Cardiopulmonary exercise testing in cardiovascular disease

INTRODUCTION — 

While most exercise tests are designed to assess for myocardial ischemia, cardiopulmonary exercise tests (CPET) are primarily conducted to assess for the cause of exercise limitation and to quantify the degree of cardiopulmonary fitness. This review will discuss the clinical aspects of CPET and the physiologic basis of select CPET measures. (See "Exercise capacity and VO2 in heart failure".)

The approach to differentiating cardiac and pulmonary exercise limitations is discussed in detail separately. (See "Cardiopulmonary exercise testing in the evaluation of unexplained dyspnea", section on 'Using CPET to determine the cause of dyspnea'.)

The principles of exercise physiology are discussed separately. (See "Exercise physiology", section on 'Organ system-specific roles in exercise performance'.)

CLINICAL APPLICATIONS

●Differentiating between cardiac and pulmonary exercise limitation – CPET can be used to differentiate between a cardiac, pulmonary, or combined cause of exercise limitation or dyspnea. In practice, such differentiation can be useful when considering the likelihood that an intervention will improve exercise tolerance or whether another disease may limit the efficacy of the planned intervention. For example, in patients with heart failure (HF) and chronic obstructive pulmonary disease, transplantation may not improve exercise capacity if there is a pulmonary limitation to exercise. (See "Cardiopulmonary exercise testing in the evaluation of unexplained dyspnea", section on 'Using CPET to determine the cause of dyspnea'.)

●Discrepancy between symptoms and objective findings – In patients whose symptoms do not correlate with other clinical information (eg, New York Heart Association (NYHA) class III symptoms despite mildly abnormal left ventricular function), CPET can provide an objective measure of exercise capacity that can be compared with expected values [1,2]. The traditional NYHA classification (table 1) of functional impairment in HF does not always correlate with exercise measures because it is based on the patient's symptoms rather than on objective measurements. In patients likely to adapt to the exercise limitation imposed by their disease (eg, complex congenital heart disease), formal exercise testing may reveal exercise limitations not perceived as abnormal by the patient.

●Evaluation for heart transplantation – In patients with HF in whom the severity or etiology of symptoms is unclear or in whom the prognostic information from CPET testing would be helpful, CPET is indicated. A reproducible maximum oxygen consumption (VO₂max) of less than 10 to 12 mL/kg per min suggests the presence of a poor prognosis, in which transplantation is likely to improve symptoms and prolong survival. (See "Heart transplantation in adults: Indications and contraindications".)

●Assessing response to therapy – Exercise testing can be used to evaluate the response to therapy in selected patients in whom CPET measures may alter therapeutic decisions or inform prognosis [3]. CPET measures have been used extensively as a surrogate for exercise capacity in research settings [4].

●Evaluate capacity to perform occupational work – Evaluation of exercise capacity when indicated for medical reasons in patients in whom the estimates of exercise capacity from other forms of evaluation (eg, treadmill time) are unreliable.

PATIENT PREPARATION

Medication management — In patients who will undergo CPET to assess exercise tolerance in the presence of current medical therapy, medications are typically continued at their current schedule.

Pacing — In patients with a pacemaker, the pacemaker should be set to provide rate responsiveness to avoid a heart rate limitation during exercise, and, for most patients, a treadmill test is preferred. In patients with a pacemaker without rate-responsive features programmed on or not available, the patient's exercise may be limited by heart rate. In addition, pacemakers are most sensitive to the motion of walking or running, which suggests that walking or running exercise stress may provide a more accurate measure of exercise tolerance. A cycle test may not stimulate the rate-responsive feature on some pacemakers.

EXERCISE PROTOCOL

Selecting an exercise protocol — The indication for the exercise test and the functional capabilities of the patient determine the choice of protocol:

●Cycle-ergometer testing – Cycle-ergometer testing has certain advantages over treadmill testing that include:

•Patient stability on the cycle facilitates easier measurement of blood pressure and electrocardiogram (ECG).

•Less balance is required to perform on a cycle, which may have advantages in groups of patients unable to safely walk on a treadmill. For severely impaired patients with HF, the initiation of treadmill walking requires a relatively large fraction of their total exercise capacity, especially for patients with obesity. For that reason, cycle-ergometer exercise using small power increments may be preferable in patients with obesity or severely impaired patients with HF.

The limitations of cycle-ergometer testing include:

•The rate of workload progression needs to be determined based on the patient's reported level of physical activity and clinical status. If the workload increments are too large, exercise effort may terminate before the patient reaches their true maximum effort, which will result in an underassessment of the maximal exercise capacity. Some authorities suggest that the optimal exercise duration for functional assessment on a bicycle is between 8 and 17 minutes [5].

•Cycle exercise may not stimulate the rate responsiveness feature of some pacemakers, which could lead to an underestimate of exercise capacity. (See 'Pacing' above.)

Cycle work is quantified in watts or in kilopond meters per minute (kpm/min; 1 watt equals approximately 6 kpm/min). In the first two minutes of the study, cycling is performed without resistance, followed by an increased ramping rate that typically ranges between 5 and 30 watts per minute depending on the patient's baseline physical shape until maximal exertion is reached.

●Treadmill testing – Treadmill testing exercises more muscles due to the requirement for upright posture and balance and typically results in a maximum oxygen consumption (VO₂max) that is 5 to 10 percent higher than cycle-ergometry [6]. In addition, treadmill testing is more likely to provoke rate-responsiveness features in patients with pacemakers. Due to the greater motion of walking or running, blood pressure measurement and ECG measures may be less accurate with treadmill testing.

Several treadmill protocols are used for subjects with heart disease, all combining some degree of combined speed increase and incline gain. The modified Naughton protocol is commonly used for patients with a more advanced stage of disease [7]. As with cycle testing, the rate of work increase needs to be determined based on the patient's clinical status. 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.

Monitoring — The standard monitoring for CPET includes:

●Periodic blood pressure monitoring.

●ECG monitoring.

●Mouthpiece and tubing to measure expired oxygen and carbon dioxide concentrations. This instrument is held in place with headgear. A clip is typically placed on the nose to ensure capture of all expired gas through the mouthpiece.

Cessation of exercise — Symptoms at maximal exercise that typically lead to termination of the exercise effort include muscle fatigue, exhaustion, extreme dyspnea, and lightheadedness. The predominant limiting symptom to exercise may provide a hint as to the etiology of exercise intolerance: patients who describe dyspnea as a limiting symptom more commonly have a ventilatory limitation to exercise, and those who describe leg fatigue or chest discomfort more commonly have a cardiac limitation.

A decrease in systolic blood pressure below the resting pressure is a sign of severe left ventricular dysfunction or severe outflow tract obstruction and is an indication to stop the test immediately. Cardiac arrhythmias are usually not an indication to stop the test unless sustained tachyarrhythmias develop or the clinician monitoring the test feels that further exercise is contraindicated.

Additional monitoring and testing — In selected cases, invasive testing may complement gas exchange measurements:

●Suspected HFpEF – The measurement of filling pressures during exercise, and correlation with exercise level and symptoms, may be helpful in the evaluation of patients suspected of having HF with preserved ejection fraction (HFpEF). (See "Heart failure with preserved ejection fraction: Clinical manifestations and diagnosis".)

●Mitochondrial disorders – In patients with suspected mitochondrial or skeletal muscle disease, periodic sampling of lactate during exercise may help differentiate cardiac from skeletal muscle exercise limitations. Such testing is often used in combination with right heart catheterization to measure cardiac output using the thermodilution method. (See 'Peripheral muscle and mitochondrial disease' below.)

●Suspicion of exercise-induced pulmonary hypertension –  In patients in whom there is suspicion for exercise induced pulmonary hypertension, right heart catheterization while seated or supine may be used to confirm high pulmonary artery pressures.

ASSESSING THE STUDY QUALITY — 

Measures of maximal exercise performance are only valid if a maximal exercise effort was performed in which the anaerobic or ventilatory threshold (VT) and a respiratory exchange ratio (RER) of at least 1.1 was reached:

●Ventilatory threshold – The VT is typically identified by the "V slope" method, which identifies a point at which the concentration of exhaled CO₂ increases relative to oxygen consumed (ie, the slope of the regression line of VO₂ to VCO₂ increases or inflects upward). Other methods for identifying the ventilatory threshold include the time at which end-tidal O₂ begins to rise progressively.

Common etiologies for a low ventilatory threshold include abnormal cardiac response to exercise (HF with reduced or preserved ejection fraction or valvular heart disease), abnormal oxygen extraction by the peripheral muscles (myopathies), or decreased oxygen utilization by the mitochondria (mitochondriopathies). Significant anemia will also cause a low ventilatory threshold. In patients with lung disease and pulmonary limitation to exercise, the ventilatory threshold is typically not reached, as exercise is stopped due to dyspnea before excess lactate is produced.

Physiologically, the ventilatory threshold correlates with an increase in arterial lactate concentration caused by mobilization of glycogen stores from skeletal muscle. At this point, CO₂ production can no longer be fully buffered by sodium bicarbonate.

●Respiratory exchange ratio – Another assurance of a maximal effort is when an RER value (VCO₂/VO₂) exceeds 1.1 at the highest exercise level attained. As the exercise effort continues beyond the VT, the exhaled VCO₂ begins to include washout of body stores of CO₂ in addition to metabolically generated CO₂, so that the RER can thereby exceed the metabolic "limit" of 1.0.

RER values continue to rise after exercise cessation and into recovery due to deep breathing and cessation of oxygen extraction by the muscles (eg, continued anaerobic metabolism), and values should thus be recorded only at peak exercise and not during recovery. Anecdotally, a very low carbohydrate containing diet may prevent the RER from exceeding 1.0 as the result of insufficient glycogen availability.

MEASUREMENTS OF CARDIAC PERFORMANCE

Chronotropic response to exercise — Since cardiac output is based on the product of heart rate and stroke volume, patients whose heart rate does not increase in proportion to the exercise effort may be limited by heart rate.

Heart rate reserve during exercise is best evaluated by the chronotropic index, calculated with the following formula:

This calculation allows the definition of the normal chronotropic response independent of age, resting heart rate, and functional state [8].

An abnormal chronotropic response is defined as a chronotropic index that is <80 percent for the age when not taking antiarrhythmic therapy and <62 percent when on antiarrhythmic therapy.

Patient groups in which chronotropic incompetence may be encountered include those with HF and several types of congenital heart disease including transposition of the great arteries and the Fontan circulation [9]. Chronotropic incompetence has been shown to be present in patients with a more advanced disease state and is associated with overall worse prognosis in HF with preserved ejection fraction and patients with adult congenital heart disease [9-12].

Maximum oxygen consumption (VO2max) — The VO₂max is a measure of systemic fitness as measured by oxygen consumption. It is altered by factors that affect cardiac output, oxygen transportation, or muscle uptake of oxygen. The VO₂max value is normalized to body weight (ie, mL/kg/min) and corresponds to the maximal consumption of oxygen during the exercise effort. The percent predicted VO₂max normalizes the patient's measured VO₂max to values predicted from the patient's age and sex [13].

While there is a wide range of normal values or values that represent decreased cardiopulmonary fitness, values indicative of marked cardiac limitations include VO₂max ≤20 mL/kg/min or <50 percent predicted VO₂max [14]. Specific values used for prognosis in HF are discussed separately. (See "Exercise capacity and VO2 in heart failure", section on 'Use of peak VO2'.)

In patients who exercise to the limits of their ability and whose respiratory exchange ratio (RER) exceeds 1.1, VO₂max is a reliable measure of cardiopulmonary fitness. In patients whose RER does not exceed 1.1 (eg, who stop exercising before reaching an anaerobic threshold), the VO₂max may underestimate maximal oxygen uptake, and other estimates of cardiopulmonary fitness may be more appropriate. (See 'Ventilatory efficiency (VE/VCO2)' below.)

Ventilatory efficiency (VE/VCO2) — Ventilatory efficiency is the volume of ventilation required to eliminate one liter of CO₂. Normal values are <30. A VE/VCO₂ slope >34 to 36 is associated with a higher risk of death or transplantation among ambulatory HF patients and is more closely associated with prognosis than VO₂max [15-17]. One advantage of this measure is that it can be derived in patients who cannot complete a maximal exercise effort. (See 'Assessing the study quality' above.)

It is expressed as a slope, minute ventilation (VE) versus production of CO₂ (VCO₂) in absolute values and is calculated from the ratio of physiologic dead space to tidal volume (VD/VT), the partial pressure of carbon dioxide, and a constant to account for unit conversion. The VE/VCO₂ slope provides insight into cardiopulmonary coupling and function; it correlates with resting and exercise pulmonary hypertension and is inversely associated with right ventricular function in patients with HF [18,19].

Oxygen pulse — The oxygen pulse is a measure that correlates with stroke volume. It is derived by dividing VO₂ by heart rate. The oxygen pulse normally increases with increasing work, and its value plateaus at higher heart rates.

Similar to the VO₂max, values >85 percent predicted are considered normal [14]. In addition, flattening of the O₂ pulse is abnormal and reflects a decrease in stroke volume at higher heart rates or abnormal oxygen extraction by the exercising muscles.

Oxygen uptake efficiency slope (OUES) — In the setting of submaximal exercise effort (nonidentifiable ventilatory threshold, RER <1.1, or both) the OUES is a marker of the relatively high exercise ventilation characteristic of patients with HF. Lower OUES measurements are associated with worse outcomes, although the reference cutoff values for risk are not as well established as those for the VE/VCO₂ slope [20].

Abnormal values of OUES are those below a slope of approximately 1.47. This index measures the slope of the VO₂ in L/min divided by the log of the minute ventilation in L/min throughout the exercise test.

Periodic breathing — The presence of repeating cycles of increasing and decreasing ventilation as workload increases is called "periodic breathing" or "oscillatory breathing" and signifies poor prognosis [21,22]. This pattern is attributed to several factors that are present in advanced HF, including low cardiac output resulting in longer duration of the pulmonary venous oxygenated blood to reach central receptors, low lung volume, and pulmonary congestion [23].

COMMON ETIOLOGIES OF EXERCISE LIMITATIONS

Cardiac limitation — Findings that favor a cardiac limitation include the presence of an identifiable ventilatory threshold, which, as noted above, is frequently absent in patients with severe lung disease, a normal breathing reserve (defined as the ratio of the minute ventilation at peak exercise to the maximal voluntary ventilation obtained at the baseline spirometry) of <0.8, plateauing of the O₂ pulse curve, and leg fatigue as a limiting symptom.

Pulmonary limitation — Dyspnea as a limiting symptom, inability to reach a ventilatory threshold, breathing reserve of >0.8, high heart rate reserve, and inability to decrease the end-tidal CO₂ at peak exercise are findings that favor a respiratory limitation.

Heart failure limitations — Typical CPET findings in patients with HF include reduced peak oxygen consumption (VO₂), elevated ventilatory efficiency (VE/VCO₂) slope, flattened and overall low O₂ pulse curve, and a low oxygen uptake efficiency slope.

Heart rate limitations — Chronotropic incompetence is defined as a chronotropic index of <0.8 in patients who exercise in the absence of rate or rhythm control medications or <0.62 in patients taking such medications. In patients with chronotropic incompetence as the predominant cause of exercise intolerance and reduced maximum oxygen consumption (VO₂max), the O₂ pulse slope is expected to be normal, indicating normal stroke volume augmentation and peripheral oxygen extraction with exercise.

As noted above, patients who are permanently paced should be exercised on a treadmill due to better activation of rate response module with hill strike and arm motion during exercise. (See 'Pacing' above.)

Peripheral muscle and mitochondrial disease — Early occurrence of the ventilatory threshold in patients without known heart disease should raise the suspicion of a mitochondrial or peripheral muscle disease. In patient with known mitochondrial disease or peripheral muscle disease in whom it is important to quantify the predominant source of exercise limitation, an assessment with right heart catheterization, arterial line, and gas measurement can be helpful. Early and rapid elevation of lactate levels during exercise despite increasing cardiac output by thermodilution suggests that the exercise limitation is caused by skeletal muscle dysfunction.

SPECIAL CIRCUMSTANCES

Anemia — Anemia can "mimic" a cardiac limitation to exercise. In patients with low hemoglobin, exercise test results may not reflect cardiopulmonary fitness. There is no accepted method for correcting exercise test results for the degree of anemia.

Congenital heart disease with shunting — In patients with a shunt lesion, pulmonary overflow may cause ventilation-perfusion mismatch and increase the ventilatory efficiency (VE/VCO₂) slope. In patients who underwent a Fontan operation for a congenital univentricular heart defect and lack a pumping chamber to the pulmonary circulation, the VE/VCO₂ slope is typically severely elevated, the O₂ pulse is very flat, and the maximum oxygen consumption (VO₂max) is typically moderately reduced due to underfilling of the left ventricle and elevated filling pressures [24]. In patients with lesions that cause at least moderate pulmonary valve dysfunction (eg, tetralogy of Fallot, pulmonic valve stenosis, truncus arteriosus), the VE/VCO₂ slope can also be elevated due to inadequate pulmonary blood flow during exercise and ventilation-perfusion mismatch.

Pulmonary vascular disease — Patients with pulmonary vascular disease typically have severe exertional dyspnea, reduced aerobic capacity, reduced O₂ pulse, elevated VE/VCO₂ at all times (ie, all phases of exercise and at rest), and desaturation with exercise. As such, the ventilatory threshold is challenging to identify in this group of patients. In patients with advanced stages of pulmonary vascular disease, desaturations and acidosis during exercise may increase the minute ventilation in relation to the VCO₂ and lead to "pseudo-ventilatory threshold."

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".)

SUMMARY AND RECOMMENDATIONS

●Patient preparation

•Medication management – In patients who will undergo cardiopulmonary exercise testing (CPET) to assess exercise tolerance in the presence of current medical therapy, medications are typically continued at their current schedule. (See 'Medication management' above.)

•Pacing – In patients with a pacemaker, the pacemaker should be set to provide rate responsiveness to avoid a heart rate limitation during exercise, and, for most patients, a treadmill test is preferred. (See 'Pacing' above.)

●Exercise protocol – The choice of exercise protocol depends on the patient's exercise limitations, the presence of a pacemaker, and the need for accurate blood pressure and ECG monitoring. (See 'Selecting an exercise protocol' above.)

In select patients, concomitant invasive testing may augment the findings from cycle-ergometry or treadmill testing. (See 'Additional monitoring and testing' above.)

●Study quality – Exercise performance measures are most useful when the patient provides a maximal exercise effort, which generally requires evidence of an anaerobic or ventilatory threshold (VT) and a respiratory exchange ratio (RER) of at least 1.1. (See 'Assessing the study quality' above.)

●Measures of cardiac performance

•Chronotropic response – An abnormal chronotropic response is defined as a chronotropic index that is <80 percent for the age when not taking antiarrhythmic therapy and <62 percent when on antiarrhythmic therapy. (See 'Chronotropic response to exercise' above.)

•Maximal oxygen consumption (VO₂max) – While there is a wide range of normal values or values that represent decreased cardiopulmonary fitness, values indicative of marked cardiac limitations include VO₂max ≤20 mL/kg/min or <50 percent predicted VO₂max. (See 'Maximum oxygen consumption (VO2max)' above.)

•Ventilatory efficiency (VE/VCO₂) – Ventilatory efficiency is the volume of ventilation required to eliminate one liter of CO₂. Normal values are <30. A VE/VCO₂ slope >34 to 36 is associated with a higher risk of death or transplantation among ambulatory patients with heart failure (HF). One advantage of this measure is that it can be derived in patients who cannot complete a maximal exercise effort. (See 'Ventilatory efficiency (VE/VCO2)' above.)

•Oxygen pulse – Similar to the VO₂max, values >85 percent predicted are considered normal. In addition, flattening of the O₂ pulse is abnormal and reflects a decrease in stroke volume at higher heart rates or abnormal oxygen extraction by the exercising muscles. (See 'Oxygen pulse' above.)

•Oxygen uptake efficiency slope – Oxygen uptake efficiency is impaired in patients with HF. Abnormal oxygen uptake efficiency slope (OUES) values are those below a slope of 1.47. (See 'Oxygen uptake efficiency slope (OUES)' above.)

•Periodic breathing – The presence of repeating cycles of increasing and decreasing ventilation as workload increases signifies poor prognosis. (See 'Periodic breathing' above.)

●Common etiologies of exercise limitation – Specific types of exercise limitation are characterized by specific patterns:

•Cardiac limitation (see 'Cardiac limitation' above)

•Pulmonary limitation (see 'Pulmonary limitation' above)

•HF limitation (see 'Heart failure limitations' above)

•Heart rate limitation (see 'Heart rate limitations' above)

•Peripheral muscle or mitochondrial disease limitations (see 'Peripheral muscle and mitochondrial disease' above)

●Special circumstances – Special circumstances that may result in inaccurate exercise test results include:

•Anemia (see 'Anemia' above)

•Congenital heart disease with shunting (see 'Congenital heart disease with shunting' above)

•Pulmonary vascular disease (see 'Pulmonary vascular disease' above)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Frank G Yanowitz, MD, who contributed to earlier versions of this topic review.