Post-Exercise Oxygen Uptake Recovery Delay

JACC: HEART FAILURE

VOL.

-, NO. -, 2018

ª 2018 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER

Post-Exercise Oxygen Uptake Recovery Delay A Novel Index of Impaired Cardiac Reserve Capacity in Heart Failure Cole S. Bailey, BA,a Luke T. Wooster, BS,a Mary Buswell, BS,a Sarvagna Patel, BS,a Paul P. Pappagianopoulos, MED,b Kristian Bakken, NP,b Casey White, BS,b Melissa Tanguay, MS, CEP,a Jasmine B. Blodgett, MS, CEP,a Aaron L. Baggish, MD,a Rajeev Malhotra, MD,a Gregory D. Lewis, MDa,b

ABSTRACT OBJECTIVES This study sought to characterize the functional and prognostic significance of oxygen uptake (VO2) kinetics following peak exercise in individuals with heart failure (HF). BACKGROUND It is unknown to what extent patterns of VO2 recovery following exercise reflect circulatory response during exercise in HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF). METHODS We investigated patients (30 HFpEF, 20 HFrEF, and 22 control subjects) who underwent cardiopulmonary exercise testing with invasive hemodynamic monitoring and a second distinct HF cohort (n ¼ 106) who underwent noninvasive cardiopulmonary exercise testing with assessment of long-term outcomes. Fick cardiac output (CO) and cardiac filling pressures were measured at rest and throughout exercise in the initial cohort. A novel metric, VO2 recovery delay (VO2RD), defined as time until post-exercise VO2 falls permanently below peak VO2, was measured to characterize VO2 recovery kinetics. RESULTS VO2RD in patients with HFpEF (median 25 s [interquartile range (IQR): 9 to 39 s]) and HFrEF (28 s [IQR: 2 to 52 s]) was in excess of control subjects (5 s [IQR: 0 to 7 s]; p < 0.0001 and p ¼ 0.003, respectively). VO2RD was inversely related to cardiac output augmentation during exercise in HFpEF (r ¼ 0.70) and HFrEF (r ¼ 0.73, both p < 0.001). In the second cohort, VO2RD predicted transplant-free survival in univariate and multivariable Cox regression analysis (Cox hazard ratios: 1.49 and 1.37 per 10-s increase in VO2RD, respectively; both p < 0.005). CONCLUSIONS Post-exercise VO2RD is an easily recognizable, noninvasively derived pattern that signals impaired cardiac output augmentation during exercise and predicts outcomes in HF. The presence and duration of VO2RD may complement established exercise measurements for assessment of cardiac reserve capacity. (J Am Coll Cardiol HF 2018;-:-–-) © 2018 by the American College of Cardiology Foundation.

I

mpaired exercise capacity is a cardinal feature of

to grade severity of HF (1). Although the prognostic

heart failure (HF). Peak oxygen uptake (VO 2)

implications

measured

exercise

with HF are well known (2,3), other CPET gas

testing (CPET) reflects exercise capacity and is used

exchange variables measured during exercise have

during

cardiopulmonary

of

reduced

peak

VO 2

in

patients

From the aCardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; and the bPulmonary and Critical Care Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Support was obtained from the National Institutes of Health (5R01HL131029 to Dr. Lewis) (K08HL111210 to Dr. Malhotral), the American Heart Association (15GPSGC24800006 to Dr. Lewis), and the Hassenfeld Clinical Scholars Program (Mr. Bailey, Mr. Wooster, Dr. Malhotra, and Dr. Lewis). Dr. Malhotra is a consultant for MyoKardia and Third Pole; and received grant support from the National Heart, Lung, and Blood Institute. Dr. Lewis has received contractual funding support for cardiopulmonary exercise testing core laboratory services from the NHLBI, Abbott Vascular, Ironwood, and Stealth Therapeutics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Mr. Bailey and Wooster contributed equally to this paper and are joint first authors. Drs. Malhotra and Lewis contributed equally to this paper and are joint senior authors. Manuscript received December 17, 2017; accepted January 4, 2018.

ISSN 2213-1779/$36.00

https://doi.org/10.1016/j.jchf.2018.01.007

2

Bailey et al.

JACC: HEART FAILURE VOL.

-, NO. -, 2018 - 2018:-–-

Post-Exercise Oxygen Uptake Recovery Delay in HF

ABBREVIATIONS

emerged that offer insights into multiorgan

following conditions: 1) severe valvular heart disease;

AND ACRONYMS

physiologic reserve capacity and provide ad-

2) intracardiac shunting; and 3) symptomatic, flow-

CI = confidence interval CO = cardiac output

ditive prognostic value when combined with

limiting coronary artery disease. Those who achieved

peak VO 2 (4–6).

only submaximal effort during exercise as reflected by

Gas

CPET = cardiopulmonary

exchange

patterns

immediately

following exercise provide information about

exercise testing

the

A second distinct patient cohort was studied to

exposure. Abnormally prolonged VO 2 recov-

determine the prognostic value of VO 2 recovery pat-

ery to baseline resting values following ex-

terns. This cohort consisted of consecutive patients

ercise has been observed in patients with HF

who were referred to the Massachusetts General Hos-

compared with healthy subjects (7,8). Pro-

pital for NYHA functional class II to IV symptoms, had

longed VO 2 and heart rate (HR) recovery

HFrEF with LVEF <0.45, and underwent noninvasive

following exercise both predict adverse out-

CPET from June 2011 to October 2014. We focused on

device

comes in HF (9,10). However, attempts to fit

patients with HFrEF in the noninvasive CPET cohort

LVEF = left ventricular ejection

various linear and exponential equations to

because of the well-circumscribed phenotyping pro-

fraction

VO 2 recovery patterns have not translated

vided by documented low LVEF, as opposed to our

NYHA = New York Heart

into simple metrics that are routinely incor-

limited capacity to definitively distinguish HFpEF

Association

porated into clinical CPET interpretation in

from other conditions that limit exercise capacity in

OUES = oxygen uptake

patients with HF. Furthermore, mechanistic

patients who undergo noninvasive CPET.

HFpEF = heart failure with preserved ejection fraction

HFrEF = heart failure with reduced ejection fraction

HR = heart rate LVAD = left ventricular assist

efficiency slope

consequences

of

HR <85% of predicted were also excluded (6).

exercise

HF = heart failure

metabolic

a peak respiratory exchange ratio of <1.00 and a peak

understanding of VO 2 recovery patterns in

PAWP = pulmonary arterial wedge pressure

HF remains limited. Finally, studies of VO 2 recovery in HF have focused almost exclu-

VO2 = oxygen uptake

sively on the HF with reduced ejection

VO2RD = VO2 recovery delay

fraction (HFrEF) population. We therefore

conducted a comprehensive evaluation of VO2 recovery patterns and their relationships to metabolic and hemodynamic responses to exercise in carefully phenotyped patients with HF with preserved ejection fraction (HFpEF) and HFrEF. We then investigated the prognostic significance of VO 2 recovery patterns in a distinct patient cohort.

METHODS

CARDIOPULMONARY EXERCISE TESTING. Patients

in the first cohort underwent placement of a pulmonary arterial catheter via the internal jugular vein and a systemic arterial catheter via the radial artery. Firstpass radionuclide ventriculography of both ventricles was performed at rest (OnePass GVI Medical Devices, Twinsburg, Ohio). Patients then underwent maximal incremental upright cycle ergometry (5 to 25 W/min continuous ramp following a 3-min rest period and a 3-min period of

unloaded

exercise;

MedGraphics,

St.

Paul,

Minnesota). Breath-by-breath data were binned mid 5-of-7 by the metabolic cart for analysis of gas exchange

patterns.

Simultaneous

hemodynamic

PATIENT POPULATION. We studied patients referred

measurements were obtained with exercise (Witt

to Massachusetts General Hospital for CPET between

Biomedical Inc., Melbourne, Florida), as previously

June 2011 and July 2016. This study was approved by

described (12,13). Right atrial pressure, mean pulmo-

the Partners Human Research Committee. Patients

nary artery pressure, PAWP, and systemic arterial

with complete recovery gas exchange data during the

pressures were measured in the upright position, at

3 min after peak exercise were eligible for the study.

end-expiration insert, at rest and at 1-min intervals

The initial patient cohort was derived exclusively

during exercise. Fick cardiac output (CO) was calcu-

from consecutive patients who underwent CPET with

lated at 1-min intervals throughout exercise by

invasive hemodynamic monitoring and met the

measuring VO2 and simultaneous radial arterial and

following inclusion criteria: for HFpEF, left ventricu-

mixed venous O 2 saturation to determine the oxygen

lar ejection fraction (LVEF) $0.50 with supine

extraction (C[a-v]O 2) at each minute of exercise. VO 2/

pulmonary artery wedge pressure (PAWP) $15 mm Hg

work was defined as the slope of the relationship

and New York Heart Association (NYHA) functional

between VO 2 and work from 1 min after the initiation

class II to IV; for HFrEF, LVEF <0.45 and NYHA func-

of loaded exercise to the end of exercise. Ventilatory

tional class II to IV; and for control subjects, LVEF

efficiency or VE/VCO2 slope was defined as the rela-

>0.50, supine mean pulmonary artery pressure

tionship between expired carbon dioxide per minute

<25 mm Hg, supine PAWP <15 mm Hg, and a normal

and total ventilation per minute from the start of

exercise capacity reflected by peak VO 2 $85% pre-

unloaded exercise to maximal exercise. VO2 effi-

dicted on the basis of age, gender, and height (11).

ciency slope (OUES) was defined as the relationship

Patients were excluded if they had any of the

between VO 2 and the natural log of total ventilation

JACC: HEART FAILURE VOL.

-, NO. -, 2018

Bailey et al.

- 2018:-–-

per

minute

3

Post-Exercise Oxygen Uptake Recovery Delay in HF

throughout

exercise

(5).

Following

maximal exercise, the patients recovered over a 3-

F I G U R E 1 Defining VO 2 Recovery Delay

min period, pedaling against no resistance for the first minute of recovery and sitting passively for the final 2 min of recovery. Before testing, patients were instructed to keep the mouthpiece in throughout recovery to ensure data completeness. DERIVED VO 2 RECOVERY KINETICS. Based on the

lack of any descent in VO 2 during the early part of recovery in a subset of individuals, we termed a novel metric, VO 2 recovery delay (VO 2RD), as simply the time from the end of loaded exercise until the VO 2 permanently falls below peak VO 2, as illustrated in Figure 1. Peak VO 2 was defined as the highest median breath-by-breath O 2 consumption over a 30-s interval in the last minute of exercise. Because VO 2RD measures the time until a permanent fall in VO2 below

This illustration contains data from 2 patients with heart failure who demonstrate distinct

peak levels, this metric is also well-suited to patients

patterns of VO2RD. The gray area illustrates the final portion of incremental ramp exercise.

with HF with periodic breathing during and after

VO2RD was defined as the duration of time from the end exercise until the time when oxygen

exercise (or oscillatory ventilation) (14,15). Recovery

consumption (VO2) fell permanently below peak VO2 (dashed lines). The blue line represents

VO 2 kinetics were also described by T 1/2, the time for

a patient who has an immediate decrement in VO2 following completion of the exercise period (gray area) with a resultant VO2RD value of 0 s. In contrast, the second patient’s VO2 (red line)

VO 2 to decrease to 50% of peak VO 2 adjusted for

remained at values at or above those achieved at peak exercise for 55 s after exercise before

resting VO 2 (7,16–18) and HR recovery at 2 min, as

beginning to decline. VO2 ¼ oxygen uptake; VO2RD ¼ oxygen uptake recovery delay.

previously described (10). STATISTICAL

ANALYSES. STATA

13.0

was predominantly male. As expected, HFpEF pa-

(StataCorp, College Station, Texas) was used for all

version

tients had a greater body mass index compared with

analyses. The Wilk-Shapiro test was used to deter-

control subjects, and more frequent comorbidities of

mine the normality of each continuous variable.

hypertension, diabetes mellitus, and hyperlipidemia.

Continuous measurements are presented as mean  SD for normally distributed variables and median (interquartile range) for nonnormal variables. Cate-

T A B L E 1 Baseline Characteristics

gorical data are presented as percentages. Comparisons with continuous variables involving 2 groups

Age, yrs

Control Subjects (n ¼ 22)

HFpEF (n ¼ 30)

HFrEF (n ¼ 20)

Cohort 2 (n ¼ 106)

58  13

64  10

62  11

56  13

59

50

90*†

82

were performed using either the Student t test or the

Male

Mann-Whitney test, as appropriate. Comparisons with

Body mass index, kg/m2

26.6  3.8

31.5  6.5‡

28.2  6.5

28.0  4.6

continuous variables involving 3 groups were made

Hemoglobin, g/dl

13.8  1.5

13.2  1.9

12.7  1.6

13.4  2.0

using either a 1-way analysis of variance or Kruskal-

Comorbidities

Wallis test with post hoc testing adjusted for multi-

Hypertension

45

73‡

55

39

ple comparisons, as appropriate. Fisher exact test was

Diabetes mellitus

5

33‡

25

26

Hyperlipidemia

27

73‡

60

51 84

used for comparisons of categorical data. Pearson or Spearman correlation analysis was performed, as appropriate. Mortality data were obtained from the Social Security Death Index. Kaplan-Meier survival with log rank testing and multivariable Cox regression analysis were used to determine if VO2 recovery pat-

Pharmacotherapies Diuretics

9

63‡

65*

ACE inhibitor or ARB

23

27

80*†

75

b-adrenergic blocker

9

67‡

80*

92

Aldosterone blockade

0

13

45*†

54 25  9

Rest hemodynamics

terns and other variables predict transplant-free sur-

LVEF, %

65  6

66  7

30  11*†

vival. A p value of <0.05 was considered significant.

Supine PAWP, mm Hg

93

20  5‡

20  6*

NA

Supine mPAP, mm Hg

15  4

26  6‡

26  7*

NA

3.1  0.5

2.4  0.6‡

2.2  0.5*

NA

RESULTS POPULATION CHARACTERISTICS. Baseline charac-

teristics for control (n ¼ 22), HFpEF (n ¼ 30), and HFrEF (n ¼ 20) patients are summarized in Table 1. All 3 groups were similar in age. The HFrEF population

Cardiac index, l/min/m2

Values are mean  SD or %. *p < 0.05 for comparison of HFrEF and control subjects. †p < 0.05 for comparison of HFpEF and HFrEF. ‡p < 0.05 for comparison of HFpEF and control subjects. ACE ¼ angiotensin-converting enzyme; ARB ¼ angiotensin receptor blocker; HFpEF ¼ heart failure with preserved ejection fraction; HFrEF ¼ heart failure with reduced ejection fraction; LVEF ¼ left ventricular ejection fraction; mPAP ¼ mean pulmonary arterial pressure; NA ¼ not available; PAWP ¼ pulmonary arterial wedge pressure.

4

Bailey et al.

JACC: HEART FAILURE VOL.

T A B L E 2 Peak Exercise and Hemodynamic Measurements

F I G U R E 2 VO 2 Recovery Kinetics

Control Subjects (n ¼ 22)

HFpEF (n ¼ 30)

HFrEF (n ¼ 20)

1.17  0.09

1.14  0.10

1.19  0.12

Maximum workload, W

167  57

88  29*

91  29†

VO2, % predicted

102  11

72  20*

55  13†

25.6  5.7

13.3  2.8*

13.2  2.8†

13.4  2.0

12.2  2.3

13.5  1.7

Respiratory exchange ratio

VO2, ml/kg/min C(a-v)O2, ml/dl Cardiac output, l/min

-, NO. -, 2018 - 2018:-–-

Post-Exercise Oxygen Uptake Recovery Delay in HF

16.1 (12.4–16.9) 9.3 (7.3–12.8)* 7.4 (6.2–11.6)†

Heart rate, bpm

150  18

117  26*

Stroke volume, ml

100  22

88  30

77  19†

10.4  0.8

8.3  2.0*

8.7  1.9†

VE/VCO2 slope

28.9  3.8

37.0  9.2*

43.2  13.0†

O2 saturation, %

97 (97–98)

97 (94–98)

99 (98–100)

PAWP, mm Hg

20  6

29  6*

29  9†

mPAP, mm Hg

34  8

47  9*

45  8†

HR recovery at 2 min, beats/min

41  11

23  17*

23  15†

VO2/work slope, ml/min/watt

113  25†

Values are mean  SD or median (interquartile range). *p < 0.05 for comparison of HFpEF and control subjects. †p < 0.05 for comparison of HFrEF and control subjects. HR ¼ heart rate; VO2 ¼ oxygen uptake; other abbreviations as in Table 1.

HFpEF and HFrEF patients exhibited very similar resting hemodynamic values with average resting supine

mean

pulmonary

artery

pressure

of

26  6 mm Hg and 26  7 mm Hg and PAWP of 20  5 mm Hg and 20  6 mm Hg, respectively. Measurements performed during exercise testing are provided in Table 2. All 3 groups demonstrated peak exercise respiratory exchange ratios consistent with maximal effort, as indicated by an average respiratory exchange ratio in excess of 1.10. HFpEF (13.3  2.8 ml/ kg/min) and HFrEF (13.2  2.8 ml/kg/min) patients

(A) VO2RD with median (interquartile range) for control

exhibited similarly reduced peak VO 2 levels compared

subjects and patients with HFpEF and HFrEF. (B) T1/2 with

with control subjects (25.6  5.7 ml/kg/min).

mean  SD for control subjects and patients with HFpEF and HFrEF. HFpEF ¼ heart failure with preserved ejection fraction;

POST-EXERCISE VO 2 RECOVERY KINETICS. In con-

HFrEF ¼ heart failure with reduced ejection fraction;

trol subjects, VO 2 consistently

other abbreviation as in Figure 1.

declined

almost

immediately following peak exercise. However, in patients with HF we commonly observed a prolonged VO 2RD duration (Figure 1). Post-exercise VO 2RD and T 1/2 durations are displayed for the 3 groups in

PATIENTS WITH HF STRATIFIED BY THE MEDIAN

Figure 2. Control subjects exhibited minimal VO2RD

RECOVERY DELAY. Because HFpEF and HFrEF pa-

durations with a median value of 5 s (interquartile

tients exhibited similar post-exercise VO 2RD dura-

range [IQR]:0 to 7 s) compared with 25 s (IQR: 7 to 43

tions, the 2 HF phenotypes were combined into 1 group

s) for patients with HF (p < 0.0001). HFpEF and

and stratified by the median HF VO2 RD duration of 25 s.

HFrEF patients exhibited similarly prolonged VO 2RD

The baseline characteristics of the stratified patients

(25 s [IQR: 9 to 39 s] vs. IQR: 28 s [IQR: 2 to 52 s]; p ¼

with HF are summarized in Table 3. Baseline charac-

0.99). T 1/2 was also significantly increased in patients

teristics, comorbidities, and medication exposures

with HF compared with control subjects (107  28 s

were similar between the 2 strata. There was no dif-

vs. 62  14 s; p < 0.0001) and the T 1/2 of HFpEF and

ference in resting PAWP or cardiac index in those with

HFrEF patients were similar (102  22 s vs. 114  36 s;

prolonged VO 2RD ($25 s) compared with shorter

p ¼ 0.21) (Figure 2). Additionally, HR recovery 2 min

VO2 RD (<25 s). In both the HFpEF and HFrEF cohorts,

post-exercise was attenuated in patients with HF

there was no difference in volitional effort between

relative to control subjects (Table 2).

patients with VO2 RD less than and greater than 25 s.

JACC: HEART FAILURE VOL.

-, NO. -, 2018

Bailey et al.

- 2018:-–-

Post-Exercise Oxygen Uptake Recovery Delay in HF

T A B L E 3 Baseline Characteristics and Exercise Measurements When Heart Failure Patients Are Stratified by the Median

VO 2 Recovery Delay HF VO2 RD <25 s

HFpEF VO2RD $25 s

VO2RD <25 s

HFrEF VO2RD $25 s

VO2RD <25 s

VO2 RD $25 s

Baseline N Age, yrs Male

25

25

15

15

10

10

62  9

65  11

62  9

66  11

62  10

63  12

68

64

53

47

90

90

Body mass index, kg/m2

31.9  6.8

28.5  6.2

33.9  7.5

29.1  4.5*

28.8  4.3

27.7  8.4

Hemoglobin, g/dl

12.9  1.7

13.1  1.8

12.9  1.6

13.5  2.1

12.8  1.9

12.6  1.2

60

60

NA

NA

NA

NA 60

HFpEF Comorbidities Hypertension

56

76

60

87

50

Diabetes mellitus

24

36

27

40

20

30

Hyperlipidemia

52

84†

60

87

40

80

Diuretics

68

60

67

60

70

60

ACE inhibitor or ARB

48

48

20

33

90

70

b-adrenergic blocker

68

76

60

73

80

80

Aldosterone blockade

24

28

13

13

40

50 20  6

Pharmacotherapies

Rest hemodynamics Supine PAWP, mm Hg

21  6

19  4

21  5

18  3

20  8

Supine mPAP, mm Hg

27  7

25  6

28  7

25  5

26  8

26  6

2.3  0.6

2.3  0.5

2.6  0.6

2.2  0.5

2.0  0.3

2.3  0.7

1.15  0.13

1.17  0.08

1.11  0.09

1.17  0.10

1.22  0.16

1.18  0.06

101  34

78  16†

99  34

77  19*

105  35

78  9‡

72  21

57  15†

81  23

62  12*

60  5

49  17

14.5  2.7

12.0  2.2†

14.5  2.7

12.2  2.5*

14.5  3.0

11.9  1.8‡

Cardiac index, l/min/m2 Peak exercise Respiratory exchange ratio Maximum workload, W VO2, % predicted VO2, ml/kg/min

12.2  1.9

13.2  2.3

11.8  2.2

12.6  2.4

12.8  1.3

14.2  1.9

Cardiac output, l/min

11.4 (9.2–14.0)

7.1 (5.9–8.7)†

12.6 (9.4–14.2)

7.3 (6.8–9.1)*

10.7 (8.1–12.9)

6.7 (5.9–7.0)‡

Heart rate, bpm

119  22

112  28

122  21

112  29

114  24

112  26

Stroke volume, ml

98  27

69  17†

103  33

73  18*

90  12

65  16‡

C(a-v)O2, ml/dl

9.5  1.9

7.4  1.5†

9.4  2.1

7.3  1.3*

9.6  1.4

7.7  1.9‡

VE/VCO2 slope

36.4  9.3

42.6  12.1†

35.6  9.4

38.5  9.1

37.6  9.5

48.8  13.9

O2 saturation

VO2/work slope, ml/min/W

97 (96–99)

98 (97–99)

97 (95–97)

97 (95–99)

99 (98–100)

99 (98–99)

PAWP, mm Hg

28  6

30  8

28  5

30  7

28  9

30  10

mPAP, mm Hg

46  10

46  8

47  11

47  9

45  9

44  7

VO2RD, s

7 (0–17)

43 (34–56)†

10 (5–19)

37 (33–50)*

4 (0–7)

49 (39–58)‡

T1/2, s

94  25

119  26

94  21

110  19*

95  31

133  30‡

HR recovery at 2 min, beats/min

24  15

22  17

26  16

21  18

22  15

26  16

Values are mean  SD, %, or median (interquartile range). *p < 0.05 for comparison of HFpEF $25 s and HFpEF <25 s. †p < 0.05 for comparison of HF $25 s and HF <25 s. ‡p < 0.05 for comparison of HFrEF $25 s and HFrEF <25 s. HF ¼ heart failure; VE ¼ minute ventilation; VO2RD ¼ VO2 recovery delay; other abbreviations as in Tables 1 and 2.

Exercise capacity, quantified by peak VO2 and

cohorts (Figures 3B and 3C). The evaluation of com-

maximal workload, was significantly reduced for

ponents

patients with VO 2RD $25 s compared with those

revealed that both HR and stroke volume augmen-

with VO 2RD <25 s to a similar extent in HFrEF and

tation during exercise were inversely related to

HFpEF (Table 3). Patients with HF with VO2 RD $25 s

VO 2RD (r ¼ 0.29, p ¼ 0.04 and r ¼ 0.44, p ¼

demonstrated relative inability to augment CO dur-

0.002, respectively) in patients with HF. Although

ing exercise compared with those with VO 2RD <25 s

we found a close relationship between VO 2RD and

(Figure 3A). Furthermore, strong negative correla-

the augmentation of CO in HF, there was no corre-

tions between VO 2RD and augmentation of CO with

lation between VO 2RD and the augmentation in

exercise existed in both the HFpEF and HFrEF

C(a-v)O 2 during exercise (r ¼ 0.09, p ¼ 0.51).

of

CO

augmentation

during

exercise

5

6

Bailey et al.

JACC: HEART FAILURE VOL.

-, NO. -, 2018 - 2018:-–-

Post-Exercise Oxygen Uptake Recovery Delay in HF

F I G U R E 3 Prolonged VO 2 Recovery Delay Is Associated With

Impaired Hemodynamic Response to Exercise

Augmentation in skeletal muscle oxygen extraction also did not differ between groups stratified by VO2 RD (VO 2RD #25 s vs. >25 s; 5.94  1.61 ml/dl vs. 6.45  1.74 ml/dl; p ¼ 0.29). Furthermore, there was no correlation between VO2RD and measurements of pulmonary function, including forced expiratory volume in 1 s and oxygen saturation during exercise ( r ¼ 0.15, p ¼ 0.32 and r ¼ 0.17, p ¼ 0.24, respectively). These findings suggest that VO 2RD is specific for impairment in CO reserve, rather than impairment in peripheral oxygen extraction patients with HF. VO 2RD also did not correlate with 2-min HR recovery ( r ¼ 0.11, p ¼ 0.48) or 30-s HR recovery ( r ¼ 0.27, p ¼ 0.10), indicating distinct physiologic information conferred by VO 2RD in comparison with HR recovery. An abnormally low VO 2 versus work slope is indicative of poor oxygen use and a greater reliance on anaerobic metabolism for a given workload with an increase in O2 deficit (19). We tested the hypothesis that a low VO2 versus work slope during exercise would be associated with prolonged VO 2RD because of the need to “repay the O 2 deficit” accumulated with exercise during recovery (Figure 4A). VO2 /work slope was reduced in HFpEF (8.3  2.0 ml/ min/W) and HFrEF (8.7  1.9 ml/min/W) compared with control subjects (10.4  0.8 ml/min/W) in whom this relationship was within normal expected values of 10  1.5 ml/min/W (p ¼ 0.0001 and p ¼ 0.003, respectively) (6,19). There was an inverse relationship between VO 2/work slope and VO 2RD duration in patients with HF and most patients with HF with VO 2RD $25 s demonstrated below normal oxygen use per watt of work performed (i.e., <8.5 ml/min/W) (Figure 4B). PROGNOSTIC

VALUE

OF

RECOVERY

DELAY

IN

HFrEF. We used a larger patient cohort (n ¼ 106)

(Online Table 1) undergoing noninvasive CPET to determine whether VO 2RD predicts transplant-free survival in HFrEF. The median follow-up time was 2.5 years and 23 patients died or underwent cardiac transplantation (14 deaths, 9 heart transplants), whereas 17 additional patients underwent placement of a left ventricular assist device (LVAD), which was censored for transplant-free survival analysis. As a continuous variable, VO 2RD predicted transplant-free (A) Cardiac output augmentation during exercise for the control subjects, HFpEF, and HFrEF groups is depicted as median with

survival in both univariate (Cox hazard ratio: 1.49 per 10-s increase in recovery delay; 95% confidence in-

interquartile range. HFpEF and HFrEF groups are stratified by

terval [CI]: 1.25 to 1.78; p < 0.001) and multivariable

the median heart failure VO2RD (25 s). *p ¼ 0.0015 between

Cox regression analysis adjusting for VE/VCO2 slope,

HFpEF <25 s and HFpEF $25 s. **p ¼ 0.003 between HFrEF <25 s and HFrEF $25 s. A scatter plot of cardiac output augmentation during exercise versus VO2RD for (B) HFpEF and (C) HFrEF. Spearman rank correlation is included. CO ¼ cardiac output; other abbreviations as in Figures 1 and 2.

OUES, HR recovery at 2 min, and Wasserman VO 2 % predicted (Cox hazard ratio: 1.37 per 10-s increase in recovery delay; 95% CI: 1.10 to 1.71; p ¼ 0.005) (Table 4). As a dichotomous variable, VO 2RD $25 s was associated with worse transplant-free survival

JACC: HEART FAILURE VOL.

-, NO. -, 2018

Bailey et al.

- 2018:-–-

Post-Exercise Oxygen Uptake Recovery Delay in HF

with a Cox hazard ratio of 4.9 (95% CI: 1.4 to 16.4; p ¼ 0.01). Kaplan-Meier curves stratified by VO 2RD

F I G U R E 4 Prolonged VO 2 Recovery Delay Is Associated With Reduced VO2 /Work Slope

are shown in Figure 5A, with those patients with HF having a prolonged VO 2RD exhibiting poorer outcomes (log rank p ¼ 0.0048) with 20 out of 23 events observed in the prolonged VO 2RD group. Baseline and exercise characteristics of these patients with HF stratified by VO 2RD of 25 s are shown in Online Table 1. Furthermore, VO 2RD was a better predictor of cardiac transplant-free survival than T 1/2 in multivariable analysis (Cox hazard ratio: 1.32 per 10-s increase in VO 2RD; 95% CI: 1.05 to 1.66; p ¼ 0.018; and Cox hazard ratio: 1.16 per 20-s increase in T1/2; 95% CI: 0.93 to 1.40; p ¼ 0.12). A

multioutcome

sensitivity

analysis

demon-

strated that VO2 RD consistently predicted a range of clinical outcomes in both univariate and multivariable analyses (Online Table 2). When assessing transplant/LVAD-free survival, a VO 2RD $25 s had a Cox hazard ratio of 4.0 (95% CI: 1.7 to 9.4; p ¼ 0.002) in univariate analysis and was a significant predictor independent of peak VO2 percent predicted, VE/VCO 2 slope, OUES, and HR recovery at 2 min in multivariable analysis (Cox hazard ratio: 3.1; p ¼ 0.02). In HFrEF patients, there is a close relationship between degree of impairment in percent predicted peak VO 2 (as determined by the Wasserman equation [6]) and prognosis (20). Among those patients with HF with a relatively preserved peak VO 2 percent predicted $55% (n ¼ 51), those with a prolonged VO 2RD $25 s (n ¼ 28) exhibited a trend toward

worse

transplant/LVAD-free

survival

compared with those with a shorter VO 2RD (log rank p ¼ 0.067) (Figure 5B). Furthermore, among those with reduced peak VO 2 percent predicted <55% (n ¼

(A) Oxygen uptake plotted against workload during progression of an exercise test in a representative patient with heart failure and a prolonged VO2RD of 26 s. The red area highlights the difference between normal VO2/work (10 ml/min/W) and the subject’s reduced VO2/work of 7.6 ml/min/W, which represents an O2 deficit at the tissue. (B) Scatter plot of VO2/work versus VO2RD for the combined heart failure group

55), those with a prolonged VO 2RD (n ¼ 39)

(n ¼ 50). Spearman rank correlation is included. The patients with heart failure

exhibited

with prolonged VO2RD and abnormal VO2/work (<8.5 ml/W) are denoted in red

worse

transplant/LVAD-free

survival

compared with those with a shorter VO 2RD (log rank

(n ¼ 20 of 25 with prolonged VO2RD). Abbreviations as in Figure 1.

p ¼ 0.028) (Figure 5B). Finally, the presence of peak VO 2 percent predicted of <55% and prolonged VO 2RD

conferred

significantly

increased

risk

compared with the absence of both findings (log rank p < 0.0001) (Figure 5B).

T A B L E 4 VO 2 Recovery Delay Predicts Cardiovascular Transplant-Free

Survival in HFrEF Cohort 2 (n ¼ 106) Independently of Other Prognostic CPET Variables

DISCUSSION

Cox 95% Confidence Hazard Ratio Interval p Value

In this study, we defined a novel, easily discernible

VO2RD (for every 10-s increase)

1.37

1.10–1.71

0.005

pattern of sustained VO 2 elevation following exer-

VE/VCO2 slope (for every 1 increase)

1.04

0.97–1.11

0.271 0.023

cise in patients with HF, which we term VO2RD. We found that the duration of VO2RD was directly related to the degree of impaired CO augmentation

OUES (for every 0.1 increase)

1.11

1.01–1.21

HR recovery at 2 min (for every 5 beats/min)

0.77

0.62–0.95

0.018

VO2 percent predicted (for every 1% increase)

0.95

0.92–0.99

0.006

in response to exercise in HFpEF and HFrEF. In addition, VO 2RD was prolonged in patients with HF with lower than normal oxygen use per watt of

CPET ¼ cardiopulmonary exercise testing; OUES ¼ oxygen uptake efficiency slope; other abbreviations as in Tables 1, 2, and 3.

7

8

Bailey et al.

JACC: HEART FAILURE VOL.

-, NO. -, 2018 - 2018:-–-

Post-Exercise Oxygen Uptake Recovery Delay in HF

peak VO2 percent predicted. Taken together, our

F I G U R E 5 VO 2 Recovery Delay Is a Prognostic Indicator in HFrEF

findings indicate that VO 2RD is a simple noninvasive measure of the metabolic consequences of exercise exposure in patients with HF that provides additional prognostic value beyond peak VO 2. The utility of performing precise quantification of exercise responses with CPET in patients with HF and other cardiorespiratory conditions is firmly supported by an expanding evidence basis. Multiple recent scientific statements have advocated for increased routine use of CPET in clinical practice in addition to Centers for Medicare- and Medicaidmandated use of CPET in patient selection for advanced

HF

interventions

(21).

Recommended

standardized CPET reports within these scientific statements contain numerous gas exchange CPET variables, but not a single recovery gas exchange measurement. This study addresses several limitations of studies done to date characterizing VO 2 recovery

patterns

(10,16,17,22).

First,

divergent

methods have been used to fit exponential equations to recovery patterns, but the multicomponent nature of the recovery patterns often observed in HF (i.e., a recovery overshoot or plateau period followed by an exponential decline) (Figure 1) indicates that a single equation will not suffice to describe VO 2 recovery in patients with HF. Second, most studies of recovery VO 2 kinetics have not included

comprehensive

hemodynamic

measure-

ments during exercise to provide mechanistic insights

into

prolonged

VO2

recovery.

Finally,

assessment of VO 2 recovery patterns has been confined to patients with known HFrEF despite the fact that there is an unmet need to define metrics that accurately reflect impaired cardiac reserve in patients with HFpEF. Our study is the first to investigate the easily recognizable and measurable pattern of a delay in VO 2 recovery following exercise. VO2RD is minimal (i.e., usually #5 s) in control subjects, even from a referral (A) Kaplan-Meier transplant-free survival curves for HFrEF patients (n ¼ 106)

cohort of patients undergoing evaluation of dyspnea

dichotomized by a VO2RD of 25 s. (B) Kaplan-Meier VAD/transplant-free survival curves

on exertion who proved to have normal physiologic

for HFrEF patients (n ¼ 106) stratified by peak VO2 percent predicted and VO2RD.

responses during exercise. In contrast, VO 2RD $25 s

VAD ¼ ventricular assist device; other abbreviations as in Figures 1 and 2.

was observed in half of the patients with HF in our initial cohort and more than half in our second cohort.

work performed, suggesting that a prolonged VO2RD

Although VO 2RD is a novel parameter that does

reflects an increased need to repay oxygen deficit

not lend itself to comparison with previous studies,

that

CO

the mean T 1/2 of patients with HF in our study of

augmentation lags behind the metabolic demands

accumulates

107  28 s was intermediate between that reported

imposed

by

during

exercise.

transplant/LVAD-free

exercise

VO 2RD

survival,

also

when

predicted

independently

of

by Nanas et al. (16) (90  24 s) and Scrutinio et al. (22) (152  54 s) in HFrEF populations. Notably, the

JACC: HEART FAILURE VOL.

-, NO. -, 2018

Bailey et al.

- 2018:-–-

Post-Exercise Oxygen Uptake Recovery Delay in HF

patients studied by Nanas et al. (16) included in-

recovery at 2 min, and peak VO2 percent predicted

dividuals with NYHA functional class I and average

every 10-s increase in recovery delay conferred a

peak VO 2 was higher than in our study population

37% greater hazard for cardiac transplantation or

(16.7 ml/kg/min vs. 13.3 ml/kg/min), hence it is to

death.

be expected that recovery kinetics were more rapid

STUDY LIMITATIONS. First, CPET measurements are

in the Nanas study compared with this study.

among the many variables used to select individuals

Our findings relating VO 2RD to impaired exercise

for advanced HF interventions, making it possible

CO augmentation and poor prognosis are also

that abnormal CPET findings contributed to the

consistent with those of other investigators who

development of the transplant or LVAD endpoints.

have linked measures of impaired VO 2 recovery

However, VO 2RD data were not available in any of

kinetics to functional capacity and prognosis in

the patients at the time of transplantation or LVAD

patients

and

and the transplanted patients included in this study

HFrEF (7,23–25). For example, Tanabe et al. (18)

with

dilated

cardiomyopathy

(17)

were uniformly United Network for Organ Sharing

described a strong correlation between T1/2 and

Status 1B or 1A, whereas patients undergoing LVAD

cardiac index at peak exercise in HFrEF. Our find-

implantation were uniformly INTERMACs Patient

ings extend those of Tanabe by introducing a mea-

Profile

surement

cardiac

interventions more as “rescue therapy” to avert

indices that are independent of resting hemody-

mortality rather than purely elective interventions.

namic state (i.e., exercise change in CO). Further-

Our patient cohort sizes were limited because the

more, we characterized VO 2RD in HFpEF patients in

collection of 3 min of recovery gas exchange data

whom surrogate markers for impaired CO response

was not routinely performed in our laboratory

to exercise are desirable in light of the numerous

before May 2013, when a dedicated recovery pro-

contributing factors to exercise intolerance among

tocol was created. The ease of measurement of

patients with HFpEF. We found that VO 2RD was closely

VO 2RD lends itself to confirmatory studies of its

related to CO augmentation in HFrEF and HFpEF and it

prognostic significance in larger HF studies. Addi-

was more closely linked to inability to augment stroke

tional studies are also warranted in other disease

that

correlates

with

exercise

4

or

less,

indicating

use

of

both

volume than HR. Therefore, HR augmentation and

states to further understand the specificity of

recovery patterns alone do not sufficiently capture the

VO 2RD for a circulatory insufficiency in comparison

information provided by VO 2RD.

with other sources of exercise intolerance in con-

The

close

impaired

correlations

augmentation

in

observed CO

and

between

ditions other than HF.

prolonged

The control population was limited in size (n ¼ 22)

VO 2RD, along with the observed low VO 2/work slope

because of the infrequency with which subjects

in patients with prolonged VO 2RD, support the

without significant cardiopulmonary disease are

hypothesis that VO 2RD reflects the need to repay

referred for CPET with invasive hemodynamic moni-

oxygen deficit that accumulates during exercise

toring. Furthermore, the control population cannot

when

metabolic

be considered as completely normal given that its

demands imposed by exercise. The VO 2/work slope

constituents underwent CPET for the evaluation of

below 8.5 ml/min/W observed in patients with

dyspnea. “Normal control subjects” were normal

prolonged VO 2RD is indicative of a requisite shift

based on their exercise capacity, ejection fractions,

toward anaerobic metabolism for a greater propor-

and hemodynamic measurements at rest and during

tion

exercise, but did harbor some cardiovascular disease,

CO

of

augmentation

work

performed

lags

behind

during

exercise,

with

progressive development of oxygen deficit.

such as hypertension. Use of these control patients,

Although impairment in peak VO 2 is an estab-

however, does tend to underestimate the differences

lished potent predictor of outcomes in HF, our study

between patients with HF and completely healthy

shows that VO 2RD is an additional, independent

control subjects.

predictor of cardiac transplant-free survival that offers prognostic value beyond peak VO2 and other prognostic CPET variables. We compared the prog-

ADDRESS FOR CORRESPONDENCE: Dr. Gregory D.

nostic strength of recovery delay against that of T1/2

Lewis, Cardiopulmonary Exercise Laboratory, Heart

and found that recovery delay outperformed T1/2 as a

Failure/Cardiac Transplantation, Massachusetts General

predictor of transplant-free survival. Additionally,

Hospital, Gray Bigelow 8th Floor, 55 Fruit Street, Boston,

after adjustment for VE/VCO 2 slope, OUES, HR

Massachusetts 02114. E-mail: [email protected].

9

10

Bailey et al.

JACC: HEART FAILURE VOL.

-, NO. -, 2018 - 2018:-–-

Post-Exercise Oxygen Uptake Recovery Delay in HF

PERSPECTIVES COMPETENCY IN MEDICAL KNOWLEDGE: Presence

emphasizes the importance of extending gas exchange

of a prolonged VO2RD after exercise reflects circulatory

measurements into the recovery period.

insufficiency in both HFrEF and HFpEF, correlating strongly with otherwise invasively determined measures of hemo-

TRANSLATIONAL OUTLOOK: There has been signifi-

dynamic response to exercise. VO2RD further proves to be a

cant recent growth in the recognition of gas exchange

strong prognostic marker for HFrEF that is independent of

patterns during and immediately after exercise that

other commonly used CPET variables for HF prognostica-

predict prognosis and offer insight into mechanisms of

tion, including peak VO2, ventilatory efficiency, and OUES.

exercise intolerance in heart failure. VO2RD is a novel

These findings suggest VO2RD complements exercise gas

metric to easily identify circulatory insufficiency and

exchange measurements for assessment of cardiac reserve

delayed O2 kinetics during exercise. Future studies will

capacity during noninvasive exercise testing. Furthermore,

focus on whether VO2RD performs similarly well in pre-

no recovery gas exchange measures are routinely included in

dicting outcomes in earlier stages of cardiovascular dis-

CPET report templates endorsed by recent societal scientific

ease. In addition, it is not known whether conditions

statements. These findings add to the growing evidence

beyond HF that impair exercise capacity will be associated

base supporting clinical use of CPET in patients with HF and

with similar VO2RD.

REFERENCES 1. Balady GJ, Arena R, Sietsema K, et al. Clinician’s

with chronic heart failure. Eur J Heart Fail 2001;3:

during maximal exercise and early recovery in

guide to cardiopulmonary exercise testing in adults: a scientific statement from the American Heart Association. Circulation 2010;122:191–25.

685–92.

patients with congestive heart failure. Circulation 1999;100:503–8.

2. O’Neill JO, Young JB, Pothier CE, Lauer MS. Peak oxygen consumption as a predictor of death in patients with heart failure receiving betablockers. Circulation 2005;111:2313–8. 3. Mancini DM, Eisen H, Kussmaul W, Mull R, Edmunds LH Jr., Wilson JR. Value of peak exercise oxygen consumption for optimal timing of cardiac transplantation in ambulatory patients with heart failure. Circulation 1991;83:778–86. 4. Guazzi M, Dickstein K, Vicenzi M, Arena R. Sixminute walk test and cardiopulmonary exercise testing in patients with chronic heart failure: a comparative analysis on clinical and prognostic insights. Circ Heart Fail 2009;2:549–55. 5. Malhotra R, Bakken K, D’Elia E, Lewis GD. Cardiopulmonary exercise testing in heart failure. J Am Coll Cardiol HF 2016;4:607–16. 6. Hansen JE, Sue DY, Wasserman K. Predicted values for clinical exercise testing. Am Rev Respir Dis 1984;129:S49–55. 7. Cohen-Solal A, Laperche T, Morvan D, Geneves M, Caviezel B, Gourgon R. Prolonged kinetics of recovery of oxygen consumption after maximal graded exercise in patients with chronic heart failure. Analysis with gas exchange measurements and NMR spectroscopy. Circulation 1995;91:2924–32. 8. Nanas S, Nanas J, Kassiotis C, et al. Early recovery of oxygen kinetics after submaximal exercise test predicts functional capacity in patients

9. Arena R, Guazzi M, Myers J, Peberdy MA. Prognostic value of heart rate recovery in patients with heart failure. Am Heart J 2006;151:851. 10. Fortin M, Turgeon PY, Nadreau E, et al. Prognostic value of oxygen kinetics during recovery from cardiopulmonary exercise testing in patients with chronic heart failure. Can J Cardiol 2015;31: 1259–65.

17. de Groote P, Millaire A, Decoulx E, Nugue O, Guimier P. Ducloux. Kinetics of oxygen consumption during and after exercise in patients with dilated cardiomyopathy. New markers of exercise intolerance with clinical implications. J Am Coll Cardiol 1996;28: 168–75.

progressive cycle ergometer test. Am Rev Respir Dis 1985;131:700–8.

18. Tanabe Y, Takahashi M, Hosaka Y, Ito M, Ito E, Suzuki K. Prolonged recovery of cardiac output after maximal exercise in patients with chronic heart failure. J Am Coll Cardiol 2000;35:1228–36.

12. Murphy RM, Shah RV, Malhotra R, et al. Exercise oscillatory ventilation in systolic heart failure: an indicator of impaired hemodynamic response to exercise. Circulation 2011;124:1442–51.

19. Tanabe Y, Nakagawa I, Ito E, Suzuki K. Hemodynamic basis of the reduced oxygen uptake relative to work rate during incremental exercise in patients with chronic heart failure. Int J Cardiol

11. Jones NL, Makrides L, Hitchcock C, Chypchar T, McCartney N. Normal standards for an incremental

13. Dhakal BP, Malhotra R, Murphy RM, et al. Mechanisms of exercise intolerance in heart failure with preserved ejection fraction: the role of abnormal peripheral oxygen extraction. Circ Heart Fail 2015;8:286–94. 14. Guazzi M, Myers J, Peberdy MA, Bensimhon D, Chase P, Arena R. Exercise oscillatory breathing in diastolic heart failure: prevalence and prognostic insights. Eur Heart J 2008;29:2751–9. 15. Arena R, Myers J, Abella J, et al. Prognostic value of timing and duration characteristics of exercise oscillatory ventilation in patients with heart failure. J Heart Lung Transplant 2008;27:

2002;83:57–62. 20. Arena R, Myers J, Abella J, et al. Determining the preferred percent-predicted equation for peak oxygen consumption in patients with heart failure. Circ Heart Fail 2009;2:113–20. 21. Guazzi M, Arena R, Halle M, Piepoli MF, Myers J, Lavie CJ. 2016 Focused update: clinical recommendations for cardiopulmonary exercise testing data assessment in specific patient populations. Circulation 2016;133:e694–711.

16. Nanas S, Nanas J, Kassiotis C, et al. Respiratory

22. Scrutinio D, Passantino A, Lagioia R, Napoli F, Ricci A, Rizzon P. Percent achieved of predicted peak exercise oxygen uptake and kinetics of recovery of oxygen uptake after exercise for risk stratification in chronic heart failure. Int J Cardiol

muscles performance is related to oxygen kinetics

1998;64:117–24.

341–7.

JACC: HEART FAILURE VOL.

-, NO. -, 2018

Bailey et al.

- 2018:-–-

23. Hayashida W, Kumada T, Kohno F, et al. Postexercise oxygen uptake kinetics in patients with left ventricular dysfunction. Int J Cardiol 1993;38: 63–72. 24. Sietsema KE, Ben-Dov I, Zhang YY, Sullivan C, Wasserman K. Dynamics of oxygen uptake for submaximal exercise and recovery in

Post-Exercise Oxygen Uptake Recovery Delay in HF

patients with chronic heart failure. Chest 1994; 105:1693–700. 25. Kriatselis CD, Nedios S, Kelle S, Helbig S, Gottwik M, von Bary C. Oxygen kinetics and heart rate response during early recovery from exercise in patients with heart failure. Cardiol Res Pract 2012;2012:512857.

KEY WORDS cardiopulmonary exercise testing, exercise hemodynamics, heart failure, recovery kinetics A PP END IX For supplemental tables, please see the online version of this paper.

11