Atrial fibrillation



Atrial fibrillation is a supraventricular arrhythmia, whose electrocardiographic diagnosis is based on the following:
1. absence of P waves;
2. irregular R-R intervals.
In atrial fibrillation the activation of the atria is chaotic and continuously variable, so the P waves disappear and are replaced by small waves called f waves . F waves are quite irregular, have continuous variations in morphology, voltage and f-f intervall , their frequency is very high (400-600 beats / min) and last throughout the whole cardiac cycle (they are constant) resulting in a jagged appearance of  isoelectric.

In Atrial fibrillation a large number of atrial impulse reach the atrioventricular junction (AV), but only a part of these then reach the ventricle. The AV node in this way performs a filter function. This variable block in  AV conduction cause the irregular R-R intervals .

The continuous changes of ventricular cycles is the key element in the diagnosis of atrial fibrillation and when this arrhythmia occurs with constant RR intervals you must consider other causes besides atrial fibrillation.

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It is important to distinguish a first-detected episode of AF although it is difficult to be sure about its duration and previous undetected episodes. When there 2 or more episodes, AF is classified as recurrent.  If AF terminates spontaneously, recurrent AF is considered as paroxysmal; when AF lasts > 7 days, the arrhythmia is “persistent”. Termination with antiarrhythmic drugs or DC does not change the designation. First-detected AF may be either paroxysmal or persistent AF. Persistent AF also includes long-standing AF (>1 year), frequently leading to permanent AF, if DC has failed or has not been attempted. These categories may coexist in a single patient since he/she may have several episodes of paroxysmal AF and occasionally of persistent AF, or the reverse. Regarding paroxysmal and persistent AF, it is easier to categorize a given patient by the most frequent arrhythmia presentation. The definition of permanent AF is often arbitrary. The duration of AF refers both to individual episodes and to how long the patient has been affected by the arrhythmia. Thus, a patient with paroxysmal AF may have episodes that last seconds to hours occurring repeatedly for years. Episodes of AF briefer than 30 seconds may be important in certain clinical situations involving symptomatic patients, pre-excitation or in assessing the effectiveness of therapeutic interventions. This terminology applies to episodes of AF that last more than 30 s and have no reversible cause. AF occurring in the setting of acute myocardial infarction, cardiac surgery, hyperthyroidism, pulmonary embolism, pneumonia, or other acute pulmonary disease usually is considered separately. In these conditions, correction or treatment of the underlying disorder together with management of the episode of AF usually terminates the arrhythmia without recurrence. “Lone AF” has been variously defined but usually applies to young individuals (under 60 y of age) without clinical or echocardiographic evidence of cardiopulmonary disease, including hypertension. These patients have a favourable prognosis with respect to thromboembolic events and mortality. Over time, patients may move out of the lone AF category due to aging or development of cardiac abnormalities such as enlargement of the left atrium (LA). Then, the risks of thromboembolic events and mortality rise accordingly. ‘Nonvalvular AF’ refers to patients in whom the arrhythmia develops in the absence of rheumatic mitral valve disease, a prosthetic heart valve, or mitral valve repair.



General and clinical aspects

The prevalence of atrial fibrillation in the general populationm, according to several studies,  is reported to be, the 0.5 – 1%. In the recent ATRIA North American study  the prevalence  was 0.95%, and in the British study by Stewart of 0.9%. The prevalence is relatively low in younger people and progressively increases with age.In  ATRIA study infact the prevalence was 0.1% in those aged <55 years and 9% in those aged> 80 years;  in the Framingham study, 0.5% in the age group between 50 and 59 years, 1.8 % in the range between 60 and 69, 4.8% in the range between 70 and 79 and 8.8% in the range between 80 and 89. 70% of patients with atrial fibrillation is over 65 years with a median age of 75 years. Moreover, the prevalence is higher in men than women in all age groups: 1.1% versus 0.8% in the ATRIA study. In Italy there are some national data about the prevalence of atrial fibrillation. If we refer to data of the international literature (prevalence in the general population varies between 0.5% and 1%), we can calculate that the number of patients with atrial fibrillation in our country (57 million inhabitants) is between 285,000 and 570,000 . We can expect an increasing in  the prevalence  in coming years due to aging of the general population and the increasing number of people older than 65.




AF is associated with an increased long-term risk of thromboembolic events, HF, and all-cause mortality, especially in women. The mortality rate of patients with AF is about double that of patients in normal sinus rhythm and linked to the severity of underlying heart disease. HF favours AF, AF facilitates HF, and patients with both conditions have a poorer prognosis. As a result, it is imperative to treat both conditions as well as to evaluate the role of AF on the progression and prognosis of HF. The rate of ischemic stroke in patients with nonvalvular AF is about 5% per year, 2 to 7 times that of people without AF. One of every 6 strokes develops in a patient with AF. Additionally, if we consider transient ischemic attacks and clinically ‘silent’ strokes by brain imaging, the rate of brain ischemia associated with nonvalvular AF is > 7% per year. In patients with rheumatic heart disease and AF in the Framingham Heart Study, stroke risk was increased 17-fold as compared with age-matched controls, and risk was 5 times higher than in nonrheumatic AF. It is well known that in the Manitoba Follow-up Study, AF doubled the risk of stroke independently of other risk factors. The risk of stroke increases with age; in the Framingham Study, the annual risk of stroke attributable to AF was 1.5% in participants 50 to 59 years old and 23.5% in those aged 80 to 89.




Pathophysiology of AF is complex and at present, despite research advancement due to catheter ablation strategy it is not yet well defined. Structural heart disease (e.g., coronary heart disease, hypertension, heart failure, valvular heart disease) is a common comorbidity of and risk factor for AF, although various other factors have been shown to play a role in the pathophysiology of this disorder. Understanding the pathogenesis of and risk factors for AF and using risk-scoring systems to estimate the risk for AF and stroke can facilitate treatment of this rhythm disorder and potentially minimize its morbidity, mortality, and costs. The genetic factor is involved in cases of familial AF. There are several predisposing structural and electrophysiological factors but triggers and modulating factors are also involved in the pathophysiology of AF. They include atrial dilation, Bachmann’s bundle, frequency gradients between the left and right atrium, heterogeneous refractory periods of the atria, abnormal electrical activity (ectopic foci within or outside PVs) and autonomic nervous system. Increased vagal tone shortens atrial refractory periods, creating a greater dispersion of the refractory periods and the generation of re-entry. The most frequent changes in AF are atrial fibrosis and loss of atrial muscle mass. AF causes many alterations in the atrial architecture and function that facilitate atrial remodelling and perpetuation of the arrhythmia. There are three types of atrial remodelling secondary to AF: structural, contractile, electrical. They are interrelated and contribute to maintaining the AF (“AF begets AF”). Despite these complex atrial changes, electrical disconnection of the pulmonary veins (PVs) by itself may prevent AF recurrences in many patients with paroxysmal episodes of AF strongly supporting the role of triggers in this form of AF. However, electrical and anatomical substrate modification induced by AF (atrial fibrosis) may favour re-entry which further contributes to maintain and perpetuate AF episodes. Indeed, episodes of AF may cause atrial enlargement by loss of contractility and compliance. Stretch-related growth mechanisms and fibrosis increase the extracellular matrix, especially during prolonged episodes of AF. Fibrosis is not the primary feature of AF-induced structural remodelling, although accumulation of extracellular matrix and fibrosis are associated with more pronounced myocytic changes once dilation occurs due to AF or associated heart disease. It is well known that initiation and maintenance of a tachyarrhythmia require an initiating trigger and an anatomical substrate. AF is a complex tachyarrhythmia and clinical and experimental data support a ‘focal’ mechanism involving both automaticity and multiple re-entrant wavelets. These different mechanisms may coexist in the same patient.  A focal origin of AF was supported by experimental models of aconitine and pacing-induced AF in which the arrhythmia persists only in isolated regions of atrial myocardium. The multiple-wavelet hypothesis as the mechanism of re-entrant AF was first reported by Moe and colleagues, who proposed that fractionation of wave-fronts propagating through the atria may result in self-perpetuating ‘daughter wavelets’. The number of wavelets at any time depends on the refractory period, mass, and conduction velocity in different parts of the atria. A large atrial mass with a short refractory period and delayed conduction increases the number of wavelets, favouring sustained AF. Simultaneous recordings from multiple electrodes supported the multiple-wavelet hypothesis in human subjects. For many years, the multiple-wavelet hypothesis has been the most accepted theory about the AF mechanism, but many other observations also support an abnormal atrial substrate implicating atrial vulnerability in the pathogenesis of AF. In patients with persistent AF who had undergone conversion to sinus rhythm, there was significant prolongation of intra-atrial conduction with abnormal atrial refractoriness and conduction. It has also been demonstrated that duration of episodes of AF correlates with both a decrease in atrial refractoriness and shortening of the AF cycle length, supporting the role of electrical remodelling in the maintenance of AF. The initial “focal” theory of AF generation did not receive a particular attention until a focal source for AF was for the first time identified and successfully ablated in patients with paroxysmal AF. The PVs were identified as the most frequent source of these rapidly atrial impulses, but foci were also found in other cardiac structures such as the superior vena cava, ligament of Marshall, left posterior free wall, crista terminalis, and coronary sinus. A rapidly firing atrial automatic focus is considered as trigger for AF initiation and anatomical substrate modification within or outside PVs for re-entry and maintenance of AF. Therefore, the existence of triggers for AF does not exclude the role of substrate modification in the pathophysiology of AF. In some patients with persistent AF, elimination of the muscular connections between the PV and the LA by RF energy may terminate the arrhythmia while in others the arrhythmia may persist after PV disconnection suggesting that in some patients with abnormal triggers, sustained AF essentially depends on anatomical atrial substrate modification.


Atrial electrical remodeling


Pharmacological or direct-current cardioversion of AF has a higher success rate when AF has short duration (<24 hours), while longer duration have less probability to stop AF and maintain a stable sinus rhythm. These findings support the concept ‘atrial fibrillation begets atrial fibrillation’. The increasing arrhythmia propensity has been related to progressive shortening of effective refractory periods with increasing episode duration, a phenomenon known as EP remodelling. With persistent AF, recovery of atrial mechanical function may be delayed for days or weeks after sinus rhythm and  reversal of electrical remodelling may occur at different rates.


Myocardial and hemodynamic effects of AF


During AF loss of synchronous atrial mechanical activity, irregular and rapid ventricular rates, and impaired coronary arterial blood flow, all affect the hemodynamic function. Loss of atrial contraction decrease cardiac output, especially when diastolic ventricular filling is impaired by diseases such as mitral stenosis, hypertension, hypertrophic cardiomyopathy or restrictive cardiomyopathy. Apart its effects on atrial function, a persistently elevated ventricular rate during AF may lead to tachycardia-induced dilated cardiomyopathy. Recognize this potentially reversible cause of cardiomyopathy, in which HF is a consequence and not the cause of AF is extremely important. Control of the ventricular rate may lead to reversal of cardiomyopathy. Furthermore, tachycardia may be associated with a rate-related intraventricular conduction disturbance such as left bundle-branch block, which further negatively affects the LV synchrony, exacerbates mitral regurgitation, limits ventricular filling and then lowers cardiac output. Simply controlling the ventricular rate in patients with persistent AF may reverse these effects.


Chronic heart failure and AF


Chronic heart failure and AF are 2 major disorders with interrelated conditions. It is well known that their coexistence is associated with adverse prognosis and increased mortality. Both share several common predisposing factors, but their interplay involves complex ultrastructural, electrophysiological, and neurohormonal processes that go beyond mere sharing of mutual risk factors. HF leads to structural and electrical atrial remodelling, thus creating the basis for the development and perpetuation of AF; and AF may lead to hemodynamic deterioration and the development of tachycardia-mediated cardiomyopathy. Stroke prevention by antithrombotic therapy is crucial in patients with AF and HF.  Rate control strategy remains the standard therapy for AF in heart failure because current strategies at rhythm control have so far failed to positively impact mortality and morbidity. Antiarrhythmic drug toxicity and poor efficacy are concerns. This is largely because of the shortcomings of current pharmacologic anti-arrhythmic agents. Catheter ablation strategy is promising, but long-term data are lacking. In intractable patients, ablation of the atrioventricular junction and permanent pacemaker implantation may be considered as an alternative; biventricular pacing may prevent or reduce the negative consequences of chronic right ventricular pacing. Further progress toward improved understanding the complex relationship between AF and HF should improve management strategies, including catheter ablation.


Thromboembolism in AF


AF predisposes to thromboembolism. If ischemic stroke or systemic thromboembolism occurs, early diagnosis and treatment can improve outcomes. The thromboembolic risks are reduced by guideline-adherent antithrombotic therapy with warfarin or aspirin. Future directions may include self-monitoring of the international normalized ratio and novel anticoagulants. Ischemic strokes in patients with AF are usually attributed to embolism of thrombus from the LA, but pathogenesis of thromboembolism is more complex. In patients with AF ischemic strokes may also be due to intrinsic cerebrovascular diseases (25%), while in patients 80 to 89 years old, 36% of strokes occur in those with AF. The annual risk of stroke for octogenarians with AF is between 3% and 8% per year, depending on associated stroke risk factors. It is well known that approximately half of all elderly AF patients have hypertension, which is a major risk factor for cerebrovascular disease. Carotid atherosclerosis is not substantially more frequent in AF patients with stroke than in those without AF and is probably a relatively minor contributing epidemiological factor. Warfarin is a cornerstone of oral anticoagulation for stroke prevention. Anticoagulation with warfarin in patients with AF is over twice as effective in secondary prevention of stroke as any other tested alternatives, including all other antithrombotic drugs or surgical interventions. General belief is that warfarin is capable of preventing 20 ischemic strokes for every hemorrhagic one it causes. However, the decision to prescribe oral anticoagulation with warfarin in older patients with AF remains a challenging task since bleeding risk is difficult to estimate reliably in this population.


Left atrial appendage exclusion


The source of thromboembolism in almost all patients with non-valvular AF arises from the left atrial appendage (LAA). Although anticoagulation with warfarin is the standard medical therapy for stroke prevention in patients with AF, chronic warfarin therapy is contraindicated in many patients with AF who are at risk for stroke. Mechanical exclusion of the LAA may prevent thrombus formation in the appendage and hence reduce the risk of stroke. Recently, several studies of percutaneous transcatheter delivery of dedicated LAA exclusion devices such as the Watchman device and the Amplatzer cardiac plug have shown encouraging results as an alternative to warfarin therapy for selected patients and in highly specialized centers. It should be emphasized that at present, evidence is insufficient to support LAA occlusion since this strategy may cause harm especially if incomplete exclusion occurs.


Thrombus formation


Following cardioversion, more than 80% of thromboembolic events occur during the first 3 days and almost all occur within 10 days. Atrial stunning is more pronounced in patients with AF associated with ischemic heart disease than in those with hypertensive heart disease or lone AF. Anticoagulation is recommended during cardioversion in all patients with AF lasting longer than 48 hours or of unknown duration, including lone AF except when it is contraindicated. Decreased flow within the LA/LAA during AF has been associated with spontaneous echo contrast, thrombus formation, and embolic events. This finding is due to fibrinogen-mediated erythrocyte aggregation, is not eliminated by anticoagulation, and is considered as a marker of stasis caused by AF. Predictors include LA enlargement, reduced LAA flow velocity, LV dysfunction, fibrinogen level, and hematocrit. The increasing stroke risk in patients with AF with advancing age is multifactorial. Among patients with AF, aging is associated with LA enlargement, reduced LAA flow velocity, and SEC, all of which predispose to LA thrombus formation. Aging is a risk factor for atherosclerosis, and plaques in the aortic arch are associated with stroke independent of AF. Therefore, complex thromboembolic mechanisms are operative in AF, which involve the interplay of risk factors related to atrial stasis, endothelial dysfunction, and systemic and local hypercoagulability.


Lone AF


About 30% to 45% of cases of paroxysmal AF and 20% to 25% of cases of persistent AF occur in younger patients without demonstrable underlying disease (‘lone AF’). AF can present as an isolated or familial arrhythmia, although a responsible underlying disease may appear over time. Obesity is an important risk factor for arrhythmia development. The excess risk of AF appears mediated by LA dilation, because there is a graded increase in LA size as BMI increases from normal to the overweight and obese categories. Weight reduction has been linked to regression of LA enlargement. These findings suggest a physiological link between obesity, AF, and stroke and raise the intriguing possibility that weight reduction may decrease the risk of AF. Specific cardiovascular conditions associated with AF include valvular heart disease (most often, mitral valve disease), HF, CAD, and hypertension, particularly when LVH is present. In addition, AF may be associated with HCM, dilated cardiomyopathy, or congenital heart disease, especially atrial septal defect in adults. Potential etiologies also include restrictive cardiomyopathies (e.g., amyloidosis, hemochromatosis, and endomyocardial fibrosis), cardiac tumors, and constrictive pericarditis. Other heart diseases, such as mitral valve prolapse with or without mitral regurgitation,

calcification of the mitral annulus, cor pulmonale, and idiopathic dilation of the RA, have been associated with a high incidence of AF. AF is commonly encountered in patients with sleep apnea syndrome, but whether the arrhythmia is provoked by hypoxia, another biochemical abnormality, changes in pulmonary dynamics or RA factors, changes in autonomic tone, or systemic hypertension has not been determined.


Autonomic influences in AF


Autonomic influences may play a key role in the initiation and maintenance of AF. Noninvasive measurement of autonomic tone in humans has been performed by HRV parameters, which reflect sympatho-vagal balance changes rather than the absolute level of sympathetic or parasympathetic tone. It appears that such balance is as important as absolute sympathetic or parasympathetic tone as a predictor of AF. It has been reported that fluctuations in autonomic tone as measured by HRV may occur before the onset of AF. Vagal predominance in the minutes preceding AF has been observed in some patients with structurally normal hearts, while in others a shift toward sympathetic predominance has been observed. Usually, vagally mediated AF occurs at night or after meals, while adrenergically induced AF typically occurs during the daytime in patients with organic heart disease. Parasympathetic mediated AF is the more common clinical form, and in such cases adrenergic blocking drugs or digitalis may worsen symptoms while anticholinergic drugs, like disopyramide, may be effective in preventing recurrent AF.


Clinical manifestations


 AF may develop with or without detectable heart disease. An episode of AF may be self-limited or may require an appropriate treatment for termination. Over time, the clinical characteristics of the arrhythmia may be defined as number of episodes, duration, frequency, triggers, mode of onset, and response to treatment. AF may be associated with sensation of palpitations or may be recognized by its hemodynamic or thromboembolic consequences or may be both symptomatic and asymptomatic in the same patient as detected by ambulatory ECG recordings and device-based monitoring. When the arrhythmia becomes permanent, the presence of palpitations may decreases with time or may completely disappear, particularly among the elderly. Some patients have symptoms only during paroxysmal AF or only intermittently during sustained AF. When present, symptoms of AF may vary according to the irregularity and rate of ventricular response, functional status, arrhythmia duration, and individual patient factors. Unfortunately, in some cases, the first clinical presentation may be an embolic event or aggravation of HF, but the majority of patients have palpitations, chest pain, fatigue, dyspnea, dizziness or even syncope. Polyuria may be due to atrial natriuretic peptide release, particularly when AF stops. Syncope is uncommon, but it may occur at the time of sinus rhythm restoration in patients with sinus node dysfunction or more frequently, when rapid ventricular rates develop in patients with HCM, in patients with valvular aortic stenosis, or in those with accessory pathway.


Quality of life


There is an important shift in the paradigm of the goals of AF therapy. Instead of focusing solely on the electrocardiographic outcomes of treatment and considering “rhythm versus rate control,” one needs also to consider “symptom control” as well as patient well-being. Embolic events and stroke are serious but rare complications of AF since their occurrence is associated with a marked functional impairment. Recent studies have reported that quality of life may be greatly impaired in patients with AF as compared with age-matched controls. Also, maintenance of a stable sinus rhythm over time results in improved quality of life and better exercise performance.  It has been recently suggested that patient based outcomes rather than ECG-based outcomes should be the primary goals of treatment.


Clinical evaluation


The diagnosis of AF requires an accurate history and clinical examination and is confirmed by an ECG or occasionally by bedside telemetry or ambulatory Holter monitoring. The initial evaluation should characterize the arrhythmia pattern (paroxysmal or persistent), determine its cause with potentially cardiac and/or extracardiac factors, and evaluate previous antiarrhythmic drug therapy to start a new effective antiarrhythmic strategy. Usually, AF is associated with underlying heart disease, such as hypertensive heart disease, coronary artery disease, or valvular heart diseases. Pulmonary and thyroid diseases and preexcitation syndromes are less frequently found as causes of the arrhythmia. Common triggers are alcohol, caffeine, exercise and emotional stress, but vagally mediated AF may develop during sleep or after a large meal. The physical examination reveals an irregular pulse with variation in the intensity of the first heart sound or absence of a fourth sound heard previously during sinus rhythm. Frequently, associated valvular heart disease, myocardial abnormalities, or HF may be found.




The diagnosis of AF is easy but requires ECG documentation by 12-lead ECG or at least a single-lead recording. A portable ECG recording tool can document the arrhythmia and establish the diagnosis in cases of the paroxysmal form. Implanted pacemakers or defibrillators by several memory functions permit an accurate detection of episodes of AF. History and physical examination are required to better define presence and nature of symptoms associated with AF, the of AF (first episode, paroxysmal, persistent, or permanent), as well as the onset of the first symptomatic attack. Frequency, duration, precipitating factors, previous antiarrhythmic therapy, modes of termination of AF should also be characterized and evaluated. Presence of potentially reversible conditions (e.g., hyperthyroidism or alcohol consumption) should be excluded. Electrocardiogram is useful not only to identify the rhythm (verify AF), but also to evaluate LV hypertrophy, P-wave duration and morphology, preexcitation, bundle-branch block, prior MI, and other atrial arrhythmias. Transthoracic echocardiogram is mandatory to identify valvular heart disease, to measure LA and RA size, LV size and function, peak RV pressure (pulmonary hypertension), LV hypertrophy, to exclude LA thrombus (low sensitivity), and pericardial disease. Blood tests of thyroid, renal, and hepatic function are also important. If ventricular rate during AF is difficult to manage several tests (six-minute walk test or exercise testing) may be useful or even necessary. Transesophageal echocardiography is mandatory to identify LA thrombus (in the LA appendage) and to guide cardioversion.




AF has significant morbidity and mortality consequences. Pharmacologic therapy consisting of anticoagulants, AV nodal blocking agents and antiarrhythmics, remain the primary treatment. However, several nonpharmacologic therapies for the treatment of AF have been developed. Long-term antiarrhythmic drug therapy and catheter ablation may be effective in patients with AF, but antiarrhythmic drugs currently used are partially efficacious in maintaining sinus rhythm and are considered to have substantial cardiac or extra-cardiac toxicity. Yet so far, no endpoint trial has shown reduced morbidity or mortality using these agents. Regardless of the antiarrhythmic strategy, the need for anticoagulation is based on stroke risk factors and not on whether sinus rhythm is maintained. For rhythm control, drugs are usually considered as the first choice treatment and catheter ablation as a second-line choice, especially in patients with symptomatic AF. In younger patients with symptomatic lone AF who need to maintain stable sinus rhythm, radiofrequency catheter ablation may be preferred over long-term drug therapy. Experimental and clinical studies have demonstrated that ACE inhibitors and angiotensin receptor antagonists may reduce the incidence of AF. However, the role of treatment with ACE inhibitors in long-term maintenance of sinus rhythm in patients at risk of developing recurrent AF requires further studies by large randomized trials to clarify whether this strategy may be routinely recommended.


Heart rate control versus rhythm control


The initial and subsequent approach to symptomatic AF may differ from one patient to another. For patients with symptomatic AF lasting many weeks, initial therapy may be anticoagulation and rate control, while the long-term end point is to maintain a stable sinus rhythm. When cardioversion is planned and the duration of AF is unknown or exceeds 48 h, patients who do not require long-term anticoagulation may benefit from short-term anticoagulation. If rate control is not able to control symptoms, restoration of a stable sinus rhythm represents an important long-term end point. Early cardioversion may be required if AF is associated with hypotension or exacerbation of HF. In contrast, improvement of symptoms only by rate control particularly in older patients may post-pone any attempts to convert AF restoring sinus rhythm. In some patients, when AF is due to reversible causes, as in patients with associated thyrotoxicosis or after cardiac surgery, chronic antiarrhythmic drug therapy may be unnecessary. Therefore, rate control strategy may be considered firstly in older patients with persistent AF and comorbidities while in younger individuals, particularly in the presence of paroxysmal lone AF, a rhythm control strategy has been considered as a better initial strategy. Usually, drugs with both antiarrhythmic and rate-controlling effects are useful. Treatment strategy for AF is a controversial issue. Catheter ablation is increasingly being used to treat patients with AF, and recent studies have reported success rates >80% for paroxysmal AF and > 70% for persistent AF. Therefore, catheter ablation has been recently suggested as an optimal alternative to long-term antiarrhythmic drug therapy in selected patients who failed to respond to conventional antiarrhythmic drug therapy. The short-term benefit of catheter ablation may persist over years up to 5 years after the procedure, as recently reported by our group and confirmed by other groups.  Long-term oral anticoagulant therapy with warfarin may result in multiple drug interactions requiring repeat blood testing, which worsens quality of life in many patients with AF, particularly those older with comorbidities. Dronedarone is also designed without the iodine moieties that are responsible for thyroid dysfunctions associated with amiodarone. Similar to amiodarone, dronedarone exhibits electrophysiological characteristics of all 4 Vaughan Williams classifications. Phase III clinical trials have shown dronedarone to be effective at reducing ventricular rate, reducing recurrence of AF, and reducing cardiovascular morbidity and mortality in patients with AF. However, dronedarone was associated with increased mortality in one study that included patients with severe HF and left ventricular dysfunction. Overall, dronedarone appears to be well tolerated. The most common side effects are gastrointestinal in nature and include nausea, vomiting, and diarrhea. Because of its more favourable adverse effect profile, dronedarone is likely to be a useful addition to the therapeutic management of AF. Therefore, this drug appears to have improved tolerability at the expense of decreased efficacy when compared to amiodarone. On the basis of the results of five international, multicenter, randomized clinical trials involving nearly 6300 patients, dronedarone was approved by the FDA for treatment of non-permanent AF to reduce the risk of cardiovascular hospitalization. Questions remain on the long-term safety, use in patients with heart failure, retreatment after dronedarone or amiodarone failure, and comparative efficacy with a rate control strategy.






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25.  Mesas CE, Pappone C, Lang CC, Gugliotta F, Tomita T, Vicedomini G, Sala S, Paglino G, Gulletta S, Ferro A, Santinelli V.
Left atrial tachycardia after circumferential pulmonary vein ablation for atrial fibrillation: Electroanatomic characterization and treatment.
J Am Coll Cardiol. 2004 Sept 1; 44 (5): 1071-1079.
26.  Pappone C and Santinelli V.
Prevention of Atrial Fibrillation: How important is transseptal atrial conduction in humans?
J Cardiovasc Electr. 2004 Oct; 15(10): 1118- 1119.
27.  Pappone C and Santinelli V.
The who, what, why, and how-to guide for circumferential pulmonary vein ablation.
J Cardiovasc Electrophysiol. 2004 Oct; 15 (10):1226-1230.
28.  Pappone C, Vicedomini G and Santinelli V.
Prevention of Iatrogenic Atrial Tachycardia following ablation of Atrial Fibrillation. A prospective randomized study comparing circumferential pulmonary vein ablation with a modified approach.
Circulation. 2004 Nov 9; 110 (19): 3036-3042.

29.  Pappone C, Santinelli V.

Segmental pulmonary vein isolation versus the circumferential approach: Is the tide turning? Heart Rhythm 2004; 1 (3): 326-328.
Impact Factor: 4.444
30.  Pappone C,
Pulmonary Vein Stenosis after Catheter Ablation for Atrial Fibrillation.
J Cardiovasc Electrophysiol 2003 Feb; 14 (2): 165-167.
31.  Pappone C, Rosanio S.
Evolution of non-pharmacological curative therapy for atrial fibrillation. Where do we stand today?
Int J Cardiol. 2003 Apr; 88: 135-142.
32.  Pappone C, Rosanio S, Augello G, Gallus G, Vicedomini G, Mazzone P, Gulletta S, Gugliotta F, Pappone A, Santinelli V, Tortoriello V, Sala S, Zangrillo A, Crescenzi G, Benussi S, Alfieri O.
Mortality, Morbidity and Quality of Life after Circumferential Pulmonary Vein Ablation for Atrial Fibrillation. Outcomes from a Controlled not Randomized Long-Term Study.
J Am Coll Cardiol. 2003 Jul 16; 42 (2):185-197.
33.  Pappone C,
Atrial fibrillation – a curable condition?
Eur Heart J. 2002 23(7):514-517.
34.  Pappone C, Oreto G, Rosanio S, Vicedomini G, Tocchi M, Gugliotta F, Salvati A, Dicandia C, Calabro MP, Mazzone P, Ficarra E, Di Gioia C, Gulletta S, Nardi S, Santinelli V, Benussi S, Alfieri O.
Atrial electroanatomic remodeling after circumferential radiofrequency pulmonary vein ablation.
Circulation. 2001; 104 (21):2539-2544, 2001.
35.  Pappone C, Rosanio S, Oreto G, Tocchi M, Salvati A, Dicandia C, Mazzone P, Santinelli V, Gulletta S, Vicedomini G.
Circumferential Radiofrequency Ablation of Pulmonary Vein Ostia: A New Anatomic Approach for Curing Atrial Fibrillation.
Circulation. 2000 Nov 21; 102 (21): 2619-2628.
36.   Pappone C, Oreto G, Lamberti F, Vicedomini G, Loricchio ML, Shpun S, Rillo M, Calabro MP, Conversano A, Ben-Haim SA, Cappato R, Chierchia S.
Catheter ablation of paroxysmal atrial fibrillation using a 3D mapping system.
Circulation. 1999 Sept 14; 100 (11):1203-1208.