Lone Atrial Fibrillation – An Overview

T. S. Potpara; G. Y. H. Lip

Int J Clin Pract. 2014;68(4):418-433.

Abstract and Introduction

Abstract

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.

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 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.^[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.

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Table 1. Clinical and demographical conditions associated with atrial fibrillation. ^[8,16–42]
Cardiovascular diseases/conditions	Comment/risk of AF	Other diseases/conditions	Comment/risk of AF	Demographical features, lifestyle, procedures	Comment/risk of AF
Hypertension, hypertension treatment, SBP* [12,16–18]	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]	COPD [12,22]	Present in 10–15% AF patients; a general marker of cardiovascular risk	Aging [12,16,22]	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
LVH [17]	HR 1.36 (1.03–1.80)	Hyperthyreosis [12,22,23]	TSH level: HR 1.94 (1.13–3.34)	Male gender [16,22]	OR 1.5 (1.3–1.8)
Heart failure [8,12,17,19,20]	HR 3.20 (1.99–5.16) [17] 'Diastolic' HF (i.e. HF-PEF) is also a risk factor for AF [19,20]	Diabetes mellitus [12,16]	OR 2.1 (1.5–2.8) females OR 1.7 (1.2–2.3) males	Caucasian [31–33]	Blacks have a higher burden of conventional AF risk factors, but lower risk of AF compared to whites
CAD [12,16,17,21]	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)	CKD [12,22,24]	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)	Cigarette smoking [34,35] Alcohol [36,37] Endurance sports [38]	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
Valve disease [16]	Essentially, rheumatic mitral stenosis: OR 1.8 (1.2–2.5), males OR 3.4 (2.5–4.5), females	Obesity [12,22,25] Metabolic [26] syndrome	RR 1.49 (1.36–1.64); the risk increases in parallel with BMI HR 1.88 (1.40–2.52)	Cardiothoracic surgery [12,39,40] Non-cardiothoracic surgery [12,40]	16–46% of patients 0.4–12% of patients
Cardiomyopathies [22]	20–25% of patients with HCM develop AF; primary electrical cardiac diseases, 'channelopathies', also carry a risk for AF	Obstructive sleep apnoea [12,27–29]	A general cardiovascular risk factor associated with CAD, HF, hypertension, cardiac arrhythmias and stroke	Acute inflammatory disorders [41]	AF is common among critically ill patients with sepsis
Other cardiac diseases [12,22]	Pericardial disease, congenital defects, conduction disturbances including prolonged PR interval, cor pulmonale, AVNRT, WPW	Rheumatoid arthritis [30]	Adjusted AF incidence rate ratio 1.41 (1.31–1.51)	Tall and lean stature [42]	Height: OR 1.026/cm (1.022–1.023) Body surface area: OR 4.2/m² (3.4–5.3)

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].

Table 2. Studies which investigated the clinical outcomes of 'lone' AF.
	Study	Year	Lone AF definition	Number of patients	Age >60 years (%)	Follow-up	Main findings	Main conclusions	'Lone' AF is a benign condition
1	Evans et al. [2]	1954	Non-paroxysmal AF without heart disease or thyroid toxaemia	20 (all males)	50	10 years (4 pts), 20 years (2 pts)	No adverse events (i.e., HF, TE or death)	A benign disorder with normal life expectancy; rate control with digitalis if needed	Yes
2	Brand et al. [52]	1985	AF in patients free of CAD, CHF, rheumatic and hypertensive heart disease*	43 (32 males)	56	30 years	A fivefold greater risk of stroke vs. age- and sex-matched controls; a similar CAD and CHF rates	'Lone' AF patients have significantly greater stroke rates and a distinct preponderance of preexisting ECG abnormalities (e.g., interventricular block and ST-T changes)	No
3	Kopecky et al. [53]	1987	AF in the absence of overt cardiovascular disease or precipitating illness	97 (gender not reported)	0	14.8 years per patient	94% probability of survival at 15 years; 1.3% of patients experienced a stroke (stroke rate of 0.55 per 100 person-years), no deaths	'Lone' AF in patients under 60 years is associated with a very low risk of stroke, suggesting that routine anticoagulation may not be warranted	Yes
4	Davidson et al. [54]	1989	AF in patients free of CAD, CHF, rheumatic and hypertensive heart disease	32 (19 males)	0	Mean 4.9 years (2–16)	No progression to permanent AF, CHF or CAD development; one patient experienced a stroke (stroke rate of 0.64 per 100 person-years)	Most 'lone' AF patients have symptomatic paroxysmal AF, normal left atrial size and a low rate of stroke	Yes
5	Rostagno et al. [55]	1995	No clinical evidence of any organic cardiac disease^†	106 (43 males)	? (43 pts older than 70)	Mean 6 years (1–138 months)	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	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	Yes
6	Scardi et al. [56]	1999	No evidence of organic heart disease	145 (118 males)	0% All younger than 50	Mean 10 years (1–35)	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	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	Yes/No Yes, if paroxysmal No, if chronic AF
7	Jouven et al. [57]	1999	No clinical evidence of any heart disease^‡	25 (gender not reported)	0	Average 23 years	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	'Lone' AF is associated with an increased mortality and clearly requires clinical attention; could be the first sign of an underlying cardiovascular disorder	No
8	Rienstra et al. [63]	2004	AF without any underlying disease (i.e. CAD, valvular disease, HF, cardiomyopathy, congenital heart disease, hypertension, previous TE events, diabetes mellitus or previous thyrotoxicosis)^§	89 (75 males)	? Mean age 65 ± 10	Mean 2.3 years	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	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 comorbiditiesThe rate vs. rhythm analyses: the number of end-points was low in both strategies but twice as low in patients randomised to rhythm control	Yes
9	Jahangir et al. [58]	2007	AF with no concomitant heart disease or hypertension	76 (59 males)	0	Mean 25 years	A 30-year progression to permanent AF was 29%; the overall survival was similar to age- and sex-matched 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)	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
10	Potpara et al. [59]	2010	AF with no evidence of any cardiopulmonary or other disease including hypertension and no obvious cause of a transient 'acute' AF	442 (gender not reported)	14.7	Mean 11.5 years	12 deaths (seven non-cardiac 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 all-cause mortality (0.25%) and cardiovascular mortality (0.10%)	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	Yes, with regular follow-up
11	Potpara et al. [60]	2012	AF in individuals ≤ 60 years old with no evidence of any cardiopulmonary or other disease including hypertension and no obvious precipitating factors for AF	346 (263 males)	0	Mean 12 years	Approximately a third of patients developed cardiovascular disorders during follow-up; a 10-year 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%	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	Yes, in young and otherwise healthy individuals
12	Weijs et al. [64]	2012	AF in the absence of any cardiovascular disease or comorbidities	119 (57 males)	48	1 year	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	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	Yes, even in elderly
13	Weijs et al. [65]	2013	AF in the absence of any cardiovascular disease or comorbidities	45 (27 males)	? Upper age limit was at 64 years	Mean 5 years	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	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	No
				Σ 1075^¶			7 Yes, 3 No, 3 Yes, with some caution(s)

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].