EACPR/AHA Scientific Statement

Clinical Recommendations for Cardiopulmonary Exercise Testing Data Assessment in Specific Patient Populations

Marco Guazzi, Volker Adams, Viviane Conraads, Martin Halle, Alessandro Mezzani, Luc Vanhees, Ross Arena, Gerald F. Fletcher, Daniel E. Forman, Dalane W. Kitzman, Carl J. Lavie, Jonathan Myers
https://doi.org/10.1161/CIR.0b013e31826fb946
Circulation. 2012;126:2261-2274
Originally published October 29, 2012

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Table of Contents

  • Abbreviations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2262

  • Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2262

  • What Is Cardiopulmonary Exercise Testing?. . . . . . . . .2262

  • Defining Key Cardiopulmonary Exercise Testing Variables. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2263

  • Universal Cardiopulmonary Exercise Testing Reporting Form. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2266

  • Unique Condition-Related Cardiopulmonary Exercise Testing Variables According to Test Indication. . . . . . . . . . . . . . . . . . . . . . . .2266

    • Systolic Heart Failure. . . . . . . . . . . . . . . . . . . . . . . .2266

    • Heart Failure With Preserved Ejection Fraction and Congenital Heart Disease. . . . .2267

    • Hypertrophic Cardiomyopathy. . . . . . . . . . . . . . . . . . .2268

    • Unexplained Exertional Dyspnea. . . . . . . . . . . . . . . . .2268

    • Suspected or Confirmed Pulmonary Arterial Hypertension or Secondary Pulmonary Hypertension. . . . . . . . . .2269

    • Confirmed Chronic Obstructive Pulmonary Disease or Interstitial Lung Disease . . . . . . . . . . .2269

    • Suspected Myocardial Ischemia. . . . . . . . . . . . . . . . .2269

    • Suspected Mitochondrial Myopathy. . . . . . . . . . . . .2270

  • Directions for Future Research. . . . . . . . . . . . . . . . . . .2270

  • Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2270

  • Disclosures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2271

  • Appendixes

  • 1: Universal CPX Reporting Form. . . . . . . . . . . . . . . . . .2271A

  • 2: Prognostic and Diagnostic Stratification for Patients With Heart Failure . . . . . . . . . . . . . . . . . . . .2271B

  • 3: Prognostic and Diagnostic Stratification for Patients With Confirmed or Suspected Hypertrophic Cardiomyopathy. . . . . . . . . . . . . . . . . . .2271C

  • 4: Diagnostic Stratification for Patients With Unexplained Dyspnea. . . . . . . . . . . . . . . . . . . .2271D

  • 5: Prognostic and Diagnostic Stratification for Patients With Suspected or Confirmed PulmonaryArterial Hypertension/Secondary Pulmonary Hypertension. . . . . . . . . . . . . . . . . . .2271E

  • 6: Prognostic and Diagnostic Stratification for Patients With Chronic Obstructive Pulmonary Disease or Interstitial Lung Disease. . . . . . . . . . . . . . . . . . . .2271F

  • 7: Diagnostic Stratification for Patients With Suspected Myocardial Ischemia. . . . . . . . . . . . . . . . . . . . . .2271G

  • 8: Diagnostic Stratification for Patients With Suspected Mitochondrial Myopathy. . . . . . . . . . .2271H

  • References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2272

Introduction

From an evidence-based perspective, cardiopulmonary exercise testing (CPX) is a well-supported assessment technique in both the United States (US) and Europe. The combination of standard exercise testing (ET) (ie, progressive exercise provocation in association with serial electrocardiograms [ECG], hemodynamics, oxygen saturation, and subjective symptoms) and measurement of ventilatory gas exchange amounts to a superior method to: 1) accurately quantify cardiorespiratory fitness (CRF), 2) delineate the physiologic system(s) underlying exercise responses, which can be applied as a means to identify the exercise-limiting pathophysiologic mechanism(s) and/or performance differences, and 3) formulate function-based prognostic stratification. Cardiopulmonary ET certainly carries an additional cost as well as competency requirements and is not an essential component of evaluation in all patient populations. However, there are several conditions of confirmed, suspected, or unknown etiology where the data gained from this form of ET is highly valuable in terms of clinical decision making.1

Several CPX statements have been published by well-respected organizations in both the US and Europe.1–5 Despite these prominent reports and the plethora of pertinent medical literature which they feature, underutilization of CPX persists. This discrepancy is at least partly attributable to the fact that the currently available CPX consensus statements are inherently complex and fail to convey succinct, clinically centered strategies to utilize CPX indices effectively. Likewise, current CPX software packages generate an overwhelming abundance of data, which to most clinicians are incomprehensible and abstract.

Ironically, in contrast to the protracted scientific statements and dense CPX data outputs, the list of CPX variables that have proven clinical application is concise and uncomplicated. Therefore, the goal of this writing group is to present an approach of CPX in a way that assists in making meaningful decisions regarding a patient's care. Experts from the European Association for Cardiovascular Prevention and Rehabilitation and American Heart Association have joined in this effort to distill easy-to-follow guidance on CPX interpretation based upon current scientific evidence. This document also provides a series of forms that are designed to highlight the utility of CPX in clinical decision-making. Not only will this improve patient management, it will also catalyze uniform and unambiguous data interpretation across laboratories on an international level.

The primary target audience of this position paper is clinicians who have limited orientation with CPX but whose caregiving would be enhanced by familiarity and application of this assessment. The ultimate goal is to increase awareness of the value of CPX and to increase the number of healthcare professionals who are able to perform clinically meaningful CPX interpretation. Moreover, this document will hopefully lead to an increase in appropriate patient referrals to CPX with enhanced efficiencies in patient management. For more detailed information on CPX, including procedures for patient preparation, equipment calibration, and conducting the test, readers are encouraged to review other publications that address these and other topics in great detail.1–5

What Is Cardiopulmonary Exercise Testing?

Despite advances in technologies related to diagnostic testing and the popularity of imaging techniques, assessment of exercise responses provides critical enhancement of the evaluation of patients with or suspected of having cardiovascular (CV) or pulmonary disease.6 The measurement of CRF from ET has many clinical applications, including diagnosis, evaluation of therapy, risk stratification, and to guide physical activity. While exercise tolerance is commonly estimated from treadmill or bicycle cycle ergometer work rate, CPX is a specialized subtype of ET that provides a more accurate and objective measure of CRF. CPX relies on the measurement of ventilatory gases during exercise, ie, a non-invasive procedure that involves the acquisition of expired ventilation and concentrations of oxygen (O2) and carbon dioxide (CO2) during progressive exercise. Admittedly, there are potential “patient difficulties” associated with CPX (trepidation with the testing itself, mouthpiece/nose clip/mask difficulties, perception of limits in “air” availability, etc.). However, when added to standard ET, the direct non-invasive measurement of ventilation and expired gases permits the most accurate and reproducible quantification of CRF, a grading of the etiology and severity of impairment, and an objective assessment of the response to an intervention.7,8 Moreover, over the last two decades, a particularly large volume of research has been directed toward the utility of CPX as a prognostic tool; these studies have established CPX as a scientifically sound and therefore clinically valuable method for accurately estimating prognosis in various disease states.1,9,10 As will be described in this document, studies performed on the clinical applications of CPX have had an important influence on the functional assessment of patients with confirmed/suspected CV and pulmonary disease as well as those with certain confirmed/suspected musculoskeletal disorders.

Although still underutilized, CPX has gained popularity not only due to the recognition of its clear value in the functional assessment of patients with CV, pulmonary, and musculoskeletal disease/disorders, but also because of technological advances (eg, rapid response analyzers and computer-assisted data processing) which have made this modality easier to use. Once largely under the domain of the physiologist or specialized center, CPX currently has the potential to be used for a wide spectrum of clinical applications. The basic CPX responses, O2 consumption (Vo2), minute ventilation (VE), and CO2 production (Vco2), are now easily obtainable in time-down spreadsheet format from most systems, providing a platform for straightforward data processing and interpretation. While standard ET has long been considered the gatekeeper to more expensive and invasive procedures (eg, angiography, bypass surgery, transplantation, other medical management decisions), gas exchange measurements during exercise have been demonstrated to enhance the decision-making process. CPX responses have been demonstrated to be valuable in supplementing other clinical information to optimize risk stratification for cardiac transplantation listing, medical device therapy (eg, implantable cardioverter-defibrillator and cardiac resynchronization therapy), consideration for lung resection or lung transplantation, and for a variety of pre-surgical evaluations.1,7,9–13 Because markers of ventilatory efficiency have emerged as particularly powerful prognostic markers, risk stratification paradigms that include these indices have also been proposed in recent years.1,13

Defining Key Cardiopulmonary Exercise Testing Variables14–23

The volume of data automatically generated by the software packages of CPX systems can be somewhat daunting to clinicians who do not have extensive experience with this form of ET. Moreover, the clinical significance of many of these variables, numerically and/or graphically depicted, has not been thoroughly vetted through original research. In contrast, the list of variables most pertinent in current clinical practice, and which are well substantiated by original research, is relatively concise. Key CPX variables, derived from both ventilatory expired gas analysis data and standard ET monitoring, are listed in Table 1. The intent of this table is to identify key CPX variables and to provide only succinct descriptions or their significance and normal values/responses; more detailed accounts are provided elsewhere and the reader is encouraged to review these documents for additional details.1–4,24 Of particular note, aerobic capacity is defined as peak Vo2 as opposed to maximal Vo2 in this document as the former designation is most often used in patient populations with suspected/confirmed pathophysiological processes. All of the variables listed in Table 1 are included in the one-page, universal CPX reporting form (Appendix 1). While some of these variables warrant assessment in all patients undergoing CPX, such as peak Vo2 and the peak respiratory exchange ratio (RER), others, such as the VE/Vco2 slope and exercise oscillatory ventilation (EOV) are condition specific. A more refined identification of condition-specific CPX variables is described in subsequent sections and their respective appendixes. The writing group hopes that this approach improves the ease by which the most pertinent data is identified and utilized by clinicians performing and interpreting CPX. Moreover, the majority of these variables are automatically included in reporting forms generated by current CPX system software packages.

View this table:
Table 1.

Identification and Defining Normal Responses for Key CPX Variables

Depending on system configuration, standard ET measures, such as hemodynamics and heart rate (HR), will either be reported alongside ventilatory expired gas analysis data or reported separately. In either situation, the majority of essential data is readily obtained. O2 pulse and change in Vo2/change in Watt (ΔVo2/ΔW) plots are often generated by customary CPX software systems. If this is not the case, the plots can be easily generated using the exercise data reported in time-down spreadsheet format. Examples of normal and abnormal O2 pulse and ΔVo2/ΔW plots are illustrated in Figure 1.

Figure 1.
Figure 1.

Normal (dashed line) and abnormal (solid line) example of oxygen pulse and ΔVo2/ΔW plots. Vo2, oxygen consumption; W, watts; O2, oxygen.

While VE data are graphically depicted, determination of EOV must be performed manually at this time. Given the importance of determining EOV in heart failure (HF), the writing group anticipates that the presence or absence of this abnormality, according to universally adopted criteria, will be automatically quantified by future CPX system software packages. The most frequently used criteria currently to define EOV are listed in Table 1.16 There is initial evidence to indicate that this set of EOV criteria provides more robust prognostic insight compared with other methods.25 For present clinical applications, the writing group recommends rest and exercise VE data be graphically depicted using 10-second averaged samples. This averaging interval allows for the removal of breath-by-breath signal noise while preventing excessive data smoothing and loss of the physiological phenomena that is brought about by averaging over longer intervals (ie, data used for graphic illustration listed as ≥30 second averaging). A normal ventilatory pattern is contrasted to EOV in Figure 2.

Figure 2.
Figure 2.

Examples of normal ventilatory pattern (top panel) and exercise oscillatory ventilation pattern (bottom panel). VE, minute ventilation.

Lastly, when the additional assessment of non-invasive cardiac output (Q) is performed (eg, CPX for suspected mitochondrial myopathy), the ΔQ/ΔVo2 slope can be easily determined from the ET data in time-down spreadsheet format.

Universal Cardiopulmonary Exercise Testing Reporting Form

The ability to collect all relevant CPX data in a concise and organized manner is essential for meaningful data interpretation and clinical utilization. The universal CPX reporting form included as Appendix 1 provides clinicians with the ability to collect relevant ET data that may subsequently be used for interpretation according to a patient's specific condition/test indication. It should be noted that some of the variables in the CPX reporting form will be collected irrespective of the reason for ET. This includes peak Vo2, percent-predicted peak Vo2, Vo2 at ventilatory threshold (VT), peak RER, HR, blood pressure (BP), ECG and subjective symptom data. To calculate percent-predicted peak Vo2, the writing group proposes using the equations put forth by Wasserman and Hansen,26,27 which are listed in Table 2. These equations account for several influencing factors including body habitus, mode of exercise, and sex. The aforementioned variables are relevant to all patients undergoing CPX because of their ability to universally reflect prognosis, maximal and submaximal functional capacity, exercise effort, and exertional physiology.28,29 The collection of other CPX variables included in the universal CPX reporting form are dictated by test indication and described in subsequent sections and appendixes.

View this table:
Table 2.

Predicted Peak Oxygen Consumption Equations

Unique Condition-Related Cardiopulmonary Exercise Testing Variables According to Test Indication

There are several suspected/confirmed conditions where performance of a CPX would provide clinically valuable information on diagnosis, prognosis, and/or therapeutic efficacy. However, the volume of scientific evidence supporting the value of CPX is heterogeneous across the conditions identified in subsequent sections. While the clinical use of CPX is firmly established in patients with systolic HF and unexplained exertional dyspnea, additional research, to varying degrees, is needed to further bolster support for CPX in the other patient populations identified in this document. This is not to suggest that a clinical justification for CPX cannot be made for each of the conditions listed below. Moreover, the unique condition-related CPX variables proposed for analysis are based on a sound physiological rationale, expert consensus, and current scientific evidence. The writing group feels that, based on expert opinion and currently available evidence, CPX provides valuable clinical information in all of the conditions listed in subsequent sections. Each of the following sections is accompanied by a condition-specific evaluation chart (Appendixes 2–8). These charts include key CPX variables for each test indication in a color-coded format. Responses in the green zone indicate a normal response for a given variable, while responses in the yellow and red zones indicate progressively greater abnormalities. An interpretation, based on CPX performance for key variables, is included at the end of each chart. The intent of these condition-specific charts is to greatly simplify CPX data interpretation, thereby improving clinical utility.

Systolic Heart Failure

The majority of research assessing the clinical application of CPX has been performed within the systolic HF population. Beginning in the 1980's with the landmark work by Weber et al,30 followed in 1991 with the classic investigation by Mancini et al,31 a wealth of literature has been put forth that convincingly demonstrates the ability of key CPX variables to predict adverse events and gauge disease severity.1,7,32,33 Peak Vo2 and the VE/Vco2 slope are currently the most studied CPX variables in patients with systolic HF and both demonstrate strong independent prognostic value. While there is evidence to indicate the VE/Vco2 slope is a stronger univariate predictive marker compared to peak Vo2, there is substantial evidence to indicate that a multivariate approach improves prognostic accuracy.7 Under current medical management strategies, a VE/Vco2 slope ≥45 and a peak Vo2 <10.0 mL O2 · kg−1 · min−1 are indicative of a particularly poor prognosis over the 4-year period following CPX.34 Other CPX variables have emerged in recent years that appear to further refine prognostic resolution. Specifically, EOV and the partial pressure of end-tidal CO2 (PETCO2) during rest and exercise have both demonstrated strong prognostic value in patients with systolic HF.16,35–37 Given these variables are readily available, their inclusion for prognostic assessment purposes is recommended. Lastly, there is some evidence to indicate the assessment of percent-predicted peak Vo2 may provide prognostic information,38–40 although it is not clear if such information supersedes/compliments the prognostic strength measured peak Vo2. Current evidence indicates that a percent-predicted peak Vo2 value falling below 50% indicates a poor prognosis in patients with HF.38 Research assessing the clinical value of percent-predicted peak Vo2 assessment in patients with HF should continue. However, given the disparity in the volume of supporting evidence for the prognostic value of measured peak Vo2 vs percent-predicted peak Vo2, we currently recommend the actual peak Vo2 value being considered in this patient population to gauge disease severity and prognosis. The prognostic and diagnostic stratification chart for patients with systolic HF is provided in Appendix 2. The assessment of peak Vo2, the VE/Vco2 slope, presence/absence of EOV, and rest/exercise PETCO2 should all be assessed. As values for these variables progress to the red zone, disease severity worsens and the likelihood of major adverse events (ie, death, HF decompensation to the refractory stage) becomes increasingly likely. The risk for softer endpoints, such as hospitalization due to HF, is also likely to increase as variables progress to the red zone. With respect to transplant candidacy, peak Vo2 and VE/Vco2 slope values in the red zone should be considered primary criteria for eligibility. Numerous investigations have demonstrated the aforementioned CPX variables respond favorably to pharmacological (ie, sildenafil, angiotensin receptor blockade, angiotensin converting enzyme inhibition), surgical (ie, cardiac resynchronization therapy, left ventricular assist device implantation and heart transplantation) and lifestyle (ie, exercise training) interventions appropriate for patients with systolic HF.7,41–43 Therefore, when CPX abnormalities are detected a review of the patient's clinical management strategy is recommended in order to determine whether titration of current interventions or the implementation of new interventions is warranted. In addition, standard ET variables should be included in the assessment as they may provide further information on clinical stability and prognosis. An abnormal hemodynamic and/or ECG response, as well as an abnormally low HR recovery (HRR) at one minute post-ET and report of unusual dyspnea (ie, 4/4: severely difficult, patient cannot continue17) as the primary subjective symptom eliciting test termination, provide further evidence of poor prognosis and greater disease severity.18,29,44,45

Heart Failure With Preserved Ejection Fraction and Congenital Heart Disease

Several studies are now available that support the use of CPX for gauging the level of diastolic dysfunction and assessing prognosis in patients with HF-preserved ejection fraction (HF-PEF).46–48 The VE/Vco2 slope and EOV both appear to hold the prognostic value in patients with HF-PEF at a level comparable with that found in patients with systolic HF. Moreover, several investigations similarly support the prognostic importance of CPX in the congenital heart disease population.49–51 Even so, additional research is needed in these patient populations to further elucidate the clinical value of CPX. At this time, the writing group recommends the same reporting chart be used for patients with systolic HF, HF-PEF and congenital heart disease (Appendix 2).

Hypertrophic Cardiomyopathy

Cardiopulmonary exercise testing has promising utility in regard to the assessment of patients with suspected/confirmed hypertrophic cardiomyopathy (HCM). Ventilatory expired gas anlaysis during ET can be used to demarcate functional limitations, with diagnostic and prognostic implications. While the 2002 American College of Cardiology/American Heart Association ET guidelines52 cite HCM as a relative contraindication to ET, many investigators have subsequently highlighted that the technique is safe.53–55 Not only can peak Vo2 be used as criterion by which to guide HCM management, it can also serve to distinguish left ventricular hypertrophy (LVH) associated with HCM from LVH stemming from relatively more innocuous etiologies. Athletes may, for example, have physiological hypertrophy induced by physical activity. In this context, CPX can be applied to differentiate physiological hypertrophy from LVH in HCM simply on the basis of ET performance. While athletes achieve peak Vo2's that typically exceed predicted values, only 1.5% of HCM patients have peak Vo2 exceeding predicted values,56 providing a convenient way to help recognize HCM in young adults who may have LVH but who are asymptomatic and have not been diagnosed with the condition. Measures of ventilatory efficiency, specifically the VE/Vco2 slope and PETCO2, may also be valuable in patients with HCM as abnormalities in these variables have been associated with increased pulmonary pressures as a consequence of advanced LVH-induced diastolic dysfunction.57 Moreover, recent evidence indicates aerobic capacity and ventilatory efficiency are prognostic markers in minimally symptomatic patients with obstructive HCM.58 As a provocative exercise stimulus, CPX also provides an important assessment of ECG and hemodynamics. A blunted (≤20 mm Hg increased systolic BP) or hypotensive (exercise systolic BP < resting values) exercise BP response are also common and indicate an increased risk of sudden death.59,60 Moreover, prognostic implications are even worse when abnormal hemodynamic responses are coupled to a low peak Vo2.61 While exercise-induced ventricular arrhythmias are comparatively rare, they may also be associated with high prognostic risks in some patients.62 The prognostic and diagnostic stratification chart for patients with confirmed or suspected HCM is provided in Appendix 3. Given the range of peak Vo2 values is likely to be wide in this patient population, a percent-predicted value, which has recently demonstrated prognostic value in this population,58 should be included in the assessment. A progressive decline in percent-predicted values, from green to red, is indicative of worsening disease severity and prognosis. Abnormalities in standard hemodynamic (ie, systolic blood pressure) and ECG (ie, onset of ventricular arrhythmias) variables, progressing to the red zone, are further indication or worsening disease severity and increased risk for adverse events. As values for the VE/Vco2 slope and PETCO2 progress from green to red, the likelihood of secondary pulmonary hypertension (PH), induced by HCM, is increased.

Unexplained Exertional Dyspnea

CPX possesses the unique ability to comprehensively assess the independent and integrated exertional responses of the CV and pulmonary systems. Moreover, the majority of current CPX systems have the capability to perform pulmonary function testing. Therefore, in patients presenting with unexplained exertional dyspnea, CPX is considered an important assessment to determine the mechanism of exercise intolerance.1,52 When CPX is utilized for this indication, a primary goal should be to reproduce the patient's exertional symptoms in order to optimally detect any coinciding physiologic abnormalities. The diagnostic stratification chart for patients with unexplained exertional dyspnea is provided in Appendix 4. The VE/Vco2 slope, percent-predicted peak Vo2, PETCO2 and the peak exercise VE/maximal voluntary ventilation (MVV) ratio are primary CPX variables for this assessment. Maximal voluntary ventilation should be directly measured prior to exercise as opposed to estimated using forced expiratory volume in one second (FEV1). Moreover, pulmonary function tests should be performed prior to and following CPX to determine FEV1 and peak expiratory flow (PEF).63–67 Following CPX, FEV1 and PEF should be measured at 1, 3, 5, 7, 10, 15 and 20 minutes, as responses for these variables typically worsen several minutes into recovery when exercise induced bronchospasm (EIB) is present.67 In addition to the standard hemodynamic and ECG monitoring procedures, pulse oximetry (Spo2) should also be assessed at rest, throughout ET and into recovery. Given the range of peak Vo2 values is likely to be wide in this patient population, a percent-predicted value should be included in the assessment. A progressive decline in percent-predicted values, from green to red, indicates that the physiologic mechanism resulting in exertional dyspnea is having a greater impact on functional capacity. Abnormalities in the VE/Vco2 slope and PETCO2, particularly progressing to the red zone, indicate ventilation-perfusion abnormalities induced by pulmonary vasculopathy68,69 as a potential mechanism for exertional symptoms. Patients with ventilation-perfusion abnormalities may also present with a reduced SpO2, and, in such instances, this finding portends advanced pathophysiology. Isolated abnormalities (ie, red zone) in VE/MVV, FEV1 and PEF are indicative of a pulmonary mechanism for the patient's unexplained exertional dyspnea. For FEV1 and PEF responses in the red zone, EIB should be suspected and a bronchodilator trial may be warranted. While both FEV1 and PEF have been recommended for the assessment of EIB, FEV1 is frequently assessed in isolation.65,66 Thus, a decrease in FEV1 >15% post exercise, irrespective of the PEF response, is sufficient to suspect EIB.67 Detection of hemodynamic and/or ECG abnormalities that coincide with reproduced exertional dyspnea are indicative of a CV mechanism for the patient's unexplained symptoms. Unique to CPX for this indication, a hypertensive response to exercise that coincides with exertional dyspnea and exercise intolerance may be an early indicator of HF-PEF.70,71

Suspected or Confirmed Pulmonary Arterial Hypertension or Secondary Pulmonary Hypertension

Although not currently a standard clinical indication for CPX, the body of evidence supporting the use of this form of ET in patients with suspected or confirmed pulmonary arterial hypertension (PAH) and secondary PH is growing at an impressive rate.68,69,72–82 A key value of CPX in detecting potential pulmonary vasculopathy, or gauging disease severity once a diagnosis has been made, is the ability of this exercise approach to non-invasively quantify ventilation-perfusion abnormalities. Specifically, abnormalities in the VE/Vco2 slope and PETCO2 are strongly suggestive of pulmonary vasculopathy whose etiology is either PAH or secondary PH as a consequence of other primary conditions such as HF, HCM, chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD) or systemic connective tissue diseases. Moreover, there is emerging evidence to suggest key CPX variables portend prognostic value in patients with PAH. The prognostic and diagnostic stratification chart for patients with suspected or confirmed PAH or secondary PH is provided in Appendix 5. Peak Vo2, the VE/Vco2 slope and PETCO2 are primary CPX variables in patients with suspected or confirmed PAH or secondary PH. Patients suffering from pulmonary vasculopathy, regardless of the mechanism, typically present with significantly compromised aerobic capacity. Thus, reporting peak Vo2 as an actual value, using the Weber classification system,30 is warranted. In those patients without a confirmed diagnosis, the likelihood of pulmonary vasculopathy increases as values for the VE/Vco2 slope and PETCO2 progress from green to red. In patients with a confirmed diagnosis of PAH/secondary PH, progressively worsening abnormalities of the aforementioned ventilatory efficiency variables as well as aerobic capacity are indicative of increasing disease severity. Moreover, worsening responses in these primary CPX variables are indicative of increased risk for adverse events. With respect to mode of testing, there is evidence to suggest ventilatory efficiency abnormalities are more pronounced during treadmill ET compared to cycle ergometry.83 Therefore, treadmill CPX may be optimal when assessing patients with suspected or confirmed pulmonary vasculopathy. In addition, patients with advanced PAH/secondary PH often present with an abnormal reduction in SpO2. Lastly, abnormal hemodynamic and/or ECG responses further compound concerns over increasing disease severity and prognosis in these patients.

Confirmed Chronic Obstructive Pulmonary Disease or Interstitial Lung Disease

The literature supporting the use of CPX in patients with confirmed COPD or ILD is beginning to increase, producing compelling results in support of this form of ET for these patient populations. Several investigations have demonstrated that peak Vo2 is predictive of adverse events in patients with COPD84,85 and ILD.86,87 Like patients with HF, a peak Vo2 <10 mLO2 · kg−1 · min−1 portends a particularly poor prognosis. The prognostic ability of peak Vo2 in patients with pulmonary disease has led the American College of Chest Physicians to recommend that CPX be used pre-surgically in lung resection candidates to assess postsurgical risk.88 Initial evidence also indicates the VE/Vco2 slope is a significant post-surgical prognostic marker in patients with COPD undergoing lung resection.89 Additionally, the ability of CPX to gauge ventilatory efficiency is valuable in screening for secondary PH in patients with COPD and ILD.90,91 As the VE/Vco2 slope progressively increases and PETCO2 progressively decreases above and below their normal values, respectively, the presence of secondary PH becomes more likely. The prognostic and diagnostic stratification chart for patients with COPD and ILD is provided in Appendix 6. Peak Vo2, the VE/Vco2 slope and PETCO2 are primary CPX variables for both COPD and ILD patients. As values for these variables progress to the red zone, there is an increased risk for adverse events and greater likelihood of secondary PH. Additionally, standard exercise variables progressing to the red zone compound the concern for poor prognosis in these patients.

Suspected Myocardial Ischemia

Standard graded/incremental ET procedures are a well-accepted and valuable clinical assessment tool in patients at high risk for myocardial ischemia.6,52,92 The use of ventilatory expired gas analysis for patients undergoing ET for suspected myocardial ischemia is not commonplace in the clinical setting at this time. In recent years, however, several investigations have demonstrated the potential diagnostic utility of CPX in this setting.93,94 Recent studies have found that the real-time change in the O2 pulse and ΔVo2/ΔW trajectories are most valuable when using CPX to assess for exercise-induced myocardial ischemia. Under normal physiologic conditions, both of these relationships progressively rise during maximal ET. However, left-ventricular dysfunction induced by myocardial ischemia causes both the O2 pulse and ΔVo2/ΔW trajectories to prematurely flatten or decline (See Figure 1). In a landmark study, Belardinelli et al95 performed CPX in 202 patients with a confirmed diagnosis of coronary heart disease (CHD), using 2-day stress/rest gated SPECT myocardial scintigraphy as the gold standard for myocardial ischemia. Using logistic regression, flattening of the O2 pulse and ΔVo2/ΔWR trajectories were independent predictors of exercise-induced myocardial ischemia. The sensitivity and specificity for O2 pulse+ΔVo2/ΔW flattening as criteria for exercise-induced myocardial ischemia were 87% and 74%, respectively. Comparatively, ECG criteria for exercise-induced myocardial ischemia, defined as the onset of 1.0 mm horizontal ST segment depression in at least two adjacent leads, produced a sensitivity and specificity of 46% and 66%, respectively. Of particular note, the addition of O2 pulse and ΔVo2/ΔW trajectory assessments helped to rule out ischemia in a significant portion of individuals for whom the ECG was falsely positive. As a technical note, the majority of investigations validating the clinical applications of CPX for patients with suspected myocardial ischemia to this point, including the landmark investigation by Belardinelli et al,95 used a lower extremity bicycle ergometry as the mode of testing. Thus, additional research should be conducted to determine if the diagnostic utility of CPX for myocardial ischemia is present when a treadmill is the testing mode. The diagnostic stratification chart for patients with suspected myocardial ischemia is provided in Appendix 7. Assessment of the O2 pulse and ΔVo2/ΔW trajectories are primary CPX variables. As values for these variables progress to the red zone, the likelihood of exercise-induced myocardial ischemia increases. Given that the range of peak Vo2 values is likely to be wide in patients undergoing CPX for this indication, a percent-predicted value should be included in the assessment. A progressive decline in percent-predicted values, from green to red, is indicative of poorer aerobic fitness and possibly increased coronary artery disease severity. Previous research has demonstrated lower percent-predicted aerobic fitness values to be indicative of poor prognosis.96 As with all ET procedures, standard hemodynamic and ECG variables should be assessed in patients with suspected myocardial ischemia. Abnormalities in these measures progressing to the red zone further increase the likelihood of exercise-induced myocardial ischemia and provide prognostic insight.29 Lastly, evidence suggests patients with suspected myocardial ischemia who report unusual dyspnea (ie, 4/4: severely difficult, patient cannot continue17) as the primary reason for exercise limitations have a poorer prognosis compared to those whose primary limiting symptom is lower extremity fatigue or angina.14 While research demonstrating the value of CPX in this area is promising, additional investigations are needed to further substantiate CPX for this purpose, particularly in cohorts with suspected myocardial ischemia and no prior workup bias.

Suspected Mitochondrial Myopathy

A number of genetic abnormalities exist which can lead to diminished CRF and a host of other exertional abnormalities uniquely captured by CPX.22,97 The degree of impairment in peak Vo2 appears to correlate to the severity of genetic mutation.22,98 Moreover, patients with mitochondrial myopathies have an elevated VE/Vo2 ratio at peak exercise, as the ventilatory cost of Vo2 dramatically rises due to aerobic inefficiency by affected skeletal muscle. The ability to noninvasively quantify Q during CPX in an accurate manner is now possible through foreign gas rebreathing methods.1 Using this technique, the relationship between Q (y-axis) and Vo2 (x-axis) during ET are plotted, generating a slope value. In normal circumstances, where O2 utilization and delivery are well-matched, the ΔQ/ΔVo2 slope is 5 L/min. In subjects with mitochondrial myopathies, this slope is much higher as oxygen delivery far exceeds the capacity for utilization.22 The diagnostic stratification chart for patients with suspected mitochondrial myopathy is provided in Appendix 8. Assessment of the ΔQ/ΔVo2 slope and peak VE/Vo2 are primary CPX variables. As values for these variables progress to the red zone, the likelihood of a mitochondrial myopathy increases. Moreover, the degree of abnormality in the ΔQ/ΔVo2 slope and peak VE/Vo2 response is indicative of the degree of mitochondrial mutation load. Given the range of peak Vo2 values is likely to be wide in patients undergoing CPX for this indication, a percent-predicted value should be included in the assessment. A progressive decline in percent-predicted values, from green to red, when coinciding with an abnormal ΔQ/ΔVo2 slope and peak VE/Vo2, is likewise indicative of an increasingly higher mitochondrial mutation load. When these variables are abnormal, a muscle biopsy would be warranted to obtain a definitive diagnosis. Additionally, standard hemodynamic and ECG variables should be assessed in patients with suspected mitochondrial myopathy, as abnormalities in these measures are universally indicative of CV abnormalities and increased adverse event risk.29

Directions for Future Research

The current statement provides recommendations for CPX data interpretation based upon currently available scientific evidence and expert consensus. However, there are other CPX variables that may emerge as clinically important measures in a number of the patient populations described herein. Examples of CPX variables demonstrating potential value are the oxygen uptake efficiency slope,99–101 circulatory power102 and Vo2 onset103,104 and recovery105 kinetics. Moreover, additional research is needed to further increase support for the use of CPX in certain patient populations as previously mentioned. Additional investigations into the value of CPX in females also seem warranted across all patient populations that would benefit from this form of ET. Lastly, future investigations are needed to determine if other patient populations would benefit from CPX as a component of their clinical assessment. For example, there is some initial data to indicate CPX may provide valuable information in patients with atrial fibrillation, a condition associated with ventilatory and functional abnormalities.106,107 This writing group encourages continued research into the clinical utility of CPX across all patient populations where a viable case can be made for this form of ET, addressing specific questions in need of further analysis. Future investigations in this area will lead to additional refinement of CPX utilization and data interpretation as well as improve the clinical value of this assessment technique.

Conclusions

CPX is well recognized as the gold standard aerobic ET assessment. The use of CPX is well-established in the clinical setting for both patients with systolic HF, undergoing a pre-transplant assessment, and individuals with unexplained exertional dyspnea.6,52 The evidence supporting the use of CPX in patients with confirmed or suspected PAH and secondary PH is also rapidly expanding and a strong case for the application of this ET assessment in this population can now be made. There is also emerging evidence to demonstrate CPX elicits clinically valuable information in a number of other patient populations, which are described in this document. Irrespective of the reason for the ET assessment, the utility of CPX currently suffers from an inability to easily interpret the most useful information in a way that is evidence based and specific to test indication. The present document attempts to rectify this issue by coalescing expert opinion and current scientific evidence and creating easily interpretable CPX charts that are indication-specific. It is the hope of the writing group that this document will expand the appropriate use of CPX by simplifying data interpretation, thereby increasing the clinical value of the data obtained.

Appendixes

Appendixes are available in the online text. See http://circ.ahajournals.org/lookup/doi/10.1161/CIR.0b013e31826fb946.

Disclosures

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Writing Group Disclosures

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Reviewer Disclosures

Appendix

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Appendix 1.

Universal CPX Reporting Form (Complete All Boxes That Apply for Given ET Indication)

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Appendix 2.

Prognostic and Diagnostic Stratification for Patients With Heart Failure

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Appendix 3.

Prognostic and Diagnostic Stratification for Patients With Confirmed or Suspected HCM

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Appendix 4.

Diagnostic Stratification for Patients With Unexplained Exertional Dyspnea

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Appendix 5.

Prognostic and Diagnostic Stratification for Patients With Suspected or Confirmed PAH/Secondary PH

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Appendix 6.

Prognostic and Diagnostic Stratification for Patients With COPD or ILD

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Appendix 7.

Diagnostic Stratification for Patients With Suspected Myocardial Ischemia

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Appendix 8.

Diagnostic Stratification for Patients With Suspected Mitochondrial Myopathy

Footnotes

  • The European Society of Cardiology/European Association for Cardiovascular Prevention & Rehabilitation and the American Heart Association make every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.

  • This document was approved by the European Society of Cardiology/European Association for Cardiovascular Prevention & Rehabilitation June 27, 2012, and by the American Heart Association Science Advisory and Coordinating Committee June 5, 2012.

  • The American Heart Association requests that this document be cited as follows: Guazzi M, Adams V, Conraads V, Halle M, Mezzani A, Vanhees L, Arena R, Fletcher GF, Forman DE, Kitzman DW, Lavie CJ, Myers J. Clinical recommendations for cardiopulmonary exercise testing data assessment in specific patient populations. Circulation. 2012;126:2261–2274.

  • This article has been copublished in the European Heart Journal.

  • Copies: This document is available on the World Wide Web sites of the European Society of Cardiology (www.escardio.org) and the American Heart Association (my.americanheart.org). A copy of the document is available at http://my.americanheart.org/statements by selecting either the “By Topic” link or the “By Publication Date” link. To purchase additional reprints, call 843-216-2533 or e-mail kelle.ramsay{at}wolterskluwer.com.

  • Expert peer review of AHA Scientific Statements is conducted by the AHA Office of Science Operations. For more on AHA statements and guidelines development, visit http://my.americanheart.org/statements and select the “Policies and Development” link.

  • Permissions: Multiple copies, modification, alteration, enhancement, and/or distribution of this document are not permitted without the express permission of the American Heart Association. Instructions for obtaining permission are located at http://www.heart.org/HEARTORG/General/Copyright-Permission-Guidelines_UCM_300404_Article.jsp. A link to the “Copyright Permissions Request Form” appears on the right side of the page.

  • Abbreviations

    BP
    Blood pressure
    CHD
    Coronary heart disease
    CO2
    Carbon dioxide
    COPD
    Chronic obstructive pulmonary disease
    CPX
    Cardiopulmonary exercise testing
    CRF
    Cardiorespiratory fitness
    CV
    Cardiovascular
    ECG
    Electrocardiogram
    EIB
    Exercise induced bronchospasm
    EOV
    Exercise oscillatory ventilation
    ET
    Exercise testing
    FEV1
    Forced expiratory volume in one second
    HCM
    Hypertrophic cardiomyopathy
    HF
    Heart failure
    HF-PEF
    Heart failure-preserved ejection fraction
    HR
    Heart rate
    HRR
    Heart rate recovery
    ILD
    Interstitial lung disease
    LVH
    Left ventricular hypertrophy
    MVV
    Maximal voluntary ventilation
    O2
    Oxygen
    PAH
    Pulmonary arterial hypertension
    PEF
    Peak expiratory flow
    PETCO2
    Partial pressure of end-tidal carbon dioxide
    PH
    Pulmonary hypertension
    Q
    Cardiac output
    RER
    Respiratory exchange ratio
    Spo2
    Pulse oximetry
    US
    United States
    VE
    Minute ventilation
    Vco2
    Carbon dioxide production
    Vo2
    Oxygen consumption
    VT
    Ventilatory threshold

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Circulation
October 30, 2012, Volume 126, Issue 18

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  • Clinical Recommendations for Cardiopulmonary Exercise Testing Data Assessment in Specific Patient Populations
    Marco Guazzi, Volker Adams, Viviane Conraads, Martin Halle, Alessandro Mezzani, Luc Vanhees, Ross Arena, Gerald F. Fletcher, Daniel E. Forman, Dalane W. Kitzman, Carl J. Lavie and Jonathan Myers
    Circulation. 2012;126:2261-2274, originally published October 29, 2012
    https://doi.org/10.1161/CIR.0b013e31826fb946
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