Original Article
Does permanent atrial fibrillation modify response to cardiac resynchronization therapy in heart failure patients?
A fibrilhação auricular modifica a resposta à terapêutica de ressincronização cardíaca em doentes com insuficiência cardíaca?
Ana Abreua,, , Mário Oliveiraa, Pedro Silva Cunhaa, Helena Santa Clarab, Guilherme Portugala, Inês Gonçalves Rodriguesa, Vanessa Santosb, Luís Moraisa, Mafalda Selasa, Rui Soaresa, Luísa Brancoa, Rui Ferreiraa, Miguel Mota Carmoc, on behalf of BETTER-HF investigators
a Serviço de Cardiologia, Hospital de Santa Marta, Centro Hospitalar Lisboa Central, CHLC, Lisboa, Portugal
b Centro Interdisciplinar de Estudo da Performance Humana, CIPER, Faculdade de Motricidade Humana, Universidade de Lisboa, Portugal
c Centro de Estudos de Doenças Crónicas, CEDOC, Faculdade de Ciências Médicas, Universidade Nova, Lisboa, Portugal
Received 16 June 2016, Accepted 21 February 2017
Abstract
Introduction

The benefits of cardiac resynchronization therapy (CRT) documented in heart failure (HF) may be influenced by atrial fibrillation (AF). We aimed to compare CRT response in patients in AF and in sinus rhythm (SR).

Methods

We prospectively studied 101 HF patients treated by CRT. Rates of clinical, echocardiographic and functional response, baseline NYHA class and variation, left ventricular ejection fraction, volumes and mass, atrial volumes, cardiopulmonary exercise test (CPET) duration (CPET dur), peak oxygen consumption (VO2max) and ventilatory efficiency (VE/VCO2 slope) were compared between AF and SR patients, before and at three and six months after implantation of a CRT device.

Results

All patients achieved ≥95% biventricular pacing, and 5.7% underwent atrioventricular junction ablation. Patients were divided into AF (n=35) and SR (n=66) groups; AF patients were older, with larger atrial volumes and lower CPET dur and VO2max before CRT. The percentages of clinical and echocardiographic responders were similar in the two groups, but there were more functional responders in the AF group (71% vs. 39% in SR patients; p=0.012). In SR patients, left atrial volume and left ventricular mass were significantly reduced (p=0.015 and p=0.021, respectively), whereas in AF patients, CPET dur (p=0.003) and VO2max (p=0.001; 0.083 age-adjusted) showed larger increases.

Conclusion

Clinical and echocardiographic response rates were similar in SR and AF patients, with a better functional response in AF. Improvement in left ventricular function and volumes occurred in both groups, but left ventricular mass reduction and left atrial reverse remodeling were seen exclusively in SR patients (ClinicalTrials.gov identifier: NCT02413151; FCT code: PTDC/DES/120249/2010).

Resumo
Introdução

Os benefícios da terapêutica de ressincronização cardíaca (TRC), documentados na insuficiência cardíaca (IC), poderão ser influenciados pela fibrilhação auricular (FA). Pretendemos avaliar comparativamente efeitos TRC em doentes em FA e em ritmo sinusal (RS).

Métodos

Foram estudados prospetivamente 101 doentes submetidos a TRC. Percentagens de respondedores clínicos, ecocardiográficos e funcionais, valores basais e variação de classe NYHA, fração de ejeção, volumes e massa ventriculares esquerdos, volumes auriculares, duração da prova de esforço cardiorrespiratória (PECR dur), consumo pico de oxigénio (VO2p) e eficiência ventilatória de esforço (VE/VCO2) foram comparados entre grupos FA e RS, pré-implantação TRC e nos seis meses após implantação.

Resultados

Os doentes tiveram percentagens de pacing biventricular ≥95%, com 5,7% de ablação auriculoventricular juncional. Definimos grupo FA (n=35) e grupo RS (n=66), tendo os doentes com FA idade superior, maiores volumes auriculares, menores PECR dur e VO2p pré-CRT. Percentagens de respondedores clínicos e ecocardiográficos foram idênticas nos dois grupos, mas de respondedores funcionais foram superiores nos doentes FA (71 versus 39% no grupo RS; p=0,012). Nos doentes RS verificou-se a redução significativa do volume auricular esquerdo e da massa ventricular esquerda (p=0,015 e p=0,021, respetivamente) e nos doentes com FA maior aumento da PECR dur (p=0,003) e VO2p (p=0,001; p=0,083 ajustado para idade).

Conclusão

As respostas clínica e ecocardiográfica à TRC foram semelhantes nos doentes FA e RS, com resposta funcional superior em FA. A melhoria de função e dimensões ventriculares esquerdas foi idêntica nos dois grupos, contudo redução de massa ventricular esquerda e remodelagem inversa auricular esquerda foram exclusivas de doentes RS (ClinicalTrials.gov Identifier: NCT02413151; FCT code: PTDC/DES/120249/2010).

Keywords
Heart failure, Cardiac resynchronization, Atrial fibrillation, Responder
Palavras-chave
Insuficiência cardíaca, Ressincronização cardíaca, Fibrilhação auricular, Respondedor
Introduction

Cardiac resynchronization therapy (CRT) is an important device-based, non-pharmacological treatment for chronic heart failure (HF). The multiple benefits of CRT in selected HF patients under optimized pharmacologic therapy include improvement in symptoms and quality of life, left ventricular (LV) remodeling and decreased mortality and hospital admissions for HF, and have been established by multiple large trials,1–5 leading to its recommendation in current guidelines.6 An important feature in HF is the presence of atrial fibrillation (AF), the arrhythmia most frequently associated with HF, which affects up to 45%-50% of patients, depending on the severity of HF.7,8 For HF patients still in sinus rhythm (SR), the annual incidence of AF is approximately 5%.9 AF is negatively related to prognosis, although some authors do not consider it an independent prognostic predictive factor after correction for age and comorbidities.10 Atrial arrhythmias, if not appropriately managed, may have a negative impact on the clinical benefits of CRT,11 since, in AF patients, CRT can only correct intra- and interventricular dyssynchrony. CRT is also hampered by high intrinsic ventricular rates and irregularity, leading to reduced capture, fusion and pseudo-fusion, and hence less effective biventricular pacing.12

Although the evidence from large randomized controlled trials is weak,13,14 and some authors have argued that HF patients in AF may respond less well to CRT,15–20 the European Society of Cardiology (ESC) guidelines recommend that this therapy should also be used for AF patients, as long as atrioventricular (AV) junction ablation is added in patients in whom continuous biventricular pacing is lost.6 Recently, the CERTIFY study21 showed that long-term survival after CRT among patients with AF and AV junction ablation is similar to that observed among patients in SR, and that mortality in AF patients treated with rate-reducing drugs is higher. Whether CRT is effective in the context of AF is still an important question to be addressed. The purpose of the present study was to prospectively assess the response to CRT in HF patients with permanent AF compared to those in SR.

MethodsStudy design

A prospective cohort study was performed in a single hospital center, including consecutive HF patients with systolic dysfunction selected for CRT according to current guidelines, over a period of 36 months.

The study protocol was approved by the hospital's Ethics Committee and complies with the Declaration of Helsinki. Written informed consent was obtained from all patients.

Patient selection

The patients were consecutively selected for CRT between 2012 and 2014, based on current guidelines6 and according to the following inclusion and exclusion criteria:

Inclusion criteria:

  • Moderate to severe HF (New York Heart Association [NYHA] class III-IV) under optimal medical therapy

  • Age >18 and <80 years

  • Moderate to severe LV systolic dysfunction (LV ejection fraction [LVEF] <35%)

  • QRS duration ≥120 ms

  • Ischemic or non-ischemic etiology

  • Cardiac rhythm: SR or AF

  • Stable condition for >1 month (no hospitalization for HF, no change in medication, no change in NYHA functional class).

Exclusion criteria:

  • Refusal to participate in the study for any reason

  • Inability to perform cardiopulmonary exercise testing (CPET)

  • Inability to sign informed consent

  • Unstable angina

Optimal medical therapy for HF was considered to include an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker and a beta-blocker, as recommended by the guidelines, unless contraindicated.

Patients were divided in two groups according to baseline cardiac rhythm, SR or permanent AF, confirmed by electrocardiogram (ECG).

Technical procedures

Implantation was performed as previously described.22 Patients with permanent AF underwent radiofrequency AV junction ablation whenever capture occurred less than 95% of the time. The percentage of biventricular pacing was identified by device counters, ECG and Holter in doubtful cases. All patients in the current study were provided with similar HF management following CRT implantation, including comparable and optimal pharmacologic treatment.

Assessment protocol

Clinical, echocardiographic and CPET parameters were assessed in the 48 hours before (T1) and at three and six months after CRT implantation (T2 and T3, respectively), and their variation over time (T2-T1 and T3-T1) was determined and compared between the two groups.

Clinical and electrocardiographic parameters

Age, gender, HF etiology and NYHA functional class were recorded. Cardiac rhythm, heart rate (HR) and QRS duration were determined from the ECG at inclusion and confirmed at implantation.

Cardiopulmonary exercise testing

Symptom-limited CPET was performed under HF medication, according to a modified Bruce protocol on a treadmill (Mortara Multisyn 190), with breath-by-breath gas exchange measurements (Innocor). Testing supervisors encouraged patients to exercise to exhaustion, guided by the respiratory exchange ratio (RER), with a goal of RER >1.10. Exercise test duration (CPET dur), peak oxygen consumption (VO2max), ventilatory efficiency as measured by the slope of the linear relationship between ventilation and CO2 output (VE/VCO2 slope), and HR were determined.

Echocardiographic study

Transthoracic echocardiography (GE Vivid 9) was performed to assess LVEF (by Simpson's method), LV end-diastolic and end-systolic volume (LVEDV and LVESV, respectively), LV mass (LVM), and left and right atrial volume (LAV and RAV, respectively).

Clinical and echocardiographic responders to cardiac resynchronization therapy

The proportion of CRT responders in each group was calculated and compared between the two groups.

CRT response was defined according to clinical, echocardiographic and functional parameters, as follows:

  • Clinical response to CRT – sustained improvement of at least one NYHA class;

  • Echocardiographic response – a minimum absolute 5% increase in LVEF;

  • Functional response – an absolute increase of >1 ml/kg/min in VO2max.

Response to CRT was defined by clinical, echocardiographic or functional improvement between T1 and T2 (sustained at T3) or T1 and T3.

Statistical analysis

Continuous variables were expressed as mean ± standard deviation (SD) and categorical variables as absolute values and percentages. Variations in continuous variables were determined and compared by the paired t test and the nonparametric Wilcoxon test, when appropriate, for variables with and without normal distribution, respectively. Categorical variables were compared by the chi-square test. Differences in mean ± SD between the AF and SR groups were tested with the unpaired t test or the Mann-Whitney test, according to distribution. Multivariate linear regression was used for age adjustment and for baseline adjustment for VO2max regarding change in VO2max after CRT in the AF group. A p value <0.05 was considered significant. SPSS 22.0 (IBM SPSS, Armonk, NY) was used for the statistical analysis.

ResultsPopulation sample

A total of 101 HF patients referred for CRT implantation, in class NYHA III or IV and with LVEF <35%, were included, 71 male (70%), mean age 68 years, 27.5% ischemic etiology. Of these, 35 patients (34%) were in permanent AF at the time of CRT implantation.

To achieve effective biventricular capture, two AF patients (5.7%) underwent radiofrequency AV junction ablation, while the other 33 (94.3%) were successfully treated with negative chronotropic drugs only (digoxin, beta-blockers, amiodarone) for rate control, maximizing biventricular pacing delivery.

The characteristics of the population sample and differences between groups are shown in Table 1. Patients in the AF group were older and more often male. Also, echocardiographic and functional data show more LV hypertrophy, atrial dilatation and worse functional capacity in this group, reflected by higher mean LVM, LAV and RAV, and lower mean CPET dur, VO2max and percentage predicted VO2 compared to the SR group.

Table 1.

Characteristics of patients in sinus rhythm and atrial fibrillation at baseline, before cardiac resynchronization therapy.

Baseline  SR (n=66)  AF (n=35) 
Age, years  67.4±11.8  71.4±8.9  0.024 
Male  41 (62.1%)  28 (80%)  0.066 
NYHA II  16 (24.2%)  7 (20%)  0.316 
NYHA III  48 (72.7%)  24 (68.6%)   
NYHA IV  2 (3.0%)  3 (8.6%)   
BMI (kg/m226±5  27±4  0.730 
Ischemic etiology  18 (27.3%)  10 (28.6%)  0.890 
LVEF <25%  26 (39.4%)  13 (38.2%)  0.910 
LVEF, %  25.8±7.1  26.6±7.3  0.638 
LVEDV, ml  202.2±68.2  222.3±70.5  0.188 
LVESV, ml  149.8±53.4  166.0±63.4  0.288 
LVM, g  315.86±82.16  362.31±103.69  0.06 
LAV, ml  68.1±34.6  106.9±50.8  0.006 
RAV, ml  29.5±16.2  64.0±51.6  0.0001 
CPET dur, s  432.9±250.7  242.2±183.4  0.001 
HR bas, bpm  78.6±11.6  76.6±12.7  0.48 
HR max, bpm  123±23  122±31  0.585 
VO2max, ml/kg/min  15.8±5.4  11.9±4.3  0.001 
Predicted VO2max, %  52.88±18.52  39.67±16  0.004 
QRS, ms  143.2±20.7  145.8±24.3  0.790 

AF: atrial fibrillation group; BMI: body mass index; bpm: beats per minute; CPET dur: cardiopulmonary exercise test duration; HR bas: baseline heart rate; HR max: maximum heart rate; LAV: left atrial volume; LVEDV: left ventricular end-diastolic volume; LVEF: left ventricular ejection fraction; LVESV: left ventricular end-systolic volume; NYHA: New York Heart Association class; RAV: right ventricular volume; SR: sinus rhythm group; VO2max: peak oxygen consumption.

Data are expressed as mean ± SD for continuous variables and as number and proportion (%) for categorical variables.

Clinical effects of cardiac resynchronization therapy

NYHA functional class improved significantly over time (T2-T1 and T3-T1) in both groups, with no significant difference between SR and AF, as displayed in Table 2.

Table 2.

Differences in clinical, echocardiographic and functional variables of cardiopulmonary exercise testing after cardiac synchronization therapy in patients in sinus rhythm and in atrial fibrillation.

Variable  SR (n=66)  AF (n=35)  p SR/AF 
NYHA class T1-T2  -0.97±0.78  0.0001  -0.96±0.72  0.0001  0.884 
NYHA class T1-T3  -1.14±0.85  0.0001  -1.07±0.94  0.0001  0.873 
LVEF T1-T2, %  10.71±10.44  0.0001  7.97±11.15  0.001  0.269 
LVEF T1-T3, %  12.9±11.3  0.0001  10.9±9.8  0.0001  0.305 
LVEDV T1-T2, ml  -5.90±63.60  0.393  -9.74±50.58  0.212  0.790 
LVEDV T1-T3, ml  -12.25±43.60  0.040  -15.07±45.51  0.036  0.694 
LVESV T1-T2, ml  -13.27±46.68  0.021  -27.14±59.50  0.067  0.487 
LVESV T1-T3, ml  -23.40±39.94  0.0001  -25.97±40.50  0.003  0.681 
LVM T1-T2, g  -7.51±89.87  0.922  5.66±87.19  0.778  0.867 
LVM T1-T3, g  -31.05±88.39  0.021  -12.13±95.80  0.527  0.486 
LAV T1-T2, ml  -10.2±28.81  0.093  -16.63±48.82  0.483  0.919 
LAV T1-T3, ml  -15.81±29.83  0.015  13.77±39.13  0.249  0.022 
RAV T1-T2, ml  -6.10±17.44  0.067  -9.63±19.46  0.208  0.722 
RAV T1-T3, ml  -4.46±15.04  0.247  -4.58±33.70  0.255  0.307 
HR bas T1-T3, bpm  1.7±2.3  0.77  4.8±2.9  0.09  0.451 
HR max T1-T3, bpm  1.09±3.7  0.77  9.5±5.5  0.99  0.61 
VO2max T1-T2, ml/kg/min  0.92±4.74  0.246  2.18±3.81  0.021  0.225 
VO2max T1-T3, ml/kg/min  -0.42±4.92  0.493  3.72±2.91  0.001  0.005 
CPET dur T1-T2, s  44.17±181.7  0.178  160.64±193.3  0.001  0.018 
CPET dur T1-T3, s  39.10±202.7  0.343  152.62±235.7  0.003  0.009 
VE/CO2 slope T1-T2  -5.31±9.21  0.006  -8.54±8.82  0.005  0.220 
VE/CO2 slope T1-T3  -3.1±11.6  0.36  -6.4±10.9  0.08  0.322 

AF: atrial fibrillation group; bpm: beats per minute; CPET dur: cardiopulmonary exercise test duration; HR bas: baseline heart rate; HR max: maximum heart rate; LAV: left atrial volume; LVEDV: left ventricular end-diastolic volume; LVEF: left ventricular ejection fraction; LVESV: left ventricular end-systolic volume; NYHA: New York Heart Association class; RAV: right ventricular volume; SR: sinus rhythm group; T1: before cardiac resynchronization therapy (CRT); T2: 3 months after CRT; T3: 6 months after CRT; VO2max: peak oxygen consumption.

Data expressed as mean ± SD.

Echocardiographic effects of cardiac resynchronization therapy

Changes over time after CRT (T2-T1 and T3-T1) in several echocardiographic variables showed significance in both rhythm groups (Table 2). Mean LVEF and ventricular volumes, especially LVESV, improved significantly after CRT in both SR and AF patients, without statistical difference between the groups. However, mean LV mass and LAV changed significantly, but only in SR patients at six months.

Functional effects of cardiac resynchronization therapy

Improvements in CPET dur and VO2max were only significant in AF patients. Change in VE/VCO2 slope was significant in AF and at three months in SR (Table 2). There were significant differences in variation in VO2max and CPET dur between the groups. When adjusted for age, the difference in VO2max variation loses statistical significance, but CPET dur change remains significantly different in AF, even after age adjustment. Pre- and post-CRT baseline HR was not significantly different in the two groups and post-CRT maximum HR was also similar.

Responders to cardiac resynchronization therapy

Proportions of clinical, echocardiographic and functional responders at six months in the SR and AF groups are summarized in Table 3, which shows similar percentages for clinical responders (78.6% for SR and 80.7% for AF) and for echocardiographic responders (77.4% for SR and 82.1% for AF). However, the proportion of functional responders was significantly larger in AF patients (71.4% vs. 39.3% in SR, p=0.012).

Table 3.

Proportions of clinical, echocardiographic and functional responders in sinus rhythm and atrial fibrillation patients.

Total population (n=101)  SR (n=66)  AF (n=35) 
Clinical responders, n (%)  44 (78.6%)  46 (80.7%)  NS 
Echocardiographic responders, n (%)  24 (77.4%)  23 (82.1%)  NS 
Functional responders, n (%)  26 (39.3%)  25 (71.4%)  0.012 

AF: atrial fibrillation group; SR: sinus rhythm group.

Data expressed as numbers and proportions (%).

Discussion

In the present study, patients with permanent AF, one third of the study population, showed good response to CRT in the majority of cases without the need for AV junction ablation, in contrast to several previous studies.19

To date, randomized studies on CRT have been mainly restricted to patients in SR, excluding patients in permanent AF. This contrasts with the high prevalence of CRT use in AF patients in routine clinical practice, as observed in our data (35%) and as previously indicated by ESC surveys,23,24 which indicate a prevalence of 23%.23

It is well known that the likelihood of coexistent AF and HF is strongly related to the severity of the disease represented by NYHA functional class: prevalence of 5% for NYHA class I, 10%-25% for class II/III, and 50% for class IV.10 The probable reason for the higher prevalence of AF observed in our study population is their greater clinical severity (95% NYHA class III/IV, 5% class II) compared to patients in the European cardiac resynchronization registry (78% class III/IV, 22% class I/II).23 In our sample, AF patients were older, with worse functional capacity, as in previous studies, which may have influenced the effects of CRT in AF compared to SR patients.25,26 Our data are also in accordance with the greater proportion of men among AF patients, as previously demonstrated,27 and additionally showed a higher percentage of nonischemic cardiomyopathy.

Regarding the management of our patients, which followed the consensus for mandatory continuous biventricular capture, it assured rate control and rhythm regularization, in order to maximize the clinical benefit and improve prognosis of patients with permanent AF.28 This requires AV junction ablation in some cases, since pharmacological treatment may be inadequate to control ventricular rate at rest and during exercise. In the second ESC CRT survey,24 74% of European centers implanting CRT devices scheduled AV junction ablation only in the presence of uncontrolled HR, and only a minority of centers (11%) proceeded directly to AV junction ablation, regardless of HR. Frequent biventricular pacing, as previously defined, was taken as ≥95% of biventricular capture.29 In our study, only 5.7% of AF patients underwent AV junction ablation during the first six months after implantation, the other 94.3% being treated with pharmacological therapy for HR control. The low proportion of patients needing AV junction ablation could be explained by good pharmacologic HR control with adequate dosages of beta-blockers, digoxin and other drugs with bradycardia effects, carefully titrated and increased whenever needed. Furthermore, some of these patients underwent CRT implantation due to left ventricular dysfunction, heart failure and indication for pacing due to bradyarrhythmia. However, there was no control group to compare these effects, since the other group was made up of SR patients, who might not need the same drugs or the same dosages. At this point, it is important to note that pre- and post-CRT baseline HR and maximum HR during CPET were not significantly different between SR and AF patients.

Concerning the effects of CRT in this real-life study, several clinical, echocardiographic and functional variables of exercise testing changed significantly after CRT in both SR and AF patients: NYHA class, LVEF, LVESV and VE/VCO2 slope (at three months), and LVEDV and VE/VCO2 (at six months). Similarly, some authors have shown that CRT in AF patients improves symptoms,14,30 while others suggest that CRT is only effective after AV junction ablation, which was certainly not the case in our patients. In contrast to our results, some previous studies in AF patients demonstrated that, despite similar changes in LVEF, there was less improvement in NYHA functional class.25,26,31

An important issue is the CRT response rate, bearing in mind that definitions of CRT response in the literature differ widely.32 It is interesting to observe that neither SR nor permanent AF significantly influenced the percentage of responders in this sample, either clinical (SR 78.6% vs. AF 80.7%) or echocardiographic (SR 77.4% vs. AF 82.1%). Some studies, however, have shown different results. In a meta-analysis by Wilton et al., which included 33 studies (7495 patients), a lower rate of CRT response was observed in AF patients than in SR, with no response in 34.5% vs. 26.7%, respectively (p=0.01).26 Also, a more recent study33 confirmed the benefit of CRT in HF patients with AF, although inferior to that of SR patients, with more frequent non-response. In contrast to the results of these two publications and to our own data, single-center randomized studies have demonstrated little evidence regarding CRT effectiveness in AF.34 The RAFT study35 included more patients with permanent AF than all other published studies combined. RAFT failed, however, to demonstrate a clear improvement in any clinical or surrogate outcome with CRT in patients with permanent AF, despite a trend for fewer HF hospitalizations. This poor outcome might be attributed to suboptimal delivery of CRT, because only one third of patients received ≥95% ventricular pacing.35 It should be noted that in this study many patients were in NYHA class II. To increase the percentage of pacing in AF, AV junction ablation was applied in our study, increasing CRT response.26

In the present study, there was a significant mean increase in LVEF at three and six months in both groups, which was not statistically greater in SR patients. Despite the significant decrease in both groups in mean LVESV and LVEDV (only at six months), other authors found less improvement in LVESV in AF patients.26 Mean LVM and LAV decreased significantly at six months, but only in the SR group. It is known that HF facilitates atrial remodeling, which promotes the development and maintenance of AF,36 explaining the larger LAV in AF patients. LAV was smaller in SR patients, and consequently the changes were less marked, which facilitated reverse remodeling after CRT. We may hypothesize that LA reverse remodeling and more profound LV reverse remodeling take longer (more than three months) until a significant change is achieved after CRT, and are probably positively influenced by the presence of SR.

On the other hand, regarding the functional effects as assessed by CPET, although VE/VCO2 slope decreased significantly in both groups, only patients with AF had a significant increase in CPET dur (an absolute increase three times that of SR) and also in VO2max three months after CRT. Interestingly, after adjusting for age and baseline VO2max (which was higher in SR and lower in AF patients), there was no longer a statistically significant improvement in VO2max in AF patients (multivariate linear regression, p=0.083). This shows the importance of baseline VO2max and age in the VO2max response observed after CRT in AF.

A previous study37 demonstrated that treatment of HF patients with CRT improves exercise capacity and that this increase is most substantial among patients with a lower baseline VO2max (percentage predicted for age), the authors concluding that baseline CPET can therefore be used to identify patients who are more likely to exhibit functional improvement after CRT. Those with predicted VO2max <40% had much greater improvement in VO2max. In agreement with this, our AF patients had lower mean pre-CRT VO2max (probably related to older age, and also predicted VO2max) and more improved VO2max after CRT than SR. Also, HF patients with mean baseline VO2max <14 ml/kg/min, which was the case in our AF group, benefited most from the implantation of a CRT device.38 The percentage of functional CPET responders was significantly higher in AF patients than in SR patients, for the reasons mentioned above. Despite these better values, post-CRT mean VO2max in AF did not exceed that in SR, and values at six months were similar in the two study groups.

In patients with advanced HF, variation in VO2max is an important predictor of outcomes, including clinical deterioration or death, especially in patients with ischemic cardiomyopathy or not receiving beta-blockers.39 Exercise capacity is objectively quantified by measurement of VO2max, carbon dioxide production (VCO2), and minute ventilation.40 Not surprisingly, VO2max has a strong linear correlation with both cardiac output and skeletal muscle blood flow.41 Peak exercise capacity is defined as the maximum ability of the cardiovascular system to deliver oxygen to exercising skeletal muscle and of the exercising muscle to extract oxygen from the blood.42 As a result, exercise capacity is determined by three factors: pulmonary gas exchange; cardiovascular performance, including the peripheral vascular tree; and skeletal muscle metabolism. It has been demonstrated that CRT significantly improves all ventilation and metabolic parameters of patients with HF and ventricular conduction delay. Patients with more depressed metabolic and ventilation parameters and higher HR at baseline seem to benefit most from this therapeutic approach.38 These results are in agreement with those observed in our study. AF patients were more deconditioned, with worse physical condition and lower exercise capacity, related to severe HF and aging, as demonstrated, and after CRT they had greater improvement in cardiovascular performance. Mean CPET dur increased in both groups, early at three months, with a more than three-fold change in AF patients, in whom the change was statistically significant (unlike in SR patients), attaining similar values for CPET dur after CRT. CRT did not significantly alter exercise capacity in SR patients, but this finding is not surprising in patients whose exercise capacity was not so severely impaired at baseline. This observation is consistent with the study referred to above, which demonstrated that HF patients with relatively preserved exercise capacity at baseline achieve only minor improvement in exercise capacity during CRT.38

As mentioned above, the mean decrease in VE/VCO2 slope was significant at three months in both groups, which is also an important beneficial effect of CRT, since a lower VE/VCO2 slope in HF is associated with better prognosis.43

In conclusion, beneficial effects of CRT were demonstrated in HF patients, both in permanent AF and in SR, with similar proportions of clinical and echocardiographic responders.

Both groups showed LV reverse remodeling independently of cardiac rhythm, to a larger extent in SR patients, who also showed LV mass reduction and LA reverse remodeling, which were not present in AF patients. Additionally, AF patients, initially with less exercise functional capacity, had a greater improvement, with more functional responders. According to our results, permanent AF should not by itself be considered a factor against deciding to treat selected HF patients with CRT.

Study limitations

This work, analyzing the use of CRT in HF patients in permanent AF, has the inherent limitations of an observational study. It involves a medium-sized population sample, so the present results need to be treated with caution and should be reproduced in a larger permanent AF population, preferably in a prospective controlled clinical trial on CRT in AF, to confirm its results. Longer follow-up studies are needed.

Ethical disclosuresProtection of human and animal subjects

The authors declare that no experiments were performed on humans or animals for this study.

Confidentiality of data

The authors declare that no patient data appear in this article.

Right to privacy and informed consent

The authors declare that no patient data appear in this article.

Funding

This work was supported by an FCT grant (PTDC/DES/120249/2010).

Conflicts of interest

The authors have no conflicts of interest to declare.

Acknowledgments

We are grateful to Prof. Ana Luisa Papoila and Prof. Marta Alves (Research Unit, Central Lisbon Hospital Center, CHLC, Lisbon, Portugal) for their advisory support with the statistical analysis.

References
1
S. Cazeau,C. Leclercq,Lavergne
Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay
N Engl J Med, 344 (2001), pp. 873-880 http://dx.doi.org/10.1056/NEJM200103223441202
2
W.T. Abraham,W.G. Fisher,A.L. Smith
Cardiac resynchronization in chronic heart failure
N Engl J Med, 346 (2002), pp. 1845-1853 http://dx.doi.org/10.1056/NEJMoa013168
3
A. Auricchio,C. Stellbrink,S. Sack
Long-term clinical effect of hemodynamically optimized cardiac resynchronization therapy in patients with heart failure and ventricular conduction delay
J Am Coll Cardiol, 39 (2002), pp. 2026-2033
4
M.R. Bristow,L.A. Saxon,J. Boehmer
Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure
N Engl J Med, 350 (2004), pp. 2140-2150 http://dx.doi.org/10.1056/NEJMoa032423
5
J.G.F. Cleland,J.C. Daubert,E. Erdmann
The effect of cardiac resynchronization on morbidity and mortality in heart failure
N Engl J Med, 352 (2005), pp. 1539-1549 http://dx.doi.org/10.1056/NEJMoa050496
6
M. Brignole,Auricchio,Baron-Esquivias
2013 ESC guidelines on cardiac pacing and cardiac resynchronization therapy: the task force on cardiac pacing and resynchronization therapy of the European Society of Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA)
Eur Heart J, 34 (2013), pp. 2281-2329 http://dx.doi.org/10.1093/eurheartj/eht150
7
N.K. Khan,K.M. Goode,J.G. Cleland
ECG abnormalities in an international survey of patients with suspected or confirmed heart failure at death or discharge
Eur J Heart Fail, 9 (2007), pp. 491-501 http://dx.doi.org/10.1016/j.ejheart.2006.11.003
8
A.U. Khand,A.C. Rankin,G.C. Kaye
Systematic review of the management of atrial fibrillation in patients with heart failure
Eur Heart J, 21 (2000), pp. 614-632 http://dx.doi.org/10.1053/euhj.1999.1767
9
W.H. Maisel,L.W. Stevenson
Atrial fibrillation in heart failure: epidemiology, pathophysiology, and rationale for therapy
Am J Cardiol, 91 (2003), pp. 2D-8D
10
H.J. Crijns,G. Tjeerdsma,P.J. de Kam
Prognostic value of the presence and development of atrial fibrillation in patients with advanced chronic heart failure
Eur Heart J, 21 (2000), pp. 1238-1245 http://dx.doi.org/10.1053/euhj.1999.2107
11
M. Gasparini,F. Regoli,P. Galimberti
Cardiac resynchronization therapy in patients with heart failure in atrial fibrillation
Europace, 11 (2009), pp. v82-v86 http://dx.doi.org/10.1093/europace/eup273
12
F. Leyva,S. Nisam,A. Auricchio
20 years of cardiac resynchronization therapy
J Am Coll Cardiol, 64 (2014), pp. 1047-1058 http://dx.doi.org/10.1016/j.jacc.2014.06.1178
13
M. Brignole,G. Botto,L. Mont
Cardiac resynchronization therapy in patients undergoing atrioventricular junction ablation for permanent atrial fibrillation: a randomized trial
Eur Heart J, 32 (2011), pp. 2420-2429 http://dx.doi.org/10.1093/eurheartj/ehr162
14
C. Leclercq,S. Walker,C. Linde
Comparative effects of permanent biventricular and right-univentricular pacing in heart failure patients with chronic atrial fibrillation
Eur Heart J, 23 (2002), pp. 1780-1787
15
K. Khadjooi,P.W. Foley,S. Chalil
Long-term effects of cardiac resynchronization therapy in patients with atrial fibrillation
16
M. Gasparini,A. Auricchio,F. Regoli
Four-year efficacy of cardiac resynchronization therapy on exercise tolerance and disease progression: the importance of performing atrioventricular junction ablation in patients with atrial fibrillation
J Am Coll Cardiol, 48 (2006), pp. 734-743 http://dx.doi.org/10.1016/j.jacc.2006.03.056
17
M. Gasparini,A. Auricchio,M. Metra
Long-term survival in patients undergoing cardiac resynchronization therapy: the importance of performing atrioventricular junction ablation in patients with permanent atrial fibrillation
Eur Heart J, 29 (2008), pp. 1644-1652 http://dx.doi.org/10.1093/eurheartj/ehn133
18
M. Gasparini,J.S. Steinberg,A. Arshad
Resumption of sinus rhythm in patients with heart failure and permanent atrial fibrillation undergoing cardiac resynchronization therapy: a longitudinal observational study
Eur Heart J, 31 (2010), pp. 976-983 http://dx.doi.org/10.1093/eurheartj/ehp572
19
M. Gasparini,C. Leclercq,M. Lunati
Cardiac resynchronization therapy in patients with atrial fibrillation: the CERTIFY study (Cardiac Resynchronization Therapy in Atrial Fibrillation Patients Multinational Registry)
JCHF, 1 (2013), pp. 500-507
20
C.W. Yancy,M. Jessup,B. Bozkurt
2013 ACCF/AHA Guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Developed in collaboration with the American College of Chest Physicians, Heart Rhythm Society and International Society for Heart and Lung Transplantation
Circulation, 128 (2013), pp. e240-e327 http://dx.doi.org/10.1161/CIR.0b013e31829e8776
21
K. Dickstein,P.E. Vardas,A. Auricchio
2010 Focused Update of ESC Guidelines on device therapy in heart failure: an update of the 2008 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure and the 2007 ESC guidelines for cardiac and resynchronization therapy, Developed with the special contribution of the Heart Failure Association and the European Heart Rhythm Association
Eur J Heart Fail, 12 (2010), pp. 1143-1153 http://dx.doi.org/10.1093/eurjhf/hfq192
22
J.C. Daubert,L. Saxon,P.B. Adamson
2012 EHRA/HRS expert consensus statement on cardiac resynchronization therapy in heart failure: implant and follow-up recommendations and management
Heart Rhythm, 9 (2012), pp. 1524-1576 http://dx.doi.org/10.1016/j.hrthm.2012.07.025
23
K. Dickstein,N. Bogale,S. Priori
The European cardiac resynchronization therapy survey
Eur Heart J, 30 (2009), pp. 2450-2460 http://dx.doi.org/10.1093/eurheartj/ehp359
24
E. Sciaraffia,N. Dagres,A. Hernandez-Madrid
Do cardiologists follow the European guidelines for cardiac pacing and resynchronization therapy? Results of the European Heart Rhythm Association survey
Europace, 17 (2015), pp. 148-151 http://dx.doi.org/10.1093/europace/euu395
25
G.A. Upadhyay,N.K. Choudry,A. Auricchio
Cardiac resynchronization in patients with atrial fibrillation: a meta-analysis of prospective cohort studies
J Am Coll Cardiol, 52 (2008), pp. 1239-1246 http://dx.doi.org/10.1016/j.jacc.2008.06.043
26
S.B. Wilton,A.A. Leung,W.A. Ghali
Outcomes of cardiac resynchronization therapy in patients with versus those without atrial fibrillation: a systematic review and meta-analysis
Heart Rhythm, 8 (2011), pp. 1088-1094 http://dx.doi.org/10.1016/j.hrthm.2011.02.014
27
W.B. Kannel,R.D. Abbott,D.D. Savage
Epidemiologic features of chronic atrial fibrillation: the Framingham study
N Engl J Med, 306 (1982), pp. 1018-1022 http://dx.doi.org/10.1056/NEJM198204293061703
28
A.M. Ferreira,P. Adragao,D.M. Cavaco
Benefit of cardiac resynchronization therapy in atrial fibrillation patients vs. patients in sinus rhythm: the role of atrioventricular junction ablation
Europace, 10 (2008), pp. 809-815 http://dx.doi.org/10.1093/europace/eun135
29
B.A. Koplan,A.J. Kaplan,S. Weiner
Heart failure decompensation and all-cause mortality in relation to percent biventricular pacing in patients with heart failure: is a goal of 100% biventricular pacing necessary?
J Am Coll Cardiol, 53 (2009), pp. 355-360 http://dx.doi.org/10.1016/j.jacc.2008.09.043
30
C. Linde,C. Leclercq,S. Rex,on behalf of the MUltisite STimulation In Cardiomyopathies (MUSTIC) Study Group
Long-term benefits of biventricular pacing in congestive heart failure: results from the Multisite Stimulation in cardiomyopathy (MUSTIC) study
J Am Coll Cardiol, 40 (2002), pp. 111-118
31
S. Wein,A. Voskoboinik,L. Wein
Extending the boundaries of cardiac resynchronization therapy: efficacy in atrial fibrillation, New York Heart Association class II, and narrow QRS heart failure patients
32
B.K. Fornwalt,W.W. Sprague,P. BeDell
Agreement is poor among current criteria used to define response to cardiac resynchronization therapy
Circulation, 121 (2010), pp. 1985-1991 http://dx.doi.org/10.1161/CIRCULATIONAHA.109.910778
33
C. Lopes,T. Pereira,S. Barra
Cardiac resynchronization therapy in patients with atrial fibrillation: a meta-analysis
Rev Port Cardiol, 33 (2014), pp. 717-725 http://dx.doi.org/10.1016/j.repc.2014.05.008
34
F.W. Prinzen,K. Vernooy,A. Auricchio
Cardiac resynchronization therapy: state-of-the-art of current applications, guidelines, ongoing trials, and areas of controversy
Circulation, 128 (2013), pp. 2407-2418 http://dx.doi.org/10.1161/CIRCULATIONAHA.112.000112
35
J.S. Healey,S.H. Hohnloser,D.V. Exner,on behalf of the RAFT Investigators
Cardiac resynchronization therapy in patients with permanent atrial fibrillation: results from the Resynchronization for Ambulatory Heart Failure Trial (RAFT)
36
A.E. Darby,J.P. DiMarco
Management of atrial fibrillation in patients with structural heart disease
37
S. Arora,M. Aarones,S. Aakhus
Peak oxygen uptake during cardiopulmonary exercise testing determines response to cardiac resynchronization therapy
38
A. Auricchio,M. Kloss,S.I. Trautmann
Exercise performance following cardiac resynchronization therapy in patients with heart failure and ventricular conduction delay
Am J Cardiol, 89 (2002), pp. 198-203
39
G.A. MacGowan,A. Pohwani,S. Murali
Dynamic analysis of exercise oxygen consumption predicts outcomes in advanced heart failure
Congest Heart Fail, 13 (2007), pp. 313-318
40
P.A. McElroy,J.S. Janicki,K.T. Weber
Cardiopulmonary exercise testing in congestive heart failure
Am J Cardiol, 62 (1988), pp. 35A
41
H.K. Reddy,K.T. Weber,J.S. Janicki
Hemodynamic, ventilatory and metabolic effects of light isometric exercise in patients with chronic heart failure
J Am Coll Cardiol, 12 (1988), pp. 353
42
C. Dennis
Rehabilitation of patients with coronary artery disease
Heart disease, a textbook of cardiovascular medicine, 4th ed., pp. 1382
43
D.P. Francis,W. Shamin,L. Ceri Davies
Cardiopulmonary exercise testing for prognosis in chronic heart failure: continuous and independent prognostic value from VE/VCO2 slope and peak VO2
Eur Heart J, 21 (2000), pp. 154-161 http://dx.doi.org/10.1053/euhj.1999.1863

Warning: Invalid argument supplied for foreach() in /var/www/html/includes_ws/librerias/html/item.php on line 1203
Copyright © 2017. Sociedade Portuguesa de Cardiologia

Metrics

  • Impact Factor: 1.195(2016)
  • SCImago Journal Rank (SJR):0,24
  • Source Normalized Impact per Paper (SNIP):0,398