Review on Atrial Fibrillation

AF is still the largest area of investigation in the field of clinical cardiac electrophysiology. At the time of this writing, if one enters the term ‘‘atrial fibrillation’’ into the search field of PubMed and limits their search to publications in the year 2017, there are 4,867 results. This is compared with only 1,394 entries that appear when using the term ‘‘sudden cardiac death’’ and the same search criteria. Even if one limits their interest to data from clinical trials, there is a mountain of literature published annually. Thus, the following should be viewed as only a limited representation rather than a comprehensive review of the literature published surrounding AF.


Introduction
The year 2017 has been filled with news, controversy, and turmoil on many stages, in the realms of politics, entertainment, and economics-both around the world and locally. While original investigation regarding atrial fibrillation (AF) may not be one of these areas, nevertheless, this year was still filled with very significant contributions to our field. AF is still the largest area of investigation in the field of clinical cardiac electrophysiology. At the time of this writing, if one enters the term ''atrial fibrillation'' into the search field of PubMed and limits their search to publications in the year 2017, there are 4,867 results. This is compared with only 1,394 entries that appear when using the term ''sudden cardiac death'' and the same search criteria. Even if one limits their interest to data from clinical trials, there is a mountain of literature published annually. Thus, the following should be viewed as only a limited representation rather than a comprehensive review of the literature published surrounding AF.

Atrial fibrillation: pandemic proportions
It has long been recognized that AF is an arrhythmia of pandemic proportions, with the lifetime risk of developing the disease after the age of 40 hovering at around 25%. 1 The number of individuals with AF in the United States is expected to double by the year 2050. 2 ''AF begets AF'' is a long-heralded mantra reflective of the idea that AF is a progressive diease. 3 Padfield et al., in a manuscript published in June of this year, sought to determine the rate of progression from paroxysmal to persistent AF over a 10-year period. 4 Analyzing data from the Canadian Registry of Atrial Fibrillation, they demonstrated that more than 50% of patients with paroxysmal AF over 10 years will either have progressed to having persistent AF, or have died. The rate of progression was 36.3% at 10 years. This sobering result suggests that we have a long way to effectively halt the progression of this disease despite early recognition.
AF also remains intertwined with other disease epidemics that continue to plague our health care system. The association between AF and congestive heart failure remains an incredibly common finding, with roughly 40% of patients having one of these conditions being likely to develop the other. 5 Cherian and colleagues examined the effects of AF on patients with heart failure within the ORBIT-AF registry. 6 They report that, among patients with AF, those with heart failure had a similar rate of stroke but a higher risk of death or hospitalization [hazard ratio (HR): 1.69 and 1.31, respectively) as compared with those without heart failure. In patients with a left ventricular ejection fraction o 40%, the HRs were 2.06 and 1.38, respectively. This was despite a good background of heart failure therapy. These results, while equally concerning, are notably both the result of detrimental hemodynamic effects, which may support the notion that the treatment of AF in this population should include a rhythm control strategy versus methods aimed solely at preventing thromboembolism.
Another growing health problem is the obesity epidemic. Interestingly, there are reports that detail a protective effect of obesity regarding AF, termed the ''obesity paradox.'' 7 Balla and collaborators examined the relationship of body mass index (BMI) and the risk of stroke in patients with AF 8 in patients treated in the ROCKET AF trial. 9 They found that individuals with a BMI Z 35 kg/m 2 had a lower risk of stroke when compared with their normal-weight counterparts, whether on rivaroxaban or warfarin (HR: 0.62 and 0.48, respectively). While the mechanism of this effect is secondary to increased time in the therapeutic range in the warfarin group or is related with favorable effects on the potential prothrombotic state, it remains a fact that despite this obesity paradox, there is research linking obesity with an increased risk of the development of AF 10 and the progression of paroxysmal AF to persistent AF. 11 Atrial fibrillation and stroke prevention The last several years has seen an increase in a focus on the prevention of thromboembolism secondary to AF corresponding with the growing number of treatment options beyond warfarin. This year was no exception. Boersma et al., on behalf of the EWOLUTION investigators, reported on their one-year follow-up data of left atrial appendage (LAA) occlusion with the WATCH-MANt device (Boston Scientific, Natick, MA, USA). 12 This trial included more than 1,000 patients who met the criteria for LAA occlusion according to the European Society of Cardiology guidelines 13 with or without a contraindication for anticoagulation. In the trial, 73% of patients were deemed unsuitable for anticoagulation. Thus, a mix of patients taking warfarin (16%), novel oral anticoagulants (11%), dual antiplatelet therapy (60%), single antiplatelet therapy (7%), and no therapy (6%) in the immediate peri-procedure period were included in this study. Subsequent findings indicated a high level of procedural success (98.5%) and low residual leaks 4 5mm (99.5%), with device thrombus present in 3.7% of participants. Notably, the presence of device thrombus did not correlate with anticoagulant regimen. Furthermore, the annual stroke rate was 1.1% despite a high baseline CHA 2 DS 2 -VASc score of 4.5. Thus, LAA occlusion with the WATCHMANt device (Boston Scientific, Natick, MA, USA) was deemed effective at preventing stroke even without peri-procedural anticoagulation. These data also pave the way for the ASAP-TOO trial, a randomized prospective trial investigating the effectiveness of LAA occlusion with the same device in patients who are labeled unsuitable for oral anticoagulation. 14 Hot off the press are the five-year outcomes data from the PROTECT and PREVAIL trials, which examined again the WATCHMANt device (Boston Scientific, Natick, MA, USA) versus long-term warfarin therapy in patients with nonvalvular AF. 15 Reddy and colleagues report on findings from more than 1,100 patients who were followed for five years, and demonstrate noninferiority in the composite endpoint of stroke, systemic embolism, or cardiovascular/unexplained death when compared with warfarin. However, much like the previous trials, there were significant decreases in hemorrhagic stroke, disabling stroke, cardiovascular/unexplained death, total mortality, and post-procedure bleeding. The most significant decrease was in all-cause mortality, with a demonstrated HR of 0.73 for the device as compared with warfarin. These results are extremely encouraging and, although we still do not yet have a head-to-head comparison between the WATCHMANt device (Boston Scientific, Natick, MA, USA) and novel oral anticoagulation therapy, it appears that LAA occlusion therapy should be included in our arsenal for the prevention of stroke in patients with nonvalvular AF.

Predicting atrial fibrillation
While our therapy choices for stroke prevention continue to grow, many patients will only present for the first time with a significant thromboembolic event. 16 This underscores the importance of identifying patients at risk for developing AF in a predictive manner. The PREDATE AF study presented by Nasir et al. prospectively evaluated the use of the CHA 2 DS 2 -VASc score to predict new-onset AF using implantable loop recorders (REVEAL XTt or Reveal LINQt; Medtronic, Minneapolis, MN, USA) and determined whether this led to the initiation of anticoagulant therapy. 17 In almost 250 patients with a CHA 2 DS 2 -VASc score Z 2, 22.4% were noted to have new F, defined as an episode lasting longer than six minutes, over the 18-month study period. Of these individuals, 76.4% were subsequently started on oral anticoagulation. There was no demonstrated increase in incidence of AF correlated with an increase in CHA 2 DS 2 -VASc score, but the study was likely underpowered to detect such a finding. These data, taken together with those of trials presented previously, such as the ASSERT-II trial, 18 support the use of implantable monitors to detect AF in high-risk patients.
An exciting development in the ability to predict AF is utilizing our knowledge of mechanisms or arrhythmia onset or initiation. It has been demonstrated that the autonomic nervous system plays a vital role in the modulation of cardiac arrhythmias, from sudden cardiac death to AF. 19 Increased stellate ganglia sympathetic nerve activity has been demonstrated to be associated with atrial arrhythmias 20 but requires invasive measurements to elucidate. Skin sympathetic nerve activity is a potential marker of stellate ganglia activity. Interestingly, a group of researchers from Indiana University has elegantly demonstrated simultaneous measurements of skin sympathetic nerve activity and electrocardiogram recordings. 21 From this group, Uradu and colleagues further reported based on findings from a small group of patients that skin sympathetic nerve activity increases prior to the onset and termination of atrial tachycardia and AF. 22 This technology, though only in its infancy, has a significant potential to both predict AF noninvasively and further our understanding of atrial arrhythmias. These findings may lead to the development of treatment algorithms that help to modulate autonomic activity to ensure better control of arrhythmias.

Atrial fibrillation ablation
The past year has had no shortage of literature regarding the use of catheter ablation as a treatment for AF.
While we all eagerly await the next ''big thing'' with regards to this area, 2017 still provided us with some important data to refine the technology and techniques for AF ablation.
The last several years have solidified pulmonary vein isolation (PVI) as the cornerstone of AF ablation, while suggesting that additional ablation procedures including lines or substrate targeting do not confer an additional benefit. Trials such as the STAR-AF study have suggested that this is true even in patients with persistent AF. 23 Adding to this literature, Fink et al. published the results of the Alster-LOST-AF trial. 24 One hundred twenty-four patients with persistent or longstanding persistent AF were randomized in a 1:1 fashion to undergo PVI alone or PVI with substrate modification. They reported a oneyear tachyarrhythmia-free incidence of 54% in the PVIalone group versus 57% in the group who underwent PVI with substrate ablation. Notably, the substrate ablation followed the stepwise approach. 25 As such, while these results suggest that targeted substrate ablation may not add value to PVI, the low single-procedure success rates underscore the need for further investigation regarding what is the ideal approach for catheter ablation of AF.
Despite success rates that leave room for much improvement, catheter ablation for AF still may be the best treatment for patients with advanced disease, especially those with an increased risk for poor outcomes, such as those with heart failure or cardiomyopathy. Previous trials suc as the AATAC trial have demonstrated the superiority of catheter ablation over pharmacologic therapy and associated improvements in left ventricular ejection fraction. 26 In the CAMERA-MRI trial, Prabhu and colleagues report their results of catheter ablation versus rate control for AF in a population of patients with idiopathic cardiomyopathy. 27 Specifically, they demonstrate very significant improvements in ejection fraction in the ablation group as compared with in the rate control group (ie, absolute increase of 18% versus 4.4%). Moreover, they indicate that the degree of improvement correlates with a lack of late gadolinium enhancement on cardiac magnetic resonance imaging. The single-procedure success rate in the trial was 56% off antiarrhythmics and 75% on medications. This important finding supports the idea that AF itself is an important cause of left ventricular dysfunction even when there is adequate rate control, and the lack of significant fibrosis predicts recovery. Catheter ablation for AF in this population would expect to lead to significant improvements in overall mortality given the improvements in systolic function.
In regards to ablation protocol, there were multiple reports in 2017 refining current techniques. Aryana et al. report using a time-to-isolation parameter as a means of dosing cryoablation for AF. 28 They suggest that this approach has similar results to the conventional approach while decreasing the total amount of cryoablation time, as a time-to-isolation on first application of o 60 seconds only requires a single freeze. Also, Cardosos et al. published an important meta-analysis of ablation with uninterrupted novel oral anticoagulant use 29 demonstrating equivalency to uninterrupted warfarin but with a significantly lower risk of major bleeding.
Finally, the one interesting development in catheter technology in 2017 was the first reported human studies involving a unique diamond-tip catheter with six thermocouples that allows for irrigated ablation with temperature control. Iwasawa and colleagues reported that the use of this catheter is feasible in a single-center series. 30 The authors suggest that using temperature control allows for an appropriate modulation of power so as to achieve transmurality without the risk of steam pops or char formation. Temperature feedback, of course, is used in traditional nonirrigated ablation and has long been understood to have the greatest correlation with lesion depth in standard radiofrequency (RF) ablation. 31 Temperature control capabilities have also been used previously in an internally cooled ablation catheter during AF ablation. 32 The authors of this current study demonstrate a 70% decreased RF time in comparison with that seen with conventional contact force ablation, but a 100% rate of acute procedural success. This catheter design may prove to greatly increase the efficiency of point-by-point catheter ablation.

Guidelines for atrial fibrillation
Last but certainly not least, 2017 gave us an updated consensus document for the treatment of AF. The 2017 Heart Rhythm Society/European Heart Rhythm Assocation/ European Cardiac Arrhythmia Society/Asia Pacific Heart Rhythm Society/ Sociedad Latinoamericana de Estimulación Cardíaca y Electrofisiología expert consensus statement on catheter and surgical ablation of AF, chaired by Dr. Hugh Calkins, gives us several important new takeaways. 33 First, the guidelines make a distinction in the treatment of paroxysmal versus persistent AF, that while patients with paroxysmal AF should have symptoms and fail a medication in order to reach a point of consideration for ablation, that it is reasonable to consider ablation as a first-line therapy in patients with persistent AF whether or not they have been tried on an antiarrhythmic drug. The guidelines also clearly state that ablation is reasonable in patients with heart failure or hypertrophic cardiomyopathy. These statements reflect the importance of recognizing that these individuals are at a higher risk of morbidity and mortality associated with AF. Third, the guidelines note clearly that there is strong evidence that ablation improves symptoms and left ventricular function. Lastly, they indicate that the decision to discontinue anticoagulant therapy should be based on the individual risk of thromboembolism and not the clinical outcome of the procedure.

Conclusion
I hope that this review is useful in summarizing some of the key literature published in 2017. Again, this is simply representative and not all-inclusive of the available topics, and clearly reflects my own biases. I anxiously look forward to new discoveries and innovations for the treatment of AF sure to come in 2018.