Author + information
- aDepartment of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota
- bDepartment of Pediatrics and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota
- ↵∗Address for correspondence:
Dr. Samuel J. Asirvatham, Department of Cardiovascular Diseases, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905.
In 1874, Edmé Félix Alfred Vulpian observed the irregular atrial electrical behavior and termed it “fremissement fibrillaire” (1). The magnitude of the atrial fibrillation (AF) problem ensures funding of discovery and development of diagnostic and therapeutic modalities (2). Its pathogenesis and clinical importance gained enhanced appreciation in the 1990s when early community-based studies, including the FHS (Framingham Heart Study), provided critical epidemiological data on associated risk factors and clinical outcomes (3,4). Over the past 3 decades, an explosion of ideas and research has yielded progress in the clinical treatment of AF at a time when AF is reaching epidemic proportions. Strategies to reduce overall AF-related mortality are focused on the prevention of thromboembolism.
In this issue of JACC: Clinical Electrophysiology, Leung et al. (5) examined consecutive patients referred for cardioversion and investigated the impact of clinical subtype of AF on all-cause mortality. They identified 1,773 patients who underwent cardioversion. The majority of them had persistent AF and were older, with larger body mass index, higher comorbidity burden, and higher use of beta-blockers, angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers and anticoagulation. They concluded that patients with persistent AF were more likely to die after adjusting for various comorbidities known to influence mortality.
Do the Patients With AF Die For Who They Are? (Known Known)
Most patients with AF have cardiovascular risk factors and coexisting conditions that increase their mortality risk, but the mode of death in patients with AF is poorly understood. Predictors of mortality were identified using data from the RE-LY (Randomized Evaluation of Long-Term Anticoagulant Therapy) trial, which compared dabigatran with vitamin K antagonists in >18,000 patients with AF. The strongest predictors of cardiac death were heart failure, previous myocardial infarction, abnormal conduction, and reduced renal function (6). Recent data suggest that AF is also independently associated with an increased risk of sudden cardiac death (SCD). In patients with established AF treated with anticoagulation, SCD accounts for >20% of all deaths. Patients with AF have, on average, a 2.5-fold increased risk of SCD or ventricular fibrillation compared with patients without AF (7). The mechanism underlying this possible causal association is not completely understood. Although AF and SCD share common risk factors such as heart failure or coronary artery disease, the association between AF and SCD does not seem to be entirely dependent on these risk factors and the identification of other factors that are unique to patients with AF would be of interest. Persistent AF may also be a marker of more advanced disease with a greater extent of underlying structural heart disease. Persistent AF may have proarrhythmic effects including myocardial ischemia induced by rapid AF, reduction of ventricular refractoriness during rapid AF, and electrical remodeling of the atria, characterized by shorter action potential duration and refractoriness, with similar changes that might also occur in ventricular myocytes.
Is it the Therapy For Persistent AF? (Known Unknown)
Patients with persistent AF are more likely to be on anticoagulation therapy as alluded to in the study by Leung et al. (5). Although the investigators report higher use of anticoagulation and other medications, whether death was due to adverse events especially due to anticoagulation use is not clear. Most therapeutic strategies for AF such as antiarrhythmic drugs, antithrombotics, and catheter ablation can increase mortality risk in AF as a side effect or serious adverse event. Antiarrhythmic drugs can lead to potentially lethal proarrhythmic effects (such as torsade de pointes) but also cause multisystemic side effects and thus contribute to noncardiovascular deaths. A rhythm control strategy has also been shown to unmask noncardiovascular comorbidities such as malignancies or lung pathology, thus contributing to mortality burden. How much these known factors truly affect mortality remains unknown.
What Is a Statistically Independent Risk? (Unknown Known)
As clinicians, we are often interested in prediction. We wish to know which patient will get AF and which will not, and how the given therapy will fare. Clinical trialists and epidemiologists have leveraged the use of Cox regression model for analysis of survival data and for identifying differences in survival due to treatment and prognostic factors (covariates or predictors or independent variables) in clinical trials. The Cox proportional hazards model allows one to describe the survival time as a function of multiple prognostic factors. This model relies on a fundamental assumption—the proportionality of the hazards—implying that the factors investigated have a constant impact on the hazard or risk over time. However, this is far from true especially in evaluation of cardiovascular comorbidities. For example, it is very possible that congestive heart failure, diabetes, or hypertension may worsen, or the definition of each comorbidity may change (8). There is also a concern for competing risk such as other noncardiovascular comorbidities that may affect mortality. It is important to present results for all causes and for both cause-specific hazard functions and subdistribution hazard functions. Such a practice enables a more complete understanding not only of the effects of prognostic factors but also of the absolute risks of the different outcomes in the study sample. This is critical for decision makers who may need to consider the risks of all events when making clinical decisions. Someone with a high risk of noncardiovascular mortality but with a low risk of cardiovascular mortality may be treated differently than someone with a low risk of noncardiovascular mortality and high risk of cardiovascular mortality. For instance, the latter patient may be an excellent candidate for early AF ablation procedures, whereas the former patient may not be a suitable candidate for AF ablation.
Is it Truly a Clinically Independent Risk?
In view of the strong association of AF with comorbidities, several studies have attempted to analyze whether the effects of AF on mortality are truly independent or simply a risk marker for the cumulative pre-terminal effects of comorbidities. The Olmsted County study, for instance, illustrated the very high 4-month and 1-year mortality following AF diagnosis; however, there were no changes in early (<4 months) versus late mortality (after 4 months) in the whole cohort or within the subgroup of patients without pre-morbid cardiovascular disease (9). These results and others showing that AF alone does not increase mortality, suggest that AF could simply represent a risk marker for mortality in a very sick population with multiple comorbidities.
Can We Make Persistent AF Less Persistent to Lower the Risk? (Unknown Unknown)
After initial enthusiasm, it is widely acknowledged that ablative interventions for persistent AF are far from curing AF. However, whether we can modify persistent AF to be less persistent is not known. The CABANA (Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial [NCT00911508]) will shed a light on whether ablative interventions compared with medications will affect all-cause mortality. It is recognized that lifestyle modification such as weight loss plays an important role in maintaining sinus rhythm (10). This is very likely to have some pleotropic effect on all-cause mortality.
Can We Cure Persistent AF? (True—Unknown)
The major bane of all electrophysiologists is to find a lasting cure for AF. The wide range of clinical presentation of AF and targeted therapy is fundamentally governed by the variable extent of interaction between AF triggers (or drivers) and the necessary “substrate” created by electrophysiologically and structurally remodeled atrial tissue capable of supporting and maintaining AF. The future in this realm may be related to different energy sources, additional targets such as autonomic modulation, or possibly having a nonelectrophysiologist ablate AF remains to be seen (11–13).
The report by Leung et al. (5) provides support for the view that all-cause mortality is higher for patients with persistent AF. Whether the increased mortality risk is due to the persistence of AF as a whole or simply the sum of the risks of its individual component parts is perhaps not unequivocally settled.
↵∗ Editorials published in JACC: Clinical Electrophysiology reflect the views of the authors and do not necessarily represent the views of JACC: Clinical Electrophysiology or the American College of Cardiology.
Both authors have reported that they have no relationships relevant to the contents of this paper to disclose.
All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Clinical Electrophysiology author instructions page.
- 2018 American College of Cardiology Foundation
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- Corresponding Author
- Do the Patients With AF Die For Who They Are? (Known Known)
- Is it the Therapy For Persistent AF? (Known Unknown)
- What Is a Statistically Independent Risk? (Unknown Known)
- Is it Truly a Clinically Independent Risk?
- Can We Make Persistent AF Less Persistent to Lower the Risk? (Unknown Unknown)
- Can We Cure Persistent AF? (True—Unknown)