Abstract
Atrial fibrillation (AF) is a worldwide common disease. Since 1628 research has been carried out into the pathophysiology and treatment of AF. The prevalence is high and still increasing due to the aging population. It can be seen as both a financial and a public health burden.
The symptoms vary between individuals. However, palpitations, shortness of breath, chest pain, fatigue, dizziness, and psychosocial stress are common symptoms. To diagnose AF, electrocardiographic recording (ECG) is often used. The ECG shows in most cases an absence of a P-wave and irregularity of R-R intervals.
AF is associated with an increased risk of embolic stroke, heart failure, myocardial infarction, dementia, chronic kidney disease, and mortality. Out of those risks, embolic stroke is the most dangerous.
There are also several risk factors that can increase the risk of AF. Those risk factors include aging, the male sex, hypertension, heart failure, obesity, obstructive sleep apnea, atrial dilatation, myocardial stretch, and other discussable ones.
Multiple genetic variants, both rare and common, are associated with AF. Rare variants probably disrupt normal ion channel properties.
AF is often induced by ‘triggers’, usually in the form of premature depolarizations of the atria. AF maintains itself via re-entry mechanisms, which are caused by electrical and structural remodelling of the atrium.
The treatment of AF is based on 3 main strategies: rate control, rhythm control, and anticoagulation therapy. Rate control includes the use of β-blockers, digoxin, or calcium-channel blockers. Rhythm control involves pharmacological cardioversion, electrical cardioversion, or ablation therapy.
1. Introduction
Atrial fibrillation is a frequent clinically observed cardiac arrhythmia. Due to the aging population, it becomes even more common. It can be described as a ‘cardiac arrhythmia where the rhythm is completely irregular and usually accelerated’. Patients often experience it as heart palpitations, dizziness, weaknesses, dyspnoea, and reduced tolerance of exercise. Nowadays, there is a great knowledge of the epidemiology, physical presentation, prognosis, risk factors, genetics, pathophysiology, and treatment options.
In 1628, William Harvey was the first to discover the ‘undulation/palpitation’ of the auricle of the heart.1,3 The French doctor Jean de Sénac (1693-1770) assumed there was a causality between the recurrence of congestive heart failure, stenosis of the mitral valve, irregularity of the pulse and dilatation of the heart. The Scottish James Mackenzie (1853-1925) constructed a polygraph with which he could register the arterial and venous pulse curves of the patient at the same time. He noticed that a presystolic ‘a’ wave could not be seen on the jugular phebogram during ‘pulsus irregularis perpetuus’.1
August Waller (1856-1922) is seen as the founder of the electrocardiography (ECG). He was the first to deduce the bioelectrical activity of the mammalian heart from the surface of the body. Thanks to Willem Einthoven (1860-1927), a Dutch physiologist, the first human ECG depicting atrial fibrillation was published in 1906. In a patient with an irregular and unequal pulse, he recorded an irregular rhythm of the QRS complexes, fitting for atrial fibrillation.1,2
The direct relation between absolute arrhythmia and auricular fibrillation was given by Rothberger and Winterberg. Thomas Lewis (1881-1945) was the first to describe the current observations on AF-associated clinical hemodynamic and electrocardiographic changes in 1910. He proved that the electrophysiological mechanism of atrial fibrillation involves a pathological circulation of an electrical stimulus in the atrium (‘circus movement’). In 1914, Karel Wenckebach noticed that the pulse of an arrhythmic patient became regular again after administration of kinin.1
It was only after the Second World War that the American scientist Gordon Moe changed the ‘circus movement’ theory of Lewis into the so called ‘multiple wavelet’ theory. This theory said that atrial fibrillation is maintained by re-entry circuits by multiple axis activations in the atria at the same time.1 Since several years it is thought that AF can also have a focal cause (in the pulmonary veins).8
In this essay an overview of our current knowledge about atrial fibrillation is provided. It discusses the epidemiology, physical presentation and consequences, risk factors, genetics, pathophysiology, and treatment of AF. Furthermore, the future of AF will be described.
2. Prevalence
2.1 Global prevalence
Atrial fibrillation is the most common atrial arrhythmia in adults, with a worldwide prevalence of 35.5 million patients and affecting 2.5-3.5% of populations across the world.4 However, the actual prevalence could be higher, because there are a lot of patients with AF who remain undiagnosed. This underestimation of AF is a worldwide problem. It might explain the variability in prevalence worldwide.6
The incidence of AF in developed countries is twice as high as in non-developed countries. 4,6 In Australia, Europe, and the USA, the prevalence of AF is 1-4% in adults, rising to > 13% in individuals aged > 80 years. The exact reasons of the ethnic and regional variation are probably caused by differences in study design, genetics and environmental factors.6
The incidence of AF rapidly rises with the increase of age, and the majority of the patients in developed countries are aged > 65 years. In both Japan and China (rapid developing countries) there will be an increase in the prevalence of AF, despite a predicted decrease in the total population, due to the aging population. Estimates from low-income and middle-income countries (e.g. India, Africa) are less accurate, although populations of elderly adults in these countries are similarly expected to increase. Consequently, it is likely that AF is going to be a major cause of morbidity in these regions. 6
AF affects public health financially. Most of the cost is from hospitalization, stroke and heart failure (HF) care, and loss of economic productivity. Also, from 1990 to 2010, the worldwide burden of disability-adjusted life-year loss by AF increased in both men and women.4,6 These increases reflect a growing global burden of AF in both economic and disability prospect.
The incidence and effects of AF are also influenced by sex. Women tend to be more symptomatic from AF, with longer episodes and a faster response rate of the ventricles during paroxysms. However, compared to men, women show a 46% lower age-matched risk and a lower incidence of AF. Women do have a higher risk of cardioembolic stroke from AF, though. The Copenhagen City Heart Study showed that women have a 2.5-fold increased risk of cardiovascular mortality related to AF.4 Nonetheless, there is usually a higher prevalence of AF in men than in women worldwide.
The prevalence and incidence of AF have been increasing over time and is thought to further increase in the future, due to increasing age, increasing prevalence of obesity, better survival of diseases, and better diagnosis of arrhythmias.5
2.2 Prevalence in the Netherlands
In 2016, 107.600 new disease episodes of atrial fibrillation/fluttering were registered at the general practitioner: 58.100 men and 49.400 women. 74% of the men and 85% of the women were older than 65 years. In men, most new disease episodes were registered at the age of 65-74 years and in women at the age of 75-84 years. Relatively more men were affected in all age categories: 7.3 per 1000 men and 5.9 per 1000 woman had a disease episode of atrial fibrillation in 2016. These numbers are those of new disease episodes of atrial fibrillation. They also registered the number of persons who already were diagnosed with AF: 315.100 patients (169.500 men and 145.600 women).7
There were 22.189 day admissions for atrial fibrillation in 2016: 14.704 for men and 7485 for women. Most admissions took place in the age category of 65-74 years. 62% of the men and 79% of the women were older than 65 years. The relative number of day admissions is higher in men than in women in all age categories. 7
Atrial fibrillation alone is rarely a reason for hospitalization; it is often accompanied by a co-morbidity. In 2016, there were 38.617 hospital admissions for atrial fibrillation: 21,191 men and 17.426 women. In total, and especially below 75 years, there were more hospital admissions in men than in women (251 per 100.000 men and 203 per 100.000 women). In the period 1980-2016 the absolute number of hospital admissions for atrial fibrillation increased in all age categories, relatively the strongest in the older age categories. Part of this increase is caused by the aging population. The average number of days in the hospital for atrial fibrillation was 1.4 days for men and 1.7 days for women in 2016.7
Totally, 1572 people died in 2016 of AF: 558 men and 1014 women. The average age of death was 84 years in men and 88 years in women.7
In conclusion, atrial fibrillation mainly affects the elderly and more often men than women. Men are generally younger than women when they are admitted or contacted by a doctor. Every year about 110.000 new disease episodes, 22.000 daily admissions and 40.000 hospital admissions are registered for AF.
3. Physical presentation and prognosis
We distinguish three types of AF:8
– Paroxysmal AF: the episodes end spontaneously (within 7 days).
– Persistent AF (> 7 days): the episodes can end with an intervention.
– Chronic persistent AF: the episode cannot be ended and the AF is accepted.
The symptoms can vary between individuals. Irregular heart palpitations, shortness of breath, chest pain, sleep difficulties (and thus fatigue), dizziness, and psychosocial distress are common complaints.8,9 The intensity of symptoms is related to the health-related quality of life (HRQOL). AF patients significantly have lower HRQOL than healthy individuals.9
Sometimes, patients are asymptomatic and the AF is then accidently diagnosed.8 Asymptomatic AF is less common among women than among men. Also, women are more likely to have longer duration of symptoms and to present with atypical symptoms (e.g. weakness, fatigue). These atypical symptoms might lead to a delayed diagnosis and care. All these factors might contribute to a low quality of life and more depression in women than in men with AF.10
Electrocardiographic recording (ECG) is used to confirm the presence of AF. Both a 12-lead ECG or, in case of paroxysmal AF (PAF), an ambulatory ECG (AECG) can be used.11
In most cases, the diagnosis of AF is based on 2 electrocardiographic criteria: absence of a visible P-wave on the 12-lead ECG and irregularity of R-R intervals (Figure 1). An electrocardiographic appearance of an organized type of AF is seen more often in patients with a myocardial structure that is better conserved.11
It is often difficult to distinguish between AF and atrium flutter (AFL) on a 12-lead ECG, because the relationship between those two is very close.11
Figure 1. A 12-lead ECG recording of typical AF. Absence of a visible P-wave and irregularity of R-R intervals. bpm, beats per minute Source: P Wave Analysis of the Era of Atrial Fibrillation Ablation. 2018
Because symptoms of PAF are often not specific and episodes can occur at any time, duration of ECG monitoring is a crucial thing for the detection of PAF. Today, there are new AECG recording systems that outclass the standard 24-hour Holter monitoring: external AECG monitors (1-4 weeks) and implantable AECG monitors (2-3 years).11
AF is associated with an increased risk of embolic stroke, HF, myocardial infarction (MI), dementia, chronic kidney disease, and mortality.6
Embolic stroke is the most feared complication. AF increases the risk of stroke by a factor five. However, the risk highly depends on age: increasing from 4.6% in individuals aged 50-59 years to >20% in those aged 80-89 years. The risk of stroke also varies between ethnic groups. Stroke has a worse prognosis in patients with AF than in healthy patients.6,10
AF is associated with an increased risk of dementia. This risk is associated with increased mortality.6
It is shown that AF and HF often exist side-by-side, share risk factors, and each contributes to the development of the other. Patients with HF or AF who develop the other condition have an increased risk of mortality compared with patients who have either condition alone.6
AF gives a twofold higher risk of MI after correction for cardiovascular comorbidities and other therapies.6
Furthermore, AF is associated with a 1.5-fold increase in the risk of death in men and 1.9-fold increase in women.6 So, AF increases the risk of mortality.
4. Risk factors and genetics
4.1 Risk factors
There are multiple risk factors that influence the incidence of AF (Figure 2). Aging is the predominant demographic risk factor: AF incidence is multiplied by a factor 15-20 between 35 and 85 years, whereas the prevalence rises from 1% to 15%. With aging, the amount of interstitial fibrosis and
Figure 2. AF risk factors according to the value of the relative risk Source: Risk factors and genetics of atrial fibrillation. 2014
fatty infiltrates increases. Therefore, the atrial muscle is predisposed to disturbances of electrical impulse conduction. These disturbances can lead to AF initiation and maintenance. At the cellular level, multiple abnormalities may contribute to age-related AF. Yet, the causes that connect aging and AF are unknown, despite our basic understanding.12
The male sex is also a risk factor of AF. Men show a higher incidence and prevalence than women worldwide.13
Hypertension is a common AF risk factor: the third most common risk factor and the first disease-related risk factor. By hypertension, the inducibility of atrial tachycardia and the amount of atrial fibrosis are increased. Unfortunately, we don’t know much about the pathophysiology of hypertension in AF.
Heart failure (HF) is a major AF risk factor; HF patients have a 5-fold increased risk of AF. HF causes an increase in atrial fibrosis, which is a determining factor of occurrence of AF. Coronary artery diseases (CADs) are also a substantial risk factor of AF initiation and maintenance. CADs are shown to reduce atrial refractory periods, to increase AF inducibility, to modulate electrical impulse distribution, and to cause an acceleration of atrial drivers.4,6,12
Furthermore, there is a major relationship between obesity and AF risk. Obesity increases plasma levels of free fatty acids and the visceral and epicardial adiposity. This infiltration of free fatty acids results in higher levels of biofactors, which overload the myocardium. Therefore, deterioration of the myocardial function can occur and lead to abnormal mechanism of impulse initiation and atrophy of the myocytes.12 It is thought that the growing obesity epidemic will be a major cause in the worldwide increase in the prevalence of AF.6
Obstructive sleep apnea (OSA) is recently accepted as a major risk factor of AF. Effective OSA therapy showed a decrease in the incidence of AF.4,12
Well-known risk factors of AF are atrial dilatation and myocardial stretch. Atrial stretch lead to multiple electrophysiological changes, including prolongation of late repolarization and shortening of early repolarization, changes in the electrical sources of AF, and an increased excitability. 12
Other known risk factors are chronic kidney disease, smoking, alcohol, diabetes, and thyroid dysfunction. However, their importance is still discussed.6,12
4.2 Genetics
Multiple genetic variants associated with AF have been identified. In general, lone AF (AF without risk factors) has a greater heritability than AF observed in association with other risk factors.12
Family history of AF is associated with a 40% increased risk of first-degree relatives developing AF.13 Several rare and common genetic variants that predispose to AF are known.
Rare genetic variants and AF
Rare genetic variants probably disrupt normal channel properties by causing a loss or gain of function in the affected ion channels (Table 1). These variants hamper the processes of depolarization or repolarization, which can lead to early afterdepolarizations and re-entry electrical excitation.12,15
Some variants of genes for non-ion channel proteins are also associated with AF. Molecular underlying mechanisms are not fully understood.12
Common genetic variants and AF
Genome Wide Associated Studies (GWASs) have identified several single nucleotide polymorphisms (SNPs) associated with AF. An SNP (rs2200733) located in the gene PITX2 is highly associated with AF. Other loci with SNPs located in regions that are intronic or upstream of the closest gene have been identified (Table 2).12,14,15
ANP, atrial natriuretic peptide; Aux., auxiliary; BMP, bone morphogenic protein; GOF, gain of function; LOF, loss of function; NE, no effect; NI, not investigated; Trnscrpt., transcription
Source: Risk factors and genetics of atrial fibrillation. 2014
Source: Risk factors and genetics of atrial fibrillation. 2014
5. Underlying mechanisms
AF is caused by multiple pathogenic pathways. Focal AF ‘triggers’ have been identified, usually in the form of premature depolarizations of the atria. The source of the focal triggers is in most cases atrial myocytes that make up ‘sleeves’ of the muscle that reach from the left atrium (LA) into the pulmonary veins (PVs).4,10 The cardiomyocytes in the PVs show development of pacemaker-like activity, resulting in ectopic tachycardias. This can lead to a decreased electrical refractoriness of the atria, generating AF initiation.16
Frequent firing and progressive atrial remodelling enable AF to maintain itself via re-entry within atrial heterogeneous tissue. Initially, it was thought that the multiple-wavelet hypothesis induced AF, but now another theory says that a small group of high-energy re-entrant circuits in the LA, the so called ‘rotors’, can also promote AF sometimes.4,13,16
The development of AF is linked to structural and electrical remodelling of the atria, which can be caused by the previously mentioned risk factors. Increased left atrial pressure and size can lead to disorganization of the connective tissue and interstitial fibrosis. These histologic changes slow atrial conduction velocity and increase local heterogeneous conduction and conduction block.4,10
Electrical remodelling includes occurrence of increased automaticity as a result of changed calcium handling by calcium leak of the sarcoplasmic reticulum (SR). This can also effect conduction velocity and tissue refractoriness. Atrial myocytes react by myocyte depolarization to downregulate calcium channels. These changes also result in shortening of action potential duration, advanced atrial refractoriness reducing and further generating AF.4,13
AF is also associated with inflammation. Some inflammatory markers are higher in patients with persistent AF than in those with paroxysmal AF. These markers, e.g. C-reactive protein, are linked to an increased embolic risk.4
AF initiation and maintenance also have a relation with an increased activity of the autonomic nervous system and structural fibrosis by age. Start of AF often occurs after an increase in sympathetic input, followed by an sudden parasympathetic predominance right before the initiation of AF.4,16
So, the development of AF results from multitude processes: factors that promote early atrial extension, atrial fibrosis that causes heterogeneity, inflammation, electrical remodelling and autonomic remodelling.
Treatment modalities
The treatment of AF consists of 3 main strategies: rate control, rhythm control, and anticoagulation therapy. More than one approach is often necessary for effectivity. When rate of rhythm control is used, depends on the patient (Table 3).17
Table 3 Rate versus rhythm control
AF, atrial fibrillation
Source: Medical treatment of atrial fibrillation. 2012
Rate control
Rate control can include the use of short-acting β-blockers, digoxin, non-dihydropyridine calcium-channel blockers. The heart rate can be decreased within 30 minutes from 150 beats/min or more to 100 beats/min or less. The therapy of first choice in most patients is β-blocking. If then rate control is not achieved, digoxin or a calcium-channel blocker can be added.6,17 Some patients can’t take medication, or the medication doesn’t work. In those individuals, atrioventricular node/His bundle ablation and pacemaker implantation can be used. In patients with heart failure, biventricular pacing must be considered. Specific agents of rate-control should be selected by comorbidity and lifestyle.17 A disadvantage of rate control is the risk of thromboembolic complications and the loss of atrial contraction.8
Rhythm control
Rhythm control, the restoration and maintenance of sinus rhythm, can involve pharmacological cardioversion, ablation therapy and electrical cardioversion. Pharmacological cardioversion is effective early after the onset of AF, while electrical cardioversion is more effective if AF has been present for more than 72 hours.17
Electrical cardioversion
If AF has been present for more than 48 hours, the patient should first take oral anticoagulation therapy for at least 4 weeks to reduce thromboembolic complications. The defibrillation itself should be biphasic with a shock of 200 Joule. After cardioversion, the patient should rest for 2-4 hours with electrocardiographic monitoring.17
Pharmacological cardioversion
This can be achieved with oral or intravenous medication. A number of class I, class III and multichannel blocking anti arrhythmic drugs (AADs) are available. Which one is used, depends on the underlying heart disease. After the cardioversion is successful, the effective dug is usually continued.17
Some AADs can also be used to prevent or delay the recurrence of atrial fibrillation, including class 1a (disopyramide) , class 1c (flecainide) and class 3 (amiodaron).8,17
Ablation therapy
Atrial ablation is an alternative to AAD therapy for effective reduction of recurrent AF. It is recommended when a patient have failed on at least one AAD. It is called the ‘Maze procedure’, in which multiple incisions are made in the left and right atrium to form scar tissue. Therefore, it makes the conduction of electrical activity impossible.16,17
Anticoagulation
In patients with AF, oral anticoagulation must be given as prevention of thromboembolic complications. In the left atria, a thrombus can occur due to loss of atrial contraction, which can cause a stroke. Today the risk-prediction model CHA2DS2-VASc-score is used to guide the treatment with anticoagulation. A high score relates to a greater risk of stroke and is so an indication for anticoagulation therapy. Warfarin, a vitamin K antagonist, has been the anticoagulation drug of choice. However, New Oral Anticoagulation (NOAC) seems to be as effective as vitamin K antagonists. Unfortunately, anticoagulation therapy increases the risk of haemorrhages.6,16
Conclusion and discussion
Conclusion
AF is a common disease worldwide with an increasing clinical and public health burden. The symptoms can vary between individuals and it is often diagnosed by typical findings on the ECG. It is associated with an increased risk of embolic stroke, HF, MI, dementia, chronic kidney disease and mortality. There are multiple risk factors that are associated with an increase of incidence and several genetic variants, both rare and common, that correlate with AF. AF is usually induced by focal ‘triggers’ and is maintained by a re-entry mechanism within atrial heterogeneous tissue. This re-entry mechanism is caused by structural and electrical remodelling of the atria. Today, 3 main strategies of treatment are known: rate control, rhythm control, and anticoagulation therapy. More than one approach is often necessary for effectivity.
Future perspective
Around the world, accurate data of the prevalence, risk, prognosis, prevention and treatment of AF are lacking. This shortage of data remains to be tackled in the future.
Because AF is common in elderly people, it is hypothesized that the prevalence of AF in rapid developing countries will double in the coming 2-3 decades. In addition, AF remains underdiagnosed and undertreated, even in high-income countries. There is also a major lack of knowledge about AF, due to the shortage of powerful primary prevention strategies worldwide. The risk-prediction models might be useful in the future to target the ‘at risk’ population for early intervention (e.g. treatment of risk factors and early detection by regular screening).6
Another important problem is inadequate treatment. <50% of individuals with AF received indicated therapy, although 93.5% was eligible for therapy. To solve this issue, nurse management, risk factor management, and lifestyle interventions must be applied to improve guideline adherence and outcomes.6 This type of care and management can be best provided by cross-sector and interdisciplinary teams. This includes nurses, general physicians, pharmacists, and AF specialist.18
There are also financial and medical challenges in addressing the lack of data and inadequate treatment, especially in low-and-middle-income countries. New techniques for identifying AF, such as smartphones programmes, can potentially improve the detection and monitoring of AF. In addition, mobile health consultations could help improving the treatment and follow-up of patients in rural regions. In the future, the development of inexpensive ECG devices will be required, that can be used in regions with poor access to health care.6
Current research on new anticoagulation therapy shows an enormous range of potential targets, but large scale trials must be performed to confirm the clinical benefit of these agents. Immunotherapies and nucleotide-based strategies also appear to offer beneficial pharmacokinetic and pharmacodynamic abilities.19
With the rapidly expanding knowledge of the complex genetic risk factors associated of AF, they hopefully will be able to identify new pathways involved in its pathogenesis and new pharmacological targets. Especially, the genetic association with AF and stroke is promising because it offers the possibility to identify individuals at greatest risk for AF and is possibly an opportunity to intervene before complications occur. It is anticipated that most of the genetic data will be used to improve clinical risk prediction and to guide therapies within the next few years.20
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