predictive value of cardiopulmonary exercise testing

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3-1-2021

Predictive Value of Cardiopulmonary Exercise Testing Parameters Predictive Value of Cardiopulmonary Exercise Testing Parameters

in Ambulatory Advanced Heart Failure in Ambulatory Advanced Heart Failure

Anuradha Lala

Keyur B. Shah

David E. Lanfear

Jennifer T. Thibodeau

Maryse Palardy

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Authors Authors Anuradha Lala, Keyur B. Shah, David E. Lanfear, Jennifer T. Thibodeau, Maryse Palardy, Amrut V. Ambardekar, Dennis M. McNamara, Wendy C. Taddei-Peters, J. Timothy Baldwin, Neal Jeffries, Shokoufeh Khalatbari, Cathie Spino, Blair Richards, Douglas L. Mann, Garrick C. Stewart, Keith D. Aaronson, and Donna M. Mancini

Predictive Value of CardiopulmonaryExercise Testing Parameters inAmbulatory Advanced Heart FailureAnuradha Lala, MD,a,b Keyur B. Shah, MD,c David E. Lanfear, MD, MS,d Jennifer T. Thibodeau, MD, MSCS,e

Maryse Palardy, MD,f Amrut V. Ambardekar, MD,g Dennis M. McNamara, MD,h Wendy C. Taddei-Peters, PHD,i

J. Timothy Baldwin, PHD,j Neal Jeffries, PHD,k Shokoufeh Khalatbari, MS,l Cathie Spino, SCD,m Blair Richards, MPH,l

Douglas L. Mann, MD, PHD,n Garrick C. Stewart, MD, MPH,o Keith D. Aaronson, MD, MS,f Donna M. Mancini, MD,a,b

for the REVIVAL Investigators

ABSTRACT

OBJECTIVES This study sought to determine cardiopulmonary exercise (CPX) predictors of the combined outcome of

durable mechanical circulatory support (MCS), transplantation, or death at 1 year among patients with ambulatory

advanced heart failure (HF).

BACKGROUND Optimal CPX predictors of outcomes in contemporary ambulatory advanced HF patients are unclear.

METHODS REVIVAL (Registry Evaluation of Vital Information for ventricular assist devices [VADs] in Ambulatory Life)

enrolled 400 systolic HF patients, INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support)

profiles 4-7. CPX was performed by 273 subjects 2 � 1 months after study enrollment. Discriminative power of maximal

(peak oxygen consumption [peak VO2]; VO2 pulse, circulatory power [CP]; peak systolic blood pressure � peak VO2], peak

end-tidal pressure CO2 [PEtCO2], and peak Borg scale score) and submaximal CPX parameters (ventilatory efficiency [VE/

VCO2 slope]; VO2 at anaerobic threshold [VO2AT]; and oxygen uptake efficiency slope [OUES]) to predict the composite

outcome were assessed by univariate and multivariate Cox regression and Harrell’s concordance statistic.

RESULTS At 1 year, there were 39 events (6 transplants, 15 deaths, 18 MCS implantations). Peak VO2, VO2AT, OUES,

peak PEtCO2, and CP were higher in the no-event group (all p < 0.001), whereas VE/VCO2 slope was lower (p < 0.0001);

respiratory exchange ratio was not different. CP (hazard ratio [HR]: 0.89; p ¼ 0.001), VE/VCO2 slope (HR: 1.05;

p ¼ 0.001), and peak Borg scale score (HR: 1.20; p ¼ 0.005) were significant predictors on multivariate analysis (model

C-statistic: 0.80).

CONCLUSIONS Among patients with ambulatory advanced HF, the strongest maximal and submaximal CPX predictor

of MCS implantation, transplantation, or death at 1 year were CP and VE/VCO2, respectively. The patient-reported

measure of exercise effort (Borg scale score) contributed substantially to the prediction of outcomes, a surprising and

novel finding that warrants further investigation. (Registry Evaluation of Vital Information for VADs in

Ambulatory Life [REVIVAL]; NCT01369407) (J Am Coll Cardiol HF 2021;9:226–36) © 2021 by the American College of

Cardiology Foundation.

ISSN 2213-1779/$36.00 https://doi.org/10.1016/j.jchf.2020.11.008

From the aZena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York,

USA; bDepartment of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, New York, USA;cDepartment of Medicine, Division of Cardiology, Virginia Commonwealth University, Richmond, Virginia, USA; dHeart and

Vascular Institute, Henry Ford Hospital, Detroit, Michigan, USA; eDivision of Cardiology, Department of Internal Medicine, Uni-

versity of Texas Southwestern Medical Center, Dallas, Texas, USA; fDivision of Cardiovascular Medicine, University of Michigan,

Ann Arbor, Michigan, USA; gUniversity of Colorado, Boulder, Colorado, USA; hDepartment of Medicine, Division of Cardiology,

University of Pittsburgh, Pittsburgh, Pennsylvania, USA; iDivision of Cardiovascular Sciences, National Heart, Lung, and Blood

Institute, Bethesda, Maryland, USA; jMichigan State University, East Lansing, Michigan, USA; kCenter for Devices and Radiological

Health, Food and Drug Administration, Silver Spring, Maryland, USA; lMichigan Institute for Clinical and Health Research, Uni-

versity of Michigan, Ann Arbor, Michigan, USA; mDepartment of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA;nCardiovascular Division, Washington University School of Medicine, Washington University, St. Louis, Missouri, USA; andoCardiovascular Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

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T he first report of the usefulness of peak oxy-gen consumption (peak VO2) to risk-stratifypatients with heart failure with reduced ejec-

tion fraction (HFrEF) for transplantation candidacywas published nearly 30 years ago (1). Since then,many additional maximal and submaximal measure-ments obtained during cardiopulmonary exercise(CPX) testing have demonstrated predictive value fordetermining mortality and/or heart failure (HF) hospi-talizations (2–8). Other maximal CPX parametersinclude peak circulatory power (CP) (peak VO2 � peaksystolic blood pressure), peak VO2 pulse (peak VO2/maximum heart rate), and percentage of predictedpeak VO2 (%PPVO2) (7,9,10). Submaximal parameters(i.e., parameters obtained without the subject meetingexercise criteria for maximal exercise effort) includeventilatory efficiency (slope of minute ventilation toCO2 production [VE/VCO2 slope]) (3–6), VO2 at theanaerobic threshold (VO2AT) (11), oxygen uptake effi-ciency slope (the slope of the relationship betweenpeak VO2 and log minute ventilation [oxygen uptakeefficiency slope: OUES]) (12–14), end-tidal pressure ofCO2 (PEtCO2) (15), and the presence of oscillatory venti-lation (EOV) (16,17). Most of the studies investigatingthe prognostic power of these variables included pa-tients with a range of HF severity. The independentpredictive value of self-reported effort during exercisein clinical outcomes in patients with HFrEF has notbeen investigated.

Since the first report illustrating the importance ofCPX testing for risk stratification, therapy for patientswith HFrEF has advanced with the introduction ofincreasingly effective drugs such as angiotensin re-ceptor blocker/neprilysin inhibitors (ARNI) and de-vices (e.g., chronic resynchronization therapy). Assuch, redefining the best predictors of adverse out-comes measured during CPX testing in the contem-porary high-risk HFrEF population is essential.

The REVIVAL (Registry Evaluation of Vital Infor-mation for ventricular assist devices [VADs] in Ambu-latory Life) study is a multicenter prospective cohortstudy, which enrolled 400 ambulatory advanced HFpatients, INTERMACS (Interagency Registry for Me-chanically Assisted Circulatory Support) profiles 4–7with 2-year follow-up including collection of outcomedata for death, transplantation, and durable

mechanical circulatory support (MCS) im-plantation (19). Study procedures includedscheduled CPX testing 2 months after studyentry. Accordingly, this cohort provided anideal patient population for the prospectivedetermination of the parameters derived fromCPX testing that would most strongly predictrapid clinical decline.

METHODS

STUDY POPULATION. Study entry criteriaand procedures have been published previ-ously (19) and are summarized here. Briefly,the National Heart, Lung, Blood Institute-funded REVIVAL registry included 400 pa-tients with advanced HFrEF (#35%), age 18 to80 years, who were enrolled in 21 US centersfrom July 2015 through June 2016. All pa-tients were ambulatory and reported NewYork Heart Association (NYHA) functionalclasses II to IV, receiving optimized HFmedications (angiotensin-converting enzyme[ACE] inhibitor/angiotensin receptor blockers[ARB], ARNI, beta-blockers, aldosterone antagonist,hydralazine/long-acting nitrate [required for African-American patients], and a device [implantablecardioverter-defibrillator or cardiac resynchroniza-tion therapy defibrillator]). Additional inclusioncriteria to identify patients at higher risk for theprimary composite endpoint (death, cardiac trans-plantation, or mechanical circulatory support im-plantation) included elevated natriuretic peptidelevels, low serum sodium, low peak VO2, high VE/VCO2 slope, short 6-min walk distance, poor prog-nosis based on the Seattle Heart Failure Model orHeart Failure Survival Score or more than 2 HF hos-pitalizations in the prior year. Patient Health Ques-tionnaire (PHQ-8) responses, as an assessment ofdepression, were also recorded with values of 10 to14, consistent with moderate depression and values>15 consistent with moderate-to-severe depression.Patients with any comorbidity that would limit 2-yearsurvival, taking intravenous inotropes, with renalfailure on dialysis, or with infiltrative cardiomyopa-thies were excluded. Full inclusion and exclusioncriteria are listed in the Supplemental Appendix.

An independent observational study monitoringboard oversaw the conduct of the REVIVAL study.

SEE PAGE 237

AB BR E V I A T I O N S

AND ACRONYM S

%PPVO2 = percent of

predicted peak VO2

CP = circulatory power

CPX = cardiopulmonary

exercise

EOV = oscillatory ventilation

HF = heart failure

HFrEF = heart failure with

reduced ejection fraction

MCS = mechanical circulatory

support

OUES = oxygen uptake

efficiency slope

PEtCO2 = end-tidal pressure of

CO2

VE/VCO2 slope = slope of

minute ventilation to CO2

production

VO2 = oxygen consumption

VO2AT = VO2 at the anaerobic

threshold

The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’

institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information,

visit the Author Center.

Manuscript received August 10, 2020; revised manuscript received November 3, 2020, accepted November 12, 2020.

J A C C : H E A R T F A I L U R E V O L . 9 , N O . 3 , 2 0 2 1 Lala et al.M A R C H 2 0 2 1 : 2 2 6 – 3 6 Value of CPET in Ambulatory Advanced HF

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https://www.jacc.org/author-center

The Institutional Review Board at each centerapproved the study. All subjects provided writteninformed consent before study participation.

CARDIOPULMONARY EXERCISE TESTING AND DATA

SHARING. The exercise protocol and data submissionwere standardized for all centers. CPX testing wasperformed in the fasting state while receiving stan-dard medications, using a treadmill and the 3-minincremental modified Naughton protocol (20). Priorto each exercise test, the metabolic cart was cali-brated. The subject was connected to the metaboliccart, and baseline metabolic data was collected for3 min. Heart rate, rating of perceived exertion (Borgscale 6-20) (21), and blood pressure were recorded atrest and during the last minute of each exercise stageand at peak exercise. The symptom that limitedmaximal exercise testing was recorded. These mea-surements were sent to the Data Coordinating Centerat the University of Michigan along with the raw datadownloaded from the metabolic cart as a copy-on-write (.cow) file. These files were electronicallytransmitted to the Exercise Core Laboratory through asecure server (MiShare, University of Michigan, AnnArbor, Michigan). Only centers using Sensor Medics(Yorba Linda, California) or Medical Graphics (St.Paul, Minnesota) metabolic carts (15 of 21 centers,210 tests) were able to submit electronic data thatcould be over-read by the exercise core laboratory.Six centers submitted detailed graphs and tabulardata for core laboratory review (63 tests). All testswere read at the Exercise Core Lab (D.M.M.). Datawere transferred back to the Data CoordinatingCenter through MiShare and entered into theREVIVAL OpenClinica database (Open Clinica, Wal-tham, Massachusetts).

Patients who achieved a respiratory exchange ratio(RER) of $1.05 or who achieved VO2AT at <75% ofpeak VO2 and exercised for at least 2 min wereconsidered to have performed maximal exercise(designated the maximal effort cohort); the remainingpatients were categorized as having performed sub-maximal exercise (designated the submaximal effortcohort).

Peak exercise parameters evaluated included peakVO2, %PPVO2, CP, RER, Borg scale score, difference ofPEtCO2 from peak to rest, peak PEtCO2, and peak VO2

pulse. PPVO2 was calculated from the Wasserman-Hansen formula (22). Submaximal exercise parame-ters evaluated included VO2AT, VE/VCO2 slope,OUES, and PEtCO2. The key criteria used to select theanaerobic threshold were the nadir for the ventilatoryequivalent for VO2 without change in the ventilatoryequivalent for VCO2, or the nadir for the ventilatory

equivalent for PEtO2 without change in the ventila-tory equivalent for PEtCO2 (23). The VE/VCO2 slopewas calculated from the patient’s breath-by-breathdata of VE and VCO2 plotted throughout exercise andalso measured using the VE/VCO2 value observed atthe ventilatory threshold. OUES was calculated fromthe relationship between VO2 and 30-second aver-aged minute ventilation (VE) as expressed in theequation: VO2 ¼ [(OUES � log VE)] þ B (13).

OUTCOME. Patients were followed for the REVIVALprimary composite outcome of death, durable MCSimplantation, or cardiac transplantation at 1 yearfollowing CPX.

STATISTICAL ANALYSIS. Baseline characteristics aredisplayed as mean (� SD) or median interquartileranges (25th, 75th percentiles) for normally and non-normally distributed continuous data, respectively.Categorical data are displayed as percentages. Base-line characteristics for the maximal effort cohortversus those in the submaximal effort cohort werecompared by means of independent group Student’st-tests and Wilcoxon rank sum tests, as appropriate,for continuous variables and the Fisher exact test andCochran-Armitage trend test for categorical variables.Survival free from the primary outcome in the yearfollowing CPX testing was estimated by Kaplan-Meiersurvival methodology, and results for the maximaland submaximal effort groups were compared by log-rank tests. Univariate and multivariate Cox propor-tional hazard regressions for predictors of the primarycomposite outcome were performed. A backwardstepwise selection process was used. Univariatereceiver-operating characteristics (ROC) curves at 1year display the discriminative capability of unad-justed individual CPX parameters, with correspond-ing area under the curve (AUC) displayed (0.5 ¼ noinformation; 1.0 ¼ perfect discrimination). A multi-variate AUC at 1 year was calculated to assess thediscriminative capability for the overall model. Anassociation between peak Borg scale score and PHQ-8responses was tested using a Spearman correlationanalysis. SAS version 9.4 software (Cary, North Car-olina) was used for all analyses.

RESULTS

PATIENT POPULATION. Of 400 patients enrolled, 276patients performed CPX testing. Twenty-six patientsdid not exercise at the study visit because they hadreached the primary outcome prior to that visit.Another 32 subjects could not exercise due to HFsymptoms, clinical instability, or for other reasons.The remaining 66 subjects either did not undergo CPX

Lala et al. J A C C : H E A R T F A I L U R E V O L . 9 , N O . 3 , 2 0 2 1

Value of CPET in Ambulatory Advanced HF M A R C H 2 0 2 1 : 2 2 6 – 3 6

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due to refusal or withdrawal, outside the study testwindow, or the CPX performed was not interpretable.Of the 276 CPXs performed, 237 tests were completedwithin 30 days of the second study visit. All analyseswere limited to data from these 237 subjects (Figure 1)(CONSORT diagram).

BASELINE CHARACTERISTICS. Clinical characteris-tics are shown in Table 1. The mean age was 60.4 �11.4 years, and 72% of patients were male. Ischemic(n ¼ 128; 54%) and nonischemic (n ¼ 109; 46%) car-diomyopathies were nearly equally represented.Medical therapy was optimized, with 85% of patientstaking ACE inhibitor, ARB, or ARNI and 97% takingbeta-blockers. The majority of patients had New YorkHeart Association (NYHA) functional classes II andIIIa symptoms (85%), and nearly three-fourths ofpatients were INTERMACS profiles 6 and 7 (74%). Themean duration of follow-up following CPX was 326 �91 days. Of the 237 patients, 74 (31%) performedsubmaximal tests, and 163 (69%) performed maximalstudies. Of the 163 maximal tests, 145 studies had RER>1.05, and the remaining 18 patients had RER <1.05but had VO2AT/peak VO2 <75%. Of the 74 submaximaltests, only 2 patients had an RER of >1.05, but thetiming of VO2AT/peak VO2 was >75%. The clinicalcharacteristics of patients in the maximal and sub-maximal cohorts are shown in Table 1. More men thanwomen had maximal exercise test results (p ¼ 0.005).Otherwise there were no differences between sub-jects performing submaximal and maximal exercises.

Results of the CPX test variables and 6-min walktests are shown in Table 2 stratified by submaximalversus maximal effort cohorts. Overall, the mean peakVO2 was 14.0 � 4.3 ml/kg/min. As expected, submaxi-mal exercise parameters including VE/VCO2 slope,VO2AT, and OUES were not significantly different be-tween submaximal and maximal effort groups. Thosewho performed maximal tests had significantly higherpeak parameters including peak VO2, peak VO2 pulse,CP, RER, and Borg scale scores.

OUTCOMES. There were 39 primary composite eventsthroughout the 1-year follow-up (6 transplantations,15 deaths, 18 durable MCS). Cardiac-related deathsoccurred in 10 of 15 subjects (5 from HF, 2 frommyocardial infarction, 1 sudden death, 1 pulselesselectric activity cardiac arrest, and 1 from cardiogenicshock). Of the remaining 5 noncardiac deaths, 1 wasdeemed hepatic but secondary to severe biventricularfailure; 1 was respiratory failure; 1 was vascularrelated; and the cause of death for the remaining 2patients were unknown. There were no differences inevent rates between submaximal patients andmaximal effort patients (Figure 2). Increases in VO2 and

VO2AT were associated with reduced risk of the com-posite endpoint (p < 0.005). Further, higher OUES,PEtCO2, and CP (all 3: p < 0.001) but lower VE/VCO2

slope (p < 0.001) were associated with lower risk, withsimilar RERs (Table 3).

ROC curves show the discriminative power of eachparameter, using AUC at 1 year (AUC1yr) (Figure 3). TheCPX parameter with the highest AUC was VE/VCO2

(0.79; 95% confidence interval [CI]: 0.71 to 0.86),followed by CP (0.77; 95% CI: 0.70 to 0.85).

The independent multivariate predictors ofoutcome identified by Cox regression included VE/VCO2 slope (hazard ratio [HR]: 1.05; 95% CI: 1.02 to1.09; p ¼ 0.001), CP (HR per 100-U change: 0.89;95% CI: 0.83 to 0.95; p ¼ 0.001) and peak Borg scalescore (HR: 1.20; 95% CI: 1.06 to 1.37; p ¼ 0.005)(AUC1yr ¼ 0.83; 95% CI: 0.77 to 0.8849). Whether thesubject completed the CPX with maximal or sub-maximal effort was not an independent outcomepredictor when added to these exercise parameters(p ¼ 0.57) (Table 4). Analysis was also performed us-ing only objective measurements from CPX testing(i.e., excluding patient self-reported measurementsof exercise [Borg score], while controlling for CPXmaximal versus submaximal testing; p ¼ 0.38), andthe best multivariate model then included only VE/VCO2 slope (HR: 1.04; 95% CI: 1.02 to 1.07; p ¼ 0.002)and CP (HR: 0.89; 95% CI: 0.83 to 0.96; p ¼ 0.002)model (AUC1yr ¼ 0.78; 95% CI: 0.71 to 0.86).

Analyses restricted to death alone were alsoconducted to overcome the barrier of including out-comes where data from CPX might have promptedreferral (e.g., to left ventricular assist device [LVAD]

FIGURE 1 Consort Diagram

Of the 400 patients in the REVIVAL study, 237 had CPX results within a

window; 163 had maximal test results, and the other 74 had submaximal

test results. CPX ¼ cardiopulmonary exercise, MCS ¼ mechanical circulatory

support.


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or transplantation). Because there were only 15deaths, descriptive statistics and results from uni-variate cause-specific proportional hazards modelsare shown in Supplemental Table 1. Ventilatory effi-ciency (Ve/VCO2 slope), OUES, PEtCO2 at, and peakPEtCO2, peak oxygen consumption (peak VO2), peak

VO2 pulse, and peak CP were all associated with deathas an outcome.

The MAGGIC (Meta-Analysis Global Group inChronic Heart Failure) risk score has been validatedacross multiple HF populations, including patientsenrolled in the PARADIGM study of sacubitril-

TABLE 1 Clinical Characteristics of Patients Performing CPX 2 Months � 30 Days From Enrollment

All (N ¼ 237) Submaximal (n ¼ 74) Maximal (n ¼ 163) p Value

Age, yrs 60.4 � 11.4 60.7 � 10.5 60.3 � 11.8 0.794

BMI, kg/m2 30.8 � 6.8 31.7 � 6.7 30.4 � 6.9 0.194

Heart rate, beats/min 75 � 12 75 � 11 74 � 13 0.503

Systolic blood pressure, mm Hg 110 � 16 110 � 17 110 � 15 0.691

Ejection fraction % 29 � 8 30 � 8 29 � 8 0.542

Na, mEq 139 � 3 138 � 3 139 � 3 0.147

Creatinine mg/dl 1.4 � 0.7 1.4 � 0.5 1.4 � 0.7 0.470

Females 66 (27.8) 30 (40.5)* 36 (22.1) 0.005

Ischemic cause (yes) 109 (46.0) 31 (41.9) 78 (47.9) 0.403

Race 0.967

Black 50 (21.1) 16 (21.6) 34 (20.9)

White 174 (73.4) 53 (71.6) 121 (74.3)

Other/Unknown 5 (2.1) 2 (2.7) 3 (1.8)

American Indian/Alaskan Native 1 (0.4) 1 (1.4) 0 (0.0)

Asian 3 (1.3) 0 (0.0) 3 (1.8)

More than 1 race 4 (1.7) 2 (2.7) 2 (1.2)

Hispanic ethnicity 19 (8.2) 9 (12.5) 10 (6.3) 0.125

PHQ-8 (n ¼ 229) 0.289

<10 175 (76.4) 48 (70.6) 127 (78.9)

10-14 36 (15.7) 14 (20.6) 22 (13.7)

>14 18 (7.9) 6 (8.8) 12 (7.4)

NYHA functional class 0.473

I 8 (3.4) 2 (2.7) 6 (3.7)

II 80 (33.8) 22 (29.7) 58 (35.6)

IIIa 122 (51.5) 41 (55.4) 81 (49.7)

IIIb 20 (8.4) 7 (9.5) 13 (8.0)

IV 7 (2.9) 2 (2.7) 5 (3.0)

INTERMACS profile 0.826

2, 3, 4 17 (7.2) 5 (6.8) 12 (7.3)

5 45 (19.0) 16 (21.6) 29 (17.8)

6 71 (29.9) 21 (28.4) 50 (30.7)

7 104 (43.9) 32 (43.2) 72 (44.2)

Device (n ¼ 235) 0.676

ICD 119 (50.6) 39 (52.7) 80 (49.7)

BiV pacer/ICD 116 (49.4) 35 (47.3) 81 (50.3)

ACE, ARB, or ARNI 0.245

Yes 201 (84.8) 66 (89.2) 135 (82.8)

Beta-blocker 0.439

Yes 230 (97.0) 73 (98.6) 157 (96.3)

Loop diuretic 0.403

Yes 221(93.2) 71 (95.9) 150 (92.0)

Values are mean � SD or n (%). Continuous variables used Student’s t-tests unless distributions were non-normal (e.g., creatinine), in which case Wilcoxon rank sum tests wereused. For categorical characteristics, Fisher exact tests or Cochran-Armitage trend tests (for NYHA and INTERMACS profile) as appropriate. *Added in NIH race classes fordescriptive purposes, though tests are run on White, Black, and other collapsed race variable.

ACE ¼ angiotensin-converting enzyme; ARB ¼ angiotensin receptor blocker; ARNI ¼ angiotensin receptor neprilysin inhibitor; BiV ¼ biventricular; BMI ¼ body mass index;BP ¼ blood pressure; HR ¼ heart rate; ICD ¼ implantable cardioverter-defibrillator; INTERMACS ¼ Interagency Registry for Mechanically Assisted Circulatory Support; NamEq ¼ sodium milliequivalent; NYHA ¼ New York Heart Association; PHQ-8 ¼ 8-item Patient Health Questionnaire depression scale.



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valsartan compared to enalapril therapy in patientswith chronic HFrEF. It was assessed in this cohort aswell to provide a frame of reference for the predictivevalue of the present model. The MAGGIC multivariaterisk model includes 13 independent predictors of all-cause mortality, including age, male sex, body mass

index, current smoking, diabetes, systolic bloodpressure, NYHA functional class, left ventricularejection fraction, chronic obstructive pulmonary dis-ease, HF duration >18 months, creatinine level, anduse of ACE inhibitor or ARB and beta-blocker. In thepresent cohort, the MAGGIC risk score had modest

TABLE 2 Summary of Cardiopulmonary Exercise Variables

All With CPX Testing

CPX Test

p ValueSubmaximal Maximal

Peak heart rate, beats/min 113 � 22 (237) 105 � 21 (74) 117 � 22 (163) <0.001

Peak mean arterial blood pressure, mm Hg 87.2 � 14.7 (233) 86.6 � 14.4 (72) 87.5 � 14.9 (161) 0.696

VO2AT, ml/kg/min 9.9 � 2.6 (218) 9.4 � 2.9 (56) 10.0 � 2.5 (162) 0.107

VE/VCO2 slope 36.8 � 9.4 (235) 38.7 � 11.5 (72) 35.9 � 8.1 (163) 0.064

OUES 1,553 � 538 (233) 1,504 � 633 (72) 1,574 � 491 (161) 0.403

PEtCO2, at rest 33.7 � 5.1 (219) 32.4 � 4.7 (66) 34.2 � 5.2 (153) 0.016

Peak VO2 (ml/kg/min) 14.0 � 4.3 (237) 11.4 � 3.3 (74) 15.1 � 4.2 (163) <0.001

Pulse VO2 (peak) 11.4 � 3.7 (237) 10.4 � 4.2 (74) 11.8 � 3.4 (163) 0.018

Peak PEtCO2 (ml/kg/min) 33.1 � 6.5 (224) 32.1 � 6.7 (70) 33.5 � 6.4 (154) 0.119

PEtCO2 difference 0.72 � 4.6 (219) 0.78 � 4.5 (66) 0.70 � 4.7 (153) 0.903

Peak circulatory power (peak VO2 [ml/kg/min]) � peak systolic BP 1,754 � 699 (235) 1,407 � 529 (72) 1,908 � 710 (163) <0.001

Peak RER 1.08 � 0.12 (237) 0.95 � 0.08 (74) 1.14 � 0.09 (163) <0.001

CPX test (modified Borg score at peak exercise) 15.8 � 3.0 (233) 14.7 � 3.5 (72) 16.3 � 2.6 (161) 0.001

6-min walk distance, m 352.7 � 98.1 (228) 305.3 � 100.2 (69) 373.3 � 89.9 (159) <0.001

Values are mean � SD (n).

BP ¼ blood pressure; CPX ¼ cardiopulmonary exercise; OUES ¼ oxygen uptake efficiency slope; Peak VO2 ¼ peak oxygen consumption; PEtCO2 ¼ peak end-tidal pressurecarbon dioxide; RER ¼ respiratory exchange ratio; VE/VCO2 ¼ ventilatory efficiency; VO2AT ¼ oxygen consumption at anaerobic threshold.

FIGURE 2 Kaplan-Meier Curves of Patients Who Completed Maximal Tests Versus Those Who Completed Submaximal Tests

Kaplan-Meier curves show similar rates of survival free from MCS or TXP between patients performing submaximal (blue line) versus maximal

(red line) tests. MCS ¼ mechanical circulatory support; TXP ¼ transplant.


231


discriminatory value in determining the composite ofLVAD, transplantation, or death at 1 year with an HRof 1.077 (95% CI: 1.020 to 1.136), AUC1year of 0.632(95% CI: 0.455 to 0.809). Restricted to death alone,

the HR was 1.095 (95% CI: 1.004 to 1.195), withAUC1year of 0.666 (95% CI: 0.408 to 0.925).

DISCUSSION

This study identified the CPX parameters moststrongly associated with a combined risk of implan-tation of durable MCS, cardiac transplantation, ordeath at 1 year among a large cohort of ambulatorypatients with advanced HFrEF receiving contempo-rary optimal medical therapy. Specifically, VE/VCO2

slope, a submaximal exercise parameter, and CP, amaximal exercise parameter, were identified as theonly 2 statistically significant, objectively determinedprognostic parameters. Importantly, this study alsodemonstrated that patients’ reported rating of fatigueduring exercise (Borg scale score) was independentlypredictive of this combined outcome (CentralIllustration).

Identifying markers of prognosis to guide decisionmanagement in advanced HF patients remains anarea of intense investigation. As such, after the initialdescription (1) of the value of peak VO2 to risk-stratifycardiac transplant candidates, many studies havesought to identify other parameters measured duringCPX testing as prognostic markers (2–17). The gener-alizability of those findings has been limited, how-ever, due to inclusion of patients with less severe HFon noncontemporary medical regimens. TheREVIVAL registry offers a unique opportunity todefine predictors of outcome in a contemporarycohort of advanced HFrEF patients. All patients un-derwent a uniform exercise protocol with consistentinterpretation. Due to the physical limitations of

TABLE 3 Values for Patients With and Without Primary Outcome and Univariable Cox Model Results

No Event (n ¼ 198) Transplant/VAD/Death (n ¼ 39) Hazard Ratio (95% CI) p Value

Age, yrs 60.35 (11.5) 60.56 (11.2) 0.99 (0.97–1.03) 0.938

Male, % 145/198 (73.2) 26/39 (66.7) 0.76 (0.39–1.47) 0.409

LVEF 29.48 (8.2) 26.41 (7.0) 0.95 (0.91–0.99) 0.029

Cause of HF (ischemia vs. nonischemia) 92/198 (46.5) 17/39 (43.6) 0.87 (0.460–1.631) 0.656

BMI, kg/m2 30.87 (6.9) 30.54 (6.6) 0.99 (0.95–1.04) 0.757

Peak VO2, ml/kg/min 14.37 (4.3) 11.91 (3.8) 0.86 (0.79–0.94) 0.001

Peak RER 1.08 (0.13) 1.09 (0.11) 2.10 (0.17–25.68) 0.562

VO2AT, ml/kg/min 10.09 (2.5) 8.72 (2.8) 0.83 (0.73–0.94) 0.004

VE/VCO2 slope 35.31 (8.0) 44.16 (11.9) 1.07 (1.04–1.09) <0.001

OUES 1,608.26 (529.3) 1,266.97 (496.4) 0.89 (0.83–0.95) <0.001

PEtCO2, peak exercise 33.94 (6.3) 28.41 (5.7) 0.87 (0.82–0.92) <0.001

Circulatory power 1,841.34 (700.8) 1,310.62 (494.5) 0.87 (0.81–0.92) <0.001

VO2 pulse, peak 11.52 (3.7) 10.50 (3.5) 0.93 (0.85–1.02) 0.124

Peak Borg score 15.62 (3.1) 16.84 (2.6) 1.18 (1.03–1.34) 0.013

Values are n (%) or n/N (%).

BMI ¼ body mass index; HF ¼ heart failure; LVEF ¼ left ventricular ejection fraction; OUES ¼ oxygen uptake efficiency slope; PEtCO2 ¼ peak end-tidal pressure carbondioxide; RER ¼ respiratory exchange ratio; VE/VCO2 ¼ ventilatory efficiency; VO2 ¼ oxygen consumption; VO2AT ¼ oxygen consumption at anaerobic threshold.

FIGURE 3 Receiver-Operator Curves for Submaximal and Maximal Parameters

Receiver operator curves are shown for each of the parameters, derived from both

maximal and submaximal tests. Ve/VCO2 had the highest predictive value (highest AUC)

followed by circulatory (Circ.) power. AUC ¼ area under curve; CI ¼ confidence interval;

CPX ¼ cardiopulmonary exercise; OUES ¼ oxygen uptake efficiency slope;

PEtCO2 ¼ peak end- tidal pressure CO2; ROC ¼ receiver-operating characteristics;

VE/VCO2 ¼ ventilatory efficiency; VO2 ¼ oxygen consumption; VO2AT ¼ VO2 at anaerobic

threshold.



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advanced HF patients, submaximal parameters asso-ciated with the primary outcome were also examined.

MAXIMAL PARAMETERS. CP is an interesting vari-able that incorporates peak systolic blood pressurewith peak VO2 and, as such, estimates total work.First described by Cohen-Solal et al. (9), CP wasdeveloped as an estimate of left ventricular strokework index, which on invasive CPX testing wasconsistently found to be predictive of outcome. In thepresent cohort, CP was found to be the maximalparameter most strongly associated with the com-posite outcome, although peak VO2, and peak VO2

pulse were also univariate predictors. CP may provideincremental prognostic information over peak VO2 inpatients with advanced ambulatory HF and should bereviewed as an integral part of CPX output.

SUBMAXIMAL PARAMETERS. The present analysisprovides further support for the value of the VE/VCO2

slope as it had the highest ROC and was 1 of 3 multi-variate predictors for the composite outcome at 1year. This parameter has consistently demonstrated

prognostic power that, in many studies, even excee-ded the predictive value of peak VO2 (3–6), carryingwith it the appeal of not requiring maximal exerciseeffort. The ventilatory equivalent for VCO2 (VE/VCO2

slope) can be derived using all data throughout ex-ercise, which is what was done for this analysis, or asa single point at the time of anaerobic threshold(VO2AT). The mean VE/VCO2 for the present cohortwas >34, consistent with advanced HF (5). Theprognostic significance of ventilatory efficiencymaybe even more relevant in women, who were morelikely to perform submaximal tests.

Other submaximal parameters examined includedthe end-tidal CO2 at rest and at peak exercise, both of

TABLE 4 Predictors of Outcome Adjusted for Maximal/Submaximal Effort

Hazard Ratio (95% CI) p Value

VE/VCO2 1.05 (1.02–1.09) 0.001

Circulatory power 0.89 (0.83–0.95) 0.001

Peak Borg score 1.20 (1.06–1.37) 0.005

CI ¼ confidence interval; VE/VCO2 ¼ ventilatory efficiency.

CENTRAL ILLUSTRATION Ambulatory Advanced Heart Failure Cardiopulmonary Exercise Testing

Patient-reported

0.00

0.00

0.25

0.50

0.75

1.00

0.25 0.501-Specificity

Sens

itivi

ty

0.75 1.00

Maximal effort

Submaximal effortVentilatory efficiency(VE/VCO2) slope

Borg Scale

Circulatory Power

PEtCO2Peak VO2Circ. PowerVO2 ATVO2 Pulse

VE/VCO2 SlopeAUC (95% CI)

OUES0.77 (0.68-0.85)0.72 (0.63-0.82)0.77 (0.70-0.85)0.69 (0.59-0.78)0.62 (0.32-0.92)

0.79 (0.71-0.86)0.75 (0.67-0.82)

Lala, A. et al. J Am Coll Cardiol HF. 2021;9(3):226–36.

Among patients with ambulatory advanced heart failure who underwent cardiopulmonary exercise testing, the best submaximal predictor of the combined outcome of

death, durable mechanical circulatory support, or cardiac transplantation at 1 year was the ventilatory efficiency (Ve/VCO2 slope). Circ. ¼ circulatory; OUES ¼ oxygen

uptake efficiency slope; PEtCO2 ¼ peak end- tidal pressure CO2; VO2 ¼ oxygen consumption; VO2AT ¼ VO2 at anaerobic threshold.


233


which are associated with cardiac output. An end-tidal CO2 at rest of >33 mm Hg with a 3–8 mm Hgrise during exercise generally is associated with agood prognosis, whereas lower PEtCO2 values withless than a 3 mm Hg rise with exercise predict a poorprognosis due to limited cardiac output response (15).In the present cohort, the PEtCO2 averaged 34 at restwith less than a 1 mm Hg rise in this value at endexercise, consistent with severe disease. It is inter-esting that the patients who only achieved a sub-maximal test had lower resting PEtCO2, potentiallyindicating lower resting cardiac output, althoughboth maximal and submaximal exercise groups failedto increase PEtCO2 with exercise.

OUES further extends the ventilatory efficiency byintegrating muscular function, as it correlates withthe rate of VO2 uptake by the muscles in response toventilation during exercise (12–14). In the REVIVALcohort, the average OUES was >1,400, but was stillsignificantly lower than the normal response (12).Although associated with the primary outcome, thepredictive value of OUES was inferior to that of VE/VCO2 slope. VO2 at the anaerobic threshold can bedifficult to identify with considerable inter-readervariability while interpreting studies (11). The pre-sent prime criteria for identification of the anaerobicthreshold was the nadir of the VE/VO2 ratio while theVE/VCO2 ratio remained flat (23). Although VO2ATwas a univariate predictor of outcome, it did notreach significance in the multivariate model.

A key point of emphasis is that though submaximaltests (RER <1.0) are often disregarded as not clinicallyuseful, these studies yielded meaningful prognosticinformation that can aid in risk stratification. Suchdata may help to inform shared decision-making andpotentially guide patient expectations in the ambu-latory advanced HF setting.

SUBJECTIVE MEASUREMENT OF DYSPNEA. The Borgscale is generally used as a practical tool to assess theintensity level of exercise and guide exercise training.To the best of the authors’ knowledge, there are nocontemporary reports that demonstrate the value ofpeak Borg scale achieved during exercise as a pre-dictor of outcome in the HF population. Generally,data obtained during CPX are objective, physiologi-cally measured parameters that have no subjectiveinput. In this era, when the significance of patient-reported outcomes are increasingly recognized, theauthors were humbled to observe that the sensationof greater exercise effort as measured by the Borgscale was independently associated with the 1-yearcomposite outcome. Similar to the dyspnea visualanalog scale assessments and to some extent NYHA

functional class, patient perception and assessmentof “total body effort” remains exceedingly important,both from the perspective of quality of life and forrisk stratification. Interestingly, the peak Borg scalescore was not associated with the measured index ofdepression (p ¼ 0.30). However, as the PHQ-8 ques-tionnaire only assesses degrees of depression, thepossibility that a positive mood may influence bothpersonal assessment of exercise intensity and HFoutcome cannot be excluded. The reproducibility ofthis novel and interesting finding requiresfurther investigation.

MULTIVARIATE MODELS. Previous studies devel-oped multivariate models to predict outcome exclu-sively using CPX parameters (24,25), whereas otherstudies integrated clinical variables (26,27). Keteyianet al. (24) evaluated 10 exercise variables obtainedduring treadmill testing by using the Naughton pro-tocol among 2,100 patients with HFrEF (mainly NYHAfunctional class II) from the HF-ACTION (Heart Fail-ure: A Controlled Trial Investigating Outcomes ofExercise Training) study conducted approximately 15years ago. That study found PPVO2, peak VO2, andexercise duration were the best multivariate pre-dictors of adverse outcome. Nearly a decade earlier,Myers et al. (25) developed a model from a cohort of710 patients with both HFrEF and HF with preservedEF (HFpEF) who underwent bicycle and treadmillstudies from 4 different institutions with varying ex-ercise protocols and no centralized over-reading oftests. The studies identified a VE/VCO2 slope >34, apeak VO2 <14, a PEtCO2 <33, an OUES >1.4, and heartrate recovery of <6 beats/min as the key variables forpredicting death, HF hospitalizations, heart trans-plantation, and LVAD implantation. CP was notanalyzed. Combined clinical and exercise models suchas the Metabolic Exercise test data combined withCardiac and Kidney Indexes (MECKI) score (26)include PPVO2 and VE/VCO2 slope, whereas theHeart Failure Survival Score (27) includes peak VO2,and the ACTION-HF study predictive risk modelincluded only exercise duration (18). In comparison,the present multivariate model is readily applicable tocontemporary ambulatory advanced HF patients andshows 3 powerful predictors: one maximal (CP), onesubmaximal (VE/VCO2 slope), and is the only model toinclude a patient-reported metric (Borg scale score).

STUDY LIMITATIONS. Despite efforts to be compre-hensive, there were some exercise-related variablesthat were not consistently collected and could not beexamined. Namely, exercise oscillatory ventilation isan important variable, which was not available in thetests performed using systems outside of Medical



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Graphics or Sensor Medics software. Also, heart raterecovery data and VO2 kinetics were not recorded.Despite the fact that CPX testing was part of theprotocol, events occurring prior to the scheduledsecond visit and a variety of both cardiac, noncardiac,and nonmedical reasons resulted in <70% of the pa-tients completing the study during the visit window.Even though log files were transferred by computerfor most exercise study results, in approximately 23%of the studies, breath-by-breath data were not avail-able for interpretation. Still, every effort was made toconsistently analyze all exercise data. Additionally, itis plausible that information gained from CPX testinginfluenced practice patterns to refer for LVAD ortransplantation sooner rather than later. Thus, ana-lyses were also performed with death as the soleoutcome; however, due to small numbers, multivar-iate analyses could not be performed. Nonetheless,univariate associations were similar to those seen forthe composite outcome.

CONCLUSIONS

Among a contemporary cohort of ambulatory patientswith advanced systolic HF, the strongest CPX pre-dictors of poor outcomes within 1 year (durable MCSimplantation, cardiac transplantation, or death) wereCP and VE/VCO2 slope, respectively. Patient-reportedmeasurements of exercise effort (Borg scale score)also substantially contributed to outcome prediction,a surprising and novel finding that warrants furtherinvestigation. CPX can be done safely and, undercompetent expertise, serves as a valuable componentof evaluation of patients with HF.

FUNDING SUPPORT AND AUTHOR DISCLOSURES

Supported by U.S. National Institutes of Health, National Heart, Lung,

and Blood Institute (NHLBI) contract HHSN268201100026C, and

National Center for Advancing Translational Sciences grant

UL1TR002240. The views expressed in this manuscript are those of

the authors and do not necessarily represent the views of the National

Heart, Lung, and Blood Institute (NHLBI), National Institutes

of Health, or the US Department of Health and Human Services.

Dr. Lanfear has received research grants from NHLBI (R01HL132154),

Amgen, Bayer, and Janssen; and is a consultant for Amgen, Janssen,

Ortho Diagnostics, and Novartis. All other authors have reported that

they have no relationships relevant to the contents of this paper to

disclose.

ADDRESS FOR CORRESPONDENCE: Dr. Donna M.Mancini, Department of Population Health Science andPolicy, Icahn School of Medicine at Mount Sinai, OneGustave L. Levy Place, Box 1077, New York, New York10029, USA. E-mail: [email protected].

RE F E RENCE S

1. Mancini D, Eisen H, Kussmaul W, Mull R,Edmunds LH, Wilson JR. Value of peak exerciseoxygen consumption for optimal timing of cardiactransplantation in ambulatory patients with heartfailure. Circulation 1991;83:778–86.

2. Carro U, Piepoli M, Adamopoulos S, et al. Car-diopulmonary exercise testing in systolic heartfailure in 2014: the evolving prognostic role. Eur JHeart Fail 2014;16:929–41.

3. Chua TP, Ponikowski P, Harrington D, et al.Clinical correlates and prognostic significance ofthe ventilatory response to exercise in chronicheart failure. J Am Coll Cardiol 1997;29:1585–90.

4. Kleber FX, Vietzke G, Wernecke KD, et al.Impairment of ventilatory efficiency in heart

failure: prognostic impact. Circulation 2000;101:2803–9.

5. Arena R, Myers J, Aslam A, Varughese E,Perberdy M. Peak VO2 and VE/VCO2 slope in pa-tients with heart failure: a prognostic comparison.Am Heart J 2004;147:354–60.

6. Arena R, Myers J, Abella J, et al. Developmentof a ventilatory classification system in patientswith heart failure. Circulation 2007;115:2410–7.

7. Aaronson KD, Mancini DM. Is percentage ofpredicted maximal exercise oxygen consumption abetter predictor of survival than peak exerciseoxygen consumption for patients with severeheart failure? J Heart Lung Transplant 1995;14:981–9.

8. Osada N, Chaitman B, Miller L, et al. Cardio-pulmonary exercise testing identifies low risk pa-tients with heart failure and severely impairedexercise capacity considered for heart trans-plantation. J Am Coll Cardiol 1998;31:577–82.

9. Cohen-Solal A, Tabet J, Logeart D, Bourgoin P,Tokmakova M, Dahan M. A non-invasively deter-mined surrogate of cardiac power (“circulatorypower”) at peak exercise is a powerful prognosticfactor in chronic heart failure. Eur Heart J 2002;23:806–14.

10. Lang C, Karlin P, Haythe J, Lim T, Mancini D.Peak cardiac power output, measured non-invasively, is a powerful predictor of outcome inchronic heart failure. Circ Heart Fail 2009;2:33–8.

PERSPECTIVES

COMPETENCY IN MEDICAL KNOWLEDGE: Both submaxi-

mal and maximal effort cardiopulmonary exercise testing yielded

important prognostic information for patients with advanced

HFrEF. Elevated ventilatory efficiency slopes (a submaximal

parameter) and circulatory power, which combines peak oxygen

consumption and peak systolic blood pressure (a maximal

parameter) as well as patient-reported fatigue during exercise,

predict durable mechanical circulatory support, transplantation,

or death at 1 year.

TRANSLATIONAL OUTLOOK 1: Cardiopulmonary exercise

testing yields important prognostic information for patients with

ambulatory advanced heart failure regardless of maximal effort

and should be performed in this patient population.

TRANSLATIONAL OUTLOOK 2: Patient-reported measure-

ments of exercise effort (Borg scale score) contributed sub-

stantially to outcome prediction, a surprising and novel finding

that warrants further investigation.


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mailto:[email protected]

http://refhub.elsevier.com/S2213-1779(20)30703-4/sref1













































11. Agostoni P, Corrà U, Cattadori G, et al., for theMECKI Score Research Group. Prognostic value ofindeterminable anaerobic threshold in heart fail-ure. Circ Heart Fail 2013;6:977–87.

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13. Baba R, Nagashima M, Goto M, et al. Oxygenuptake efficiency slope: a new index of cardiore-spiratory functional reserve derived from therelation between oxygen uptake and minuteventilation during incremental exercise. J Am CollCardiol 1996;28:1567–72.

14. Davies LC, Wensel R, Georgiadou P, et al.Enhanced prognostic value from cardiopulmonaryexercise testing in chronic heart failure by non-linear analysis: oxygen uptake efficiency slope.Eur Heart J 2006;27:684–90.

15. Matsumoto A, Itoh H, Eto Y, et al. End tidalCO2 decreases during exercise in cardiac patients.J Am Coll Cardiol 2000;36:242–9.

16. Olson L, Arruda-Olson A, Somers V, Scott C,Johnson B. Exercise oscillatory ventilation:instability of breathing control associated withadvanced heart failure. Chest 2008;133:474–81.

17. Corrà U, Pistono M, Mezzani A, et al. Sleep andexertional periodic breathing in chronic heart

failure: prognostic importance and interdepen-dence. Circulation 2006;113:44–50.

18. O’Connor CM, Whellan DJ, Wojdyla D, et al.Factors related to morbidity and mortality in pa-tients with chronic heart failure with systolicdysfunction: the HF-ACTION predictive risk scoremodel. Circ Heart Fail 2012;5:63–71.

19. Aaronson KD, Stewart GC, Pagani FD, et al.Registry evaluation of vital information for VADsin Ambulatory Life (REVIVAL): rationale, design,baseline characteristics, and inclusion criteriaperformance. J Heart Lung Transplant 2020;39:7–15.

20. Naughton J, Seveluis G, Balke B. Physiologicalresponses of normal and pathologic subjects to amodified work capacity test. J Sports Med 1963;3:201–7.

21. Borg G. Perceived exertion as an indicator ofsomatic stress. Scand J Rehabil Med 1970;2:92–8.

22. Hassen J, Sue D, Wasserman K. Predictedvalues in clinical exercise testing. Am Rev RespirDis 1984;129:S49–55.

23. Wasserman K, Whipp B, Koyal S, Beaver W.Anaerobic threshold and respiratory gas ex-change during exercise. J Appl Physiol 1973;35:236–43.

24. Keteyian S, Patel M, Kraus W, Brawner C, et al.Variables measured during cardiopulmonary exer-

cise Testing as predictors of mortality in chronicsystolic heart failure. J Am Coll Cardiol 2016;67:780–9.

25. Myers J, Arena R, Dewey F, et al.A cardiopulmonary exercise testing score for pre-dicting outcomes in patients with heart failure. AmHeart J 2008;156:1177–82.

26. Agostoni P, Corrà U, Cattadori G, et al., for theMECKI Score Research Group. Metabolic exercisetest data combined with cardiac and kidney in-dexes, the MECKI score: a multiparametricapproach to heart failure prognosis. Int J Cardiol2013;167:2710–8.

27. Aaronson KD, Schwartz JS, Chen TM, Wong KL,Goin JE,Mancini DM.Development andprospectivevalidation of a clinical index to predict survival inambulatory patients referred for cardiac transplantevaluation. Circulation 1997;95:2660–7.

KEY WORDS ambulatory heart failure,cardiac transplant, cardiopulmonary exercisestress test, mechanical circulatory support,predictors

APPENDIX For a supplemental appendix andtable, please see the online version of thispaper.



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predictive value of cardiopulmonary exercise testing

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