Abstract
Background:
Currently, excess ventilation has been grounded under the relationship between minute-ventilation/carbon dioxide output (). Alternatively, a new approach for ventilatory efficiency () has been published.
Objective:
Our main hypothesis is that comparatively low levels of between chronic heart failure (CHF) and chronic obstructive pulmonary disease (COPD) are attainable for a similar level of maximum and submaximal aerobic performance, conversely to long-established methods ( slope and intercept).
Methods:
Both groups performed lung function tests, echocardiography, and cardiopulmonary exercise testing. The significance level adopted in the statistical analysis was 5%. Thus, nineteen COPD and nineteen CHF-eligible subjects completed the study. With the aim of contrasting full values of and for the exercise period (100%), correlations were made with smaller fractions, such as 90% and 75% of the maximum values.
Results:
The two groups attained matched characteristics for age (62±6 vs. 59±9 yrs, p>.05), sex (10/9 vs. 14/5, p>0.05), BMI (26±4 vs. 27±3 Kg m2, p>0.05), and peak (72±19 vs. 74±20 %pred, p>0.05), respectively. The slope and intercept were significantly different for COPD and CHF (27.2±1.4 vs. 33.1±5.7 and 5.3±1.9 vs. 1.7±3.6, p<0.05 for both), but average values were similar between-groups (10.2±3.4 vs. 10.9±2.3%, p=0.462). The correlations between 100% of the exercise period with 90% and 75% of it were stronger for (r>0.850 for both).
Conclusion:
The is a valuable method for comparison between cardiopulmonary diseases, with so far distinct physiopathological mechanisms, including ventilatory constraints in COPD.
Keywords:
Chronic Obstructive Pulmonary Disease; Heart Failure; Exercise; Exercise Test
Resumo
Fundamento:
Atualmente, o excesso de ventilação tem sido fundamentado na relação entre ventilação-minuto/produção de dióxido de carbono (). Alternativamente, uma nova abordagem para eficiência ventilatória () tem sido publicada.
Objetivo:
Nossa hipótese principal é que níveis comparativamente baixos de entre insuficiência cardíaca crônica (ICC) e doença pulmonar obstrutiva crônica (DPOC) são atingíveis para um nível semelhante de desempenho aeróbico máximo e submáximo, inversamente aos métodos estabelecidos há muito tempo (inclinação e intercepto).
Métodos:
Ambos os grupos realizaram testes de função pulmonar, ecocardiografia e teste de exercício cardiopulmonar. O nível de significância adotada na análise estatística foi 5%. Assim, dezenove indivíduos elegíveis para DPOC e dezenove indivíduos elegíveis para ICC completaram o estudo. Com o objetivo de contrastar valores completos de e para o período de exercício (100%), correlações foram feitas com frações menores, como 90% e 75% dos valores máximos.
Resultados:
Os dois grupos tiveram características correspondentes para a idade (62±6 vs 59±9 anos, p>.05), sexo (10/9 vs 14/5, p>0,05), IMC (26±4 vs 27±3 Kg m2, p>0,05), e pico (72±19 vs 74±20 % pred, p>0,05), respectivamente. A inclinação e intercepto foram significativamente diferentes para DPOC e ICC (207,2±1,4 vs 33,1±5,7 e 5,3±1,9 vs 1,7±3,6, p<0,05 para ambas), mas os valores médios da foram semelhantes entre os grupos (10,2±3,4 vs 10,9±2,3%, p=0,462). As correlações entre 100% do período do exercício com 90% e 75% dele foram mais fortes para (r>0,850 para ambos).
Conclusão:
A é um método valioso para comparação entre doenças cardiopulmonares, com mecanismos fisiopatológicos até agora distintos, incluindo restrições ventilatórias na DPOC.
Palavras-chave:
Doença Pulmonar Obstrutiva Crônica; Insuficiência Cardíaca; Exercício Físico; Teste de Esforço
Introduction
Quantifying the degree of ventilatory efficiency during cardiopulmonary exercise testing (CPET) using the ventilatory equivalent for carbon dioxide output () slope can be effective for grading clinical severity and estimating morbidity and mortality risk of patients with heart failure (HF).11 Ramos RP, Alencar MC, Treptow E, Arbex F, Ferreira EM, Neder JA. Clinical Usefulness of Response Profiles to Rapidly Incremental Cardiopulmonary Exercise Testing. Pulm Med. 2013;2013:359021. doi: 10.1155/2013/359021.
https://doi.org/10.1155/2013/359021...
2 Phillips DB, Collins SÉ, Stickland MK. Measurement and Interpretation of Exercise Ventilatory Efficiency. Front Physiol. 2020;11:659. doi: 10.3389/fphys.2020.00659.
https://doi.org/10.3389/fphys.2020.00659...
3 Corrà U, Agostoni PG, Anker SD, Coats AJS, Leiro MGC, de Boer RA, et al. Role of Cardiopulmonary Exercise Testing in Clinical Stratification in Heart Failure. A Position Paper from the Committee on Exercise Physiology and Training of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2018;20(1):3-15. doi: 10.1002/ejhf.979.
https://doi.org/10.1002/ejhf.979...
-44 van Iterson EH, Johnson BD, Borlaug BA, Olson TP. Physiological Dead Space and Arterial Carbon Dioxide Contributions to Exercise Ventilatory Inefficiency in Patients with Reduced or Preserved Ejection Fraction Heart Failure. Eur J Heart Fail. 2017;19(12):1675-85. doi: 10.1002/ejhf.913.
https://doi.org/10.1002/ejhf.913...
This is because the slope variable can be used to provide information on whether abnormally high ventilation relative to metabolic demand is likely to be driven by factors such as high ventilation and perfusion mismatch and/or abnormal regulation of metabolic acidosis. In addition, the slope also mirrors excess ventilation secondary to limited oxidative capacity and hyperactivated muscle afferents in HF, leading to hypocapnia and earlier exhaustion.44 van Iterson EH, Johnson BD, Borlaug BA, Olson TP. Physiological Dead Space and Arterial Carbon Dioxide Contributions to Exercise Ventilatory Inefficiency in Patients with Reduced or Preserved Ejection Fraction Heart Failure. Eur J Heart Fail. 2017;19(12):1675-85. doi: 10.1002/ejhf.913.
https://doi.org/10.1002/ejhf.913...
However, when a specific disease affecting the airways and breathing mechanics is present, such as in patients with chronic obstructive pulmonary disease (COPD), the slope measurement can represent pathophysiological processes that are unlikely to explain the low ventilatory efficiency typical of HF.33 Corrà U, Agostoni PG, Anker SD, Coats AJS, Leiro MGC, de Boer RA, et al. Role of Cardiopulmonary Exercise Testing in Clinical Stratification in Heart Failure. A Position Paper from the Committee on Exercise Physiology and Training of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2018;20(1):3-15. doi: 10.1002/ejhf.979.
https://doi.org/10.1002/ejhf.979...
4 van Iterson EH, Johnson BD, Borlaug BA, Olson TP. Physiological Dead Space and Arterial Carbon Dioxide Contributions to Exercise Ventilatory Inefficiency in Patients with Reduced or Preserved Ejection Fraction Heart Failure. Eur J Heart Fail. 2017;19(12):1675-85. doi: 10.1002/ejhf.913.
https://doi.org/10.1002/ejhf.913...
5 Neder JA, Di Paolo M, O’Donnell DE, Palange P. On the Complexities of Measuring Exercise "Ventilatory Efficiency" in Obstructive Lung Diseases. Pediatr Pulmonol. 2020;55(2):280-2. doi: 10.1002/ppul.24556.
https://doi.org/10.1002/ppul.24556...
6 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;189:134-40. doi: 10.1016/j.ijcard.2015.03.422.
https://doi.org/10.1016/j.ijcard.2015.03...
-77 Ferrazza AM, Martolini D, Valli G, Palange P. Cardiopulmonary Exercise Testing in the Functional and Prognostic Evaluation of Patients with Pulmonary Diseases. Respiration. 2009;77(1):3-17. doi: 10.1159/000186694.
https://doi.org/10.1159/000186694...
In patients with COPD, low ventilatory efficiency during CPET is commonly associated with dynamic hyperinflation, high ventilatory constraint, and restricted tidal volume (VT) expansion.55 Neder JA, Di Paolo M, O’Donnell DE, Palange P. On the Complexities of Measuring Exercise "Ventilatory Efficiency" in Obstructive Lung Diseases. Pediatr Pulmonol. 2020;55(2):280-2. doi: 10.1002/ppul.24556.
https://doi.org/10.1002/ppul.24556...
This phenotype means that even in those with advanced COPD, it is not rare for there to be an absence of HF patterned hyperventilation during CPET,88 Muller PT, Saraiva EF. Ventilatory Inefficiency During Graded Exercise in COPD: A Pragmatic Approach. Clin Physiol Funct Imaging. 2021;41(1):103-9. doi: 10.1111/cpf.12674.
https://doi.org/10.1111/cpf.12674...
9 Neder JA, Arbex FF, Alencar MC, O’Donnell CD, Cory J, Webb KA, et al. Exercise Ventilatory Inefficiency in Mild to End-Stage COPD. Eur Respir J. 2015;45(2):377-87. doi: 10.1183/09031936.00135514.
https://doi.org/10.1183/09031936.0013551...
-1010 Smith JR, van Iterson EH, Johnson BD, Borlaug BA, Olson TP. Exercise Ventilatory Inefficiency in Heart Failure and Chronic Obstructive Pulmonary Disease. Int J Cardiol. 2019;274:232-6. doi:10.1016/j.ijcard.2018.09.007.
https://doi.org/10.1016/j.ijcard.2018.09...
meaning that the slope does not increase in tandem with the factors implicated with abnormally high ventilation. Therefore, because making cross-patient comparisons of ventilatory efficiency using the slope can be challenging, we recently described an alternative method for evaluating ventilatory efficiency, which is proposed to allow for direct comparison across patient types.88 Muller PT, Saraiva EF. Ventilatory Inefficiency During Graded Exercise in COPD: A Pragmatic Approach. Clin Physiol Funct Imaging. 2021;41(1):103-9. doi: 10.1111/cpf.12674.
https://doi.org/10.1111/cpf.12674...
In this study, we aimed to compare exercise ventilatory efficiency derived using our alternative methodology between patients with HF and those with COPD.88 Muller PT, Saraiva EF. Ventilatory Inefficiency During Graded Exercise in COPD: A Pragmatic Approach. Clin Physiol Funct Imaging. 2021;41(1):103-9. doi: 10.1111/cpf.12674.
https://doi.org/10.1111/cpf.12674...
We hypothesized that low exercise ventilatory efficiency quantified using our alternative technique is clinically and physiologically comparable between patients with HF and those with COPD at both submaximal and maximal levels of metabolic demand.66 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;189:134-40. doi: 10.1016/j.ijcard.2015.03.422.
https://doi.org/10.1016/j.ijcard.2015.03...
,1010 Smith JR, van Iterson EH, Johnson BD, Borlaug BA, Olson TP. Exercise Ventilatory Inefficiency in Heart Failure and Chronic Obstructive Pulmonary Disease. Int J Cardiol. 2019;274:232-6. doi:10.1016/j.ijcard.2018.09.007.
https://doi.org/10.1016/j.ijcard.2018.09...
11 Harvey-Dunstan TC, Singh SJ, Steiner MC, Morgan MD, Evans RA. Are the Measurement Properties of Incremental Exercise Tests Similar between Patients with COPD and CHF?. Chron Respir Dis. 2019;16:1479973119887965. doi: 10.1177/1479973119887965.
https://doi.org/10.1177/1479973119887965...
12 Thirapatarapong W, Armstrong HF, Bartels MN. Comparison of Cardiopulmonary Exercise Testing Variables in COPD Patients with and without Coronary Artery Disease. Heart Lung. 2014;43(2):146-51. doi: 10.1016/j.hrtlng.2013.12.005.
https://doi.org/10.1016/j.hrtlng.2013.12...
-1313 Teopompi E, Tzani P, Aiello M, Ramponi S, Visca D, Gioia MR, et al. Ventilatory Response to Carbon Dioxide Output in Subjects with Congestive Heart Failure and in Patients with COPD with Comparable Exercise Capacity. Respir Care. 2014;59(7):1034-41. doi: 10.4187/respcare.02629.
https://doi.org/10.4187/respcare.02629...
Materials and methods
This prospective and cross-sectional study was reviewed and approved by the human research ethics committee of the Federal University of Mato Grosso do Sul (UFMS) (CEP number 44517121.0.0000.0021), and adhered to the human research medical and ethical standards outlined in the Declaration of Helsinki, with voluntary provision of verbal and written informed consent.
Participants and study design
There were 38 participants included in this study who were recruited from outpatient cardiology and pulmonology clinics. Participants underwent comprehensive clinical evaluations and testing throughout three study visits, including pulmonary function testing (PFTs), resting transthoracic echocardiography (TTE), and CPET in the pulmonology department of the UFMS.
Study inclusion criteria required patients with COPD to demonstrate a forced expiratory volume (FEV1)/forced vital capacity (FVC) ratio less than the Low Limit of Normal (LLN) and an FEV1<60%; or for patients with HF, individuals must have demonstrated a left ventricular (LV) ejection fraction percentage consistent with either reduced or preserved ejection fraction (HFrEF and HFpEF, respectively). In addition, only subjects with the presence of signs and symptoms typical of HF in the three categories of history, physical findings, and chest X-ray after a careful cardiologist´s evaluation and who presented clinical stability were included. Regardless of diagnosis, potential participants must have been clinically stable for more than 30 days to perform CPET. Patients were also required to be free of other conditions that could have primarily accounted for the termination of CPET, such as peripheral arterial disease, restrictive pulmonary disease, musculoskeletal disorders, bronchial asthma, or bronchiectasis. Subjects who were unable to perform the proposed stress tests, who were actively participating in a rehabilitation program, and who presented severe intercurrences (e.g., angina cordis) were also excluded. Abstinence of narcotic and/or alcohol dependence was also required of patients before participation in this study.
Individuals meeting study inclusion criteria performed PFTs on the first study visit. On the second and third study visits, participants underwent TTE and CPET, respectively. Participants remained on standard medications for the management of COPD or HF on testing days. However, participants were asked to abstain from taking depressant/stimulant medications or ingesting caffeine on testing days.
Pulmonary function tests
Participants performed PFTs according to guidelines of the European Respiratory Society/American Thoracic Society.1414 Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. Standardisation of Spirometry. Eur Respir J. 2005;26(2):319-38. doi: 10.1183/09031936.05.00034805.
https://doi.org/10.1183/09031936.05.0003...
,1515 Graham BL, Brusasco V, Burgos F, Cooper BG, Jensen R, Kendrick A, et al. Executive Summary: 2017 ERS/ATS Standards for Single-Breath Carbon Monoxide Uptake in the Lung. Eur Respir J. 2017;49(1):16E0016. doi: 10.1183/13993003.E0016-2016.
https://doi.org/10.1183/13993003.E0016-2...
The same Vmax 22 system (Viasys, Yorba Linda, USA, 2011) was used for all PFTs and was calibrated before each series of tests according to manufacturer recommendations and concerning the Brazilian population.1616 Neder JA, Andreoni S, Peres C, Nery LE. Reference Values for Lung Function Tests. III. Carbon Monoxide Diffusing Capacity (Transfer Factor). Braz J Med Biol Res. 1999;32(6):729-37. doi: 10.1590/s0100-879x1999000600008.
https://doi.org/10.1590/s0100-879x199900...
,1717 Pereira CA, Sato T, Rodrigues SC. New Reference Values for Forced Spirometry in White Adults in Brazil. J Bras Pneumol. 2007;33(4):397-406. doi: 10.1590/s1806-37132007000400008.
https://doi.org/10.1590/s1806-3713200700...
Standard doppler echocardiography
Transthoracic pulsed-wave Doppler-echocardiography was performed by a cardiologist-sonographer who had extensive experience in acquiring images in both HF and COPD patients. Images and parameters were acquired with a standard device (Vivid S5™, General Electrics, Israel, 2015), complying with recommended guidelines.1818 Neder JA, Nery LE, Peres C, Whipp BJ. Reference Values for Dynamic Responses to Incremental Cycle Ergometry in Males and Females Aged 20 to 80. Am J Respir Crit Care Med. 2001;164(8 Pt 1):1481-6. doi: 10.1164/ajrccm.164.8.2103007.
https://doi.org/10.1164/ajrccm.164.8.210...
Participants were in the left lateral decubitus position during image acquisition using the parasternal long-axis, apical four and two chambers, and subcostal views. Measurement of cardiac cavities and thickness of the interventricular septum and posterior wall of the LV were acquired using M-mode imaging. The LV ejection fraction percentage was quantified using Simpson's Bi-plane method.
Cardiopulmonary exercise testing (CPET)
Each CPET was performed on a Vsprint 200 model cycle ergometer (Viasys, Yorba Linda, CA, USA, 2011) in a dedicated clinical exercise testing laboratory. The same metabolic cart (Vmax Encore 29, Viasys, Yorba Linda, CA, USA, 2011) was used for all CPETs and was calibrated before each test according to the manufacturer's guidelines.
In patients with COPD, following a 2-min rest period and a 1-min unloaded cycling phase at 0.0 Watts, the ramp-slope work rate was 5 for individuals with FEV1<1.0 L or 10 for those with FEV1≥1.0 L.1919 Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, et al. Recommendations for Chamber Quantification: a Report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, Developed in Conjunction with the European Association of Echocardiography, a Branch of the European Society of Cardiology. J Am Soc Echocardiogr. 2005;18(12):1440-63. doi: 10.1016/j.echo.2005.10.005.
https://doi.org/10.1016/j.echo.2005.10.0...
In patients with HF, participants performed a rest and unloaded phase similar to COPD, which was followed by a 2-minute incremental step-wise exercise at a range of 10 to 20 Watts.
Physiological data were recorded at rest and every 2-min throughout CPET until achieving peak exercise, which was defined as the time point where an increase in workload could no longer be met with an appropriate pedal cadence for more than 10 seconds. Breath-by-breath measurements of oxygen uptake (), carbon dioxide output (), minute ventilation (), respiratory rate (fR),VT, etc. were recorded throughout CPET. Heart rate (HR) and rhythm were monitored via 12-lead electrocardiography (Cardiosoft®, USA, 2012). Measurements of arterial oxyhemoglobin saturation (SpO2, DIXTAL, Manaus, Brazil, 2010) were acquired using pulse oximetry at rest and throughout testing. Exercise reference values for selected variables were presented.2020 Hsia D, Casaburi R, Pradhan A, Torres E, Porszasz J. Physiological Responses to Linear Treadmill and Cycle Ergometer Exercise in COPD. Eur Respir J. 2009;34(3):605-15. doi: 10.1183/09031936.00069408.
https://doi.org/10.1183/09031936.0006940...
Sample size, data processing and statistical analysis
The sample size was calculated as previously reported for HF in a multisite study,2121 Keteyian SJ, Brawner CA, Ehrman JK, Ivanhoe R, Boehmer JP, Abraham WT, et al. Reproducibility of Peak Oxygen Uptake and Other Cardiopulmonary Exercise Parameters: Implications for Clinical Trials and Clinical Practice. Chest. 2010;138(4):950-5. doi: 10.1378/chest.09-2624.
https://doi.org/10.1378/chest.09-2624...
with a mean absolute difference of 2.5 and a within-subject SD of 1.7 for slope. For an unpaired design, this proved that n=19 in each group was a sufficient number of subjects to reach a power > 0.82% with an α=0.05. Of note, for healthy subjects,2222 Davis JA, Sorrentino KM, Ninness EM, Pham PH, Dorado S, Costello KB. Test-Retest Reliability for Two Indices of Ventilatory Efficiency Measured During Cardiopulmonary Exercise Testing in Healthy Men and Women. Clin Physiol Funct Imaging. 2006;26(3):191-6. doi: 10.1111/j.1475-097X.2006.00674.x.
https://doi.org/10.1111/j.1475-097X.2006...
a 95% confidence interval of 2.3 and a similar within-subject SD of 1.7 for slope also proved that n=19 in each group was an adequate number of subjects to reach the desired power (>80%).
The individual collected data samples were analyzed breath-by-breath, with values exceeding 3 times the standard deviation of the local average being excluded. Thus, the slope and intercept of the ratio were obtained by simple linear regression of the type: , where "a" is the slope, and "b" is the value of the intercept, including data from loading exercise to peak.11 Ramos RP, Alencar MC, Treptow E, Arbex F, Ferreira EM, Neder JA. Clinical Usefulness of Response Profiles to Rapidly Incremental Cardiopulmonary Exercise Testing. Pulm Med. 2013;2013:359021. doi: 10.1155/2013/359021.
https://doi.org/10.1155/2013/359021...
In agreement with our hypothesis, we also evaluated two new ventilation parameters: the CO2 output constant rate ( slope) and the ventilatory efficiency (). The two new variables have been described recently.88 Muller PT, Saraiva EF. Ventilatory Inefficiency During Graded Exercise in COPD: A Pragmatic Approach. Clin Physiol Funct Imaging. 2021;41(1):103-9. doi: 10.1111/cpf.12674.
https://doi.org/10.1111/cpf.12674...
Briefly, the slope was obtained in a manner similar to that described for the oxygen uptake efficiency slope, that is, taking the base 10th logarithm of on the x-axis against on the y-axis. This relationship results in a characteristic quadratic function in most cases. The parameter "b" of the linear part of the equation type was termed ( slope). To calculate , this value of "b" was taken as a percentage of a predicted theoretical value of maximum possible under hypothetical conditions, that is, an estimated ceiling of at the predicted maximal voluntary ventilation (MVV) level (see Central Figure and supplementary material for more details). This approach proved to be more sensitive to the discrimination of severity of obstruction and diffusive pulmonary disorder in individuals with COPD88 Muller PT, Saraiva EF. Ventilatory Inefficiency During Graded Exercise in COPD: A Pragmatic Approach. Clin Physiol Funct Imaging. 2021;41(1):103-9. doi: 10.1111/cpf.12674.
https://doi.org/10.1111/cpf.12674...
and smokers without COPD.2323 Muller PT, Orro GG, Barbosa GW, Saraiva E. A New Ventilatory Efficiency Index and Accuracy for Early Lung Diffusion Impairment in Non-COPD Smokers. Respir Physiol Neurobiol. 2021;289:103670. doi: 10.1016/j.resp.2021.103670.
https://doi.org/10.1016/j.resp.2021.1036...
For comparisons between full values for the exercise period (100% or maximum), correlations were made between these values and smaller fractions, such as 90% and 75% of the maximum values.
Continuous data are expressed as mean±standard deviation (SD). Categorical variables were compared between groups using the χ2 (chi-square) statistic. All continuous variables were analyzed for distribution by the Shapiro-Wilk test. Unpaired Student's t-tests were performed for the comparison of baseline characteristics between groups. Pearson product-moment correlation coefficient testing was performed to evaluate univariate relationships. Two-tailed significance was determined using an alpha level set at 0.05. The statistical program SPSS 20.0 was used for all statistical analyses (SPSS, IBM Corp®, USA, 2011).
Results
Baseline characteristics
Basic demographic and clinical characteristics for both patient groups are reported in Table 1, showing groups were matched for age, sex, body mass index (BMI), and peak (%pred and ). Overall cardiac function and pulmonary function differed between HF and COPD groups as expected, whereas HF patients exhibited a higher frequency of comorbidities. Despite both groups demonstrating a similar level of aerobic capacity, a distinct ventilatory limitation to exercise was present in COPD. The significantly higher oxygen pulse in HF as compared with COPD was likely attributable to effects from a greater presence of rate-limiting therapies depressing the rise in HR in HF.
Clinical, Lung function, TT echocardiographic, and Incremental Exercise Testing (CPET) data for selected variables. Comparative data between COPD versus HF
Ventilatory efficiency at maximal performance
Table 2 and Figure 1 report group comparisons for slope, intercept, and . The slope and intercept were significantly different between COPD and HF (27.2±1.4 vs. 33.1±5.7 and 5.3±1.9 vs. 1.7±3.6, p<0.05 for both, Figures 1 A and 1 B, respectively), whereas did not differ significantly between groups (Figure 1 C, p=0.462).
Average±SD and range values for slope, CO2 constant-rate, and ventilatory efficiency () for COPD vs. HF subjects
Box-plot depicting average values and 5-95 percentile distribution for slope, intercept, and in comparing COPD vs. HF.
Ventilatory efficiency at submaximal performance
Table 2 and Figure 2 illustrate the response at 100%, 90%, and 75% of the total exercise time frame, as well as the relationship. At submaximal exercise intensities, only 75% slope was significantly different between COPD and HF ( versus , respectively, Table 2, p<0.05). However, correlations between measurements at 100% and those at 90% and 75% were strong for and slope (r>0.850 for all, Figures 2 A, 2B, 2C and 2D, respectively).
Scatter-plots representing correlations between 100% exercise time-frame data for and slope, and the respective 90% and 75% submaximal data of the original complete test, in comparing COPD (Ochre circles) and HF (Grey circles).
Ventilatory efficiency and peak
Separate correlations involving peak and both and relationship are illustrated in Figure 3. Correlation strength for and slope with peak was moderate-to-high for COPD and HF (r=0.604/r=0.590 and r=0.851/r=0.767, p<0.001 for all, Figures 3 C and 3 D, respectively). However, correlations involving the slope and intercept with peak were not significant (r=0.090/r=0.086, and r=0.162/r=0.100, p>0.05 for all, Figures 3 A and 3 B, respectively for COPD/HF).
Scatter-plots representing correlations between peak and slope (A), intercept (B), slope (C), and (D) for COPD (Ochre circles) and HF (Grey circles).
Discussion
This is the first study to describe the comparison of between COPD and HF patients matched for age, sex, and exercise capacity. In contrast to the significant differences between groups for the slope, these data suggest that does not significantly differ between groups in the presence of no significant differences for peak. The also demonstrates a moderate-to-strong correlation with peak for both COPD and HF patients, whereas the slope does not correlate with peak for either group. Thus, although no causality can be concluded based on the present study design, there is potential clinical utility in using the as a marker of exercise ventilatory efficiency when advanced disease affecting the airways and ventilatory mechanics is likely to confound the use of traditional thresholds for interpreting the slope.
Determinants of ventilatory efficiency in HF and COPD
Patients with COPD or HF demonstrate a multitude of pathophysiological factors that can trigger excessive ventilation during exercise, even at low intensities. Two common factors affecting ventilatory efficiency in both patient groups are an increase in the dead space to tidal volume ratio (VD/VT) and abnormally high ventilatory neural drive relative to metabolic demand.2424 Neder JA, Rocha A, Berton DC, O’Donnell DE. Clinical and Physiologic Implications of Negative Cardiopulmonary Interactions in Coexisting Chronic Obstructive Pulmonary Disease-Heart Failure. Clin Chest Med. 2019;40(2):421-38. doi: 10.1016/j.ccm.2019.02.006.
https://doi.org/10.1016/j.ccm.2019.02.00...
However, the effect these factors have on lessening ventilatory efficiency is not typically observed in the same manner when comparing the slope between COPD and HF patients.
In mild COPD, arterial microangiopathy is suggested to play a major role in the increase in VD/VT.2525 O’Donnell DE, Neder JA, Elbehairy AF. Physiological Impairment in Mild COPD. Respirology. 2016;21(2):211-23. doi: 10.1111/resp.12619.
https://doi.org/10.1111/resp.12619...
,2626 Elbehairy AF, Ciavaglia CE, Webb KA, Guenette JA, Jensen D, Mourad SM, et al. Pulmonary Gas Exchange Abnormalities in Mild Chronic Obstructive Pulmonary Disease. Implications for Dyspnea and Exercise Intolerance. Am J Respir Crit Care Med. 2015;191(12):1384-94. doi: 10.1164/rccm.201501-0157OC.
https://doi.org/10.1164/rccm.201501-0157...
However, in advanced disease, it is suggested that the loss of vascular bed volume and destruction of air spaces provoked by long-term exposure to dynamic hyperinflation (DH) expands total VD to lessen ventilatory efficiency.99 Neder JA, Arbex FF, Alencar MC, O’Donnell CD, Cory J, Webb KA, et al. Exercise Ventilatory Inefficiency in Mild to End-Stage COPD. Eur Respir J. 2015;45(2):377-87. doi: 10.1183/09031936.00135514.
https://doi.org/10.1183/09031936.0013551...
,2727 Neder JA, Berton DC, Marillier M, Bernard AC, O’Donnell DE. Inspiratory Constraints and Ventilatory Inefficiency are Superior to Breathing Reserve in the Assessment of Exertional Dyspnea in COPD. COPD. 2019;16(2):174-81. doi: 10.1080/15412555.2019.1631776.
https://doi.org/10.1080/15412555.2019.16...
A decrease in inspiratory reserve volume also follows DH, eventually limiting VT expansion and contributing to the increase in VD/VT. Although increased ventilatory neural drive can also be present, deranged ventilatory mechanics can often be expected to mute any subsequent effect on the slope.2828 O’Donnell DE, Elbehairy AF, Faisal A, Webb KA, Neder JA, Mahler DA. Exertional Dyspnoea in COPD: the Clinical Utility of Cardiopulmonary Exercise Testing. Eur Respir Rev. 2016;25(141):333-47. doi: 10.1183/16000617.0054-2016.
https://doi.org/10.1183/16000617.0054-20...
,2929 O’Donnell DE, Laveneziana P, Webb K, Neder JA. Chronic Obstructive Pulmonary Disease: Clinical Integrative Physiology. Clin Chest Med. 2014;35(1):51-69. doi: 10.1016/j.ccm.2013.09.008.
https://doi.org/10.1016/j.ccm.2013.09.00...
In contrast, in patients with HF, particularly in those with reduced ejection fraction, the abnormal loss of ventilatory efficiency is strongly linked to a chronic state of hyper-sympathoexcitation stemming from dysfunctional metaboreceptor, mechanoreceptor, baroreceptor, and/or chemoreceptor pathways.44 van Iterson EH, Johnson BD, Borlaug BA, Olson TP. Physiological Dead Space and Arterial Carbon Dioxide Contributions to Exercise Ventilatory Inefficiency in Patients with Reduced or Preserved Ejection Fraction Heart Failure. Eur J Heart Fail. 2017;19(12):1675-85. doi: 10.1002/ejhf.913.
https://doi.org/10.1002/ejhf.913...
,3030 Weatherald J, Sattler C, Garcia G, Laveneziana P. Ventilatory Response to Exercise in Cardiopulmonary Disease: the Role of Chemosensitivity and Dead Space. Eur Respir J. 2018;51(2):1700860. doi: 10.1183/13993003.00860-2017.
https://doi.org/10.1183/13993003.00860-2...
31 Agostoni P, Guazzi M. Exercise Ventilatory Inefficiency in Heart Failure: Some Fresh News Into the Roadmap of Heart Failure with Preserved Ejection Fraction Phenotyping. Eur J Heart Fail. 2017;19(12):1686-9. doi: 10.1002/ejhf.940.
https://doi.org/10.1002/ejhf.940...
-3232 Piepoli M, Ponikowski P, Clark AL, Banasiak W, Capucci A, Coats AJ. A Neural Link to Explain the "Muscle Hypothesis" of Exercise Intolerance in Chronic Heart Failure. Am Heart J. 1999;137(6):1050-6. doi: 10.1016/s0002-8703(99)70361-3.
https://doi.org/10.1016/s0002-8703(99)70...
The additional inability of VD/VT to fall and normalize as exercise commences because of high and heterogeneous ventilation-to-perfusion mismatching also plays an important role in the exaggerated loss of ventilatory efficiency in these patients.3131 Agostoni P, Guazzi M. Exercise Ventilatory Inefficiency in Heart Failure: Some Fresh News Into the Roadmap of Heart Failure with Preserved Ejection Fraction Phenotyping. Eur J Heart Fail. 2017;19(12):1686-9. doi: 10.1002/ejhf.940.
https://doi.org/10.1002/ejhf.940...
Ventilatory inefficiency for hf and copd at maximal performance
Comparisons for the slope and intercept between COPD and HF have been inconsistently reported in the literature, possibly because there has been a lack of consistent clinical and functional capacity (exercise) matching when comparisons have been performed.66 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;189:134-40. doi: 10.1016/j.ijcard.2015.03.422.
https://doi.org/10.1016/j.ijcard.2015.03...
,1010 Smith JR, van Iterson EH, Johnson BD, Borlaug BA, Olson TP. Exercise Ventilatory Inefficiency in Heart Failure and Chronic Obstructive Pulmonary Disease. Int J Cardiol. 2019;274:232-6. doi:10.1016/j.ijcard.2018.09.007.
https://doi.org/10.1016/j.ijcard.2018.09...
However, when group matching has occurred, there is evidence to suggest that when peak is greater than 16 , the slope does not differ between COPD and HF.1313 Teopompi E, Tzani P, Aiello M, Ramponi S, Visca D, Gioia MR, et al. Ventilatory Response to Carbon Dioxide Output in Subjects with Congestive Heart Failure and in Patients with COPD with Comparable Exercise Capacity. Respir Care. 2014;59(7):1034-41. doi: 10.4187/respcare.02629.
https://doi.org/10.4187/respcare.02629...
However, despite there being no differences in the slope between groups, given that COPD patients demonstrated a significantly higher intercept than HF, it is suggested that the loss of ventilatory efficiency is less severe in COPD than in HF.1313 Teopompi E, Tzani P, Aiello M, Ramponi S, Visca D, Gioia MR, et al. Ventilatory Response to Carbon Dioxide Output in Subjects with Congestive Heart Failure and in Patients with COPD with Comparable Exercise Capacity. Respir Care. 2014;59(7):1034-41. doi: 10.4187/respcare.02629.
https://doi.org/10.4187/respcare.02629...
By contrast, these data suggest that ventilatory efficiency does not differ between COPD and HF when compared using the metric and when patients are matched for clinical age, sex, and exercise capacity.
Submaximal ventilatory inefficiency and peak
Previous studies described significant associations between fractions of 50%, 75%, and 90% with 100% exercise time (from start to peak) for the OUES and showed coefficients of correlation similar to that found for 3333 van Laethem C, Sutter J, Peersman W, Calders P. Intratest Reliability and Test-Retest Reproducibility of the Oxygen Uptake Efficiency Slope in Healthy Participants. Eur J Cardiovasc Prev Rehabil. 2009;16(4):493-8. doi: 10.1097/HJR.0b013e32832c88a8.
https://doi.org/10.1097/HJR.0b013e32832c...
,3434 Baba R, Nagashima M, Goto M, Nagano Y, Yokota M, Tauchi N, et al. Oxygen Uptake Efficiency Slope: A New Index of Cardiorespiratory Functional Reserve Derived from the Relation between Oxygen Uptake and Minute Ventilation During Incremental Exercise. J Am Coll Cardiol. 1996;28(6):1567-72. doi: 10.1016/s0735-1097(96)00412-3.
https://doi.org/10.1016/s0735-1097(96)00...
This may be one more way of calculating ventilatory efficiency in physically or intellectually limited populations for clinical purposes.3535 Mendonca GV, Borges A, Wee SO, Fernhall B. Oxygen Uptake Efficiency Slope During Exercise in Adults with Down Syndrome. J Appl Res Intellect Disabil. 2018;31(5):897-904. doi: 10.1111/jar.12449.
https://doi.org/10.1111/jar.12449...
The majority of studies are concordant for moderate correlations between slope and peak for COPD and HF,99 Neder JA, Arbex FF, Alencar MC, O’Donnell CD, Cory J, Webb KA, et al. Exercise Ventilatory Inefficiency in Mild to End-Stage COPD. Eur Respir J. 2015;45(2):377-87. doi: 10.1183/09031936.00135514.
https://doi.org/10.1183/09031936.0013551...
,3636 Clark AL, Swan JW, Laney R, Connelly M, Somerville J, Coats AJ. The Role of Right and Left Ventricular Function in the Ventilatory Response to Exercise in Chronic Heart Failure. Circulation. 1994;89(5):2062-9. doi: 10.1161/01.cir.89.5.2062.
https://doi.org/10.1161/01.cir.89.5.2062...
37 Tabet JY, Beauvais F, Thabut G, Tartière JM, Logeart D, Cohen-Solal A. A Critical Appraisal of the Prognostic Value of the VE/VCO2 Slope in Chronic Heart Failure. Eur J Cardiovasc Prev Rehabil. 2003;10(4):267-72. doi: 10.1097/00149831-200308000-00008.
https://doi.org/10.1097/00149831-2003080...
38 Davies SW, Emery TM, Watling MI, Wannamethee G, Lipkin DP. A Critical Threshold of Exercise Capacity in the Ventilatory Response to Exercise in Heart Failure. Br Heart J. 1991;65(4):179-83. doi: 10.1136/hrt.65.4.179.
https://doi.org/10.1136/hrt.65.4.179...
-3939 Guazzi M, Labate V, Cahalin LP, Arena R. Cardiopulmonary Exercise Testing Reflects Similar Pathophysiology and Disease Severity in Heart Failure Patients with Reduced and Preserved Ejection Fraction. Eur J Prev Cardiol. 2014;21(7):847-54. doi: 10.1177/2047487313476962.
https://doi.org/10.1177/2047487313476962...
despite some negative results for linear correlations.4040 Moore B, Brubaker PH, Stewart KP, Kitzman DW. VE/VCO2 Slope in Older Heart Failure Patients with Normal versus Reduced Ejection Fraction Compared with Age-Matched Healthy Controls. J Card Fail. 2007;13(4):259-62. doi: 10.1016/j.cardfail.2006.12.005.
https://doi.org/10.1016/j.cardfail.2006....
41 Clark AL, Volterrani M, Swan JW, Coats AJ. The Increased Ventilatory Response to Exercise in Chronic Heart Failure: Relation to Pulmonary Pathology. Heart. 1997;77(2):138-46. doi: 10.1136/hrt.77.2.138.
https://doi.org/10.1136/hrt.77.2.138...
-4242 Guazzi M, Reina G, Tumminello G, Guazzi MD. Alveolar-Capillary Membrane Conductance is the Best Pulmonary Function Correlate of Exercise Ventilation Efficiency in Heart Failure Patients. Eur J Heart Fail. 2005;7(6):1017-22. doi: 10.1016/j.ejheart.2004.10.009.
https://doi.org/10.1016/j.ejheart.2004.1...
In COPD subjects, the predominance of more severe obstructive phenotype (GOLD III-IV) is associated with weaker correlations.99 Neder JA, Arbex FF, Alencar MC, O’Donnell CD, Cory J, Webb KA, et al. Exercise Ventilatory Inefficiency in Mild to End-Stage COPD. Eur Respir J. 2015;45(2):377-87. doi: 10.1183/09031936.00135514.
https://doi.org/10.1183/09031936.0013551...
The absence of significant correlations between slope and peak for COPD and HF in our study presumably results from the narrow range for both variables in a smaller number of subjects in the study. However, both slope and showed moderate-to-strong associations with peak. We speculate that the rate of clearance for each 10-fold increase in is more mechanistically linked to maximal aerobic capacity than relationship, and further studies are warranted to elucidate the underpinning mechanisms.
Strengths, limitations of the study and clinical implications
This study has some strengths and limitations that should be addressed. The new comprehensive approach for ventilatory efficiency calculation associated with well-paired groups for two common diseases could be shown for the first time that, despite profound pathophysiological differences underpinning abnormal relationship during the incremental exercise, ventilatory inefficiency might be very similar. This opens a new avenue for comparative prognostic studies, for instance, as the slope has been considered an important prognostic index for HF but scarcely studied for COPD subjects given the above-explained limitations. Moreover, the possibility of submaximal analysis of the ventilatory efficiency for physically or intellectually limited subjects is advantageous. As a limitation, we consider some grades challenging for the calculation of the new index (). Certainly, automatized calculations could help clinicians. In this sense, we have uploaded and hosted free R-program codes for direct CO2 output constant rate and calculations (GitHub®).
Conclusions
This study demonstrates for the first time that when exercise ventilatory efficiency is evaluated using the variable and compared between patients with HF and COPD matched for age, sex, and aerobic capacity, ventilatory efficiency does not differ between groups. Because the loss of ventilatory efficiency cannot be interpreted using the same thresholds of abnormality for the slope from HF to COPD, this study provides preliminary evidence supporting the use of the variable when comparisons of ventilatory efficiency between patient groups must account for advanced obstructive disease affecting the airways and ventilatory mechanics. This could be particularly useful for COPD/HF overlapping when, theoretically, the ventilatory inefficiency in HF could be masked by ventilatory constraints due to COPD, reducing the power of the prognostic evaluation for slope.
Acknowledgments
The authors would like to thank the technical support team for their help and Dr. Erlandson Saraiva for his kind assistance.
*Supplemental Materials
For additional information, please click here.
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31Agostoni P, Guazzi M. Exercise Ventilatory Inefficiency in Heart Failure: Some Fresh News Into the Roadmap of Heart Failure with Preserved Ejection Fraction Phenotyping. Eur J Heart Fail. 2017;19(12):1686-9. doi: 10.1002/ejhf.940.
» https://doi.org/10.1002/ejhf.940 -
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» https://doi.org/10.1016/s0002-8703(99)70361-3 -
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» https://doi.org/10.1097/HJR.0b013e32832c88a8 -
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36Clark AL, Swan JW, Laney R, Connelly M, Somerville J, Coats AJ. The Role of Right and Left Ventricular Function in the Ventilatory Response to Exercise in Chronic Heart Failure. Circulation. 1994;89(5):2062-9. doi: 10.1161/01.cir.89.5.2062.
» https://doi.org/10.1161/01.cir.89.5.2062 -
37Tabet JY, Beauvais F, Thabut G, Tartière JM, Logeart D, Cohen-Solal A. A Critical Appraisal of the Prognostic Value of the VE/VCO2 Slope in Chronic Heart Failure. Eur J Cardiovasc Prev Rehabil. 2003;10(4):267-72. doi: 10.1097/00149831-200308000-00008.
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» https://doi.org/10.1136/hrt.65.4.179 -
39Guazzi M, Labate V, Cahalin LP, Arena R. Cardiopulmonary Exercise Testing Reflects Similar Pathophysiology and Disease Severity in Heart Failure Patients with Reduced and Preserved Ejection Fraction. Eur J Prev Cardiol. 2014;21(7):847-54. doi: 10.1177/2047487313476962.
» https://doi.org/10.1177/2047487313476962 -
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» https://doi.org/10.1016/j.cardfail.2006.12.005 -
41Clark AL, Volterrani M, Swan JW, Coats AJ. The Increased Ventilatory Response to Exercise in Chronic Heart Failure: Relation to Pulmonary Pathology. Heart. 1997;77(2):138-46. doi: 10.1136/hrt.77.2.138.
» https://doi.org/10.1136/hrt.77.2.138 -
42Guazzi M, Reina G, Tumminello G, Guazzi MD. Alveolar-Capillary Membrane Conductance is the Best Pulmonary Function Correlate of Exercise Ventilation Efficiency in Heart Failure Patients. Eur J Heart Fail. 2005;7(6):1017-22. doi: 10.1016/j.ejheart.2004.10.009.
» https://doi.org/10.1016/j.ejheart.2004.10.009
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Sources of fundingThis study was partially funded by Universidade Federal do Mato Grosso do Sul and a grant from the Dean of Research and Graduate Studies (grant number HUMB.280322).
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Study associationThis article is part of the thesis of master submitted by Gerson Gatass Orro de Campos from Universidade Federal do Mato Grosso do Sul.
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Ethics approval and consent to participateThis study was approved by the Ethics Committee of the Universidade Federal do Mato Grosso do Sul under the protocol number 44517121.0.0000.0021. All the procedures in this study were in accordance with the 1975 Helsinki Declaration, updated in 2013. Informed consent was obtained from all participants included in the study.
Edited by
Publication Dates
-
Publication in this collection
29 Apr 2024 -
Date of issue
2024
History
-
Received
21 Aug 2023 -
Reviewed
28 Nov 2023 -
Accepted
18 Jan 2024