Atrial Fibrillation and Heart Failure: Untangling a Modern Gordian Knot

Accepted Manuscript Atrial Fibrillation and Heart Failure: Untangling a Modern Gordian Knot Allan C. Skanes, MD, Anthony S.L. Tang, MD PII:

S0828-282X(18)31057-2

DOI:

10.1016/j.cjca.2018.07.483

Reference:

CJCA 3021

To appear in:

Canadian Journal of Cardiology

Received Date: 1 May 2018 Revised Date:

24 July 2018

Accepted Date: 30 July 2018

Please cite this article as: Skanes AC, Tang ASL, Atrial Fibrillation and Heart Failure: Untangling a Modern Gordian Knot, Canadian Journal of Cardiology (2018), doi: 10.1016/j.cjca.2018.07.483. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Atrial Fibrillation and Heart Failure: Untangling a Modern Gordian Knot

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Allan C. Skanes, MD, Anthony S.L. Tang, MD London Heart Rhythm Program Western University London, Ontario, Canada

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Corresponding Author: Allan Skanes 339 Windermere Road London, Ontario, Canada N6A 5A5, [email protected] Ph: 519 663-3746 Fax: 519 663-3782

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Abstract: Heart Failure (HF) and atrial fibrillation (AF) share common risk factors and frequently co-exist. Both are highly prevalent in our aging population, and mortality associated with the combination is significantly higher than for each alone. An intricate link exists between AF and HF, including interrelated mechanisms and pathophysiology. Asymptomatic LV systolic or diastolic dysfunction can exacerbate or be exacerbated by AF resulting in HF with reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF). A number of treatment strategies have improved symptoms, exercise tolerance and quality of life for patients with HF, but few have resulted in alteration in prognosis. Sinus rhythm, achieved pharmacologically, has not altered important outcomes including cardiovascular or total mortality in patients with HF. Recent studies, using catheter ablation to achieved sinus rhythm, appear to have significant impact on symptoms, heart function and possibly mortality. Until future studies can confirm or clarify the impact of catheter ablation on outcomes, the field remains cautious but optimistic that better treatment strategies for patients with HFrEF and HFpEF are within reach.

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Brief Summary: Heart Failure (HF) and atrial fibrillation (AF) are intricately linked and highly prevalent in our aging population. Mortality associated with the combination is significantly higher than for each alone. Sinus rhythm, achieved pharmacologically, has not altered cardiovascular or total mortality in patients with HF. Catheter ablation appears to impact symptoms, heart function and possibly mortality, but studies have significant limitations. Future studies are needed to confirm or clarify the impact of catheter ablation on outcomes.

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Heart failure (HF) and atrial fibrillation (AF) are inexorably linked and frequently co-exist.1-3 They share common risk factors, including aging, hypertension, diabetes, obesity, sleep apnea and coronary disease. Over half of patients with HF develop AF at some point.4 AF can induce severe HF through a mechanism of tachycardia-induced cardiomyopathy (TICM).5 AF can be driven by the high filling pressures and atrial stretch associated with HF. As patients present with both HF and AF, deciphering the relative contribution of each to the whole is an intractable problem, like untangling a Gordian Knot. A trial of sinus rhythm would seem to disentangle the two, but sinus rhythm is often short-lived. Lasting sinus rhythm in HF patients, often requires a combination of intravenous or oral amiodarone, cardioversion and one or more catheter ablations.6, 7 As rate control is often far simpler, should the effort to attain and maintain sinus rhythm be undertaken and if so for whom? Stakes are high. AF is associated with a 40% increase in total mortality when seen in patients with HF.8 AF and HF are prevalent conditions, commonly associated with aging, and costly to manage.9 Annual direct and indirect costs of HF alone have been estimated at $30 billion in the US.9 A number of strategies are available to treat AF in the setting of HF, each with variable reported effects on mortality, symptoms, heart function, and healthcare utilization. Importantly, patients, physicians and payers may attach different importance to each outcome. What are the potential benefits of sinus rhythm in this population, and are they worth it to patients, the healthcare system and society at large? Unraveling the knot that is AF and HF is indeed a complex problem. This review article will provide a state of the art look at the implications of managing AF in the setting in HF. The impact of sinus rhythm will be discussed in light of recent ablation trials. Selected ongoing trials, that promise to provide important new data and new insights will also be highlighted. The traditional terms HF with reduced ejection fraction (HFrEF, left ventricular (LV) EF<45%) and HF with preserved ejection fraction (HFpEF, LVEF≥45%) will be used throughout.10 When not specified, HF will refer to HFrEF. Heart failure with mid-range ejection fraction (HFmEF 40-49%) has been rarely used in studies making it difficult to use in this review.10

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Scope of the problem: Although much of the recent focus has been on stroke prevention, AF has been associated with a doubling of cardiovascular mortality and a five-fold increase in incident HF.11 Three times as many deaths were sudden or heart failure-related, compared to stroke-related (37% versus under 10%) in the RELY study.12 Further, heart failure admissions complicated by AF are associated with higher mortality, and repeat readmission.13 Among patients with AF, HF has been associated with a doubling of mortality regardless of whether the HF was pre-existing or concurrently diagnosed the same day.14 Problems Untangling Cause and Effect from Temporal Trends: It is not always clear whether AF is an independent risk factor for the development of HF, or if AF is a marker for worse disease and prognosis. Cross-sectional and prospective cohort studies have provided limited insights. These studies frequently report rates of incident HF with prevalent AF, and vice versa, making it challenging to tease apart any potential causation for HFrEF or HFpEF (figure 1A). This is not unexpected if one considers the causal relationship between AF and HF along a hypothetical spectrum of potential reversibility, with AF-mediated TICM at one end (AF clearly causing reversible HF) and AF late after myocardial infarction with LV dysfunction near the other (pre-

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existing, irreversible HF clearly causing AF). Studies enrolling patients, variably along such a spectrum, are expected to report differing prognoses and response to therapy. The resulting inter-study variability makes combining and comparing studies in this area very challenging. This important consideration needs to be top of mind as evidence is reviewed and discussed. Recent data from a Framingham cohort of patients with newly diagnosed AF, showed interesting insights into the interrelationship between AF and HF. Among 1737 patients with new AF, the majority (63%) never developed HF.4 Only 12% had HF diagnosed concurrently with incident AF; 16% developed incident HF after AF diagnosis. Nonetheless, when present, prevalent and interim HF doubled the risk of incident AF. In the same cohort, incident HF, both HFpEF and HFrEF, was dramatically increased in the presence of pre-existing AF to rates that approach those in patients with asymptomatic LV dysfunction.14 In addition, mortality associated with the combination of AF and HF was significantly higher than for each alone (see figure 2).4 A recent analysis of the Women’s Health Study demonstrated that new onset (incident) AF was associated with a 9-fold increase in risk of new HF to 17.4 per 1000 patient years over 6.8 years.15 Further, new HF was associated with doubling of all-cause, and tripling of cardiovascular mortality.16 The interrelationship of AF and HF may be due to common elements in pathophysiology. TICM, due to a reversible rate-related calcium-mediated reduction in LV function has been well described.5 In addition, the hemodynamic and neurohormonal changes induced by both HFrEF and HFpEF, although different, result in altered atrial physiology that promotes AF.17, 18 Once triggered, AF can result in further rapid deterioration in hemodynamics manifest as symptomatic HF even in otherwise asymptomatic patients with LV systolic or diastolic dysfunction. Understanding the mechanisms by which one affects the other may provide unique therapeutic options in the future.

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Heart Failure-induced Atrial Remodeling: The impact of HF on the atria occurs through a number of mechanisms including direct hemodynamic, neurohormonal and subcellular (Ca2+ handling) effects resulting in both structural and electrical remodeling (figure 1B).19 Elevated filling pressures result in atrial stretch, progressive volume overload, and ultimately increased atrial volumes.20,21 Chronic atrial stretch disrupts atrial intercellular coupling and increases intercellular collagen deposition, resulting in significant conduction abnormalities favouring AF.22 Pacing-induced HF, induces increased LA volume, atrial hypertrophy and regions of dense fibrosis resulting in significant conduction heterogeneity and AF inducibility.23 This pattern of “structural remodeling” is different from that seen in pure electrical atrial remodeling that is produced by rapid atrial rates alone.24-27 In addition, neurohormonal systems are activated in heart failure, resulting in high sympathetic tone, activation of the renin renin-angiotensin-aldosterone system. The result is elevated epinephrine, angiotensin II, inflammatory cytokines and TGF-B, all of which may promote or mediate atrial fibrosis.5 Beyond structural remodeling, profound and complex effects on atrial Ca2+ handling have been well studied.19, 28 Alterations in cellular calcium loading, under high sympathetic tone can result in diastolic calcium release resulting in delayed after depolarizations (DADs). It is speculated that DADs (or perhaps early after depolarizations, (EADs) generated via a similar

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mechanisms) result in ectopic firing from the pulmonary veins. Pulmonary vein ectopy in the presence of significant conduction abnormalities, results in electrical wave break up and reentry. In sum, the effects of HF, either HFrEF or HFpEF, are profound, widespread, and result in both arrhythmogenesis and a structurally remodeled atrium prone to very abnormal conduction and widespread reentry. The combined effects of heart failure on the atrium are progressive and appear to be related to the severity of the heart failure symptoms, varying from 5-10% in NYHA class I to close to 50% in class IV patients.29

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Atrial Fibrillation’s Impact on Heart Failure: With the onset of AF, hemodynamics worsen in patients with asymptomatic LV dysfunction (systolic or diastolic) or pre-existing HF. Rapid, irregular rates result in reduced diastolic filling times. Impaired cardiac output results despite any compensation in atrial reservoir and conduit function by pre-existing atrial enlargement. AF also results in loss of atrial mechanical function (atrial kick) through loss of electrical mechanical coordination, over and above that previously lost by atrial enlargement and fibrosis.1, 2 In addition, tachycardia-mediated cardiomyopathic changes can result in LV enlargement with LV systolic dysfunction to varying degrees. Defects in calcium handling are seen, resulting in abnormal force-frequency relationship in the myocardium.5 The myopathic changes can result in subtle worsening of pre-existing LV dysfunction (see below) or severe, but potentially reversible LV dilation and dysfunction even in patients with previously structurally normal hearts.5

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Atrial Remodeling in HFpEF: Is it different? Because of its strong association with AF, its unique pathophysiology, epidemiology and management, HFpEF is worthy of separate discussion and consideration. It is estimated that \ one-third to one-half of all HF patients present with HFpEF.30, 31 Coincident with a diagnosis of HFpEF, risk adjusted mortality rises almost to the level for patients with HFrEF, especially for those with concomitant AF.32 AF and HFpEF are both strongly associated with hypertension, obesity, diabetes, sleep apnea and aging.32, 33 The high prevalence of hypertension, and other co-morbidities, in an aging population frequently produce vascular and ventricular stiffening, senescent changes in myocardial extracellular matrix and impaired relaxation, even in the absence of hypertrophy. A profound effect on the atria occurs, resulting in reduced wall stress, LA stretch, dilation and fibrosis. Although poorly studied, the resulting structural and electrical remodeling is likely similar to that found in HFrEF.19 As such, patients with symptomatic (HFpEF) or asymptomatic diastolic dysfunction are at high risk for the development of AF. Not only can HFpEF (or asymptomatic diastolic dysfunction) result in AF, AF has been temporally associated with incident HFpEF.30 As discussed earlier, the contribution of the atrium to LV filling is greatly impaired with the onset of AF. Recent cohort studies have looked at the temporal associations of HFpEF and AF, both new (incident) AF in the setting of existing (prevalent) HF and vice versa. Up to 60% of patients in clinical trials with HFpEF have AF.34 Among a population with newly diagnosed HFpEF, 29% had preexisting AF for at least 3 months while 23% were diagnosed with AF concurrently.35 Patients with HFpEF and AF were older, had higher BNP levels as well as larger left atrial (LA) volumes compared to those in sinus rhythm. Incident AF was later diagnosed in 32% of this HFpEF cohort, with age and diastolic dysfunction

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strongly associated with progression to AF.35 A recent Framingham analysis found that prevalent AF nearly doubled the rate of incident HFpEF versus HFrEF. 4,36 A new diagnosis of AF is a strong predictor of new HFpEF over time. In a Dutch cohort, rates of new HFpEF were 4-times higher (4.90 per 1000 patient years after AF versus 0.85 without AF).37 New AF was also associated with a 4-fold increase in mortality compared to those without AF.37 These and other data have strengthened calls for HF prevention strategies to be developed, similar to stroke prevention strategies implemented with the onset of AF. Without overt signs of HF, the diagnosis of HFpEF, in the setting of AF can be challenging. Symptoms of HF, fatigue, breathlessness and exercise intolerance, are frequently associated with both diagnoses. In addition, making an echocardiographic diagnosis of diastolic dysfunction in AF can be technically challenging. BNP levels can be independently influenced by obesity and renal failure confounding the diagnosis of HFpEF.34 Over 90% of patients recently investigated for dyspnea, using invasive exercise testing, had occult HFpEF based on an increase in pulmonary capillary wedge pressure to ≥ 25mmHg during exercise.38 While selection bias may have overestimated the prevalence of HFpEF, these provocative results highlight the inherent diagnostic challenge and the close interrelationship of HFpEF and AF. Recently, four potentially modifiable risk factors associated with the development of HF after incident AF have been reported; systolic BP > 120mmHg, BMI > 30, smoking and diabetes. Importantly, a graded 40 to 86% reduction in risk of HF was achieved in those who were able to control or modify 2, 3 or all four risk factors.15

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MANAGEMENT: Upstream Therapy: Blockade of the renin-angiotensin-aldosterone system may limit atrial fibrosis and AF associated with its activation in HFrEF.39 Eplerenone, an aldosterone antagonist, reduced AF in the EMPHASIS-HF study, in patients with mild HF, low EF, already on angiotensin converting enzyme inhibitors (ACE-I) or angiotensin receptor blockade (ARB).40 While not the primary endpoint, incident AF was reduced to 2.7% compared to 4.5% with placebo. Animal work suggests that eplerenone reduces atrial fibrosis, dilation and progression to persistent AF.41 A recent study, in patients with predominantly LVEF ≥ 45%, NYHA II-III symptoms and BNP > 1000, showed that the combination of mineralocorticoid antagonism (MRA), statins, ACE-I and/or ARB, and cardiac rehabilitation modestly improved the rate of sinus rhythm 1 year after cardioversion (75% vs 63%, p=0.042).42 No doubt future studies are being planned to determine how and to what degree targeted therapy can alter outcomes in HFpEF. Two further studies, IMPRESS and PARAGON, will provide insight into the impact of spironolactone and sacubitril/valsartan (Entresto) respectively on HFpEF. Hopefully, these trials will help fill the treatment gap for aging patients with hypertension, AF and HFpEF. STROKE PREVENTION HF has been recognized as an independent risk factor for adjusted stroke risk in AF, without distinction between HFrEF and HFpEF.43, 44 The Canadian Cardiovascular Society (CCS) CHADS-65 algorithm recommends oral anticoagulation (OAC) for any patient age ≥ 65 years or with a single CHADS factor including HF.43 Two recent systematic reviews demonstrated no differences in stroke rates or HF hospitalizations between patients with HFpEF or HFrEF,45 but

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showed reductions in stroke (14%), major bleeding (24%) and intracranial hemorrhage (41%) rates comparable to the large randomized trials.46 Consistent with CCS guidelines, patients with HF should be strongly considered for direct oral anticoagulation (DOAC) use preferentially over warfarin therapy. As with any patients, the use of a specific agent should be individualized based on other factors, such as age, renal function, body mass index etc.

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Rate versus Rhythm Rate Control of AF in Patients with HF: Although AF has been associated with increased mortality in patients with HF, pharmacologically maintained sinus rhythm has not been shown to improve outcomes compared to adequate rate control.47 Both the AFFIRM and RACE II studies have guided rate control for patients with AF, but fewer than 25% of patients in these trials had HF.48, 49 Guidelines have accepted lenient (HR < 100-110bpm) rate control for asymptomatic patients, but it remains unclear if these rates are adequate for patients with either HFpEF or HFrEF. In general, beta-blockade and calcium channel blockade are first line therapy for rate control, with the latter reserved for those with preserved EF.43 Use of adjuvant digoxin therapy in refractory patients with HFrEF, is controversial. Amiodarone has also been used for rate control alone, in those refractory to first line therapy. Failure to provide adequate rate control can result in reversible TICM in some patients (see above). It appears that mild forms of TICM may be present even in adequately rate controlled patients with HFrEF, evidenced by improvements in LVEF upon AV junction ablation or sinus rhythm (see below). As such, AV junction ablation with subsequent pacing can be used as more definitive rate control therapy in refractory patients. A trial of sinus rhythm can also be implemented in selected patients, recognizing the challenges in maintaining sinus rhythm if AF is long-standing and atrial remodeling advanced.

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AV Junction Ablation with or without CRT AV junction ablation (AVJA) and right ventricular pacing continues to be used in highly symptomatic patients with drug refractory AF with reasonably normal LV function, to improve symptoms, quality of life (QOL), healthcare utilization and exercise duration over short-term follow-up.50,51-53 Importantly, compared to pharmacological and possibly inadequate rate control, LV dysfunction has also improved.54 More recently, a number of studies have raised concerns about the potential impact of long-term RV apical pacing especially in patients with abnormal LV function.55,56 Percentage pacing beyond 40% has been associated with a substantial increase in death or HF among patients with existing LV dysfunction and devices.55 A similar finding was seen in patients paced over 6 years with normal LV function and narrow baseline QRS complex. Cumulative percentage paced was a strong predictor of HF hospitalization with a tripling of risk with ventricular pacing greater than 40%.57 A number of studies have investigated the use of bi-ventricular pacing (BiVP) in patients undergoing AVJA, especially when baseline LV dysfunction is present. Two systematic reviews of patients with mild LV dysfunction (LVEF ~ 45%), have demonstrated modest improvement in QOL, LVEF (+2.6%) and hospitalizations for HF.52, 53, 58 No mortality benefit was seen. Although, not in patients undergoing AVJA, the BLOCK HF (Biventricular versus Right Ventricular Pacing in Heart Failure Patients with Atrioventricular Block) study demonstrated that BiVP reduced a combination of death, urgent HF management or LV

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remodeling in patients undergoing pacing for AV block with mild LV dysfunction and mild HF (0.74; 95% CI, 0.60 to 0.90).59 In addition, BiVP improved NYHA class, QOL and reduced LV volume echo indices compared to RV pacing, with morbidity/mortality outcomes predicted by changes in LV end systolic volume index.60 Based on these accumulating data, most clinicians will consider using CRT in patients undergoing AVJA with EF ≤ 45%, but not routinely in patients with normal LV function.44 At the time of pulse generator change, however, implanting physicians are re-evaluating HF symptoms, LVEF or both in patients with high percentage RV apical pacing (> 40%), with a view to upgrading those with symptomatic LV dysfunction.61

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RHYTHM CONTROL: Pharmacological Rhythm Control Maintenance of sinus rhythm, pharmacologically, has not improved mortality outcomes in patients with HF, due to LV dysfunction, when compared to adequately rate controlled AF. AF-CHF, the largest and most rigorous study in this area, randomized 1376 patients with NYHA II-III HF due to LV dysfunction (mean EF 27%) to sinus rhythm, facilitated predominantly by amiodarone, or rate control.47 No improvement in total or cardiovascular mortality, worsening HF, stroke, or a composite of these was seen.47 Unlike the AFFIRM study, where post-hoc analysis showed that sinus rhythm was associated with a substantial survival advantage,62 patients maintaining sinus rhythm in the AF-CHF study were afforded no obvious improvement in cardiovascular mortality, total mortality, or worsening HF.63 Based on these data, there is no compelling argument for a widespread pharmacological rhythm control approach in patients with AF and symptomatic HFrEF. While the widespread institution of a rhythm control strategy does not appear to be warranted, selective use of rhythm control is appropriate to improve symptoms, especially when exacerbated by AF.10 Amiodarone is preferred for rhythm control in HFrEF for safety reasons, especially with severe LV dysfunction.43 It can also be used intravenously or orally as a rate control agent in refractory cases, especially in anticipation of DC cardioversion to facilitate sinus rhythm.64 While not associated with mortality improvements, sinus rhythm, facilitated by amiodarone, has been associated with improvements in LV function, QOL and BNP levels compared to placebo, in a small trial of patients with HF and persistent AF. Only 66% of patients maintained sinus rhythm at 1 year demonstrating the challenges of rhythm control in this population. Nonetheless, all endpoints were improved to a greater degree in those patients maintaining sinus rhythm.65 Dofetilide has been found to improve rates of sinus rhythm and HF hospitalization compared to placebo, especially in those with AF at baseline.66 Rates of cardiovascular or arrhythmic death was unchanged, but Torsades occurred in 25 patients, most often within 3 days of starting dofetilide, making in-hospital initiation a requirement for use. Its modest anti-arrhythmic effect and complexity of use make dofetilide seldom used and less preferred than amiodarone. Catheter Ablation to Maintain Sinus Rhythm: Impact on Symptoms and LV Function With the evolution of catheter ablation for AF, investigators readdressed whether sinus rhythm would improve outcomes in patients with HFrEF over a rate control strategy.67 The first, PABACHF (Pulmonary Vein Antrum Isolation versus AV Node Ablation with Bi-Ventricular Pacing for

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Treatment of Atrial Fibrillation in Patients with Congestive Heart Failure), randomized 80 patients with drug-refractory persistent AF, LV dysfunction and NYHA class II-III symptoms to pulmonary vein isolation (PVI) or rate control using AVJA and BiVP. Freedom from AF was achieved 6 months after PVI in 71% of patients off drugs and 88% of patients receiving antiarrhythmic drugs. PVI was associated with significant improvements in QOL, six-minute walk distance (6MWD) (340 m vs. 297 m, p<0.001), and LVEF (35% vs. 28%, p< 0.001). By demonstrating improvements in QOL, 6MWD and LVEF, this small study suggested that sinus rhythm, facilitated by PVI, might be preferred to rate control in patients with NYHA II-III HF due to LV dysfunction. Vaidya et al. in a meta-analysis of seven randomized studies (425 patients) showed that catheter ablation was associated with greater increases in LVEF compared to pharmacological rate control (+6.5%, 95%CI:+0.6 to +12.) and AVJA (+9.0%, 95% CI:+6.3 to +11.7).68 Numerous cohort studies have demonstrated similar improvements in symptoms, exercise tolerance and LV function in patients with HFrEF undergoing catheter ablation of AF. Two recent systematic reviews showed qualitatively similar results.69, 70 Single procedure freedom from AF was 56.5% and 60%, but rose to 81.8% with more than one procedure and anti-arrhythmic drug use.69 Mean LVEF increased by 13% in both analyses (13.3%, 95% CI: 10.8%-15.9%), although heterogeneity was high. The percentage with LVEF< 35% fell from 25% to 10% in follow-up.70 In addition, improvements in QOL and exercise tolerance were found.69 These data are very intriguing and suggest that mild forms of reversible cardiomyopathy are present in many patients with AF and HFrEF despite apparent rate control. A recent very small, multicenter trial (CAMERA MRI) showed that catheter ablation resulted in low AF burden of 1.6 ± 5.0% and a mean improvement in LVEF of 18 ± 13%, versus 4.4 ± 13% despite adequate rate control. Normalization of EF occurred in 58% versus 9%. More interestingly, patients with LV late gadolinium enhancement on cardiac MR had much less improvement in LVEF (11.6% vs 22.3%, p=0.01) and lower rates of normalization (29% vs 73%, p<0.01) suggesting a more permanent substrate for ongoing LV dysfunction and HF.71 The accumulated message from these studies is appealing; that sinus rhythm, achieved by catheter ablation, with minimal anti-arrhythmic use, substantially improves QOL, exercise tolerance, and LVEF in selected patients with HFrEF. Limitations need to be remembered when interpreting these studies. Although commonly performed and accepted, echocardiographic assessment of EF is rhythm, afterload and heart rate dependent. As such, improvements in EF may not fully represent improvements in LV contractility per se. In addition, by their nature, ablation studies universally lack blinding without which there continues to be concern about the unbiased assessment of “softer” symptom and imaging-based outcomes. Some have suggested that sham procedures are needed to fully understand the impact of ablation on meaningful outcomes. The AATAC Study: Beyond Symptoms and LV Function Unlike the studies already discussed, the AATAC (Ablation Versus Amiodarone for Treatment of Persistent Atrial Fibrillation in Patients with Congestive Heart Failure and an Implanted Device) trial randomized 203 patients with persistent AF, LV dysfunction (mean EF 30%) and NYHA class II-III symptoms to sinus rhythm facilitated by catheter ablation or amiodarone.72 This open-

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label, blinded endpoint (PROBE) trial, maintained sinus rhythm in 70% over 2 years in 102 patients undergoing 1.4 ± 0.6 catheter ablation procedures compared to 34% (95%CI 25%-44%, p<0.001) randomized to amiodarone. Importantly, freedom from AF was accurately assessed using intracardiac atrial electrogram recordings from dual chamber ICD or CRT devices. Ablation was associated with significantly greater improvements in EF (8.1±4 versus 6.2±5.0 p=0.02), 6MWD (22±41 versus 10±37 p=0.02), and QOL (Minnesota Living With HF score, (11±19 versus 6±17, p=0.04), with those free from AF accruing the greater improvements. In addition, the ablation group had fewer unplanned hospitalizations, (31% versus 57%, RR 0.55, 95%CI 0.390.76, p<0.001) and surprisingly, fewer deaths (8 versus 18, RR 0.44; 95% CI, –0.20 to 0.96; NNT 10 patients). Probably because of small sample size, specific criteria for patient selection, and lack of blinding in the AATAC study, there has not been overwhelming adoption of a catheter ablation approach to manage persistent AF in patients with HFrEF. In addition, the authors report that single procedure rates of sinus rhythm varied considerably by center (range 29-61%) suggesting that the results may not be easily generalizable beyond high volume centers. A recent systematic review, however, demonstrated single and multi-procedure success rates, including use of anti-arrhythmic drugs of 56.5% and 81.8% for catheter ablation in patients with LV dysfunction.69 As catheter ablation success rates improve in this population, this approach may be more widely adopted to improve symptoms, EF and hospitalization rates.

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The CASTLE AF Study: Impact of Sinus Rhythm on Mortality The AATAC study first suggested that maintenance of sinus rhythm, using catheter ablation could result in better clinical outcomes including mortality. The Catheter Ablation versus Standard Conventional Therapy in Patients with Left Ventricular Dysfunction and Atrial Fibrillation (CASTLE-AF) trial tested this hypothesis in a similar population of patients, with similar design and longer follow-up.73 Patients with LV dysfunction (EF median ~32%), NYHA class II-IV symptoms, who had failed, were unable or unwilling to take an anti-arrhythmic drug were randomized to pharmacological rate or rhythm control versus catheter ablation. Twothirds of patients had persistent AF. While sinus rhythm was encouraged, rate control, when used, targeted a ventricular rate of 60 to 80 bpm at rest and 90 to 115 bpm during moderate exercise. The primary outcome was death from any cause or unplanned HF hospitalization. After a 5-week medical run-in phase initiated after randomization, 179 remained in the ablation arm and 184 in the medical therapy arm. After 37.8 months, fewer patients undergoing catheter ablation met the primary endpoint (51 patients [28.5%] vs. 82 patients [44.6%]; HR, 0.62; 95% confidence interval [CI], 0.43 to 0.87; p=0.007). Likewise, the group undergoing ablation had fewer deaths, (24 [13.4%] vs. 46 [25.0%]; HR, 0.53; 95% CI, 0.32 to 0.86; p=0.01), and fewer unplanned HF hospitalizations (37 [20.7%] vs. 66 [35.9%]; HR, 0.56; 95% CI, 0.37 to 0.83; p=0.004), or died from cardiovascular causes (20 [11.2%] vs. 41 [22.3%]; HR, 0.49; 95% CI, 0.29 to 0.84; p=0.009). The Kaplan Meier curves for worsening heart failure appeared to separate earlier, certainly by 1 year, whereas the curves for death did not separate until after 3 years. Sinus rhythm, recorded by intracardiac electrograms, was maintained in 63.1% (25% on amiodarone) after 1.3 +/- 0.5 ablations compared to 21.7% (31% on amiodarone) with medical therapy at 60 months. Percentage of time in AF (burden) fell from 50% to under 30% in the

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ablation arm but remained unchanged with medical therapy. Mean EF increased by 8% (interquartile range, 2.2 to 19.1) in the ablation arm but remained unchanged in the medical therapy arm. EF increased significantly by 12 months and remained elevated throughout. Although changes in EF were seen almost exclusively in the sub-group with persistent AF, a full two-thirds (68%) of patients undergoing ablation had EF increased to ≥ 35%. Are the impressive results of CASTLE-AF too good to be true? Unfortunately, as enumerated in a recent editorial, CASTLE-AF has numerous limitations including use of a “modified” intention to treat analysis, imbalances in baseline characteristics, concerns of adequacy of heart failure treatment in each arm, imbalances in censuring of events including during follow-up and others that could impact the primary endpoint.74 Despite sensitivity analyses supporting the results, the impact attributable to catheter ablation and sinus rhythm in CASTLE-AF remains less than clear and in need of reproduction. Fortunately, ongoing, more rigorous studies, including the RAFT-AF study, are underway. They may provide further insights into the impact of sinus rhythm and catheter ablation on a number of endpoints including HF hospitalizations and all-cause mortality in the case of RAFT-AF (see table 1). Until such time, a widespread approach to catheter ablation for the sole purposes of impacting HF hospitalization or mortality appears unwarranted.

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Reconciliation of the data: Is it the patient, the drug or the rhythm? AF-CHF, the largest and most rigorous randomized control trial in this area, failed to show any significant benefit of sinus rhythm when facilitated by amiodarone over rate control alone. Yet, there is a growing enthusiasm for catheter ablation, based on an increasing weight of data of variable quality, suggesting that sinus rhythm, when facilitated by catheter ablation, results in improved outcomes. Improvements in EF, QOL, exercise tolerance, HF hospitalizations and even total mortality have been reported. Can we reconcile these data without simply dismissing all ablation studies due to limitations? Could differences in patient selection have contributed to different outcomes in the ablation trials compared to AF-CHF? Specifically, could inadvertent selection of patients with more reversible substrates for HF have contributed to different results in the ablation studies? The CAMERA AF study, although small, found that the extent of LV scar, as measured by late gadolinium enhancement, predicted EF reversibility with catheter ablation.71 The extent to which patients with relatively “reversible” substrates were enrolled in each study (AF-CHF, AATAC, CASTLE-AF) is impossible to be ascertained. The proportion with ischemic versus nonischemic etiologies for LV dysfunction, however, were somewhat different in the studies. A non-ischemic etiology for LV dysfunction was estimated in one-third of patients in AF-CHF, up to 40% in AATAC and 60% of the ablation arm in CASTLE-AF. Perhaps subtle forms of TICM were present to variable degrees in each study, contributing to different outcomes. Identifying subgroups of patients with varying potentials for significant substrate reversibility, as performed in CAMERA AF, may clarify some of this issue. Is it possible that the benefits of sinus rhythm were balanced by a negative impact of amiodarone on hospitalization and mortality in patients with HFrEF? Amiodarone has been associated with a higher mortality compared to placebo among a subgroup of patients with NYHA III HF in the SCD-HeFT study.75 AF was not highly prevalent in SCD-HEFT such that perhaps any amiodarone-associated benefit of sinus rhythm could not be realized. On the other hand, a

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recent patient-level pooled analysis of the AFFIRM and AF-CHF studies showed similar, but no worse adjusted rates of all-cause mortality, cardiovascular mortality and cardiovascular hospitalization associated with amiodarone use regardless of LV function.76 What role does AF burden play? Could amiodarone have no negative impact, but poorer rates of sinus rhythm resulting in poorer outcomes? At first analysis, it appears that amiodarone was associated with low rates of AF burden in AF-CHF, comparable to those reported in AATAC and CASTLE-AF (see figure 3). Amiodarone treated patients spent 15.0 ± 1.8% of their time in AF compared to 42.2 ± 1.9% in the rate control group in pooled AF-CHF AFFIRM analyses.76 Superficially, these rates compare favourably to those reported in CASTLEAF. AF burden was less than 30% in the ablation arm compared to as high as 60% in the medical therapy group. Importantly, “AF burden” was measured very differently. Both ablation trials (AATAC, CASTLE-AF) used implanted devices for continuous sensing of AF. AFFIRM and AF-CHF, consistent with practice at the time, relied on intermittent ECG recordings in follow-up. Although less likely with persistent AF, paroxysmal AF burden can be underestimated with intermittent ECG monitoring alone. As such, true AF burden was likely underestimated based on intermittent ECG assessment. Residual unmeasured AF burden, if substantial, could have limited the impact of the rhythm control arm. Greater differences in AF burden documented in the ablation trials might have resulted in greater impact of sinus rhythm on outcomes. Unfortunately, a number of inherent limitations to the ablation studies make it impossible to know for sure. All eyes will be on the more rigorous RAFT-AF study to help clarify the impact of sinus rhythm, facilitated by catheter ablation, on clinically important endpoints.

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According to the myth, Alexander the Great, “untangled” the Gordian knot by slicing it with his sword, thus providing a simple solution to a complex problem, by thinking “outside the box”. Unfortunately, for clinicians faced with a patient with AF and HF, no sword exists; the knot remains as entangled as ever. Attempts to think outside the box, by using catheter ablation, have been unconvincing to a great many, leaving an ongoing complex problem. Understanding causation, assessing the potential for reversibility and determining how to achieve improved outcomes remain as difficult as ever. On one hand, AF-CHF tells us that rhythm control, as a widespread, approach offers no added benefit over rate control alone. On the other, one often wonders if the current patient may be part of a subgroup that could attain meaningful benefit from sinus rhythm. Some patients with HF and LV dysfunction are difficult to rate control. Do such patients have mild residual TICM that sinus rhythm could potentially reverse? Studies showing substantial improvements in EF with sinus rhythm in rate-controlled patients suggest that this is possible. A tool or scheme that could determine a priori potential for HF reversibility, such as an AI algorithm or imaging, as suggested by CAMERA AF, would be ideal. Such a tool could identify subgroups of patients, big or small, for whom meaningful benefit of sinus rhythm could be tested in clinical trials. It is critical that such clinical trials are methodologically rigorous such that, whether positive or negative, the results are universally accepted by the cardiovascular community as a whole. Without highly credible data, it will be impossible to untangle the AF HF knot.

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Acknowledgements: Dr. Skanes and Dr. Tang are Cardiac Arrhythmia Network of Canada (CANet) investigators. Thank you to Stephanie Skanes, BSc, for assistance with figures throughout the manuscript.

Table 1. Trials Currently Underway for Treatment of AF and HF Trial

Treatment Registration #

IMPRESS-AF

Spironolactone 250 NCT02673463

PARAGONHF

LCZ696 NCT01920711

RAFT-AF

Catheter Abl NCT01420393

412

AFARC-LVF

Catheter Abl NCT02509754

180

CATCH AF

Catheter Abl NCT02686749

220

LVEF 25-35%

Medical Rate or Rhythm control

216

ICD or CRT, any PAF or PeAF, LVEF ≤ 35%

Medical Rate or Rhythm control

1° endpoint

placebo

Exercise Tolerance (O2 consumption)

M AN U

Perm AF HFpEF (LVEF ≥ 55%) HFpEF (LVEF ≥ 45%, + NT-proBNP) HFrEF or HFpEF PeAF, PAF

Comparator

SC

Population

Valsartan

Medical or device-based rate control Medical or device-based rate control

TE D

PeAF, LVEF ≤ 35%

EP

Catheter Abl NCT00652522

4822

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AMICA

n

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Disclosures: Dr. Skanes has received research funding from Biosense Webster and has receive honoraria for speaking from Bayer, Servier, and Pfizer. Dr. Tang has received research funding from Medtronic. He is the Principal Investigator for the RAFT-AF study.

CV death or HF hospitalization* All cause mortality or HF hospitalization Improvement in LVEF > 35%, NHYA II 1st hospitalization for HF, or recurrence of AF or CV

LVEF by echo

Followup

Completion date

2 yrs

December 2018

Up to 57 mos

March 2019

Min 2 yrs

January 2020

1 yr

1 yr

February 2019

1 yr

Abl = ablation, Perm = permanent, CV=cardiovascular, PeAF = persistent AF, PAF = high-burden paroxysmal AF, * AF will be secondary outcome

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Figure Legends:

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Figure 1. AF and HF are inexorably linked. A. Unlike patients without AF, patients with prevalent AF are at high risk for incident HF. Patients with prevalent HF are at high risk of incident AF, especially compared to those with no HF. B. Mechanisms by which AF and HF selfperpetuate. LA=left atrium, MR = mitral regurgitation, TR = tricuspid regurgitation. Modified from reference 1.

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Figure 2. Interrelationship of AF and HF. A. Prevalent HF greatly increases the risk of incident AF. B. Prevalent AF greatly increases the incidence of both HFrEF and HFpEF. C. Mortality is increased in those with both AF and HF of either sub-type. Modified from Sanathankrisnan et al. (reference 4).

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Figure 3. Percentage atrial fibrillation in follow-up in A. AF-CHF study and B. CASTLE AF study. Note differences in y-axis. Although measures of AF “burden” appear similar, due to differences in method of assessment, burden of AF is much lower in CASTLE-AF study. Modified from references 47 and 73 appendix.

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