Evolution of Paroxysmal Atrial Fibrillation to Persistent or Permanent Atrial Fibrillation: Predictors of Progression
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Credits:Jayasree Pillarisetti, Akshar Patel, Kenneth Boc, Sudharani Bommana, Youssef Sawers, Subbareddy Vanga, Hari Sayana, Warren Chen, Jayanth Nath, James Vacek, Dhanunjaya Lakkireddy
University of Kansas Hospitals, Kansas City, KS
Corresponding Author : Dhanunjaya Lakkireddy MD, FACC, Director – Center for Excellence in Atrial Fibrillation & EP Research, Bloch Heart Rhythm Center, Mid America Cardiology @ University of Kansas Hospitals, 3901, Rainbow Blvd, Kansas City, KS 66196.
Key Words: Atrial Fibrillation, progression, paroxysmal & permanent
Introduction – Paroxysmal
atrial fibrillation (PAF) eventually progresses to persistent and permanent AF.
The predictors of progression from PAF to persistent and permanent AF are
poorly understood.
Methods – Electronic medical
records of 437 patients with PAF were reviewed in a retrospective cohort study.
Patients were followed in time and progression to persistent/permanent AF was
recorded. Demographic, clinical and echocardiographic information was
collected. A logistic regression analysis was performed to identify predictors
of progression to persistent/permanent AF.
Results – Over a mean
duration of 57.3±55.9 months, 32.4% of patients progressed to
persistent/permanent AF. Mean age of the population was 67.9±13.4 years with
57% males and 92% Caucasian. Univariate analysis identified higher body higher
mass index (BMI), cardiomyopathy, diabetes, valvular heart disease (VHD), larger left
atrial size (LA) and higher pulmonary artery pressure as predictors of
progression. Multivariate logistic regression analysis larger left atrial size
(OR 1.46, CI 1.05-2.04, P 0.002), cardiomyopathy (OR 2, CI 1.1- 3.3, P 0.003), and
moderate to severe valvular heart disease (OR 3.3, CI 1.4-5, P 0.008) as
significant predictors of progression to persistent/permanent AF.
Conclusion – Our study shows
that PAF patients with larger LA, valvular heart disease and cardiomyopathy
predict progression of PAF to persistent/permanent AF. Higher BMI and
cardiomyopathy predicted progression to persistent AF while larger LA size and
VHD predicted progression to permanent AF.
Atrial fibrillation (AF) is the
most common arrhythmia in the world and is associated with significant
morbidity and mortality. AF increases the risk for stroke, heart failure and
mortality [1
- 3].
Incidence and prevalence of AF increases with age and the risk doubles with
each advancing decade [4
- 6].
While there are 2.3 million people with AF currently, it is estimated that the
prevalence of AF increases to 6 million by year 2050 in the United States alone [7].
AF frequently starts as paroxysmal
atrial fibrillation (PAF) and gradually progresses to permanent atrial
fibrillation in about 77% of patients over a time period of 14 years despite
anti-arrhythmic therapy as shown in a study by Kato et al [8].
Epidemiological studies and animal models suggest that AF begets AF
since the fibrillating myocardium causes electrical remodelling that further
perpetuates AF [9, 10]. Diabetes,
hypertension, heart failure, obesity, obstructive sleep apnea, myocardial
infarction and valvular diseases are some of the known risk factors for AF [4, 11
- 15].
However, the factors that cause progression of AF from paroxysmal to persistent
and permanent AF are poorly understood.
The NHLBI workshop
recently indicated that secondary prevention of AF is the most feasible
strategy to prevent AF [16].
For this however, it is necessary to understand the factors that cause
recurrent AF as well as its progression. Identifying the factors that cause
progression of AF would identify targets for secondary prevention. While some
older studies have identified factors of progression from PAF to chronic AF
there are very few studies which specifically looked at predictors of
progression to persistent and permanent AF separately.
In this study we attempted to
identify those clinical, echocardiographic and treatment variables that might
influence the progression of AF from a paroxysmal type to a persistent and
permanent form.
A retrospective study was conducted
at a large academic center (University of Kansas Hospitals, Kansas City, KS)
and electronic medical records were reviewed. All patients with PAF diagnosed
at any time point between 1999 and 2007 and followed in the cardiology clinics
were included. Patients whose initial diagnosis was persistent or permanent AF
were excluded.
Patients with PAF were followed
over time until April 2009 and records at every clinical encounter were
reviewed for progression to persistent or permanent AF. Paroxysmal, persistent
and permanent AF was defined according to the ACC/AHA guidelines [17].
Spontaneous conversion of AF to sinus rhythm or termination within 24 hours of
onset was considered paroxysmal. If cardioversion was required or if AF
persisted beyond 7 days, it was classified as persistent. AF refractory
to cardioversion and long lasting AF was classified as permanent AF.
Patients who presented to the ER within 7 days of onset of symptoms and were
cardioverted were classified as persistent and were excluded from the study if
this was the first episode. Patients presenting to the ER with a new episode of
AF with remote history of cardioversion were also excluded. Patients whose
history could not be confirmed were excluded.
Electronic medical records of patients with PAF thus obtained were reviewed for clinical and demographic information. They were divided into two groups. Group 1 included patients who progressed to persistent or permanent AF. Group 2 included patients who continued to remain in PAF till April 2009. Differences in baseline demographic and clinical characteristics between the two groups were identified. BMI, LA size, left ventricular size, pulmonary artery (PA) pressure, ejection fraction and serum creatinine were analyzed as continuous variables while the remainder of the variables were analyzed as categorical variables. Diastolic dysfunction and valvular heart disease (VHD) were analyzed as binary variables and were considered as present when echocardiographic findings reported moderate to severe dysfunction (Grade 2 and grade 3 of diastolic dysfunction and moderate to severe mitral and aortic valve disease). Cardiomyopathy was defined as present if any patient had a documented diagnosis of ischemic, non-ischemic or hypertrophic obstructive cardiomyopathy in the medical record. Medication use was considered at baseline when patients had PAF and had not yet progressed. Mortality data was obtained from social security death index.
Categorical data is expressed as percentages and continuous data as means and
standard deviation. Chi-square analysis and t-tests were performed for
categorical and continuous data respectively. Univariate logistic regression
analysis was performed to identify univariate predictors of progression to
persistent and permanent AF. Multivariate logistic regression was then
performed from univariate predictors. A p value of 0.15 from univariate
analysis was considered significant to enter into the regression model. A sub
analysis was then performed to identify the univariate and multivariate
predictors of progression to persistent AF and permanent AF separately. P value
of 0.05 was considered significant. SAS 9.1.3 version (SAS Institute Inc, Cary , NC ) was used for the analyses.
A total of 437 patients were identified to have PAF. Among these patents 32.4% (n=142) progressed to persistent or permanent AF over a mean duration of 57.5±55.3 months (group 1). The remaining 67.5% (n=295) of patients continued to be in PAF (group-2) followed over a mean of 90.7±60.5 months. Mean age of the population was 67.9±13.4 years with 57% males and 92% Caucasian origin. Mean EF was 52±16%. Mean LA size was 4.2±0.7cm. See table 1 for baseline characteristics in the two groups. Mean duration of follow-up in group 2 patients with PAF was 7.5 years (median 82 months, range 7- 425 months). Minimum, maximum and median follow-up duration in the group 1 was 1 month, 215 months and 38.2 months respectively.. Univariate analysis identified higher body mass index (BMI), diabetes, cardiomyopathy, valvular heart disease, larger LA size and higher PA pressure as predictors of progression (See table 2). Multivariate logistic regression analysis revealed larger left atrial size (OR 1.46, CI 1.05-2.04, P 0.02), cardiomyopathy (OR 2, CI 1.2- 3.3, P 0.009), and moderate to severe VHD (OR 3.3, CI 1.6-5, P 0.0014) as significant predictors of progression to persistent/permanent AF. There was no difference in mortality in both groups 1 and 2 (10.4% vs. 10.5%, p 0.99). Similarly there was no significant difference in the incidence of stroke between group 1 (0.25%) and group 2 (0.01%).
Table 1: Comparison of AF patients who progressed to persistent/permanent AF vs those who did not progress.
|
Table 2: Predictors of AF progression from paroxysmal to persistent or permanent form by Univariate Analysis.
|
Among the 142 patients who progressed to persistent/permanent AF, 111 patients (78%) progressed to persistent AF and 44 patients (31%) progressed to permanent AF. Of the 44 permanent AF patients, 11 patients initially turned persistent who then converted to permanent AF while the rest of 33 patients directly progressed from PAF to permanent AF (Figure 1). On sub-analysis, univariate predictors for
progression to persistent AF were higher BMI, larger LA size, VHD and
cardiomyopathy. Predictors of progression from PAF to persistent AF on
multivariate analysis were higher BMI (OR 1.05, CI 1.01-1.09, P 0.01) and
cardiomyopathy (OR 2.5, CI 1.25-5, P 0.008).
Figure 1: Shows the progression of AF from paroxysmal to persistent and permanent forms
|
Predictors for progression
from paroxysmal to permanent AF alone were also studied which showed larger LA
size, higher PA pressure, VHD and cardiomyopathy as univariate predictors and
larger LA size (OR 2.4, CI 1.3-4.2, P 0.002) and VHD (OR 3.1, CI 1.3-7.6, P
0.008) as multivariate predictors. Mean LA size in patients with PAF was
4.1±0.7 cm while the mean LA size in patients who progressed to permanent AF
was 4.7±0.7cm. The 11 patients who progressed from persistent to permanent AF
were not included in this analysis and their number was too small to define
this group of patients.
Our results indicate that larger LA
size, moderate to severe VHD and cardiomyopathy predict progression of PAF to
persistent or permanent AF. Higher BMI and cardiomyopathy predicted progression
to persistent AF while larger LA size and VHD predicted progression to
permanent AF.
While prior studies have
looked at the progression of PAF to chronic AF [8,
18] our study
evaluated the predictors of progression to persistent and permanent AF
separately. Also,previous studies did not include many potentially predictive
echocardiographic and treatment variables although they were observational
studies [19,
20]. In our study we
have included a comprehensive list of echocardiographic and treatment variables
to study their effect on AF progression.
Thirty two percent of
patients with PAF progressed to persistent/permanent AF in our study which is
slightly higher than the 20% progression rate noted in an European survey [21].
Our study results are similar to a Canadian cohort study where age, presence of
cardiomyopathy, largerLA size and valvular disease were identified as
significant predictors [18].
Our study is further distinguished by the inclusion of all echocardiographic
and treatment factors in the statistical model.
Although age is a known
risk factor for AF, our study did not identify age as a predictor of
progression to permanent AF. The average age of patients in our study was 68
years. Risk factors that predict progression can generally be classified in to
modifiable risk factors and non- modifiable risk factors. While age is an
unmodifiable risk factor, the other factors (LA size, cardiomyopathy and VHD)
identified in our study could be modified to some extent by early intervention.
Identification of modifiable risk factors is important to design interventions
that prevent progression of AF by targeting these risk factors. Cardiomyopathy
and valvular heart diseases cause increased left atrial pressure and wall
stretch. Larger left atrium in turn perpetuates of AF.
This is supported by recent studies which suggest that structural changes of the heart result in substrate changes that support reentrant tachycardias [22]. In fact, even in lone AF patients, one recent study demonstrated abnormalities in the atria. The study showed electrophysiologic and electro anatomic abnormalities like atrial dilatation, lower mean atrial voltage, prolonged conduction times, slower conduction velocities, impaired sinus node function and increased effective refractory period disputing the role of electrical remodeling as the cause of perpetuation of AF and argue that these changes termed as the “second factor” contribute to perpetuation of AF more than the electrical remodeling in itself [23]. Hence it is all the more important to prevent and treat the underlying structural changes in the heart like the larger LA size, cardiomyopathic changes and changes brought about by VHD. Interventions such as optimal treatment of cardiomyopathy, attempts at reduction of diastolic pressure to reduce LA size and early surgical treatment of valvular diseases may prevent the progression to persistent/permanent AF. In addition to these secondary prevention strategies, primary prevention strategies can also be employed before onset of AF.
On subanalysis, BMI and
cardiomyopathy were found to be a predictor for progression to persistent AF in
our study. BMI has also previously been shown to be a risk factor for
progression in a recent study [24].
Several reasons were cited for this including neurohormonal activation,
obstructive sleep apnea, arterial thickness and increased inflammation related
to obesity [25
- 27].
Thus attempts at reducing the BMI are also helpful in preventing progression of
this disease and larger randomized therapeutic trials directed at this issue
are needed. LA size and VHD have been identified as a predictors of
progression to permanent AF by multiple studies including ours [8,
18]. These factors
probably induce underlying substrate changes that promote progression of AF to
a more permanent form without going through the persistent stage. It is
important to understand that left atrial enlargement is a primary manifestation
of uncontrolled HTN, diastolic dysfunction, VHD and cardiomyopathy. Attempts
could be made to prevent left atrial enlargement by early and effective
treatment of the above mentioned risk factors. Early ablation of PAF may also
prevent LA enlargement and thus prevent the progression to permanent AF. A
recent study by Pappone et al. showed the
effectiveness of catheter ablation in preventing the progression of PAF [28].
Age related progressive left atrial enlargement may not be modifiable; however
all the above mentioned factors become increasingly apparent in older patients.
Early surgical treatment of mitral and aortic valvular diseases would also help
prevention of AF progression.
We hoped to see a
positive impact from the use of statins and ACE inhibitors, which have been
shown to prevent occurrence of AF possibly by modifying the atrial substrate [29
- 31].
Hirayama et al have shown that ACE inhibitors are effective in preventing AF
progression [32].
In our study that mostly consisted of a Caucasian American population, ACE
inhibitors/ARBs failed to show this effect. Our study also failed to show any
effect of statins or AAT agents on progression of the disease. Similarly
nicotine use which has been shown to induce atrial fibrosis failed to show any
affect on the progression of AF in our study [33].
This is possibly related to the relatively smaller number of patients studied.
Further studies need to be done prospectively on large patient numbers to study
the mechanics of progression of the disease. Specifically a large prospective
study evaluating the impact of statins, angiotensin converting enzyme inhibitors
(ACEI), angiotensin receptor blockers (ARBs), beta blockers (BB) and
anti-arrhythmic agents (AAT) on progression of AF is very essential. Our study
also highlights a group of people who converted to permanent AF from PAF
without going through the persistent stage. Mechanisms that underlie this
phenomenon should also be studied.
This is a
retrospective study. Clinical information is based on electronic medical review
and was thus dependent on documentation. However, the long duration of
follow-up provided strength to the study.
Moderate to severe valvular heart disease, larger left atrial size and cardiomyopathy predict progression of PAF to persistent/permanent AF. While higher BMI and cardiomyopathy predict progression to persistent AF, larger LA size and significant VHD predict progression to permanent AF directly. Prospective randomized studies that evaluate modifiable risk factors are needed and studies should be geared towards understanding the mechanism of LA enlargement.
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