Following the literature search 95 papers were included for this
review, including 11 review articles. In Figure 1 a flow diagram of the
article selection is depicted. The content of the selected articles will
be presented following three subcategories: risk factors and triggers,
catheter ablation and surgical ablation.
Subclinical Coronary Artery Disease
Although CAD is not included within the definition of LAF,
subclinical CAD has been linked to LAF. This was found in a cardiac
computed tomography angiography based study among 115 patients
with LAF compared to a matched healthy population in sinus
rhythm.27
Subclinical CAD may also be a marker for vascular disease in
general. The incidence of vascular diseases and cardiovascular events
in LAF patients has been described in several studies. In a follow-up
study Weijs et al showed that clinical important CAD occurred twice
as often in LAF patients compared to controls. Furthermore, LAF
patients were younger at the time of onset and developed a more
severe disease profile (heart failure, cerebrovascular accidents (CVA) and/or myocardial infarction).26
Another issue is microvascular dysfunction: atrial myocardial
perfusion abnormalities and coronary flow reserve impairment have
been confirmed in patients with LAF. This, however, most possibly
is a complication of the rhythm disorder itself, since it is partially
reversible after cardioversion.32,33
It has been demonstrated that patients with LAF and left
atrial enlargement (LAE) have an increased risk for developing
cardiovascular disease, including stroke, myocardial infarction and
heart failure.34
Guidelines suggest a maximum LA volume index of ≥ 40ml/m2
(≈50mm) in the definition of LAF.3 Though Osranek et al concluded
from a multivariable analysis (n = 46) that LAF patients with a LA
volume of already >32ml/m2 (≈41mm) had worse event-free survival.
In a larger population of over 100 LAF patients, Weijs et al did not
find any patient with a maximal diameter of >50mm and therefore
concluded that if the diameter is >50mm, additional investigation for
underlying diseases should be performed.35
However, whether LAE is the cause or the consequence of LAF
remains uncertain. Reant et al demonstrated reverse remodeling
of the LA and improvement of left ventricular (LV) diastolic and
systolic functions after restoration of sinus rhythm in patients with
LAF.36 Suarez et al depicted that in LAF patients LA size increased
with an average of 5.6mm compared to baseline measurements. This
was more profound in patients with persistent LAF, hence they
concluded that LAF may cause LAE.37
A larger LA volume is an independent predictor of LAF
recurrences. This was found in a cohort study of almost 100 patients:
recurrence rates of 90% in patients with dilated atria and only 30% in
non-dilated atria.38 The definition of ‘dilated’ is not stated.
In 12-lead surface electrocardiogram studies among paroxysmal
LAF patients compared to healthy subjects, longer maximum P-wave
durations and more important, differences between maximum and
minimum P-wave duration were noted. Among others changes in
atrial size could cause these observations. However, in one study with
P-wave changes, the dimensions of the LA among LAF patients and
healthy controls were identical.39,40 Hence, changes in the P-wave
also could be a cause of LAF. In a study by Jurrko et al the duration
of the P-wave was only marginally prolonged and no difference in
amplitude was observed.41
Left Ventricular Diastolic Dysfunction
Diastolic dysfunction mostly is an initial manifestation of a heart
disease, although it is not used as an exclusion criterion for the
diagnosis of LAF. Jaïs et al thoroughly investigated a cohort of 28 LAF patients; transthoracic and transesophageal echocardiograms
were performed and hemodynamic evaluation of the left heart
was conducted transseptally during the ablation procedure. No
echocardiographic evidence of diastolic dysfunction could be found,
only a bigger inferosuperior LA dimension was seen (51 ± 10 versus
40 ± 6 mm). Hemodynamic evaluation showed a significantly higher
end-diastolic LV pressure and also a higher nadir of the LA Y
descent. They concluded that LV diastolic dysfunction relates to LA
dilatation and stretch, and is present in patients with LAF.42 Another
study did show echocardiographic LV diastolic dysfunction, with
normalization of diastolic function during sinus rhythm.36
Echocardiographic evaluation of LAF patients by Kosmala et al
showed that even if LV systolic and diastolic functions are normal,
LA performance may be compromised. Lower values of acceleration
time of the systolic phase of pulmonary venous flow and higher
deceleration times, which corresponds with LA relaxation and
compliance, were observed compared to controls.43
Hypertension causes hemodynamic changes of the LA, resulting
in elevated LA pressure and LAE. Furthermore, hypertension causes
activation of the renin-angiotensin-aldosterone system, inducing LA
fibrosis. These changes can predispose to non-LAF.44
In a population of 32 patients with LAF, Katritsis et al found that
almost half of them (44%) suffered from occult arterial hypertension
and, except for one, they had arrhythmia recurrences despite treatment
with ablation or AADs.45 Most probably the same hemodynamic changes as in non-LAF, account for LAF.
On the contrary, Rostagno et al reported an incidence of only 8%
of hypertension among LAF patients during a 7-year follow-up
period. However, in this study hypertension was defined as a blood
pressure >160/90 mmHg. Furthermore, LAF was diagnosed by a
mobile coronary care unit cardiologist on the basis of one clinical
examination.20
In a cohort of LAF patients who underwent catheter ablation
procedures compared with matched controls, it was found that LAF
patients had significantly elevated peripheral pulse, central pulse and
augmentation pressure. Patients with highest levels of pressures (i.e.,
increased aortic stiffness) had higher recurrence rates. The causes
of this aortic stiffness, except for hypertension, are not completely
clear.46
Chen et al observed an association between increased carotid
intima-media thickness and arterial stiffness with LAF. Arterial
stiffness was found to be higher in persistent than paroxysmal LAF
patients.47 These findings suggest that LAF, like non-LAF, may be
due to vascular disease.
Electrophysiological Abnormalities
Numerous alterations in atrial electrophysiological properties can
either precede the occurrence of LAF, or can develop as a consequence
of the arrhythmia. In this, among others, loss of myocardial voltage,
conduction slowing and abnormality, altered sinus node function and
prolonged atrial refractoriness have been demonstrated to be present
in patients with LAF.48,49
Patients with LAF have shown to have slowing of atrial conduction,
which is considered a possible substrate for enhanced inducibility
and spontaneous occurrence of the arrhythmia.50
LV endomyocardial biopsies were performed in a small cohort
of 14 LAF patients. All of the patients showed abnormalities: 3
showed cardiomyopathic changes, 3 active myocarditis and 8 either
non-specific necrosis or fibrosis, or both. The 3 patients with active
myocarditis converted to sinus rhythm after adding steroids to the
AADs. A note is that this group of patients was selected because of
severity and unresponsiveness to usual therapy.25 The results of this
study could not be confirmed by others.51
Many other studies searched for a correlation between markers of
inflammation and LAF. Especially C-reactive protein (CRP) has been
related to arrhythmia development, recurrences and persistence.52
CRP is produced in the liver as response to interleukin-6 (IL-6), and
therefore also IL-6 has been related to LAF, as well as to the prothrombotic
state. Patton et al found an underlying rheumatologic
condition in one-fourth of the women with LAF which also supports
the hypothesis of underlying inflammation.11 On the other hand,
Ellinor et al could not find significant difference in CRP levels
between subjects with LAF and controls.53 However, all studies
performed are small and give contradictory results, and whether the
inflammation parameters are due to an underlying disease, or are
elevated because the initiation of the arrhythmia is not clarified.
Out of all the biochemical markers which could be related to LAF,
the natriuretic peptides have been researched most thoroughly. Li and
Wang demonstrated increased serum B-natriuretic peptide (BNP)
Figure 1: Flowchart of systematic literature search and study selection levels in patients with paroxysmal LAF. They could not objectify differences in LA diameter and LV ejection fraction, but they did
neither assess diastolic function parameters nor LA volume.54 Lee
et al did show correlations between BNP levels and LA volumes,
pulmonary artery systolic pressure and E/E’ratios (ratio of mitral
peak velocity of early filling to early diastolic mitral annular velocity)
in LAF patients which reflects early LV dysfunction and LAE.55
Figure 1. Flowchart of systematic literature search and study selection
Apart from BNP, atrial natriuretic peptide (ANP) is also a
biomarker of cardiac contractile dysfunction. Unlike BNP, ANP
levels are found to be normal in LAF patients.56
Apelin, which is an endogenous peptide hormone with a role in
angiotensin and vasopressin systems, is reported to be significantly
lower in patients with LAF compared to healthy subjects. Apelin
levels increase early in the course of heart failure and are decreased
in chronic heart failure. This may define disturbance of the cardiac
humoral axis in patients with LAF.57
Familial Predisposition and Genetic Factors
The identification of genetic susceptibility may be of importance
to provide a basis for therapeutic options and prevention strategies.
People with relatives suffering from LAF are at higher risk for
developing the arrhythmia than the general population. Furthermore,
patients with LAF more often have a first-degree family member
with LAF or non-LAF than non-LAF patients.17,58 The strongest
risk is young age at onset, multiple affected relatives and first-degree
relatives.19
Several variants in genes have been associated with non-LAF and
LAF. For example, genetic variation in genes involved in electrical
signaling can be a substrate for electrical disturbances.16 Olesen et
al performed genomic screening of DNA among 192 patients under
40 years of age diagnosed with LAF. They found 8% of the alleles
of genes previously associated with AF to harbor a genetic variant,
which is twice the percentage compared to the control group. Of
the patients with a genetic variant, 21% had one or more affected
first-degree family members.18 These findings suggest that in LAF
patients an inherited trait may be important.
As previously mentioned, age above 60 years is an exclusion for
LAF, but this number is considered arbitrary and in many LAF studies
patients exceeding the age of 60 were included anyway. Jahangir et
al followed a cohort of 76 patients initially diagnosed with LAF and an age below 60 years at time of diagnosis. The risk for stroke
was similar in the first 25 years of follow-up but was significantly
worse at 30 years. Thromboembolic complications occurred only after
the development of risk factors, including advanced age. Older age
at time of diagnosis was the only univariate predictor of increased
mortality and in a multivariable analysis age was the only risk
factor for stroke and mortality.5 Also Kopecky et al stated that LAF
occurring in patients with an age above 60 years is a marker for a
substantial increase in cardiovascular events. In LAF patients over 60
years they found a 5% event rate per person per year, compared to 1%
in age- and gender-matched persons without LAF.59 Though, in both
articles an overall survival similar to an age- and sex-matched healthy
population was found.
Obesity is associated with a 3 to 8% increased risk for developing
non-LAF with each unit increase in body mass index (BMI). No
data on obesity are available for LAF patients, except for data on high
coffee consumption in combination with obesity: this is associated
with an increased risk of persistent LAF.9 Somewhat contradictory,
in LAF patients a tall and slender stature is found to be a risk factor
for developing the arrhythmia. Besides this, pectus excavatum is also
accompanied with a higher risk.15,60,61
Obstructive Sleep Apnea Syndrome
OSAS is associated with cardiac arrhythmias, possibly due to
hypoxemia, hypercapnia, elevated catecholamines, changes in de
automatic nervous system and blood pressure. Furthermore, an
elevated intrathoracic pressure (caused by inspiration against an
obstructed airway) can cause increased transmural pressure and atrial
stretch. However, Porthan et al could not find a higher incidence
of OSAS in LAF patients compared to gender- and age-matched
controls.12
In a retrospective cohort of a group of marathon runners compared
with inactive men, a higher incidence of LAF was found. In the group
of marathon runners an echocardiogram was performed showing a
higher LA volume, which may be the reason for the high incidence
of LAF.10 Mont et al found that patients with LAF performed more
hours of moderate and of heavy physical activity, and also had a larger
LA.15
Besides a larger LA, fluctuation of the autonomic tone could be
operative in the existence of LAF since vagal stimulation (most of
the arrhythmias develop after sport exercise) results in shortening
of the atrial effective refractory period and hyperpolarization of
atrial fibers, leading to increased conduction velocity. This same
mechanism could be the case in LAF occurring during sleep. In
the latter the parasympathetic nervous system also could play a
role. Though, a relative hypoglycemia with associated hypokalemia
and hypomagnesemia may also increase the risk of LAF in these
situations.11,60,62
Alcohol has a direct toxic effect on cardiomyocytes, causes a
hyperadrenergic state with impaired vagal tone and it may increase
the intra atrial conduction time.63 Already more than 30 years ago
the “holiday heart syndrome” was described: LAF after excessive
intake of alcohol.64 Now we also know that more than 3 drinks a
day in chronic consumption results in an increased risk.65 In a group
of 88 LAF patients below 45 years, Krishnamoorthy et al described triggering of the arrhythmia because of alcohol and/or drugs in 1 out
of 4 LAF patients. In the follow-up period 6 patients had further
paroxysms, all of whom continued to abuse either alcohol or drugs.14
Another stimulant which could induce LAF is caffeine. Mattioli et
al found that coffee consumption increases in case of acute stress and
leads to a greater risk of LAF. Patients with continued high coffee
consumption are at increased risk for developing persistent LAF.9
Last to mention is smoking. In a univariate analysis of almost 400
LAF patients, it was found that there was a significant association
with smoking.66
Myocardial muscle extensions covering the outside of the pulmonary
veins (PVs) are considered to be the major sources, with bursts of
rapid discharges, for initiating both LAF and non-LAF.67 Based on
this finding, ablation of the ostium or antrum of the PVs became the
cornerstone of endocardial catheter ablation procedures. Different
techniques can be performed to achieve PV isolation: segmental/
ostial (ablation inside or very close to each PV ostia), circumferential
(lesions 1-2cm outside each PV ostia) and circumferential/antral
(ablation lesions to the antrum of the PVs). Next to PV isolation,
other options are: linear lesions (LA roof line and mitral isthmus),
complex fractionated atrial electrograms (ablation of areas found
with mapping), ablation of LA autonomic ganglionated plexi located
in epicardial fat pads, nest ablation (ablation of fibrillar myocardium,
mapping guided) and complete isolation of the coronary sinus, LA
appendage, superior vena cava, vein of Marshall or thoracic veins.29,30
A study by Bourke et al, published in 2005, reported on PV
isolation in patients with LAF. They performed radiofrequency
ablation inside the PVs and close to the ostium. Initially only PVs
with arrhythmogenic behavior (spontaneous depolarizations) were
targeted, later in the study all four veins were isolated. In patients
resistant to cardioversion despite PV isolation, a mitral isthmus line
and roof line were created. After six months 55% of 100 patients
were in stable sinus rhythm, only 17% was also off AADs.68 Ablation
inside or close to the ostium of the PV has been abandoned in order to
prevent PV stenosis. Teh et al performed PV isolation in 11 patients.
In the persistent LAF group also additional linear ablation along
the LA roof was conducted. Over a mean follow-up period of 10
months no recurrences were observed. They could not find evidence
for reverse remodeling of the atrial substrate and even found evidence
of further progression.69
Antral ablation was performed by Fredersdorf et al: 45 out of 60
AF and non-LAF patients were freed of the arrhythmia after a mean
follow-up of 19 months. It is unclear if the patients were also off
AADs. Of these 45 patients, 50% were LAF patients. A significant
reduction of LA volume was present in the LAF group, which was
absent in non-LAF patients. This LA volume reduction, however,
was not accompanied by a better clinical outcome defined as freedom
of the arrhythmia.70
The Venice Chart consensus committee advises to consider firstline
ablation in very symptomatic patients with paroxysmal LAF
(or only minimal disease), to limit arrhythmia progression to more
persistent forms. In all other patients, catheter ablation is only
advised in second line. Isolation of the PVs is found to be sufficient
in all forms, except for persistent LAF, where linear lesions or other
options should be considered.3,30,71
The first successful surgical treatment of non-LAF was performed by Dr. Cox in 1987.72 The Cox-Maze procedure is progressively
modified over time. The most recent method is the Cox-Maze IV,
where the linear lesions are performed with bipolar radiofrequency
ablation instead of to ‘cut and sew’ (Cox-Maze III). The necessary
lesions comprise PV isolation, a right atrial (RA) set (e.g. ablation
lines up to superior vena cava and down to inferior vena cava across
the RA free wall toward the atrioventricular groove) and a LA set
(e.g. closure of LA appendage and ablation line across the floor of the
left atrium towards the orifice of left inferior PV). This operation can
be done either through a median sternotomy or a minimal-invasive
thoracotomy, both requiring cardiopulmonary bypass.73
Several other surgical ablation techniques are presently performed:
PV isolation alone, PV isolation with a LA lesion set (with or without
ganglionic plexus evaluation and destruction) and a hybrid approach
(combined epicardial and endocardial ablation). These procedures
can be performed through thoracoscopy and without necessity for
cardiopulmonary bypass.
The Venice Chart consensus committee advises to perform surgery
after failure of one or more catheter ablation procedures. Hence, for
very symptomatic paroxysmal LAF patients this will be the second
line option, for mostly all other patients surgical ablation will be
performed as third line therapy. Surgery as first line therapy can be
considered in:
symptomatic patients undergoing other surgical procedures,
asymptomatic patients undergoing other surgical procedures
with only a minimal extra risk for adding ablation,
patients with contraindications to anticoagulation
patients who suffered from CVA despite adequate
anticoagulation and
patients with a clot in the LA appendage.
The advised lesion set depends on whether the arrhythmia is
paroxysmal, persistent or long-standing persistent.30 In the latter
mentioned group no LAF patients will be included since patients
who, for example, need to undergo surgery or have contraindications
for catheter ablation, mostly will be non-LAF patients.
Although surgical ablation is generally performed in a later stage
than catheter ablation, surprisingly, literature on surgical approach in
patients with LAF seems to be more extensive compared to catheter
ablation, including some review articles.74,75
The original cut-and-sew Cox-Maze III has been compared to
the ablation-assisted procedure Cox-Maze IV. The ablation-assisted
intervention required less time. Furthermore the outcome showed
90% of the patients in sinus rhythm and 84% off AADs at 24
months, compared to respectively 93% and 82% at a mean of 3.6
years of follow-up for the cut-and-sew method.76,77 In other studies
the success-rate (sinus rhythm achieved) of the Cox-Maze III was
79%78 and of the Cox-Maze IV procedure 77% to 87%.79,80
Cui et al performed PV isolation and ligation of the LA appendage
in 81 LAF patients. At 12 months 80% of paroxysmal LAF patients
were in sinus rhythm, 75% of the persistent group and 67% of longstanding
persistent group. No clear information is given about AAD
use.81 Ma et al found a success rate of 89% after 12 months in 45
patients. Besides PVI in the paroxysmal patients, they added LA
appendage ligation and ganglionic plexus ablation in the persistent
and long-persistent group which resulted in a success rate of 85% at
one year of follow-up. Both mentioned groups were also off AADs.82
In other studies, performing PV isolation plus LA appendage ligation
and/or ganglionated plexi ablation, success rates varied between 72% and 87%.83-88
Lastly, the hybrid procedures should be mentioned. Comparing
the results of hybrid versus thoracoscopic procedures after one year,
the results are in favor of the hybrid approach with 91% of the
patients in sinus rhythm versus 82%. When excluding the longstanding
persistent patients, the results are even more in favor of the
hybrid approach with 82% versus 44%.89,90 The same research group
compared results of hybrid monopolar vs. hybrid bipolar procedures,
with unsatisfactory results in the monopolar group but much better
outcomes in the bipolar group, especially in the persistent and longpersistent
LAF patients.91,92
