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Relation of the Prognostic Value of Ventilatory Efficiency to BodyMass Index in Patients With Heart Failure

Paul Chase, MEda,*, Ross Arena, PhDb, Jonathan Myers, PhDd, Joshua Abella MDc,Mary Ann Peberdy, MDc, Marco Guazzi, MD, PhDe, and Daniel Bensimhon, MDa

The ventilatory efficiency, minute ventilation (VE)/carbon dioxide production (VCO2),slope consistently provides valuable prognostic information in patients with heart failure(HF). Patients with a higher body mass index (BMI) have demonstrated an improvedprognosis in the HF population, a phenomenon that has been termed the “obesity para-dox.” The purpose of this study was to evaluate the prognostic ability of the VE/VCO2 slopeaccording to BMI in patients with HF. Seven-hundred four patients with HF (555 men, 149women, mean age 56.8 � 13.4 years, ejection fraction 33.1 � 13.3%) with a BMI >18.5kg/m2 underwent cardiopulmonary exercise testing. Subjects were divided into 3 BMIsubgroups (18.5 to 24.9, 25.0 to 29.9, and >30 kg/m2). Each subject was tracked for majorcardiac events (death, transplantation, left ventricular assist device implantation) for 2years after testing. There were 86 major cardiac events (71 deaths, 10 transplantations, 5left ventricular assist device implantations) during the 2-year tracking period (overallannual event rate 8.2%). The VE/VCO2 slope was the strongest prognostic marker in eachBMI subgroup. Subjects in the highest BMI group had the lowest mean VE/VCO2 slope andthe lowest rate of major cardiac events of the 3 groups. Multivariate Cox regression analysisshowed that peak VO2 did not add additional prognostic value to the VE/VCO2 slope andwas removed from the regression for each BMI subgroup. In conclusion, the findings of thepresent study indicate that VE/VCO2 slope maintains prognostic value irrespective of BMIin patients with HF. © 2008 Elsevier Inc. All rights reserved. (Am J Cardiol 2008;101:

348–352)

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besity is associated with alterations in pulmonary functionnd mechanics, leading to increased potential for obstruc-ive sleep apnea, obesity/hypoventilation syndrome, dys-nea on exertion, and exercise intolerance. It has been wellstablished that the ventilatory efficiency, minute ventila-ion (VE)/carbon dioxide production (VCO2), slope andeak oxygen consumption (VO2) consistently provide valu-ble prognostic information in patients with heart failureHF).1–6 Several recent studies have shown that the VE/CO2 slope outperforms peak VO2 in predicting major

ardiac events. To our knowledge, the effect of obesity onhe VE/VCO2 slope and the prognostic power of cardiopul-

onary exercise testing in patients with HF have not beenully evaluated. The purpose of this study was to evaluatehe prognostic ability of the VE/VCO2 slope in patients withF across the spectrum of body mass index (BMI).

aLeBauer Cardiovascular Research Foundation, Greensboro, Northarolina; bDepartments of Physical Therapy and cInternal Medicine, Vir-inia Commonwealth University, Richmond, Virginia; dVA Palo Altoealth Care System, Cardiology Division, Stanford University, Palo Alto,alifornia; and eUniversity of Milano, San Paolo Hospital, Cardiopulmo-ary Laboratory, Cardiology Division, University of Milano, San Paoloospital, Milano, Italy. Manuscript received June 16, 2007; revised manu-

cript received and accepted August 24, 2007.*Corresponding author: Tel: 336-832-2546; fax: 336-832-7746.

AE-mail address: paul.chase@mosescone.com (P. Chase).

002-9149/08/$ – see front matter © 2008 Elsevier Inc. All rights reserved.oi:10.1016/j.amjcard.2007.08.042

ethods

his study is a multicenter analysis including patients withF from cardiopulmonary exercise laboratories at San Pa-lo Hospital (Milan, Italy), Virginia Commonwealth Uni-ersity (Richmond, Virginia), LeBauer Cardiovascular Re-earch Foundation (Greensboro, North Carolina), and theA Palo Alto Health Care System and Stanford University

Palo Alto, California). A total of 704 patients with chronicF and tested between March 18, 1993 and March 5, 2007ere included. Inclusion criteria consisted of a diagnosis ofF,7 stable HF symptoms and medications for �1 monthefore exercise testing, a BMI �18.5 kg/m2 (lower thresh-ld of normal), and evidence of left ventricular systolicnd/or diastolic dysfunction by 2-dimensional echocardiog-aphy performed within 1 month of exercise testing. Sub-ects were classified as having systolic HF if they presentedith a left ventricular ejection fraction �45%. Subjects with

n ejection fraction �50% and clinical evidence of HF werelassified as having diastolic dysfunction.8 As our group hasone previously,3,4 patients with diastolic dysfunction (14%f entire group) were grouped with subjects with nonisch-mic HF for analysis. Subjects received routine follow-upare at the 4 institutions included in this study. All subjectsompleted a written informed consent and institutional re-iew board approval was obtained at each institution.

Symptom-limited cardiopulmonary exercise testing waserformed in all patients using treadmill9 or cycle ergom-try10 ramping protocols. A treadmill was used for testing in

merican centers, whereas a lower extremity cycle ergome-

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349Heart Failure/Ventilatory Efficiency and BMI

er was used in the European center. Ventilatory expired gasnalysis was performed using a metabolic cart at all 4enters (Medgraphics CPX-D or ULTIMA PFX, Minneap-lis, Minnesota; Parvo Medics TrueOne 2400, Sandy, Utah;r Sensormedics Vmax29, Yorba Linda, California). Beforeach test, the equipment was calibrated in standard fashionsing reference gases. In addition, each center routinelyalidated its metabolic exercise testing equipment by exer-ising a healthy subject at a submaximal steady rate toerify that measured VO2 matched estimated VO2 from theorkload.11 Previous studies have demonstrated that opti-al peak VO2 and VE/VCO2 slope prognostic threshold

alues are similar irrespective of mode of exercise in pa-ients with HF.12 We therefore did not create subgroupsased on type of exercise. Standard 12-lead electrocardio-rams were obtained at rest, at each minute during exercise,nd for �5 minutes during the recovery phase; blood pres-ure was measured using a standard cuff sphygmomanom-ter. VE, VO2, VCO2, and other cardiopulmonary variablesere acquired breath by breath and averaged over 10- or5-second intervals. Peak VO2 and peak respiratory ex-hange ratio were expressed as the highest averaged sam-les obtained during the exercise test. VE and VCO2 values,cquired from initiation of exercise to peak, were input intopreadsheet software (Microsoft Excel, Microsoft Corp.,ellevue, Washington) to calculate the VE/VCO2 slope by

east squares linear regression (y � mx � b, m � slope).revious work by our group and others has shown that thisethod of calculating the VE/VCO2 slope is prognostically

ptimal.13,14

Using hospital and outpatient chart review, subjects wereollowed for major cardiac-related events (heart transplan-

able 1verall group characteristics and body mass index subgroup comparisons

ariable Overall Group(n � 704)

ge (yrs)* 56.8 � 13.4MI (kg/m2)† 28.6 � 5.9en/women 555 (79%)/149 (21%)

jection fraction (%) 33 � 13ew York Heart Association classI 134 (19%)II 289 (41%)III 253 (36%)IV 27 (4%)F cause (nonischemic/ischemic)* 346 (49%)/358 (51%)readmill/bicycle* 494 (70%)/210 (30%)O2 (ml O2/kg/min) 16.8 � 6.4O2 (L O2/min)† 1.42 � 0.63E/VCO2 slope‡ 33.8 � 8.7eak respiratory exchange ratio§ 1.07 � 0.17rescribed angiotensin-converting enzyme

inhibitor�529 (75%)

rescribed diuretic* 424 (60%)rescribed � blocker* 438 (62%)

* BMI-III significantly different from BMI-I and BMI-II, p �0.01;† All 3 BMI groups significantly different, p �0.001;‡ BMI-I significantly different from BMI-II and BMI-III, p �0.01;§ BMI-I significantly different from BMI-II, p �0.05;� BMI-II significantly different from BMI-I and BMI-III, p �0.05.

ation, left ventricular assist device implantation, and car- c

iac-related death) for 2 years after cardiopulmonary exer-ise testing. Any death with a cardiac-related dischargeiagnosis was considered an event. Clinicians conductinghe cardiopulmonary exercise testing were not involved inhe end-point adjudication.

Subjects were divided into 3 subgroups according toMI (BMI-I � 18.5 to 24.9 kg/m2, BMI-II � 25 to 29.9g/m2, BMI-III � �30.0 kg/m2). All continuous data areeported as means � SDs and categorical data as percent-ges. One-way analysis of variance was used to assessifferences in key continuous variables and chi-square anal-sis assessed differences in key categorical variables amongMI subgroups. Tukey honestly significant difference wassed to determine BMI subgroups that were significantlyifferent when the 1-way analysis of variance p value was0.05. Kaplan-Meier analysis assessed survival character-

stics of the 3 BMI subgroups. Log-rank test determinedtatistical significance on Kaplan-Meier analysis. Univariatend multivariate Cox regression analyses were used to as-ess the prognostic value of BMI and of key baseline andardiopulmonary variables in the overall cohort. The fol-owing survival analyses were also performed in each BMIubgroup: (1) multivariate Cox regression analysis assessedhe prognostic value of the VE/VCO2 slope, peak VO2, age,jection fraction, and HF cause; (2) receiver operating char-cteristic curve analysis was used to assess VE/VCO2 slopelassification schemes; and (3) Kaplan-Meier analysis as-essed survival characteristics of the VE/VCO2 slope ac-ording to optimal thresholds defined by receiver operatingharacteristic curve analysis. Log-rank test determined sta-istical significance on Kaplan-Meier analysis. Statisticalifferences with a p value �0.05 were considered signifi-

18.5–24.9 kg/m2

n � 198)BMI-II 25.0–29.9 kg/m2

(n � 260)BMI-III �30 kg/m2

(n � 246)

14.7 58.1 � 12.2 53.7 � 131.7 27.3 � 1.5 35 � 4.6

4%)/52 (26%) 227 (87%)/33 (13%) 191 (78%)/55 (22%)13 34 � 13 32 � 13

8%) 56 (22%) 42 (17%)4%) 106 (41%) 96 (39%)2%) 89 (34%) 104 (42%)%) 9 (4%) 4 (2%)3%)/112 (57%) 113 (44%)/147 (56%) 147 (60%)/99 (40%)5%)/69 (35%) 170 (65%)/90 (35%) 195 (79%)/51 (21%)6.6 17 � 6.3 16.6 � 6.50.57 1.41 � 0.57 1.68 � 0.749.5 33.5 � 8.0 32.2 � 8.50.17 1.09 � 0.18 1.06 � 0.16

5%) 187 (72%) 194 (79%)

4%) 148 (57%) 169 (69%)9%) 151 (58%) 171 (70%)

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esults

verall group characteristics and BMI subgroup compari-ons are listed in Table 1. Subjects in BMI-III group wereounger, had a lower VE/VCO2 slope, had a higher absoluteeak VO2 (liters per minute), were more often exercised onhe treadmill, were more often diagnosed with nonischemicF, and were more often prescribed an angiotensin-convert-

ng enzyme inhibitor, � blocker, and diuretic than subjectsn the 2 lower BMI groups. No differences in peak relativeO2 (milliliters of O2 per kilogram per minute) or ejection

raction were noted among the 3 subgroups.There were 86 major cardiac events (71 deaths, 10 heart

ransplantations, and 5 left ventricular device implantations)uring the 2-year tracking period. The annual event rate forhe overall group was 8.2%. The 2-year event rates for theMI-I, BMI-II, and BMI-III subgroups were 10.8%, 8.6%,nd 5.5%, respectively. Kaplan-Meier analysis for the 3MI subgroups is shown in Figure 1. The difference invent-free survival was significantly different with the BMI-II group, demonstrating the most favorable outcome. Thereas a significantly higher risk of major cardiac events for

he combined BMI-I and BMI-II groups compared with theMI-III group (hazard ratio 1.8, 95% confidence interval.1 to 2.9, p � 0.03).

Univariate and multivariate Cox regression analyses forhe overall group are listed in Tables 2 and 3, respectively.he VE/VCO2 slope, peak relativeVO2, peak absolute VO2,jection fraction, and BMI were significant univariate pre-

igure 1. Kaplan-Meier analysis for 2-year major cardiac-related eventsccording to BMI (I � 18.5 to 24.9 kg/m2, 32 major cardiac events, 83.8%vent free; II � 25.0 to 29.9 kg/m2, 34 major cardiac events, 86.9% eventree; III � �30.0 kg/m2, 20 major cardiac events, 91.9% event free;og-rank 6.2, p �0.05).

able 2nivariate Cox regression analysis for overall group

ariable Chi-square p Value

E/VCO2 92.6 �0.001bsolute VO2 36.4 �0.001jection fraction 30.5 �0.001MI 7.2 0.007ge 0.72 0.4F cause 0.09 0.76

ictors of risk. Of these, the VE/VCO2 slope was the most c

obust prognostic marker. In multivariate analysis, peakbsolute VO2 and ejection fraction were the only variableso add significant prognostic value to the VE/VCO2 slopend were retained in the regression.

Multivariate Cox regression analyses for each BMI sub-roup are listed in Table 4. The VE/VCO2 slope was thetrongest predictor of major cardiac events. Ejection frac-ion was retained in the multivariate regression for theMI-I and BMI-III subgroups, whereas age was retained in

he BMI-II subgroup. Peak absolute VO2 was not a signif-cant multivariate predictor in any of the BMI subclassesresidual chi-square �3.8, p �0.05). All other variablesere removed from the multivariate regression.Receiver operating characteristic curve results for the

E/VCO2 slope are listed in Table 5. As expected, areander the receiver operating characteristic curve was signif-cant for all 3 BMI subgroups. The optimal prognostichreshold was similar for the BMI-II and BMI-III subgroupsut higher in the BMI-I subgroup.

Kaplan-Meier analysis for the VE/VCO2 slope prognos-ic thresholds in each BMI subgroup are displayed in Figure. Each threshold effectively discriminated between sub-ects who were event free and those who had a major

able 3ultivariate Cox regression analysis in overall group

ariable Chi-square p Value

E/VCO2 slope 92.6 �0.001jection fraction 20.5† �0.001*bsolute VO2 10.1† 0.001*MI 2.4† 0.13F cause 0.38† 0.54ge 0.01† 0.92

* Retained in multivariate regression.† Residual chi-square.

able 4ultivariate Cox regression analyses in each body mass index subgroup

ariable Chi-square p Value

MI-I 18.5–24.9 kg/m2

VE/VCO2 slope 27.5 �0.001Ejection fraction 9.9† 0.002*Age 2.9† 0.09HF cause 1.7† 0.19Relative VO2 0.03† 0.86MI-II 25.0–29.9 kg/m2

VE/VCO2 slope 25.1 �0.001Age 6.6† 0.01*Relative VO2 3.6† 0.06Ejection fraction 1.3† 0.26HF cause 0.72† 0.4MI-III �30.0 kg/m2

VE/VCO2 slope 25.3 �0.001Ejection fraction 13† �0.001*Age 2.2† 0.14Relative VO2 0.89† 0.35HF cause 0.15† 0.7

* Retained in multivariate regression.† Residual chi-square.

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351Heart Failure/Ventilatory Efficiency and BMI

iscussion

umerous recent studies have shown that the VE/VCO2lope outperforms peak VO2 in stratifying risk in patientsith HF. Thus, our present investigation was designed to

valuate whether the VE/VCO2 slope would retain its prog-ostic power in an obese population with HF and couldvercome some of the inherent shortcomings of peak VO2n this group. Our data show that, despite similar peakelative VO2 results, patients in the BMI-III group hadignificantly lower VE/VCO2 slopes, and there was an ap-arent trend for the slope to decrease with increasing BMI.urthermore, consistent with previous reports (the obesityaradox), the annual event rate in the BMI-III group wasomparatively low, and the event rate tended to decreaseith increasing BMI.This inverse relation between BMI and VE/VCO2 slope

as independent of peak VO2 (absolute or relative). How-ver, the optimal prognostic threshold for the VE/VCO2lope was identical to most of previous reports, which didot account for BMI. The findings of the present studyurther support the clinical utilization of cardiopulmonaryxercize testing and in particular the VE/VCO2 slope, toelp stratify risk in patients with HF across a wide range ofemographics.

Because obesity and HF can have significant effects onentilation, the potential mechanisms underlying the de-rease in VE/VCO2 slope with increasing BMI in our studyeserves further discussion. First, patients with HF pre-cribed � blockers have shown improved outcomes (untilhe peak VO2 is decreased to �10 ml O2/kg/min)15 and aower VE/VCO2 prognostic threshold value.16 In our data-et, significantly more patients in the BMI-III group wererescribed �-blocker therapy, and thus it may be argued thathe lower VE/VCO slope and improved prognosis in this

able 5eceiver-operating characteristic curve analysis for ventilatory efficiency

MI (kg/m2) Receiver Operator Characteristic Area (95% CI) Opt

8.5–24.9 0.75 (0.67–0.83)5.0–29.9 0.8 (0.73–0.87)30.0 0.77 (0.67–0.87)

CI � confidence interval.

igure 2. Kaplan-Meier analysis for the VE/VCO2 slope in subgroups BMIMI-II, VE/VCO2 slopes �34.3 (line A) and �34.3 (line B) (log-rank 33

log-rank 14.1, p �0.001).

2roup compared with thinner subjects may be associated w

ith the differential use of � blockers. However, when theata were analyzed using only patients treated with � block-rs, subjects in the BMI-III group still had a lower meanE/VCO2 slope and event rate than did subjects in the

ower BMI groups. Furthermore, patients in the BMI-IIIroup were prescribed more medications overall, whichay have had some influence on the event rate of this group.

n addition, age is accepted as an independent risk factor fororbidity and mortality. In our dataset, patients in theMI-III group were younger than those in the other 2roups. Regardless, in the overall group age was neither anivariate nor a multivariate predictor of events and was aignificant multivariate predictor only in the BMI-II group.

Perhaps the easiest explanation for the obesity paradox ishat obese patients with HF may have more symptoms ofxertional dyspnea and fatigue due to mechanical limita-ions related to their obesity. In addition, the increased workequired for obese patients during weight-bearing exerciseay have further exacerbated these mechanical limitations.hus, for a given degree of exercise intolerance or peakO2, this population may exhibit less severe disease, fromcirculatory perspective, than their thinner counterparts and

n turn have lower VE/VCO2 slopes and better prognosis.ther posited explanations for the obesity paradox include aigher metabolic reserve, lower levels of circulating B-typeatriuretic peptide, and increased cardiopulmonary fitnessue to the extra work involved in performing activities ofaily living.17,18 These were not investigated in our study.

Conversely, obesity is associated with changes in pul-onary function at rest, particularly decreases in end-expi-

atory lung volume, increased work and energy cost ofreathing, increased partial pressure of arterial carbon di-xide, and decreased hypercapnic ventilatory responses,19

hich would appear to lower the VE/VCO slope but

each body mass index subgroup

reshold Sensitivity/Specificity Hazard Ratio (95% CI) p Value

66/78 6.9 (3.0–16.0) �0.00167/79 7.8 (3.4–18.0) �0.00168/75 5.6 (2.0–15.3) �0.001

CO2 slopes �36.1 (line A) and �36.1 (line B) (log-rank 27.3, p �0.001);.001); and BMI-III, VE/VCO2 slopes �34.0 (line A) and �34.0 (line B)

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352 The American Journal of Cardiology (www.AJConline.org)

oncerning the effects of obesity on cardiopulmonary pa-ameters in subjects who are older, have a BMI �35 kg/m2,r are complicated by other co-morbidities such as obstruc-ive sleep apnea, obesity hypoventilation syndrome, and HFall conditions associated with a decreased ventilatory effi-iency and cardiac prognosis). Further research is necessaryo clearly understand the effects of obesity on cardiopulmo-ary mechanics in a diverse population of patients with HFnd how these apparently pathologic changes may paradox-cally be associated with improved outcomes.

We acknowledge potential limitations to our study. Themajor limitations of this investigation are that (1) we did

ot document any previous diagnosis of sleep apnea (centralr obstructive), which could cause an increased level ofatigue and dyspnea; (2) the small number of women, whichay limit extrapolation of these data to women; (3) a small

umber of patients with advanced New York Heart Asso-iation class IV symptoms; and (4) no measurement of bodyomposition, which may change the prognostic utility ofeak VO2.

1. Mancini DM, Eisen H, Kussmaul W, Mull R, Edmunds LH Jr, WilsonJR. Value of peak exercise oxygen consumption for optimal timing ofcardiac transplantation in ambulatory patients with heart failure. Cir-culation 1991;83:778–786.

2. Chua TP, Ponikowski P, Harrington D, Anker SD, Webb-Peploe K,Clark AL, Poole-Wilson PA, Coats AJ. Clinical correlates and prog-nostic significance of the ventilatory response to exercise in chronicheart failure. J Am Coll Cardiol 1997;29:1585–1590.

3. Arena R, Myers J, Aslam SS, Varughese EB, Peberdy MA. Peak VO2and VE/VCO2 slope in patients with heart failure: a prognostic com-parison. Am Heart J 2004;147:354–360.

4. Arena R, Myers J, Abella J, Peberdy MA, Bensimhon D, Chase P,Guazzi M. Development of a ventilatory classification system in pa-tients with heart failure. Circulation 2007;115:2410–2417.

5. Kleber FX, Vietzke G, Wernecke KD, Bauer U, Opitz C, Wensel R,Sperfeld A, Glaser S. Impairment of ventilatory efficiency in heartfailure: prognostic impact. Circulation 2000;101:2803–2809.

6. Ponikowski P, Francis DP, Piepoli MF, Davies LC, Chua TP, DavosCH, Florea V, Banasiak W, Poole-Wilson PA, Coats AJ, Anker SD.Enhanced ventilatory response to exercise in patients with chronicheart failure and preserved exercise tolerance: marker of abnormalcardiorespiratory reflex control and predictor of poor prognosis. Cir-

culation 2001;103:967–972.

7. Hunt SA. ACC/AHA 2005 guideline update for the diagnosis andmanagement of chronic heart failure in the adult: a report of theAmerican College of Cardiology/American Heart Association TaskForce on Practice Guidelines (Writing Committee to Update the 2001Guidelines for the Evaluation and Management of Heart Failure). J AmColl Cardiol 2005;46(suppl):e1–e82.

8. Cheitlin MD, Armstrong WF, Aurigemma GP, Beller GA, BiermanFZ, Davis JL, Douglas PS, Faxon DP, Gillam LD, Kimball TR, et al.ACC/AHA/ASE 2003 guideline update for the clinical application ofechocardiography: summary article: a report of the American Collegeof Cardiology/American Heart Association Task Force on PracticeGuidelines (ACC/AHA/ASE Committee to Update the 1997 Guide-lines for the Clinical Application of Echocardiography). Circulation2003;108:1146–1162.

9. Arena R, Humphrey R, Peberdy MA, Madigan M. Predicting peakoxygen consumption during a conservative ramping protocol: impli-cations for the heart failure population. J Cardiopulm Rehabil 2003;23:183–189.

0. Guazzi M, Reina G, Tumminello G, Guazzi MD. Improvement ofalveolar-capillary membrane diffusing capacity with exercise trainingin chronic heart failure. J Appl Physiol 2004;97:1866–1873.

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3. Arena R, Myers J, Aslam S, Varughese EB, Peberdy MA. Technicalconsiderations related to the minute ventilation/carbon dioxide outputslope in patients with heart failure. Chest 2003;124:720–727.

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