Atrial fibrillation (AF) is one of the most common persistent clinical arrhythmias, usually with an atrial excitation rate of 300 to 600 beats/min, and often with a fast and irregular ventricular rate. The prevalence of atrial fibrillation increases with age, reaching up to 10% in people over the age of 75. Within the next 30 years, atrial fibrillation will become one of the most prevalent cardiovascular diseases worldwide. The reasons for the rapid increase in the prevalence of atrial fibrillation, although unclear (1C4), are generally believed to be closely related to the growth of coronary heart disease, hypertension and heart failure. The conventional wisdom is that atrial fibrillation is mainly caused by ischemia, secondary to atherosclerosis or other heart diseases, and the rest of those atrial fibrillation without coronary heart disease, rheumatic heart disease, heart failure and hypertension are called isolated or idiopathic atrial fibrillation.
These patients do not have an obvious cause and have a better prognosis during long-term follow-up. As the causes and mechanisms of atrial fibrillation have been studied in depth in recent years, it is believed that atrial fibrillation is an arrhythmia that can be genetically related, and that factors such as obesity, metabolic syndrome, excessive alcohol consumption, apnea, excessive endurance exercise, changes in autonomic tone, inflammation, etc. may play a role behind the seemingly isolated atrial fibrillation.
1. Isolated or idiopathic atrial fibrillation was proposed
In 1954 Evan and Swann (5) described a group of patients with atrial fibrillation with no cardiac findings by correlative examination and proposed the term isolated atrial fibrillation. Some investigators defined it as idiopathic atrial fibrillation. Although widely used, isolated AF is generally considered to account for only a minority of patients with AF, although occasional estimates of approximately 30% have been made in some reports.
Over the past 20 years, knowledge about the etiology and mechanisms of AF and new types of heart disease has continued to expand. The currently known risk factors associated with AF are listed in Table 1. multidisciplinary and technological advances have and will continue to uncover the mechanisms by which various etiologies contribute to AF. Although we cannot currently determine the exact mechanism in every patient with AF, we have moved from the formulation of a vague concept to a more realistic scientific classification. In the near future, at some point we will be able to classify AF according to its mechanism. Most patients with atrial fibrillation do not have traditional heart disease and may be influenced by multiple factors rather than a single cause. These influences can lead to changes in the structure of the heart, which can be recently detected by imaging and can be considered as new types of heart disease.
Table I Risk factors for atrial fibrillation
Conventional risk factors
Advanced age
Male
Coronary artery disease
Hypertension
Heart Failure
Valvular heart disease
Diabetes mellitus
Hyperthyroidism
Other
Uncertain risk factors
Chronic obstructive pulmonary disease
Enlarged left atrium
Atrial conduction block
Left ventricular diastolic insufficiency
Left ventricular hypertrophy
Obesity
Obstructive sleep apnea syndrome
Genetic factors
Other
Emerging risk factors
Subclinical atherosclerosis
Critical hypertension (between 120/80 and 140/90 mmHg)
Chronic kidney disease
Subclinical hyperthyroidism
Inflammation
Elevated natriuretic peptide
Large pulse pressure difference
Excessive endurance exercise
Excessive alcohol intake
Increased body weight
Excess birth weight
Smoking
Caffeine intake
Racial differences
Other
2. Variability in the definition of isolated atrial fibrillation
Current atrial fibrillation guidelines define adult patients <60 years of age with atrial fibrillation without a clinical history of comorbid cardiopulmonary disease or evidence of cardiac ultrasonography (10,11). The existing guidelines do not specify which comorbidities must be excluded to be considered isolated AF. This broad definition has led to inconsistencies in the criteria for isolated AF among different investigators, resulting in confusion. In a literature search (HTTP://www.ncbi.nlm.nih.gov/pubmed; search terms "isolated AF" and "idiopathic AF"), there were 125 articles on isolated AF. The exclusion criteria were sometimes retrospectively analyzed according to the 10th Revision of the International Classification of Diseases, adding to its imprecision. For example, coronary atherosclerotic heart disease risk factors were often excluded in the literature (69% of studies). However, even in these studies, there was no uniform definition to exclude coronary heart disease. Similarly for age criteria, only 23% of the studies excluded patients aged >60 years. The definition of 60 years is subjective and arbitrary and not based on any clear pathophysiological basis.
In addition to history and physical examination, the most common tests used in the literature to exclude concomitant disease are usually 12-lead body surface ECG, transthoracic echocardiography and laboratory tests for thyroid dysfunction, diabetes mellitus, C-reactive protein, and white blood cell count. In most studies, exercise stress tests were performed only when coronary artery disease was clinically suspected. Left ventricular diastolic function has only been measured in recent years, not to mention cardiac magnetic resonance imaging or the evaluation of other novel heart disease types.
Another factor to consider is that underlying cardiac disease tends to develop over time, on a continuum. Early unrecognized etiologies may gradually be detected by modern screening tools.
3. Prevalence of isolated atrial fibrillation reported
The prevalence of isolated AF varies widely, ranging from 0.2% to 68%, depending on the definition of isolated AF, study population, and diagnostic tools (14,15). the Framingham Heart Study reported a prevalence of 11% for isolated AF, with hypertension defined using > 160 / 95 mm Hg criteria, without echocardiographic ECG assessment. In the Olmsted cohort study, isolated atrial fibrillation accounted for 2% to 4% (14,16,17). Recent German network registry studies (AFNET), the European Heart Survey study (Euro Heart Survey), and the Global Survey of Patients with Atrial Fibrillation study (REALISE-AF) reported prevalence of isolated AF of 12%, 10%, and 5%, respectively (18C20). If a stricter definition is applied in the European Heart Survey, the prevalence of isolated is only 3% (21). In hospital-based studies, prevalence varies from 2% to 45%, again depending on the clinical characteristics of the patient (22C25). A greater proportion of patients with paroxysmal AF are diagnosed with isolated AF compared to persistent AF (26).
4. Isolated atrial fibrillation and imaging
It is controversial whether simple enlargement of the left atrium is cardiac disease. Left atrial enlargement may be a cause or consequence of atrial fibrillation (27). The best techniques to detect the structure and function of the left atrium continue to progress. The simplest is P-wave time measurement. m-mode and 2-dimensional echocardiography quantify left atrial size and volume. M-mode analysis of the left atrial internal diameter does not accurately reflect the size of the left atrium because of its asymmetric shape and the nonuniformity of atrial enlargement (28,29). In contrast, left atrial volume index has been shown to provide a more accurate assessment compared with gold standard imaging techniques such as magnetic resonance imaging to predict the risk of cardiovascular disease.
Another recent innovation is the application of two-dimensional speckle tracking techniques in echocardiographic evaluation of the atria to determine the strain or strain rate of the atrial muscle. In addition, a large number of studies have shown a strong relationship with left atrial strain with atrial remodeling and the degree of atrial myocardial fibrosis. Because of its high spatial resolution, magnetic resonance imaging is the gold standard for left atrial volume measurement, but compared with transthoracic echocardiography, routine magnetic resonance imaging is impractical in patients with atrial fibrillation. In recent years, delayed gadolinium enhancement MRI examinations, for example, have been used to determine the degree of atrial fibrosis in AF (30,31). Although these findings are at an early stage of research, the ability to identify early changes in atrial structure would undoubtedly be beneficial in determining the presence or absence of heart disease.
Although it is generally accepted that the diagnosis of isolated AF requires the exclusion of ventricular systolic dysfunction, the effect of ventricular diastolic dysfunction is often not considered. However, a large body of data suggests that hypertension, left ventricular hypertrophy, ventricular diastolic dysfunction, atrial enlargement, and atrial fibrillation may be a continuous pathophysiologic process. Ventricular diastolic dysfunction coexists with other atrial fibrillation risk factors including age, obesity, and diabetes mellitus and has not been identified as an independent risk factor. Clinical studies have reported that the presence of atrial fibrillation in patients with heart failure with reduced left ventricular function suggests a poor prognosis (34C36). Right ventricular insufficiency in chronic obstructive pulmonary disease and other non-cardiac causes of pulmonary hypertension should not be ignored either.
5. Isolated atrial fibrillation and genetic studies
A genetic association with AF has been established in the Framingham (37), Icelandic (38), and Danish (39) population studies. A family history of atrial fibrillation is associated with a 40% increased risk of atrial fibrillation, and genetically associated atrial fibrillation appears to be more common in isolated or early-onset atrial fibrillation (40C44). Multiple variants, both rare and common, have been identified in association with AF. Genome-wide association studies have identified at least 10 different common variant loci (48C52). Patients with isolated AF are frequently found to have genetic mutations in a range of cardiac ion channels, structural proteins and signaling molecules, with nearly 20 genes associated with atrial fibrillation.
6. Pathophysiological mechanisms of isolated atrial fibrillation
Clinical atrial fibrillation is the result of an interaction between trigger foci and maintenance mechanisms (i.e., substrates) (45-47). Atrial fibrillation is often triggered by premature beats originating in the pulmonary veins. Abnormalities in the tissue structure and function of the left atrium-pulmonary vein junction and the nearby ganglion plexus increase the triggering activity of the pulmonary vein muscle cuff. Atrial fibrillation in different populations may have similar mechanisms, and electrical isolation of the pulmonary veins can be successfully treated with or without traditional risk factors for atrial fibrillation. Mechanistically, extensive AF ablation can also alter the maintenance substrate of AF (54) or the autonomic ganglia (49). Electrical and structural remodeling in patients with AF together contribute to the maintenance of AF.
There are two possible mechanisms for the maintenance of AF: first, the local driving foci, or rotor (rotor) theory, and second, the multinomial wave foldback theory. In the CONFIRM pilot study (59), 2-3 relatively fixed rotors were found in the left and right atria of each patient by a large and detailed specimen analysis. However, it has also been shown that rotors are variable and stable rotors are less common, and that the duration of atrial fibrillation correlates with the number and complexity of rotors. As a result of chronic atrial traction in atrial fibrillation, this leads to massive activation of pro-myocardial fibrosis and hypertrophic signaling pathways, causing fibroblast proliferation and differentiation and collagen synthesis. The accumulation of extracellular collagen fibers causes an electrical loss of coupling between myocardial bundles, and the resulting conduction abnormalities lead to folding, conduction block, and/or electro-mechanical separation.
Likewise, inflammatory changes may play an important role in the maintenance of AF, especially the recurrence of AF. In a study of patients with isolated AF, atrial myocardial biopsy revealed local lymphoid mononuclear cell infiltration and fibrosis as the most common pathologic changes (67). Myocarditis may contribute to the development of AF by shortening atrial expiration, slowing conduction, and oxidative damage leading to apoptosis and remodeling of atrial myocytes. In addition downregulation and/or spatial redistribution of cellular connexins (an intercellular gap junction protein), which regulate intercellular electrical coupling in remodeling (68,69), resulting in impaired conduction is also an important factor contributing to the development of AF.