CLINICAL RESEARCH: HEART FAILURE
Periodic breathing during incremental exercise predicts mortality in patients with chronic heart failure evaluated for cardiac transplantation
Joao J. Leite, MD, PhD*,*,
Alfredo J. Mansur, MD, PhD*,
Humberto F. G. de Freitas, MD*,
Paulo R. Chizola, MD*,
Edimar A. Bocchi, MD, PhD*,
Mario Terra-Filho, MD, PhD*,
J. Alberto Neder, MD, PhD and
Geraldo Lorenzi-Filho, MD, PhD*
* Division of Respiratory Disease–Heart Institute (InCor), University of São Paulo Medical School, São Paulo, Brazil
Centre for Exercise Science and Medicine (CESAME), Institute of Biomedical & Life Sciences (IBLS), University of Glasgow, Glasgow, United Kingdom
Manuscript received August 19, 2002;
revised manuscript received November 11, 2002,
accepted November 27, 2002.
* Reprint requests and correspondence: Dr. Joao J. Leite, Instituto do Coração, Rua Dr. Eneas Carvalho de Aguiar 44, CEP: 05403-000, São Paulo-SP, Brazil.
pnejoao{at}incor.usp.br
 |
Abstract
|
|---|
OBJECTIVES: We hypothesized that exercise-related periodic breathing (EPB) would be associated with poor prognosis in advanced chronic heart failure (CHF).
BACKGROUND: Patients with CHF might present instability of the ventilatory control system characterized by cyclic waxing and waning of tidal volume (periodic breathing [PB]). This condition is associated with several deleterious circulatory and neuro-endocrine responses; in fact, PB in awake and asleep patients has been identified as an independent risk factor for cardiac death. During exercise, however, the prognostic value of PB is still unknown in CHF patients awaiting heart transplantation.
METHODS: Eighty-four patients with established CHF (65 male, 19 female) were submitted to clinical evaluation, echocardiogram, ventricular scintigraphy, determination of resting serum norepinephrine levels, and an incremental cardiopulmonary exercise test on cycle ergometer. Patients were followed for up to 49.7 months (median = 15.3), and 26 patients (30.9%) died during this period.
RESULTS: Twenty-five of 84 patients presented EPB (29.7%). The following variables were related to mortality according to Kaplan-Meier and univariate Cox regression analysis: EPB (p = 0.004), New York Heart Association class (p = 0.04), serum norepinephrine (p = 0.06), peak oxygen uptake (ml·min–1·kg–1 and % predicted; p = 0.085 and p = 0.10, respectively), slope of the ratio of change in minute ventilation to change in carbon dioxide output during exercise (p = 0.10), and scintigraphic left ventricular ejection fraction (p = 0.10). Cox multivariate analysis identified EPB as the only independent variable for cardiac death prediction (p = 0.007). Therefore, EPB alone was associated with a 2.97-fold increase in risk of death in this population (95% confidence interval = 1.34 to 6.54).
CONCLUSIONS: Exercise-related periodic breathing independently predicts cardiac mortality in CHF patients considered for heart transplantation.
|
Abbreviations and Acronyms
| | CHF | = chronic heart failure | | CSR | = Cheyne-Stokes respiration | | EPB | = exercise-related periodic breathing | | LVEF | = left ventricular ejection fraction | | NYHA | = New York Heart Association | | PaCO2 | = arterial carbon dioxide pressure | | PB | = periodic breathing | | PETCO2 | = end-tidal partial pressure for carbon dioxide |  CO2 | = carbon dioxide output | | Vds | = dead space volume | | E | = minute ventilation | | O2 | = oxygen uptake | | VT | = tidal volume |
|
Chronic heart failure (CHF), a leading cause of morbidity worldwide, is closely related to increased prevalence of lethal cardiac events (1). Recent developments in surgical treatment of CHF imply that patients at high risk of such catastrophic outcomes should be actively sought for. Accordingly, several predictors of poor clinical prognosis in CHF have been recognized: low left ventricular ejection fraction (LVEF) (2), enlarged left atrium with mitral regurgitation (3), increased left ventricular cavity width (4), and increased sympathetic nerve activity (5). Unfortunately, however, this extensive group of predicting factors still lacks accuracy for outcome prediction, and the prevalence of fatal cardiac events in CHF populations is still excessive (1).
Exercise intolerance is a hallmark of advanced, symptomatic CHF (1). Low maximum oxygen consumption (peak O2), for instance, has been widely used for risk stratification in this patient population (6–8). Peak O2, however, has a limited prognostic power even when circulatory-limited patients are evaluated (9,10). More recently, an increased ventilatory response to the metabolic demand, as inferred by a steeper slope of the ratio of change in minute ventilation to change in carbon dioxide output ( E/CO2) during progressive exercise, has been proposed to improve outcome prediction (11,12). In fact, hyperventilation and low arterial CO2 at rest and during sleep (13) are associated with cyclic waxing and waning of tidal volume (VT) in CHF patients, a condition known as periodic breathing (PB) (13,14). Interestingly, a severe form of PB characterized by ventilatory oscillations interposed with central apneas or hypopneas (Cheyne-Stokes respiration [CSR]) has been identified as an independent predictor of mortality in awake (15) and asleep patients with CHF (16,17). In this context, Corrà et al. (18) have recently shown that exercise-related PB (EPB) also holds prognostic implications in a clinically heterogeneous group of cardiac patients who have been submitted to cardiopulmonary exercise testing. Considering that the prognostic value of a given variable is highly dependent on specific population characteristics, it is not known whether these findings could be extrapolated for patients at higher risk of cardiac death (i.e., those with end-stage disease considered for heart transplantation).
We therefore sought to investigate the clinical value of EPB in predicting cardiac death in a group of patients with advanced CHF who were under evaluation for heart transplantation. To gain further insight into the pathophysiologic mechanisms underlying this condition, we also contrasted the functional characteristics of the ventilatory control system in patients with and in those without EPB.
|
Methods
|
|---|
Patient population.
The study group was comprised of 84 consecutive patients (mean age [± SD] = 45 ± 10 years, 65 males and 19 females) with an established diagnosis of CHF who had clinical and/or functional indication for cardiac transplantation. Forty-four patients were classified as New York Heart Association (NYHA), class III and the remaining patients as class II. Although 12 patients were initially classified as class IV, no patients remained in this class after optimal clinical management. Inclusion criteria were as follows: more than six-month history of CHF (actual values being 73.9 ± 48.0 months), unchanged medication within the last month, and no acute coronary event within six months preceding the study. Patients with body mass index above 30 kg·m–2 and other clinical conditions such as hepatic, hematologic, renal, infectious, or pulmonary diseases (including smokers) were also excluded because they are not considered suitable candidates in our transplantation program (19).
Etiology of heart failure was dilated cardiomyopathy in 48 cases (56.5%), ischemic in 15 (17.7%), Chagas’ disease in 11 (12.9%), alcoholic in 4 (4.7%), rheumatic in 5 (5.9%), and post-partum in 2 patients (2.4%). Data were pooled for analysis only after certification that there was no significant effect of specific disease prevalence on EPB frequency. Current medication included digoxin (92%), angiotensin-converting enzyme inhibitors (88%), furosemide (88%), hydrochlorotyazide (30%), potassium chloride (19%), beta-blockers (6%), amiodarone (11%), spironolactone (7%), and nitrates (7%). Seventy-three patients (86.9%) presented in sinus rhythm, and 11 (13.1%) were in chronic atrial fibrillation. Informed consent as approved by the Institutional Medical Ethics Committee was obtained from all subjects.
Resting evaluation.
Doppler echocardiogram with color flow imaging was performed in A and B modes using a multifrequency electronic transducer (Apogee 800Plus, Advanced Technology Laboratories, Bothell, Washington). Gated blood pool scintigraphy in a semi-recumbent position was carried out with a scintigraphic chamber LEM-Plus (Siemens Gammasonics Inc., Des Paines, Illinois) and a low-energy collimator using intravenous pyrophosphate followed by injection of erythrocytes labeled with technetium-99m (30 mCi). Electrocardiogram-triggered diastolic and systolic images (64 x 64 pixels) were obtained in left anterior oblique view for the LVEF calculation. Serum epinephrine levels were measured after 1 h of rest from antecubital venous blood (n = 64) using a high-performance liquid chromatography-pulsed electrochemical detector (model 464, Waters, Milford, Massachusetts).
Exercise studies.
Cardiopulmonary exercise tests were performed on an electromagnetic-braked cycle ergometer following a ramp-incremental protocol to the limit of tolerance. Pulmonary gas exchange and ventilatory variables were obtained from calibrated signals derived from rapidly responding gas analyzers and a pneumotachograph (CPX System, Medical Graphics Corp., St. Paul, Minnesota). The following variables were recorded breath-by-breath and expressed as the moving average of eight breaths: pulmonary oxygen uptake (O2, l·min–1), pulmonary carbon dioxide output (CO2, l·min–1), minute ventilation (E, l·min–1), and end-tidal partial pressure for CO2 (PETCO2, mm Hg). Peak O2 values were compared with those predicted by Hansen et al. (20), considering gender, age, and height. The slope of E/CO2 was determined by regression analysis throughout the linear phase of this submaximal relationship (11,12).
Assessment of PB.
Periodic breathing during exercise was established [EPB(+)] according to the following criteria present on ventilation measurements: 1) three or more regular oscillations (i.e., clearly discernible from inherent data noise); 2) regularity was defined if the standard deviation of three consecutive cycle lengths (time between 2 consecutive nadirs) was within 20% of the average; 3) minimal average amplitude of ventilatory (E) oscillation of 5 l (peak value minus the average of two in-between consecutive nadirs) (Fig. 1).
Follow-up events on prognosis.
The study end point was cardiac death. The four heart transplantation cases were considered as censored data at the day of surgery. The patients were followed for up to 49.7 months (median 11.3 months; interquartile range 6.0 to 21.8 months) on regular visits to the outpatient clinic at least twice a year. Information of the absent patients was obtained by telephone call; all deaths were confirmed through evaluation of medical recordings.
Statistical analysis.
Mean and standard deviations (SD) were obtained for values in subjects grouped according to clinical outcome and presence or not of EPB. Kaplan-Meier log-rank and univariate Cox regression analysis were used to correlate categorical or continuous variables to time-to-event, respectively. Meaningful correlated variables (p < 0.10) were then included in a multivariate stepwise forward conditional Cox regression analysis. Significance of the regression coefficients was assessed by considering the asymptotic normality property of maximum likelihood estimates (Wald statistic). Serum norepinephrine data were excluded from the multivariate analysis because only 62 patients had serum determination. Kaplan-Meier cumulative survival curves were constructed and compared using the Mantel-Haenszel log-rank test. Student t test and chi-squared tests were applied as appropriate for between-groups comparison. The p value of a type I error was established at 0.05 for all hypothesis tests.
|
Results
|
|---|
Population characteristics.
Maximum exercise capacity was consistent with that expected in patients with advanced CHF; actual peak O2 values were 16 ± 5.2 ml·min–1·kg–1·min–1 or 51 ± 15.1% of predicted. Resting echocardiographic data showed severe heart damage with reduced LVEF (35 ± 6.6%) and increased left ventricle end-diastolic and end-systolic and left atrium diameters (74 ± 11.4 mm, 63 ± 12.0 mm, and 47 ± 7.5 mm, respectively). Similarly, scintigraphic evaluation showed a severely reduced LVEF (22 ± 7.4%), and resting serum norepinephrine levels were typically elevated (582 ± 278.6 µg·dl–1).
Clinical and functional correlates of EPB.
Twenty-five of 84 patients (29.7%) presented EPB; cardiac deaths were identified in 26 subjects (30.9%). The one-year and two-year cumulative survival rates were 82% and 57%, respectively. We first investigated possible clinical and functional differences between EPB(+) and EPB(–) patients. As shown in Table 1, EPB(+) patients presented lower peak O2, higher E/CO2 slope, and lower pre-exercise PETCO2 values than EPB(–) patients (p < 0.01). On the other hand, there were no significant between-group differences in relation to the other variables, including LVEF. We also found similar time delays from initial symptoms of CHF to exercise testing in both patient groups (22.9 ± 7.5 vs. 20.6 ± 5.8 months; p = 0.21). Furthermore, we found a marginally significant association between higher functional classification and EPB: 17 of 25 of EPB(+) patients (68%) were classified as NYHA class III, but only 27 of 59 of EPB(–) patients (45.7%) were in this class (p < 0.06).
EPB and cardiac death.
Time-corrected univariate regression analysis depicted the following variables as predictors of mortality: EPB(+) (log-rank = 7.98; p = 0.004); NYHA functional classification (log-rank = 4.00, p = 0.04); serum norepinephrine (Wald =3.50; p = 0.06); O2 [ml·min–1·kg–1] (log-rank = 2.95; p = 0.085) and [% predicted] (Wald = 2.68; p = 0.10); E/CO2 slope (Wald = 2.65; p = 0.10); and scintigraphic LVEF (Wald = 2.59; p = 0.10). Conversely, age, gender, resting PETCO2 values, and echocardiographic LVEF were not significantly associated with mortality (p > 0.10).
The multivariate analysis demonstrated that EPB was the only independent predictor of cardiac death (i.e., no other variable could be added to the final model) (p = 0.007). Therefore, the risk of death for EPB(+) patients was 2.97 times greater than for EPB(–) patients (95% confidence interval = 1.34 to 6.54). Figure 2 depicts the Kaplan-Meier survival curves for both groups: one- and two-year cumulative survival rates were 89% to 63% and 67% to 45% for EPB(–) and EPB(+) patients, respectively. Similar results were obtained when we considered transplantation (n = 4) as the final event.
View larger version (16K):
[in this window]
[in a new window]
|
Figure 2 Kaplan-Meier survival curve for patients presenting with or not presenting with periodic breathing during dynamic exercise [EPB(+) and EPB(–), respectively]. Note that EPB(+) patients presented a significantly higher time-adjusted mortality rate (p < 0.01), independent of clinical and functional data.
|
|
|
Discussion
|
|---|
We have prospectively investigated the role of EPB in predicting cardiac death in a group of patients with advanced CHF under evaluation for heart transplantation. The novel findings of our study were: 1) EPB was frequent (about 30%) and easily recognized by using clinically useful criteria; 2) it almost tripled the average risk of cardiac death (Fig. 2), independent of traditional demographic, clinical, and resting functional variables; and 3) EPB was associated with steeper E/CO2 slope during exercise and low PETCO2 at rest (i.e., excessive ventilatory response). This seems to constitute the first study to demonstrate the practical value of this disorder in predicting mortality in patients with end-stage CHF in evaluation for heart transplantation. Our results, therefore, suggest that evidence of EPB during routine cardiopulmonary exercise testing should be sought and clinically valued for risk stratification in this specific patient population.
Cardiopulmonary exercise testing has an established role for prognostic evaluation of patients with CHF. It is well known, for example, that reduction of peak O2 relates to poor prognosis in this population (6,7)—as we could confirm in the present study. However, interpretation of peak O2 values is fraught with complexities in patient populations. The multifactorial etiology of exercise limitation in this syndrome implies that limited cardiac output might not be the sole culprit for an eventually reduced peak O2. In fact, other cardio-respiratory and metabolic disturbances are common in CHF: recent data demonstrate that evaluation of submaximal exercise is useful to unravel these disorders (11,12,21). In this context, our findings are particularly relevant because identification of EPB does not depend on patients’ maximal effort or attainment of a truly circulatory-limited peak O2.
Prognosis of EPB.
Respiratory instability has long been associated with poor prognosis in CHF (14). In fact, evidence that this disorder is frequent among CHF patients (22,23) and is an independent and powerful predictor of mortality, whether during the day (15) or night (16,17), is accruing. Several studies have now demonstrated that CSR during sleep is associated with recurrent hypoxia, increased number of awakenings, enhanced sympathetic activity, and poor prognosis (13,14,16,17,22,23). In these patients, episodes of PB induce fluctuations in heart rate, blood pressure, and gases that are associated with activation of neuro-endocrine responses and a state of chronic sympathetic over-activity—well-known triggers of lethal ventricular arrhythmias (14). Indeed, Javaheri and Corbett (24) found a high prevalence of ventricular tachycardia in CHF patients with hypocapnia and central apnea, suggesting a possible mechanism for the cardiac deaths related to CSR. The same pathophysiologic mechanisms could be associated with mortality in EPB: several daily episodes of exertion-related ventilatory instabilities would elicit a chronic status of systemic neuro-endocrine and circulatory over-activation with harmful effects on the failing heart.
More recently, Corrà et al. (18) found a significant association between EPB and cardiac death in a study involving a population of CHF patients in different stages of the disease who were referred for CPX evaluation. Our longitudinal study further extends their findings by showing that in a selected group of very limited patients considered for cardiac transplantation, EPB is more frequent (30% vs. 12%) and an even more powerful predictor of mortality than in their series of patients with a broader clinical spectrum. In fact, we were unable to add any other variable in the predictive model for cardiac death when EPB was considered. This finding contrasts with those of Corrà et al., who found that peak O2 and LVEF were also predictors of major cardiac events. Interestingly, our data suggest that identification of EPB is not related to duration of the disease: we were unable to find significant differences in time delay from initial symptoms of CHF to exercise testing in EPB(+) versus EPB(–) patients.
Our data, therefore, seem to be particularly relevant in clinical terms, because this sample epitomizes a population under increased risk of sudden cardiac death (i.e., a group for which ominous predictors should be especially sought). In addition, the present study shed light on the pathophysiologic determinants of EPB: an excessive ventilatory response to the metabolic demand is likely to play a role in the genesis of this disorder (Table 1).
Relationship between CHF and periodic breathing.
Periodic breathing is characterized by a periodic and cyclic waxing and waning of VT. Cheyne-Stokes respiration, for instance, is a severe form of PB in which apneas or hypopneas are alternated with periods of ventilatory oscillation. The mechanisms involved in the etiology of PB are multifactorial and not completely understood. It seems likely, however, that it represents a clinical manifestation of instability of the respiratory control center (14).
It has long been recognized that the central respiratory controllers are strongly influenced by chemoreceptor activity, especially by the level at which the mean arterial pressure for CO2 (PaCO2) is regulated (CO2 set-point) (14). In fact, low PaCO2 plays a major role in the pathogenesis of CSR in CHF (13,14). It has been demonstrated, for instance, that these patients are typically hypocapnic at rest and asleep (13). Furthermore, inhalation of low concentrations of CO2 during sleep is able to abolish CSR in conjunction with a small, but significant, increase in PaCO2 (25). In CHF patients, hypocapnia might be caused by over-stimulation of the ventilatory control center due to chronic pulmonary congestion (26,27) and increased central (28) and peripheral (29) chemosensitivity. Circulatory delay could also increase the lag time between pulmonary gas-exchanging capillaries and carotid chemoreceptors with consequent increase in gain of the feedback loop. These effects are prone to further contribute to the underlying instability of the respiratory center (14).
Periodic breathing during exercise.
The physiologic adjustments during dynamic exercise can produce additional sources of excessive ventilatory response and, therefore, promote further instabilities (30,31). Exercise stimulation of the over-active ergoreceptors during exercise may excessively stimulate the respiratory centers. Group III and IV afferents can respond to accumulated by-products of muscle metabolism and changes in local vascular peripheral conductance (32). Exercise-induced pulmonary capillary congestion, as we have previously demonstrated (33), may also activate lung stretch receptors (14,27). In addition, an excessive ventilatory response could be associated with increased "wasted" ventilation due to enlarged physiologic dead space volume (Vds) and/or reduced VT (i.e., higher Vds/VT ratio during exercise) (34).
The linear relationship between E and CO2 that characteristically develops during most of the incremental phase of dynamic exercise (E/CO2) has been used as an index of the ventilatory efficiency based on the following reasoning (34):
From this construct, it is clear that an increased E/CO2 slope might be related to reduced CO2 set-point (i.e., hyperventilation) and/or an enlarged dead space fraction of the breath (i.e., a tachypneic breathing pattern). In our study, EPB(+) patients presented not only higher E/CO2 slope but also lower resting PETCO2 (Table 1). Unfortunately, however, excessive Vds is associated with a positive arterial-end tidal CO2 pressure gradient (i.e., PETCO2 can underestimate PaCO2 by an unknown amount when the "wasted" ventilation is increased). Considering that we did not directly measure PaCO2 or other indexes of pulmonary gas exchange efficiency, we cannot rule out that Vds/VT was disproportionately increased in the more severe patients (i.e., those who presented higher prevalence of EPB) (Table 1). Even taking into consideration these limitations, we consider that our data are consistent with the hypothesis that excessive ventilation during exercise might further contribute to respiratory instability and, therefore, development of EPB in end-stage CHF.
Study limitations.
Although the criteria we used to define EPB could have underestimated its true prevalence, we reasoned that a more sophisticated analysis (such as power spectral analysis) (35) would be prone to hamper the practicality of this approach in clinical settings. Indeed, similar criteria for EPB identification have been recently demonstrated to be reliable and reproducible (18); nevertheless, we recognize that the present study lacks a formal test–retest analysis for EPB reproducibility.
We found only a weak association between LVEF and mortality. This finding could be related to the small variability of this measurement in a relatively homogeneous population with advanced disease. However, it is worth noting that other well-known predictors of mortality, such as functional status, peak O2, and norepinephrine levels, were significantly related to death (see Results). It is conceivable that the introduction of newer, more effective drugs after the initial cardiopulmonary exercise testing may have favorably changed the prognosis and, therefore, may lessen the importance of PB in predicting mortality. In addition, some specific characteristics of our sample should be taken into consideration for analysis of the study results. First, no NYHA class IV patient was evaluated; as discussed in Methods, however, 12 patients had been classified as class IV before optimal clinical management. Second, Chagas’ disease was the specific etiology of CHF in 12.9% of the patients; as mentioned, we were unable to identify an independent effect of CHF etiology on EPB frequency. Finally, these patients were typically younger than those evaluated by other authors. Although the effect of age on EPB is to date unknown, we cannot rule out the possibility that our main outcome was influenced by this demographic characteristic.
Clinical implications.
Our study provides original evidence that in CHF patients awaiting heart transplantation EPB is common, can be easily recognized, and constitutes a powerful predictor of mortality. Therefore, EPB on routine cardiopulmonary exercise testing should be looked for, reported, and clinically valued for risk stratification in CHF patients considered for heart transplantation.
|
Acknowledgments
|
|---|
We thank Leila Marise de Oliveira for her dedicated work at the Laboratory of Cardiopulmonary Exercise Testing of InCor. The authors are also grateful to Mariana Cúri for her assistance in the statistical analysis.
|
References
|
|---|
1. Garg R, Yusuf S. Epidemiology of congestive heart failure. Barnett DB, Pouler H, Francis GS. Congestive Heart Failure—Pathophysiology and Treatment. New York, NY: Marcel Dekker; 1993. p. 9–25
2. Aaronson KD, Schwartz JS, Chen T, et al. Development and prospective validation of a clinical index to predict survival in ambulatory patients referred for cardiac transplant evaluation. Circulation. 1997;95:2660–2667[Abstract/Free Full Text]
3. Blondheim DS, Jacobs LE, Kotler MN, et al. Dilated cardiomyopathy with mitral regurgitation: decreased survival despite a low frequency of left ventricular thrombus. Am Heart J. 1991;122:763–771[CrossRef][Medline]
4. Lee TH, Hamilton MA, Stevenson LW, et al. Impact of left ventricular cavity size on survival in advanced heart failure. Am J Cardiol. 1993;72:672–676[CrossRef][Medline]
5. Madsen BK, Keller N, Christiansen E, et al. Prognostic value of plasma catecholamines, plasma renin activity and plasma atrial natriuretic peptide at rest and during exercise in congestive heart failure: comparison with clinical evaluation, ejection fraction and exercise capacity. Card Fail. 1995;1:207–216
6. Mancini DM, Eisen H, Kussmaul WR, Mull L, Edmunds H, 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[Abstract/Free Full Text]
7. Van den Broek AS, Van Veldhuisen DJ, De Graeff PA, et al. Comparison between New York Heart Association Classification and peak oxygen consumption in the assessment of functional status and prognosis in patients with mild to moderate chronic congestive heart failure secondary to either ischaemic or idiopathic dilated cardiomyopathy. Am J Cardiol. 1992;70:359–363[CrossRef][Medline]
8. Mudge GH, Goldstein S, Addonizio LJ, et al. 24th Bethesda Conference: cardiac transplantation. Task Force 3: recipient guidelines/prioritization. J Am Coll Cardiol. 1993;22:21–31[Medline]
9. Kao W, Winkle EM, Johnson MR, et al. Role of maximal oxygen consumption in establishment of heart transplantation candidacy for heart failure patients with intermediate exercise tolerance. Am J Cardiol. 1997;79:1124–1127[CrossRef][Medline]
10. Opasich C, Pinna GD, Bobbio M, et al. Peak oxygen consumption in chronic heart failure: toward efficient use in the individual patient. J Am Coll Cardiol. 1998;31:766–775[Abstract/Free Full Text]
11. MacGowan GA, Janosko K, Cecchetti A, et al. Exercise related ventilatory abnormalities and survival in congestive heart failure. Am J Cardiol. 1997;79:1264–1266[CrossRef][Medline]
12. Chua TP, Ponikowski P, Harrington D, et al. Clinical correlates and prognostic significance of ventilatory response to exercise in congestive heart failure. J Am Coll Cardiol. 1997;29:1585–1590[Abstract]
13. Naughton M, Benard D, Tam A, et al. Role of hyperventilation in the pathogenesis of central sleep apnea in patients with congestive heart failure. Am Rev Respir Dis. 1993;148:330–338[Medline]
14. Lorenzi-Filho G, Bradley D. Cardiac function in sleep apnea. Pack A. Sleep Apnea. New York: Marcel Dekker; 2002. p. 377–410
15. Andreas S, Hagenah G, Möller C, et al. Cheyne-Stokes respiration and prognosis in congestive heart failure. Am J Cardiol. 1996;78:1260–1264[CrossRef][Medline]
16. Hanly P, Zuberi-Khokhar N. Increased mortality associated with Cheyne-Stokes respiration in patients with congestive heart failure. Am J Respir Crit Care Med. 1996;153:272–276[Abstract]
17. Lanfranchi PA, Braghiroli A, Bosimini E, et al. Prognostic value of nocturnal Cheyne-Stokes respiration in chronic heart failure. Circulation. 1999;99:1435–1440[Abstract/Free Full Text]
18. Corrà U, Giordano A, Bosimini E, et al. Oscillatory ventilation during exercise in patients with chronic heart failure: clinical correlates and prognostic implications. Chest. 2002;121:1572–1580[Abstract/Free Full Text]
19. Bocchi EA, Bellotti EA, Moreira LFP, et al. Mid-term results of heart transplantation, cardiomyoplasty, and medical treatment of refractory heart failure caused by idiopathic dilated cardiomyopathy. J Heart Lung Transpl. 1996;15:736–745[Medline]
20. Hansen JE, Sue DY, Wasserman K. Predicted values for clinical exercise testing. Am Rev Respir Dis. 1984;129(Suppl):S49–S55[Medline]
21. Hollenberg M, Tager IB. Oxygen uptake efficiency slope: an index of exercise performance and cardiopulmonary reserve requiring only submaximal exercise. J Am Coll Cardiol. 2000;36:194–201[Abstract/Free Full Text]
22. Javaheri S, Parker TJ, Liming JD, et al. Sleep apnea in 81 ambulatorymale patients with stable heart failure: types and their prevalences, consequences and presentations. Circulation. 1998;97:2154–2159[Abstract/Free Full Text]
23. Sin D, Fitzgerald F, Parker JD, et al. Risk factors for central and obstructive sleep apnea in 450 men and women with congestive heart failure. Am J Respir Crit Care Med. 1999;160:1101–1106[Abstract/Free Full Text]
24. Javaheri S, Corbett WS. Association of low PaCO2 with central sleep apnea and ventricular arrhythmias in ambulatory patients with stable heart failure. Ann Intern Med. 1998;128:204–207[Abstract/Free Full Text]
25. Lorenzi-Filho G, Ranking F, Bies I, et al. Effects of inhaled CO2 and O2 on Cheyne-Stokes respiration in patients with heart failure. Am J Respir Crit Care Med. 1999;159:1490–1498[Abstract/Free Full Text]
26. Solin P, Bergin P, Richardson M, et al. Influence of pulmonary capillary wedge pressure on central apnea in heart failure. Circulation. 1999;99:1574–1579[Abstract/Free Full Text]
27. Lorenzi-Filho G, Azevedo ER, Parker JD, Bradley TD. Relationship of PaCO2 to pulmonary wedge pressure in heart failure. Eur Respir J. 2002;19:37–40[Abstract/Free Full Text]
28. Javaheri S. A mechanism of central sleep apnea in patients with heart failure. N Engl J Med. 1999;341:949–954[Abstract/Free Full Text]
29. Ponikowski P, Chua TP, Anker SD, et al. Peripheral chemoreceptor hypersensitivity—an ominous sign in patients with chronic heart failure. Circulation. 2001;104:544–549[Abstract/Free Full Text]
30. Piepoli M, Clark AL, Volterrani M, et al. Contribution of muscle afferents to the hemodynamic, autonomic and ventilatory responses to exercise in patients with chronic heart failure. Circulation. 1996;93:940–952[Abstract/Free Full Text]
31. Francis D, Davies LC, Piepoli M, et al. Origin of oscillatory kinetics of respiratory gas exchange in chronic heart failure. Circulation. 1999;100:1065–1070[Abstract/Free Full Text]
32. Haouzi P, Hill JM, Lewis BK, et al. Responses of group III and IV muscle afferents to distension of the peripheral vascular bed. J Appl Physiol. 1999;87:545–553[Abstract/Free Full Text]
33. Brasileiro FC, Leite JJ, Vargas FS, et al. High-resolution CT scan in evaluation of exercise-induced interstitial pulmonary edema in cardiac patients. Chest. 1997;111:157–182
34. Whipp BJ, Pardy RL. Breathing during exercise. Macklem PT, Mead J. Handbook of Physiology, Respiration, Pulmonary Mechanics. Washington: American Physiological Society; 1986. p. 605–629
35. Lorenzi-Filho G, Dajani HR, Leung RS, et al. Entrainment of blood pressure and heart rate oscillations by periodic breathing. Am J Respir Crit Care Med. 1999;159:1147–1154[Abstract/Free Full Text]
This article has been cited by other articles:
|
|
|
|
 
M. Guazzi, J. Myers, M. A. Peberdy, D. Bensimhon, P. Chase, and R. Arena
Exercise oscillatory breathing in diastolic heart failure: prevalence and prognostic insights
Eur. Heart J.,
November 2, 2008;
29(22):
2751 - 2759.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. K. Somers, D. P. White, R. Amin, W. T. Abraham, F. Costa, A. Culebras, S. Daniels, J. S. Floras, C. E. Hunt, L. J. Olson, et al.
Sleep Apnea and Cardiovascular Disease: An American Heart Association/American College of Cardiology Foundation Scientific Statement From the American Heart Association Council for High Blood Pressure Research Professional Education Committee, Council on Clinical Cardiology, Stroke Council, and Council on Cardiovascular Nursing In Collaboration With the National Heart, Lung, and Blood Institute National Center on Sleep Disorders Research (National Institutes of Health)
Circulation,
September 2, 2008;
118(10):
1080 - 1111.
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. K. Somers, D. P. White, R. Amin, W. T. Abraham, F. Costa, A. Culebras, S. Daniels, J. S. Floras, C. E. Hunt, L. J. Olson, et al.
Sleep Apnea and Cardiovascular Disease: An American Heart Association/American College of Cardiology Foundation Scientific Statement From the American Heart Association Council for High Blood Pressure Research Professional Education Committee, Council on Clinical Cardiology, Stroke Council, and Council on Cardiovascular Nursing In Collaboration With the National Heart, Lung, and Blood Institute National Center on Sleep Disorders Research (National Institutes of Health)
J. Am. Coll. Cardiol.,
August 19, 2008;
52(8):
686 - 717.
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Lorenzi-Filho and P. R. Genta
A New Straw in the Genesis of Cheyne-Stokes Respiration
Chest,
July 1, 2008;
134(1):
7 - 9.
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. H. Manisty, K. Willson, J. E. R. Davies, Z. I. Whinnett, R. Baruah, Y. Mebrate, P. Kanagaratnam, N. S. Peters, A. D. Hughes, J. Mayet, et al.
Induction of oscillatory ventilation pattern using dynamic modulation of heart rate through a pacemaker
Am J Physiol Regulatory Integrative Comp Physiol,
July 1, 2008;
295(1):
R219 - R227.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Garcia-Touchard, V. K. Somers, L. J. Olson, and S. M. Caples
Central Sleep Apnea: Implications for Congestive Heart Failure
Chest,
June 1, 2008;
133(6):
1495 - 1504.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. J. Olson, A. M. Arruda-Olson, V. K. Somers, C. G. Scott, and B. D. Johnson
Exercise Oscillatory Ventilation: Instability of Breathing Control Associated With Advanced Heart Failure
Chest,
February 1, 2008;
133(2):
474 - 481.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Ingle
Prognostic value and diagnostic potential of cardiopulmonary exercise testing in patients with chronic heart failure
Eur J Heart Fail,
February 1, 2008;
10(2):
112 - 118.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Agostoni, A. Apostolo, and R. K. Albert
Mechanisms of Periodic Breathing During Exercise in Patients With Chronic Heart Failure
Chest,
January 1, 2008;
133(1):
197 - 203.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Brack, I. Thuer, C. F. Clarenbach, O. Senn, G. Noll, E. W. Russi, and K. E. Bloch
Daytime Cheyne-Stokes Respiration in Ambulatory Patients With Severe Congestive Heart Failure Is Associated With Increased Mortality
Chest,
November 1, 2007;
132(5):
1463 - 1471.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. T. La Rovere, G. D. Pinna, R. Maestri, E. Robbi, A. Mortara, F. Fanfulla, O. Febo, and P. Sleight
Clinical relevance of short-term day-time breathing disorders in chronic heart failure patients
Eur J Heart Fail,
September 1, 2007;
9(9):
949 - 954.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Guazzi, R. Raimondo, M. Vicenzi, R. Arena, C. Proserpio, S. Sarzi Braga, and R. Pedretti
Exercise oscillatory ventilation may predict sudden cardiac death in heart failure patients.
J. Am. Coll. Cardiol.,
July 24, 2007;
50(4):
299 - 308.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Tumminello, M. Guazzi, P. Lancellotti, and L. A. Pierard
Exercise ventilation inefficiency in heart failure: pathophysiological and clinical significance
Eur. Heart J.,
March 2, 2007;
28(6):
673 - 678.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Palange, S. A. Ward, K-H. Carlsen, R. Casaburi, C. G. Gallagher, R. Gosselink, D. E. O'Donnell, L. Puente-Maestu, A. M. Schols, S. Singh, et al.
Recommendations on the use of exercise testing in clinical practice
Eur. Respir. J.,
January 1, 2007;
29(1):
185 - 209.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
X.-H. Ning, S.-H. Chen, N. E. Buroker, C.-S. Xu, F.-R. Li, S.-P. Li, D.-S. Song, M. Ge, O. M. Hyyti, M. Zhang, et al.
Short-cycle hypoxia in the intact heart: hypoxia-inducible factor 1{alpha} signaling and the relationship to injury threshold
Am J Physiol Heart Circ Physiol,
January 1, 2007;
292(1):
H333 - H341.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Guazzi
Letter by Guazzi Regarding Article "Sleep and Exertional Periodic Breathing in Chronic Heart Failure: Prognostic Importance and Interdependence"
Circulation,
July 18, 2006;
114(3):
e53 - e53.
[Full Text]
[PDF]
|
|
|
|
|
|
|
U. Corra, M. Pistono, A. Mezzani, A. Braghiroli, E. Bosimini, M. Gnemmi, P. Giannuzzi, A. Giordano, and P. Lanfranchi
Response to Letter Regarding Article "Sleep and Exertional Periodic Breathing in Chronic Heart Failure: Prognostic Importance and Interdependence"
Circulation,
July 18, 2006;
114(3):
e54 - e54.
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. P. Ribeiro
Periodic Breathing in Heart Failure: Bridging the Gap Between the Sleep Laboratory and the Exercise Laboratory
Circulation,
January 3, 2006;
113(1):
9 - 10.
[Full Text]
[PDF]
|
|
|
|
|
|
|
U. Corra, M. Pistono, A. Mezzani, A. Braghiroli, A. Giordano, P. Lanfranchi, E. Bosimini, M. Gnemmi, and P. Giannuzzi
Sleep and Exertional Periodic Breathing in Chronic Heart Failure: Prognostic Importance and Interdependence
Circulation,
January 3, 2006;
113(1):
44 - 50.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Authors/Task Force Members, K. Swedberg, Writing Committee:, J. Cleland, H. Dargie, H. Drexler, F. Follath, M. Komajda, L. Tavazzi, O. A. Smiseth, et al.
Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005): The Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology
Eur. Heart J.,
June 1, 2005;
26(11):
1115 - 1140.
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Scharf, Y. K. Cho, K. E. Bloch, C. Brunckhorst, F. Duru, K. Balaban, N. Foldvary, L. Liu, R. C. Burgess, R. Candinas, et al.
Diagnosis of Sleep-Related Breathing Disorders by Visual Analysis of Transthoracic Impedance Signals in Pacemakers
Circulation,
October 26, 2004;
110(17):
2562 - 2567.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A.-M. Sinha, E. C. Skobel, O.-A. Breithardt, C. Norra, K. U. Markus, C. Breuer, P. Hanrath, and C. Stellbrink
Cardiac resynchronization therapy improves central sleep apnea and Cheyne-Stokes respiration in patients with chronic heart failure
J. Am. Coll. Cardiol.,
July 7, 2004;
44(1):
68 - 71.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. D. Bradley
The ups and downs of periodic breathing: Implications for mortality in heart failure
J. Am. Coll. Cardiol.,
June 18, 2003;
41(12):
2182 - 2184.
[Full Text]
[PDF]
|
|
|
|
Top
Abstract
Methods
] within 20% of their average), and ample (minimum amplitude [h] of 5 l·min–1) minute ventilation (