communication is usually not possible with the mouthpiece apparatus.
Symptoms at maximal exercise that result in test termination include muscle fatigue, exhaustion, extreme dyspnea, and lightheadedness. Cardiac arrhythmias are usually not an indication to stop the test unless sustained tachyarrhythmias develop or the physician monitoring the test feels that further exercise is contraindicated.
A decrease in systolic blood pressure below the resting pressure is a sign of severe left ventricular dysfunction and an indication to stop the test. However, many patients with HF fail to significantly increase their systolic pressure during exercise because of left ventricular dysfunction.
Ventilatory anaerobic threshold determination — There are several methods for estimating the ventilatory threshold (VAT) from the respiratory gas data . The VAT or the VO2 at the onset of anaerobic metabolism is visually identified as the onset of a disproportionate rise in VE/VO2 relative to VE/VCO2. This occurs because CO2 production rather than O2 consumption is driving ventilation; a rise in VE/VO2 without a change in VE/Vco2 indicates that ventilation is increasing in parallel with the increased CO2 production that occurs with anaerobic metabolism.
The VAT is usually visually detected from the plotted breath-by-breath data. The VAT can also be visually identified as a disproportionate rise of VCO2 or VE relative to VO2 or a disproportionate rise in end-tidal O2 relative to end-tidal CO2.
Unfortunately, there is considerable inter- and intra-observer variability in the visual detection of the onset of anaerobic metabolism from the breath-by-breath data . To overcome this problem, computer-detection algorithms have been developed to more objectively measure the anaerobic threshold. One successful approach is called the "V-slope method" (figure 5) .
With this method, the breath-by-breath VCO2 data are plotted against VO2, and the computer selects the upper and lower slopes by a least-square linear regression technique. The intersection of the two slopes identifies the anaerobic threshold. One can also visually select the breakpoint from the plot of VCO2 versus VO2 with less ambiguity than when using the ventilatory equivalent data.
CLINICAL APPLICATIONS — The American College of Cardiology/American Heart Association (ACC/AHA) Update of Practice Guidelines for Exercise Testing listed the following indications for ordering a functional VO2 exercise test (table 1) [14,15]:
●Evaluation of exercise capacity and response to therapy in patients with heart failure (HF) who are being considered for heart transplantation. A reproducible VO2max of less than 10 to 12 mL/kg per min is one of the minimum requirements for consideration for transplantation. (See "Heart transplantation in adults: Indications and contraindications".)
●Assistance in the differentiation of cardiac versus pulmonary limitations as a cause of exercise-induced dyspnea or impaired exercise capacity when the cause is uncertain.
●Evaluation of exercise capacity when indicated for medical reasons in patients in whom the estimates of exercise capacity from exercise test time or work rate are unreliable.
A scientific statement from the AHA and a joint scientific statement from the European Association for Cardiovascular Prevention and AHA provide guidance on clinical applications for cardiopulmonary exercise testing, including evaluation of patients with heart failure, unexplained dyspnea, and skeletal muscle disorders [8,16].
The functional VO2 exercise test is a global test of a patient's cardiorespiratory capacity, since it reflects the entire oxygen transport system beginning with the lungs and pulmonary circulation, including the heart, the oxygen-carrying capacity of the blood, the peripheral circulation, and the skeletal muscles. This objective global assessment offers advantages over other methods to assess the severity of HF:
●The traditional New York Heart Association classification of functional impairment in HF is not always accurate because it is based upon a patient's symptoms rather than on objective criteria (table 2) .
●Resting central hemodynamics, such as cardiac index, ejection fraction, and pulmonary capillary wedge pressures do not always correlate well with functional impairment measured during exercise testing .
●The symptoms of exercise intolerance in HF, such as dyspnea on minimal exertion, fatigue, or both, result from a complex interplay of mechanisms originating from both the central and peripheral components of the oxygen transport system. These symptoms are nonspecific and may also be due to medication side effects or other coexisting conditions that may or may not be related to the underlying heart disease.
Thus, the exercise test is often helpful for classifying disease severity for treatment decisions and in the differential diagnosis of exercise intolerance and symptoms of dyspnea and fatigue (figure 2). Knowledge of the factors that can adversely affect the Fick equation parameters and result in a low VO2max combined with the results of functional exercise testing and other ancillary tests (eg, pulmonary function tests) often leads to the correct diagnosis.
Prognosis of heart disease — The parameters obtained during functional exercise testing also have prognostic importance. Several studies have found that ventilatory parameters are better predictors of HF mortality than VO2max [17,18]. In a study of 470 patients, for example, an abnormal elevation in the ratio of peak minute ventilation to CO2 production (VE/VCO2 ≥44.7) was the strongest predictor of death during 1.5-year follow-up .
An enhanced ventilatory response to exercise is a marker of decreased ventilatory efficiency, and is predictive of outcome in patients with preserved exercise capacity. In one study of 123 patients with a VO2max ≥18 mL/kg per minute, the three-year survival was significantly lower in those with a VE/VCO2 >34 (57 versus 93 percent for VE/VCO2 ≤34) . (See "Exercise capacity and VO2 in heart failure".)
Most studies of functional exercise testing in heart failure focused primarily on patients with systolic dysfunction. The prognostic importance of peak VO2 and VE/VCO2 was evaluated in a mixed population of 409 HF patients with both systolic and diastolic dysfunction . Depending upon the definition of diastolic HF that was applied (ie, HF with an left ventricular ejection fraction ≥40, ≥45 or ≥50 percent), the number of patients with diastolic HF and the optimal predictors of outcome varied. However, regardless of which definition was used, both peak VO2 and the VE/VCO2 slope were predictors of one year event-free survival (mortality and cardiac-related hospitalization) in patients with diastolic HF.
An objective grading system that is based upon values of VO2max and the anaerobic threshold has been proposed that is especially applicable to patients with chronic HF (table 3) . Because of the close relationship between VO2max and the maximal cardiac index, the grading system provides an excellent measure of disease severity.
This classification, although widely used, can be criticized because it fails to consider age, sex, and weight differences in VO2max that occur in normal subjects. VO2max declines with age and is lower in women than in men; as a result, it may be more appropriate to use age- and sex-specific normal values and to classify impairment as a percentage reduction from these normal values. Formulas for predicting VO2max in normal sedentary adults have been published for both cycle ergometry and treadmill testing .
Functional exercise testing may have long-term predictive value in patients with coronary heart disease. This was illustrated in a study of over 12,000 men who were referred for cardiac rehabilitation (post-myocardial infarction, post-coronary artery bypass graft surgery, or new ischemic heart disease) . At a median follow-up of 7.9 years, VO2max <15, 15 to 22, and >22 mL/kg per min were associated with adjusted hazard ratios for cardiac death of 1.0, 0.62, and 0.39, respectively; similar values were noted for all-cause mortality. The only other significant predictors of cardiac mortality in the different groups were smoking and digoxin therapy.
It is important that physicians performing these tests understand the different procedures for analyzing and interpreting the respiratory gas data. Knowledge of calibration techniques and equipment maintenance is also an important prerequisite in providing accurate functional assessments in the exercise laboratory. It is likely that the number of exercise VO2 studies will increase in the future as new and innovative therapies for chronic HF become available.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Heart failure in adults" and "Society guideline links: Stress testing and cardiopulmonary exercise testing".)
●The Fick equation states that oxygen uptake equals cardiac output times the arterial-mixed venous oxygen content difference. (See 'Aerobic parameters' above.)
●The VO2max reflects the maximal ability of a person to take in, transport, and use oxygen, and it defines that person's functional aerobic capacity. VO2max has become the "gold standard" laboratory measure of cardiorespiratory fitness and is the most important parameter measured during functional exercise testing. Although some investigators insist that a VO2 plateau occurs at near maximal exercise, this is not always seen. It has been suggested that the term "peak VO2" be used instead of VO2max to define this situation. (See 'Aerobic parameters' above.)
●The major factor limiting VO2max in patients with heart failure (HF) is the marked reduction in stroke volume response to exercise with smaller reductions in maximal heart rate and maximal a-v O2 content difference. (See 'Aerobic parameters' above.)
●The modified Naughton protocol is recommended for treadmill exercise testing in patients with HF. (See 'Exercise test protocols' above.)
●A reproducible VO2max of less than 10 to 12 mL/kg per min is one of the minimum requirements for consideration for transplantation. (See 'Clinical applications' above and "Heart transplantation in adults: Indications and contraindications".)
●The exercise test is often helpful for classifying disease severity for treatment decisions and in the differential diagnosis of exercise intolerance and symptoms of dyspnea and fatigue (figure 2). (See 'Clinical applications' above.)
●An objective grading system that is based upon values of VO2max and the anaerobic threshold has been proposed that is especially applicable to patients with chronic HF (table 3). (See 'Prognosis of heart disease' above.)
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