Ventilatory Efficacy After Transcatheter Aortic Valve Replacement Predicts Mortality and Heart Failure Events in Elderly Patients

Abstract

Background: We aimed to clarify the predictors of death or heart failure (HF) in elderly patients who undergo transcatheter aortic valve replacement (TAVR).

Methods and Results: We prospectively enrolled 83 patients (age, 83±5 years) who underwent transthoracic echocardiography (TTE) and cardiopulmonary exercise testing (CPET) with impedance cardiography post-TAVR. We investigated the association of TTE and CPET parameters with death and the combined outcome of death and HF hospitalization. Over a follow-up of 19±9 months, peak oxygen uptake (V̇O₂) was not associated with death or the combined outcome. The minimum ratio of minute ventilation (V̇E) to carbon dioxide production (V̇CO₂) and the V̇E vs. V̇CO₂ slope were higher in patients with the combined outcome. After adjusting for age, sex, Society of Thoracic Surgeons score and peak V̇O₂, ventilatory efficacy parameters remained independent predictors of the combined outcome (minimum V̇E/V̇O₂: hazard ratio, 1.108; 95% confidence interval, 1.010–1.215; P=0.031; V̇E vs. V̇CO₂ slope: hazard ratio, 1.035; 95% confidence interval, 1.001–1.071; P=0.044), and had a greater area under the receiver-operating characteristic curve. The V̇E vs. V̇CO₂ slope ≥34.6 was associated with higher rates of the combined outcome, as well as lower cardiac output at peak work rate during CPET.

Conclusions: In elderly patients, lower ventilatory efficacy post-TAVR is a predictor of death and HF hospitalization, reflecting lower cardiac output at peak exercise.

Transcatheter aortic valve replacement (TAVR) is now widely used for managing severe aortic stenosis (AS) in patients with intermediate-to-high risk.^1,2 However, the 1-year mortality rates after TAVR vary widely and remain high (5–24%).^3–8 The Society of Thoracic Surgeons (STS) score is a well-known predictor of death and perioperative complications,⁹ but does not provide sufficiently accurate predictions in aged patients who undergo TAVR.^10–12

Peak oxygen uptake (V̇O₂) is one of the most important predictors of death in cardiac patients regardless of cardiovascular disease,¹³ because it is regulated by multiple factors such as cardiac function, skeletal muscle function, autonomic nerve function, anemia, and vascular function, which are deteriorated in heart failure (HF).¹⁴ Other predictors of death in HF patients include the minimum value of the ventilatory equivalent of carbon dioxide (V̇E/V̇CO₂) during incremental stress testing, as well as the slope of the minute ventilation vs. carbon dioxide production (V̇E vs. V̇CO₂) relationship.^15–18 The excellent predictive capabilities of these parameters are related to their relationship with ventilation/perfusion (V/Q) mismatch,^14–18 because diminished pulmonary blood flow is a sensitive marker of deteriorated cardiac function. However, the usefulness of peak V̇O₂, minimum V̇E/V̇CO₂ and V̇E vs. V̇CO₂ slope parameters as prognostic factors in TAVR patients remains unclear.

We hypothesized that parameters obtained via cardiopulmonary exercise testing (CPET) would be associated with the rates of mortality and HF hospitalization post-TAVR in elderly Japanese patients. In this study, we aimed to examine the relationship between CPET parameters and the combined outcome of death and hospitalization after TAVR.

Methods

Patients and Study Design

In this prospective study, we recruited 83 consecutive patients with severe AS who underwent TAVR between 2015 and 2017 at the Gunma Prefectural Cardiovascular Center. The exclusion criteria were: death within 1 month of TAVR, unstable physical condition or stroke in the early phase after TAVR, central nervous system disease, severe joint problems preventing the use of an ergometer, refusal to participate, and failure to adequately turn the ergometer pedal upon attempting CPET (e.g., because of knee problems). Finally, we prospectively enrolled 58 patients (Figure 1). The patients underwent CPET together with impedance cardiography within 1 month after successful TAVR. Transthoracic echocardiography (TTE) parameters were evaluated pre- and post-TAVR.

Figure 1.

Flow chart of patient enrolment and evaluation. CHF, congestive heart failure; CPET, cardiopulmonary exercise testing; TAVR, transcatheter aortic valve replacement.

The patients were followed for >1 year after CPET to record any deaths or HF hospitalization events. The primary endpoint was the correlation between peak V̇O₂ and death. The secondary endpoints were peak V̇O₂, anaerobic threshold (AT), peak V̇O₂/heart rate, minimum V̇E/V̇CO₂, V̇E vs. V̇CO₂ slope, delta V̇O₂/delta work rate (WR), tau, peak or mean aortoventricular pressure gradient, max. velocity, paraventricular leakage, E/A, decertation time, and E/E’ and its correlation with the combined outcomes of death and HF hospitalization after TAVR.

We then analyzed the relationship of TTE and CPET with cardiovascular parameters during CPET and with death and the combined outcome.

CPET Protocol and Data Collection

The CPET parameters were evaluated during symptom-limited CPET using a mask, an upright cycle ergometer (StrengthErgo8; Mitsubishi Electric Engineering, Tokyo, Japan), and ECG equipment (ML-9000; Fukuda Denshi Ltd., Tokyo, Japan).¹⁴ CPET was performed 2–4 h after the patient had consumed a light meal. The test began with 3 min of rest and 3 min of warm-up exercise at 0 W, followed by a continuous increase in WR by 1 W every 6 s until exhaustion, as recommended by Buchfuhrer et al.¹⁹ Exhaustion was defined as a score ≥17 points for leg exhaustion on the Borg scale.²⁰ Relevant parameters (V̇O₂, V̇CO₂, and V̇E) were measured on a breath-by-breath basis using a gas analyzer (MINATO 300S; Minato Science Co. Ltd, Osaka, Japan).

AT was measured using the V-slope method.²¹ Peak V̇O₂ was defined as V̇O₂ at peak WR during exercise. Minimum V̇E/V̇CO₂ was defined as the lowest value of the V̇E-to-V̇CO₂ ratio during exercise. The V̇E vs. V̇CO₂ slope was defined as the slope of the linear regression line describing the behavior of V̇E during incremental exercise up to the respiratory compensation point on the plot of V̇E as a function of V̇CO₂.²² All CPET parameters were evaluated by consensus among 3 cardiologists.

Impedance Cardiography Protocol and Data Collection

Cardiac output (CO) during CPET was evaluated using impedance cardiography equipment (PhysioFlow Lab-1; Manatec Biomedical, Paris, France). The PhysioFlow system facilitates non-invasive monitoring of various hemodynamic parameters and has been reported to provide continuous, accurate, reproducible, and sensitive measurements of CO and other parameters,^23,24 which are not inferior to those obtained using the predicate device thermodilution Swan-Ganz catheter.²⁵ In brief, a constant sinusoidal alternating current (1.8 mA, 75 kHz) was applied between 2 electrodes placed on the supraclavicular fossa at the left base of the neck and along the xiphoid. The associated voltage was detected using 2 inner electrodes parallel to the current path. This voltage was transmitted to an amplifier, and an impedance signal (z) was produced. The stroke volume was calculated using the following formula proposed by Sramek-Bernstein: volume of electrically participating intrathoracic tissue×ventricular ejection time×index of contractility, which is the ratio of the peak rate of change in the thoracic bioimpedance (d Z/d t_max) to the thoracic fluid index or total thoracic impedance.²⁶ CO was calculated based on the heart rate and stroke volume. Content arteriovenous oxygen difference was calculated by peak V̇O₂ diveded by peak CO.²⁷ Impedance cardiography is a useful tool for evaluating CO during cycle ergometer exercise in patients with heart disease.²⁸

Follow-up After CPET

As all patients were at the same hospital, they continued to visit every 2–3 months for regular check-ups after TAVR. Therefore, all patients could be followed after CPET. Mortality was defined as all-cause death, including cardiovascular causes. HF hospitalization was defined as hospitalization requiring intravenous therapy for an HF-related event, which was diagnosed based on major symptoms (breathlessness, orthopnea, fatigue, ankle swelling) and signs (elevated jugular venous pressure, hepatojugular reflux, 3rd heart sound, laterally displaced apical impulse).²⁹

Statistical Analysis

Statistical analyses were performed using the Statistical Package for Social Sciences version 20 (IBM Corp., Armonk, NY, USA). All data are expressed as mean±standard deviation, median (25–75th percentiles), or frequency (percentage). Statistical power calculations estimated a minimum required sample size of 52 patients (power 0.80; α=0.05). Quantitative data were analyzed using Student’s t-test, the Mann-Whitney test, chi-square test, or Pearson’s correlation test, as appropriate. Univariate and multivariable Cox proportional hazard models were used to identify predictors of death and HF hospitalization. Receiver-operating characteristic (ROC) curve analysis was used to identify the optimal cutoff of the strongest predictors of event-free survival during follow-up. Kaplan-Meier event-free curves were plotted for the CPET parameters. Statistical significance was defined at P<0.05 in all analyses.

Ethics Considerations

This study was approved by the Ethics Committee of the Gunma Prefectural Cardiovascular Center and registered with the University Hospital Medical Information Network (trial registration no.: UMIN000019716). All patients enrolled in this study provided written informed consent for participation.

Results

Baseline Clinical Characteristics

The patient characteristics are summarized in Table 1 and Table 2. The mean age was 83±5 years, and 30.4% of patients were male. The 6- and 12-month mortality rates after TAVR were 6% and 11%, respectively. Peak V̇O₂ was 11.3±3.3 mL/min/kg. The minimum V̇E/V̇CO₂ was 45.0±6.8 and the V̇E vs. V̇CO₂ slope was 40.2±10.9, with a significant correlation between these parameters (R=0.69, P<0.01).

Table 1. Characteristics of the Study Population

Characteristic	Value (n=58)
Age, years	83±5
Male sex	28 (30)
Body weight, kg	52±11
BMI, kg/m2	22.1±3.6
BSA, m2	1.4±0.2
STS score	6.23±2.84
EuroSCORE II score	3.3±2.7
Mean diameter of the valve used for TAVR, mm	25±2
Outcome
Death	5
HF hospitalization	10
Comorbidities
Previous CABG	25 (27)
Previous PCI	24 (26)
Diabetes mellitus	36 (39)
Hypertension	44 (48)
Dyslipidemia	36 (39)
COPD	5 (5)
Hb, g/dL	11.8±1.8
Creatinine, mg/dL	1.0±0.4
eGFR, mL/min/1.73 m2	51.8±20.0
Echocardiographic findings before TAVR
Aortic area, cm2	0.68±0.17
Mean AV gradient, mmHg	50.6±17.1
Peak AV gradient, mmHg	81.1±28.9
LVEF, %	62.0±10.5
E/E’	17.0±8.4
Hemodynamic and metabolic response
Resting HR, beats/min	75±14
Peak HR, beats/min	105±19
Peak V̇O2, mL/min/kg	11.3±3.3
Peak V̇O2, %	50.0±15.6
Peak work rate, W	38.9±19.6
Minimum V̇E/V̇CO2	45.0±6.5
V̇E/V̇CO2 slope	40.8±12.4
Peak V̇O2/HR	5.6±1.8
Peak V̇O2/HR, %	56.5±15.8
Peak gas exchange ratio	1.04±0.11
Peak Borg score for leg fatigue	18±2
Peak Borg score for dyspnea	15±2

Values are presented as average±standard deviation or frequency (percentage), as appropriate. The estimated glomerular filtration rate (eGFR) was calculated as 0.741×175[Cre (mg/dL)]^−1.154×(age)^−0.203 for males and 0.741×175[Cre (mg/dL)]^−1.154×(age)^−0.203×0.739 for females, where Cre refers to creatinine level. AV, aortoventricular; BMI, body mass index; BSA, body surface area; CABG, coronary artery bypass graft; COPD, chronic obstructive lung disease; EuroSCORE, European System for Cardiac Operative Risk Evaluation; Hb, hemoglobin; HF, heart failure; HR, heart rate; LVEF, left ventricular ejection fraction; PCI, percutaneous coronary intervention; STS score, Society of Thoracic Surgeons score; TAVR, transcatheter aortic valve replacement; V̇E, minute ventilation; V̇CO₂, carbon dioxide production; V̇O₂, oxygen uptake.

Table 2. Characteristics of the Study Population Stratified According to the Combined Endpoint of Mortality and HF Hospitalization Post-TAVR

Characteristic	Outcome (−) (n=43)	Outcome (+) (n=15)	P value
Age, years	83±5	84±4	0.76
Male sex	21 (49)	7 (47)	0.89
Body weight, kg	52±11	52±9	0.96
BMI, kg/m2	22.0±3.7	22.3±3.6	0.78
NYHA classification	1.67±0.47	1.57±0.51	0.49
HF hospitalization before TAVR procedure	29 (63)	8 (53)	0.53
B-type natriuretic peptide, pg/mL	120 [48–223]	311 [95–558]	0.20
STS score	6.11±2.90	6.83±2.67	0.39
Comorbidities
Previous CABG	7 (16)	2 (13)	0.79
Previous PCI	20 (47)	5 (33)	0.38
Diabetes mellitus	13 (30)	6 (40)	0.49
Hypertension	33 (77)	11 (73)	0.79
Dyslipidemia	28 (65)	8 (53)	0.42
COPD	4 (9)	1 (7)	0.52
Hb, g/dL	11.5±1.8	10.9±1.6	0.14
Creatinine, mg/dL	1.0±0.5	1.0±0.3	0.67
eGFR, mL/min/1.73 m2	50.6±21.3	50.9±15.1	0.80
Echocardiographic findings before TAVR
Aortic area index, cm2/m2	0.68±0.18	0.70±0.15	0.69
Mean AV gradient, mmHg	52.4±18.2	45.1±12.6	0.15
Peak AV gradient, mmHg	84.0±31.1	72.9±19.6	0.20
Max velocity, m/s	4.5±0.8	4.3±0.7	0.34
LVEF, %	62±11	61±10	0.86
E/A	0.68 [0.56–1.04]	0.81 [0.65–0.95]	0.53
Deceleration time, s	268 [228–299]	190 [187–322]	0.39
E/E’	17.2±8.8	16.5±7.4	0.79
LVDd, mm	43±7	43±9	0.81
LVDs, mm	28±8	28±9	0.91
IVST, mm	13±2	13±2	0.54
PWT, mm	12±2	12±3	0.73
Stroke volume, mL	43±15	54±26	0.37
Echocardiographic findings after TAVR
Aortic area index, cm2/m2	1.11±0.21	1.10±0.29	0.95
Mean AV gradient, mmHg	10.0±4.0	11.1±5.1	0.79
Peak AV gradient, mmHg	19.1±7.3	20.3±9.9	0.86
Max velocity, m/s	4.5±0.8	4.3±0.7	0.68
LVEF, %	63±8	62±10	0.67
E/A	0.68 [0.56–1.04]	0.81 [0.65–0.95]	0.91
Deceleration time, s	268 [228–299]	190 [187–322]	0.75
E/E’	18.2±7.8	19.4±6.7	0.64
LVDd, mm	42±6	43±8	0.85
LVDs, mm	27±7	28±7	0.71
IVST, mm	12±1	13±3	0.46
PWT, mm	12±2	12±2	0.89
Stroke volume, mL	49±13	46±23	0.82
Paraventricular leakage	Severe 0, moderate 0, mild 4 (9)	Severe 0, moderate 0, mild 3 (20)	0.54
Hemodynamic and metabolic response
Resting HR, beats/min	75±13	73±16	0.55
DeltaV̇O2/delta work rate, mL·W/min·kg	6.9±2.4	6.5±2.5	0.65
AT, mL/min/kg	10.1±2.3	9.4±1.7	0.40
Peak HR, beats/min	106±18	101±21	0.44
Peak V̇O2, mL/min/kg	11.5±3.5	10.6±2.3	0.34
Peak V̇O2, %	50.9±16.7	47.4±11.6	0.46
Peak work rate, watts	41±20	32±15	0.14
Minimum V̇E/V̇CO2	43.6±6.6	48.9±5.8	<0.01
V̇E vs. V̇CO2 slope	37.9±8.9	46.6±13.8	<0.01
Peak V̇O2/HR	5.7±1.9	5.2±1.2	0.36
Peak V̇O2/HR, %	57.0±14.6	54.9±19.4	0.66
Peak gas exchange ratio	1.04±0.10	1.02±0.14	0.49
Peak Borg score for leg fatigue	18±2	19±2	0.30
Peak Borg score for dyspnea	15±2	15±2	0.30
Peak minute ventilation, L/min	26.2±9.4	29.1±10.4	0.32
Peak tidal volume, mL	942±349	989±252	0.64
Peak respiratory rate, /min	28.8±5.8	29.5±5.2	0.73
Peak cardiac output, mL/min	7.6±2.8	6.4±1.6	0.19
Content arteriovenous oxygen difference, mL/100 mL	8.04±2.66	8.63±1.67	0.48
Peak endtidal carbon dioxide, %	5.26±0.62	4.75±0.40	0.14
Medications
β-blocker	9 (21)	5 (33)	0.33
ARB/ACEI	26 (61)	10 (67)	0.67
CCs	24 (56)	5 (33)	0.13
Diuretis	13 (30)	8 (53)	0.11

Data are presented as average±standard deviation, mediation values [25–75th percentiles] or frequency (percentage), as appropriate. P-values were obtained using analysis of variance, the chi-square test, Student’s t-test or Mann-Whitney test and refer to the differences between groups with the outcome (+) and without the outcome (−). The eGFR was calculated as 0.741×175[Cre (mg/dL)]^−1.154×(age)^−0.203 for males and 0.741×175[Cre (mg/dL)]^−1.154×(age)^−0.203×0.739 for females, where Cre refers to creatinine level. ARB/ACEI, angiotensin II receptor blocker/angiotensin-converting enzyme inhibitor; AT, anaerobic threshold; CCB, calcium-channel blocker; IVST, interventricular septum thickness; LVDd, left ventricular end-diastolic diameter; LVDs, left ventricular end-systolic diameter; NYHA, New York Heart Association; PWT, posterior left ventricular wall thickness. Other abbreviations as in Table 1.

Relationship of CPET and TTE Parameters With Outcomes

The patients were followed for 19±9 months (median, 19 months; 25% percentile, 12 months; 75% percentile, 24 months), during which 5 patients died and 10 were hospitalized for HF. Peak V̇O₂ was not significantly associated with death or the combined outcome. Among the TTE and CPET parameters, only the V̇E vs. V̇CO₂ slope and minimum V̇E/V̇CO₂ were associated with the combined outcome of death and HF hospitalization (Table 2).

Relationship of CPET Parameters With Mortality and HF Events

The results of the univariate and multivariable analyses for predictors of the combined outcome are summarized in Table 3. The V̇E vs. V̇CO₂ slope and minimum V̇E/V̇CO₂ were the only significant predictors on univariate analysis and remained independent predictors even after adjusting for age, sex, STS score, and peak V̇O₂ (V̇E vs. V̇CO₂ slope: hazard ratio, 1.035 per unit increase; 95% confidence interval [CI], 1.001–1.071; P=0.044; minimum V̇E/V̇CO₂: hazard ratio, 1.108 per unit increase; 95% CI, 1.101–1.215; P=0.031), as well as after adjusting for other potential confounders.

Table 3. Univariable and Multivariable Analyses for Predictors of the Combined Outcome of Death and HF Hospitalization

Predictor	Unadjusted model			Model 1: adjusted for age and sex			Model 2: adjusted for age, sex, STS score, peak V̇O2			Model 3: adjusted for age, sex, Hb, eGFR
	P value	HR	95% CI	P value	HR	95% CI	P value	HR	95% CI	P value	HR	95% CI
Peak V̇O2	0.333	0.924	0.789– 1.084	0.327	0.916	0.77– 1.091	–	–	–	0.348	0.914	0.758– 1.103
V̇E vs. V̇CO2 slope	0.015	1.036	1.007– 1.065	0.018	1.038	1.006– 1.07	0.044	1.035	1.001– 1.071	0.036	1.037	1.002– 1.073
Minimum V̇E/V̇CO2	0.021	1.094	1.015– 1.18	0.012	1.104	1.022– 1.192	0.031	1.108	1.01– 1.215	0.013	1.102	1.021– 1.191
STS score	0.281	1.094	0.929– 1.289	0.318	1.027	0.361– 2.92	–	–	–	0.257	1.121	0.921– 1.365

P values obtained by Wald test. The eGFR was calculated as 0.741×175[Cre (mg/dL)]^−1.154×(age)^−0.203 for males and 0.741×175[Cre (mg/dL)]^−1.154×(age)^−0.203×0.739 for females, where Cre refers to creatinine level. CI, confidence interval. Other abbreviations as in Table 1.

ROC curve analysis was conducted for peak V̇O₂, V̇E vs. V̇CO₂ slope, minimum V̇E/V̇CO₂, and STS score. The area under the curve (AUC) was significant for the V̇E vs. V̇CO₂ slope (AUC=0.734, 95% CI, 0.607–0.861; P=0.008; sensitivity, 1.00; specificity, 0.500; optimal cutoff, 34.6) and for minimum V̇E/V̇CO₂ (AUC=0.705, 95% CI, 0.564–0.845; P=0.019; sensitivity, 0.80; specificity, 0.595; optimal cutoff, 45.2) (Figure 2). Kaplan-Meier analysis showed that a high V̇E vs. V̇CO₂ slope (≥34.6) (log-rank χ², 9.602; P<0.01) and high minimum V̇E/V̇CO₂ (≥45.2) (log-rank χ², 7.423; P<0.01) were significantly associated with high rates of death and HF hospitalization during follow-up (Figure 3).

Figure 2.

Receiver-operating characteristic curve analysis of metabolic response parameters as predictors of death and heart failure hospitalization. The following values were obtained: for V̇E vs. V̇CO₂ slope, AUC=0.734 (95% CI, 0.607–0.861), P=0.008, optimal cutoff of 34.6, sensitivity=1.00, specificity=0.500; for minimum V̇E/V̇CO₂, AUC=0.705 (95% CI, 0.564–0.845), P=0.019, optimal cutoff of 45.2, sensitivity=0.80, specificity=0.595; for peak V̇O₂, AUC=0.446 (95% CI, 0.285–0.607), P=0.538, optimal cutoff of 12.2, sensitivity=0.200, specificity=0.728; for STS score, AUC=0.578 (95% CI, 0.415–0.741), P=0.375. AUC, area under the curve; CI, confidence interval; STS, Society of Surgeons; V̇E, minute ventilation; V̇CO₂, carbon dioxide production; V̇O₂, oxygen uptake.

Figure 3.

Kaplan-Meier curves for survival free from death and heart failure hospitalization as a function of cardiopulmonary exercise testing parameters. High V̇E vs. V̇CO₂ slope (≥34.6) and high minimum V̇E/V̇CO₂ (≥45.2) were significantly correlated with high rates of the combined outcome of death and heart failure hospitalization. V̇E, minute ventilation; V̇CO₂, carbon dioxide production; V̇O₂, oxygen uptake.

Cardiovascular Parameters During CPET in TAVR Patients With Exercise Limitations

We stratified patients according to the optimal cutoff values of the V̇E vs. V̇CO₂ slope (low, <34.6; high, ≥34.6) and minimum V̇E/V̇CO₂ (low, <45.2; high, ≥45.2). We then compared the corresponding groups (high vs. low ventilatory efficacy) in terms of CO from rest to peak WR. We found that at peak WR, CO was significantly greater in patients with a low V̇E vs. V̇CO₂ slope (8.4±3.2 vs. 6.6±1.5 L/min, P=0.02) and low minimum V̇E/V̇CO₂ (8.2±3.4 vs. 6.4±1.7 L/min, P=0.04) (Figure 4).

Figure 4.

Cardiac output (CO) data stratified according to the ventilatory efficacy parameters during cardiopulmonary exercise testing. V̇E vs. V̇CO₂ slope was defined as high (≥34.6) or low (<34.6). Minimum V̇E/V̇CO₂ was also defined as high (≥45.2) or low (<45.2). Data are reported for 4 time points: at rest, during warm-up, at the anaerobic threshold (AT), and at peak work rate (Peak). (A) CO differed with V̇E vs. V̇CO₂ slope at Peak, and low V̇E vs. V̇CO₂ slope was associated with higher values of CO (8.4±3.4 vs. 6.6±1.7 L/min, P=0.02). (B) CO differed with minimum V̇E/V̇CO₂ at Peak, and low minimum V̇E/V̇CO₂ was associated with higher values of CO (8.2±3.2 vs. 6.4±1.5 L/min, P=0.04). V̇E, minute ventilation; V̇CO₂, carbon dioxide production; V̇O₂, oxygen uptake.

Although the pre- and post-TAVR TTE parameters at rest did not differ significantly between patients with high and low ventilatory efficacy parameters, peak tidal volume (TV) in patients with low V̇E vs. V̇CO₂ slopes was greater than in those with high slopes (1,007±425 vs. 844±295 mL, P=0.04). Other parameters, including STS score, hemoglobin levels, estimated glomerular filtration rate, peak V̇O₂, peak WR, peak ratio of V̇O₂ to heart rate, and peak endtidal carbon dioxide were also greater among patients with high ventilatory efficacy (i.e., low V̇E vs. V̇CO₂ slope and low minimum V̇E/V̇CO₂) (Supplementary Tables 1,2).

Discussion

Main Findings and Overall Considerations

In this study, we found that the combined outcome of death and HF hospitalization after TAVR was significantly correlated with the V̇E vs. V̇CO₂ slope and minimum V̇E/V̇CO₂, but no such association was noted for peak V̇O₂ or STS score. A high V̇E vs. V̇CO₂ slope (≥34.6) and high minimum V̇E/V̇CO₂ (≥45.2) were significantly associated with high rates of the combined outcome. Additionally, patients with a low V̇E vs. V̇CO₂ slope and low minimum V̇E/V̇CO₂ had significantly greater CO at peak WR. To our knowledge, this is the first report to propose high V̇E vs. V̇CO₂ slope and high minimum V̇E/V̇CO₂, which reflect lower CO during exercise, as predictors of death and HF hospitalization in elderly Japanese patients who undergo TAVR. Our study’s cohort also had the oldest HF patients to undergo CPET reported to date.

The 1-year mortality rates after TAVR remain unacceptably high, with the PARTNER trial reporting 24.2% mortality³ and real-world studies of transfemoral TAVR reporting 18% in Belgium,⁴ 21.7% in France,⁵ and 18.5% in the UK.⁸ The K-TAVI registry, which maintains data from a previous study of transfemoral TAVR in Japan, reported 1-year survival rates of 95.5% for elderly patients aged 84.8±6.0 years, of whom 35.5% were male and among whom the STS score was 7.4±5.8%.⁷ The PREVAIL JAPAN study reported 6-month mortality rates of 5.6% for elderly patients aged 83.2±6.5 years, of whom 35.1% were male and among whom the STS score was 7.79±3.43%.⁶ In our present study, which also enrolled elderly Japanese patients (83±5 years) who underwent transfemoral TAVR, 30% of patients were male, the STS score was 6.23±2.84, and the 6- and 12-month mortality rates were 6% and 11%, respectively. Our present results thus corroborate previous findings regarding TAVR mortality rates among the elderly Japanese.

Previous studies have produced conflicting findings regarding the validity of the STS score as a predictor of early or late mortality after TAVR.^10–12 In our study, there was no correlation between STS score and the combined outcome. In contrast to previous reports, our study assessed HF hospitalization and death at 1 year. Furthermore, ventilatory efficacy parameters during CPET, which showed larger AUCs in the ROC analysis than the STS score, correlated with the rates of mortality and HF hospitalization.

Relationship of Ventilatory Efficacy With Mortality and HF Hospitalization Events

Peak V̇O₂ is one of the most important predictors of death in cardiac patients, regardless of cardiovascular disease.¹³ Compared with left ventricular ejection fraction (LVEF), peak V̇O₂ is a stronger predictor of death in severe HF.³⁰ However, in our study of TAVR patients, peak V̇O₂ was not significantly associated with the combined outcome of death and HF hospitalization, whereas low ventilatory efficacy (i.e., high values of the CPET parameters V̇E vs. V̇CO₂ slope and minimum V̇E/V̇CO₂) was associated with a poor combined outcome.

Mezzani et al suggested that peak V̇O₂ is not an accurate predictor of death when the peak gas exchange ratio is <1.15,³¹ which is in agreement with our present observations. Specifically, our patients showed a low peak gas exchange ratio (1.04±0.11 at maximum endurance) even though the exercise was conducted until exhaustion (Borg score for leg fatigue, 18±2). This is likely related to the fact that, because of muscle weakness, elderly patients with HF are less likely to reach a peak gas exchange ratio ≥1.15. Indeed, patients with severe HF tend to be more elderly and to have lower body mass index and lower waist circumference.³² Furthermore, elderly patients with HF tend to be sarcopenic or frail.³³

It is important to note that many of the studies that reported peak V̇O₂ as a predictor of death or hospitalization for HF have included patients aged 50–65 years,^13,30 whereas studies that enrolled older HF cohorts found the V̇E vs. V̇CO₂ slope to be the better predictor. Our present study, which enrolled the oldest HF cohort examined to date (83±5 years), found that the V̇E vs. V̇CO₂ slope was the best among several predictors studied, with peak V̇O₂ showing no significant association with the combined outcome of death and HF hospitalization. The study by Davies et al, which enrolled the oldest HF cohort examined prior to our present study (75.9±4.5 years), reported a better predictive ability for V̇E vs. V̇CO₂ slope than for peak V̇O₂ (AUC on ROC curve analysis: 0.82 vs. 0.76).³⁴ Other authors reported similar findings in HF populations of various ages: Ingle et al in patients aged 63±12 years,¹⁵ Kleber et al in patients aged 51±10 years,²² and Myers et al in patients aged 57±14 years.³⁵ In a meta-analysis of HF patients, Poggio et al found that the V̇E vs. V̇CO₂ slope was at least as good as peak V̇O₂ for predicting cardiovascular events.³⁶ Moreover, the prevalence of chronic obstructive pulmonary disease (COPD), which reflects low ventilatory efficacy, is higher in patients older than 70 years than in younger patients.³⁷ Taken together, these observations strongly suggest that ventilatory efficacy parameters during CPET may serve as useful predictors of death and HF hospitalization in elderly patients with chronic HF, especially after TAVR. Furthermore, as the present study enrolled the oldest TAVR cohort of HF patients examined to date, our findings highlight the value of examining the predictors of cardiovascular events in very elderly patients with chronic HF.

Dissociation Between Parameters Reflecting Ventilatory Efficacy

Although the V̇E vs. V̇CO₂ slope and minimum V̇E/V̇CO₂ have already been reported as predictors of death and HF hospitalization in patients with HF,^{17,18,35,38,39} it remains unclear which of them parameters is the stronger predictor. For example, regarding death in patients with HF, Arena et al¹⁷ and Bol et al¹⁸ found that the V̇E vs. V̇CO₂ slope was the stronger predictor, whereas Myers et al³⁵ and Mejhert et al³⁸ found the V̇E/V̇CO₂ ratio to be the better predictor. In our study of patients with AS, both parameters were independent predictors of death and HF hospitalization after TAVR.

The V̇E vs. V̇CO₂ slope and minimum V̇E/V̇CO₂ are similar in value and strongly correlated.^15–17,40 In previous studies, the optimal cutoffs for predicting death or transplantation were 33–35 for V̇E vs. V̇CO₂ slope and 33–35 for minimum V̇E/V̇CO₂, and the 2 parameters had a correlation coefficient of 0.85–0.92.^{15,17,35,36,39,40} In our study, the optimal cutoff for V̇E vs. V̇CO₂ slope was 34.6, which is similar to previously reported cutoffs for this parameter. On the other hand, the correlation between V̇E vs. V̇CO₂ slope and minimum V̇E/V̇CO₂ was weaker (correlation coefficient, 0.69), and the optimal cutoff for minimum V̇E/V̇CO₂ was 45.6, which did not provide significant predictive capabilities.

Generally, V̇E/V̇CO₂ decreases from rest to the respiratory compensation point, and then starts to increase.^15,40 However, in our study, 72% of patients did not reach the respiratory compensation point during incremental exercise testing because of leg muscle weakness. This means that, for 72% of the participants in this study, the observed minimum V̇E/V̇CO₂ is not the true minimum (representative case illustrated in Figure 5). On the other hand, the method of measuring the V̇E vs. V̇CO₂ slope is simpler, involving plotting V̇E as a function of V̇CO₂ during incremental exercise and then evaluating the V̇E vs. V̇CO₂ relationship using linear regression analysis. Moreover, the V̇E vs. V̇CO₂ slope can be evaluated even under conditions of low WR during incremental exercise testing.^17,22 Moreover, on ROC curve analysis, the AUC was greater for the V̇E vs. V̇CO₂ slope than for the minimum V̇E/V̇CO₂ (Figure 2). Because the V̇E vs. V̇CO₂ slope cutoff value obtained in this study (34.6) is compatible with values reported in previous studies and provides an accurate prediction of death and HF hospitalization (sensitivity, 1.00; specificity, 0.500), the V̇E vs. V̇CO₂ slope may be more suitable than minimum V̇E/V̇CO₂ for the prediction of death and HF hospitalization among aged patients undergoing TAVR.

Figure 5.

Dissociation between minimum V̇E/V̇CO₂ and V̇E vs. V̇CO₂ slope according to data obtained from an 85-year-old female patient who underwent cardiopulmonary exercise testing after transcatheter aortic valve replacement. (A) Leg fatigue (Borg score, 20) was noted at peak work rate (WR; 25 W). The yellow line shows the gas exchange ratio (R), which was 0.94 at peak WR. Minimum V̇E/V̇CO₂ was 48.1 in this case and V̇E/V̇CO₂ did not show a nadir pattern because the patient did not reach the respiratory compensation point because of muscle weakness. (B) Plot of V̇E (L/min) vs. V̇CO₂ (mL/min), with points plotted every 7 breaths. The V̇E vs. V̇CO₂ slope was 38.4. The V̇E vs. V̇CO₂ slope could be evaluated even under conditions of low WR during incremental exercise testing. We observed dissociation between the minimum V̇E/V̇CO₂ and V̇E vs. V̇CO₂ slope. HR, heart rate; V̇E, minute ventilation; V̇CO₂, carbon dioxide production; V̇O₂, oxygen uptake.

Significance of CPET Parameters Reflecting High Ventilatory Efficacy

We found that, although the LVEF and other TTE parameters at rest did not differ with the ventilatory efficacy parameters (Supplementary Tables 1,2), CO at peak WR was significantly greater in patients with high ventilatory efficacy. Moreover, peak endtidal CO₂ in patients with high ventilatory efficacy parameters was higher than in those with lower parameters (Supplementary Tables 1,2). Peak endtidal CO₂ is one of the parameters of peak CO during exercise testing.⁴¹ This observation supports our finding that high ventilatory efficacy parameters correlate with peak CO during exercise.

However, peak CO itself was not associated with the combined outcome in this study (Table 2). The V̇E vs. V̇CO₂ slope and minimum V̇E/V̇CO₂ reflect ventilatory efficacy, which also reflects V/Q mismatch.^14–18 These parameters depend on lung function and chemoreceptor activity, in addition to CO during exercise.⁴² Moreover, the peak TV in patients with a lower V̇E vs. V̇CO₂ slope was significantly higher than in those with higher slopes (Supplementary Table 1). A single breath requires approximately 150 mL of dead space.⁴³ Therefore, lower RR and high TV reflect high ventilatory efficacy at a similar V̇E. Although peak RR did not differ between the high and low V̇E vs. V̇CO₂ slope groups in our study, it is possible that the higher peak TV reflects high ventilatory efficacy in addition to the higher peak CO in the lower V̇E vs. V̇CO₂ group.

It is important to note that the CPET parameters reflecting the ventilatory efficacy parameters were affected by age, peak V̇O₂, peak WR, hemoglobin levels, estimated glomerular filtration rate, and STS score. These findings indicate that, in addition to CO and ventilation pattern, muscle metabolism, blood iron content, and kidney function may be important modulators of death and HF hospitalization risk. The good predictive capability of CPET parameters reflecting ventilatory efficacy (especially V̇E vs. V̇CO₂ slope) may be because they reflect not only CO and ventilation, but also other body functions that are likely to be compromised in aged patients who undergo TAVR.

Study Limitations

Ventilatory efficacy parameters may be affected by hyperventilation or other conscious breathing states, both at rest and during exercise.⁴⁰ In our study, all patients were instructed to breathe naturally, and CPET was started only after stable breathing was achieved. Therefore, the effect of abnormal ventilation on our data is likely minimal. The patients with COPD were using inhaler devices or other medications. We did not evaluate their respiratory function for TAVR therapy. Patients with COPD comprise more than 24% of heart disease patients over the age of 70 years.³⁷ It is possible that the number of patients with COPD was higher in our study.

Another limitation is that many patients enrolled in our study, including those who died or were hospitalized for cardiovascular events, were receiving β-blocker medication, which is known to decrease death in AS patients. Thus, the actual rates of death or cardiovascular events may be higher than observed in this study. In addition, several studies of death after TAVR in patients with severe AS were multicenter studies, whereas ours was a single center with a relatively small number of patients. Future multicenter studies are needed to confirm our findings.

Conclusions

We found that a higher V̇E vs. V̇CO₂ slope and higher minimum V̇E/V̇CO₂ correlated with higher rates of death and HF hospitalization after TAVR, and that these parameters were better predictors than peak VO₂ and STS score. Furthermore, high ventilatory efficiency on post-TAVR CPET (i.e., low V̇E vs. V̇CO₂ slope and low minimum V̇E/V̇CO₂) is associated with high CO at peak WR. Finally, in terms of predictive power, the V̇E vs. V̇CO₂ slope at a cutoff value of 34.6 was comparable to predictors proposed in previous studies based on similar populations and using more accurate yet demanding measuring methods. Given its ease of measurement in clinical practice, a V̇E vs. V̇CO₂ slope ≥34.6 represents an accurate and convenient predictor of high mortality and HF cardiovascular hospitalization rates in elderly Japanese patients undergoing TAVR.

Acknowledgments

We thank Yasuyuki Kobayashi and colleagues from the Physiology Department.

Disclosures

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. The authors have no competing interests to declare.

Supplementary Files

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-19-0273

References

• 1.   Bonow RO, Brown AS, Gillam LD, Kapadia SR, Kavinsky CJ, Lindman BR, et al. ACC/AATS/AHA/ASE/EACTS/HVS/SCA/SCAI/SCCT/SCMR/STS 2017 Appropriate Use Criteria for the Treatment of Patients With Severe Aortic Stenosis: A Report of the American College of Cardiology Appropriate Use Criteria Task Force, American Association for Thoracic Surgery, American Heart Association, American Society of Echocardiography, European Association for Cardio-Thoracic Surgery, Heart Valve Society, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, Society for Cardiovascular Magnetic Resonance, and Society of Thoracic Surgeons. J Am Coll Cardiol 2017; 70: 2566–2598.
• 2.   Baumgartner H, Falk V, Bax JJ, De Bonis M, Hamm C, Holm PJ, et al. 2017 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J 2017; 38: 2739–2791.
• 3.   Smith CR, Leon MB, Mack MJ, Miller DC, Moses JW, Svensson LG, et al. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med 2011; 364: 2187–2198.
• 4.   Bosmans JM, Kefer J, De Bruyne B, Herijgers P, Dubois C, Legrand V, et al. Procedural, 30-day and one year outcome following CoreValve or Edwards transcatheter aortic valve implantation: Results of the Belgian national registry. Interact Cardiovasc Thorac Surg 2011; 12: 762–767.
• 5.   Gilard M, Eltchaninoff H, Iung B, Donzeau-Gouge P, Chevreul K, Fajadet J, et al. Registry of transcatheter aortic-valve implantation in high-risk patients. N Engl J Med 2012; 366: 1705–1715.
• 6.   Sawa Y, Takayama M, Mitsudo K, Nanto S, Takanashi S, Komiya T, et al. Clinical efficacy of transcatheter aortic valve replacement for severe aortic stenosis in high-risk patients: The PREVAIL JAPAN trial. Surg Today 2015; 45: 34–43.
• 7.   Takimoto S, Saito N, Minakata K, Shirai S, Isotani A, Arai Y, et al. Favorable clinical outcomes of transcatheter aortic valve implantation in Japanese patients: First report from the post-approval K-TAVI Registry. Circ J 2016; 81: 103–109.
• 8.   Moat NE, Ludman P, de Belder MA, Bridgewater B, Cunningham AD, Young CP, et al. Long-term outcomes after transcatheter aortic valve implantation in high-risk patients with severe aortic stenosis: The U.K. TAVI (United Kingdom Transcatheter Aortic Valve Implantation) Registry. J Am Coll Cardiol 2011; 58: 2130–2138.
• 9.   Wendt D, Osswald BR, Kayser K, Thielmann M, Tossios P, Massoudy P, et al. Society of Thoracic Surgeons score is superior to the EuroSCORE determining mortality in high risk patients undergoing isolated aortic valve replacement. Ann Thorac Surg 2009; 88: 468–474; discussion 474–475.
• 10.   Silva LS, Caramori PR, Nunes Filho AC, Katz M, Guaragna JC, Lemos P, et al. Performance of surgical risk scores to predict mortality after transcatheter aortic valve implantation. Arq Bras Cardiol 2015; 105: 241–247.
• 11.   Rogers T, Alraies MC, Moussa Pacha H, Bond E, Buchanan KD, Steinvil A, et al. Clinical frailty as an outcome predictor after transcatheter aortic valve implantation. Am J Cardiol 2018; 121: 850–855.
• 12.   Bleiziffer S, Bosmans J, Brecker S, Gerckens U, Wenaweser P, Tamburino C, et al. Insights on mid-term TAVR performance: 3-year clinical and echocardiographic results from the CoreValve ADVANCE study. Clin Res Cardiol 2017; 106: 784–795.
• 13.   Myers J, Prakash M, Froelicher V, Do D, Partington S, Atwood JE. Exercise capacity and mortality among men referred for exercise testing. N Engl J Med 2002; 346: 793–801.
• 14.   Wasserman K. Principles of exercise testing & interpretation, including pathophysiology and clinical applications. 3rd edn. Philadelphia: Lippincott Williams & Wilkins, 1999.
• 15.   Ingle L, Sloan R, Carroll S, Goode K, Cleland JG, Clark AL. Prognostic significance of different measures of the ventilation-carbon dioxide relation in patients with suspected heart failure. Eur J Heart Fail 2011; 13: 537–542.
• 16.   Sullivan MJ, Higginbotham MB, Cobb FR. Increased exercise ventilation in patients with chronic heart failure: Intact ventilatory control despite hemodynamic and pulmonary abnormalities. Circulation 1988; 77: 552–559.
• 17.   Arena R, Myers J, Aslam SS, Varughese EB, Peberdy MA. Peak VO2 and VE/VCO2 slope in patients with heart failure: A prognostic comparison. Am Heart J 2004; 147: 354–360.
• 18.   Bol E, de Vries WR, Mosterd WL, Wielenga RP, Coats AJ. Cardiopulmonary exercise parameters in relation to all-cause mortality in patients with chronic heart failure. Int J Cardiol 2000; 72: 255–263.
• 19.   Buchfuhrer MJ, Hansen JE, Robinson TE, Sue DY, Wasserman K, Whipp BJ. Optimizing the exercise protocol for cardiopulmonary assessment. J Appl Physiol Respir Environ Exerc Physiol 1983; 55: 1558–1564.
• 20.   Borg G. Perceived exertion as an indicator of somatic stress. Scand J Rehabil Med 1970; 2: 92–98.
• 21.   Beaver WL, Wasserman K, Whipp BJ. Bicarbonate buffering of lactic acid generated during exercise. J Appl Physiol 1986; 60: 472–478.
• 22.   Kleber FX, Vietzke G, Wernecke KD, Bauer U, Opitz C, Wensel R, et al. Impairment of ventilatory efficiency in heart failure: Prognostic impact. Circulation 2000; 101: 2803–2809.
• 23.   Richard R, Lonsdorfer-Wolf E, Charloux A, Doutreleau S, Buchheit M, Oswald-Mammosser M, et al. Non-invasive cardiac output evaluation during a maximal progressive exercise test, using a new impedance cardiograph device. Eur J Appl Physiol 2001; 85: 202–207.
• 24.   White SW, Quail AW, de Leeuw PW, Traugott FM, Brown WJ, Porges WL, et al. Impedance cardiography for cardiac output measurement: An evaluation of accuracy and limitations. Eur Heart J 1990; 11(Suppl I): 79–92.
• 25.   Belardinelli R, Ciampani N, Costantini C, Blandini A, Purcaro A. Comparison of impedance cardiography with thermodilution and direct Fick methods for noninvasive measurement of stroke volume and cardiac output during incremental exercise in patients with ischemic cardiomyopathy. Am J Cardiol 1996; 77: 1293–1301.
• 26.   Charloux A, Lonsdorfer-Wolf E, Richard R, Lampert E, Oswald-Mammosser M, Mettauer B, et al. A new impedance cardiograph device for the non-invasive evaluation of cardiac output at rest and during exercise: Comparison with the “direct” Fick method. Eur J Appl Physiol 2000; 82: 313–320.
• 27.   Vignati C, Apostolo A, Cattadori G, Farina S, Del Torto A, Scuri S, et al. Lvad pump speed increase is associated with increased peak exercise cardiac output and VO2, postponed anaerobic threshold and improved ventilatory efficiency. Int J Cardiol 2017; 230: 28–32.
• 28.   Chiba Y, Maehara K, Yaoita H, Yoshihisa A, Izumida J, Maruyama Y. Vasoconstrictive response in the vascular beds of the non-exercising forearm during leg exercise in patients with mild chronic heart failure. Circ J 2007; 71: 922–928.
• 29.   Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC): Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016; 37: 2129–2200.
• 30.   Mancini DM, Eisen H, Kussmaul W, Mull R, Edmunds LH, Wilson JR. Value of peak exercise oxygen consumption for optimal timing of cardiac transplantation in ambulatory patients with heart failure. Circulation 1991; 83: 778–786.
• 31.   Mezzani A, Corra U, Bosimini E, Giordano A, Giannuzzi P. Contribution of peak respiratory exchange ratio to peak VO2 prognostic reliability in patients with chronic heart failure and severely reduced exercise capacity. Am Heart J 2003; 145: 1102–1107.
• 32.   Shiba N, Nochioka K, Miura M, Kohno H, Shimokawa H; CHART-2 Investigators. Trend of westernization of etiology and clinical characteristics of heart failure patients in Japan: First report from the CHART-2 study. Circ J 2011; 75: 823–833.
• 33.   Narumi T, Watanabe T, Kadowaki S, Takahashi T, Yokoyama M, Kinoshita D, et al. Sarcopenia evaluated by fat-free mass index is an important prognostic factor in patients with chronic heart failure. Eur J Intern Med 2015; 26: 118–122.
• 34.   Davies LC, Francis DP, Piepoli M, Scott AC, Ponikowski P, Coats AJ. Chronic heart failure in the elderly: Value of cardiopulmonary exercise testing in risk stratification. Heart 2000; 83: 147–151.
• 35.   Myers J, Arena R, Oliveira RB, Bensimhon D, Hsu L, Chase P, et al. The lowest VE/VCO2 ratio during exercise as a predictor of outcomes in patients with heart failure. J Card Fail 2009; 15: 756–762.
• 36.   Poggio R, Arazi HC, Giorgi M, Miriuka SG. Prediction of severe cardiovascular events by VE/VCO2 slope versus peak VO2 in systolic heart failure: A meta-analysis of the published literature. Am Heart J 2010; 160: 1004–1014.
• 37.   Fukuchi Y, Nishimura M, Ichinose M, Adachi M, Nagai A, Kuriyama T, et al. COPD in Japan: The Nippon COPD Epidemiology study. Respirology 2004; 9: 458–465.
• 38.   Mejhert M, Linder-Klingsell E, Edner M, Kahan T, Persson H. Ventilatory variables are strong prognostic markers in elderly patients with heart failure. Heart 2002; 88: 239–243.
• 39.   Guazzi M, Myers J, Arena R. Cardiopulmonary exercise testing in the clinical and prognostic assessment of diastolic heart failure. J Am Coll Cardiol 2005; 46: 1883–1890.
• 40.   Sun XG, Hansen JE, Garatachea N, Storer TW, Wasserman K. Ventilatory efficiency during exercise in healthy subjects. Am J Respir Crit Care Med 2002; 166: 1443–1448.
• 41.   Matsumoto A, Itoh H, Eto Y, Kobayashi T, Kato M, Omata M, et al. End-tidal CO₂ pressure decreases during exercise in cardiac patients: Association with severity of heart failure and cardiac output reserve. J Am Coll Cardiol 2000; 36: 242–249.
• 42.   Apostolo A, Laveneziana P, Palange P, Agalbato C, Molle R, Popovic D, et al. Impact of chronic obstructive pulmonary disease on exercise ventilatory efficiency in heart failure. Int J Cardiol 2015; 189: 134–140.
• 43.   Hall JE. Guyton and Hall textbook of medical physiology, 12th edn. Philadelphia: Saunders, 2011.