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Competing Interests: Disclosures The author has no conflicts of interest to disclose.

Atrial fibrillation (AF) has undoubtedly become one of the most well-studied arrhythmias today in terms of pathophysiology and diagnostic and therapeutic (interventional) electrophysiology. Although it lends itself to an apparently easy diagnosis on the surface electrocardiography, myriad electromechanical mechanisms underlie its origin. We have now reached an era of technology that makes AF not only "treatable" but potentially "curable." This article aims at walking through the historical "corridors" and "mazes" that led to the present day understanding of this common yet complex arrhythmia.

Atrial fibrillation (AF) undoubtedly has become one of the most well studied arrhythmias today in terms of pathophysiology and diagnostic and therapeutic (interventional) electrophysiology. Although it lends itself to an apparently easy diagnosis on a surface ECG, myriad electromechanical mechanisms underlie its origin. An era of technology has been reached that makes AF not only "treatable" but also potentially "curable." This article aims at walking through the historical corridors and maze that have led to the present-day understanding of this most common yet complex arrhythmia.

The calcium channel antagonists are a mature group of drugs directed at cardiovascular diseases including hypertension, angina, peripheral vascular disorders and some arrhythmic conditions. Their sites and mechanisms of actions have been well explored over the past two decades and their interactions at the alpha(1) subunit of L-type channels (Ca(V)1.1-1.4) have made them valuable molecular tools for channel classification and localization. With the realization that other members of the voltage-gated calcium channel family exist--Ca(V)2.1-2.3 and Ca(V)3.1-3.3--considerable effort has been directed to drug discovery at these channel types where therapeutic prospects exist for a variety of disorders including pain, epilepsy, affective disorders, neurodegenerative disorders, etc. In contrast to the situation with the L-type channel antagonists success in developing small molecule antagonists of therapeutic utility for these other channel types has thus far been lacking. The reasons for this are explored and potential new directions are indicated including male fertility, bone growth, immune disorders, cancer and schistosomiasis.

The author reviews the history of atrial fibrillation, the most common sustained cardiac arrhythmia. The chaotic irregularity of arterial pulse was clearly acknowledged by most of physicians of the ancient China, Egypt and Greece. William Harvey (1578-1657), who first described the circulatory system appropriately, was probably the first to describe fibrillation of the auricles in animals in 1628. The French "clinical pathologist", Jean Baptist de Sénac (1693-1770) was the first who assumed a correlation between "rebellious palpitation" and stenosis of the mitral valve. Robert Adams (1791-1875) also reported in 1827 the association of irregular pulses and mitral stenosis. The discovery of digitalis leaf in 1785 by William Withering (1741-1799) brought relief to patients with atrial fibrillation and congestive heart failure by reducing the ventricular rate. From an analysis of simultaneously recorded arterial and venous pressure curves, the Scottish Sir James Mackenzie (1853-11925) demonstrated that a presystolic wave cannot be seen during "pulsus irregularis perpetuus", a term very first used by Heinrich Ewald Hering (1866-1948). Arthur Cushny (1866-1926) noted the similarity between pulse curves in clinical "delirium cordis" and those in dogs with atrial fibrillation. The first human ECG depicting atrial fibrillation was published by Willem Einthoven (1860-1927) in 1906. The proof of a direct connection between absolute arrhythmia and atrial fibrillation was established by two Viennese physicians, Carl Julius Rothberger and Heinrich Winterberg in 1909. Sir Thomas Lewis (1881-1945), the father of modem electrocardiography, studied electrophysiological characteristics of atrial fibrillation and has shown that its basic perpetuating mechanism is circus movement of electrical impulse (re-entry). After him, the major discoveries relating to the pathophysiology and clinical features of atrial fibrillation in the 20th century stemmed from Karel Frederick Wenckebach (1864-1940), Gordon Moe (1915-1989), Bernhard Lown (*1921) and Maurits Allessie. Over the past ten years, awareness has increased of transcatheter radiofrequency and cryoablation of non-valvular atrial fibrillation and the battle against formation of intraatrial thrombi for preventing cerebral thromboembolism.

This article was written as part of the 75th anniversary celebration of the British Pharmacological Society (BPS). It discusses antiarrhythmic drug research conducted by members of BPS, and as published in the British Journal of Pharmacology (BJP). BPS members, past and present, as well as antiarrhythmic manuscripts published in the BJP have been identified. From these data, the article attempts to semiquantitatively summarize results published in the journal, but only quotes selected manuscripts and individuals. Apologies are offered for omissions and errors, but as in any history, a writer's biases and opinions are unavoidable.

At the end of the 19th century, there was both experimental and clinical evidence that coronary artery obstruction causes ventricular fibrillation and sudden death and that fibrillation could be terminated by electric shocks. The dominant figure at that time was McWilliam, who in 1923 complained that "little attention was given to the new view for many years." This remained so for many decades. It was not until the 1960s that the medical profession became aware of the magnitude of the problem of sudden death and began to install coronary care units where arrhythmias could be monitored and prompt defibrillation could be delivered. This approach was pioneered by Julian in 1961. Milestones that allowed this development were open-chest defibrillation by Beck, closed-chest defibrillation by Zoll, cardiac massage by Kouwenhoven et al., and development of the DC defibrillator by Lown. In 1980, Mirowski et al. implanted the first implantable cardioverter defibrillator (ICD) in a patient. Thereafter, the use of the ICD increased exponentially. Several randomized trials, largely in patients with coronary artery disease and left ventricular dysfunction or in patients with documented lethal arrhythmias, showed beyond doubt that the ICD is superior to antiarrhythmic drug therapy in preventing sudden death, although a number of trials showed no effect. Trials on antiarrhythmic drugs were disappointing. Sodium channel blockers and "pure" potassium channel blockers actually increase mortality, calcium channel blockers have no effect, and, although amiodarone reduces arrhythmic death, it had no effect on total mortality in the 2 largest trials. Only the beta-blockers have been proven to reduce the incidence of sudden death, but their effect appears not to be related to the suppression of arrhythmias but rather to the reduction in sinus rate. Drugs that prevent ischemic events, or lessen their impact, such as anticoagulants, statins, angiotensin-converting enzyme inhibitors, and aldosteron antagonists, all reduce the incidence of sudden death.

The history of cardiac rhythm disorders including antiarrhythmic drugs and electrotherapeutical tools is long and fascinating. In the beginning, there was not simply the anatomy and physiology of the heart, but also analysis of the pulse, which indicates the activity of the heart. Thus, like any other field of medicine, the study of arrhythmias has a distinctive past. Our current level of knowledge is not the result of a straight, linear progression any more than there is a static, established, monolithic body of thought dominating this field. Instead, our knowledge of arrhythmias today is the result of many competitive, sometimes serendipitous, scientific realizations, of which a few proved useful enough to pursue and eventually led to real advancements. Looking at the worldwide development of rhythmology it can be said that considerable contributions came from Germany in the last few centuries. Arrhythmology--past, present and future--includes clearly German investigators as pioneers of the field. The growing clinical importance of electric cardiac stimulation has been recognized and renewed as Zoll in 1952 described a successful resuscitation in cardiac standstill by external stimulation. The concept of a fully automatic implantable cardioverter-defibrillator system for recognition and treatment of ventricular flutter/fibrillation was first suggested in 1970. The first implantation of the device in a human being was performed in February 1980. By early 1997, 17 years after the first human implantation more than 100,000 ICD systems had been implanted worldwide. Further developments concern new pharmacological compounds, modern cardioverter-defibrillators, radiofrequency ablation, particularly pulmonary vein ablation in atrial fibrillation, innovative pacemakers including preventive pacing techniques, probably laser therapy and perhaps the automatic implantable pharmacological defibrillator. The advances in the field of therapeutic application of pharmacologic and electrical means as well as alternative methods will continue as rapidly as before in order to give us further significant aid in taking care of the patient.

The evidence which I have just summarized establishes priority of publication concerning the action of digitalis for Erasmus Darwin, but on every other ground, Withering deserves full credit for the discovery. Charles Darwin, the medical student, had been informed of its action by his father and had attempted to account for it on the basis of improvement of lymphatic drainage. But the work, accomplished by the first Charles Darwin is less significant than the abundant evidence of his intellectual ability and precocity, and I have ventured to lay the details of his career before you because of their intrinsic interest and in the hope that the information will serve in a small way to clarify the unsolved problem of the relation of nature to nurture in establishing mental traits and capacities.

Between 1962, when the Kefauver-Harris Drug Amendments were passed, and 1996, 20 pharmaceutical compounds were approved and labeled by the FDA as effective antiarrhythmic drugs for some specified cardiac arrhythmia. Drug research and development in the 1970s and 1980s were focused on treatment of premature ventricular beats as a marker for sudden cardiac death and ventricular tachycardia. The Cardiac Arrhythmia Suppression Trial in 1989 irrevocably altered this approach. Recent drug development programs have targeted atrial fibrillation (AF) as epidemiologic data have predicted an increase in the incidence of AF as the United States population ages, and as treating premature ventricular beats has fallen from favor. The FDA, the scientific community, and the pharmaceutical industry have all participated in and been affected by this evolution in drug development.

Over the last several decades there has been an impressive expansion in the study and management of cardiac arrhythmias. New developments in diagnostic and interventional clinical electrophysiology as well as research at the cellular tissue and whole heart levels have improved our understanding of the mechanisms of arrhythmias and have allowed the development of new and effective treatment modalities. During the 1960s (Early Decade-Enabling) the first lifesaving measures such as cardiac resuscitation, external defibrillation, and temporary pacing were introduced in the new coronary care units. Cardiac catheterization and reproducible techniques for recording of intracardiac potentials were developed. The decade of 1970 to 1980 (Middle Decade-Diagnosis) was characterized by the development of programmed stimulation for initiation and termination of arrhythmias. This represented a real revolution in clinical cardiology that led to the understanding of the nature of several tachyarrhythmias and related them to experimental mechanisms of arrhythmogenesis. In the same decade, two other diagnostic tools emerged for assessing cardiac arrhythmias and monitoring the efficacy of antiarrhythmic drug therapy: ambulatory ECG monitoring and exercise testing. In addition, the impact of antiarrhythmic drugs on ionic currents was studied and drug classifications based on these properties appeared. The decade 1980-1990 (Recent Decade-Therapy), witnessed the development of interventional electrophysiology techniques such as transcatheter ablation, and the use of cardiac surgery for the ablation of arrhythmogenic substrates. Another major advance was the design of implantable devices capable of recognizing tachyarrhythmias and treating them by programmed stimulation or defibrillation shocks. In parallel, the efficacy and safety of antiarrhythmic drugs has been reassessed and new compounds are being developed.(ABSTRACT TRUNCATED AT 250 WORDS)

An historical outline of antiarrhythmic therapy is presented. At its beginning treatment was based on empirical data and later on electrophysiologic studies; now it is supported on direct knowledge of ionic currents flowing through the cell membrane during different phases of cellular potentials. It has been possible to reach the present stage of knowledge by starting with clinical observations which permitted the introduction of quinidine in therapy, to the choice of specific agents based upon their effects on ionic movements and the mechanisms maintaining active arrhythmias. These mechanisms can be divided into three groups: circus movement, reentry and discharges of ectopic foci. On these bases, it is justified the use of drugs which prolong the refractory period of myocardial fibers in the first group, of those which enlarge the local block in the second and of those which flatten prepotential or depress systolic depolarization in the third.