Atrial fibrillation overview

# Overview
Atrial fibrillation (AF or afib) is a cardiac arrhythmia (abnormal heart rhythm) that involves the two upper chambers (atria) of the heart. Atrial fibrillation is an irregularly irregular heartbeat due to the chaotic firing of the impulses in the atrium. In this rhythm, the atrium is stimulated chaotically by a wide number of ectopic foci of electrical activity. Although several clinical classification plans and protocols have been proposed, none of them fully account for all aspects of atrial fibrillation. The American Heart Association, American College of Cardiology, and the European Society of Cardiology have proposed a classification system based on simplicity and clinical relevance. This classification system contains four main categories of atrial fibrillation; detected or diagnosed, paroxysmal, persistent, and permanent. In atrial fibrillation, the normal electrical impulses that are generated by the sinoatrial node are overwhelmed by disorganized electrical impulses that originate in the atria and pulmonary veins, leading to the conduction of irregular impulses to the ventricles. This results in an irregular heartbeat which may occur in episodes lasting from minutes to weeks or continuously for many years. The most common cause of atrial fibrillation is atrial dilation associated with hypertension. Approximately 1/3 of patients have familial atrial fibrillation which is due to an underlying genetic disorder. Given the number of patients who undergo coronary artery bypass grafting in the developed world, this is an increasing underlying cause of atrial fibrillation. Other general causes include the advancing age of the population, the hemodynamic stress of heart failure and valvular heart disease, myocardial ischemia, a variety of inflammatory disorders, pulmonary diseases, alcohol and drug abuse, and endocrine disorders. Atrial fibrillation must be distinguished from other common atrial arrhythmias which include atrial flutter, atrial tachycardia, atrioventricular nodal reentry tachycardia, paroxysmal supraventricular tachycardia,  and Wolff-Parkinson-White syndrome. Atrial fibrillation (AF) is the most common arrhythmia and its risk increases with age (8% of people over the age of 80 have Atrial fibrillation). This is mostly because the risk for heart disease and other conditions that can cause atrial fibrillation also increases with increasing age. Atrial fibrillation accounts for 1/3 of hospital admissions for cardiac rhythm disturbances, and the rate of admissions for Atrial fibrillation has risen in recent years. Men are more likely than women to have the condition. In the United States, Atrial fibrillation (AF) is more common among Caucasians than African-Americans or Hispanic Americans. Screening for atrial fibrillation is generally not performed, although a study of routine pulse checks or electrocardiograms during routine office visits found that the annual rate of atrial fibrillation diagnosis in elderly patients improved from 1.04% to 1.63%. Atrial fibrillation can be complicated by embolic events including stroke and systemic embolization. The atrial kick (active filling of the left ventricle by atrial contraction) often contributes importantly to the filling of the left ventricle, and the loss of the atrial kick can be associated with the development of congestive heart failure. Atrial fibrillation is often asymptomatic, and is not in itself generally life-threatening, but may result in palpitations, fainting, chest pain, or congestive heart failure. The absence of P waves on the electrocardiogram with an irregularly irregular atrial rhythm is diagnostic of atrial fibrillation. Performing an echocardiogram in the setting of atrial fibrillation is essential to evaluate certain pathologies of the heart such as valvular heart disease, hypertrophy, presence of thrombus, and presence of pericardial disease. Furthermore, some parameters of cardiac functionality including the size and ejection fraction of the left ventricle can also be reported in echocardiogram. Atrial fibrillation may be treated with medications which either slow the heart rate or revert the heart rhythm back to normal sinus rhythm. Synchronized electrical cardioversion may also be used to convert atrial fibrillation to a normal heart rhythm. Surgical and catheter-based therapies may also be used to prevent recurrence of atrial fibrillation in certain individuals. Patients with atrial fibrillation are often given anticoagulants such as warfarin to reduce the risk of stroke.

# Historical Prespetive
The first time atrial fibrillation was described was between 1696 and 2598 BC by a Chinese physician named Huang Ti. He described atrial fibrillation as a disease with irregular pulses and tremulous beats. William Harvey was the first one who found out atrium as the origin of the abnormal pulse in 1628. Jean-Baptiste de Senac (16931770) and Robert Adams (1827) were the first who mentioned atrium as the main origin of atrial fibrillation. For the first time in 1894 Theodor Wilhelm Engelmann introduced multi foci origins of irregular pulses in the atrial fibrillation. Disappearance of presystolic a wave in the jugular phlebogram was first detected by Mackenzie (18531925). First time in 1906 an electrical tracing (ECG) of atrial fibrillation was published by Einthoven. William Withering was the first one who introduced the therapeutic properties of the digitalis leaf (digitalis purpurea) in 1785.

# Classification
Although several clinical classification plans and protocols have been proposed, none of them fully account for all aspects of atrial fibrillation. Previously the American Heart Association (AHA), American College of Cardiology (ACC), and the European Society of Cardiology (ESC) had proposed a classification system based on simplicity and clinical relevance. More recently, another classification has been proposed by a task force writing group which composed of experts representing seven organizations: the American College of Cardiology (ACC), the American Heart Association (AHA), the Asia Pacific Heart Rhythm Society (APHRS), the European Cardiac Arrhythmia Society (ECAS), the European Heart Rhythm Association (EHRA), the Society of Thoracic Surgeons (STS), and the Heart Rhythm Society (HRS). Still there are some shared definitions in almost all classification systems. Atrial fibrillation that terminates spontaneously or with intervention within 7 days of onset is considered a paroxysmal atrial fibrillation. On the other hand atrial fibrillation that lasts more than 7 days is named persistent atrial fibrillation. Long standing (or permanent) atrial fibrillation is referred to a atrial fibrillation that lasts for more than a year.

# Pathophysiology
Numerous triggers such as sympathetic or parasympathetic stimulation, ectopic activity in muscular sleeves, atrial stretch, premature atrial beats and accessory AV (atrio-ventricular) pathways have been responsible in initiation of atrial fibrillation. Younger patients with paroxysmal atrial fibrillation may have ectopic foci of electrical activity in the pulmonary vein. While the pulmonary vein is a common source of these ectopic foci, there may also be foci present in the atrium itself. Unfortunately the reason why the pulmonary vein turns to an arrhythmogenic foci is not fully understood. It seems that structure of the pulmonary vein makes it potential for re-entry formation which can lead to atrial fibrillation. Presence of the aformentioned triggers produce re-enterant wavelets of electrical activity due to shortened effective refractory period (ERP). Furthermore mechanosensitivity of cardiac myocytes is thought to play a pivotal role in initiation of atrial fibrillation. Mechanisms such as altered myocyte stress/strain, catecholamine release secondary to atrial stretch and activation of G-protein coupled pathways have been introduced in the pathogenesis of atrial fibrillation. Dilatation of the atria can be due to structural abnormalities such as hypertension, valvular heart disease and congestive heart failure that can cause a rise in the intra-cardiac pressures. Once dilatation of the atria has occurred, this begins a chain of events that leads to the activation of the renin aldosterone angiotensin system (RAAS) and subsequent increase in matrix metaloproteinases and disintegrin, which leads to atrial remodeling and fibrosis, with loss of atrial muscle mass. In addition any inflammatory state that affects the heart can cause fibrosis of the atria. This is typically due to sarcoidosis but may also be due to autoimmune disorders that create autoantibodies against myosin heavy chains. There are numerous evidences for presence of a relationship between autonomic nervous system and it's function and the atrial electrophysiology and atrial fibrillation development. Multiple associated genes to atrial fibrillation have been found. Connexin 40, potassium voltage-gated channels, natriuretic peptide precursor A and lamin A/C are some of the known genes that are related to atrial fibrillation pathogenesis. The presence of atrial fibrillation often reflects the presence of an underlying cardiac or lung disease. Indeed, the proportion of patients with lone atrial fibrillation is low (approximately 12% of cases). On gross pathology atrial enlargement has been found with echocardiographic evaluations as a consequence of atrial fibrillation. On microscopic pathology lateralization of gap junctional proteins (such as connexin 43 (Cx43),  connexin 40 (Cx40) and N-cadherin) have been found. Furthermore there is an approximately 57% reduce in connexin 43 (Cx43) in right atrium appendages and walls.

# Causes
The most common cause of atrial fibrillation is atrial dilation associated with hypertension. Atrial fibrillation can be caused by several organic cardiac diseases, but it has also been reported to have a familial etiology in some patients. Approximately 1/3 of patients have familial atrial fibrillation which is due to an underlying genetic disorder.  In developed countries, hypertensive heart disease and coronary heart disease are the two most common causes of atrial fibrillation. However, rheumatic heart disease is associated with a higher incidence of atrial fibrillation in developing countries. Life threatening conditions such as acute coronary syndromes, electrolyte imbalance, dehydration, hypoxia, pulmonary embolism, myocarditis and pericarditis should be identified and promptly treated. Other general causes such as the advancing age of the population, the hemodynamic stress of heart failure and valvular heart disease, myocardial ischemia, a variety of inflammatory disorders, pulmonary diseases, alcohol, drug abuse, and endocrine disorders.

# Differentiating Atrial Fibrillation from other Diseases
Atrial fibrillation has to be differentiated from other diseases such as atrial flutter, atrial tachycardia, atrioventricular nodal reentry tachycardia (AVNRT), multifocal atrial tachycardia, paroxysmal supraventricular tachycardia and Wolff-Parkinson-White syndrome. The differentiating features are largely based on both EKG findings and cardiovascular examinations.

# Epidemiology and Demographics
Incidence of atrial fibrillation is approximately less than 0.1% per year in those under 40 years of age. On the other hand incidence rate increases to greater than 1.5% per year in women over 80 age and greater than 2% per year in men over 80 years of age. The atrial fibrillation prevalence in the general population is 0.4%. Prevalence of atrial fibrillation has been estimated to be even more, since many cases of atrial fibrillation remain asymptomatic for a long time. Atrial fibrillation is associated with a 1.5 to 1.9 fold increase in the risk of death. The incidence of atrial fibrillation increases with age (median age of 75 years). Prevalence of atrial fibrillation has been reported to be higher among Caucasians (European ancestry) and it is more common in males compared to females.

# Risk Factors
Numerous risk factors have been found for atrial fibrillation. There are some reversible risk factors such as alcohol drinking and alcohol withdrawal, caffeine, cocaine, stimulant and smoking. Furthermore risk factors such as hypertension, diabetes, obesity and sedentary lifestyle can be considered as reversible conditions that can increase the chance of atrial fibrillation development. On the other hand risk factors such as hypertrophic obstructive cardiomyopathy, heart failure, chronic renal failure and positive familial history have been introduced as irreversible risk factors in atrial fibrillation. There are also conditions that have been recognized as risk factors for ischemic stroke or systemic embolization in patients with non-valvular atrial fibrillation, such as advanced age, impaired left ventricular systolic function, hypertension and diabetes. Male sex, diuretic use and cardiac or thoracic surgery are also among other known risk factors.

# Screening
Early diagnosis of atrial fibrillation and proper prophylactic treatment can prevent numerous related complications, such as stroke and mortality. Since patients older than 65 are more prone to atrial fibrillation and the aforementioned complications, it has been recommended to perform screening at least in this age group. Electrocardiogram (12-lead ECG) has been introduced as the gold standard method for atrial fibrillation screening. Nevertheless atrial fibrillation screening can be done by simply checking pulse. The other reason to support atrial fibrillation screening is the cost effectiveness of it.

# Natural History, Complications and Prognosis
The natural tendency of atrial fibrillation is to become a chronic condition. Based on epidemiological studies atrial fibrillation starts as the paroxysmal form and then evolves to the permanent form eventually in some cases. Numerous complications in association to atrial fibrillation (such as impaired cardiac output, stroke, heart failure and Cognitive disturbances) have been recognized. Although after introduction of anticoagulant treatment rate of stroke and consequently risk of death have been decreased. In a study done on Swedish patients with atrial fibrillation risk of stroke is 25 per 1,000 person/year in patients treated with anticoagulants, compared to 45 per 1,000 person/year risk of stroke in AF patients who didn't received anticoagulant therapy. The occurrence of atrial fibrillation in the setting of ST elevation MI is associated with a poor prognosis including a 40% rise in the risk of mortality in meta-analyses.

# Diagnosis

## History and Symptoms
Patients with atrial fibrillation could have a history of symptoms related to atrial fibrillation, but being asymptomatic can not exclude atrial fibrillation. Indeed, it is not uncommon to identify atrial fibrillation on a routine physical examination or electrocardiogram (ECG), as it may be asymptomatic in many cases. In patients who are not asymptomatic, symptoms such as palpitations, exercise intolerance or fatigue, and dizziness could be reported. Symptoms such as chest pain, dyspnea, and syncope could also be seen in more serious cases.

## Physical Examination
Some physical examination findings of atrial fibrillation include irregularly irregular pulse, possible high blood pressure, and other sign of congestive heart failure. The hemodynamic stability of the patient should be first assessed. The patient should also be examined for the presence of reversible causes of atrial fibrillation. A study of routine pulse checks during routine office visits, found that the annual rate of atrial fibrillation diagnosis in elderly patients altered from 1.04% to 1.63%. This implies that routine examination has 64% (1.04/1.63) sensitivity and should be done regularly. Thyroid exmaination should be considered, specially in younger patients with atrial fibrillation. In patients with dyspnea, tachypnea could be detected and a finding such as rales would suggest heart failure.

## Electrocardiogram
Atrial fibrillation is diagnosed with the electrocardiogram, an investigation performed routinely whenever irregular heartbeat is suspected.  Characteristic findings are the absence of P waves, with unorganized electrical activity in their place, and irregularity of R-R interval due to irregular conduction of impulses to the ventricles. If paroxysmal atrial fibrillation is suspected and 12-lead ECG is normal, usage of a 24-hour ambulatory ECG monitor is recommended. Typical electrocardiogram findings in a patient with atrial fibrillation are absent P waves, irregularly irregular ventricular response rate, and an atrial rate that ranges from 400 to 700 BPM. A rapid, irregular, sustained, wide-QRS-complex tachycardia strongly suggests atrial fibrillation (AF) with conduction over an accessory pathway or atrial fibrillation (AF) with underlying bundle-branch block.

## Chest X-Ray
A chest-x-ray is not usually used a s the main diagnostic tool for atrial fibrillation; nevertheless, it could be abnormal when conditions such as pulmonary diseases or heart failure is the etiology of atrial fibrillation.

## Echocardiogram
Performing an echocardiogram in the setting of atrial fibrillation is essential to identify certain characteristics of the heart, including valvular heart disease, hypertrophy, presence of thrombus, the size and function of the left ventricle, the size of the atria, and the possible presence of pericardial disease. transesophageal echocardiogram is more sensitive, compared to the transthoracic echocardiography. Echocardiography is essential to identify some of the characteristics in the setting of atrial fibrillation, such as valvular heart disease, atrial size, left ventricle (LV) size and function, and peak right ventricle pressure (pulmonary hypertension).

## Cardiac MRI
Cardiac magnetic resonance imaging may be used to assess the structure and the function of the atria in patients with atrial fibrillation. Recent studies suggest that late gadolinium enhancement (LGE) cardiac magnetic resonance imaging (MRI) is a powerful tool to detect atrial fibrosis and atrial fibrillation related remodelings. Detection of atrial fibrosis with late gadolinium enhancement (LGE) cardiac magnetic resonance imaging (MRI) can be helpful for patient selection for ablation treatment. Moreover, this diagnostic tool can be use to detect thrombosis within the atrium.

## Other Imaging Studies
Two other diagnostic studies include the Holter monitor to assess symptomatic episodes of atrial fibrillation over a 24 hour period and exercise stress testing to assess how patients' heart rate responds to exertion. The main benefits to performing an exercise stress test are to reproduce exercise induced atrial fibrillation, and to exclude ischemia before initiating treatment with type 1C antiarrhythmic medications.

# Treatment
Atrial fibrillation may be treated with medications which either slow the heart rate or revert the heart rhythm back to normal sinus rhythm.  Synchronized electrical cardioversion may also be used to convert AF to a normal heart rhythm.  Surgical and catheter-based therapies may also be used to prevent recurrence of AF in certain individuals.  People with AF are often given anticoagulants such as warfarin to reduce the risk of stroke.
Among patients in whom there is normal atrioventricular conduction, fibrillatory or irregular impulses that vary in timing, amplitude and shape are present which are in turn associated with the rapid irregular ventricular response that characterizes atrial fibrillation.

## Rate Control
Rate and rhythm control is the first step in treatment of hemodynamically stable patients with acute (less than 48 hours) atrial fibrillation. It is also considered as a first step treatment for patients who developed atrial fibrillation after a cardiac surgery.Atrial fibrillation with rapid ventricular rate is a common finding in many hospitalized patients. The ventricular rate may be increased up to 150-170. It is essential to bring the ventricular rate down to less than 110 because a rapid ventricular response can cause hemodynamic instabilities and tachycardia mediated cardiomyopathies (heart failure). Atrial fibrillation (AF) can cause disabling and annoying symptoms. Palpitations, angina, lassitude (weariness), and decreased exercise tolerance are related to rapid heart rate and inefficient cardiac output caused by atrial fibrillation (AF). This can significantly increase mortality and morbidity, which can be prevented by early and adequate treatment of the atrial fibrillation (AF).

## Cardioversion
Cardioversion is a medical procedure by which an abnormally fast heart rate (tachycardia) or cardiac arrhythmia is converted to a normal rhythm. When rate control is not successful enough or when it is not able to improve the symptoms of patients rhythm control (either pharmacological or electrical) should be considered. Electrical cardioversion involves the restoration of normal heart rhythm through the application of a defibrillator. The pharmalogical method is performed with usage of medications, such as amiodarone, dronedarone, procainamide, ibutilide, propafenone or flecainide. Whichever method of cardioversion is used, approximately 50% of patients relapse within one year, although the continued daily use of oral antiarrhythmic drugs may extend this period. There are numbers of indications for electrical cardioversion treatment in atrial fibrillation patients. Arrhythmia longer than 48 hours, hemodynamic instability, decompensated heart failure, and ischemia are some of the conditions the electrical cardioversion can be used. Pharmacological (also known chemical) cardioversion refers to restoring the heart's rhythm to normal through pharmacological agents such as amiodarone, propafenone, and flecainide. Such medications work by altering the hearts electrical properties to suppress the abnormal heart rhythms and restore a normal rhythm and can be administered orally or intravenously. The treatment can be carried either in an in-patient or out-patient setting.

## Anticoagulation
Oral anticoagulation is used to prevent stroke and systemic embolization and is considered a mainstay of atrial fibrillation management. Anticoagulation is recommended for atrial fibrillation (AF) patients who are at high risk for stroke based on CHADS2-VASc score who do not have an unacceptable risk of bleeding (HAS-BLED score). Treatment with anticoagulation can be done with warfarin, or one of the novel oral anticoagulants (NOACs). Four novel oral anticoagulants (NOACs) have been approved for use in nonvalvular atrial fibrillation (AF) as alternatives to warfarin. Anti-platelet therapy is not recommended for stroke reduction in atrial fibrillation (AF).

## Maintenance of Rate Control and Sinus Rhythm
Maintenance of sinus rhythm could be reached by using anti-arrhythmic drug therapy in patients with atrial fibrillation and it is specially recommended in symptomatic patients. There are six anti-arrhythmic drugs recommended and available for sinus rhythm maintannace in atrial fibrillation (AF). Choosing the proper anti-arrhythmic drug based on patient's underlying diseases and possible side effects is critical. Moreover, all of the anti-arrhythmic drugs (AADs) should be discontinued if a patient's (atrial fibrillation (AF) becomes permanent. Catheter-based ablation is an alternative to anti-arrhythmic drugs (AADs) therapy that could be considered as a first-line option at experienced centers.

## Surgery

### Radiofrequency Ablation
In patients with atrial fibrillation where rate control drugs are ineffective and it is not possible to restore sinus rhythm using cardioversion, non-pharmacological alternatives are available. One of the techniques used is called catheter ablation, where the bundle of cells that pace the heart in the atrioventricular node, are destroyed using radiofrequency energy source, the dominant energy source for catheter ablation. Cryoablation has more recently been developed as a tool for atrial fibrillation (AF) ablation procedures. Other energy sources and tools are in various stages of development and/or clinical investigation. There are three classes of indications for using catheter ablation for atrial fibrillation (AF). The cornerstone for most atrial fibrillation ablation procedures are ablation strategies that target the pulmonary veins and/or pulmonary vein antrum while electrical isolation is the goal. Due to high risk of thromboembolism in patients with atrial fibrillation, careful attention and starting anticoagulation in atrial fibrillation patients before, during, and after ablation is important. Moreover, possible complications and adverse effects associated with catheter ablation in atrial fibrillation patients should be considerd.

### Maze Procedure
The Maze procedure is a surgical treatment option for some patients with atrial fibrillation. In this procedure, a series of incisions in a cross-like pattern is made on the atria, which blocks the abnormal atria circuits, hence eliminating the atrial fibrillation. A number of improvements have been made to this surgical procedure since it was first invented. Recently, various methods of minimally invasive maze procedures have been developed; these procedures are collectively named minimaze, mini versions of the original maze surgery.

## Primary Prevention
Although no certain primary prevention has been introduced for atrial fibrillation (AF), some medications may prevent the atrial fibrillation development in specific patients. Amiodarone, a beta blocker, or a Calcium-channel blocker may be helpful to prevent atrial fibrillation in patients who undergone cardiac surgery. Moreover, treatment with ACE inhibitor or ARB may lower the chance of atrial fibrillation development in hypertensive patients.

## Secondary Prevention
Secondary prevention is a necessary step to lower the risk of some atrial fibrillation related complications, such as stroke, transient ischemic attack (TIA), bleeding and hospitalization. For instance, dronedarone is a medication that may help to decrease the need for hospitalization in atrial fibrillation patients. In addition alcohol abstinence can prevent both recurrent arrhythmia and bleeding in atrial fibrillation patients.