Dec 16, 2015 | Mrinal Yadava, MD
Education

Atrial fibrillation (AFib) is idiomatically referred to as 'l'arythmie complete', literally meaning 'the complete arrhythmia.' The reference here is to the fact that all known arrhythmia mechanisms including triggered activity, enhanced automaticity, and re-entry have been implicated in its pathophysiology. Over the last 20 years as our understanding of the clinical significance of AFib has evolved, there has been a massive surge in efforts to delineate underlying mechanisms of the arrhythmia. This paroxysm of interest has greatly advanced our understanding of the condition and has revolutionized treatment paradigms.

The history of AFib, however, goes well beyond the last 20 years and is uniquely storied. One of the earliest written descriptions was by the Yellow Emperor of China in his book Huan Ti Nei Ching Su Wen (Classics of Internal Medicine), written in 2000 BC.

"When the pulse is irregular and tremulous and the beats occur at intervals, then the impulse of life fades." – The Yellow Emperor

The first 'modern day' account was by English physician, William Harvey in 1628. He is credited with directly observing fibrillating auricles in open chest animal models.

"But I … have noticed, that after the heart proper, and even the right auricle were ceasing to beat and appeared on the point of death, an obscure movement, undulation/palpitations had clearly continued in the right auricular blood itself for as long as the blood was perceptibly imbued with warmth and spirit." – William Harvey

In 1775, William Withering first demonstrated a benefit of digitalis purpurea (purple foxglove) in AFib. In a particular case of a patient with a weak and irregular pulse, five droughts containing Fol Digital Purp oz iv resulted in a "more full and regular pulse". It is humbling to think that over 200 years, and a multitude of research grants later, digitalis and its derivatives (digitoxin, digoxin) still represent one of our most effective therapies for AFib.

At the turn of the century Rothberger and Winterberg conducted the first experiments aimed at delineating mechanisms of AFib. They suggested that AFib was the result of increased activity of a single ectopic focus. It was around this time that Willem Einthoven was in the process of developing the electrocardiogram (ECG). In association with Einthoven, Sir Thomas Lewis, an English physician, conducted electrophysiological experiments on patients with AFib. He was the first to suggest that the fine diastolic oscillations on ECG represented fibrillatory activity of the atrium. He hypothesized that reentrant waves (or circus movements) were the most plausible explanation for AFib perpetuation. For the ensuing 30 years, re-entry was believed to be the definitive mechanism for AFib.

In 1949, Scherf and Terranova developed a canine model of AFib. They applied aconitine, a sodium channel agonist, to the epicardial surface of the atria, resulting in induction of AFib. On cooling the area, AFib disappeared, with resumption on warming. This observation saw a resurgence of the ectopic focus hypothesis.

While re-entry and the ectopic focus theory could explain the pathophysiology of paroxysmal AFib, some questioned the stability of these mechanisms to maintain chronic AFib. In the 1950s, Gordon Moe developed a canine model of AFib by rapidly pacing the atrium with simultaneous vagal stimulation. After induction of AFib he isolated the appendage with a clamp. While the appendage stopped fibrillating, the atrium continued to do so. He concluded that AFib is sustained by "randomly wandering wave fronts, ever changing in number and direction", and that a critical mass of tissue is needed to sustain AFib. He was also the first to suggest that the mechanisms for AFib initiation and perpetuation may be independent of each other. This came to be known as the multiple wavelet theory, and was widely subscribed to till Michel Haïssaguerre's pioneering work in the 1990's.

In 1998, Haïssaguerre et al., demonstrated that AFib could be terminated by catheter-based isolation of ectopic pulmonary vein triggers. This breakthrough spawned a renewed interest in AFib, and instigated the current barrage in AFib-related research. Even today pulmonary vein isolation remains the gold standard of AFib therapy, and the basic procedure is grossly unchanged from that described by Haïssaguerre.

In discussing the history of AFib, one would be remiss not to mention the current 'rotor' theory. Rotors are defined as functional obstacles around which spiral reentry circuits are organized. The first demonstration of spiral wave conduction was made in a sheep ventricle muscle slice by Davidenko et al., in 1990.

Subsequently, data from computer models and optical mapping of isolated animal hearts by José Jalife and others corroborated this theory.

So, that brings us squarely back in to the present. We have indeed come a long way in figuring out the pathophysiology of this perplexing condition and in developing targeted therapies. At the same time, it is interesting to note that our current understanding of AFib, including pulmonary vein foci and spiral currents, are not wholly disparate to those proposed by Lewis and Scherf. The future of AFib is likely in treating patients on an individual basis. Could different mechanisms have varying contributions to the AFib burden in individual patients? And if so, could individualizing therapies hold the key to mitigating morbidity? Other facets of AFib that are incompletely understood are the role of lifestyle modifications and diet on AFib, as well as the correlation between atrial myopathy and increased stroke risk.

It is said that tomorrow is the future yesterday. If this is extrapolated to our journey understanding the nuances of this enigmatic condition, surely exciting times lie in store.

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This article was authored by Mrinal Yadava, MD, a fellow in training at Oregon Health & Science University.