Reviews
Is Progression From Paroxysmal to Sustained Atrial Fibrillation Bad News?
2022 年 86 巻 2 号 p. 176-181
詳細
2022 年 86 巻 2 号 p. 176-181
Atrial fibrillation (AF) is the most common sustained arrhythmia and associated with increased morbidity and mortality resulting from thromboembolism and heart failure. AF often presents initially as paroxysmal and may progress to a sustained form over time. Sustained forms of AF may be associated with increased symptoms and cardiovascular morbidity, and AF progression may be associated with increased risk of clinically adverse events and outcomes. The present review discusses the clinical factors of arrhythmia progression and risk stratification available to assess the probability of AF progression. Furthermore, currently available treatment options for preventing AF progression are explored and evaluated.
Atrial fibrillation (AF) is the most common cardiac arrhythmia and associated with increased morbidity and mortality resulting from thromboembolism and heart failure (HF).1 In clinical practice, AF is classified as follows: paroxysmal AF (PAF: episodes of arrhythmia that terminate spontaneously), persistent AF (episodes that continue for >7 days and are not self-terminating), and permanent AF (ongoing long-term episodes).2 The natural history of AF is progression from silent and undiagnosed to PAF, and subsequently sustained (persistent or permanent) AF (SAF),3,4 which has been evaluated in previous studies. The European Heart Survey reported that progression of AF occurred in 15% patients at 1 year.5 The Canadian Registry of Atrial Fibrillation (CARAF) investigators6 demonstrated that the probability of progression by 1 year was 8.6% and thereafter there was a slow but steady progression to 24.7% by 5 years. Other studies have demonstrated that AF progression is common but variable, ranging from approximately 2% to 20% per patient-year (Table). Regarding Japanese AF patients, Senoo et al showed that the annual rate of AF progression was 6.0%/year in the Shinken Database,7 and we reported 4.2%/year in the Fushimi AF Registry.8 A meta-analysis showed that the pooled incidence of AF progression was 8.1% per patient-year of follow-up.9
| Study | n | Age (years) |
Annual rate of AF progression (%) |
Risk factors | |||||
|---|---|---|---|---|---|---|---|---|---|
| Age | HF | HTN | LA dilatation |
Structural heart disease |
Other | ||||
| Takahashi et al41 (1981) | 94 | 60 | 20.2–25.3 | Rheumatic valve |
AF paroxysm |
||||
| Petersen et al42 (1986) | 426 | 66 | 33.1 | Heart disease |
TE | ||||
| Kopecky et al43 (1987) | 88 | 44 | 12 | ||||||
| Rostagno et al44 (1995) | 106 | 63 | 4.7 | ||||||
| Sakamoto et al19 (1995) | 137 | 62.4, 70.1 |
22 | 〇 | 〇 | 〇 | EF ≤0.76 | CTR ≥50%, Fwave ≥2 mm |
|
| Abe et al45 (1997) | 122 | 61 | 11.5 | 〇 | P wave abnormality |
||||
| Al-Khatib et al46 (2000) | 231 | 60 | 8 | 〇 | |||||
| Kato et al4 (2004) | 171 | 58.3 | 5.7 | 〇 | 〇 | MI, VHD | |||
| Ruigómez et al47 (2005) | 418 | 67, 73 |
11 | VHD | Alcohol | ||||
| Kerr et al6 (2005) | 757 | 64 | 8.6 | 〇 | 〇 | CM, AS, MR | |||
| Jahangir et al48 (2007) | 71 | 44.2 | 31 | 〇 | QRS abnormality |
||||
| Tsang et al23 (2008) | 3,248 | 71 | 3.6 | 〇 | Obesity | ||||
| de Vos et al5 (2010) | 1,219 | 64 | 15 | 〇 | 〇 | 〇 | COPD, stroke/TIA |
||
| Camm et al36 (2011) | 5,171 | 66 | 31 | 〇 | 〇 | AF ≥3 months, Rate-control |
|||
| De Vos et al35 (2012) | 2,137 | 65.1 | 15 | 〇 | 〇 | Rate-control | |||
| Potpara et al34 (2012) | 346 | 43.2 | 33.5 | 〇 | 〇 | 〇 | |||
| Barret et al49 (2013) | 253 | 67 | 24 | 〇 | 〇 | 〇 | COPD, stroke/TIA |
||
| Senoo et al7 (2014) | 1,176 | 61.4 | 6.0 | CM | Asymptomatic, male |
||||
| Im et al20 (2015) | 434 | 71.7 | 10.7 | 〇 | 〇 | MR | Atrial arrhythmia |
||
| Padfield et al21 (2017) | 755 | 61.2 | 8.6 | 〇 | 〇 | MR, AS, LVH | |||
| Ogawa et al8 (2018) | 4,045 | 72.8 | 4.2 | 〇 | CM | Alcohol, longer time since first detection |
|||
| De With et al33 (2018) | 468 | 46 | 2.0 | 〇 | DBP | ||||
| Uetake et al50 (2019) | 306 | 65.6 | 12 (medication), 0.7 (RFCA) |
〇 | Diastolic wall strain |
||||
The circle symbol indicate that the risk factor was significant in the study. AF, atrial fibrillation; AS, aortic stenosis; CM, cardiomyopathy; COPD, chronic obstructive pulmonary disease; CTR, cardiothoracic ratio; DBP, diastolic blood pressure; EF, ejection; fraction; HF, heart failure; HTN, hypertension; LA, left atrium; LVH, left ventricular hypertrophy; MI, myocardial infarction; MR, mitral regurgitation; RFCA, radiofrequency catheter ablation; TE, thromboembolism; TIA, transient ischemic attack; VHD, valvular heart disease.
In this review, we describe the mechanisms underlying AF progression, summarize recent studies assessing the risk factors for AF progression, and discuss the clinical implications of the progression of AF.
The types of AF are defined in accordance with the 2014 AHA/ACC/HRS2 and 2016 ESC10 guidelines for the management of patients with AF. PAF is defined as self-terminating AF, in most cases within 48 h. Some AF paroxysms may continue for up to 7 days, but persistent AF is defined as AF that lasts longer than 7 days, including episodes that are terminated by cardioversion, either with drugs or by direct current cardioversion, after ≥7 days. Permanent AF is defined as AF that is accepted by the patient (and physician). SAF includes both persistent AF and permanent AF. In contrast, the incidence of AF progression is not well defined, and the definition of AF progression has varied among previous studies, but is commonly the changing of the type of AF from paroxysmal to sustained (persistent or permanent).
Pathophysiological mechanisms of AF have been described in detail in recent reviews.11–13 AF episodes are initiated by triggers that predominantly originate from the pulmonary veins, acting on a vulnerable substrate. Ectopic activity can produce reentry-initiating unidirectional block in a vulnerable substrate. The vulnerable substrate is characterized by the presence of short refractory periods and slow conduction. This substrate is caused by electrical remodeling (alterations in electrical cell-to-cell connections via gap-junctions) and structural remodeling (notably increased fibrosis). Atrial remodeling is promoted by several AF risk factors.14 AF maintenance depends on the degree of electrical and structural remodeling of the atrium. Wijffels et al15 showed that continuous rapid atrial pacing leads to progressive shortening of the atrial effective refractory period and increased duration of AF once it is induced. The longer the duration of AF, the longer the AF was maintained, the so-called “AF begets AF”. Many previous studies have identified molecular, cellular, and tissue-level differences between patients with paroxysmal and persistent AF.12 Nonetheless, it is considered that AF progression is primarily caused by advances in atrial remodeling resulting from the persistent effects of risk factors developing to AF and AF-induced remodeling.
Because AF progression strongly depends on progression of the atrial vulnerable substrate and the many clinical comorbidities that promote atrial remodeling, many clinical risk factors that are independently associated with AF progression have been reported in previous studies (Table).
Several studies have identified advancing age as a risk factor for AF progression that is itself inherently progressive. Previous studies demonstrated that the duration of AF or the interval to first AF detection was associated with AF progression. Advancing age or longer duration of AF leads atrial structural remodeling through multiple mechanisms to AF progression. HF and biomarkers associated with HF have also been associated with AF progression. It is shown that using B-type natriuretic peptide improves prediction of AF progression compared with conventional risk stratification.16,17 HF is itself also often progressive and AF may promote HF, constructing loops that may further promote AF progression (HF begets AF and AF begets HF).18 Additionally, underlying left atrial dilatation and structural heart disease are well-recognized factors associated with progression of AF.4,6,19–21 Moreover, obesity and chronic obstructive pulmonary disease (COPD) are also independent risk factors of AF progression by promoting inflammation and oxidative stress.22,23 As other known and emerging AF risk factors, alcohol, prior stroke, and certain ECG features are suggested to contribute to AF progression (Figure 1). In a meta-analysis, age, hypertension, and follow-up duration were associated with a higher rate of AF progression.9
Various risk factors associated with higher incidence of progression atrial fibrillation of AF identified in previous studies (Table). COPD, chronic obstructive pulmonary disease; CV, cardioversion; LA, left atrium.
Recently, the HATCH score (Hypertension, Age ≥75 years, Transient ischemic attack [TIA] or stroke, COPD, and HF) was proposed for predicting progression of AF.5 However, factors included in the HATCH score were not independent predictors of AF progression in the Fushimi AF Registry.8 Therefore, the MB-LATER score (Male, Bundle brunch block, Left atrium ≥47 mm, Type of AF, and Early Recurrent AF)24 was proposed, and Deng et al reviewed that it outperformed the HATCH score in regard to predicting the progression of AF.25 However, risk stratification schemes for predicting the progression of AF have not been fully established.
It is widely known that the progressed forms of AF are harder to treat. A meta-analysis showed that success rates of catheter ablation for AF are significantly lower for persistent AF than for PAF,26,27 and permanent AF represents an advanced, therapy-resistant form of AF. In addition, patients with sustained forms of AF have worse outcomes.28 In several studies of patients with cardiac implantable electronic devices, the burden of AF or atrial high-rate episodes (AHRE) was associated with a higher risk of stroke.29–31 Additionally, patients with a higher AHRE burden are more likely to suffer from worsening HF, whereas patients with a lower AHRE burden do not exhibit increasing risk for worsening HF.32 Although the burden of AF is a major driver of outcomes in AF patients, the progression of AF itself was independently related to adverse outcomes in several previous studies.8,16,33
In the Belgrade Atrial Fibrillation Study, progression of AF was related to adverse events (including thromboembolism and congestive HF) in patients with newly diagnosed lone AF.34 The clinical outcomes of patients who exhibited progression of AF were worse compared with patients demonstrating no AF progression with respect to hospital admissions and major cardiovascular events.5 These previous studies demonstrated that adverse events occurred more frequently in patients with AF progression than in those without progression, but did not show when these events occurred, whether before, during or after AF progression. De With et al reported that after AF progression, patients had a higher rate of cardiovascular events.33
In the Fushimi AF Registry, we reported that progression of AF was significantly associated with an increased risk of ischemic stroke or systemic embolism (SE) and hospitalization for HF during progression from the paroxysmal to sustained type of AF.8 In patients with progression of AF, we divided the follow-up period into 3 distinct periods: pre-progression period, defined as before the time of the last PAF; peri-progression period, defined as the 1-year period of changing from PAF to SAF; and post-progression period, defined as the time of the first SAF. As shown in Figure 2A, the incidence rates of clinical events were similar between PAF patients with progression during the pre-progression period and PAF patients without progression, and between PAF patients with progression during the post-progression period and SAF patients. The incidence rates of ischemic stroke/SE and hospitalization for HF during the peri-progression period were highest among the other time periods. On multivariate Cox regression analysis, progression of AF was significantly associated with an increased risk of ischemic stroke/SE and hospitalization for HF during the peri-progression period, compared with PAF without progression and SAF (Figure 2B). Progression of AF was also significantly associated with a higher risk of ischemic stroke/SE during the post-progression period, compared with PAF without progression. We demonstrated that the risk of adverse events temporarily increased during the the peri-progression period.8
Crude event rate of ischemic stroke/SE and hospitalization for HF in the Fushimi AF Registry (A). Adjusted hazard ratios for ischemic stroke/SE and hospitalization for HF in PAF patients with AF progression, compared with those without progression and SAF. (B) Hazard ratios adjusted by sex, age ≥75 years, comorbidities, and prescriptions. Figure has been modified from Ogawa et al.8 AF, atrial fibrillation; CI, confidence interval; HF, heart failure; PAF, paroxysmal atrial fibrillation; SAF, sustained (persistent/permanent) atrial fibrillation; SE, systemic embolism.
In comparison with a rate-control strategy, patients treated with a rhythm-control strategy are less likely to show progression to a sustained form. For example, in the RECORD AF registry, patients who received Class Ic antiarrhythmic drugs (AAD) had less AF progression than those who received other pharmacological therapies.35,36 In contract, the Euro Heart Survey showed that taking AAD was not significantly associated with a reduction in AF progression.5 In PAF patients, catheter ablation offers better restoration and maintenance of sinus rhythm, compared with AAD.37 Jongnarangsin et al also demonstrated that catheter ablation appeared to reduce the rate of AF progression, as compared with a historical control group of pharmacologically treated PAF patients.38 A systematic review including observational studies reported on AF progression specifically after catheter ablation, and concluded that AF ablation is associated with significantly reduced progression to persistent forms compared with the general population.39 A recent randomized controlled trial (the ATTEST trial) revealed that catheter ablation was superior to AAD therapy in delaying the progression of AF.40 These studies suggest that catheter ablation may be a more effective treatment option for delaying AF progression comparing with AAD therapy, thereby potentially offering the clinical advantage of a reduction in subsequent adverse outcomes.
The AF progression rate and associated risk factors differ among previous studies, and thus have not been well-established. AF progression is associated with increased risk of clinical adverse events and outcomes. Catheter ablation may reduce progression of AF during the period of PAF, and the incidence of adverse outcomes associated with AF progression. Efforts to identify and risk stratify patients at risk of AF progression, as well as optimize the management of such patients, are needed.
Dr. Ogawa has no disclosures to make. Dr. Akao received lecture fees from Pfizer, Bristol-Myers Squibb, Boehringer Ingelheim, Bayer Healthcare and Daiichi Sankyo.
