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Original Research: Sleep Disorders |

Exercise End-Tidal CO2 Predicts Central Sleep Apnea in Patients With Heart FailureHyperventilation Predicts Central Sleep Apnea FREE TO VIEW

Ivan Cundrle, Jr, MD, PhD; Virend K. Somers, MD, PhD, FCCP; Bruce D. Johnson, PhD; Christopher G. Scott, MS; Lyle J. Olson, MD
Author and Funding Information

From the International Clinical Research Center and Department of Anesthesiology and Intensive Care (Dr Cundrle), St. Anna’s University Hospital Brno, and Faculty of Medicine (Dr Cundrle), Masaryk University, Brno, Czech Republic; and the Division of Cardiovascular Diseases (Drs Somers, Johnson, and Olson) and Department of Biomedical Statistics and Informatics (Mr Scott), Mayo Clinic, Rochester, MN.

CORRESPONDENCE TO: Lyle J. Olson, MD, Division of Cardiovascular Diseases, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: olson.lyle@mayo.edu


FUNDING/SUPPORT: Dr Cundrle was supported by the European Regional Development Fund Project FNUSA-ICRC (No. CZ.1.05/1.1.00/02.0123), European Social Fund, and State Budget of the Czech Republic. This work was supported by the Mayo Foundation; American Heart Association [Grant 04-50103Z]; National Heart, Lung, and Blood Institute [Grant HL65176]; and the National Center for Research Resources [Grant 1ULI RR024150], a component of the National Institutes of Health (NIH) and the NIH Roadmap for Medical Research. This work was also supported by grants from the Respironics Foundation; ResMed Foundation; and Sorin, Inc.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;147(6):1566-1573. doi:10.1378/chest.14-2114
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BACKGROUND:  Increased CO2 chemosensitivity and augmented exercise ventilation are characteristic of patients with heart failure (HF) with central sleep apnea (CSA). The aim of this study was to test the hypothesis that decreased end-tidal CO2 by cardiopulmonary exercise testing predicts CSA in patients with HF.

METHODS:  Consecutive ambulatory patients with New York Heart Association II to III HF were prospectively evaluated by CO2 chemosensitivity by rebreathe, cardiopulmonary exercise testing, and polysomnography (PSG). Subjects were classified as having either CSA (n = 20) or no sleep apnea (n = 13) by PSG; a central apnea-hypopnea index (AHI) ≥ 5 was used to define CSA. Subgroups were compared by t test or Mann-Whitney test and data summarized as mean ± SD. P < .05 was considered significant.

RESULTS:  At rest, subjects with CSA had higher central CO2 chemosensitivity (Δminute ventilation [V. e]/Δpartial pressure of end-tidal CO2 [Petco2], 2.3 ± 1.0 L/min/mm Hg vs 1.6 ± 0.4 L/min/mm Hg, P = .02) and V. e (15 ± 7 L/min vs 10 ± 3 L/min, P = .02) and lower Petco2 (31 ± 4 mm Hg vs 35 ± 4 mm Hg, P < .01) than control subjects. At peak exercise, the ventilatory equivalents per expired CO2 (V. e/V. co2) was higher (43 ± 9 vs 33 ± 6, P < .01) and Petco2 lower (29 ± 6 mm Hg vs 36 ± 5 mm Hg, P < .01) in subjects with CSA. In addition, CO2 chemosensitivity, peak exercise V. e/V. co2, and Petco2 were independently correlated with CSA severity as quantified by the AHI (P < .05). Peak exercise Petco2 was most strongly associated with CSA (OR, 1.29; 95% CI, 1.08-1.54; P = .01; area under the curve, 0.88).

CONCLUSIONS:  In patients with HF and CSA, ventilatory drive is increased while awake at rest and during exercise and associated with heightened CO2 chemosensitivity and decreased arterial CO2 set point.

In patients with heart failure (HF), central sleep apnea (CSA) is recognized on polysomnography (PSG) as Cheyne-Stokes respiration characterized by a crescendo-decrescendo breathing pattern with hyperventilation alternating with compensatory apnea.1,2 In HF case series, the reported frequency of CSA has ranged from 21% to 50%36 and has been associated with increased mortality.7 Despite high pretest probability for sleep apnea, routine PSG for patients with HF has not been endorsed because of cost considerations; an insufficient number of laboratories to accommodate the large number of potential referrals; and lack of controlled, prospective studies demonstrating benefit of intervention for sleep-disordered breathing on cardiovascular outcomes.8,9 However, as more effective therapy for CSA emerges,1012 improved recognition of patients with HF to refer to PSG for definitive diagnosis may improve outcomes.13

An enhanced exercise ventilatory response and augmented CO2 chemosensitivity are frequently observed in patients with HF, and each has been shown to correlate with the severity of CSA as measured by the apnea-hypopnea index (AHI).1420 Patients with HF and CSA breathe more closely to the apneic CO2 threshold, which predisposes to hypopnea and apnea.15 Prior investigation demonstrated that hypocapnea detected by arterial blood gas measurement is sensitive and specific for prediction of CSA in patients with HF.14 This observation suggests that noninvasive estimates of CO2, including transcutaneous measurement, and the partial pressure of end-tidal CO2 (Petco2) at cardiopulmonary exercise testing also predict CSA, although this has not yet been firmly established.2022

We hypothesized that Petco2 measured during cardiopulmonary exercise testing predicts CSA in patients with HF. Accordingly, the aim of this study was to evaluate the relationship of CO2 chemosensitivity and exercise ventilation and gas exchange to the presence of CSA in patients with HF.

Subject Selection

Subjects were consecutive, clinically stable, symptomatic ambulatory outpatients with HF with no symptom progression, no hospitalization, and no change in HF management in the prior 3 months. Inclusion criteria were left ventricular ejection fraction (LVEF) ≤ 35% and New York Heart Association (NYHA) class II to III symptoms despite > 3 months of optimal pharmacotherapy.23 Exclusion criteria were unstable symptoms or inability to perform cardiopulmonary exercise testing. All subjects gave written informed consent. This study was conducted in accordance with the Declaration of Helsinki and approved by the Mayo Clinic Institutional Review Board (IRB #1729-03). All procedures followed institutional and Health Insurance Portability and Accountability Act guidelines.

Exercise Testing

All subjects underwent cardiopulmonary exercise testing, including measurement of metabolic gas exchange as previously described.24 Exercise ventilation and gas exchange were assessed by metabolic cart (MGC Diagnostics Corporation); measures included peak oxygen consumption, CO2 output, Petco2, tidal volume (Vt), minute ventilation (V. e), and breathing frequency. Data were collected continuously and reported as averages obtained over the final 30 s of each workload. Derived measures included the respiratory exchange ratio and ventilatory equivalents per expired CO2 (V. e/V. co2). Our group has previously shown that V. e/V. co2 is highly correlated with the slope of ΔV. eV. co2 at submaximal and peak exercise.25

CO2 Chemosensitivity

CO2 chemosensitivity was measured by a modified rebreathe technique as previously described.26 Subjects breathed from a mouthpiece connected to a rebreathing bag, which included 5% CO2 and balance oxygen at study initiation. Petco2 was monitored by mass spectroscopy as were breath-to-breath changes of V. e by a pneumotachograph. The slope of ΔV. e/ΔPetco2 was used as an index of central CO2 chemosensitivity. Three runs were performed per subject and values reported as the mean.

Polysomnography

Full diagnostic PSG was performed in the Mayo Clinic Center for Translational Science Activities. All PSGs were digitally recorded on an E-Series digital PSG acquisition system (Compumedics Limited). Per published guidelines,27 subjects were considered to have CSA if the total AHI (events/h) was > 5 with > 50% disordered-breathing events of central origin. Subjects were classified into two groups based on PSG findings for comparison: (1) CSA or (2) no sleep apnea. Subjects with OSA or mixed OSA/CSA were excluded from analysis.

Clinical Characteristics

Clinical characteristics were reviewed and recorded for each subject. Characteristics included age, sex, NYHA class, BMI, LVEF, medications, presence or absence of atrial fibrillation, and prior treatment by cardiac resynchronization therapy.

Statistical Analysis

The Shapiro-Wilk test was used to evaluate normality. Comparisons between subjects were made by the Student t test and Mann-Whitney U test. Differences in proportions were tested by the two-tailed Fisher exact test and statistical dependence by the Spearman rank test. Logarithmic transformation was performed for variables with nonnormal distribution. Multiple regressions were performed after controlling for sex and age for evaluation of log AHI and other parameters for detection of CSA. Multivariate logistic regression was performed after controlling for sex and age to analyze the strength of the association of measured end points with CSA. Decision statistics (2 × 2 tables) were calculated for several cutoff values of rest and peak Petco2 and CO2 chemosensitivity and for the composite of rest Petco2 and CO2 chemosensitivity. Data are summarized as mean ± SD. P < .05 was considered statistically significant. Statistical analysis was done using Statistica 12.0 (StatSoft Inc) and SAS, version 9.3 (SAS Institute Inc) software.

Fifty-six subjects with HF were enrolled in the study. Of these, 11 were given a diagnosis of mixed sleep apnea and 12 with OSA. These subjects were excluded from further analysis. Of the remaining 33 subjects with HF, 20 with CSA (61%) and 13 with no sleep apnea (39%) (AHI ≤ 5) formed the study cohort. Comparison of the two groups (CSA vs no sleep apnea) demonstrated no differences in age, BMI, LVEF, NYHA class, and mean nocturnal oxygen saturation; subjects with CSA were mostly men (14 [70%]) (Table 1). No significant differences existed between the two groups for medications and frequency of atrial fibrillation, and none of the subjects had undergone cardiac resynchronization therapy.

Table Graphic Jump Location
TABLE 1 ]  Comparison of Clinical Characteristics by Subject Group

Data are presented as mean ± SD unless otherwise indicated. AHI = apnea-hypopnea index; CSA = central sleep apnea; LVEF = left ventricular ejection fraction; NYHA = New York Heart Association.

Subjects with CSA had higher CO2 chemosensitivity (2.3 ± 1.0 L/min/mm Hg vs 1.6 ± 0.4 L/min/mm Hg, P = .02). Cardiopulmonary ventilatory and gas exchange measures at rest demonstrated that subjects with CSA had lower Petco2 and higher V. e and tended to have a higher V. e/V. co2. Similarly, at 50% peak (ie, submaximal) exercise, subjects with CSA had higher Vt, V. e, and V. e/V. co2, and lower Petco2. At peak exercise, V. e/V. co2 remained higher and Petco2 lower in subjects with CSA (Table 2).

Table Graphic Jump Location
TABLE 2 ]  Comparison of Cardiopulmonary Exercise Ventilation by Subject Group

Data are presented as mean ± SD. fb = breathing frequency; Petco2 = partial pressure of end-tidal CO2; RER = respiratory exchange ratio; V. e = minute ventilation; V. e/V. co2 = ventilatory equivalents per expired CO2; V. o2 = oxygen consumption; Vt = tidal volume. See Table 1 legend for expansion of other abbreviation.

The severity of CSA quantified by the AHI was significantly and inversely correlated with Petco2 at rest and submaximal and peak exercise. The AHI also significantly positively correlated with V. e at rest and submaximal exercise, Vt at submaximal and peak exercise, and V. e/V. co2 at peak exercise. In addition, the AHI significantly correlated with CO2 chemosensitivity (Table 3).

Table Graphic Jump Location
TABLE 3 ]  Spearman Rank Correlation and Multiple Regression for AHI

NS = nonsignificant; ΔV. e/ΔPetco2 = central CO2 chemosensitivity. See Table 1 and 2 legends for expansion of other abbreviations.

Multiple regression analysis adjusted for potential confounders frequently associated with CSA (age, sex)13,28 demonstrated that the AHI remained significantly correlated with CO2 chemosensitivity, V. e at submaximal exercise, Petco2 at rest and submaximal and peak exercise, and V. e/V. co2 at peak exercise (Table 3). CO2 chemosensitivity was also independently associated with submaximal and peak exercise Petco2 (b = −0.38, F = 1.7, P = .04, and b = −0.40, F = 2.2, P = .02, respectively).

Logistic regression analysis showed that CO2 chemosensitivity, Petco2 at rest and submaximal and peak exercise, and V. e/V. co2 at peak exercise were significantly associated with the presence of CSA (Table 4). Receiver operating characteristic analysis demonstrated that peak exercise Petco2 was the strongest independent predictor of CSA (area under the curve, 0.88; P = .01). The best cutoff value of peak exercise Petco2 for detection of CSA was 33 mm Hg, which yielded a sensitivity of 80% and specificity of 85% (Table 5). Subjects with peak Petco2 levels ≤ 33 mm Hg (n = 18) were highly likely to have CSA with a positive likelihood ratio of 5.2 (95% CI, 1.4-19). By comparison, decision statistics for rest parameters significantly associated with CSA yielded lower sensitivity and specificity, or both. The best rest Petco2 cutoff value (33 mm Hg) yielded a sensitivity of 80% and a specificity of 62%, whereas the best CO2 chemosensitivity cutoff value (2 L/min/mm Hg) yielded a sensitivity of 40% and a specificity of 77%. A composite of these two rest parameters yielded a sensitivity of 88% and a specificity of 67%.

Table Graphic Jump Location
TABLE 4 ]  Logistic Regression for CSA

AUC = area under curve. See Table 1, 2, and 3 legends for expansion of other abbreviations.

Table Graphic Jump Location
TABLE 5 ]  2 × 2 Decision Statistics: Peak Exercise Petco2 for Detection of CSA

−LR = negative likelihood ratio; +LR = positive likelihood ratio; NPV = negative predictive value; PPV = positive predictive value. See Table 1 and 2 legends for expansion of the other abbreviations.

The novel observations of this study are that peak exercise Petco2 is independently associated with the presence and severity of CSA as quantified by the AHI and is the strongest predictor for CSA by receiver operating characteristic analysis. Furthermore, we made, to our knowledge, the unique observations in a single-study cohort that subjects with CSA breathe with significantly higher V. e and lower Petco2 at rest and higher V. e, Vt, and V. e/V. co2 and lower Petco2 during submaximal exercise and that each of these measures significantly correlates with the severity of CSA as quantified by AHI.

Javaheri and Corbett14 demonstrated decreased arterial CO2 by blood gas analysis in patients with CSA while awake at rest, whereas others have shown lower rest transcutaneous CO2 or Petco2.22,29,30 During exercise, Arzt et al13 demonstrated V. e/V. co2 to be independently associated with AHI in subjects with HF and CSA. Similarly, Roche et al22 and Meguro et al20 showed significantly higher V. e/V. co2 slope, whereas Roche et al22 demonstrated lower rest and peak exercise Petco2 in subjects with HF and CSA. However, two subsequent studies did not confirm these observations.20,21 In addition, Arzt et al13 did not observe decreased Petco2 in patients with CSA, whereas Roche et al22 did not demonstrate an independent association of peak Petco2 and CSA. Meguro et al20 observed no correlation of V. e/V. co2 slope and AHI, whereas Koike et al21 did not show a significant association between Petco2 at rest and peak exercise and AHI. The differences between the present study observations and these prior reports may be attributable to differences in the severity of both HF and CSA because the subjects in the current study may have had more advanced HF with lower LVEF and higher AHI.

An inverse association of exercise Petco2 and AHI has not been consistently observed in prior studies of subjects with CSA.20,21 Moreover, few previous studies compared rest and exercise ventilatory measures for the detection of CSA.13,21,22 In the present subject cohort, we demonstrated that exercise Petco2 was more strongly associated with CSA than rest Petco2, CO2 chemosensitivity, or a composite of these two parameters. At peak exercise, the subjects with HF also had a significantly higher V. e/V. co2 and lower Petco2 than patients with no sleep apnea, and these measures significantly correlated with the magnitude of AHI even after adjustment for age and sex.

In contrast to Arzt et al,13 Petco2 in the present study was more strongly associated with CSA than V. e/V. co2. Indeed, in the study by Arzt et al,13 rest Petco2 was not significantly lower in patients with CSA. This apparent discrepancy from the present findings may be explained by more advanced HF in the current subjects or by different inclusion criteria used for the control and study groups.13 In the present study, subjects with peak exercise Petco2 ≤ 33 mm Hg were more likely to have CSA; a peak exercise Petco2 cutoff value of 33 mm Hg yielded a sensitivity of 80% and a specificity of 85%. Especially important is the relatively high specificity (ie, low false-positive findings) that further increases with the lowering of the cutoff value.

In the present study, exercise parameters, especially the peak Petco2, were more strongly associated with CSA than the rest parameters. Several prior studies have shown patients with CSA to have more advanced HF.3133 Multiple factors associated with HF may contribute to the increased ventilatory response to exercise, including lung congestion, ergoreflex activation, ventilation/perfusion mismatch, and lactic acidosis.34,35 Therefore, heightened ventilatory drive with exercise may identify a subgroup of individuals at increased risk for CSA.

As previously shown by others,15,19 we observed that CO2 chemosensitivity was significantly elevated in subjects with CSA. However, to our knowledge, this study is the first to demonstrate that CO2 chemosensitivity is independently associated with both the presence and the severity of CSA as well as with submaximal and peak exercise Petco2 in patients with HF and CSA. These observations support the concept previously suggested by others that CO2 chemosensitivity plays an important role in the pathogenesis of CSA.19,36

Because patients with CSA typically do not snore, this diagnosis may not be clinically suspected despite its high frequency in patients with HF. Because adaptive servoventilation may prove superior to CPAP for the treatment of sleep-disordered breathing in patients with HF,37,38 recognition of clinical phenotypes associated with CSA may prove important for patient referral for PSG. For this reason, the present observations regarding the relationship of exercise ventilation to CSA may have clinical implications. Cardiopulmonary exercise testing often is used for assessment of functional capacity and risk stratification in patients with HF. Exclusion of subjects with other types of sleep apnea prevents recommendation of cardiopulmonary exercise testing as a screening method for CSA in patients with HF. However, in the present selected study cohort, we show peak exercise Petco2 to be strongly associated with CSA, suggesting that cardiopulmonary exercise testing may promote recognition of patients at increased risk for CSA.

Limitations

The study cohort was small, and there were more men than women in the CSA group, although this sex distribution is consistent with previous reports.4 The AHI is the standard measure in clinical practice and was used as the measure of CSA severity; however, loop gain has been shown to quantify the severity of ventilatory instability in both OSA and CSA.39 To characterize the CSA phenotype, the present study cohort was highly selected. In contrast to CSA, OSA is associated with airway obstruction and chronic hypoventilation.40 Vulnerability to airway obstruction is also characteristic of mixed sleep apnea.41 Therefore, subjects with OSA or mixed sleep apnea were excluded from analysis. The excluded subjects with OSA had significantly lower ventilatory drive, and subjects with mixed sleep apnea tended to hyperventilate less than patients with CSA, although this difference was not significant (data not shown). The present study subjects had moderate to severe HF, and those with CSA appeared to have more advanced HF than control subjects, although the differences were not statistically significant. Multiple prior reports have demonstrated that patients with more advanced HF are more likely to have CSA.3133 The current study design allowed us to describe the CSA phenotype, but it prevents the generalization of these findings to the overall HF population.

Patients with HF and CSA have lower Petco2 at rest and both lower Petco2 and higher V. e/V. co2 at submaximal and peak effort during cardiopulmonary exercise testing compared with patients with HF and no sleep apnea. These findings are consistent with abnormal ventilatory control while awake, including increased ventilatory drive at rest and during exercise as well as during sleep in patients with HF and CSA. These observations suggest that findings at cardiopulmonary exercise testing may promote recognition of the CSA phenotype in patients with HF.

Author contributions: L. J. O. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. I. C. contributed to the data analysis and interpretation and writing of the manuscript; V. K. S. and B. D. J. contributed to the data interpretation and revision of the manuscript; C. G. S. contributed to the statistical analysis, data reporting, and writing of the manuscript; and L. J. O contributed to the study planning, data interpretation, and writing of the manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Somers has been a consultant for ResMed; Cardiac Concepts, Inc; GlaxoSmithKline plc; Sepracor Inc; Deshum Medical, LLC; Respicardia, Inc; and Medtronic plc. Drs Cundrle, Johnson, and Olson and Mr Scott have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsors had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript. This work is solely the responsibility of the authors and does not necessarily represent the official view of National Center for Research Resources or National Institutes of Health.

AHI

apnea-hypopnea index

CSA

central sleep apnea

HF

heart failure

LVEF

left ventricular ejection fraction

NYHA

New York Heart Association

Petco2

partial pressure of end-tidal CO2

PSG

polysomnography

V. e

minute ventilation

V. e/V. co2

ventilatory equivalents per expired CO2

Vt

tidal volume

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Randerath WJ, Nothofer G, Priegnitz C, et al. Long-term auto-servoventilation or constant positive pressure in heart failure and coexisting central with obstructive sleep apnea. Chest. 2012;142(2):440-447. [PubMed]
 
Sands SA, Edwards BA, Kee K, et al. Loop gain as a means to predict a positive airway pressure suppression of Cheyne-Stokes respiration in patients with heart failure. Am J Respir Crit Care Med. 2011;184(9):1067-1075. [PubMed]
 
Bradley TD, Rutherford R, Lue F, et al. Role of diffuse airway obstruction in the hypercapnia of obstructive sleep apnea. Am Rev Respir Dis. 1986;134(5):920-924. [PubMed]
 
Gay PC. Complex sleep apnea: it really is a disease. J Clin Sleep Med. 2008;4(5):403-405. [PubMed]
 

Figures

Tables

Table Graphic Jump Location
TABLE 1 ]  Comparison of Clinical Characteristics by Subject Group

Data are presented as mean ± SD unless otherwise indicated. AHI = apnea-hypopnea index; CSA = central sleep apnea; LVEF = left ventricular ejection fraction; NYHA = New York Heart Association.

Table Graphic Jump Location
TABLE 2 ]  Comparison of Cardiopulmonary Exercise Ventilation by Subject Group

Data are presented as mean ± SD. fb = breathing frequency; Petco2 = partial pressure of end-tidal CO2; RER = respiratory exchange ratio; V. e = minute ventilation; V. e/V. co2 = ventilatory equivalents per expired CO2; V. o2 = oxygen consumption; Vt = tidal volume. See Table 1 legend for expansion of other abbreviation.

Table Graphic Jump Location
TABLE 3 ]  Spearman Rank Correlation and Multiple Regression for AHI

NS = nonsignificant; ΔV. e/ΔPetco2 = central CO2 chemosensitivity. See Table 1 and 2 legends for expansion of other abbreviations.

Table Graphic Jump Location
TABLE 4 ]  Logistic Regression for CSA

AUC = area under curve. See Table 1, 2, and 3 legends for expansion of other abbreviations.

Table Graphic Jump Location
TABLE 5 ]  2 × 2 Decision Statistics: Peak Exercise Petco2 for Detection of CSA

−LR = negative likelihood ratio; +LR = positive likelihood ratio; NPV = negative predictive value; PPV = positive predictive value. See Table 1 and 2 legends for expansion of the other abbreviations.

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