Hart Metab. (2014) 64:31-36 How to interpret cardiopulmonary exercise tests Marco Guazzi, MD, PhD, FACC Heart Failure Unit and Cardiopulmonary Laboratory, Cardiology, LR.C.C.S., Policinico San Donato, University of Milan, Italy Correspondence: Marco Guazzi, Heart Failure Unit-Cardiology, IRCCS Poicinico San Donato, University of Milano, Piazza E. Malan 2, 20097 San Donato Milanese, Mitzno, aly E-mai: marco.guazzi@unimi.it Abstract Exercise intolerance and related symptoms are cardinal manifestations of most cardiopulmonary dis- orders. Assessing the functional response with gas exchange analysis by cardiopulmonary exercise testing (CPX) is now the gold standard for thoroughly assessing the pathophysiological derangements behind these diseases. CPX provides an assessment of the integrative response involving the pul- monary, cardiovascular, muscular, and cellular oxidative systems, which are not adequately reflected thorough the measurement of individual organ system function. Accordingly, CPX is now being used in a wide spectrum of clinical settings for evaluation of undiagnosed exercise intolerance, and the test's, popularity is increasing dus to recent statements and offical documents that have provided simplified and easy-to-apply reports that may consistently help the practicing clinician with their interpretations and clinical directions. m Heart Metab. 2014;64:31-36 Keywords: plications and use of exercise testing with oe tees ett atc diogram (ECG) and blood pressure monitoring, have been expanding in recent years and is now part of routine clinical diagnostic studies." ‘A growing appreciation for this test has been pos- sible due to the development of rapidly responding electronic gas analyzers to replace the more demand- ing chemical methods for measuring respiratory gases ‘and to the development of flow meters that can mea- ‘sure instantaneous flow and volume. This has greatly decreased the technical ime, and therefore, the cost to do gas exchange measurements Test-to-test repeat- abilly and high reliance of data recorded are other significant features that have contributed to a preferred use compared with other exercise testing modalties.® -ardiopulmonary exercise; oxygen consumption; ventilation inefficiency These tests are referred to as cardiopulmonary exer- cise tests (CPXs) because the cardiovascular and pulmonary systems are assessed when gas exchange is measured during exercise. The purposes for which CPXs are currently being applied attest to its growing importance in cardiopul- monary medicine. This approach is useful in terms of assessing the mechanism of exercise intolerance, evaluating disability, making activity and training recommendations, quantifying responses to therapy, and predicting outcomes. Due to these distinctive features, CPX has received a particular amount of atlention in recent years; numerous studies have adopted CPX variables as end points over the last decade, and the test, with allits features, Is becoming ‘more commen in daily clinical practice." nMarco Guazz Interpreting cardiopulmonary exercise tests Abbreviations ATP: adenosine triphosphate; GPX: cardiopulmonary ‘exercise test; ECG: electrocerdiogram; HR: heart rate: MW: maximum voluntary ventiation; RER: respira- tory exchange rate; Wd: ventilation/pertusion [ratio]; Ve ventilation; p,: oxygen consumption; WR: work rate ‘The present review addresses how to broadly interpret CPX results and how data can be inter- preted in cases of disorders of the heart and the lung. Therefore, a translation from pathophysiological bases to clinical implications is provided. Mechanisms for exercise intolerance and cardiopulmonary exercise test diagnoses Exercise necessitates an increase in gas transport between the air and the mitochondria. This vital physi- ological coupling occurs due to a correct matching between several systems; primarily the pulmonary, cardiovascular, and muscular systems. Exercise intol- erance is caused by any disease state that disrupts the normal gas-exchange coupling between the external and internal ventilation. ‘The basic requirement to sustain muscular activity is an increase in cellular respiration for the production and regeneration of adenosine triphosphate (ATP). To ‘support the increase in cellular respiration, there is a need for an increase in O, and CO, transport between the cells and the external airways. This increase must match the rate of cellular respiration except for the following: () transient lags allowed by the capacitance in the transport system; (i) O, stores on the venous, side of the circulation; and (ji) small stores of high- energy phosphate in the form of creatine phosphate in the myooytes. There are @ series of pathophysiological ques- tions relevant for the clinician to ask when caring for patients with exercise intolerance due to dyspnea and/or fatigue. Primariy, the clinician should deter- mine whether the metabolic demand for the given exercise is increased ([e, obesity), and if the exercise is limited by impaired O, flow (eg, carciac, pulmonary, or peripheral disease, or an anemic condition), or impaired O, utilzation (eg, muscle glycolytic problem or mitochondrial enzyme defect). Also relevant to the pathophysiology is whether there is an abnormal 2 Hart Metab. (2014) 64:31-36 degree of ventilation pertusion (W/Q) ratio mismatch- ing (e, cardiac and pulmonary disease}. Despite the complex pathophysiological interaction between biological systems during exercise, the simplified CPX approach for diagnostic standardization of exercise intolerance uses a nine-panel graphic array exempi- fied in Figure 1 (normal healthy subject. Panel 3. Oxygen consumption (VO,) vs work rate (WR) is the panel suggested to start with because it shows the true exercise performance by displaying VO, at peak exercise that may difer from maximum Vo, (VO,max), where the percent predicted can be determined by appropriate reference equations. This ppanel is also useful because it describes the pattern of increase in VO,,, which may often be abnormal in patients with carciovascular disorders depending on the specific pathophysiological condition. Linearity is a prerequisite for a normal response to exercise, ‘and, in healthy subjects, the slope of VO, increase over O, uptake is 10 mL/min! After reviewing the plots in panel 3, the others are relevant to go into the pathophysiological state of coupling of the above mentioned main organ systems, Panel 1. Minute ventiation (We) vs WR. This near relationship normally recognizes three patterns with the frst change in slope corresponding to the switch to a prevalent anaerobic metabolism determining an increase in Ve for the augmented CO, release due to lactate tamponade and a second one close to exer- cise termination due to the ventilator compensatory response. Panel 2. Heart rate (HR) and VO,/HR (O, pulse) vs WR. O, pulse is a surrogate measure of stroke vol ume considering VO, as cardiac output (CO=stroke volume x HR) x arteriovenous oxygen difference (2-v] (©). Considering the C(a-v)O, diference content, O, pulse mirrors the stroke volume. Panel 4. Ve vs VOO,. This is a linear relation- ship until compensation for metabolic acidosis. The slope of the linear part is steep when the exercise physiologic dead spaceltidal volume ratio (Vos/V1) is increased, Panel 5. HR vs VO, and VCO, vs WO,. HR increases linearly with VO, to the predicted maximum innormal subjects. n patients with cardiac disease or pulmonary vascular disease, the increase may lose its inearity with HR increasing progressively, but more rapidly, than VO,. Up to the anaerobic threshold, ‘VCO, increases linearly with WO, with a slope of oneHeart Metab. (2014) 64-31-36 Cr slightly less than one. Then, VCO, increases more rapidly and the steepening of the slope depends on the rate of lactic acid buffering Panel 6. Ventiatory equivalent for O, and CO, (WeNICO, and WeNVCO,) vs WR. VO, decreases to a nadir at the anaerobic threshold, and VCO, decreases to a nadir at the ventilatory compensatory point. Both values are high with pulmonary vascular occlusive disease. Panel 7. Vi vs Ve. The patients’ vital capacity ‘and inspiratory capacity (IC) are shown on the Vr Manco Guazzi Interpreting cardiopulmonary exercise tests axis and measured maximum voluntary ventilation (MV) is shown on the Ve axis, With airflow imitation, maximal exercise Ve approximates MW. Thus, the breathing reserve ((MVV-Ve] at maximal exercise) is approximately zero, The breathing reserve cannot be predicted from resting pulmonary function measure ments alone. With restrictive lung disease, Vr may approximate the IC at low work rates and the respira tory rate may excessively increase. Panel 8. Respiratory exchange ratio (RER; VCO,VO). This usually starts at approximately 1 2 3 ena $1Ritetnn) ¢VO/HR (nL) © WO, Wni) Veo, Win » , 1s ao]. 1s ‘ ul » ' 2 0 i wo | oa | 06 " | ot | 02, 0 | 0 TER tomy | 0 TS Romy 7% a tey wats vats ws 4 5 6 vein SHR) OVD: Und mWwion Ovi, » 1 ew * 10 ra ul 0 9 wo 2 ray 0 Pe oR | 0 o 3 06 2» & o oe a | a * ae 0 of 0 6 & 1 & s o& Tt & 0B RT ts amy wats 7 ‘ 9 wa nek © 0, whoo 28 35) uo | Pe x ssl | 20 ‘i 100 ls ° as} 0 2 ul ® 08 0 | | | femenaomettee a on » a ok - o rr er er er er ar 0% US Racmay wits wits Fig. 1 Te rie -panel graphic array used i the CPX approach for clagnostc standardization of exercise intolerance uses. ‘Abbreations: CPX, cadopumonay erase testing: HR, hoa aa: Ye, vennsten VO, cxyger cancun: YOO, aban dude cancun: Vr tia value; Pr, a a cxygan anion; PxtCO,, arta pressure of carbon dx 2Marco Guazz Interpreting cardiopulmonary exercise tests 0.8 and increases to above 1.0, which is above the anaerobic threshold. Acute hyperventiation at rest and intial exercise stages yields a RER>1 Panel 9. Endt-tidal pressure of carbon dioxide (PeICO,) and end-tidal oxygen tension (PerCO,) vs WR. Low PerCO, reflects either hyperventilation cor a high V/G mismatching. The RER signals if the hyperventilation is acute, Arterial blood gases or knowledge of plasma HCO,.- differentiates chronic hyperventilation from V/€) mismatching, ‘The report in specific disorders What is useful in heart failure and coronary artery disease? In heart failure (HF), VO, is markedly below the pre- dicted normal value, and a major exercise limitation is a defect in cardiac output increase. Since cardiac output increases linearly with VO, and Cla-vO, is approximately maximal even in advanced HF, VO, may be generally considered a valid surrogate of cardiac output. When cardiac output falls to increase appropriately, the relationship between VO,WR decreases as WR increases. This change may be {gradual (shallow) rather than abrupt like the change in \VO,/WR slope (fattening) observed when the myocar- ium becomes ischemic." In coronary artery disease, the occurrence of VO,/WR flattening is accompanied by a reduction in the slope of the O, pulse increase ‘and may offer suitable clinical information in the clin cal framework of coronary artery disease. In a report comparing sensitivity and specificity of GPX criteria with standard exercise-ECG criteria for diagnosis of cardiac ischemia, CPX provided a much higher sens tivity (87%) and specificity (749) than standard ECG (46% and 68%, respectively) When flattening and EOG abnormalities concur during the test, the ECG shows evidence of myocardial ischemia at work rates ‘soon after the WO,/WR flattening, ‘Along with VO,, a series of ventlatory variables provide relevant insights in the data interpretation of cardiac patients, primarily, HF patients.” Ve ineff- ciency is a typical manifestation that is conventionally defined by looking at the rate of increase in Ve vs VCO, (Figure 1, plot 6). This relationship is assessed as Ve vs VOO, oF, less commonly, by the ratio at anaerobic threshold or at the nadir point ofthe ratio. The information obtained by these variables is not 4 Hart Metab. (2014) 64:31-36 conly diagnostic, but also especialy usetul in the clni- cal and prognostic assessment of patient follow-up. 4 class Ve severity classification has been identified and proposed! and is now suggested by statements from Balady et al and Guazzi et al as basic parts of the report in cardiac patients.'2 The origin of an increased and inefficient ven- tlatory response to exercise is multifactorial and primarily reflects how left ventricular dysfunction may impair lung physiology and both central and periph- eral ventilatory control.” For these latter peripheral mechanisms, main putative factors are an impaired chemoreflex sensitivity and regulation along with early developing acidosis High VeVCO, slopes are observed in patients with moderate to severe forms of pulmonary hyper- tension, and end-tidal CO, is @ determinant that becomes clinically and prognostcally relevant.® Another ventilatory abnormality peculiar to some HEF patients is the pattem of oscilatory gas kinetics Classified as exertional oscilatory ventilation (EOV), a pattern that resembles, in some instances, the occur- rence of Cheyne-Stokes respiration during sleep? This s an ominous sign of disease severity that is now recognized in up to 30% of symptomatic HF patients with a simiar rate in heart failure with reduced ejec- tion fraction and heart failure with preserved ejection fraction? What is useful in pulmonary lung diseases and arterial pulmonary hypertension? Exercise limitation in patients with respiratory disease is complex, multifactorial, and may be diffcutt to establish and clearly quantitate. Ventilatory limiting factors include decreased ventllatory capacity (mostly due to mechanical factors; Figure 1, plot 7), abnormal gas exchange (le, hypoxemia and increased VDV1), and respiratory muscle dysfunction ‘As for cardiac patients, the literature pertaining to patients with obstructive lung disease emphasizes the relevance of VO, (Figure 1, plot 3) as a primary variable to be addressed as a peak VO,<10 mL/ min/kg portends a particularly poor prognosis (Figure 1, plot 3). The role of deconditioning in patients with chronic cardiopuimonary disease and in patients after heart, heart/lung, or lung transplantation has. increased awareness of the role of peripheral limitation inHeart Metab. (2014) 64-31-36 exercise performance and the importance of con- sidering this as a contributing factor in their exercise limitation, ‘The prognostic ability of peak VO, in patients with pulmonary disease has led the American College of ‘Chest Physicians to recommend that CPX be used presurgically in lung resection candidates to assess postsurgical risk.” Initial evidence also indicates the Ve'N/CO, slope isa significant postsurgical prognostic marker in patients with chronic obstructive pulmonary disease (COPD) undergoing lung resection (Figure 1, plot 6)."* ‘Akey value of GPX in detecting potential pulmo- nary vascular limitation and the role of vasculopathy, or gauging disease severity once a diagnosis has been made, is the abilty of this exercise approach to noninvasively quantity W/Q abnormalities. ‘Specifically, abnormalities in the Ve/VCO, slope and PexCO, (Figure 1, plot 9) are strongly suggestive of pulmonary vasculopathy whose etiology is either Manco Guazzi Interpreting cardiopulmonary exercise tests idiopathic or secondary pulmonary hypertension as a consequence of other primary conditions such as heart failure, hypertrophic cardiomyopathy, COPD, interstitial lung disease, or systemic connective tissue diseases."*"* Universal cardiopulmonary exercise test report In the recent joint European Association for Cardiovascular Prevention & Rehabiltation/American Heart Association statement on CPX application, a major goal has been to provide a universal report that may allow collecting all relevant GPX data in a concise and organized manner, which seems essen- tial for meaningful data interpretation and clinical ultlization. Specifically, the universal CPX reporting form (Figure 2) provides clinicians with the ability to collect relevant data that may subsequently be used for interpretation according to a patient's specific condition/test indication. Exercise modality: [] Treadmill [] Lower extremity ergometer Protocol Peak VO, (mL O,ekg" min) VO, at Vr (mL O,kg? min) Peak RER Per cent-predicted peak VO, (%)* ‘VENOO, slope EOV [] Yes []No Pe1GO, (mmHg) Resting: Increase during ET: ‘VeNVO, at peak ET AVO/AVO," VEN PEF (Umin): Pre-ET Post-ET pulse trajectory {Sentinal ise froughout ET [] Early and sustained plateau [ Dectne ‘AVO,/AWR trajectory (J Continual rise throughout ET | ] Early and sustained plateau [ Decline Resting HR (p.m) Resting BP (mmHg) Resting pulse oximetry (96) Peak HR (0.p.m.) Peak BP (mmHg) Peak pulse oximetry (9) Percent of age-predicted maximal | Maximal workioad HA® HRR at 1 min (beats) [] Treadmill speec/grade: LU Cycler ergometer Watts: ECG eriteria ECG description {] No arthythmias/ectopyrST-segment changes Arythmias/Ectopy/ST-segment changes: not exercise limiting Anmytnmias/Ectopy/ST- segment changes: exercise limiting Subietve symptoms cheak box for pmary termination ort) PET) Angina {| BysenoeaL} ‘Additional notes Fig. 2 Universal CPX report. [Abbeelations: 2¥G/AV0, change caraaecufpu/enange okygen consumption BP loo pressure: CPX. caraonumonay eves etn: AO. change oxygen consumptichanges n Wats: ECG, aecrocaragram EOY, ours escy vane ET. ora ast: HR heart rate: HAR, haart rato recor. MV mauinalvountay erator: O,ongan PEF peak expat flow Pex, al ress ER, respatery exchange a; APE. rating of prcaved exarion VM, peak mute vatatan/ meal vokntay venation: WPVCO,, mnt venison ‘carton done producto; ¥/VO,, mt ‘Use squats proposed by Wasserman. "Requtes retreating tecnique, ‘Dvsty masses MW at baseina. Fars O, pase and 4VO,/2WR pl! fom witaton of ET ese vai raed or assesses lectrricaly braked ey ergoreter shout a used farting, “Use equation pack HAV220-a) x 100 Reprinted wth permiasion Creation, 2012.1262267-2274. © 2012 Amercan Hew Aazockten, he 8Marco Guazz Interpreting cardiopulmonary exercise tests It should be noted that the CPX reporting form is primarily focused on the most common cardio- vascular and pulmonary diseases. However, other reported variables may be relevant in conditions that are less frequent, but may stil be a matter of useful investigation in the presence of exercise limitation (eg, mitochondrial myopathy and peripheral vascular disease). Conclusions Applications and use of CPX in the cardiology arena is increasing and is now included in the routine clinical Giagnostic workup of patients with cardiopulmonary disorders. Data interpretation for diagnostic and prognostic purposes is based on physiological prin- ciples sustaining the matching between the external and internal ventilation and O, transport. The most recent statements and official documents have provided simplified easy-to-apply reports that may consistently help the practicing clinicians in their dally clinical practice. m REFERENCES 1. Balady Gu, Ados PA, Comoss P, eta. Core components of ‘cardiac. rehabitalon/secondary prevention programs: A statement for healthcare professionals trom the American Heart Association and the American Associaton of Cardiovascular and Pumonary Rehabilitation. Circulation ‘2000; 102:1069-1073, 2. Gunz M, Adame V, Conraads Vet al: European Association for Carcovascular Prevention & Rehabiltation: American Heart Assocation, EACPRUAHA scent staloment. Cinica recommendations for cardiopulmonary exercise testing ‘data assassment in specific patient populations. Circulation 2012;126:2261-2274, 10. " 12, 13, %4 16. Hart Metab. (2014) 64:31-36 Guazai M. Reproducity of cardiopulmonary exorcise test ‘arabes: gating into an adonal strength of the tet, Eur J Prev Carlo. 2014;21:442-444 ‘Arona R, Myers J, Abela J etal. Determining the preferred percent predicted equation for peak oxygen corsumption in pationts with heart false, Circ Heart Fai. 2000;2:1 13-120. Wasserman K, Hansen JE, Sue DY, eta. Prncines of Exercise Testing and interpretation. Sth ed. Philadelphia, PA: Lippincott \Witams & Wins; 2012. elardneli A, Lacaanrce F, Carla Ft al. Exercise-induced ryocardial ischaemia detected by cardiopulmonary exercise testing, Eur Heart J. 2008:24:1304-1313, ‘Arona R, Myers J, Guazzi M. The clinical and research applications of aerobic capacty and ventiatory etciency in heart falure: an evidence-based review. Hoart Fa Rov 2008: 13:285-260. (Guaza M, Raina G, Tumminello G, Guazz! MD. Exercise ven lation inaiciency and cardiovascular mortally in heat fare: the crcl independent prognostic value of the arterial COZ Partial pressure. Eur Heart J 2005:26:472-480. Guazzi M. eating exercise oscilatory ventlation in heart fale: the deta that may matter. Eur Respir J 2012:40:1075-1077. (09a, Nishimura, Teukino M, Sato S, Haj T Anais ofthe factors related to moat in ehyoric obstructive pulmonary disease: role of exercise capacity and heath status. Am J ospt Ort Care Med. 2008:167:544-549, Hiraga T, Macha R, Orica Ye a Prognostic predictors for ‘urvilin pationts wth COPO Using carcopuimonary exercise teating, Cin Physiol Funct imaging. 2000:23:924-331 Clee GL, Shalazand §, Grifin JP, Keenan A, Botiger CT; ‘American College of Chest Physicians. Physiologic evaluation Cf the patent with ung cancer being considered for resectional surgery? ACCP evidenced:based clinical practice qudeinas (2nd ection) Chest. 2007:132:1618-177S. Tocco A, Guglielmo My, Gardno R, et a. Exercise ventilatory Inefceney and moray in patients with chronic obstructive puimonary disease undergoing surgery fr non-smal-cet ung cancer Eur J Cariothorac Surg. 2010;38:14-19. HoWerda S, Bogaad HJ, Goepenhott H, Postmus PE, Boonstra A, Vonk-Noordegraat A. Carviopulmonary exercise test characterisics in patients with chronic obstructive puimonary aisease and associated pulmonary hypertension. asptation. 2008;76:160-167. Gaser §, Noga O, Koch 8, etal impact of pulmonary hyper tension on gas exchange and exercise capac in patents vith pumonary fixosis. Respir Med. 2009;109:317-928.