Atrial fibrillation

Atrial fibrillation (AF or A-fib) is the most common cardiac arrhythmia (abnormal heart rhythm), and involves the two upper chambers (atria) of the heart. Its name comes from the fibrillating (i.e., quivering) of the heart muscles of the atria, instead of a coordinated contraction. It can often be identified by taking a pulse and observing that the heartbeats do not occur at regular intervals. However, a stronger indicator of AF is the absence of P waves on an electrocardiogram (ECG or EKG), which are normally present when there is a coordinated atrial contraction at the beginning of each heart beat. Risk increases with age, with 8% of people over 80 having AF.

In AF, 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 conduction of irregular impulses to the ventricles that generate the heartbeat. The result is an irregular heartbeat, which may occur in episodes lasting from minutes to weeks, or it could occur all the time for years. The natural tendency of AF is to become a chronic condition. Chronic AF leads to a small increase in the risk of death.

Some people are asymptomatic despite having frequent episodes, while others experience symptoms that are troubling or incapacitating. Whilst AF is not in itself generally considered immediately life-threatening, it may result in palpitations, fainting, chest pain, or congestive heart failure. People with AF usually have a significantly increased risk of stroke (up to 7 times that of the general population). Stroke risk increases during AF because blood may pool and form clots in the poorly contracting atria and especially in the left atrial appendage (LAA). The level of increased risk of stroke depends on the number of additional risk factors. If a person with AF has none, the risk of stroke is similar to that of the general population. However, many people with AF do have additional risk factors and AF is a leading cause of stroke. Atrial fibrillation may be treated with medications which either slow the heart rate or revert the heart rhythm back to normal. 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 protect them from stroke.

Classification
The American College of Cardiology (ACC), American Heart Association (AHA), and the European Society of Cardiology (ESC) recommend in their guidelines the following classification system based on simplicity and clinical relevance.

All atrial fibrillation patients are initially in the category called first detected AF. These patients may or may not have had previous undetected episodes. If a first detected episode self-terminates in less than 7 days and then another episode begins later on, the case has moved into the category of paroxysmal AF. Although patients in this category have episodes lasting up to 7 days, in most cases of paroxysmal AF the episodes will self-terminate in less than 24 hours. If instead the episode lasts for more than 7 days, it is unlikely to self-terminate, and it is called persistent AF. In this case, the episode may be still terminated by cardioversion. If cardioversion is unsuccessful or it is not attempted, and the episode is ongoing for a long time (e.g. a year or more), the patient's AF is called permanent.

Episodes that last less than 30 seconds are not considered in this classification system. Also, this system does not apply to cases where the AF is a secondary condition that occurs in the setting of a primary condition that may be the cause of the AF.

Using this classification system, it's not always clear what an AF case should be called. For example, a case may fit into the paroxysmal AF category some of the time, while other times it may have the characteristics of persistent AF. One may be able to decide which category is more appropriate by determining which one occurs most often in the case under consideration.

In addition to the above four AF categories, which are mainly defined by episode timing and termination, the ACC/AHA/ESC guidelines describe additional AF categories in terms of other characteristics of the patient.


 * Lone atrial fibrillation (LAF) - absence of clinical or echocardiographic findings of other cardiovascular disease (including hypertension), related pulmonary disease, or cardiac abnormalities such as enlargement of the left atrium, and age under 60 years
 * Nonvalvular AF - absence of rheumatic mitral valve disease, a prosthetic heart valve, or mitral valve repair
 * Secondary AF - occurs in the setting of a primary condition which may be the cause of the AF, such as acute myocardial infarction, cardiac surgery, pericarditis, myocarditis, hyperthyroidism, pulmonary embolism, pneumonia, or other acute pulmonary disease

Signs and symptoms
Atrial fibrillation is usually accompanied by symptoms related to a rapid heart rate. Rapid and irregular heart rates may be perceived as palpitations, exercise intolerance, and occasionally produce angina (if the rate is faster and puts the heart under strain) and congestive symptoms of shortness of breath or edema. Sometimes the arrhythmia will be identified only with the onset of a stroke or a transient ischemic attack (TIA). It is not uncommon for a patient to first become aware of AF from a routine physical examination or ECG, as it may be asymptomatic in many cases.

As most cases of atrial fibrillation are secondary to other medical problems, the presence of chest pain or angina, symptoms of hyperthyroidism (an overactive thyroid gland) such as weight loss and diarrhea, and symptoms suggestive of lung disease would indicate an underlying cause. A history of stroke or TIA, as well as hypertension (high blood pressure), diabetes, heart failure and rheumatic fever, may indicate whether someone with AF is at a higher risk of complications.

Rapid heart rate
Presentation is similar to other forms of rapid heart rate (tachycardia), and in some cases may actually be asymptomatic. The patient may complain of palpitations or chest discomfort. The rapid heart rate may result in the heart being unable to provide adequate blood flow and oxygen delivery to the rest of the body. Therefore, common symptoms may include shortness of breath which often worsens with exertion (dyspnea on exertion), shortness of breath when lying flat (orthopnea), and sudden onset of shortness of breath during the night (paroxysmal nocturnal dyspnea), and may progress to swelling of the lower extremities (peripheral edema).Due to inadequate blood flow, patients may also complain of light-headedness, may feel like they are about to faint (presyncope), or may actually lose consciousness (syncope).

The patient may be in significant respiratory distress. Due to inadequate oxygen delivery, the patient may appear blue (cyanosis). By definition, the heart rate will be greater than 100 beats per minute. Blood pressure will be variable, and often difficult to measure as the beat-by-beat variability causes problems for most digital (oscillometric) non-invasive blood pressure monitors. It is most concerning if consistently lower than usual (hypotension). Respiratory rate will be increased in the presence of respiratory distress. Pulse oximetry may confirm the presence of hypoxia related to any precipitating factors such as pneumonia. Examination of the jugular veins may reveal elevated pressure (jugular venous distention). Lung exam may reveal rales or crackles, which are suggestive of pulmonary edema. Heart exam will reveal an irregular but rapid rhythm.

Association with other conditions

 * Central sleep apnea (CSA) – A study found that the prevalence of atrial fibrillation among patients with idiopathic central sleep apnea was significantly higher than the prevalence among patients with obstructive sleep apnea or no sleep apnea (27%, 1.7%, and 3.3%, respectively). There was a total of 180 subjects with  60 people in each of the 3 groups. Possible explanations for the association between CSA and AF are a causal relationship between the two conditions, or an abnormality of central cardiorespiratory regulation.
 * Left atrial enlargement
 * Mitral stenosis

Diagnosis
The evaluation of atrial fibrillation involves diagnosis, determination of the etiology of the arrhythmia, and classification of the arrhythmia. A minimal evaluation should be performed in all individuals with AF. This includes a history and physical examination, ECG, transthoracic echocardiogram, and case specific bloodwork. Depending upon given resources, afflicted individuals may benefit from an in-depth evaluation which may include correlation of the heart rate response to exercise, exercise stress testing, chest X-ray, trans-esophageal echocardiography, and other studies.

If a patient presents with a sudden onset of severe symptoms other forms of tachyarrhythmia must be ruled-out, as some may be immediately life threatening, such as ventricular tachycardia. While most patients will be placed on continuous cardiorespiratory monitoring, an electrocardiogram is essential for diagnosis.

Provoking causes should be sought out. A common cause of any tachycardia is dehydration, as well as other forms of hypovolemia. Acute coronary syndrome should be ruled out. Intercurrent illness such as pneumonia may be present.

Screening
Screening for atrial fibrillation is not generally performed, although a study of routine pulse checks or ECGs during routine office visits found that the annual rate of detection of AF in elderly patients improved from 1.04% to 1.63%; selection of patients for prophylactic anticoagulation would improve stroke risk in that age category.

This estimated sensitivity of the routine primary care visit is 64%. This low result probably reflects the pulse not being checked routinely or carefully.

When ECGs are used for screening, the SAFE trial found that electronic software, primary care physicians and the combination of the two had the following sensitivities and specificities:
 * Interpreted by software: sensitivity = 83%, specificity = 99%
 * Interpreted by a primary care physician: sensitivity = 80%, specificity = 92%
 * Interpreted by a primary care physician with software: sensitivity = 92%, specificity = 91%

Minimal evaluation
The minimal evaluation of atrial fibrillation should generally be performed in all individuals with AF. The goal of this evaluation is to determine the general treatment regimen for the individual. If results of the general evaluation warrant it, further studies may then be performed.

History and physical examination
The history of the individual's atrial fibrillation episodes is probably the most important part of the evaluation. Distinctions should be made between those who are entirely asymptomatic when they are in AF (in which case the AF is found as an incidental finding on an ECG or physical examination) and those who have gross and obvious symptoms due to AF and can pinpoint whenever they go into AF or revert to sinus rhythm.

Routine bloodwork
While many cases of AF have no definite cause, it may be the result of various other problems (see below). Hence, renal function and electrolytes are routinely determined, as well as thyroid-stimulating hormone (commonly suppressed in hyperthyroidism and of relevance if amiodarone is administered for treatment) and a blood count.

In acute-onset AF associated with chest pain, cardiac troponins or other markers of damage to the heart muscle may be ordered. Coagulation studies (INR/aPTT) are usually performed, as anticoagulant medication may be commenced.

Electrocardiogram


Atrial fibrillation is diagnosed on an electrocardiogram (ECG), an investigation performed routinely whenever an irregular heart beat is suspected. Characteristic findings are the absence of P waves, with unorganized electrical activity in their place, and irregular R-R intervals due to irregular conduction of impulses to the ventricles. However, irregular R-R intervals may be difficult to determine if the rate is extremely rapid.

QRS complexes should be narrow, signifying that they are initiated by normal conduction of atrial electrical activity through the intraventricular conduction system. Wide QRS complexes are worrisome for ventricular tachycardia, although in cases where there is disease of the conduction system, wide complexes may be present in A-Fib with rapid ventricular response.

If paroxysmal AF is suspected but an ECG during an office visit only shows a regular rhythm, AF episodes may be detected and documented with the use of ambulatory Holter monitoring (e.g. for a day). If the episodes are too infrequent to be detected by Holter monitoring with reasonable probability, then the patient can be monitored for longer periods (e.g. a month) with an ambulatory event monitor.

Echocardiography
A non-invasive transthoracic echocardiogram (TTE) is generally performed in newly diagnosed AF, as well as if there is a major change in the patient's clinical state. This ultrasound-based scan of the heart may help identify valvular heart disease (which may greatly increase the risk of stroke), left and right atrial size (which indicates likelihood that AF may become permanent), left ventricular size and function, peak right ventricular pressure (pulmonary hypertension), presence of left atrial thrombus (low sensivity), presence of left ventricular hypertrophy and pericardial disease.

Significant enlargement of both the left and right atria is associated with long-standing atrial fibrillation and, if noted at the initial presentation of atrial fibrillation, suggests that the atrial fibrillation is likely to be of a longer duration than the individual's symptoms.

Extended evaluation
An extended evaluation is generally not necessary in most individuals with atrial fibrillation, and is only performed if abnormalities are noted in the limited evaluation, if a reversible cause of the atrial fibrillation is suggested, or if further evaluation may change the treatment course.

Chest X-ray
A chest X-ray is generally only performed if a pulmonary cause of atrial fibrillation is suggested, or if other cardiac conditions are suspected (particularly congestive heart failure.) This may reveal an underlying problem in the lungs or the blood vessels in the chest. In particular, if an underlying pneumonia is suggested, then treatment of the pneumonia may cause the atrial fibrillation to terminate on its own.

Transesophageal echocardiogram
A normal echocardiography (transthoracic or TTE) has a low sensitivity for identifying thrombi (blood clots) in the heart. If this is suspected - e.g. when planning urgent electrical cardioversion - a transesophageal echocardiogram (TEE or TOE where British spelling is used) is preferred.

The TEE has much better visualization of the left atrial appendage than transthoracic echocardiography. This structure, located in the left atrium, is the place where thrombus is formed in more than 90% of cases in non-valvular (or non-rheumatic) atrial fibrillation or flutter. TEE has a high sensitivity for locating thrombi in this area and can also detect sluggish bloodflow in this area that is suggestive of thrombus formation.

If no thrombus is seen on TEE, the incidence of stroke, (immediately after cardioversion is performed), is very low.

Ambulatory Holter monitoring
A Holter monitor is a wearable ambulatory heart monitor that continuously monitors the heart rate and heart rhythm for a short duration, typically 24 hours. In individuals with symptoms of significant shortness of breath with exertion or palpitations on a regular basis, a holter monitor may be of benefit to determine if rapid heart rates (or unusually slow heart rates) during atrial fibrillation are the cause of the symptoms.

Exercise stress testing
Some individuals with atrial fibrillation do well with normal activity but develop shortness of breath with exertion. It may be unclear if the shortness of breath is due to a blunted heart rate response to exertion due to excessive AV node blocking agents, a very rapid heart rate during exertion, or due to other underlying conditions such as chronic lung disease or coronary ischemia. An exercise stress test will evaluate the individual's heart rate response to exertion and determine if the AV node blocking agents are contributing to the symptoms.

Cause
AF is linked to several cardiac causes, but may occur in otherwise normal hearts. Known associations include:
 * Hypertension (High blood pressure)
 * Primary heart diseases including coronary artery disease, mitral stenosis (e.g. due to rheumatic heart disease or mitral valve prolapse), mitral regurgitation, hypertrophic cardiomyopathy (HCM), pericarditis, congenital heart disease, previous heart surgery
 * Lung diseases (such as pneumonia, lung cancer, pulmonary embolism, sarcoidosis)
 * Excessive alcohol consumption ("binge drinking" or "holiday heart syndrome"). Even otherwise healthy middle-aged women who consumed more than 2 drinks daily were 60% more likely to develop AF.
 * Hyperthyroidism
 * Carbon monoxide poisoning
 * Dual-chamber pacemakers in the presence of normal atrioventricular conduction.
 * A family history of AF may increase the risk of AF. A study of more than 2,200 AF patients found that 30 per cent had parents with AF. Various genetic mutations may be responsible.
 * Friedreich's ataxia

Morphology
The primary pathologic change seen in atrial fibrillation is the progressive fibrosis of the atria. This fibrosis is primarily due to atrial dilation, however genetic causes and inflammation may have a cause in some individuals. One study found that atrial dilation can occur as a consequence of AF, although another study found that AF by itself does not cause it.

Dilation of the atria can be due to almost any structural abnormality of the heart that can cause a rise in the intra-cardiac pressures. This includes valvular heart disease (such as mitral stenosis, mitral regurgitation, and tricuspid regurgitation), hypertension, and congestive heart failure. 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. Mutation of the lamin AC gene is also associated with fibrosis of the atria that can lead to atrial fibrillation.

Once dilation 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. This process is not immediate, and experimental studies have revealed patchy atrial fibrosis may precede the occurrence of atrial fibrillation and may progress with prolonged durations of atrial fibrillation.

Fibrosis is not limited to the muscle mass of the atria, and may occur in the sinus node (SA node) and atrioventricular node (AV node), correlating with sick sinus syndrome. Prolonged episodes of atrial fibrillation have been shown to correlate with prolongation of the sinus node recovery time, suggesting that dysfunction of the SA node is progressive with prolonged episodes of atrial fibrillation.

Electrophysiology
The normal electrical conduction system of the heart allows the impulse that is generated by the sinoatrial node (SA node) of the heart to be propagated to and stimulate the myocardium (muscle of the heart). When the myocardium is stimulated, it contracts. It is the ordered stimulation of the myocardium that allows efficient contraction of the heart, thereby allowing blood to be pumped to the body.

There are multiple theories about the etiology of atrial fibrillation. An important theory is that in atrial fibrillation, the regular impulses produced by the sinus node for a normal heartbeat, are overwhelmed by rapid electrical discharges produced in the atria and adjacent parts of the pulmonary veins. Sources of these disturbances are either automatic foci, often localized at one of the pulmonary veins, or a small number of reentrant sources (rotors) harbored by the posterior wall of the left atrium near the junctions with the pulmonary veins. The pathology progresses from paroxysmal to persistent AF as the sources multiply and localize anywhere in the atria. Because recovery of the atria from excitation is heterogeneous, the electrical waves generated by the AF sources undergo repetitive, spatially distributed breakup and fragmentation in a process known as "fibrillatory conduction". Another theory is the multiple wavelet theory first formulated by Moe, which was experimentally proven by Allessie et al.

AF can be distinguished from atrial flutter (AFL), which appears as an organized electrical circuit usually in the right atrium. AFL produces characteristic saw-toothed F-waves of constant amplitude and frequency on an ECG whereas AF does not. In AFL, the discharges circulate rapidly at a rate of 300 beats per minute (bpm) around the atrium. In AF, there is no regularity of this kind, except at the sources where the local activation rate can exceed 500 bpm.

Although the electrical impulses of AF occur at a high rate, most of them do not result in a heart beat. A heart beat results when an electrical impulse from the atria passes through the atrioventricular (AV) node to the ventricles and causes them to contract. During AF, if all of the impulses from the atria passed through the AV node, there would be severe ventricular tachycardia resulting in severe reduction of cardiac output. This dangerous situation is prevented by the AV node since its limited conduction velocity reduces the rate at which impulses reach the ventricles during AF.

Management
The main goals of treatment are to prevent circulatory instability and stroke. Rate or rhythm control are used to achieve the former, while anticoagulation is used to decrease the risk of the latter. If cardiovascularly unstable due to uncontrolled tachycardia, immediate cardioversion is indicated.

Anticoagulation
Anticoagulation can be achieved through a number of means including the use of aspirin, heparin, warfarin, and dabigatran. Which method is used depends on a number issues including: cost, risk of stroke, risk of falls, compliance, and speed of desired onset of anticoagulation.

Rate control versus rhythm control using drugs
AF can cause disabling and bothersome symptoms. Palpitations, chest discomfort, anxiety, and decreased exercise tolerance are related to rapid heart rate and inefficient cardiac output caused by AF. Furthermore, AF with a persistent rapid rate can cause a form of heart failure called tachycardia induced cardiomyopathy. This can significantly increase mortality and morbidity, which can be prevented by early and adequate treatment of the AF.

There are two ways to approach these symptoms using drugs: rate control and rhythm control. Rate control lowers the heart rate closer to normal, usually 60 to 100 bpm, without trying to convert to a regular rhythm. Rhythm control restores normal heart rhythm in a process called cardioversion and maintains the normal rhythm with drugs. Studies suggest that rhythm control is most important in the acute setting AF, while rate control is more important in the chronic phase. As far as mortality is concerned, the AFFIRM trial showed that there is lower mortality using rate control with anticoagulation treatment versus rhythm control treatment and the difference increases up to 5 years (end of study).

The AFFIRM study also showed no difference in risk of stroke in patients who have converted to a normal rhythm with anti-arrhythmic treatment, compared to those who have only rate control. AF is associated with a reduced quality of life, and while some studies indicate that rhythm control leads to a higher quality of life, the AFFIRM study did not find a difference.

A further study focused on rhythm control in patients with AF with concomitant heart failure, based on the hypothesis that AF confers a higher mortality risk in heart failure. In this setting, rhythm control offered no advantage compared to rate control. However, the diagnosis and progression of atrial fibrillation and other cardiovascular disease requires further investigation. In patients with a fast ventricular response, intravenous magnesium significantly increases the chances of successful rate and rhythm control in the urgent setting without major side-effects. A patient with fluctuating vital signs, mental status changes, preexcitation, or chest pain often will go to immediate treatment with synchronized DC cardioversion. Otherwise the decision of rate control versus rhythm control using drugs is made. This is based on a number of criteria that includes whether or not symptoms persist with rate control.

Rate control
Rate control is achieved with medications that work by increasing the degree of block at the level of the AV node, effectively decreasing the number of impulses that conduct into the ventricles. This can be done with:


 * Beta blockers (preferably the "cardioselective" beta blockers such as metoprolol, atenolol, bisoprolol, nebivolol)
 * Non-dihydropyridine calcium channel blockers (i.e. diltiazem or verapamil)
 * Cardiac glycosides (i.e. digoxin) - have limited use, apart from in the sedentary elderly patient

In addition to these agents, amiodarone has some AV node blocking effects (particularly when administered intravenously), and can be used in individuals when other agents are contraindicated or ineffective (particularly due to hypotension).

Diltiazem has been shown to be more effective than either digoxin or amiodarone.

Cardioversion
Cardioversion is a noninvasive conversion of an irregular heartbeat to a normal heartbeat using electrical or chemical means:
 * Electrical cardioversion involves the restoration of normal heart rhythm through the application of a DC electrical shock.
 * Chemical cardioversion is performed with drugs, such as amiodarone, dronedarone, procainamide, dofetilide, ibutilide, propafenone or flecainide.

Vernakalant has been found to safely and rapidly convert new onset atrial fibrillation.

Ablation
If rhythm control is desired and cannot be maintained by medication or cardioversion then catheter ablation may be attempted.

Thromboembolism
In atrial fibrillation, the lack of an organized atrial contraction can result in some stagnant blood in the left atrium (LA) or left atrial appendage (LAA). This lack of movement of blood can lead to thrombus formation (blood clotting). If the clot becomes mobile and is carried away by the blood circulation, it is called an embolus. An embolus proceeds through smaller and smaller arteries until it plugs one of them and prevents blood from flowing through the artery. This process results in end-organ damage due to loss of nutrients, oxygen, and removal of cellular waste products. Thrombus can form anywhere in the body, while emboli follow the blood circulation to specific points in the body. Emboli in the brain may results in a ischemic stroke or transient ischemic attack (TIA).

More than 90% of cases of thrombi associated with non-valvular atrial fibrillation evolve in the left atrial appendage. However, the LAA lies in close relation to the free wall of the left ventricle and thus the LAA's emptying and filling, which determines its degree of blood stagnation, may be helped by the motion of the wall of the left ventricle, if there is good ventricular function.

If the LA is enlarged, there is an increased risk of thrombi that originate in the LA. Moderate to severe, non-rheumatic, mitral regurgitation (MR) reduces this risk of stroke. This risk reduction may be due to a beneficial stirring effect of the MR blood flow into the LA.

Mitral valve
Atrial fibrillation and a corresponding enlargement of the left atrium may cause an increase in the perimeter of the mitral valve. The somewhat circular perimeter of the mitral valve is defined by the mitral annulus.

With a normal sinus rhythm, the mitral annulus undergoes dynamic changes during the cardiac cycle. For example, at the end of diastole the annular area is smaller than at the end of systole. A possible reason for this dynamic size difference is that the coordinated contraction of the left atrium acts like a sphincter about the mitral annulus and reduces its size. This may be important for mitral valve competence so that it does not leak when the left ventricle pumps blood. However, when the left atrium fibrillates, this sphincter action is not possible and may contribute to, or result in, mitral regurgitation in some cases.

Epidemiology
Atrial fibrillation is the most common arrhythmia found in clinical practice. It also accounts for 1/3 of hospital admissions for cardiac rhythm disturbances, and the rate of admissions for AF has risen in recent years. Strokes from AF account for 6-24% of all ischemic strokes. Between 3-11% of those with AF have structurally normal hearts. Approximately 2.2 million individuals in the United States and 4.5 million in the European Union have AF.

The incidence of atrial fibrillation increases with age. The prevalence in individuals over the age of 80 is about 8%. In developed countries, the number of patients with atrial fibrillation is likely to increase during the next 50 years, due to the growing proportion of elderly individuals.

History
Because the diagnosis of atrial fibrillation requires measurement of the electrical activity of the heart, atrial fibrillation was not truly described until 1874, when Edmé Félix Alfred Vulpian observed the irregular atrial electrical behavior that he termed "fremissement fibrillaire" in dog hearts. In the mid-eighteenth century, Jean-Baptiste de Sénac made note of dilated, irritated atria in people with mitral stenosis. The irregular pulse associated with AF was first recorded in 1876 by Carl Wilhelm Hermann Nothnagel and termed "delirium cordis", stating that "[I]n this form of arrhythmia the heartbeats follow each other in complete irregularity. At the same time, the height and tension of the individual pulse waves are continuously changing". Correlation of delirium cordis with the loss of atrial contraction as reflected in the loss of a waves in the jugular venous pulse was made by Sir James MacKenzie in 1904. Willem Einthoven published the first ECG showing AF in 1906. The connection between the anatomic and electrical manifestations of AF and the irregular pulse of delirium cordis was made in 1909 by Carl Julius Rothberger, Heinrich Winterberg, and Sir Thomas Lewis.