ORIGINAL ARTICLE

Circulation Reports
Circ Rep 2020; 2: 271 – 279
doi: 10.1253/circrep.CR-20-0021

Heart Failure

Heart Failure With Preserved Ejection Fraction vs.
Reduced Ejection Fraction― Mechanisms of Ventilatory Inefficiency
During Exercise in Heart Failure ―Shingo Tsujinaga, MD, PhD; Hiroyuki Iwano, MD, PhD; Yasuyuki Chiba, MD;
Suguru Ishizaka, MD; Miwa Sarashina, MD; Michito Murayama;
Masahiro Nakabachi; Hisao Nishino; Shinobu Yokoyama;
Kazunori Okada, PhD; Sanae Kaga, PhD; Toshihisa Anzai, MD, PhD
Background: Ventilatory inefficiency during exercise assessed using the lowest minute ventilation/carbon dioxide production (V̇E/
V̇CO2) ratio was recently proven to be a strong prognostic marker of heart failure (HF) regardless of left ventricular ejection fraction(LVEF). Its physiological background, however, has not been elucidated.
Methods and Results: Fifty-seven HF patients underwent cardiopulmonary exercise testing and exercise-stress echocardiography.
The lowest V̇E/V̇CO2 ratio was assessed on respiratory gas analysis. Echocardiography was obtained at rest and at peak exercise.
LVEF was measured using the method of disks. Cardiac output (CO) and the ratio of transmitral early filling velocity (E) to early
diastolic tissue velocity (e’) were calculated using the Doppler method. HF patients were divided into preserved EF (HFpEF) andreduced EF (HFrEF) using the LVEF cut-off 40% at rest. Twenty-four patients were classified as HFpEF and 33 as HFrEF. In HFpEF,
age (r=0.58), CO (r=−0.44), e’ (r=−0.48) and E/e’ (r=0.45) during exercise correlated with the lowest V̇E/V̇CO2 ratio (P<0.05 for all).
In contrast, in HFrEF, age (r=0.47) and CO (r=−0.54) during exercise, but not e’ and E/e’, correlated with the lowest V̇E/V̇CO2 ratio.
Conclusions: Loss of CO augmentation was associated with ventilatory inefficiency in HF regardless of LVEF, although lungcongestion determined ventilatory efficiency only in HFpEF.
Key Words: Cardiopulmonary exercise testing; Exercise-stress echocardiography; Heart failure; Lowest minute ventilation/carbon
dioxide production ratio; Ventilatory efficiency

Despite development of treatment strategies for heart
failure (HF), the clinical outcome is still poor, withan event-free survival of around 30% per 5 years
both in HF patients with reduced left ventricular (LV)ejection fraction (EF; HFrEF) and in those with preserved
EF (HFpEF).1 To improve outcome, adequate management
according to risk stratification is important, but accurate
prediction of cardiovascular events is still challenging, anda reliable predictor is needed to facilitate development of a
useful prediction model in HF. Cardiopulmonary exercise
testing (CPX) has been widely used to estimate risk foradverse outcomes in patients with chronic HF, and peakoxygen consumption (V̇O2) has been established as aprognostic marker in chronic HF.2,3 Meanwhile, in recent

years, research has focused on ventilatory efficiency during
exercise assessed on minute ventilation/carbon dioxide
production (V̇E/V̇CO2) using CPX. The V̇E/V̇CO2 slope iscalculated using the range from the point at which theminute ventilation during the ramp load begins to increase
to the respiratory compensation (RC) point, and the lowest
V̇E/V̇CO2 ratio is calculated using the lowest value fromanaerobic threshold (AT) to RC point.4,5 V̇E and V̇CO2
correlate very well and represent a non-invasive index toestimate ventilatory inefficiency.4,5 The higher V̇E/V̇CO2 is,the more impaired the ventilation efficiency, and this ratio
has been found to be as powerful a predictor of adverse
outcomes in HF patients as peak V̇O2 is.4–6 These associations between ventilatory efficiency and clinical outcome

Received March 2, 2020; accepted March 4, 2020; J-STAGE Advance Publication released online April 7, 2020   Time for primary
review: 2 days
Department of Cardiovascular Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo(S.T., H.I., Y.C., S.I., M.S., T.A.); Diagnostic Center for Sonography (M.M.), Division of Clinical Laboratory and Transfusion
Medicine (M.N., H.N., S.Y.), Hokkaido University Hospital, Sapporo; and Faculty of Health Sciences, Hokkaido University,
Sapporo (K.O., S.K.), Japan
Mailing address: Hiroyuki Iwano, MD, PhD, Department of Cardiovascular Medicine, Faculty of Medicine and Graduate Schoolof Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo 060-8638, Japan.   E-mail: h-iwano@med.hokudai.ac.jp
All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: cr@j-circ.or.jp
ISSN-2434-0790
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TSUJINAGA S et al.

Figure 1.  Subject selection process. Hb,hemoglobin; HF, heart failure; HFpEF, heart
failure with preserved ejection fraction;
HFrEF, heart failure with reduced ejection
fraction; LVEF, left ventricular ejection fraction.

have been observed both in HFrEF and HFpEF, although
the physiological response to exercise is different between
these 2 entities.7,8 Several investigators have investigatedthe pathophysiological mechanisms for impaired ventilatory
efficiency in HFrEF,9–11 but no studies have focused on the
differences in determinants of ventilatory efficiency between
HFrEF and HFpEF. If there were differences in these
determinants between HFrEF and HFpEF, these would
help to elucidate a therapeutic target in these entities.
Therefore, the aim of this study was to identify the physiological determinants of ventilatory efficiency in HF patients
according to LVEF status using exercise-stress echocardiography.

Methods
Subjects and Protocol
The screening process in this study is shown in Figure 1.
The present study prospectively enrolled 168 consecutive
and chronic HF patients admitted to Hokkaido University
Hospital for the management of HF and referred for clinically indicated CPX from July 2016 to March 2018. Fromthe 168 patients, we excluded those with atrial fibrillation(AF) or flutter, inducible myocardial ischemia, significant
left-sided valve disease (with the exception of secondary
mitral regurgitation; MR), moderate or severe aortic
regurgitation, aortic stenosis, mitral stenosis, primary MR
assessed on Doppler echocardiography according to theguidelines,12 prosthetic valve replacement, obstructive
hypertrophic cardiomyopathy, peripheral artery disease,obvious anemia (hemoglobin <10 g/dL), congenital heartdisease, respiratory disease, pericardial disease, and LV
assist device implantation. Accordingly, 63 HF patientswere eligible for the present analysis. HFpEF was definedas HF symptoms or signs, elevated B-type natriuretic
peptide (BNP; >35 pg/mL), plus evidence of echocardiographic abnormalities such as LV hypertrophy, left atrial(LA) enlargement, or evidence of diastolic function in thepresence of LVEF ≥40%.13 HFrEF was defined as HF
symptoms or signs, and reduced LVEF (<40%) as per theguidelines.13 After confirmation that HF was stable, CPX
and exercise-stress echocardiography were performed
without discontinuing β-blockers. The present study was
performed in accordance with the Declaration of Helsinki
and the ethics standards of the responsible committee onhuman experimentation (institutional and national). The
study protocol was approved by the institutional review
board of the Hokkaido University Hospital and written
informed consent was obtained from all the patients.
CPX
Symptom-limited CPX was performed with the use of an
upright electromechanical bicycle ergometer (Aerobike
75XLII; Combi Wellness, Tokyo, Japan) using a ramp
protocol as previously described.14 Peak oxygen consumption (V̇O2), defined as the highest value of maximum V̇O2
in the test, was measured using simultaneous respiratory
gas analysis with a breathing apparatus (Aeromonitor
AE-300S; Minato Medical Science, Osaka, Japan). The
maximum work, peak respiratory exchange, and AT

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Mechanisms of Ventilatory Inefficiency in HF

273

Table 1. Baseline Clinical Characteristics
Variable

Overall(n=57)

HFpEF(n=24)

HFrEF(n=33)

P-value†Age (years)

58±15

57±16

59±15

0.67

Male

35 (61)15 (63)20 (61)

0.93

BSA (m2)

1.67±0.21

1.67±0.20

1.66±0.20

0.38

SBP (mmHg)

107±18117±13100±18<0.01

DBP (mmHg)

64±12

67±10

61±12

0.03

Heart rate (beats/min)

67±11

66±12

68±11

0.41

11 (20)9 (38)

2 (6)NYHA functional class
  I

<0.01

  II

20 (36)8 (33)

12 (36)  III

26 (46)7 (29)

19 (58)20 (35)

3 (13)

17 (52)

Cardiac disease  Dilated cardiomyopathy<0.01   Ischemic heart disease

8 (14)

4 (17)

4 (13)   Hypertensive heart disease

6 (11)2 (8)

4 (13)  HCM

7 (12)

4 (17)3 (9)  Others

16 (28)11 (46)5 (16)

Comorbidity  Hypertension

22 (39)13 (54)9 (33)

0.08  Dyslipidemia

26 (46)

13 (54)13 (39)0.25  Diabetes mellitus

11 (19)2 (8)9 (27)

0.04

Medication   ACEI or ARB

49 (86)

19 (79)30 (91)0.11  β-blockers

45 (79)14 (58)31 (94)<0.01  Calcium antagonists

6 (11)

4 (17)

2 (6)

0.23

  Loop diuretics

33 (58)8 (33)

25 (76)<0.01  MCRA

25 (44)3 (13)

22 (67)<0.01  Tolvaptan

12 (21)0 (0)12 (36)<0.01  Statin

25 (44)12 (50)13 (39)0.18  Aspirin

10 (18)4 (17)

6 (18)

0.80  Hemoglobin (g/dL)

13.5±2.1

13.8±1.713.3±2.4

0.43   Total protein (g/dL)

7.0±0.6

7.0±0.5

6.9±0.6

0.58

Laboratory data  Albumin (g/dL)

4.1±0.4

4.2±0.4

4.1±0.4

0.19   Total bilirubin (mg/dL)

0.8±0.4

0.8±0.4

0.8±0.3

0.83  Creatinine (mg/dL)

0.9±0.3

0.8±0.3

1.0±0.3

0.13  Triglyceride (mg/dL)

110 (81–145)

117 (91–189)

102 (78–129)

0.06
0.38

  HDL-C (mg/dL)

54±17

57±18

52±17

  LDL-C (mg/dL)

112±32113±58112±290.89  HbA1c (%)

6.0±0.6

5.8±0.4

6.1±0.7

0.07  BNP (pg/mL)

145 (60–352)

74 (50–150)

248 (126–468)<0.01  LVMI (g/m2)

118 (90–149)

95 (87–123)

128 (105–151)

0.02  LVEF (%)

39±14

53±9

28±6

<0.01

Echocardiography data   Stroke volume (mL)

58±17

64±12

54±18

0.03

  CO (L/min)

3.8±1.0

4.2±0.9

3.5±1.0<0.01  s’ (cm/s)

5.4±1.5

6.3±1.4

4.7±1.2<0.01  e’ (cm/s)

5.4±2.1

6.1±2.1

4.8±1.9

0.02  E/A ratio

1.3±0.8

1.2±0.8

1.3±0.7

0.79  E/e’ ratio

14.0±5.812.1±5.1

15.4±5.9

0.03  LAVI (mL/m2)

46±20

38±17

51±21

0.01

  TRPG (mmHg)

21±9

23±11

19±6

0.13

    None or trivial

27 (47)17 (71)

10 (30)    Mild

21 (37)5 (21)

16 (48)    Moderate

9 (16)2 (8)

7 (16)  MR

0.03(Table 1 continued the next page.)
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TSUJINAGA S et al.

Variable

Overall(n=57)

HFpEF(n=24)

HFrEF(n=33)

P-value†

CPX data   Peak heart rate (beats/min)

119±29128±28112±28<0.01   Peak load (W)93±40

108±41

76±32

<0.01

  Peak RER

1.2±0.1

1.2±0.1

1.2±0.1

0.90  Peak V̇O2 (mL/kg/min)

17.8±5.2

20.0±5.8

16.0±4.1<0.01  AT (mL/kg/min)

11.0±3.2

11.6±2.8

10.5±3.6

0.26

34±7

33±8

36±6

0.15

  Lowest V̇E/V̇CO2 ratio

Data given as mean ± SD, n (%) or median (IQR). †HFpEF vs. HFrEF. ACEI, angiotensin-converting enzyme inhibitor;

ARB, angiotensin II receptor blocker; AT, anaerobic threshold; BNP, brain natriuretic peptide; BSA, body surface
area; CO, cardiac output; CPX, cardiopulmonary exercise testing; DBP, diastolic blood pressure; e’, average of thepeak early diastolic myocardial velocity from septal and lateral sites of the mitral annulus; E, peak early diastolic filling
velocity; HbA1c, hemoglobin A1c; HCM, hypertrophic cardiomyopathy; HDL-C, high-density lipoprotein cholesterol;
HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; LAVI, left
atrial volume index; LDL-C, low-density lipoprotein cholesterol; LVEF, left ventricular ejection fraction; LVMI, left
ventricular mass index; MCRA, mineral corticoid receptor antagonists; MR, mitral regurgitation; NYHA, New YorkHeart Association; RER, respiratory exchange ratio; s’, average of the peak systolic myocardial velocity from septal
and lateral sites of the mitral annulus; SBP, systolic blood pressure; TRPG, tricuspid regurgitation pressure gradient;V̇E/V̇CO2, minute ventilation/carbon dioxide production; V̇O2, oxygen consumption.

determined by the V-slope method15 were also measured.
The lowest V̇E/V̇CO2 ratio during exercise was measured
as a parameter of ventilatory efficiency during exercise,
which has been reported as a stable marker of ventilatory
inefficiency across laboratory sites, exercise mode, genderand age.5
Exercise-Stress Echocardiography
Exercise-stress echocardiography using a supine bicycle
ergometer (Angio V2; Lode BV, Groningen, Netherlands)
and iE33 ultrasound system with S5-1 transducer (Philips
Ultrasound, Bothell, WA, USA) was performed ≤7 days
after CPX. The mean time from CPX to exercise-stressechocardiography was 3±2 days. To adjust the workload
during stress echocardiography, we determined peakworkload as 80% of the CPX peak workload. Echocardiography including 2-D Doppler imaging was acquired at
rest and peak exercise. Echocardiography measurements
were obtained in accordance with the current guidelines of
the European Association of Cardiovascular Imaging/
American Society of Echocardiography.16 LVEF was
measured using the method of disks. LV mass was calculated according to the Devereux formula. Doppler imagingof LV outflow was recorded in the apical long-axis view andthe time-velocity integral was measured for the estimationof stroke volume. Cardiac output (CO) was calculated as
stroke volume×heart rate. Transmitral Doppler flow wasrecorded and peak early (E) and late diastolic velocity (A)were measured. Septal and lateral peak systolic annularvelocity (s’) as well as early diastolic peak of mitral annularvelocity (e’) were measured from the apical 4-chamber viewusing pulsed-wave tissue Doppler imaging, and the averageof the septal and lateral velocities was used for subsequent
analysis. The ratio of E to e’ (E/e’) was calculated.
Definition of Ventilatory Insufficiency
Ventilatory insufficiency was determined using the cut-off
of lowest V̇E/V̇CO2 ratio ≥33 during CPX.4
Statistical Analysis
Quantitative variables are expressed as mean ± SD if
normally distributed, and as median (IQR) if non-normally
distributed. Qualitative variables are reported using fre-quency and percentage. Parametric unpaired t-test or nonparametric Wilcoxon test was used to compare quantitative
variables. To identify differences in hemodynamic andechocardiographic parameters between rest and peak
exercise, the paired t-test was used for comparisons ofcontinuous variables. The chi-squared test was used tocompare qualitative variables. Pearson’s correlation coefficient was used to examine the relationship between
continuous variables. Linear regression analysis was used
to identify cofactors associated with the lowest V̇E/V̇CO2
ratio. Moreover, we assessed associations between echocardiographic parameters and the lowest V̇E/V̇CO2 ratio
after adjustment for age, body surface area (BSA), andplasma BNP level, which were selected as significant clinicaldeterminants of the lowest V̇E/V̇CO2 ratio. For all tests,
P<0.05 was considered statistically significant. Statisticalanalyses were performed using JMP Pro 13.1.0 (SASInstitute, Cary, NC, USA).

Results
Patient Characteristics
Of the 63 eligible HF patients, 6 patients were excluded
due to insufficient echocardiography image quality during
exercise. Therefore, the final subjects consisted of 57
patients: 24 patients classified as having HFpEF and 33
with HFrEF. The baseline characteristics are listed inTable 1. Age, sex and BSA were similar in both groups.
Systolic blood pressure was significantly higher in HFpEF
than HFrEF, although heart rate was similar in bothgroups. HFrEF patients had more severe HF symptoms
than HFpEF patients. There was a tendency for dilated
cardiomyopathy to be more frequent and ischemic heartdisease to be less frequent in the HFrEF group. The
HFrEF group was more likely to have diabetes mellitus
and to be treated with β-blockers, loop diuretics, mineral
corticoid receptor antagonist and tolvaptan than the
HFpEF group. BNP was lower in HFpEF than in HFrEF
patients. With regard to the echocardiography parameters,
LV mass index was larger and LVEF, stroke volume, andCO were lower in HFrEF than in HFpEF patients. E/e’
was higher and LA volume index was larger in the HFrEF
group. Secondary MR was more apparent in the HFrEF

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275

Table 2. Patient Characteristics vs. Ventilatory Efficiency Status
Overall (n=57)
Variable

Lowest V̇E/
V̇CO2 ratio<33 (n=29)

HFpEF (n=24)

Lowest V̇E/
V̇CO2 ratio≥33 (n=28)

P-value

HFrEF (n=33)

Lowest V̇E/
V̇CO2 ratio<33 (n=14)

Lowest V̇E/
V̇CO2 ratio≥33 (n=10)

P-value

Lowest V̇E/
V̇CO2 ratio<33 (n=15)

Lowest V̇E/
V̇CO2 ratio≥33 (n=18)

P-value
0.03

Age (years)

52±15

64±13

<0.01

52±16

65±11

0.03

53±13

64±15

Male

19 (66)16 (57)0.52

10 (71)5 (50)

0.29

9 (60)

11 (61)0.95

BSA (m2)

1.73±0.23

1.59±0.17

0.01

1.75±0.23

1.57±0.12

0.04

1.72±0.24

1.61±0.19

0.04  At rest

116±19106±150.02

123±18117±140.39

110±17

99±12

0.05

  During exercise

164±30145±250.01

173±27164±210.36

156±31134±200.03  At rest

65±9

68±12

0.33

68±10

65±13

0.64

62±8

69±11

0.06

  During exercise

112±16

95±19

<0.01

121±10

97±20

<0.01

103±16

94±20

0.17

Ischemic etiology

2 (7)7 (25)

0.04

1 (7)

3 (30)

0.03

1 (7)

4 (22)

0.04

NYHA class III

6 (21)

19 (68)<0.01

2 (14)

5 (50)

0.03

4 (29)

14 (78)<0.01

SBP (mmHg)

Heart rate
(beats/min)

Hb (g/dL)

14.0±2.2

13.0±1.8

0.06

14.1±1.6

13.2±1.90.21

13.9±2.712.9±1.8

0.20

Creatinine (mg/dL)

0.9±0.2

1.0±0.4

0.09

0.8±0.2

0.9±0.40.69

0.9±0.3

1.1±0.4

0.11

BNP (pg/mL)

119(50–243)214(81–462)0.03

72(52–148)104(63–203)0.23

148(61–364)341(157–579)

0.03

<0.01

CPX data   Peak workload (W)

117±36

69±28

<0.01

134±35

77±27

<0.01

100±2864±29  AT (mL/kg/min)

12.1±3.6

9.8±2.4<0.01

12.6±2.8

10.1±2.2

0.03

11.5±4.2

9.6±2.6

0.12  Peak V̇O2
(mL/kg/min)

20.6±4.7

14.8±3.9<0.01

23.2±4.7

15.7±4.1<0.01

18.2±3.4

14.3±3.9

<0.01

110
(90–135)127(95–162)0.33

98(88–117)95(75–154)0.66

125(100–144)

133(111–178)

0.24

Echocardiographydata  LVMI (g/m2)  LVEF (%)    At rest

40±16

37±15

0.46

53±13

55±10

0.66

29±5

27±7

0.55

    During exercise

47±19

42±19

0.34

63±16

64±12

0.83

33±6

30±9

0.28

    At rest

64±14

52±17

<0.01

68±8

59±15

0.07

61±18

48±17

0.04

    During exercise

74±18

58±21

<0.01

82±16

69±19

0.04

67±18

50±20

0.02

    At rest

4.1±0.9

3.4±0.9<0.01

4.5±0.7

3.7±0.9

0.02

3.8±1.0

3.3±0.9

0.12    During exercise

8.4±2.4

5.3±2.3<0.01

10.1±1.7

6.5±2.5<0.01

6.9±1.9

4.6±2.0<0.01  Change rate in CO
during exercise

2.1±0.5

1.5±0.4<0.01

2.2±0.4

1.7±0.50.02

1.9±0.5

1.4±0.3<0.01    At rest

5.7±1.6

5.1±1.3

0.10

6.8±1.5

5.6±0.9

0.04

4.7±0.94.7±1.4

0.87    During exercise

7.6±2.5

6.1±2.0

0.02

8.9±2.6

7.4±1.7

0.03

6.3±1.75.3±1.7

0.10    At rest

6.0±2.4

4.7±1.4

0.01

7.0±2.2

4.9±1.2

0.01

5.1±2.2

4.6±1.6

0.42    During exercise

8.8±3.8

6.2±2.6<0.01

11.3±3.4

7.6±2.7

0.01

6.3±2.1

5.3±2.1

0.22   Stroke volume (mL)  CO (L/min)  s’ (cm/s)  e’ (cm/s)  E/e’    At rest

12.4±4.915.7±6.2

0.03

10.4±3.8

14.5±5.9

0.04

14.3±5.2

16.4±6.4

0.33    During exercise

14.4±7.2

20.1±11.6

0.04

11.3±3.715.1±4.3

0.04

18.3±8.4

24.5±12.3

0.17  Change in E/e’during exercise

2.2±3.9

4.5±7.3

0.13

0.8±1.7

0.6±3.1

0.69

3.8±4.9

8.1±7.3

0.14  LAVI (mL/m2)

42±18

50±22

0.18

38±15

38±22

0.97

46±20

56±21

0.18

  TRPG (mmHg)    At rest

19±6

22±10

0.43

22±7

24±15

0.70

17±4

20±7

0.25

    During exercise

34±14

39±14

0.19

31±21

36±14

0.59

35±10

42±13

0.15

  Increase in MR
to more thanmoderate

5 (17)

12 (43)

0.01

1 (7)

1 (10)

0.93

4 (27)

11 (61)

0.02

Data given as mean ± SD, n (%) or median (IQR). Hb, hemoglobin. Other abbreviations as in Table 1.

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Table 3. Determinants of Lowest V̇E/V̇CO2 Ratio
Variable

HFpEF

HFrEF

r

P-valuer

P-value

Age

0.58

<0.01

0.47

<0.01

BSA

−0.41

0.04

−0.45

0.01

SBP at rest

0.04

0.84

−0.31

0.08

SBP during exercise

0.15

0.47

−0.28

0.13

Heart rate at rest

0.07

0.75

0.27

0.12

Heart rate during exercise

−0.51

0.01

−0.23

0.20

Hemoglobin

−0.38

0.06

−0.21

0.24

Creatinine

0.39

0.06

0.13

0.46

Log BNP

0.15

0.48

0.40

0.03

Stroke volume at rest

−0.25

0.24

−0.30

0.09

Stroke volume during exercise

−0.14

0.50

−0.44

0.02

CO at rest

−0.20

0.33

−0.24

0.18

CO during exercise

−0.44

0.04

−0.54

<0.01

LVEF at rest

−0.16

0.45

−0.14

0.44

LVEF during exercise

−0.07

0.76

−0.26

0.15

s’ at rest

−0.24

0.27

−0.18

0.30

s’ during exercise

−0.05

0.81

−0.44

0.01

e’ at rest

−0.41

0.04

−0.21

0.25

e’ during exercise

−0.48

0.03

−0.26

0.18

E/e’ at rest

0.39

0.04

0.24

0.19

E/e’ during exercise

0.45

0.03

0.20

0.33

TRPG at rest

0.19

0.43

0.35

0.07

TRPG during exercise

0.22

0.44

0.33

0.11

Abbreviations as in Table 1.

group. With regard to CPX data, peak heart rate and peakload were higher in the HFpEF group, and respiratoryexchange ratio (RER) was similar between the groups withan average of >1.15, suggesting that adequate stress could
be achieved in both groups. Peak V̇O2 was higher in
HFpEF than in HFrEF patients. AT and the lowest V̇E/
V̇CO2 ratio were almost identical in the 2 groups.
Exercise-Stress Echocardiography
During exercise, heart rate was increased in both groups(HFpEF, 66±12 to 111±12 beats/min, P<0.05; HFrEF,
68±12 to 99±12 beats/min, P<0.05) whereas stroke volume
was increased in only HFpEF patients (HFpEF, 64±12 to
77±18 mL, P<0.05; HFrEF, 54±18 to 58±20 mL, P<0.05),
resulting in greater achievement in CO in HFpEF than in
HFrEF (8.6±2.7 vs. 5.8±2.2 L/min, P<0.01). Heart rate atpeak exercise was significantly lower than that during CPX(112±16 vs. 119±29 beats/min, P=0.03) although there wasa strong correlation between them (r=0.82). HFpEF
patients had higher LVEF (63±14% vs. 31±8%, P<0.01), s’(8.2±2.3 vs. 5.8±1.8 m/s, P<0.01), and e’ (9.7±3.6 vs.
5.7±2.1 m/s, P<0.01) at peak exercise than the HFrEF
patients. In contrast, HFrEF patients had higher E/e’
(16.4±6.7 vs. 21.7±11.0, P<0.01) than HFpEF patients.
Tricuspid regurgitation pressure gradient at peak exercise
was not different between the groups (HFpEF vs. HFrEF,
34±16 vs. 39±12 m/s, P=n.s.). Fifteen HFrEF patients (45%)
had increased MR to more than moderate whereas only 2
HFpEF patients (8%) had an increase in MR.
Ventilatory Inefficiency: Patient Characteristics
Comparisons of clinical and stress test parameters arelisted in Table 2. Patients with ventilatory inefficiency had
higher age, lower BSA and CO during exercise as well as
lower rate of change of CO during exercise than those
without, consistent with previous reports.4,5,10 Peak workload as well as peak V̇O2 was markedly reduced in patientswith ventilatory insufficiency, suggesting reduced exercise
capacity in these patients. Similar results were observed inboth the HFrEF and HFpEF groups. Intriguingly, significantly lower heart rate, s’, and e’, and higher E/e’ during
exercise were observed in the ventilatory inefficiency groupcompared with the preserved ventilatory efficiency patients,
only in the HFpEF group. Change in E/e’ during exercise,
however, was not significantly different according toventilatory efficiency status in the overall patient group orin the HFpEF and HFrEF groups.
Determinants of Lowest V̇E/V̇CO2 Ratio
On univariable analysis to determine the lowest V̇E/V̇CO2
ratio in HFpEF and HFrEF (Table 3), age was significantly
and positively correlated with the lowest V̇E/V̇CO2 ratio,
whereas BSA was negatively correlated with the lowest
V̇E/V̇CO2 ratio in each group. Plasma BNP was positively
correlated with the lowest V̇E/V̇CO2 ratio in HFrEF but
not in HFpEF. Other parameters were not associatedwith the lowest V̇E/V̇CO2 ratio. Of the echocardiographic
parameters at rest, LVEF and CO were not associated withthe lowest V̇E/V̇CO2 ratio in both groups, whereas e’ andE/e’ were associated the lowest V̇E/V̇CO2 ratio only in
HFpEF. In contrast, at exercise, CO was significantly andnegatively correlated with the lowest V̇E/V̇CO2 ratio,
whereas LVEF was not correlated with the lowest V̇E/
V̇CO2 ratio in both groups. Interestingly, both e’ and E/e’Circulation Reports Vol.2, May 2020

Mechanisms of Ventilatory Inefficiency in HF

277

Figure 2.   Correlations between the lowest minute ventilation/carbon dioxide production (V̇E/V̇CO2) ratio and echocardiographic
parameters (A) at rest and (B) at peak exercise in patients with heart failure with preserved ejection fraction (HFpEF,) and heart
failure with reduced ejection faction (HFrEF). e’, early diastolic mitral annular velocity; E, early diastolic transmitral flow velocity;
LVEF, left ventricular ejection fraction.

during exercise were significantly correlated with thelowest V̇E/V̇CO2 ratio in HFpEF, but not in HFrEF(Figure 2).
These associations were significant after adjustment forage, BSA, and plasma BNP level (Table 4).

Discussion
In the present study, we investigated associations between
the lowest V̇E/V̇CO2 ratio and echocardiography parameters during exercise in chronic HF patients, and found an
apparent difference in hemodynamic determinants of the

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278

TSUJINAGA S et al.

Table 4. Correlations Between Echocardiography Parameters and Lowest V̇E/V̇CO2 Ratio†
Variable

HFpEF

HFrEF

β

P-valueβP-value

CO at rest

−0.06

0.74

−0.05

0.76

CO during exercise

−0.41

0.03

−0.39

0.04

LVEF at rest

−0.16

0.41

−0.11

0.49

LVEF during exercise

−0.30

0.15

−0.13

0.47

e’ at rest

−0.19

0.51

−0.11

0.55

e’ during exercise

−0.36

0.04

−0.05

0.81

E/e’ at rest

0.26

0.26

0.01

0.98

E/e’ during exercise

0.44

0.04

0.07

0.70

†After adjustment for age, BSA and plasma BNP. β, standardized beta coefficient. Abbreviations as in Table 1.

lowest V̇E/V̇CO2 ratio: CO as well as e’ and E/e’ during
exercise in HFpEF; but only CO during exercise and not e’or E/e’ in HFrEF. This suggests that blunted response in
CO to exercise could determine ventilatory inefficiency
both in HFpEF and HFrEF, whereas LV relaxation andsubsequent lung congestion was associated with ventilatory
inefficiency only in HFpEF. To the best of our knowledge,
this is the first study to directly evaluated relationships
between the lowest V̇E/V̇CO2 ratio and exercise-stressechocardiographic parameters according to LVEF status.
Recent reports have shown the usefulness of V̇E/V̇CO2
slope during exercise as a prognostic marker in HF
patients,17–19 and increasing attention is being paid to theclinical significance of V̇E/V̇CO2 in the field of HF. Despite
the prognostic utility, knowledge of physiological determinants of V̇E/V̇CO2 is still insufficient in HF. Because carbon
dioxide production, the denominator of V̇E/V̇CO2, reflects
effective alveolar perfusion, V̇E/V̇CO2 slope has been considered to reflect ventilation-perfusion mismatch during
exercise.20–23 In HF, it is reasonable that loss of CO response
reduces V̇CO2, and lung congestion increases V̇E throughthe pulmonary vagus reflex, resulting in ventilation-perfusion mismatch during exercise. Therefore, CO and lungcongestion are expected to be the main determinants ofventilatory efficiency at exercise in HF. In accordance withthis theory, the associations of declining CO at rest or
exercise, elevated mean pulmonary artery pressure or
pulmonary artery wedge pressure during exercise withelevated V̇E/V̇CO2 slope during exercise in HFrEF, in
addition to elevated pulmonary vascular resistance,increased pulmonary dead space, and skeletal muscle
dysfunction, have been noted as influencing factors.5,24,25
In HFpEF, increased mean pulmonary artery pressure andpulmonary vascular resistance at rest were reported to be
associated with elevated V̇E/V̇CO2 slope.26
Consistent in part with the previous observations, wefound that CO during exercise was associated with the lowest
V̇E/V̇CO2 ratio independently of other clinical factors in
HFrEF. However, E/e’, a parameter of LV filling pressure,was not a significant indicator of this in the current HFrEF
population, which is in contrast to the study by Ponikowski
et al.27 Because the present HFrEF patients had moreadvanced HF signs, manifesting as severely reduced LVEF
of 28% on average and worse HF symptoms (NYHA class
III in 58%), LV relaxation could have been highly impaired
and elevated LV filling pressure could frequently be present
even at rest and, as a result, the impact of LV relaxation
reserve and of exercise-induced lung congestion might havebeen reduced in the present study. In addition, approximately half of the HFrEF patients had increased MR to
more than moderate during exercise, in association withseverely reduced LV systolic function, which could haveresulted in reduced forward CO and subsequent accentuation of the influence of reduced CO on respiratory efficiency
in HFrEF patients. In addition, it is well known that suchpatients in advanced HF have skeletal muscle dysfunction.
Therefore, ergoreflex response, responsible for eliciting an
exaggerated ventilatory drive during exercise, might havebeen disordered. As previously reported,24 alteration ofergoreflex might also have affected the lowest V̇E/V̇CO2
ratio in the present HFrEF patients.
In contrast, we showed that both CO and E/e’ during
exercise were associated with the lowest V̇E/V̇CO2 ratio in
HFpEF. Given the hemodynamics of HFpEF, which ischaracterized as blunted CO reserve and abnormal elevationof LV filling pressures during exercise,8 the present observation is expected, although it had not been previously
clarified. Further invasive study using exercise-stress rightheart catheterization is needed to confirm these findings.
Study LimitationsFirst, as a single-center study, the sample size was small
and the present results need to be confirmed in a larger
population. In addition, we classified the patients using an
LVEF cut-off of 40% because of the small sample size, andtherefore the HFpEF group included HF with mid-range
LVEF. The present observations thus can be interpreted asa differentiation of patients with apparent LV systolic
dysfunction and those with relatively preserved LVEF.
Second, due to the exclusion of 105 of 168 patients becauseof the diversity of HF in clinical practice, this narrows down
the population to which the conclusions can be applied. In
contrast, this strict selection could exclude potential
confounding factors that would affect the assessment of
LV diastolic function or of time-velocity integral of LV
outflow. Third, to avoid the instability of echocardiographic
parameters due to irregular heart beat, we excluded patientswith AF, which frequently coexists in HF. Therefore thepresent results cannot be applied to patients with AF, andneed to be tested in these patients by analyzing multiple
heart beats. Fourth, because exercise-stress echocardiography
was performed separately to CPX, the difference in postureand duration between the tests would have weakened therelationship between the lowest V̇E/V̇CO2 ratio and theexercise-stress echocardiography parameters. Moreover,heart rates at peak exercise were slightly but significantly

Circulation Reports Vol.2, May 2020

Mechanisms of Ventilatory Inefficiency in HF
higher in CPX than in exercise-stress echocardiography,
which might have weakened the relationships between theparameters of these examinations. However, the strong
correlations between these heart rates could justify the useof the parameters obtained from 2 separate examinations.
Finally, we used lowest V̇E/V̇CO2 ratio as a marker of
respiratory inefficiency in the present study, which has beenreported to be a stable parameter unaffected by physician
judgement of AT point. In contrast, lowest V̇E/V̇CO2
needs to be measured after the RC point and therefore
depends on the sufficiency of the workload during CPX.
Although the accuracy of V̇E/V̇CO2 in the present study
has been confirmed using peak RER, caution is needed tocheck this point when used in other laboratories not familiar
with the use of this parameter.

Conclusions
In HFpEF, CO as well as lung congestion during exercise
could determine ventilatory efficiency. In contrast, in
HFrEF, CO, but not lung congestion, during exercise could
determine ventilatory efficiency.
Disclosures
The authors declare no conflicts of interest.

IRB Information
The present study was approved by the institutional review board of
the Hokkaido University Hospital (reference no.: 015-0440).

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