Author + information
- Received February 26, 2018
- Revision received May 31, 2018
- Accepted June 7, 2018
- Published online September 17, 2018.
- Ikutaro Nakajima, MDa,b,
- Takashi Noda, MD, PhDa,∗ (, )
- Hideaki Kanzaski, MD, PhDa,
- Tsukasa Kamakura, MD, PhDa,
- Mitsuru Wada, MDa,
- Kohei Ishibashi, MD, PhDa,
- Yuko Inoue, MD, PhDa,
- Koji Miyamoto, MD, PhDa,
- Hideo Okamura, MD, PhDa,
- Satoshi Nagase, MD, PhDa,
- Takeshi Aiba, MD, PhDa,
- Shiro Kamakura, MD, PhDa,
- Teruo Noguchi, MD, PhDa,
- Satoshi Yasuda, MD, PhDa,
- Yoshihiro J. Akashi, MD, PhDb and
- Kengo F. Kusano, MD, PhDa
- aDivision of Cardiology, National Cerebral and Cardiovascular Center Japan, Suita Osaka, Japan
- bDivision of Cardiology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan
- ↵∗Address for correspondence:
Dr. Takashi Noda, Division of Cardiology, National Cerebral and Cardiovascular Center Japan, 5-7-1 Fujishiro-dai, Suita, Osakato 565-8565, Japan.
Objectives This study aimed to clarify the clinical impact of transient atrial fibrillation (AF) attacks themselves and the efficacy of cardiac resynchronization therapy (CRT) in patients with intermittent AF.
Background The benefit of CRT in patients with intermittent AF, especially the effect of the AF attacks themselves, remains unclear.
Methods Among our cohort of 269 consecutive CRT patients, we compared the percent of biventricular pacing (BIVP%) and other clinical characteristics between patients with intermittent AF and those with sinus rhythm (SR).
Results During a median follow-up of 942 days (interquartile range: 379 to 1,464 days) a total of 22 patients, including 59% of CRT responders, developed heart failure (HF) due to a transient AF attack itself, and that accounted for 21% of all HF events. The BIVP% during the AF attacks was significantly lower than that during SR (p < 0.05). When compared to the SR groups, patients with intermittent AF had a significantly higher risk of developing HF or death (hazard ratio: 2.2; 95% confidence interval: 1.3 to 3.8). However, the patients who received a BIVP% of ≥90% during AF attacks were comparable to those with SR (hazard ratio: 1.2; 95% confidence interval: 0.4 to 3.0).
Conclusions A substantial number of patients developed HF due to transient AF attacks themselves even in the CRT responders, and the reason was mainly due to the loss of the BIVP%.
- atrial fibrillation
- biventricular pacing rate
- cardiac resynchronization therapy
- clinical outcome
- heart failure
Atrial fibrillation (AF) is a common comorbidity among heart failure (HF) patients with a reduced left ventricular (LV) systolic function and is associated with significant morbidity and mortality specifically in those patients (1–3). Cardiac resynchronization therapy (CRT) has been proven to significantly improve the prognosis in selected patients with sinus rhythm (SR) (4,5), however, the benefit of CRT seems to be attenuated in patients with AF based on the recent clinical trials (6,7).
The current guidelines do not distinguish between paroxysmal or permanent AF, and it remains unclear whether patients with intermittent atrial tachyarrhythmias could gain similar beneficial effects from CRT as patients with SR. Recently, by using device detection algorithms, relevant studies have revealed that even in patients with a small AF burden or new-onset AF after CRT, intermittent atrial tachyarrhythmias have been observed to be associated with a worse prognosis than in patients with SR (8–10).
The majority of the studies referring to AF in patients with CRT have focused on the prevalence and prognostic implications, and only limited studies have investigated how intermittent atrial tachyarrhythmias, including paroxysmal and persistent AF themselves, affect the hemodynamics and attenuate the clinical benefit of CRT.
Accordingly, the present study was designed 2-fold. First, we assessed whether the AF attack itself directly caused HF events and clarified how the AF attack affected CRT patients. Second, we evaluated the impact of intermittent AF on the mortality and morbidity after CRT implantations during the long-term follow-up.
Patients and study protocol
All patients receiving CRT at the National Cerebral and Cardiovascular Center Japan between 2009 to 2014 were prospectively registered. The eligibility for CRT was based on the international guidelines (11,12), including advanced HF (New York Heart Association [NYHA] functional class II, III, or IV), a depressed LV function (LV ejection fraction ≤ 35%), and a wide QRS complex (>120 ms). The characteristics at baseline, data of the implant procedure, data of all follow-up visits, and data through remote telemetry were recorded. No patients with an atrioventricular junction ablation (AVJA) during the perioperative period of the CRT were included in the present study.
Clinical assessment and follow-up
The first evaluation with a device interrogation was held 1 month after CRT implantation. Sequentially, the patients underwent a clinical assessment and device interrogation every 3 to 6 months. The assessment included an evaluation of the NYHA functional class, electrocardiogram, and echocardiogram, of which the parameters were assessed according to the Simpson’s biplane method: LV ejection fraction (LVEF), LV end-systolic volume, LV end-diastolic volume, and left atrial volume. The CRT responders were defined as having a reduction in the LV end-systolic volume of >15% at the 6-month follow-up compared to that at baseline. Patients who died before 6 months were considered nonresponders.
Diagnostics of AF and biventricular pacing
We analyzed the continuous monitoring by using an AF detection algorithm via implantable devices and AF was defined as high-rate atrial episodes (≥180 beats per min) lasting for at least 10 min (13). According to the AF guidelines, the type of AF was defined as follows: 1) permanent AF indicated a daily mean AF burden of ≥23 h over the evaluation period; 2) persistent AF indicated ≥7 consecutive days of AF of ≥23 h/day; 3) paroxysmal AF: ≥1 d of AF of ≥6 h, and 4) SR indicated all other patients (14). Intermittent AF was defined as paroxysmal AF and persistent AF in this study.
The type of AF was assessed during the first 3 months post-implantation excluding the first month as the blanking period and the longest AF burden of a single event was accepted. The percentage of biventricular pacing (BIVP%) was calculated as the number of paced or sensed ventricular beats over a given period. The BIVP% was estimated during the total lifetime, AF periods, non-AF periods, and HF events that developed. Premature ventricular contractions were also recorded by the devices. Further, the algorithm, ventricular triggered LV or biventricular pacing, was defined as captured biventricular pacing in this study.
The clinical outcomes including all-cause deaths, decompensated HF, and appropriate or inappropriate implantable cardioverter-defibrillator (ICD) shocks were monitored. On the basis of a review of the medical records and information of the device interrogation, the date of the onset was assigned for all AF episodes, HF events, and ICD shock events.
The onset of HF was defined as the initial day of developing HF symptoms or signs including exacerbation of the dyspnea on exertion, orthopnea, paroxysmal nocturnal dyspnea, general fatigue, weight gain, or edema based on the medical history. Although we used the objective nature of the definition of the onset of AF using the device detection algorithm, it was difficult to distinguish the symptoms of HF from AF in some patients if the patients presented with supposed HF symptoms on the same day as the onset of AF. In such cases, the onset of HF was separately defined as the day of the physician’s objective diagnosis of acute decompensated heart failure (ADHF).
To clarify AF induced adverse events, the episodes of all HF events with concurrent AF episodes were extracted. AF induced HF (AF-HF) was defined as an event involving decompensated HF preceding the onset of AF within 7 days before the onset of HF, and without any other triggering factors including acute ischemia, infections, anemia, or breaking life restrictions.
The continuous data are expressed as the mean ± SD for a normal distribution, or the median (25th and 75th percentiles) for a skewed distribution. Dichotomous data are presented as numbers and percentages. The proportions were compared with the chi-square test or Fisher exact test, as appropriate. A comparison of the continuous data was performed with the Student t test for paired and unpaired data. Nonparametric data were compared using the Wilcoxon rank sum test.
The cumulative event rates (HF hospitalization, death, ICD shocks) were analyzed by the Kaplan-Meier method. Those analyses were started at the time of the AF designation and only included patients without events during the first 90 days after CRT implantation. A Cox proportional hazards model was used to assess the impact of intermittent AF at baseline and the BIVP% during AF on the clinical events. We adjusted for any relevant variables including the age, sex, NYHA functional class, proportion of a left bundle branch block morphology, LVEF, QRS duration, left atrial volume, serum creatinine ≥1.4 mg/dl, and use of beta-blockers. Hazard ratios (HRs) with 95% confidence intervals (CIs) and 2-sided p values were reported. A 2-tailed p value of <0.05 was considered statistically significant. All statistical analyses were performed with JMP 12 software (SAS Institute, Inc., Cary, North Carolina).
The data from 269 consecutive patients receiving a CRT device with the intent to perform BIVP were collected. Of those, 26 were excluded for various reasons, including loss to follow-up, death within 1 month, an LV lead malfunction, lack of an atrial lead, or an extremely low value of the BIVP% (<50%). The remaining 243 CRT recipients were included in the analysis. The median follow-up time was 942 days (interquartile range: 379 to 1,464 days). The baseline characteristics are summarized in Table 1.
Approximately one-half (49%) of our cohort had no history of AF (SR group), 60 (25%) patients had a history of paroxysmal AF, 12 (5%) had a history of developing persistent AF, and the remaining 51 (21%) had permanent AF during the initial 3-month diagnostic phase. According to our definition, 72 (30%) patients were classified as having intermittent AF. As shown in Table 1, when compared with the patients with SR, the patients with intermittent AF contained a higher rate of NYHA functional class IV patients and the patients with persistent AF had a larger left atrial volume.
AF and sequential HF events
During the follow-up, 88 (36%) of the eligible patients developed ADHF with a total of 191 episodes. A total of 43 patients (71 episodes) developed ADHF without any AF (HF only) and 45 participants (120 episodes) developed both AF and ADHF. Of those, 22 patients (40 episodes) developed AF-HF based on the definition, and the last 80 episodes had other triggers (Figure 1). Notably, 21% of the total HF events were due to temporal AF attacks.
The clinical characteristics and follow-up data of the patients with AF-HF are shown in Table 2. More than one-half (55%) of the patients with AF-HF were prescribed amiodarone and 4 (18%) subjects underwent radiofrequency catheter ablation of AF before the CRT implantation. After initiating the CRT, the mean NYHA functional class improved from 3.2 ± 0.6 to 2.5 ± 1.0 (p < 0.01) and 13 (59%) patients were responders. The mean time from the onset of AF to developing HF was 3.2 days. After the first AF-HF event, 96% of the patients were administered further treatments, including radiofrequency catheter ablation of AF (23%) and additional medications (64%); however, nearly one-third (32%) of the patients developed repeated episodes of AF-HF.
Impact on the BIVP% from AF episodes and HF events
When outside the AF period, the BIVP% was maintained at a similarly high level in the patients with SR and intermittent AF. The BIVP% was also high (median 99%) in patients with permanent AF during their constant AF. On the other hand, the BIVP% significantly dropped and varied temporarily during the AF periods in the patients with intermittent AF (p < 0.001) and the BIVP% decreased an average of 16 ± 22% from SR (Figure 2).
Regarding the HF episodes, the BIVP% was held at a high level (median 97%) during the episodes with ADHF without AF (Figure 2, “HF Only”) and it was significantly higher when compared to that of the ADHF episodes with AF (Figure 2, “AF + ADHF”) (p = 0.01). Among the episodes of AF + ADHF, despite the better BIVP% during AF + ADHF episodes with other triggers except AF (Figure 2, “Other Triggers”), there was a smaller BIVP% and greater variation compared with the episodes with HF only (p = 0.03). In contrast, the BIVP% during the AF-HF episodes decreased remarkably and 82% of the AF-HF patients had a BIVP% <90%. Moreover, the BIVP% during AF-HF was significantly lower compared to that both during the episodes with HF only (p = 0.003) and other triggers (p = 0.02). On the other hand, among the patients who developed AF-HF, 18% of them could maintain a BIVP% of >98% during the HF episodes; however, all those patients had recurrences whenever AF temporally occurred again.
Mortality and morbidity
The 4-year cumulative event rates of HF or death were 21% for SR, 46% for intermittent AF, and 47% for permanent AF (Figure 3A). Regarding the SR group, patients with intermittent AF had more than double the risk of HF/death (adjusted HR: 2.2; 95% CI: 1.3 to 3.8; p = 0.005), and similarly those with permanent AF had a higher risk (adjusted HR: 2.7; 95% CI: 1.5 to 5.0; p = 0.002) as well.
In addition, the 4-year cumulative event rates for all ICD shocks including both appropriate and inappropriate device shocks were 11% for SR, 31% for intermittent AF, and 15% for permanent AF (Figure 3B). Compared to the SR group, the intermittent AF group had greater than double the risk of all ICD shocks (adjusted HR: 2.9; 95% CI: 1.4 to 6.1; p = 0.004) and they had a higher risk of both appropriate (adjusted HR: 3.5; 95% CI: 1.7 to 7.9; p = 0.001) and inappropriate device shocks (adjusted HR: 7.9; 95% CI: 2.5 to 35.0; p < 0.001). The results of the multivariate time-dependent Cox regression analysis for each clinical outcome are shown in Table 3.
To clarify the influence of the BIVP% during AF on the clinical outcome, we divided the patients with intermittent AF into 2 groups depending on whether their BIVP% during AF periods was more than 90% (AF + BIVP% ≥ 90%) or not (AF + BIVP% < 90%), and then compared them to the patients with SR. Based on the Kaplan-Meier analysis, the incidence of HF/death was similar between the patients with AF + BIVP% ≥ 90% and patients with SR (p = 0.77). In contrast, the patients with an AF + BIVP% < 90% had a higher incidence of HF/death than both the patients with an AF + BIVP% ≥ 90% and those with SR (p = 0.004, p < 0.0001; respectively) (Figure 4). In the multivariable analysis, the patients with an AF + BIVP% ≥ 90% had a similar risk for the incidence of HF/death as the patients with SR (adjusted HR: 1.2; 95% CI: 0.4 to 3.0; p = 0.74). However, the patients with an AF + BIVP% < 90% had a higher risk (adjusted HR: 3.3; 95% CI: 1.4 to 7.9) than both the patients with an AF + BIVP% ≥ 90% and those with SR (all p < 0.01).
The main findings of our study on the clinical significance of intermittent AF in CRT patients can be summarized as follows: 1) a significant portion of the patients developed AF-HF, even CRT responders; 2) the BIVP% decreased and varied significantly during AF periods; 3) the BIVP% remarkably decreased when AF-HF occurred; 4) both the patients with intermittent AF and permanent AF had a worse clinical outcome after BIVP than the patients with SR; and 5) the patients with a higher BIVP% during temporary AF periods had a similar clinical outcome as those with SR. In the present study, we showed how intermittent atrial tachyarrhythmias themselves participated in the adverse events and attenuated the clinical benefit from the CRT.
We provided new information regarding the incidence of HF subsequent to temporal AF attacks among patients with CRT and also showed the direct relationship to the reduction in the BIVP%. The reasons why AF affects the hemodynamics may be due to tachycardia-related contractile dysfunction, a loss of atrial systole, and an irregular ventricular rhythm. Above all, an uncontrolled tachycardia with a loss of the BIVP% may indicate a strong exacerbation factor of HF.
A higher BIVP% was observed during HF with other triggers even with a comorbidity of AF as compared to AF-HF episodes. This finding may indicate that the greater loss of the BIVP% was 1 of the main reasons why AF itself directly caused HF. Several possible explanations could account for the fact that the BIVP% notably decreased when AF-HF occurred. One possibility is that the patients who developed AF-HF may have easily lost their BIVP% during AF, and the other is that a decreasing BIVP% may have induced hemodynamic deterioration, and the latter may have directly predisposed to the former.
Importantly, a significant proportion of patients recurrently developed similar episodes of AF-HF even among the CRT responders, once AF occurred. Gasparini et al. (15) showed that CRT patients with permanent AF who received AVJA had a significantly better outcome than the patients with drug-treated AF, and a similar long-term survival to the patients with SR. Our findings suggest that AVJA even for the patients with intermittent AF may be reasonable to improve their outcomes. Conversely, several recent reports have shown the effectiveness of biventricular pacing fusion with the intrinsic activation (16,17). Sweeney et al. (16) reported that the QRS fusion complex, representing wavefront interference during biventricular pacing, predicts reverse remodeling during CRT in the patients with left bundle branch block. Van Gelder et al. (17) also showed that the hemodynamic maximal benefit was obtained when LV pacing fusion with intrinsic conduction over the present right bundle occurred. Thus, intrinsic atrioventricular conduction is preferable for some specific patients and the decision to perform AVJA for intermittent patients with AF remains controversial.
Presumably, catheter ablation of AF is thought to be another option for a solution. Marrouche et al. (18) reported the efficacy of AF ablation in HF patients with systolic dysfunction. According to the report, catheter ablation of AF was associated with lower rates of mortality or HF hospitalization along with reducing the AF burden and improving the LVEF. However, this trial included a relatively small number of patients with CRT and could not show the benefit of AF ablation for these patients based on the subgroup analysis. In fact, some portion of the patients in our cohort underwent AF ablation before or after the CRT; however, most of the patients developed AF again even after the AF ablation. Further studies are needed to clarify the efficacy of AF ablation for CRT patients.
Intermittent AF and clinical outcomes
Our study found that adverse cardiac events including HF/death and delivered device shocks were more common in patients with intermittent AF than in those with SR. Several clinical trials have shown a worse prognosis in patients with a small AF burden and those results support our findings (8–10). Development of AF itself has been considered to indicate a marker of a potentially worse cardiac status. Thus, we speculated that the difference in the clinical outcome was mainly due to the difference in the underlying substrate. However, our present results indicated the strong factor for a worsening clinical outcome was a decreasing BIVP% due to the AF attack itself. Conversely, the clinical outcome after CRT for patients with intermittent AF whose BIVP% was maintained highly during temporal AF periods could have been similar to that for patients with SR.
In the past study regarding ICD patients, patients with intermittent AF had a significantly increased risk only for inappropriate shocks (19). Differing from general ICD patients, our finding suggested that CRT patients with intermittent AF may have a prognostic implication for both appropriate and inappropriate shocks.
A potential weakness of this study was that the patients with intermittent AF included those with more severe HF as compared to those with SR, and the influence of this factor regarding the response to CRT could not be ruled out. Furthermore, it is important to emphasize that some of the patients might have had unrecognized common modifying factors that affected both the AF and HF, which made it difficult to clearly distinguish whether they were AF triggering events or not. Finally, the BIVP% investigated in this analysis was based on a device-measured BIVP% and it may have included ineffective complete and consistent BIVP capture. Thus, the actual effective BIVP capture may have been overestimated.
Among the patients with CRT, intermittent AF has prognostic implications for HF and delivering device shocks. A significant proportion of the patients developed HF due to a temporal AF attack itself even among CRT responders. Once AF occurred, the BIVP% significantly decreased and the patients with a lower BIVP% during temporal AF periods exhibited a worse clinical outcome. These temporal AF episodes with a significant decrease in the BIVP% could be relate to the attenuation of the CRT benefit in patients with intermittent AF.
COMPETENCY IN MEDICAL KNOWLEDGE: The clinical benefit of CRT in patients with intermittent AF is attenuated by the temporal atrial tachyarrhythmia attack itself. AF-HF has unignorable impacts on their worsened clinical outcomes and those patients have a high possibility of recurrences whenever AF temporally occurs again. A significant decrease in the BIVP% during temporal AF periods was related to a poor prognosis, thus maintaining a high BIVP% level during AF periods may have prognostic implication. Hence, controlling AF itself or attempting to achieve a higher BIVP% during AF is a critical issue for patients with intermittent AF.
TRANSLATIONAL OUTLOOK: Additional studies are needed to directly evaluate the hemodynamics during temporal AF periods in patients with CRT. From the viewpoint of understanding the pure influence of uncaptured BIVP during AF, the protocol excluding the effects of tachycardia-related contractile dysfunction, a loss of atrial systole, and an irregular ventricular rhythm should be discovered. Clinically, further studies concerning the effects of atrioventricular junction ablation in CRT patients with intermittent AF are necessary.
This study was supported by the intramural research fund (25-4-7, Dr. Kusano) for cardiovascular diseases of the National Cerebral and Cardiovascular Center, and trust research and joint research funds of Medtronic Japan Co., Ltd. Drs. Noda and Kusano have received personal fees from Medtronic Japan Co., Ltd. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Clinical Electrophysiology author instructions page.
- Abbreviations and Acronyms
- acute decompensated heart failure
- atrial fibrillation
- atrioventricular junction ablation
- biventricular pacing percentage
- cardiac resynchronization therapy
- heart failure
- implantable cardioverter defibrillator
- left ventricle/ventricular
- New York Heart Association
- sinus rhythm
- Received February 26, 2018.
- Revision received May 31, 2018.
- Accepted June 7, 2018.
- 2018 American College of Cardiology Foundation
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