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Does Exercise Ventilatory Inefficiency Predict Poor Outcome in Heart Failure Patients With COPD? Maria Clara Alencar, MD; Flavio F. Arbex, MD; Aline Souza, PT; Adriana Mazzuco, PT; Priscila A. Sperandio, PT; Alcides Rocha, PT; Daniel M. Hirai, PT; Frederico Mancuso, MD; Danilo C. Berton, MD; Audrey Borghi-Silva, PT; Dirceu Almeida, MD; Denis E. O’Donnel, MD, FRCPC; J. Alberto Neder, MD, FRCPC

■ PURPOSE: To investigate whether the opposite effects of heart failure (HF) and chronic obstructive pulmonary disease (COPD) on exercise ventilatory inefficiency (minute ventilation [V· E]-carbon dioxide output [V· CO2] relationship) would negatively impact its prognostic relevance. ■ METHODS: After treatment optimization and an incremental cardiopulmonary exercise test, 30 male patients with HF-COPD (forced expiratory volume in 1 second [FEV1] = 57% ± 17% predicted, ejection fraction = 35% ± 6%) were prospectively followed up during 412 ± 261 days for major cardiac events. ■ RESULTS: Fourteen patients (46%) had a negative outcome. Patients who had an event had lower echocardiographically determined right ventricular fractional area change (RVFAC), greater ventilatory inefficiency (higher V· E/V· CO2 nadir), and lower end-tidal CO2 (PETCO2) (all P < .05). Multivariate Cox models revealed that V· E/V· CO2 nadir >36, ΔPETCO2(PEAK-REST)≥2 mm Hg, and PETCO2PEAK≤33 mm Hg added prognostic value to RVFAC≤45%. Kaplan-Meyer analyses showed that although 18% of patients with RVFAC>45% had a major cardiac event after 1 year, no patient with RVFAC>45% and V· E/V· CO2 nadir ≤36 (or PETCO2PEAK>33 mm Hg) had a negative event. Conversely, although 69% of patients with RVFAC≤45% had a major cardiac event after 1 year, all patients with RVFAC≤45% and ΔPETCO2(PEAK-REST)≥2 mm Hg had a negative event. ■ CONCLUSION: Ventilatory inefficiency remains a powerful prognostic marker in HF despite the presence of mechanical ventilatory constraints induced by COPD. If these preliminary findings are confirmed in larger studies, optimal thresholds for outcome prediction are likely greater than those traditionally recommended for HF patients without COPD.

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cardiopulmonary exercise test heart failure lung disease prognosis Author Affiliations: Divisions of Respirology (Drs Alencar, Arbex, and Neder, Mss Souza and Sperandio, and Messrs Rocha and Hirai) and Cardiology (Drs Mancuso and Almeida), Federal University of Sao Paulo, Brazil; Respiratory Investigation Unit and Laboratory of Clinical Exercise Physiology, Queen’s University and Kingston General Hospital, Kingston, Ontario, Canada (Mr Hirai and Drs O’Donnel and Neder); Department of Physiotherapy, Federal University of Sao Carlos, Brazil (Mss Mazzuco and BorghiSilva); and Division of Respirology, Federal University of Rio Grande do Sul, Porto Alegre, Brazil (Dr Berton). All authors have read and approved the manuscript. The authors declare no conflicts of interest. Correspondence: J. Alberto Neder, MD, FRCPC, Queen’s University, 102 Stuart St, Kingston, ON K7L 2V6, Canada ([email protected]). DOI: 10.1097/HCR.0000000000000212

Excessive ventilation (V· E) to metabolic demand (carbon dioxide production [V·CO2]) during a rapidly incremental cardiopulmonary exercise test (CPET) is a key

negative prognostic marker in heart failure (HF)1 even in those with preserved exercise capacity.2 Although varying among individuals, the underlying mechanisms

454 / Journal of Cardiopulmonary Rehabilitation and Prevention 2016;36:454-459

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are essentially linked to enlarged physiological dead space (VD) and/or increased neural ventilatory drive because of a plethora of afferent stimuli.3 The final consequence is a faster rate of increase in V·E for a given change in V·CO2 (ie, steeper V·E/V·CO2 slope)4 or a higher V·E for a given V·CO2 (high V·E/V·CO2 ratio)5 (ie, ventilatory inefficiency). Moreover, a combination of reduced partial pressure of carbon dioxide in arterial blood (PaCO2) due to alveolar hyperventilation, a shallow and fast breathing pattern, and poor pulmonary perfusion secondary to low cardiac output may further decrease resting and exercise end-tidal PCO2 (PETCO2) in those with poorer prognosis.6 In this context, there is growing recognition that the phenotype expression and clinical course of HF are strongly modulated by comorbidities.7 Unfortunately, the influence of prevalent comorbidities on the prognostic relevance of ventilatory inefficiency has not been systematically investigated. Chronic obstructive pulmonary disease (COPD) is a common comorbidity of HF (“overlap”),8 which has a potential to influence the prognostic power of ventilatory inefficiency. Importantly, mechanical ventilatory constraints with progressive COPD severity may impair the rate of increase in V·E and actually reduce the V·E/V·CO2 slope9 despite an enlarged VD/tidal volume ratio.10 The same mechanisms can shift the PaCO2 set point upward and further decrease the V·E/V·CO2 slope in severe COPD.3,11 In sharp contrast with HF, therefore, PETCO2 may increase during exercise in COPD, reflecting higher PaCO2 and/or late emptying of less ventilated alveoli with elevated PCO2.10 Interestingly, there is some evidence that overlap patients might display higher V·E/V·CO2 than those with COPD-free HF12 although this has not been consistently found.13 Thus, it remains unknown whether the potential opposite effects of HF and COPD on the V·E/V·CO2 relationship1-5,8-11 might negatively influence the prognostic relevance of ventilatory inefficiency in overlap patients. We prospectively evaluated a well-defined group of overlap patients who were followed up in a specialized referral center. Our primary hypothesis was that ventilatory inefficiency would remain a significant prognostic marker in patients with HF despite the mechanical ventilatory constraints resulting from coexistent COPD.

METHODS Men, 40 years or older, with previously established smoking-related COPD and echocardiographic evidences of HF with reduced left ventricular ejection fraction (80% presented with systemic hypertension, hypercholesterolemia, and coronary artery disease), moderate decrements in ejection fraction (35 ± 6%), and moderate impairment in lung function (forced expiratory

volume in 1 second [FEV1] = 57% ± 17% predicted, residual volume = 125% ± 37% predicted, and DLCO= 51% ± 13% predicted). Most patients (73%) had HF due to underlying coronary artery disease and/or previous myocardial infarction. Patients reporting chronic dyspnea (modified Medical Research Council score ≥2) and impaired daily life activities (New York Heart Association score ≥2) were 80% and 93%, respectively. During the followup period of 962 days (412 ± 261 days, median = 359), 14 patients (46%) had major cardiac events (8 deaths). As shown in Table 1,

T a b l e 1 • Clinical, Resting Functional, and Exercise Responses in Overlap Patients Presenting (+) or Not Presenting (−) With a Major Cardiac Event During the Followupa Event (−) n = 16

Event (+) n = 14

65.5 ± 6.9

68.3 ± 9.1

26.2 ± 3.9

26.5 ± 4.1

NYHA score I-II/III-IV, n (%)

11 (69)/5 (31)

9 (64)/5 (36)

mMRC dyspnea score 0-1/2-4, n (%)

5 (31)/11 (69)

1 (7)/13 (93)b

63.3 ± 16.8

66.7 ± 17.5

FEV1/FVC prebronchodilator

64 [52-70]

63 [55-67]

FEV1/FVC postbronchodilator

64 [51-68]

58 [48-64]

35.7 ± 5.5

34.5 ± 7.8

41.7 ± 18.7

55.3 ± 29.9

10 [7-12]

20 [9-30]

RVDIAM, mm

35.3 ± 6.1

37.6 ± 9.1

RVFAC, %

49.0 ± 8.3

40.7 ± 11.7b

65.0 ± 14.5

62.4 ± 15.1

14.9 ± 3.4

14.0 ± 4.2

115 ± 25

113 ± 21

36 [31-41]

39 [37-45]b

35.1 ± 7.0

45.4 ± 11.7b

2.6 ± 2.9

−1.8 ± 6.6b

PETCO2REST, mm Hg

31 ± 4

31 ± 3

PETCO2PEAK, mm Hg

33 ± 5

28 ± 5b

ΔPETCO2(PEAK-REST), mm Hg

2±4

−3 ± 5b

General characteristics Age, y 2

BMI, kg/m

Lung function FEV1, % predicted

Echocardiogram LVEF, % 2

LA volume, mL/m E/e′

Cardiopulmonary exercise test . Peak VO2, % pred . Peak VO2, mL/kg/min Peak HR, bpm . . VE/VCO2 nadir . . VE/VCO2 slope . . VE/VCO2 intercept

Abbreviations: BMI, body mass index; E, mitral flow velocity; e’, myocardial diastolic motion; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; HR, heart rate; LA, left atrium; LVEF, left ventricular ejection fraction; mMRC, modified Medical Research Council scale; NYHA, New York Heart · Association; PETCO2, end-tidal partial pressure for CO2; RVDIAM, right ventricular diameter (base); RVFAC, right ventricular fractional area change; VCO2, carbon · · dioxide output; VE, minute ventilation; VO2, oxygen uptake. a Data are reported as mean ± SD or median [interquartile range]. b P < .05.


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among the resting variables, only right ventricular fractional area change (RVFAC) by echocardiography was lower in event patients (P < .05). CPX revealed that despite similar peak V·O2, event patients had greater ventilatory inefficiency (either expressed as V·E/V·CO2 slope or V·E/V·CO2 nadir) and lower exercise PETCO2 (all P < .05). After ROC curve analyses, multivariate Cox hazards regression models revealed that V·E/V·CO2 nadir >36, ΔPETCO2(PEAK-REST)≥2 mm Hg, and PETCO2PEAK≤33 mm Hg (but not V·E/V·CO2 slope >39 or V·O2peak45% had a major cardiac event after 1 year (Figure 1A), no patient with RVFAC>45% and V·E/V·CO2 nadir ≤36 (Figure 1B) or PETCO2PEAK>33 mm Hg (Figure 1D) had a negative event. Conversely, although 69% of patients with RVFAC≤45% had a major cardiac event after 1 year (Figure 1A), all patients with RVFAC≤45% and ΔPETCO2(PEAK-REST)≥2 mm Hg had a major cardiac event (Figure 1C).

DISCUSSION In this prospective study, we found that CPET-based markers of ventilatory inefficiency (increased V·E/V·CO2 nadir) and abnormal capnography (greater exerciseinduced decrements in and lower peak PETCO2) added to low right ventricular systolic function (RVFAC) to predict the risk of major cardiac events in patients with HF with coexistent COPD. Our data indicated that ventilatory (and pulmonary gas exchange) inefficiency during CPET remains a powerful prognostic marker even in patients with HF showing mechanical ventilatory limitations to exercise due to COPD. These preliminary findings in selected patients who were carefully followed up in

a specialized referral center for HF-COPD coexistence should be confirmed in larger cohorts. Because of the pronounced ventilatory inefficiency in HF-COPD overlap, it is likely that the optimal cut-offs for outcome are greater than those currently recommended for HF.1,4-6 There is overwhelming evidence that ventilatory inefficiency evaluated during incremental CPET is a key prognostic factor in HF. Although there have been previous attempts to characterize the impact of COPD on ventilatory inefficiency in HF,12,13 the current investigation is the first to show the prognostic relevance of ventilatory inefficiency in overlap patients. It is noteworthy, however, that the majority of our patients had mild to moderate airflow obstruction, at least based on FEV1, which might have facilitated a substantial increase in V·E during exercise. Although it could be argued that this is unlikely to be found in patients with severe airflow obstruction, patients’ mean FEV1 was considerably lower than in the previous studies by Guazzi et al12 (72.9%) and more recently by Apostolo et al13 (68.9%). Nevertheless, the prognostic power of ventilatory inefficiency (and the proposed thresholds) in overlap patients with more severe airflow obstruction requires further investigation. A number of mechanisms may explain why, despite the mechanical ventilatory constraints induced by COPD,9,10 overlap patients still presented with “excessive” ventilatory response to exercise. For instance, the negative effects of impaired pulmonary perfusion due to low cardiac output14 may compound with derangements in pulmonary microvasculature, hypoxia-induced pulmonary vasoconstriction, and the compressing effects of regional hyperinflation to further compromise pulmonary blood flow and increase alveolar VD.10 Moreover, the combined effects of increased operational lung volumes

T a b l e 2 • Major Cardiac Event Prediction Based on Final Models From Multivariate Cox Proportional Hazards Analyses Models

β

SE

P Value

HR (95% CI)

A

RVFAC≤45%

1.304

0.594

.02

3.68 (1.15-11.81)

B

RVFAC≤45% . . VE/VCO2 nadir >36

1.228

0.605

.04

3.41 (1.04-11.17)

1.319

0.667

.04

3.73 (1.01-13.82)

RVFAC≤45%

1.147

0.609

.05

3.14 (0.95-10.38)

ΔPETCO2(PEAK-REST)≥2 mm Hg

1.378

0.589

.01

3.96 (1.25-12.58)

RVFAC≤45%

1.395

0.624

.02

4.03 (1.18-13.71)

PETCO2PEAK≤33 mm Hg

2.064

1.066

.05

7.87 (0.97-63.60)

C

D

Abbreviations: β, regression coefficient; HR, hazard ratio; PETCO2, end-tidal partial pressure for CO2; RVFAC, right ventricular fractional area change; SE, standard · · error; VCO2, carbon dioxide output; VE, minute ventilation.

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Ventilatory Inefficiency and Prognosis / 457


Figure 1. Kaplan-Meier survival curves for (A) resting right ventricular fractional area change (RVFAC) by echocardiography; (B) RVFAC plus exercise ventilation (V· E)/carbon dioxide output (V· CO2) ratio at its nadir; (C) RVFAC plus peak exercise rest differences (Δ) in end-tidal partial pressure for CO2 (PETCO2); and (D) RVFAC plus PETCO2 at peak exercise. Optimal thresholds were established by ROC curve analyses. Abbreviation: ROC, receiver-operating characteristics.

(COPD)10 and increased lung elastance (HF) may act to decrease exercising tidal volume, thereby further increasing VD/tidal volume ratio. In line with these considerations, we found higher optimal prognostic thresholds for V·E/V·CO2 nadir (>36) and V·E/V·CO2 slope (>39) than commonly suggested for HF (>30 to 34).1 If further corroborated in large cohort studies, these preliminary results could confirm earlier assertions by Guazzi and coworkers12 that present dichotomous thresholds for ventilatory inefficiency variables in HF might not be applicable to overlap patients. An easily obtained measurement of right ventricular systolic performance (RVFAC) emerged as a particularly powerful prognosticator in our study. It is thus likely that negative consequences of overlapping on pulmonary arterial vasculature substantially burdened the right ventricle. Interestingly, these findings are in

remarkable agreement with those recently reported by Guazzi et al15 in patients with COPD-free HF showing that relevant prognostic insights can be gained when an index of right ventricle-pulmonary circulation coupling (tricuspid annular plane systolic excursionpulmonary artery systolic pressure relationship) is combined with measurements of exercise ventilation. A major limitation of this study is its small sample size. Despite its preliminary nature, however, this was a prospective study in which both HF and COPD treatment were carefully optimized by the joint efforts of cardiologists and pulmonologists. We are therefore confident that our results reflect the ominous consequences of HF and COPD coexisting and not uncommon inadequacies in pharmacological treatment approach (eg, lack of β-blockers due to COPD-related concerns or insufficient bronchodilator treatment due to HF).7,8


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CONCLUSION Ventilatory inefficiency during CPET adds important prognostic information to echocardiographic estimates of right ventricular systolic dysfunction in ventilatoryconstrained patients with HF-COPD overlap. Owing to the pronounced ventilatory inefficiency in these patients, optimal thresholds for outcome prediction are likely greater than those traditionally recommended for HF.1,4-6

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6. Arena R, Guazzi M, Myers J, et al. Prognostic value of capnography during rest and exercise in patients with heart failure. Congest Heart Fail. 2012;18:302-307. 7. Vader JM, Rich MW. Team-based care for managing noncardiac conditions in patients with heart failure. Heart Fail Clin. 2015;11:419-429. 8. Rutten FH, Cramer M-JM, Lammers J-WJ, Grobbee DE, Hoes AW. Heart failure and chronic obstructive pulmonary disease: an ignored combination? Eur J Heart Fail. 2006;8:706-711. 9. Neder JA, Arbex FF, Alencar MCN, et al. Exercise ventilatory inefficiency in mild to end-stage COPD. Eur Respir J. 2015;45:377-387. 10. O’Donnell DE, Laveneziana P, Webb K, Neder JA. Chronic obstructive pulmonary disease: clinical integrative physiology. Clin Chest Med. 2014;35:51-69. 11. Teopompi E, Tzani P, Aiello M, et al. Ventilatory response to carbon dioxide output in subjects with congestive heart failure and in patients with COPD with comparable exercise capacity. Respir Care. 2014;59:1034-1041. 12. Guazzi M, Myers J, Vicenzi M, Bensimhon D, Chase P, Pinkstaff S, Arena R. Cardiopulmonary exercise testing characteristics in heart failure patients with and without concomitant chronic obstructive pulmonary disease. Am Heart J 2010;160:900-905. 13. Apostolo A, Laveneziana P, Palange P , et al. Impact of chronic obstructive pulmonary disease on exercise ventilatory efficiency in heart failure. Int J Cardiol. 2015;189:134-140. 14. Guazzi M, Labate V, Cahalin LP, Arena R. Cardiopulmonary exercise testing reflects similar pathophysiology and disease severity in heart failure patients with reduced and preserved ejection fraction. Eur J Prev Cardiol. 2014;21:847-854. 15. Guazzi M, Naeije R, Arena R, et al. Echocardiography of right ventriculo-arterial coupling combined to cardiopulmonary exercise testing to predict outcome in heart failure. Chest. 2015;148:226-234.

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