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European Heart Journal Advance Access published online on August 5, 2008
European Heart Journal, doi:10.1093/eurheartj/ehn361
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Permanent atrial fibrillation affects exercise capacity in chronic heart failure patients

Piergiuseppe Agostoni1,2,*, Michele Emdin3, Ugo Corrà4, Fabrizio Veglia1, Damiano Magrì1, Calogero C. Tedesco1, Emanuela Berton5, Claudio Passino3, Erika Bertella1, Federica Re6, Alessandro Mezzani4, Romualdo Belardinelli7, Chiara Colombo1, Rocco La Gioia8, Marco Vicenzi9, Alberto Giannoni3, Domenico Scrutinio8, Pantaleo Giannuzzi4, Claudio Tondo6, Andrea Di Lenarda5, Gianfranco Sinagra5, Massimo F. Piepoli10 and Marco Guazzi9

1 Centro Cardiologico Monzino, IRCCS, Istituto di Cardiologia, Università di Milano, via Parea 4, 20138 Milano, Italy
2 Division of Respiratory Disease and Critical Care Medicine, University of Washington, Seattle, WA, USA
3 Istituto di Fisiologia Clinica, CNR, Pisa, Italy
4 Divisione di Cardiologia, Laboratory for the analysis of cardiorespiratory signals, IRCCS, Fondazione S. Maugeri, Veruno, Novara, Italy
5 Cardiovascular Department, ‘Ospedali Riuniti’ and University, Trieste, Italy
6 Cardiology Division, Cardiac Arrhythmias and Heart Failure Unit, San Camillo Forlanini Hospital/Catholic University of Sacred Heart, Roma, Italy
7 Divisione di Cardiologia, Ospedale Lancisi, Ancona, Italy
8 Division of Cardiology and Cardiac Rehabilitation, IRCCS, Fondazione S. Maugeri, Cassano Murge, Bari, Italy
9 Divisione di Cardiologia, Unità Operativa Cardiopolmonare, Ospedale San Paolo, Milano, Italy
10 Heart Failure Unit, Cardiac Unit, Polichirurgico G. da Saliceto Hospital, Cantone del Cristo, Piacenza, Italy

Received 28 February 2008; revised 10 July 2008; accepted 17 July 2008.

* Corresponding author. Tel: +39 02 58002299, Fax: +39 02 58002283, Email: piergiuseppe.agostoni{at}unimi.it


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Aims: The influence of permanent atrial fibrillation on exercise tolerance and cardio-respiratory function during exercise in heart failure (HF) is unknown.

Methods and results: We retrospectively compared the results of 942 cardiopulmonary exercise tests, performed consecutively at seven Italian laboratories, in HF patients with atrial fibrillation (n = 180) and sinus rhythm (n = 762). By multivariable logistic regression analysis, peak VO2 (OR 0.376, 95% CI 0.240–0.588, P < 0.0001), O2pulse (VO2/heart rate, HR) (OR 0.236, 95% CI 0.152–0.366, P < 0.0001), VCO2 (OR 3.97, 95% CI 2.163–7.287, P < 0.0001), and ventilation (OR 1.38, 95% CI 1.045–1.821, P = 0.0231) were independently associated with atrial fibrillation. Anaerobic threshold (AT) was identified in 132 of 180 (73%) atrial fibrillation and in 649 of 762 (85%) sinus rhythm patients (P = 0.0002). By multivariable logistic regression analysis, only peak VO2 (OR 0.214, 95% CI 0.155–0.296, P < 0.0001) was independently associated with unidentified AT. At AT, atrial fibrillation HF patients had higher HR (P < 0.0001) and higher VO2 (P < 0.001) compared with sinus rhythm HF patients. Among AT variables, by multivariable logistic regression analysis, only HR was an independent predictor of atrial fibrillation.

Conclusion: In HF patients with permanent atrial fibrillation, exercise performance is reduced as reflected by reduced peak VO2. The finding of unidentified AT is associated with a poor performance. In atrial fibrillation patients, VO2 is higher at AT whereas lower at peak. This last observation raises uncertainties about the use of AT data to define performance and prognosis of HF patients with atrial fibrillation.

Key Words: Heart failure • Atrial fibrillation • Cardiopulmonary exercise testing • Anaerobic threshold


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Permanent atrial fibrillation, defined as atrial fibrillation present for at least 1 year with no interruption, is reported to occur in at least 20% of patients with chronic heart failure (HF)1 with the greatest prevalence in the more severe stages of the syndrome.2,3 Permanent atrial fibrillation is associated with poor prognosis4 and high incidence of malignant cardiac arrhythmias.5 In HF, cardiopulmonary exercise test (CPET) allows to objectively evaluate the exercise limitation and to assess prognosis. Atrial fibrillation is associated with a reduction in exercise performance in healthy subjects and in patients with different pathological conditions including hypertensive and cardiac patients without HF.6–8 Instead, reports on the effects of atrial fibrillation on exercise capacity in HF patients are conflicting.9–12 However, atrioventricular junction ablation has been recommended for an efficacious cardiac resynchronization therapy in HF subjects with atrial fibrillation13,14 and, more recently, ablation of the atrial substrate in HF patients has provided clinical evidence that restoration of sinus rhythm is associated with amelioration of cardiac function and improved exercise performance.15,16

Several CPET parameters are valuable in assessing the severity and prognosis of HF. Among those most frequently utilized, there are parameters related to oxygen consumption (VO2), such as peak VO2, VO2 at anaerobic threshold (AT), and oxygen pulse (O2pulse = VO2/heart rate), as well as parameters related to the efficiency of ventilation such as ventilation (VE)/carbon dioxide production (VCO2) slope and VE/VCO2 at AT.17–19 In particular, peak VO2 and VE/VCO2 slope are strong independent indicators of HF prognosis.20,21

The present study was conceived to evaluate the influence of atrial fibrillation on exercise tolerance and exertional cardiorespiratory adaptations in a sizeable cohort of unselected HF patients, consecutively collected but retrospectively examined. Accordingly, we compared the results of CPETs performed in HF patients with and without atrial fibrillation by the most experienced cardiopulmonary exercise laboratories in Italy.


   Methods
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 Methods
Results
 Discussion
 References
 
Study population
CPETs were performed in seven Italian exercise laboratories by physicians unaware of the study purpose (Table 1). Two experts (M.P. and R.B.), of two laboratories not involved in patients’ recruitment, reviewed data analysis. The study cohort consisted of HF subjects, reflecting clinical practice in general cardiology secondary and tertiary referral centers. All maximal, symptoms-limited, CPETs performed in a time range variable between 1 and 4 years, in chronic HF patients who met the study inclusion/exclusion criteria, were collected. Inclusion criteria were stable (>1 month) NYHA functional class I to III chronic HF, capability of performing an exercise test and patients’ statement that they had achieved their maximal effort. Exclusion criteria were history of pulmonary embolism, primary valvular heart disease, pericardial disease, severe obstructive lung disease, clinical significant peripheral vascular disease, anaemia (haemoglobin concentration <11 g/dL), exercise-induced angina, ST-segment changes or severe arrhythmias, exercise-induced AV blocks, or presence of any clinical co-morbidity which might interfere with exercise performance. A total of 942 consecutive patients who performed CPET were collected from the different laboratories. Patients were grouped according to the presence or absence of permanent atrial fibrillation. Because the sample size (see below) was considered sufficient we did not ask for other CPETs. Left ventricle ejection fraction (LVEF) was non-invasively assessed by the Simpsons’ method.22


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  		Table 1 General characteristic of patients according to the center where cardiopulmonary exercise test was performed

 
Cardiopulmonary exercise tests
CPETs were done on a treadmill (one laboratory) or a cyclo-ergometer (six laboratories). Table 1 presents exercise protocol and metabolic carts used in the different exercise laboratories. The exercise protocols were set to achieve peak exercise in {approx}10 min. In all cases, breath-by-breath expiratory gases and ventilation analysis were performed. AT was measured with the V-slope analysis from the plot of VCO2 vs. VO2 on equal scales.23 The AT value was confirmed by ventilatory equivalents and end-tidal pressures of CO2 and O2. If no agreement was obtained, the AT was considered not identified. The VO2/work rate relationship was evaluated throughout the entire exercise. The VE/VCO2 slope was calculated as the slope of the linear relationship between VE and VCO2 from 1 min after the beginning of loaded exercise to the end of the isocapnic buffering period.

Statistical analysis
All continuous data are expressed as mean ± SD. Peak exercise and AT measurements are means over 20 s. Continuous variables were compared between groups by unpaired t-test and analysis of covariance (ANCOVA) adjusting for age, gender, and study center; categorical variables were compared with {chi}2 test. Multivariable logistic regression analysis with stepwise selection of variables [peak VO2 % of predicted, mL/min, mL/min/kg, peak VCO2, VE/VCO2 slope, peak heart rate, NYHA functional class, AT identified, peak O2pulse, peak respiratory exchange ratio (RER = VCO2/VO2), peak VE, peak tidal volume, peak respiratory rate] was used to identify predictors independently associated with atrial fibrillation or with a un/identifiable AT. To test the robustness of our model we also employed an epidemiological approach by forcing into the model potential confounders (age, gender, center were the study was performed, and LVEF). Odds ratios were computed on standardized variables, thus they represent the risk increase for 1 SD increment. Moreover, the consistency and reliability of the identified subset of predictors was tested by an internal iterative cross-validation procedure. At each step the dataset was randomly split in half: the independent predictors were selected in the first half (training set) and the resulting model was tested for significance in the second half (testing set). To account for the sample size reduction, an alpha level of 0.15, instead of 0.05, was employed. The procedure was repeated 100 times with different random splits. Although a general consensus for a specific reliability threshold has not been reached, however, a predictor can be considered as very reliable if it is selected and confirmed at least 70% of the times. Conversely, <30%, the predictor should be considered very questionable. Eventually, the linearity assumption for logistic regression was assessed by categorizing continuous variables in quartiles and plotting the coefficient against the midpoint of each quartile. Power analysis was made retrospectively. A sample size of 180 atrial fibrillation and 762 sinus rhythm patients allowed a statistical power of 80% to detect as significant a difference of 1 mL/kg/min in peak VO2 ({alpha} = 0.05). One mL/min/kg was considered the smallest clinical relevant VO2 difference in HF patients. A P-value <0.05 was considered as statistically significant. All tests were two-sided. The SAS software (v. 8.02, SAS Institute Inc., Cary, NC, USA) was used to perform all analyses.


   Results
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 Methods
 Results
Discussion
 References
 
Data of the laboratory where treadmill was used and that of the other six laboratories where a cyclo-ergometer was used are reported combined. Principal findings (reduced exercise tolerance, percentage of unidentified AT, clinical and functional characteristics associated with unidentified AT, and clinical presentation of atrial fibrillation patients without AT) were all identical when the single ‘treadmill’ center was excluded form the analytical model.

Stable sinus rhythm was present in 762 subjects and permanent atrial fibrillation in 180 cases. Patients’ characteristics and therapy are reported in Table 2. Atrial fibrillation subjects were older, more likely male, with lower LVEF, higher NYHA class, and used more frequently diuretic therapy.


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  		Table 2 General characteristics of study groups divided according to cardiac rhythm

 
As an average, both sinus rhythm and atrial fibrillation patients performed a maximal or near-maximal exercise as inferable from the elevated RER reached by both groups at peak exercise (Table 3). Adjusting for age, gender, and study center, sinus rhythm patients had higher peak exercise VO2, O2pulse, and workload achieved, while peak exercise heart rate was lower compared with atrial fibrillation. The VE/VCO2 slope showed a trend towards higher values in atrial fibrillation patients without reaching statistical significance (Table 3). By multivariable logistic regression analysis, peak VO2 mL/min/kg (OR 0.376, 95% CI 0.240–0.588, P < 0.0001), O2pulse (OR 0.236, 95% CI 0.152–0.366, P < 0.0001), VCO2 (OR 3.97, 95% CI 2.163–7.287, P < 0.0001), and VE (OR 1.38, 95% CI 1.045–1.821, P = 0.02) were independently associated with atrial fibrillation. Very similar results were obtained after forcing into the model age, gender, center where the tests were done, and LVEF. The internal cross-validation procedure confirmed a good reliability of the selected independent predictors of atrial fibrillation with the following percentages of selection and confirmation, respectively: VO2 mL/min/kg 70 and 99%; O2pulse 100 and 100%; VCO2 71 and 99%; and VE 72 and 76%. The linearity assumption for logistic regression was satisfied for all variables. It is of note that multivariable coefficients for VE and VCO2 had opposite signs with respect to univariate coefficients as an effect of a strong collinearity with the other variables. Therefore, the role of VE and VCO2 as independent predictors should be considered with caution.


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  		Table 3 Cardiopulmonary exercise test data in study groups according to cardiac rhythm

 
AT was identified in 132 of 180 (73%) atrial fibrillation and in 649 of 762 (85%) sinus rhythm patients, (P < 0.002). Atrial fibrillation patients presented at AT a higher VO2, heart rate, and lower O2pulse (Table 3). By multivariable logistic regression analysis, only heart rate at AT (OR 1.905, 95% CI 1.525–2.318, P < 0.0001) was independently associated with atrial fibrillation.

We investigated whether the presence of an unidentified AT was per se an index of more severe HF regardless of cardiac rhythm (Table 4). Compared with patients with identified AT, patients with unidentified AT had higher incidence of atrial fibrillation, were more frequently women, lower LVEF and exercise performance, and abnormally elevated VE/VCO2 slope. By multivariable analysis, only peak VO2 mL/min/kg (OR 0.214, 95% CI 0.155–0.296, P < 0.0001) was independently associated with unidentified AT. We also evaluated whether, in each HF population (sinus rhythm and atrial fibrillation), the identification of AT was affecting CPET results. In both patient populations, an unidentified AT was associated with more advanced HF as inferable by several measurements including reduced peak VO2, workload achieved, VO2/work slope, LVEF, and higher VE/VCO2 slope.


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  		Table 4 General characteristics and cardiopulmonary exercise test data in patients with and without identified anaerobic threshold

 

   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
This study has several and novel relevant findings: (i) in chronic HF patients, permanent atrial fibrillation is associated with more compromised exercise performance; (ii) the lack of identification of AT is associated with more impaired exercise performance either in the entire HF population, or considering independently atrial fibrillation and sinus rhythm patients; (iii) heart rate was higher in atrial fibrillation patients at AT and peak exercise; and (iv) opposite from peak exercise VO2, VO2 at AT was higher in atrial fibrillation subjects.

The present study is the joint effort of seven among the most qualified cardiopulmonary exercise laboratories in Italy dedicated to HF. Cyclo-ergometer was preferred to treadmill for cardiopulmonary exercise testing in six of seven laboratories. We pooled the data of the laboratory (Table 1) where treadmill was used with the others because the results were similar. Furthermore, we performed statistical analyses adjusting for the study center, together with age and gender.

The 20% incidence of atrial fibrillation in our population is similar to that previously reported in HF population of similar gender distribution and age.1–3 Also the observation that atrial fibrillation patients were predominantly male and older is in line with previous studies.24 Thus, it is understandable why atrial fibrillation patients had higher NYHA class, lower LVEF, lower peak VO2, and were more often treated with diuretics. However, with regards to exercise performance, lower peak VO2 but not VE/VCO2 was an independent predictor of atrial fibrillation at multivariable analysis. It is of note that both peak VO2 and VE/VCO2 slope are independent indicators of HF prognosis20,21 with the former more directly related to cardiac performance. Indeed, albeit we did not measure cardiac output during exercise, being the O2pulse lower, it is likely that stroke volume was lower at peak exercise in atrial fibrillation patients. The O2pulse is stroke volume xartero-venous O2 difference and it is considered a reliable index of stroke volume in the absence of exercise induced hypoxemia and severe anaemia, as it is the case in HF.17 Taken together, these findings are in line with the higher severity of HF observed in patients with atrial fibrillation.

AT was unidentified in 27% of patients with atrial fibrillation and 15% of sinus rhythm patients. The unidentified AT was associated with poorer exercise performance both in atrial fibrillation and sinus rhythm HF patients. This is probably due to a greater perfusion/contraction mismatch in the working muscles of patients with severe HF which implies an intramuscular uneven onset of anaerobic metabolism.25 AT is used to confirm the clinical value of CPET information obtained at peak exercise26 and it has been proposed as a strong alternative to peak VO227 being independent from exercise protocol and exercise duration.28 Unexpectedly, we observed in HF patients with atrial fibrillation compared with sinus rhythm patients lower peak VO2 but, at AT, higher VO2 and heart rate, and lower O2pulse. The paradox of a lower VO2 at peak but an higher VO2 at AT is likely related to the higher chronotropic response to exercise in atrial fibrillation patients. Indeed, among all the AT variables examined, only heart rate was independently associated with atrial fibrillation. The reduced O2pulse implies a reduced stroke volume because changes in O2 artero-venous content are unlikely. Therefore, in atrial fibrillation, the increased heart rate response is likely due to an increased sympathetic drive triggered to maintain cardiac output. It should be noted that the correlation between VO2 and cardiac output in HF is particularly strong at AT so that cardiac output can be precisely estimated from VO2 at AT.29 Regardless of the haemodynamic reasons for the higher VO2 at AT in HF patients, these data cast some doubts about the use of AT to evaluate exercise performance in HF patients with atrial fibrillation.

In conclusions, in HF patients with permanent atrial fibrillation exercise performance is reduced and peak VO2 rather than VE/VCO2 slope seems to better reflect exercise limitation. The finding of unidentified AT is associated with a poor performance. Finally, AT VO2 data are opposite to peak exercise VO2 data. This observation raises uncertainties about the use of AT data to define performance and prognosis of HF patients with atrial fibrillation supporting the need of multiparametric evaluation of CPET in disease states.

Conflict of interest: none declared.


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 Introduction
 Methods
 Results
 Discussion
 References
 

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