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European Journal of Heart Failure 2007 9(9):949-954; doi:10.1016/j.ejheart.2007.06.009
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© 2007 European Society of Cardiology

Clinical relevance of short-term day-time breathing disorders in chronic heart failure patients

Maria Teresa La Roverea,*, Gian Domenico Pinnaa, Roberto Maestria, Elena Robbia, Andrea Mortarab, Francesco Fanfullaa, Oreste Feboa and Peter Sleightc

a Divisione di Cardiologia, Pneumologia e Bioingegneria, Fondazione "Salvatore Maugeri", IRCCS, Istituto Scientifico di Montescano 27040 Montescano, (Pavia), Italy
b Dipartimento di Cardiologia, Policlinico di Monza Monza, Italy
c Cardiovascular Medicine, John Radcliffe Hospital University of Oxford, Oxford, UK

* Corresponding author. Tel.: +39 385 2471; fax: +39 385 61386. Email address: mtlarovere{at}fsm.it


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Clinical implications and...
 References
 
Background: Periodic Breathing (PB, waxing and waning of tidal volume in which hyperventilation alternates with periods of apnoea or hypopnoea), is common during sleep and wakefulness in patients with Heart Failure (HF) and may increase mortality.

Aim: To assess the effect of short-term, day-time PB on prognosis, in HF patients.

Methods: We prospectively studied 380 consecutive HF referrals who had a 10 min, supine day-time respiratory recording. We related PB (adjusted for known predictors) to total cardiac mortality, during a median follow-up of 41 months.

Results: Day-time PB occurred in 145/380 patients who had more severe HF and more compromised left ventricular function (p<0.005). Survival curves began to separate after 10 months and diverged steadily over the next 4 years with a cumulative risk of 41% (PB) vs 26% (No-PB), p<0.002. PB was independently predictive of increased cardiac mortality when entered into a clinical prognostic model (including NYHA Class, LVEF, LVEDD, Systolic Arterial Pressure, beta-blocker treatment, peak VO2 and blood urea) with a RR: 1.8, 95% CI 1.20–2.81.

Conclusion: In advanced HF the presence of PB during a short day-time recording adds to known predictors of cardiac mortality. This may have practical implications for trials of HF therapy.

Key Words: Heart failure • Respiration • Prognosis • Sleep • Mortality

Received April 12, 2007; Accepted June 20, 2007


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Clinical implications and...
 References
 
Nocturnal breathing disorders in the form of periodic breathing (PB, waxing and waning of tidal volume in which hyperventilation alternates with periods of apnoea or hypopnoea), are common in patients with heart failure (HF) [1] and are associated with an adverse prognosis [2,3]. PB also occurs during day-time, in both the resting supine condition [4-6] and during exercise [7,8] possibly contributing to poor prognosis.

PB is associated with transient hypoxia [9], increased sympathetic activity [10] and haemodynamic oscillations [9,11]. These factors could worsen left ventricular function and/or increase serious arrhythmia and might therefore contribute to increase mortality by increasing the likelihood of both pump failure and sudden death. Whether PB in HF patients simply reflects poor cardiac function, or whether it "independently" hastens the progression of the disease and worsens prognosis is debatable [1,12]. Since many prognostic variables are interrelated with PB, the definition of a prognostic model including PB should carefully control for all potential confounders.

Polysomnography-based identification of PB in HF patients is expensive, technically demanding, and not widely available. It is possible that shorter-term assessments performed during the day-time on resting supine HF patients, might also be valuable in providing prognostic information, and could help in the selection of patients who would best benefit from more complex evaluation.

We therefore evaluated whether day-time supine PB might be a risk factor for cardiac mortality, independent of major clinical and functional variables, in a large cohort of HF patients.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Clinical implications and...
 References
 
We prospectively studied 380 consecutive patients in sinus rhythm with dilated ischaemic or non-ischaemic cardiomyopathy, referred between January 1995 and July 2001 for assessment and therapy (including heart transplantation). Sinus rhythm was necessary for a separate analysis of autonomic function. Patients were excluded if they had pulmonary or neurological disease, myocardial infarction within 6 months, cardiac surgery, recently changed therapy (within 2 weeks), or any other disease likely to limit survival. Patients were treated with angiotensin converting enzyme-(ACE)-inhibitors (86%), diuretics (97%), digitalis (63%), beta-blockers (34%), and amiodarone (25%).

All patients gave written informed consent; the study was approved by the local Science and Ethics Committee.

2.1. Respiratory study
Studies were carried out in the morning, after 30 min of supine rest. All patients underwent 10 min recordings of lung volume (LV) (inductance plethysmography, Respitrace Plus, Non-Invasive Monitoring Systems Inc., Miami Beach, FL), while breathing spontaneously. Instantaneous tidal volume (ITV) was derived from the LV signal [13]; both signals were carefully scored by an experienced analyst (ER).

PB was defined as a repeated oscillation of ITV with regularly recurring hyperventilation and hypopnoea (or apnoea) [14], with a greater than 25% variation in peak to trough values of tidal volume [15] (Fig. 1). PB was considered sustained if present in more than 75% of the 10 min record.


Figure 01
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  		Fig. 1 Derivation of the instantaneous tidal volume (ITV) from the lung volume signal (LV). In the top panels of A and B, end-inspiratory and end-expiratory points of the LV are shown (circles) together with the two cubic splines fitting these points. Their difference is the ITV signal (bottom panels). The variation in peak to trough values of tidal volume is computed and if >25%, the breathing pattern is classified as Periodic Breathing. According to this definition, the breathing pattern in A is classified as Periodic Breathing, while the one in B as normal breathing.

 
To determine whether a short-term day-time recording provides a reliable "qualitative" estimate of breathing pattern, repeated recordings were performed three days apart in 15 patients (age 58±11 years, NYHA class 2.8±0.8, LVEF 31±6%). At first recording PB was observed in 8 patients while the remaining seven exhibited a normal breathing pattern. At the second recording breathing pattern was reproducible in all but one patient who changed his pattern from periodic to normal.

2.2. Study variables and follow-up data
Within 1 week of the short-term respiratory study, all patients underwent 2-D echocardiography, cardiopulmonary exercise testing, 24-hour Holter recording and routine blood tests.

During follow-up, patients were periodically re-evaluated and hospitalised if clinically unstable. Where appropriate, the date and mode of death, and information regarding transplantation were recorded. The majority of cardiac deaths (including urgent heart transplantation) occurred in hospital, or were ascertained from chart review and/or telephone interviews (with relatives or the referring physician). Time-to-event information, as well as demographic, clinical, functional and short-term respiratory data recorded at baseline, were entered into a dedicated database.

2.3. Statistical analysis
Descriptive statistics are given as mean±SD. To assess group differences, the Mann-Whitney U test was used for continuous measures and the Chi-square test for categorical variables. A p<0.05 was considered statistically significant.

Survival analysis was for total cardiac death (including urgent heart transplantation). Patients who died of non-cardiac causes (e.g., cancer or accidental death) and those who underwent elective heart transplantation (i.e. patients who were not under intensive support at the time of transplantation) were censored.

Survival curves were estimated by the Kaplan-Meier method and compared by the log-rank test. The association between the breathing pattern and the outcome was assessed by univariable and multivariable Cox regression analysis. Multivariable analysis was carried out by first building a prognostic model based on known clinical and functional risk factors. These variables were pre-selected from Table 1 on the basis of the strength of association with the outcome shown by previous studies in the same or similar populations [16-18]. We excluded deceleration time (high number of missing measurements), and left ventricular (LV) end systolic diameter (LVESD) (high correlation with LV end diastolic diameter (LVEDD), r=0.94, p<0.0001), and kept the following: sex, ischaemic cardiomyopathy (yes/no), NYHA class (III-IV vs I-II), mean RR, systolic arterial pressure, LV ejection fraction (LVEF), LVEDD, blood urea nitrogen (BUN), sodium, peak VO2, beta-blocker treatment (yes/no). We fitted a Cox proportional hazards regression model to all these variables and eliminated less predictive factors using a backward elimination procedure at the 0.25 significance level.


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  		Table 1 Baseline clinical and functional characteristics in patients with normal breathing and with periodic breathing (PB) during short-term day-time recordings

 
Then, to determine whether the breathing pattern carried independent prognostic information, we entered the corresponding indicator variable (PB yes/no) into the clinical prognostic model and assessed its statistical significance. To validate modelling results, we used the bootstrap method [19]. Briefly, 500 bootstrap samples, each containing 380 subjects, were obtained from the original dataset using random sampling with replacement. Then the multivariable modelling procedure was repeated in each bootstrap sample and the percentage of times the breathing pattern significantly (p<0.05) added to the clinical variables was computed.

The assumption of proportional hazards in fitted prognostic models was tested by plotting smoothed scaled Schoenfeld residuals with 95% confidence intervals. In case of violation of the assumption in a covariate, we tested for the interaction between the covariate and time [20].

All statistical analyses were carried out using the SAS/STAT statistical package, release 8.02 (SAS Institute Inc., Cary, NC, USA).


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Clinical implications and...
 References
 
Day-time PB was observed in 145/380 patients (38%). The clinical characteristics of patients with and without breathing disorders are reported in Table 1. Patients with PB were more frequently male, significantly sicker (higher NYHA class) than patients with a normal breathing pattern, had higher heart rate, more compromised left ventricular function and blood chemistry. Moreover they showed a significant increase in non-sustained ventricular tachycardia (NSVT). No significant differences were observed for the number of ventricular premature contractions (VPCs) per hour, or peak oxygen consumption.

During a median follow-up of 41 months (range 0.4-60), 122 (32%) patients experienced the study outcome (cardiac death or heart transplant). The cardiac mortality rate was 26% in patients with normal respiratory pattern and 41% in patients with breathing disorders ({chi}2=9.2, p=0.002).

Fig. 2 shows the survival curves according to the presence or absence of PB during short-term day-time respiratory recording. A clear change in the behaviour of the curves can be observed around the 10th month of follow-up. In fact, in the first 10 months no difference in the mortality rate can be seen, however, the two curves clearly diverge after that time. Thus, the indicator variable for PB during short-term respiratory recording failed on two counts to satisfy the assumption of required proportional hazards in the fitted regression models — i.e. non-homogeneous according to the analysis of Schoenfeld residuals, and the significant interaction with time (p=0.027). Hence, all subsequent analyses were carried out considering only the 327 patients with a follow-up time longer than 10 months (with 90 cardiac deaths) [20].


Figure 02
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  		Fig. 2 Kaplan-Meier survival curves for the end-point of total cardiac mortality. Patients with periodic breathing during a short-term day-time recording had a significantly worse prognosis than patients with a normal breathing pattern.

 
The presence of PB during the short-term recording was significantly related to total cardiac mortality ({chi}2=12.2, Relative Risk, RR 2.1, 95% CI 1.4-3.2, p=0.0005).

Day-time PB was also independently predictive when entered into the clinical prognostic model. Full results of the fitted model are reported in Table 2. It can be seen that the presence of day-time PB is associated with an almost doubled risk of cardiac death, independently of clinical and functional parameters.


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  		Table 2 Predictive value of day-time periodic breathing (PB) adjusting for covariates: results of Cox regression analysis

 
Bootstrap validation indicated that these results were not likely to be chance findings; the presence of day-time PB added prognostic information to the clinical model at the 0.05 significance level in 83% of the 500 sample replications.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Clinical implications and...
 References
 
We have shown for the first time in a large study that an abnormal breathing pattern obtained from a short-term recording during the day-time was associated with an adverse prognosis in patients with moderate to severe heart failure. We found that PB not only predicted cardiac mortality, but did so independently of other well known prognostic factors. This could have considerable implications for screening and/or for future trials of PB treatment.

4.1. PB and total cardiac mortality
Several groups have studied the prognostic impact of breathing disorders during sleep in patients with severe HF. Lanfranchi et al. [3] found (in 62 patients) that an apnoea/hypopnoea index ≥30/h was a powerful and independent predictor of total cardiac mortality in a multivariate model which included non-invasive parameters such as ejection fraction, NYHA class, deceleration time of early filling, and baroreflex sensitivity (as a marker of autonomic function). Similarly, Sin et al. [21] found (in 66 patients) that patients with PB and central sleep apnoea had a significantly increased mortality or cardiac transplantation rate, compared with patients without PB and central sleep apnoea, independent of a number of clinical covariates (age, sex, NYHA class, LVEF, cause of HF). On the other hand Roebuck et al. [22] (78 patients) did not find any prognostic value from sleep apnoea. In the 36 patients studied by Andreas et al. [4] day-time but not nocturnal PB was related to increased mortality.

Ponikowski et al. [5], applied power spectral analysis on a waking 30-minute recording of respiration in 74 stable patients with HF, and found that cyclical respiration predicted a poor 2-year survival, independent of peak oxygen consumption.

Our study extends these observations to a large population of consecutive patients with HF and assesses the independent predictive value of PB against a large set of clinical and functional variables. Moreover, in contrast to previous studies (and in particular the only two studies which evaluated respiratory patterns in the day-time), the impact of PB on prognosis has been analyzed by a rigorous evaluation, which included the most important predictors of outcome in HF patients.

4.2. PB pathophysiology in HF
Increased circulatory delay and augmented gain in the chemoreflex control of breathing, in addition to hypocapnia from pulmonary congestion related hyperventilation, are recognized key factors in generating a self-sustaining ventilatory oscillation [23-26]. Although the mechanism of PB is still debated, mathematical models have provided good support to the central role of the loss of stability in the closed-loop chemical control of ventilation [23,27]. In the specific context of day-time occurrence of PB in HF, we previously tested the instability hypothesis and found a remarkable consistency between experimental observations and theoretical expectations [24].

On these grounds it has been suggested that PB mainly represents the effect rather than a potentially concomitant cause of impaired left ventricular function. Whether PB is itself a cause of further deterioration is uncertain [1]. In our study overall, patients with PB did have more severe systolic and diastolic dysfunction. But, we also found that the presence of PB adds prognostic value to these indices of cardiac function or of severity. This suggests that PB per se (and its associated hypoxia and sympathetic activation) might play a causal role in further worsening the progression of the disease, especially since we found that PB did not appear to worsen prognosis until about 10 months of observation. This implies that PB - although related to a worse haemodynamic status - requires some time to exploit its deleterious effects. This behaviour of the survival curves is similar to the delayed benefit seen in long term trials of cholesterol lowering with statin therapy in coronary artery disease patients [28]. We can speculate that hypoxia and sympathetic oscillations associated with PB might themselves cause a vicious cycle of further deterioration.

Why has this delayed harm not appeared in previous sleep studies of PB in heart failure? One possibility is that our definition of PB during day-time recordings as "a greater than 25% variation in tidal volume" is insufficiently severe to lead to an immediate increase in mortality, but is a marker for patients who will later develop more severe and more prolonged oscillations — sleep studies have used a definition of a 50% variation in tidal volume [3]. Another point is that the presence or absence of PB in our short day-time record is only dichotomized information (yes/no), while previous studies could define the exposure to risk on the basis of a quantitative assessment of abnormal breathing severity [3].


   5. Clinical implications and conclusions
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Clinical implications and...
References
 
Heart failure represents a major public health problem in developed countries, affecting 1-2% of the population, and despite optimal medical treatment, is still a major cause of death and disability. Disordered breathing during sleep occurs frequently in patients with HF; central apnoeas predominate and occur in 40% [29] to 70% [3] of patients. We found a day-time PB prevalence of 40% in our study. This prevalence might be an underestimate, since we deliberately excluded higher risk patients with atrial fibrillation. This emphasizes the major importance of PB as independent predictor of total mortality, even in this relatively lower risk population in sinus rhythm.

Since PB is largely a consequence of HF, optimal medical treatment is a prerequisite for estimating the true prevalence and pathophysiological implications of the phenomenon. The prevalence of day-time PB has never been assessed in large studies. However, in a previous publication from our group in 1997 [6], we reported a prevalence of 64%, this probably reflects differences in HF management. Indeed, beta-blockers were used in less than 5% of patients in the original series, compared with 34% of patients in the current study. According to current treatment guidelines [30] this might appear to be a relatively low percentage, but it is consistent with population data for current beta-blocker use [31], as opposed to use in clinical trials. Moreover, it has to be emphasized that beta-blocker use did not affect the predictive value of PB in the present study; mortality was higher in the presence of PB independently of beta-blockers use (no BB: 52% vs 35%, p=0.01; BB: 33% vs 18%, p=0.07).

Although several treatments have been shown to reduce the abnormality of breathing and to improve cardiac function, in HF patients with central apnoeas [32], the impact on prognosis is not well defined, and requires larger studies.

Polysomnography is expensive, technically demanding and not widely available and would thus be impractical to use for screening large populations of HF patients. A short (10 min) day-time recording of respiration may be a useful method for selecting patients for more complex investigation. Obtaining information on PB from day-time recordings could be of great practical and financial importance, particularly in large multicenter trials of HF therapy.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Clinical implications and...
 References
 

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G. D. Pinna, R. Maestri, A. Mortara, P. Johnson, D. Andrews, P. Ponikowski, T. Witkowski, E. Robbi, M. T. La Rovere, and P. Sleight
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