Catheter ablation of atrial fibrillation and outcomes in heart failure patients: seeking the treasure in the CASTLE

Dr. Nattel received his MD from McGill University in 1974 and undertook Internal Medicine and Clinical Pharmacology training at McGill between 1974 and 1978. He then obtained Cardiology clinical and basic research training at Indiana University and University of Pennsylvania (1978–81) before joining the faculty at McGill in 1981. In 1987, he transferred to the University of Montreal and Montreal Heart Institute, where he directed the Research Centre between 1990 and 2004. He is presently Paul-David Chair in Cardiovascular Electrophysiology at the University of Montreal and Director of the Electrophysiology Research Program at the Montreal Heart Institute, where he continues to practice clinical cardiology. He is Editor in Chief of the Canadian Journal of Cardiology, Associate Editor of Cardiovascular Research, and is on the editorial board of a number of other journals including Cardiovascular Research, Circulation Research, Circulation Arrhythmia and Electrophysiology, Drugs, JACC, JACC Clinical Electrophysiology, Journal of Molecular and Cellular Cardiology, Journal of Cardiovascular Electrophysiology, Journal of Cardiovascular Pharmacology, and Nature Reviews in Cardiology. His research focuses on clinically-relevant mechanisms of cardiac bioelectricity, particularly AF, proarrhythmia, cardiac remodelling, ion channel molecular physiology, and mechanisms of drug action. His lab uses a wide range of molecular, cellular, whole-animal and theoretical methods to gain insights into clinically-relevant basic mechanisms, and identify novel therapeutic targets. He has supervised over 160 research trainees, published over 630 papers in peer-review journals, has an h index of 125 and is a Fellow of the Royal Society of Canada (Academy of Science), the Royal College of Physicians of Canada, the American College of Cardiology, and the Heart Rhythm Society. Heart failure (HF) and atrial fibrillation (AF) are common conditions of increasing prevalence that often coexist.1 They have a mutually reinforcing pathophysiology, such that each increases the risk of the other. There are reasons to believe that maintenance of normal sinus rhythm (SR) might improve outcomes in patients with concomitant AF and HF, which have led to large-scale randomized trials to study the effects of rhythm control, primarily with anti-arrhythmic drug therapy, on outcomes in patients with AF and HF.2 In the AF-CHF study,2 rhythm-control did not improve outcomes in HF-patients, even when the analysis was restricted only to patients successfully maintaining SR.3 One possible explanation of these results is that the potential beneficial effects of SR-maintenance were being obscured by adverse consequences of anti-arrhythmic drug therapy, and that the results might be different if SR were produced by catheter ablation.2,3 This notion was supported by early results showing substantial improvements in cardiac function of HF patients after catheter ablation of AF,4 and further reinforced by randomized studies showing improved cardiac function5 and reduced mortality6 in HF-patients with AF subjected to catheter ablation vs. alternative therapies. The Catheter Ablation vs. Standard Conventional Therapy in Left Ventricular Dysfunction and Atrial Fibrillation (CASTLE-AF) study was a multi-centre, randomized trial designed to compare catheter ablation of AF with conventional therapy in patients with HF and concomitant AF.7 Patients were required to have symptomatic AF and HF, a left ventricular ejection fraction (LVEF) under 35%, failure of anti-arrhythmic drug therapy and an implantable device (implanted defibrillator with or without resynchronization pacing) capable of remote rhythm monitoring. About 2/3 of the patients had persistent AF, with almost 1/3 of the total having a >1-year AF history (long-standing persistent AF). AF-ablation involved pulmonary-vein isolation, as well as additional lesions selected at the discretion of the treating electrophysiologists, all of whom were highly experienced. A total of 398 patients were enrolled between 2008 and 2016, from a total of 33 sites. The results of the study are highly impressive. The ablation group had statistically significant, about 40–50% decreases in the primary endpoint (a combination of all-cause mortality and HF-hospitalization), in death from any cause and in cardiovascular death. Subgroup analysis showed that the main benefits were accrued in patients with less severe disease; notably, patients with LVEF < 25%, with HF Class > 2, with diabetes, with defibrillators for a history of prior malignant arrhythmia and those >65-years old did not show significant benefit from ablation. The study had some limitations- long accrual time, open design (so bias could theoretically enter into management decisions), and a relatively small study population. In addition, the survival benefit did not begin until after 3 years of trial enrolment, which is curious. The potential clinical implications of this study are substantial and will undoubtedly be the subject of extensive analysis and discussion. However, the goal of the present paper is to consider the implications of CASTLE-AF for our understanding of fundamental mechanisms underlying heart disease and for future basic research directions. Likely the single most important insight that CASTLE-AF provides is that AF is bad for patients with HF. This has long been suspected,2 based on many lines of evidence. However, much of the evidence to date has been indirect data showing that HF-patients with AF have a worse prognosis than those with SR. It was unclear whether the worse prognosis is due to AF itself or to the fact that AF-patients often have a range of other comorbidities that contribute to the AF substrate and also impair the overall prognosis, especially in the presence of HF. The results of CASTLE-AF,7 as well as those of other recent randomized trials of ablation for patients with HF and AF,4–6 show convincingly that AF is bad for HF. The obvious next question is why AF is bad for HF. This is a question for basic scientists: what are the fundamental mechanisms through which AF impairs outcomes in HF? Atrial contraction provides a small but discrete contribution to cardiac function,8 the loss of which might promote the deterioration of HF. More information is needed to understand how important this contribution is in HF, and whether its loss can contribute to functional deterioration. Heart rate is a key determinant of outcomes in HF-patients.9 Acceptable rate-control for AF-patients is defined in a very crude way, with most society guidelines recommending a target resting heart rate under 100 bpm.10 In the CASTLE-AF trial, the target rate was 60–80 bpm at rest,7 which might still leave many patients with a resting heart rate greater than that usually achieved in HF-patients with SR. While there are a lot of clinical data pointing to an important role of HR in controlling HF-related remodelling, the AF paradigm might provide a striking example to address experimentally. The irregularity of cardiac rhythm during AF may also contribute to ventricular dysfunction, with greater irregularity of cardiac cycles producing potentially detrimental effects on cardiac contractility.11 Any basic study of the role of heart rate in HF subjects with AF will also need to consider the importance of rhythm irregularity, if any, over, and above absolute rate. Finally, a poorly appreciated area is the neuroendocrine function of the atrium. Neurohormonal effects are recognized to be a key determinant of adverse remodelling and deleterious outcomes in HF-patients. The atria are a rich source of necrohormones, producing most of the body’s circulating natriuretic peptides.12 It is quite conceivable that AF-induced enhancement of atrial-derived neurohormone release13 contributes to adverse ventricular remodelling in HF. More needs to be learned about the neuroendocrine function of the atrium and the effects of its dysregulation on cardiac remodelling. Further basic research into the mechanisms by which AF impairs outcomes in HF would be of interest and might lead to new treatment opportunities. The next question is why AF-ablation improves outcomes in HF patients, whereas rhythm control with anti-arrhythmic drugs does not. An obvious potential answer is that ablation is much more effective at SR-maintenance. While drug-therapy maintained SR about 60% of the time in the AF-CHF trial2 and about 50% of the time in CASTLE-AF,7 patients managed with ablation were in SR closer to 75% of the time.7 This does not seem like such an enormous difference, but looked at in terms of AF-burden, the latter was reduced around half (from 50% to 25%) by AF-ablation in CASTLE-AF. So in part, the better result with ablation likely reflects the adverse effects of AF discussed above and the consequent benefits of preventing it. Patients did have to ‘fail’ anti-arrhythmic drugs (which could include simply not wanting to take them, though we do not know how often that was the case) in order get into CASTLE-AF. It is possible that this selected for a specific population, though it is far from obvious how this could have bequeathed a greater likelihood of benefiting from ablation. Another major consideration could be the adverse effects of anti-arrhythmic agents, which were long ago postulated to explain the neutral results of AF-CHF2 by countering the benefits of SR-maintenance. This possibility argues for more careful basic-science thoughts about mechanisms of anti-arrhythmic action and the search for novel mechanism-based therapeutic approaches,14 since it is unlikely that ablation techniques will be either feasible or effective for the entire population with AF and significant left-ventricular dysfunction. A final issue is the practice of ablation itself. It was clearly successful in the hands of the CASTLE-AF investigators who used it, improving SR-maintenance and more importantly hard outcomes. Further improvement in ablation methods, particularly for persistent AF, will require continuing basic research to improve techniques as well as our understanding of the theoretical basis for optimization of the results.15 We will also need to understand better the mechanistic basis determining the patient-specific response to AF-ablation in the HF population. The patients with the greatest risk factors (advanced age, diabetes, more severe HF) did not improve their outcomes with ablation in CASTLE-AF. We also need to know whether that finding will change with better methods, or whether the determinants of benefit in less sick patients fail to apply to the sicker population, and other approaches are needed for them. In any case, the results of CASTLE-AF will give us lots of food for thought and accordingly many opportunities for more insightful/clinically applicable basic research in the future. The Canadian Institutes of Health Research (Foundation Grant 148401) and the Heart and Stroke Foundation of Canada (G-16-00012708). Conflict of interest: none declared.

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