Lone atrial fibrillation - an overview.

REVIEW ARTICLE

Lone atrial fibrillation – an overview T. S. Potpara,1,2 G. Y. H. Lip3 Linked Comment: Lip. Int J Clin Pract 2014; 68: 408–9.

1

Cardiology Clinic, Clinical Centre of Serbia, Belgrade, Serbia 2 Faculty of Medicine, University of Belgrade, Belgrade, Serbia 3 Centre for Cardiovascular Sciences, City Hospital, University of Birmingham, Birmingham, UK Correspondence to: Dr Tatjana S. Potpara, Cardiology Clinic, Clinical Centre of Serbia, Visegradska 26, 11000 Belgrade, Serbia Tel./Fax: +381 11 3616319 Email: [email protected]

Disclosure None.

SUMMARY

Introduction Since its first description in humans at the beginning of the 20th century (1), atrial fibrillation (AF) has come a long way from a misperception of a relatively harmless substitute for normal sinus rhythm to understand that the arrhythmia is associated with significant cardiovascular morbidity and mortality (2–4), mostly because of ischemic stroke (which is often deleterious in the setting of AF) and heart failure (HF) (5–8). In addition, AF may reduce exercise tolerance or impair the quality of life (8–10). At least 2% of general population is currently affected by AF (11,12), and the number is expected to rise in the next several decades (13), presumably because of the increasing number of individuals with ‘novel’ risk factors for AF (e.g., obesity), improved survival of patients with structural heart diseases, aging of the general population and increased awareness of AF among physicians and patients (14,15). A number of underlying cardiac and non-cardiac disorders may predispose to AF (Table 1) (16–42). Nonetheless, AF sometimes develops in younger individuals without any evident cardiac or other dis-

418

Review criteria

Atrial fibrillation (AF) sometimes develops in younger individuals without any evident cardiac or other disease. To refer to these patients who were considered to have a very favourable prognosis compared with other AF patients, the term ‘lone’ AF was introduced in 1953. However, there are numerous uncertainties associated with ‘lone’ AF, including inconsistent entity definitions, considerable variations in the reported prevalence and outcomes, etc. Indeed, increasing evidence suggests a number of often subtle cardiac alterations associated with apparently ‘lone’ AF, which may have relevant prognostic implications. Hence, ‘lone’ AF patients comprise a rather heterogeneous cohort, and may have largely variable risk profiles based on the presence (or absence) of overlooked subclinical cardiovascular risk factors or genetically determined subtle alterations at the cellular or molecular level. Whether the implementation of various cardiac imaging techniques, biomarkers and genetic information could improve the prediction of risk for incident AF and risk assessment of ‘lone’ AF patients, and influence the treatment decisions needs further research. In this review, we summarise the current knowledge on ‘lone’ AF, highlight the existing inconsistencies in the field and discuss the prognostic and treatment implications of recent insights in ‘lone’ AF pathophysiology.

We searched MEDLINE and Google Scholar using the terms ‘lone atrial fibrillation’, ‘lone atrial fibrillation epidemiology’, ‘natural history of lone atrial fibrillation’, ‘lone atrial fibrillation risk assessment’ and ‘lone atrial fibrillation what do we know’ and manually reviewed the references in English language. Abstracts from international cardiovascular meetings were studied to identify unpublished data.

Message for the clinic ‘Lone’ AF patients (i.e., those younger than 60 years without any comorbid disease, including hypertension) may have largely different risk profiles because of the presence of overlooked subclinical cardiovascular risk factors or genetically determined subtle alterations at the cellular or molecular level. Hence, a careful clinical work-up at presentation and regular follow-up with clinical risk factors re-assessment is mandatory for patients diagnosed with ‘lone’ AF.

ease. To refer to these patients who were considered to have a very favourable prognosis compared with other AF patients, the term ‘lone’ AF was introduced (2). However, there are numerous uncertainties associated with ‘lone’ AF, including inconsistent entity definitions, considerable variations in the reported prevalence and outcomes, etc. (43,44). Indeed, increasing evidence suggests a number of often subtle cardiac alterations associated with apparently ‘lone’ AF, which may have relevant prognostic implications (43). In this review, we summarise the current knowledge on ‘lone’ AF, highlight the existing inconsistencies in the field and discuss the prognostic and treatment implications of recent insights in ‘lone’ AF pathophysiology.

The original descriptions of ‘lone’ AF The term lone auricular fibrillation was proposed in 1953, based on the cohort of 20 AF patients without underlying heart disease and six earlier reports, published between 1930 and 1949 (2). The observations were confined to the ‘established’ (i.e. non-paroxysª 2013 John Wiley & Sons Ltd Int J Clin Pract, April 2014, 68, 4, 418–433. doi: 10.1111/ijcp.12281

ª 2013 John Wiley & Sons Ltd Int J Clin Pract, April 2014, 68, 4, 418–433

HR 1.36 (1.03–1.80) HR 3.20 (1.99–5.16)(17) ‘Diastolic’ HF (i.e. HF-PEF) is also a risk factor for AF (19,20) AMI: RR 3.62 (2.59–5.07) Angina pectoris: RR 2.84 (1.91–4.21) ST-T wave abnormalities: RR 2.21 (1.62–3.00)

Essentially, rheumatic mitral stenosis: OR 1.8 (1.2–2.5), males OR 3.4 (2.5–4.5), females

20–25% of patients with HCM develop AF; primary electrical cardiac diseases, ‘channelopathies’, also carry a risk for AF Pericardial disease, congenital defects, conduction disturbances including prolonged PR interval, cor pulmonale, AVNRT, WPW

LVH (17) Heart failure (8,12,17,19,20)

Valve disease (16)

Cardiomyopathies (22)

A general cardiovascular risk factor associated with CAD, HF, hypertension, cardiac arrhythmias and stroke Adjusted AF incidence rate ratio 1.41 (1.31–1.51)

Obstructive sleep apnoea (12,27–29)

Rheumatoid arthritis (30)

RR 1.49 (1.36–1.64); the risk increases in parallel with BMI HR 1.88 (1.40–2.52)

CKD stage 1–2: OR 2.67 (2.04–3.48) CKD stage 3: OR 1.68 (1.26–2.24) CKD stage 4–5: OR 3.52 (1.73–7.15)

CKD (12,22,24)

Obesity (12,22,25) Metabolic (26) syndrome

TSH level: HR 1.94 (1.13–3.34) OR 2.1 (1.5–2.8) females OR 1.7 (1.2–2.3) males

Present in 10–15% AF patients; a general marker of cardiovascular risk

COPD (12,22)

Hyperthyreosis (12,22,23) Diabetes mellitus (12,16)

Comment/risk ofAF

Other diseases/conditions

Tall and lean stature (42)

Cardiothoracic surgery (12,39,40) Non-cardiothoracic surgery (12,40) Acute inflammatory disorders (41)

Cigarette smoking (34,35) Alcohol (36,37) Endurance sports (38)

Male gender (16,22) Caucasian (31–33)

Aging (12,16,22)

Demographical features, lifestyle, procedures

Height: OR 1.026/cm (1.022–1.023) Body surface area: OR 4.2/m2 (3.4–5.3)

AF is common among critically ill patients with sepsis

The most consistent single independent risk factor for AF; with each decade of life, the risk of AF increases by 2.1-fold (1.8–2.5) in males and 2.2-fold (1.9–2.6) in females OR 1.5 (1.3–1.8) Blacks have a higher burden of conventional AF risk factors, but lower risk of AF compared to whites Current smokers: RR 1.51 (1.07–2.12) Former smokers: RR 1.49 (1.14–1.97) HR 1.14 (1.04–1.26) – patients with pre-existent cardiovascular disease OR 5.29 (3.57–7.85) – males 16–46% of patients 0.4–12% of patients

Comment/risk of AF

SBP, systolic blood pressure; OR, odds ratio (95% confidence interval); HR, hazard ratio (95% confidence interval); LVH, left ventricular hypertrophy; HF, heart failure; HF-PEF, heart failure with preserved left ventricular ejection fraction; CAD, coronary artery disease, including myocardial infarction; AMI, acute myocardial infarction; RR, relative risk (95% confidence interval); AVNRT, atrioventricular nodal re-entrant tachycardia; WPW, Wolff–Parkinson–White syndrome; HCM, hypertrophic cardiomyopathy; COPD, chronic obstructive pulmonary disease; CKD, chronic kidney disease; BMI, body mass index. *Even SBP levels within the nonhypertensive range (defined as SBP ≤ 140 mmHg) were associated with incident AF in the Women’s Health Study (18).

Other cardiac diseases (12,22)

CAD (12,16,17,21)

A pooled risk estimate for AF with hypertension: OR 1.73 (1.31–2.28) (12) Hypertension treatment: HR 1.80 (1.48–2.18) (17) SBP*: HR 1.21 (1.11–1.33)(17)

Comment/risk of AF

Hypertension, hypertension treatment, SBP* (12,16–18)

Cardiovascular diseases/conditions

Table 1 Clinical and demographical conditions associated with atrial fibrillation (8,16–42)

Lone atrial fibrillation 419

420

Lone atrial fibrillation

mal) form of AF, as paroxysmal AF was believed to be a separate entity, possibly of different aetiology. The original ‘lone’ AF cohort was carefully characterised, and the diagnostic work-up was the state of the art at that time (a detailed history, careful clinical examination, blood pressure measurement, electrocardiogram, phonocardiogram, cardioscopy with barium swallow and chest radiography were undertaken to exclude cardiomegaly, pulmonary congestion, left atrial dilatation, mitral stenosis, cardiac infarction, constrictive pericarditis and hypertension). A radioactive iodine test was used to exclude thyroid toxaemia. All 20 patients were men aged 38–72 years (mean 56 years), which had led to the conclusion that ‘lone’ AF was particularly prevalent among men and not exclusively confined to elderly people. Resting ventricular rate without medication was ≤ 90 bpm and many patients were asymptomatic (AF was often discovered accidentally, at medical examination for other reasons). A 10-year follow-up was available in four patients, and two were followed up for 20 years. During that time, no cardiac enlargement or pulmonary congestion was observed at cardioscopy and there were no clinical signs of HF or thromboembolism, indicating that long-term prognosis and life expectancy were not affected by ‘lone’ AF. Given the low risk of thromboembolism and other AF-related complications, reassurance and rate control by digitalisation (if needed) were the only recommended therapies for ‘lone’ AF.

Contemporary definitions of ‘lone’ AF Sixty years following the first description, current guidelines define ‘lone’ AF as any AF in patients ≤ 60-year old without clinical or echocardiographic evidence of any cardiopulmonary disease including hypertension (45,46) or AF in younger patients without any identifiable comorbidities (47). ‘Lone’ AF should be distinguished from idiopathic AF, the term which is often used to describe AF of unidentifiable cause in patients older than 60 years (46,48). Such a distinction is clinically justified, as the lifetime incidence of stroke rises sharply starting from age of 55 (for a decade, the risk increases from 5.9% to 11.0% in men and from 3.0% to 7.2% in women AF patients), reaching the threshold for oral anticoagulation therapy at age of 65 or above even in the absence of other stroke risk factors (5,22,49). Indeed, an observational study of 55 AF patients who would have been diagnosed with ‘lone’ AF if they had not been older than 60 years at the time of diagnosis (their mean age was 74 years) found that survival of these patients was similar to age- and sex-

matched controls during the median 9.6-year followup, but the cardiovascular event rate [a composite of stroke, transient ischemic attack (TIA) or myocardial infarction] was significantly higher, and the survival rates free of stroke or TIA were significantly lower in the AF group (5.0% vs. 1.3% per person-year and 80% vs. 98%, respectively, both p < 0.01) (50).

Prevalence, clinical course and longterm outcomes of ‘lone’ AF Similar to AF with an underlying disease, ‘lone’ AF is more frequent in males (male-to-female ratio of 3– 4:1) (51–53,56,60,61). Male preponderance is more striking in sporadic ‘lone’ AF compared with familial AF, possibly because of a concealed X-linked recessive AF in males with negative family history and apparently sporadic AF, whose mothers and sisters might be the healthy carriers (62). However, familial and sporadic ‘lone’ AF are clinically indistinguishable. Aging is closely related with the risk of incident AF. Overall, the prevalence of AF in individuals younger than 60 years is < 1%, whilst ~10% of those ≥ 80 have AF (13,51). However, the true prevalence of ‘lone’ AF is unknown, ranging between 1.6% and 30% of all AF cases in the published reports which used variable definitions of ‘lone’ AF with respect to the age limit, left atrial size and associated hypertension (2,52–60). In general, data on the natural history and prognosis of ‘lone’ AF are sparse. The clinical perception of ‘lone’ AF mostly stems from the results of a relatively small number of observational studies (2,52– 60,64,65) and a post hoc analysis from one randomised trial, which compared rate vs. rhythm control in patients with non-valvular AF (63) (Table 2). These studies have certain limitations, including the small cohorts wherein some patients even were not truly ‘lone’ AF because of older age (2,52,55,59,63– 65) or hypertension (52,55,57,63). The studies yielded conflicting results, but most of them suggested that ‘lone’ AF is a benign disorder with outcomes comparable to the general adult population (Table 2). The largest of the ‘lone’ AF studies, with 346 carefully characterised newly diagnosed ‘lone’ AF patients and a 12-year follow-up (60), demonstrated that these patients do have a favourable prognosis as long as they have truly ‘lone’ arrhythmia. However, with aging and/or the occurrence of cardiovascular comorbidities in such patients, the risk of development of AF-related complications (e.g., thromboembolic events or HF) increases (60). A recent study suggested that ‘lone’ AF patients develop cardiovascular ª 2013 John Wiley & Sons Ltd Int J Clin Pract, April 2014, 68, 4, 418–433

Evans et al. (2)

Brand et al. (52)

Kopecky et al. (53)

Davidson et al. (54)

Rostagno et al. (55)

Scardi et al. (56)

1

2

3

4

5

6

Study


1999

1995

1989

1987

1985

1954

Year

No evidence of organic heart disease

No clinical evidence of any organic cardiac disease†

AF in patients free of CAD, CHF, rheumatic and hypertensive heart disease

AF in the absence of overt cardiovascular disease or precipitating illness

AF in patients free of CAD, CHF, rheumatic and hypertensive heart disease*

Non-paroxysmal AF without heart disease or thyroid toxaemia

Lone AF definition

56

0

0

43 (32 males)

97 (gender not reported)

32 (19 males)

145 (118 males)

0% All younger than 50

? (43 pts older than 70)

50

20 (all males)

106 (43 males)

Age > 60 years (%)

Number of patients

Table 2 Studies which investigated the clinical outcomes of ‘lone’ AF

Mean 10 years (1–35)

Mean 6 years (1–138 months)

Mean 4.9 years (2–16)

14.8 years per patient

30 years

10 years (4 pts), 20 years (2 pts)

Follow-up

Progression to chronic AF in 23% patients; the rate of TE was 3.1% vs. 16.3% (0.36 vs. 1.3 per 100 person-years) in patients with paroxysmal vs. chronic AF; CHF (one patient) and death (three patients) occurred only in chronic AF

No progression to permanent AF, CHF or CAD development; one patient experienced a stroke (stroke rate of 0.64 per 100 person-years) Progression to permanent AF in five patients (4.7%); five patients had stroke (stroke rate of 1% per year); mortality similar to age-matched controls

94% probability of survival at 15 years; 1.3% of patients experienced a stroke (stroke rate of 0.55 per 100 personyears), no deaths

A fivefold greater risk of stroke vs. age- and sexmatched controls; a similar CAD and CHF rates

No adverse events (i.e., HF, TE or death)

Main findings

Low rates of progression to permanent AF, stroke and mortality; the cumulative survival rate of 78% at 8 years; mortality higher in elderly, but not greater than age-matched mortality derived from life-insurance data The prognosis of ‘lone’ AF is not homogenous – it appears to be excellent in young individuals with the paroxysmal form, whilst chronic ‘lone’ AF confers an increased risk of embolic complications and increased mortality rates

A benign disorder with normal life expectancy; rate control with digitalis if needed ‘Lone’ AF patients have significantly greater stroke rates and a distinct preponderance of preexisting ECG abnormalities (e.g., interventricular block and ST-T changes) ‘Lone’ AF in patients under 60 years is associated with a very low risk of stroke, suggesting that routine anticoagulation may not be warranted Most ‘lone’ AF patients have symptomatic paroxysmal AF, normal left atrial size and a low rate of stroke

Main conclusions

Yes/No Yes, if paroxysmal No, if chronic AF

Yes

Yes

Yes

No

Yes

‘Lone’ AF is a benign condition


Jouven et al. (57)

Rienstra et al. (63)

Jahangir et al. (58)

7

8

9

Study

Table 2 Continued

2007

2004

1999

Year

AF with no concomitant heart disease or hypertension

AF without any underlying disease (i.e. CAD, valvular disease, HF, cardiomyopathy, congenital heart disease, hypertension, previous TE events, diabetes mellitus or previous thyrotoxicosis)§

No clinical evidence of any heart disease‡

Lone AF definition

? Mean age 65 10

0

76 (59 males)

0

Age > 60 years (%)

89 (75 males)


Number of patients

Mean 25 years

Mean 2.3 years

Average 23 years

Follow-up

Individuals with ‘lone’ AF had a fourfold cardiovascular death rate (32% vs. 8%), the same non-cardiovascular death rate (20% vs. 21%) and higher total death rate (52% vs. 29%) vs. controls As compared to AF patients with a concomitant cardiac disease, ‘lone’ AF patients scored higher on 7 of 8 SF-36 scales; 3 ‘lone’ AF patients died (3%) vs. 33 (8%) controls (all three ‘lone’ AF patients died from bleeding during the OAC use); TE complications occurred in 2% of ‘lone’ AF patients vs. 8% of those with a comorbidity; no CHF occurred in the ‘lone’ AF group A 30-year progression to permanent AF was 29%; the overall survival was similar to age- and sexmatched Minnesota population; the probability of survival free of CHF was 97% and 85% at 15 and 30 years, respectively, and the probability of survival free of stroke was 94% and 88% at 15 and 25 years, respectively (similar to the expected rates)

Main findings

Yes

QoL was almost comparable to healthy controls; cardiovascular morbidity and mortality uncommon (and predominantly caused by bleeding); elderly ‘lone’ AF patients have a favourable outcome and higher QoL as compared to AF patients with comorbidities The rate vs. rhythm analyses: the number of end-points was low in both strategies but twice as low in patients randomised to rhythm control Age at diagnosis was the sole multivariable risk factor for stroke, total mortality and cardiac mortality All patients who experienced stroke had developed ≥ 1 stroke risk factor Aging and/or developing other cardiovascular risk factors strongly influences ‘lone’ AF progression and complications; therefore, screening for comorbidities is essential in ‘lone’ AF

Yes, with caution if aged > 45 years at diagnosis or develop cardiovascular risk factors during follow-up

No


‘Lone’ AF is associated with an increased mortality and clearly requires clinical attention; could be the first sign of an underlying cardiovascular disorder

Main conclusions

422 Lone atrial fibrillation


Potpara et al. (59)

Potpara et al. (60)

Weijs et al. (64)

10

11

12

Study

Table 2 Continued


2012

2012

2010

Year

AF in the absence of any cardiovascular disease or comorbidities

AF in individuals ≤ 60 years old with no evidence of any cardiopulmonary or other disease including hypertension and no obvious precipitating factors for AF

AF with no evidence of any cardiopulmonary or other disease including hypertension and no obvious cause of a transient ‘acute’ AF

Lone AF definition

Age > 60 years (%)

14.7

0

48

Number of patients


346 (263 males)

119 (57 males)

1 year

Mean 12 years

Mean 11.5 years

Follow-up

12 deaths (seven noncardiac and five cardiovascular deaths); low annual rates of any TE, stroke or transitory ischemic episodes (0.44%, 0.21% and 0.18%, respectively), as well as the annual rates of allcause mortality (0.25%) and cardiovascular mortality (0.10%) Approximately a third of patients developed cardiovascular disorders during follow-up; a 10year progression to permanent AF was 26.1%; TE events occurred in 14 patients (4.0%); a 10-year survival free of TE was 97.3%, and multivariable risk factors for TE were the development of hypertension or CAD; a 10-year survival free from CHF was 95.9%, and multivariable risk factor for CHF was the progression to permanent AF; only five patients died – the 10-year survival was 99.6% No significant difference in LA size between older and younger patients; progression to permanent AF in only two patients; no cardiovascular events during 1-year follow-up

Main findings

All-cause and cardiovascular mortality of ‘lone’ or idiopathic AF patients are similar to mortality rates of the general population in Serbia Close monitoring for prevention (or early detection) of newly developed cardiovascular risk factors is necessary A generally favourable prognosis of ‘lone’ AF; the long-term outcome is strongly influenced by aging and development of underlying heart disease; a thorough screening, prevention and treatment of associated comorbidities is mandatory Progression to permanent AF despite active treatment in young, otherwise apparently healthy AF patients may serve as an additional risk stratification clinical tool to identify those with subclinical cardiac structural alterations and an increased risk for adverse cardiovascular events Idiopathic AF may present at advanced age and even then it is not associated with significant atrial enlargement, AF progression or an adverse short-term outcome

Main conclusions

Yes, even in elderly

Yes, in young and otherwise healthy individuals

Yes, with regular follow-up



Weijs et al. (65)

2013

Year

AF in the absence of any cardiovascular disease or comorbidities

Lone AF definition

? Upper age limit was at 64 years

45 (27 males)

Σ 1075¶

Age > 60 years (%)

Number of patients

Mean 5 years

Follow-up

7 Yes, 3 No, 3 Yes, with some caution(s)

CVD occurred significantly more often in idiopathic AF compared with SR controls (49% vs. 20%), most frequently hypertension and CAD; 3 AF (7%) and no SR patients died; there were two strokes (in AF patients); AF patients were significantly younger at the time of CV event (59 9 vs. 64 5 years), and LA diameter increased in 15 AF (75%) vs. eight SR patients

Main findings

Idiopathic AF patients develop CVD more often, earlier in time and at younger age compared with healthy SR controls; age, history of AF, and posterior wall width were significant predictors of CVD Detection and treatment of CVD in an early stage could improve the prognosis, and it seems prudent to regularly check idiopathic AF patients for the development of CV disease

Main conclusions

No


AF, atrial fibrillation; HF, heart failure; TE, thromboembolism; CAD, coronary artery disease; CHF, congestive heart failure; QoL, quality of life; ECG, electrocardiogram; CVD, cardiovascular disease; SR, sinus rhythm; LA, left atrium. *Many patients actually did have hypertension. †The blood pressure cut off was at 160/90 mmHg. ‡Some ‘lone’ AF patients might have had hypertension (mean systolic and diastolic blood pressures were 149 20 and 88 15 mmHg, respectively), and one patient had left ventricular hypertrophy. §Mean systolic and diastolic blood pressures were 134 15 and 83 10 mmHg, respectively. ¶Patients from (59) are also included in (58).

13

Study

Table 2 Continued

424 Lone atrial fibrillation



disease more often, at younger age and with a more severe disease profile compared with healthy controls in sinus rhythm (65). However, the study was rather small (only 41 ‘lone’ AF patients) and the findings could be just a play of chance. Another study observed that as many as 44% of patients originally thought to have ‘lone’ AF may actually have occult hypertension (66). Taken together, these data suggest that ‘lone’ AF patients should have a regular clinical follow-up dedicated to the primary and secondary prevention of cardiovascular disease and AF-related complications. Paroxysmal (i.e., self-terminating) ‘lone’ AF has been suggested to implicate a better prognosis in terms of thromboembolic events and mortality, as compared to chronic ‘lone’ arrhythmia (56). Indeed, majority of ‘lone’ AF patients present with paroxysmal arrhythmia and have a relatively low rate of progression to permanent AF over a long-term followup (58,60). In the Belgrade AF study, for example, < 10% of patients initially had a permanent arrhythmia. However, the progression from paroxysmal to chronic AF subsequently occurred in 27% of patients (at 11.9 7.5 years following the AF diagnosis) and was an independent marker for adverse cardiovascular events (60). In the original description of ‘lone’ AF, the authors had emphasised that there was no increase in the left atrial size during follow-up (at least as assessed using chest radiography). More recently, it has been shown that ‘lone’ AF patients with increased left atrial volume (>32 ml/m2), either at diagnosis or during the follow-up, subsequently experienced adverse cardiovascular events including stroke (67).

Evolving concept(s) of ‘lone’ AF Since the time ‘lone’ AF had been first described, a substantial amount of data has been accumulated indicating a considerable diversity of AF patients who could be diagnosed with ‘lone’ AF if the earlier definitions of ‘lone’ AF were used.

Is ‘lone’ AF heritable? Increasing evidence suggests that AF is heritable. Population-based studies have demonstrated familial clustering of AF, suggesting that parental AF increases the risk of AF in offspring and that a family history of AF could improve the risk prediction of new-onset AF (68,69). A nationwide, populationbased study which specifically investigated the familial aggregation of ‘lone’ AF demonstrated a 3.5-fold greater risk of ‘lone’ AF in individuals with positive family history as compared to those without such a ª 2013 John Wiley & Sons Ltd Int J Clin Pract, April 2014, 68, 4, 418–433

history. The risk of early AF occurrence dramatically increased with increasing number of relatives with ‘lone’ AF and younger age of these relatives at AF onset (>fivefold if AF occurred before the age of 40) (70). Traditional mapping techniques (e.g., linkage and candidate gene sequencing) have screened particular genes for causative mutations, based on assumptions on their potential pathophysiologic role in AF, and a number of mutations in sodium, potassium and calcium channel subunits, as well as in gap-junction and non-ion channel proteins have been reported (43,71–73). Large-scale candidate gene sequencing and genome-wide association studies documented several common gene or single nucleotide polymorphisms including those encoding the renin-angiotensin-aldosterone system (RAAS), calcium handling, neurohumoral and lipoprotein pathways, gap-junction proteins, ion-channels, interleukins, signalling molecules and mediators of other molecular pathways (43,73). However, only a few of these polymorphisms associated with AF could be replicated in other independent cohorts, perhaps because of the relatively small samples and heterogeneous nature of the candidate gene studies (74,75). Genome-wide association studies recently identified several genetic loci indicating novel pathways involved in the susceptibility to AF (76–79). For example, multiple susceptibility signals on chromosome 4q25 have been reported, and fine mapping of the 4q25 locus near PITX2 revealed a number of single nucleotide polymorphisms, which was successfully replicated in another cohort (80). The PITX2 locus is involved in development of myocardial sleeves in the pulmonary veins and in the formation of sinus node (33,81,82). The PITX2 deficit predisposes to atrial arrhythmias in the experimental model (33). In humans, higher PITX2 expression levels were found in the left atrium than in the right atrium or ventricles (83), whilst the expression levels were significantly decreased in patients with permanent AF compared to controls, which, in turn, influenced sodium channel and potassium channel expression (84). A recent meta-analysis of genome-wide associated studies identified six novel susceptibility loci or near plausible candidate genes for AF (85), thus contributing to a complex genetic background of susceptibility to AF. Overall, these findings suggest that cardiac ion-channels, transcription factors involved in cardiopulmonary development and signalling molecules could serve as common pathways involved in the development of AF even in patients without evident underlying cardiac or other disease (71). Studies on familial aggregation demonstrated a comparable risk of ‘lone’ AF in full and half-siblings

425

426


(70), which could reflect some interaction between environmental factors (e.g., cigarette smoking, increased alcohol consumption or vigorous sports activity) and a genetic predisposition to AF (34–38). Indeed, along with the ‘traditional’ AF risk factors such as aging, cardiovascular and other diseases, etc., other conditions have been also associated with AF in apparently healthy individuals (Table 1) (43,44). Furthermore, certain social characteristics including the type of personality, anger and hostility and acute life stress have been shown to increase the susceptibility to AF (86,87), and AF may be induced by many drugs including inotropic agents (dopamine), cholinergics (acetylcholine), adenosine, bronchodilatators (especially sympathicomimetic inhalants), corticosteroids, cytostatics, central nervous system drugs (anticholinergics, dopamine agonists, antidepressants, antipsychotics, anaestetics) and others (88). These precipitating factors may interact with a variable level of genetically determined susceptibility to AF, thus leading to the occurrence of AF.

Ethnicity and lone AF Evidence suggests significant ethnic differences in the susceptibility to AF, with greater risk of AF in Caucasians compared with African Americans (although the latter have a higher burden of traditional AF risk factors) (31,32). Analysis of the Cardiovascular Health Study and Atherosclerosis Risk in Communities Study cohorts demonstrated a strong independent predictivity of European ancestry for the occurrence of AF in each cohort (a combined estimated hazard ratio was 1.17, 95% CI: 1.07–1.29, p = 0.001 for each 10% increase in European ancestry) (32).

Electroanatomical insights Atrial fibrillation results from a complex interplay of triggers, modulators and substrate, with numerous alterations in the atrial electrophysiological properties and structure, which may either precede the occurrence of AF or develop as a consequence of sustained arrhythmia, or both (43,89,90). Various triggers (e.g., an acute or chronic atrial stretch, ectopic focal discharge from the pulmonary veins, etc.) can initiate AF (90–93), whilst alterations in autonomic nervous system play an important role in both the initiation and maintenance of AF (90,94–99). The persistence of AF also requires a substrate which is capable of sustaining the arrhythmia. Indeed, numerous structural and functional alterations of atrial myocardium (from the macroscopic down to the molecular level) have been identified in relation to AF (89,90). Atrial dilatation and fibrosis are the ultimate common macro-manifesta-

tions of cardiac adaptation to various underlying structural heart diseases (90), and atrial fibrosis is deemed to be one of the most important factors in the formation of a structural substrate for AF (100). The principal electrophysiological markers of the atrial pro-fibrillatory state are reduced atrial effective refractory period (ERP), attenuated ERP rate adaptation and reduced impulse conduction velocity (89), which result from a number of alterations in the structure and/or function of intracellular components, ion-channels, signalling pathways, extracellular matrix, myocardial cell spatial orientation, etc. (90). In turn, as demonstrated in the animal experimental models with chronic rapid atrial pacing, AF itself results in the complex atrial electrical, contractile and structural remodelling, which further contributes to the AF persistence and progression (i.e., ‘AF begets AF’) (89,101). Large epidemiological studies have shown the progressive nature of AF. In most instances, AF initially presents with self-terminating recurrent paroxysms, and these episodes become progressively longer over the years until the chronic AF is eventually established (102). However, AF-related atrial remodelling processes in humans are less well understood. In experimental models, atrial electrical remodelling occurs within hours (or days) and is reversible, whilst structural changes (which are usually irreversible) occur following weeks or months of persistent AF (90,101). The exact time course of AF-related atrial remodelling in humans is largely unknown. Nonetheless, human ‘lone’ AF has been classically viewed as a ‘focal’ AF with the pulmonary veins ectopic activity serving as the trigger (and only driver) of a self-perpetuating disease which ultimately may result in a chronic AF with pronounced atrial remodelling because of the arrhythmia itself (91), in opposite to a substrate-based AF which occurs as a consequence of atrial remodelling because of a structural heart disease (e.g., mitral stenosis, hypertension, etc.) (90). Indeed, studies of intra-operatively obtained human atrial specimens demonstrated that increased atrial fibrosis, with excessive collagen accumulation in the extracellular space, is a structural correlate of AF (103,104). However, these studies showed that the presumed correlations of age, underlying heart disease or clinical AF type (i.e., paroxysmal or chronic arrhythmia, AF progression, etc.) and the degree of atrial remodelling are relatively weak in humans (104,105). Whilst atrial fibrosis was clearly increased in the tissue samples of patients with history of AF as compared to those without, the extent of fibrosis was largely comparable in patients with paroxysmal vs. more sustained AF, or in ‘lone’ AF patients vs. those with AF plus mitral valve disease, ª 2013 John Wiley & Sons Ltd Int J Clin Pract, April 2014, 68, 4, 418–433


and there was no correlation of atrial fibrosis with age (i.e., atrial samples from age-matched AF-free patients contained negligibly low amounts of fibrofatty tissue, even in very old patients) (104,105). Along with atrial fibrosis, isolated atrial myocardial perfusion abnormalities and coronary flow reserve impairment indicative of microvascular dysfunction have been observed in ‘lone’ AF patients (106,107). Following its validation in an experimental model (108), electroanatomical bipolar voltage mapping is now used for substrate definition during clinical electrophysiological studies in AF patients, and delayed enhancement magnetic resonance imaging (DE-MRI) has been used to detect and quantify atrial fibrosis (109,110). These tools provided growing evidence that there are no profound differences in the degree of atrial remodelling between ‘lone’ AF patients and those with AF plus an underlying comorbidity, and that the extent of atrial remodelling is variable and poorly correlates with AF duration, even in ‘lone’ AF patients (90,109–112). Furthermore, in contrast to the well documented potential for reverse human atrial remodelling late following the alleviation of a chronic atrial stretch (e.g., after mitral commissurotomy for severe mitral stenosis) (113), large body of evidence suggest that ‘SR does not beget SR’ following the termination of AF (i.e., the vulnerability to AF and risk of AF perpetuation often extend beyond the time course of expected reversal of atrial remodelling) indicating that ‘a second factor’ (i.e., structural alteration) is responsible for AF recurrence (114). In a study of 11 ‘lone’ AF patients, not only that the substrate did not reverse after successful ablation of AF, but electroanatomical mapping revealed a progressive atrial remodelling in the next ≥ 6 months (115).

Quo vadis? Hence, the concept of human ‘lone’ AF as a self-perpetuating electrical disorder has been challenged, and it was proposed that (at least in some patients) apparently ‘lone’ AF may be an arrhythmic manifestation of a structural atrial disease which has recently been described as fibrotic atrial cardiomyopathy (FACM) (111). The disease is chronic, progressive, most probably genetically determined and may have different expressions, from mild to severe atrial fibrosis, with clinical variations from asymptomatic disease to multiple arrhythmias (e.g., AF, atrial tachycardias, sinus node disease, etc.), atrial mechanical dysfunction and thromboembolic complications (111,116). Identifying FACM in its subclinical form, before the occurrence of AF, would perhaps facilitate the primary prevention of AF and AF-related complications. ª 2013 John Wiley & Sons Ltd Int J Clin Pract, April 2014, 68, 4, 418–433

Electrophysiological insights Numerous AF triggers have been described, including those within the pulmonary veins and non-pulmonary vein triggers (e.g., the left atrial posterior wall, superior and inferior vena cava, crista terminalis, fossa ovalis, coronary sinus, behind the Eustachian ridge, along the ligament of Marshall and adjacent to the AV valve annuli), and areas with complex fractionated atrial electrograms have been suggested to represent the potential substrate sites for AF (117). However, in contrast to the factors that may trigger AF, the ‘electrical’ mechanisms that sustain once triggered paroxysmal or persistent AF are less well defined (90–92). There are two prevailing hypotheses of AF sustenance: the multiwavelet hypothesis, which proposes continuously meandering electrical waves (118) and the localised source hypothesis, which has been based on the experimental models wherein organised reentrant circuits (rotors) or focal impulses disorganise into AF (119–121) and was recently documented in humans (122). Whilst ablation based on the multiwavelet hypothesis often has little acute periprocedural impact, the focal impulses and electrical rotors modulation ablation at patient-specific AF-sustaining sources was able to terminate or slow persistent and paroxysmal AF in most cases and substantially improved long-term elimination of AF compared with conventional ablation alone (i.e., isolation of the pulmonary veins) in a prospective cohort-case study (122). The onset of AF (particularly paroxysmal) is often preceded by altered autonomic activity (89,94). It has been believed that patients with structural heart disease tend to show a sympathetic pattern, whilst ‘lone’ AF patients more frequently have AF in the setting of increased vagal tone (89,94,123). However, evidence suggests that the onset of ‘lone’ AF is associated with a change in autonomic balance rather than an increase in vagal or sympathetic drive alone (94,117,123). The local (intrinsic) cardiac autonomic nervous system, with its major ganglionated plexi located in epicardial fat pads at the border of the pulmonary veins antrum and within the ligament of Marshall, can significantly modulate myocardial electrophysiological properties and is increasingly considered as a target for AF ablation (117).

Diagnostic and treatment implications Despite growing insights into the AF pathophysiology, management of AF patients remains challenging because of the arrhythmia complexity, with essentially unpredictable recurrence and progression rates, largely variable susceptibilities to stroke and HF and variable treatment responses in a given AF patient.

427

428


Hence, AF patients require an individualised approach, with detailed initial assessment, personalised treatment and regular follow-up. Importantly, these challenges are points for intensive research which should facilitate clinical management of AF.

Subclinical ‘lone’ AF risk factors not to be overlooked Many subclinical risk factors may predispose to AF in apparently healthy individuals. For example, an increased intima-media thickness or the presence of mitral annulus calcification (indicating a subclinical atherosclerosis) has been shown to predispose to AF, and mitral annulus calcification was found to be an independent predictor of increased cardiovascular morbidity and mortality in AF patients (124–128). A recent analysis showed that increasing systolic blood pressure levels, even within the normotensive range, were associated with incident AF in females (18). Obesity is a well-known risk factor for AF (25). However, in contrast to intrathoracic or visceral abdominal fat, pericardial fat was found to be associated with prevalent AF and AF burden independent of age, body mass index or left atrial size (129,130). An increased risk of AF has been also found in individuals with abnormal parameters of left ventricular diastolic function in the absence of clinically manifested HF (19,20). Using multislice computed tomography, a small study (150 AF patients vs. 148 controls) found that AF patients had asymptomatic obstructive coronary artery disease more often than controls (131). Furthermore, it has been shown that even mild chronic kidney disease is associated with an increased prevalence of AF (24). Indeed, some comorbidities such as peripheral vascular disease or obstructive sleep apnoea, for example, may be overlooked if not particularly searched for in apparently healthy AF patients. Importantly, peripheral vascular disease is a well-documented independent risk factor for stroke in AF patients (hazard ratio 1.93; 95% CI: 1.70–2.19) (132), and obstructive sleep apnoea (Table 1) has been associated with endothelial dysfunction and impaired myocardial perfusion in otherwise healthy individuals (133).

Noninvasive assessment of ‘lone’ AF substrate Clinical electrophysiological studies and DE-MRI have revealed significant atrial functional and structural alterations in ‘lone’ AF patients (111). The transthoracic echocardiography indices of left atrial remodelling are easily (and quickly) obtained in clinical practice and readily available in most centres. Available data suggest that two-dimensional specle tracking echocardiography can detect early left atrial functional impairment (occurring before evident

structural remodelling) and that left atrial strain and strain rate correlate well with the extent of atrial fibrosis (as quantified DE-MRI) and may be helpful in predicting the outcomes in AF patients (134–137). However, the role of these parameters for risk stratification, treatment decisions and outcome prediction in ‘lone’ AF needs further investigation. Increasing attention has been directed towards biomarkers which could enhance AF risk prediction and provide further insights into the pathophysiology of AF, and perhaps contribute to a better identification of potential novel targets for treatment. An analysis of 3120 Framingham Heart Study participants tested the association of incident AF and a panel of 10 candidate biomarkers, which were chosen as the representatives of various pathophysiological pathways that may be operative in AF (43,138,139). The panel included markers of inflammation (C-reactive protein and fibrinogen), neurohormonal activation [B-type natriuretic peptide (BNP) and N-terminal proatrial natriuretic peptide], oxidative stress and endothelial dysfunction (homocysteine), the RAAS function (rennin and aldosterone), thrombosis and endothelial function (D-dimer and plasminogen activator inhibitor type 1) and microvascular damage (urinary albumin excretion) and was significantly associated with incident AF (p < 0.001). After multivariable adjustment, the stepwise-selection models identified BNP and C-reactive protein to be associated with AF (hazard ratio of 1.62; 95% CI: 1.41– 1.85 and 1.25; 95% CI: 1.07–1.45, respectively). However, only BNP improved risk stratification beyond well-established clinical risk factors for AF (139). The inactive N-terminal BNP fragment (NT-proBNP) was the strongest marker of increased risk of incident AF in the Cardiovascular Health Study (140). Many of these biomarkers have been shown to predict AF recurrence following cardioversion or AF ablation, AF perpetuation, AF-related stroke and other cardiovascular events (115,138). Several biomarkers have been also studied in ‘lone’ AF, including C-reactive protein (141,142), NT-proBNP (143), apelin (144) and markers of endothelial dysfunction and prothrombotic state (e.g., soluble E-selectin, von Willebrandt factor and soluble thrombomodulin, P-selectin, etc.) (145,146). Furthermore, a potential role of cardiac troponin in AF-related stroke risk assessment has been suggested in the recent reports from the two large randomised clinical trials which compared novel oral anticoagulants dabigatran or apixaban with warfarin for stroke prevention in nonvalvular AF [the RE-LY (Randomised Evaluation of Long-Term Anticoagulation Therapy) and ARISTOTLE (Apixaban for the Prevention of Stroke in ª 2013 John Wiley & Sons Ltd Int J Clin Pract, April 2014, 68, 4, 418–433


Subjects with Atrial Fibrillation) trials, respectively] (147,148). Overall, available evidence suggest that a multimarker assessment approach could improve risk stratification and treatment decisions, as well as the prediction of treatment responses and outcomes in patients with non-valvular AF including those with ‘lone’ AF. However, further testing and verification in various large AF cohorts is needed to elucidate the exact role of biomarkers in early detection and clinical management of AF (138).

The role of AF genetic testing Similar efforts towards better risk stratification and a more personalised approach to treatment of AF have been made with respect to the increasing knowledge on the genetic aspects of AF (71–74,76–86). Genetic information might improve the prediction of newonset AF, AF-related morbidity (e.g., stroke or HF) or mortality, AF progression, rhythm management and thromboprophylaxis. However, there is insufficient evidence to recommend routine testing for genetic variation in the management of patients with AF (149).

Thromboprophylaxis in ‘lone’ AF patients Available evidence suggests that ‘lone’ AF patients have a low risk of AF-related stroke and systemic embolism as long as they stay free of well-known clinical stroke risk factors (60). The CHA2DS2-VASc score for stroke risk assessment in AF, which contains clinically relevant stroke risk factors [i.e., congestive heart failure (CHF), hypertension, age ≥ 75 years, diabetes mellitus, previous stroke/TIA, vascular disease, age 65–74 years and sex categoryfemale gender], by definition equals 0 in male ‘lone’ AF patients and 1 in females with ‘lone’ AF. The score has been validated in many different AF cohorts, against several other scores, and was uniformly proven superior for identification of AF patients at truly low risk of stroke (i.e., all AF patients with a score of 0, or 1 as a result of female gender) (150). In a cohort of 345 patients with firstdiagnosed ‘lone’ AF from the Belgrade AF Study, patients were free of stroke as long as they had a CHA2DS2-VASc score of 0, and the CHA2DS2-VASc score was the only tested risk stratification scheme with a significant independent predictive ability for thromboembolism amongst ‘lone’ AF patients, whilst the CHADS2 (CHF, hypertension, age > 75 years, diabetes mellitus and previous stroke or TIA) and Van Walraven (previous stroke/TIA, treated/ untreated hypertension, angina/previous myocardial infarction and diabetes mellitus) scores were significant only in the univariate analysis (151). According to the current guidelines, ‘lone’ AF patient do not ª 2013 John Wiley & Sons Ltd Int J Clin Pract, April 2014, 68, 4, 418–433

need any long-term thromboprophylaxis, but regular re-assessment of stroke risk is mandatory (22).

Can we cure ‘lone’ AF? ‘Lone’ AF patients often present with paroxysmal AF and have relatively low rates of AF progression over a long time (53–65). Randomised clinical trials which compared AF ablation vs. antiarrhythmic drug therapy for rhythm control uniformly reported superior efficacy of AF ablation during a 12-month follow-up, particularly in AF patients without significant underlying comorbidities (117). However, given the growing insights into the diversity of AF patients who were previously believed to have a ‘purely electrical’ disorder, AF ablation cannot be expected to cure the arrhythmia in all ‘lone’ AF patients. Indeed, young apparently healthy AF patients may need a complex procedures which combine the pulmonary veins isolation with linear lesions in the left atrium, non-pulmonary vein triggers ablation, complex fractionated atrial electrograms ablation, focal impulse and rotor modulation, ablation of ganglionated plexi, etc. (117,118,122,152). Again, cardiac imaging, biomarkers and genetic assessment might improve the identification of AF patients in whom a successful rhythm control is more likely. Stand-alone surgical treatment of AF using the Cox–Maze procedure has never been widely adopted because of its complexity and invasiveness (22). A recent report of a single-centre experience in 212 consecutive ‘lone’ AF patients over two decades compared the original cut-and-sew to the ablationassisted Cox–Maze procedure (which used bipolar radiofrequency and cryoenergy to create the original lesion pattern) and found high success rates with 90% freedom from AF and 84% freedom from AF off antiarrhythmics at 2 years (153).

Conclusions Increasing evidence suggests that AF is associated with numerous more or less evident alterations in cardiac function and structure even in the young, apparently healthy AF patients, thus making the diagnosis of ‘lone’ AF increasingly meaningless. Growing insights into the complexity of AF pathophysiology suggest a considerable diversity of patients who are presently diagnosed with ‘lone’ AF. Although these patients by definition have no evident cardiopulmonary or other disease, they may have largely different risk profiles based on the presence (or absence) of overlooked subclinical cardiovascular risk factors or genetically determined subtle alterations at the cellular or molecular level. Intuitively, it seems that of all AF patients those with ‘lone’ AF would gain a particular benefit from an

429

430


early AF detection and treatment (or even the primary prevention of the arrhythmia). However, whether the implementation of various cardiac imaging techniques, biomarkers and genetic information could improve the prediction of risk for incident AF and risk

References 1 Prystowsky EN. The history of atrial fibrillation: the last 100 years. J Cardiovasc Electrophysiol 2008; 19: 575–82. 2 Evans W, Swann P. Lone auricular fibrillation. Br Heart J 1954; 16: 189–94. 3 Lewis T. Auricular fibrillation. Clinical Disorders of the Heart Beat: A Handbook for Practitioners and Students, 3rd edn. New York: Paul B Hoeber (Copyright London, England: Shaw and Sons), 1916: 82–98. 4 Benjamin EJ, Wolf PA, D’Agostino RB, Silbershatz H, Kannel WB, Levy D. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation 1998; 98: 946–52. 5 Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991; 22: 983–8. 6 Menke J, L€ uthje L, Kastrup A, Larsen J. Thromboembolism in atrial fibrillation. Am J Cardiol 2010; 105: 502–10. 7 Marini C, De Santis F, Sacco S et al. Contribution of atrial fibrillation to incidence and outcome of ischemic stroke: results from a population-based study. Stroke 2005; 36: 1115–9. 8 Wang TJ, Larson MG, Levy D et al. Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality: the Framingham Heart Study. Circulation 2003; 107: 2920–5. 9 Atwood JE, Myers JN, Tang C, Reda DJ, Singh SN, Sing BN. Exercise capacity in atrial fibrillation: a substudy of the Sotalol-Amiodarone Atrial Fibrillation Efficacy Trial (SAFE-T). Am Heart J 2007; 153: 566–72. 10 Thrall G, Lane D, Carroll D, Lip GY. Quality of life in patients with atrial fibrillation: a systematic review. Am J Med 2006; 119: 448e1–19. 11 Heeringa J, van der Kuip DAM, Hofman A et al. Prevalence, incidence and lifetime risk of atrial fibrillation: the Rotterdam study. Eur Heart J 2006; 27: 949–53. 12 Ball J, Carrington MJ, McMurray JJV, Stewart S. Atrial fibrillation: profile and burden of an evolving epidemic in the 21st century. Int J Cardiol 2013; doi: 10.1016/j.ijcard.4 2012.12.093. 13 Go AS, Hylek EM, Phillips KA et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 2001; 285: 2370–5. 14 Naccarelli GV, Varker H, Lin J, Schulman KL. Increasing prevalence of atrial fibrillation and flutter in the United States. Am J Cardiol 2009; 104: 1534–9. 15 Ziegler PD, Glotzer TV, Daoud EG et al. Detection of previously undiagnosed atrial fibrillation in patients with stroke risk factors and usefulness

16

17

18

19

20

21

22

23

24

25

26

27

28

assessment of ‘lone’ AF patients, and influence the treatment decisions needs further research. Meanwhile, a careful clinical work-up at AF presentation, with regular clinical re-assessment of diagnosed ‘lone’ AF patients is mandatory.

of continuous monitoring in primary stroke prevention. Am J Cardiol 2012; 110: 1309–14. Benjamin EJ, Levy D, Vaziri SM, D’Agostino RB, Belanger AJ, Wolf PA. Independent risk factors for atrial fibrillation in a population-based cohort. The Framingham Heart Study. JAMA 1994; 271: 840–4. Schanbel RB, Sullivan LM, Levy D et al. Development of a risk score for atrial fibrillation in the community; the Framingham Heart Study. Lancet 2009; 373: 739–45. Conen D, Tedrow UB, Koplan BA, Glynn RJ, Buring JE, Albert CM. Influence of systolic and diastolic blood pressure on the risk of incident atrial fibrillation in women. Circulation 2009; 119: 2146–52. Vogel MV, Slusser JP, Hodge DO, Chen HH. The natural history of preclinical diastolic dysfunction. A population-based study. Circ Heart Fail 2012; 5: 144–51. Rosenberg MA, Gottdiener JS, Heckbert SR, Mukamal KJ. Echocardiographic diastolic parameters and risk of atrial fibrillation: the Cardiovascular Health Study. Eur Heart J 2012; 33: 904–12. Krahn AD, Manfreda J, Tate RB, Mathewson FA, Cuddy TE. The natural history of atrial fibrillation: incidence, risk factors, and prognosis in the Manitoba Follow-up Study. Am J Med 1995; 98: 476–84. Camm AJ, Lip GY, De Caterina R et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Europace 2012; 14: 1385–413. Heeringa J, Hoogendoorn EH, van der Deure WM et al. High-normal thyroid function and risk of atrial fibrillation: the Rotterdam study. Arch Intern Med 2008; 168: 2219–24. Baber U, Howard VJ, Halperin JL et al. Association of chronic kidney disease with atrial fibrillation among adults in the United States: REasons for Geographic and Racial Differences in Stroke (REGARDS) Study. Circ Arrhythm Electrophysiol 2011; 4: 26–32. Wanahita N, Messerli FH, Bangalore S, Gami AS, Somers VK, Steinberg JS. Atrial fibrillation and obesity – results of a meta-analysis. Am Heart J 2008; 155: 310–5. Watanabe H, Tanabe N, Watanabe T et al. Metabolic syndrome and risk of development of atrial fibrillation: the Niigata Preventive Medicine Study. Circulation 2008; 117: 1255–60. Schoonderwoerd BA, Smit MD, Pen L, Van Gelder IC. New risk factors for atrial fibrillation: causes of “not-so-lone atrial fibrillation”. Europace 2008; 10: 668–73. Gami AS, Hodge DO, Herges RM et al. Obstructive sleep apnea, obesity and the risk of incident atrial fibrillation. J Am Coll Cardiol 2007; 49: 565–71.

29 Butt M, Dwivedi G, Khair O, Lip GY. Obstructive sleep apnea and cardiovascular disease. Int J Cardiol 2010; 139: 7–16. 30 Lindhardsen J, Ahlehoff O, Gislason GH et al. Risk of atrial fibrillation and stroke in rheumatoid arthritis: Danish nationwide cohort study. BMJ 2012; 344: e1257. 31 Borzecki AM, Bridgers DK, Liebschutz JM, Kader B, Kazis LE, Berlowitz DR. Racial differences in the prevalence of atrial fibrillation among males. J Natl Med Assoc 2008; 100: 237–45. 32 Marcus GM, Alonso A, Peralta CA et al. European ancestry as a risk factor for atrial fibrillation in African Americans. Circulation 2010; 122: 2009– 15. 33 Rienstra M, McManus DD, Benjamin EJ. Novel risk factors for atrial fibrillation. Useful for risk prediction and clinical decision making? Circulation 2012; 125: e941–6. 34 Heeringa J, Kors JA, Hofman A, van Rooij FJA, Witteman JCM. Cigarette smoking and risk of atrial fibrillation: the Rotterdam Study. Am Heart J 2008; 156: 1163–9. 35 Chamberlain AM, Agarwal SK, Folsom AR et al. Smoking and incidence of atrial fibrillation: results from the Atherosclerosis Risk in Communities (ARIC) study. Heart Rhythm 2011; 8: 1160– 6. 36 Mandyam MC, Vedantham V, Scheinman MM et al. Alcohol and vagal tone as triggers for paroxysmal atrial fibrillation. Am J Cardiol 2012; 3: 364–8. 37 Liang Y, Mente A, Yusuf S et al.; ONTARGET and TRANSCEND Investigators. Alcohol consumption and the risk of incident atrial fibrillation among people with cardiovascular disease. CMAJ 2012; 184: E857–66. 38 Abdulla J, Nielsen JR. Is the risk of atrial fibrillation higher in athletes than in the general population? A systematic review and meta-analysis Europace 2009; 11: 1156–9. 39 Kaireviciute D, Aidietis A, Lip GYH. Atrial fibrillation following cardiac surgery: clinical features and preventive strategies. Eur Heart J 2009; 30: 410–25. 40 Chelazzi C, Villa G, De Gaudio AR. Postoperative atrial fibrillation ISRN Cardiol 2011; 2011: 203179. doi:10.5402/2011/203179. 41 Walkey AJ, Greiner MA, Heckbert SR et al. Atrial fibrillation among medicare beneficiaries hospitalized with sepsis: incidence and risk factors. Am Heart J 2013; 165: 949–55. 42 Hanna IR, Heeke B, Bush H et al. The relationship between stature and the prevalence of atrial fibrillation in patients with left ventricular dysfunction. J Am Coll Cardiol 2006; 47: 1683–8. 43 Potpara TS, Lip GY. Lone atrial fibrillation: what is known and what is to come. Int J Clin Pract 2011; 65: 446–57. 44 Potpara TS, Lip GY. Lone atrial fibrillation: where are we now? Hosp Pract (1995) 2011; 39: 17–31.



45 Camm JA, Kirchof P, Lip GYH et al. Guidelines for the management of atrial fibrillation. The task force for the management of atrial fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010; 31: 2369–429. 46 Fuster V, Ryden LE, Cannom DS et al.; American College of Cardiology Foundation/American Heart Association Task Force. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ ESC 2006 guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/ American Heart Association Task Force on practice guidelines. Circulation 2011; 123: e269-367. 47 Healey JS, Parkash R, Pollak T, Tsang T, Dorian P; the CCS Atrial Fibrillation Guidelines Committee. Canadian cardiovascular society atrial fibrillation guidelines 2010: etiology and initial investigations. Can J Cardiol 2011; 27: 27–30. 48 Kopecky SL. Idiopathic atrial fibrillation: prevalence, course, treatment, and prognosis. J Thromb Thrombolysis 1999; 7: 27–31. 49 Marinigh R, Lip GYH, Fiotti N, Giasante C, Lane DA. Age as a risk factor stroke in atrial fibrillation patients. J Am Coll Cardiol 2010; 56: 827–37. 50 Kopecky SL, Gersh BJ, McGoon MD et al. Lone atrial fibrillation. A marker for cardiovascular risk. Arch Intern Med 1999; 159: 1118–22. 51 Miyasaka Y, Barnes ME, Gersh BJ et al. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation 2006; 114: 119–25. 52 Brand FN, Abbott RD, Kannel WB, Wolf PA. Characteristics and prognosis of lone atrial fibrillation. 30-year follow-up in the Framingham Study. JAMA 1985; 254: 3449–53. 53 Kopecky SL, Gersh BJ, McGoon MD et al. The natural history of lone atrial fibrillation. A population-based study over three decades. N Engl J Med 1987; 317: 669–74. 54 Davidson E, Rotenberg Z, Weinberger I, Fuchs J, Agmon J. Diagnosis and characteristics of lone atrial fibrillation. Chest 1989; 95: 1048–50. 55 Rostagno C, Bacci F, Martelli M, Naldoni A, Bertini G, Gensini GF. Clinical course of lone atrial fibrillation since first symptomatic arrhythmic episode. Am J Cardiol 1995; 76: 837–9. 56 Scardi S, Mazzone C, Pandullo C, Goldstein D, Poletti A, Humar F. Lone atrial fibrillation: prognostic differences between paroxysmal and chronic forms after 10 years of follow-up. Am Heart J 1999; 137: 686–91. 57 Jouven X, Desnos M, Guerot C, Ducimetiere P. Idiopathic atrial fibrillation as a risk factor for mortality. Eur Heart J 1999; 20: 896–9. 58 Jahangir A, Lee V, Friedman PA et al. Long-term progression and outcomes with aging in patients with lone atrial fibrillation. A 30-year follow-up study. Circulation 2007; 115: 3050–6. 59 Potpara T, Grujic M, Marinkovic J, Vujisic-Tesic B, Ostojic M, Polovina M. Mortality of patients with lone and idiopathic atrial fibrillation is similar to mortality in general population of Serbia. Vojnosanit Pregl 2010; 67: 132–5. 60 Potpara TS, Stankovic GR, Beleslin BD et al. A 12-year follow-up study of patients with newly-diagnosed lone atrial fibrillation: implications of arrhythmia progression on prognosis: the


61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

Belgrade Atrial Fibrillation Study. Chest 2012; 141: 339–47. Potpara TS, Marinkovic JM, Polovina MM et al. Gender-related differences in presentation, treatment and long-term outcome in patients with first-diagnosed atrial fibrillation and structurally normal heart: the Belgrade atrial fibrillation study. Int J Cardiol 2012; 161: 39–44. Chen LY, Herron KJ, Tai BC, Olson TM. Lone atrial fibrillation: influence of familial disease on gender predilection. J Cardiovasc Electrophysiol 2008; 19: 802–6. Rienstra M, Hagens VE, Van Valdhuisen DJ et al. Clinical characteristics of persistent lone atrial fibrillation in the RACE study. Am J Cardiol 2004; 94: 1486–90. Weijs B, Pisters R, Nieuwlaat R et al. Idiopathic atrial fibrillation revisited in a large longitudinal clinical cohort. Europace 2012; 14: 184–90. Weijs B, de Vos CB, Tieleman RG et al. The occurrence of cardiovascular disease during 5-year follow-up in patients with idiopathic atrial fibrillation. Europace 2013; 15: 18–23. Katritsis DG, Toumpoulis IK, Giazitzoglou E et al. Latent arterial hypertension in apparently lone atrial fibrillation. J Interv Card Electrophysiol 2005; 13: 203–7. Osranek M, Bursi F, Bailey KR et al. Left atrial volume predicts cardiovascular events in patients originally diagnosed with lone atrial fibrillation: three-decade follow-up. Eur Heart J 2005; 26: 2556–61. Fox CS, Parise H, D’Agostino RB et al. Parental atrial fibrillation as a risk factor for atrial fibrillation in offspring. JAMA 2004; 291: 2851–5. Lubitz SA, Yin X, Fontes JD et al. Association between familial atrial fibrillation and risk of new-onset atrial fibrillation. JAMA 2010; 304: 2263–9. Oyen N, Ranthe MF, Carstensen L et al. Familial aggregation of lone atrial fibrillation in young persons. J Am Coll Cardiol 2012; 60: 917–21. Lubitz SA, Ellinor PT. Personalized medicine and atrial fibrillation: will it ever happen? BMC Med 2012; 10: 155. Mahida S, Lubitz SA, Rienstra M, Milan DJ, Ellinor PT. Monogenic atrial fibrillation as pathophysiological paradigms. Cardiovasc Res 2011; 89: 692– 700. Olesen MS, Bentzen BH, Nielsen JB et al. Mutations in the potassium channel subunit KCNE1 are associated with early-onset familial atrial fibrillation. BMC Med Genet 2012; 13: 24. Schnabel RB, Kerr KF, Lubitz SA et al. Large-scale candidate gene analysis in whites and African Americans identifies IL6R polymorphism in relation to atrial fibrillation: the National Heart, Lung and Blood Institute’s Candidate Gene Associations Resource (CARE) project. Circ Cardiovasc Genet 2011; 4: 557–64. Sinner MF, Lubitz SA, Pfeufer A et al. Lack of replication in polymorphisms reported to be associated with atrial fibrillation. Heart Rhythm 2011; 8: 403–9. Gudbjartsson DF, Arnar DO, Helgadottir A et al. Variants conferring risk of atrial fibrillation on chromosome 4q25. Nature 2007; 448: 353–7. K€a€ab S, Darbar D, van Noord C et al. Large scale replication and meta-analysis of variants on chro-

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

431

mosome 4q25 associated with atrial fibrillation. Eur Heart J 2009; 30: 813–9. Benjamin EJ, Rice KM, Arking DE et al. Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry. Nat Genet 2009; 41: 879–81. Ellinor PT, Lunetta KL, Glazer NL et al. Common variants in KCNN3 are associated with lone atrial fibrillation. Nat Genet 2010; 42: 240–4. Lubitz SA, Sinner MF, Lunetta KL et al. Independent susceptibility markers for atrial fibrillation on chromosome 4q25. Circulation 2010; 122: 976–84. Mommersteeg MT, Brown NA, Prall OW et al. Pitx2c and nkx2-5 are required for the formation and identity of the pulmonary myocardium. Circ Res 2007; 101: 902–9. Mommersteeg MT, Hoogaars WM, Prall OW et al. Molecular pathway for the localized formation of the sinoatrial node. Circ Res 2007; 100: 354–62. Kirchhof P, Kahr PC, Kaese S et al. Pitx2c is expressed in the adult left atrium, and reducing pitx2c expression promotes atrial fibrillation inducibility and complex changes in gene expression. Circ Cardiovasc Genet 2011; 4: 123–33. Chinchilla A, Daimi H, Lozano-Velasco E et al. Pitx2 insufficiency leads to atrial electrical and structural remodeling linked to arrhythmogenesis. Circ Cardiovasc Genet 2011; 4: 269–79. Ellinor PT, Lunetta KL, Albert CM et al. Meta-analysis identifies six new susceptibility loci for atrial fibrillation. Nat Genet 2012; 44: 670–5. Eaker ED, Sullivan LM, Kelly-Hayes M, D’Agostino RB Sr, Benjamin EJ. Anger and hostility predict the development of atrial fibrillation in men in the Framingham Offspring Study. Circulation 2004; 109: 1267–71. Mattioli AV, Bonatti S, Zennaro M, Mattioli G. The relationship between personality, socioeconomic factors, acute life stress and the development, spontaneous conversion and recurrences of acute lone atrial fibrillation. Europace 2005; 7: 211–20. Van der Hooft CS, Heeringa J, van Herpen G, Kors JA, Kingma JH, Stricker BH. Drug-induced atrial fibrillation. J Am Coll Cardiol 2004; 44: 2117–24. Allessie MA, Boyden PA, Camm JA et al. Pathophysiology and prevention of atrial fibrillation. Circulation 2001; 103: 769–77. Schotten U, Verheule S, Kirchhof P, Goette A. Pathophysiological mechanisms of atrial fibrillation: a translational appraisal. Physiol Rev 2011; 91: 265–325. Haissaguerre M, Jais P, Shah DC et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med 1998; 339: 659–66. Jais P, Hocini M, MacLe L et al. Distinctive electrophysiological properties of pulmonary veins in patients with atrial fibrillation. Circulation 2002; 106: 2479–85. Chen SA, Tai CT. Catheter ablation of atrial fibrillation originating from the non-pulmonary vein foci. J Cardiovasc Electrophysiol 2005; 16: 229–32. Huang JL, Wen ZC, Lee WL, Chang MS, Chen SA. Changes of autonomic tone before the onset of paroxysmal atrial fibrillation. Int J Cardiol 1998; 66: 275–83.

432


95 Herweg B, Dalal P, Nagy B, Schweitzer P. Power spectral analysis of heart period variability of preceding sinus rhythm before initiation of paroxysmal atrial fibrillation. Am J Cardiol 1998; 82: 869– 74. 96 Zimmermann M, Kalusche D. Fluctuation in autonomic tone is a major determinant of sustained atrial arrhythmias in patients with focal ectopy originating from the pulmonary veins. J Cardiovasc Electrophysiol 2001; 12: 285–91. 97 Chang C-M, Wu T-J, Zhou S-M et al. Nerve sprouting and sympathetic hyperinnervation in a canine model of atrial fibrillation produced by prolonged right atrial pacing. Circulation 2001; 103: 22–5. 98 Sharifov OF, Fedorov VV, Beloshapko GG, Glukhov AV, Yushmanova AV, Rosenshtraukh LV. Roles of adrenergic and cholinergic stimulation in spontaneous atrial fibrillation in dogs. J Am Coll Cardiol 2004; 43: 483–90. 99 Patterson E, Lazzara R, Szabo B et al. Sodium-calcium exchange initiated by the Ca2+transient: an arrhythmia trigger within pulmonary veins. J Am Coll Cardiol 2006; 47: 1196–206. 100 Nattel S. Defining “culprit mechanisms” in arrhythmogenic cardiac remodeling. Circ Res 2004; 94: 1403–5. 101 Allessie M, Ausma J, Schotten U. Electrical, contractile and structural remodeling during atrial fibrillation. Cardiovasc Res 2002; 54: 230–46. 102 Kerr CR, Humphries KH, Talajic M et al. Progression to chronic atrial fibrillation after the initial diagnosis of paroxysmal atrial fibrillation: results from the Canadian Registry of Atrial Fibrillation. Am Heart J 2005; 149: 489–96. 103 Kostin S, Klein G, Szalay Z, Hein S, Bauer EP, Schaper J. Structural correlate of atrial fibrillation in human patients. Cardiovasc Res 2002; 54: 361– 79. 104 Boldt A, Wetzel U, Lauschke J et al. Fibrosis in left atrial tissue of patients with atrial fibrillation with and without underlying mitral valve disease. Heart 2004; 90: 400–5. 105 Platonov PG, Mitrofanova LB, Orshanskaya V, Ho SY. Structural abnormalities in atrial walls are associated with presence and persistency of atrial fibrillation but not with age. J Am Coll Cardiol 2011; 58: 2225–32. 106 Frustaci A, Chimenti C, Bellocci F, Morgante E, Russo MA, Maseri A. Histological substrate of atrial biopsies in patients with lone atrial fibrillation. Circulation 1997; 96: 1180–4. 107 Skalidis EI, Hamilos MI, Karalis IK, Chlouverakis G, Kochiadakis GE, Vardas PE. Isolated atrial microvascular dysfunction in patients with lone recurrent atrial fibrillation. J Am Coll Cardiol 2008; 51: 2053–7. 108 Callans D, Ren JF, Michele J, Marchlinski FE, Dillon SM. Electroanatomic left ventricular mapping in the porcine model of healed anterior myocardial infarction. Correlation with intracardiac echocardiography and pathological analysis. Circulation 1999; 100: 1744–50. 109 Oakes RS, Badger TJ, Kholmovski EG et al. Detection and quantification of left atrial structural remodeling with delayed-enhancement magnetic resonance imaging in patients with atrial fibrillation. Circulation 2009; 119: 1758–67.

110 Akoum N, Daccarett M, McGann C et al. Atrial fibrosis helps select the appropriate patient and strategy in catheter ablation of atrial fibrillation: a DE-MRI guided approach. J Cardiovasc Electrophysiol 2011; 22: 16–22. 111 Kottkamp H. Human atrial fibrillation substrate: towards a specific fibrotic atrial cardiomyopathy. Eur Heart J 2013, doi:10.1093/eurheartj/eht194 (last accessed on June 15, 2013). 112 Teh AW, Kistler PM, Lee G et al. Electroanatomic remodeling of the left atrium in paroxysmal and persistent atrial fibrillation patients without structural heart disease. J Cardiovasc Electrophysiol 2012; 23: 232–8. 113 John B, Stiles MK, Kuklik P et al. Reverse remodeling of the atria after treatment of chronic stretch in humans. J Am Coll Cardiol 2010; 55: 1217–26. 114 Stiles MK, John B, Wong CX et al. Paroxysmal lone atrial fibrillation is associated with abnormal atrial substrate. Characterizing the “Second Factor”. J Am Coll Cardiol 2009; 53: 1182–91. 115 Teh AW, Kistler PM, Lee G et al. The long-term effects of catheter ablation for lone atrial fibrillation. Progressive atrial electroanatomic substrate remodeling despite successful ablation. Heart Rhythm 2012; 9: 473–80. 116 Kottkamp H. Fibrotic atrial cardiomyopathy: a specific disease/syndrome supplying substrates for atrial fibrillation, atrial tachycardia, sinus node disease, AV node diseases, and thromboembolic complications. J Cardiovasc Electrophysiol 2012; 23: 797–9. 117 Calkins H, Kuck KH, Cappato R et al. 2012 HRS/ EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design. Europace 2012; 14: 528–606. 118 Allessie MA, de Groot NM, Houben RP et al. The electropathological substrate of longstanding persistent atrial fibrillation in patients with structural heart disease: longitudinal dissociation. Circ Arrhythm Electrophysiol 2010; 3: 606–15. 119 Vaquero M, Calvo D, Jalife J. Cardiac fibrillation: from ion channels to rotors in the human heart. Heart Rhythm 2008; 5: 872–9. 120 Skanes AC, Mandapati R, Berenfeld O, Davidenko JM, Jalife J. Spatiotemporal periodicity during atrial fibrillation in the isolated sheep heart. Circulation 1998; 98: 1236–48. 121 Sahadevan J, Ryu K, Peltz L et al. Epicardial mapping of chronic atrial fibrillation in patients: preliminary observations. Circulation 2004; 110: 3293– 9. 122 Narayan SM, Krummen DE, Shivkumar K, Clopton P, Rappel WJ, Miller JM. Treatment of atrial fibrillation by the ablation of localized sources: CONFIRM (Conventional Ablation for Atrial Fibrillation with or Without Focal Impulse and Rotor Modulation) trial. J Am Coll Cardiol 2012; 60: 628–36. 123 Coumel P. Autonomic influences in atrial tachyarrhythmias. J Cardiovasc Electrophysiol 1996; 7: 999–1007. 124 Tomita T, Takei M, Saikawa Y et al. Role of autonomic tone in the initiation and termination of paroxysmal atrial fibrillation in patients without

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

structural heart disease. J Cardiovasc Electrophysiol 2003; 14: 559–64. Fox CS, Parise H, Vasan RS et al. Mitral annular calcification is a predictor for incident atrial fibrillation. Atherosclerosis 2004; 173: 291–4. Lorenz MW, Marcus HS, Bots ML, Rosvall M, Sitzer M. Prediction of clinical cardiovascular events with carotid intima-media thickness. Circulation 2007; 115: 459–67. Chen LY, Foo DC, Wong RC et al. Increased carotid intima-media thickness and arterial stiffness are associated with lone atrial fibrillation. Int J Cardiol 2013. doi: 10.6 1016/j.ijcard.2013.04.034. Potpara TS, Vasiljevic ZM, Vujisic-Tesic BD et al. Mitral annular calcification predicts cardiovascular morbidity and mortality in middle-aged patients with atrial fibrillation: the Belgrade Atrial Fibrillation Study. Chest 2011; 140: 902–10. Thanassoulis G, Massaro JM, O’Donnell CJ et al. Pericardial fat is associated with prevalent atrial fibrillation: the Framingham Heart Study. Circ Arrhythm Electrophysiol 2010; 3: 345–50. Batal O, Schoenhagen P, Shao M et al. Left atrial epicardial adiposity and atrial fibrillation. Circ Arrhythm Electrophysiol 2010; 3: 230–6. Nucifora G, Schuijf JD, Tops LF et al. Prevalence of coronary artery disease assessed by multislice computed tomography coronary angiography in patients with paroxysmal or persistent atrial fibrillation. Circ Cardiovasc Imaging 2009; 2: 100–6. Olesen JB, Lip GYH, Lane DA et al. Vascular disease and stroke risk in atrial fibrillation: a nationwide cohort study. Am J Med 2012; 125: 826.e13-23. Butt M, Khair OA, Dwivedi G, Shantsila A, Shantsila E, Lip GYH. Myocardial perfusion by myocardial contrast echocardiography and endothelial dysfunction in obstructive sleep apnea. Hypertension 2011; 58: 417–24. Kuppahally SS, Akoum N, Burgon NS et al. Left atrial strain and strain rate in patients with paroxysmal and persistent atrial fibrillation: relationship to left atrial structural remodeling detected by delayed-enhancement MRI. Circ Cardiovasc Imaging 2010; 3: 231–9. Saha SK, Anderson PL, Caracciolo G et al. Global left atrial strain correlates with CHADS2 risk score in patients with atrial fibrillation. J Am Soc Echocardiogr 2011; 24: 506–12. Hong J, Gu X, An P et al. Left atrial functional remodeling in lone atrial fibrillation: a two-dimensional speckle tracking echocardiographic study. Echocardiography 2013. doi: 10.1111/ echo.12200. Shaikh AY, Maan A, Khan UA et al. Speckle echocardiographic left atrial strain and stiffness index as predictors of maintenance of sinus rhythm after cardioversion for atrial fibrillation: a prospective study. Cardiovasc Ultrasound 2012; 10: 48. Hijazi Z, Oldgren J, Siegbahn A, Granger CB, Wallentin L. Biomarkers in atrial fibrillation: a clinical review. Eur Heart J 2013; 34: 1475–80. Schnabel RB, Larson MG, Yamamoto JF et al. Relations of biomarkers of distinct pathophysiological pathways and atrial fibrillation incidence in the community. Circulation 2010; 121: 200–7. Patton KK, Ellinor PT, Heckbert SR et al. N-terminal pro-B-type natriuretic peptide is a major



141

142

143

144

145

146

predictor of the development of atrial fibrillation: the Cardiovascular Health Study. Circulation 2009; 120: 1768–74. Hatzinikolaou-Kotsakou E, Tziakas D, Hotidis A et al. Relation of C-reactive protein to the first onset and the recurrence rate in lone atrial fibrillation. Am J Cardiol 2006; 97: 659–61. Ellinor PT, Low A, Patton KK, Shea MA, MacRae CA. C-reactive protein in lone atrial fibrillation. Am J Cardiol 2006; 97: 1346–50. Ellinor PT, Low AF, Patton KK, Shea MA, MacRae CA. Discordant atrial natriuretic peptide and brain natriuretic peptide levels in lone atrial fibrillation. J Am Coll Cardiol 2005; 45: 82–6. Ellinor PT, Low AF, MacRae CA. Reduced apelin levels in lone atrial fibrillation. Eur Heart J 2006; 27: 222–6. Freestone B, Chong AY, Nuttall S, Blann AD, Lip GYH. Soluble E-selectin, von Willebrand factor, soluble thrombomodulin, and total body nitrate/ nitrite product as indices of endothelial damage/ dysfunction in paroxysmal, persistent, and permanent atrial fibrillation. Chest 2007; 132: 1253–8. Fu R, Wu S, Wu P, Qiu J. A study of blood soluble P-selectin, fibrinogen, and von Willebrand fac-


147

148

149

150

151

tor levels in idiopathic and lone atrial fibrillation. Europace 2011; 13: 31–6. Hijazi Z, Oldgren J, Andersson U et al. Cardiac biomarkers are associated with an increased of stroke and death in patients with atrial fibrillation: a randomized evaluation of long-term anticoagulation therapy (RE-LY) substudy. Circulation 2012; 125: 1605–16. Wallentin L, Hijazi Z, Siegbahn A et al., on behalf of the ARISTOTLE Investigators. High sensitivity troponin-T for risk stratification in atrial fibrillation during treatment with apixaban or warfarin. Eur Heart J 2012; 33(Abstract Supplement 1): 19–338. Ackerman MJ, Priori SG, Willems S et al. HRS/ EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). Heart Rhythm 2011; 8: 1308–39. Lip GY. Stroke and bleeding risk assessment in atrial fibrillation: when, how, and why? Eur Heart J 2013; 34: 1041–9. Potpara TS, Polovina MM, Licina MM, Marinkovic JM, Prostran MS, Lip GY. Reliable identifica-

433

tion of “truly low” thromboembolic risk in patients initially diagnosed with “lone” atrial fibrillation: the Belgrade atrial fibrillation study. Circ Arrhythm Electrophysiol 2012; 5(2): 319–26. 152 Narayan SM, Krummen DE, Clopton P, Shivkumar K, Miller JM. Direct or Coincidental Elimination of Stable Rotors or Focal Sources May Explain Successful Atrial Fibrillation Ablation: On-Treatment Analysis of the CONFIRM (CONventional ablation for AF with or without Focal Impulse and Rotor Modulation) Trial. J Am Coll Cardiol 2013; 62: 138–47. 153 Weimar T, Schena S, Bailey MS et al. The Cox-Maze procedure for lone atrial fibrillation: a single-center experience over 2 decades. Circ Arrhythm Electrophysiol 2012; 5: 8–14.

Paper received July 2013, accepted August 2013

Quinidine treatment of chronic lone atrial fibrillation.

Lone atrial fibrillation: does it exist?

Biomarkers in atrial fibrillation: an overview.

Extra Atrial Disease in Patients with "Lone" Atrial Fibrillation.

Paroxysmal Lone Atrial Fibrillation Is Associated With An Abnormal Atrial Substrate: Characterizing The "Second Factor".

The Cox-Maze IV procedure for lone atrial fibrillation.

Persistent lone atrial fibrillation--its prognosis after clinical diagnosis.

Thoracoscopic radiofrequency ablation for lone atrial fibrillation: box-lesion technique.

Onset of lone atrial fibrillation during labor under epidural analgesia.

Persistent lone atrial fibrillation: clinicopathologic study of 19 cases.

The relationship between erectile dysfunction and paroxysmal lone atrial fibrillation.

Catheter Ablation of Atrial Fibrillation: An Overview for Clinicians.

Changes in left atrial size in patients with lone atrial fibrillation.

Long-term results of surgical minimally invasive pulmonary vein isolation for paroxysmal lone atrial fibrillation.

Risk of Arrhythmia Recurrence After Successful Ablation of Lone Atrial Fibrillation.

Mutational spectrum of the NKX2-5 gene in patients with lone atrial fibrillation.

Gain-of-function mutations in potassium channel subunit KCNE2 associated with early-onset lone atrial fibrillation.

Long-Termendurance Sport Practice Increases The Incidence Of Lone Atrial Fibrillation Inmen: A Follow-Up Study.

Chronic Kidney Disease and Atrial Fibrillation: A Contemporary Overview.

A brief overview of surgery for atrial fibrillation.

Functional Characterization of Rare Variants Implicated in Susceptibility to Lone Atrial Fibrillation.

Clinical and Echocardiographic Factors Affecting Tricuspid Regurgitation Severity in the Patients with Lone Atrial Fibrillation.

Lone Atrial Fibrillation Is Associated With Impaired Left Ventricular Energetics That Persists Despite Successful Catheter Ablation.

Estrogen receptor 1 gene (TA)n polymorphism is associated with lone atrial fibrillation in men.