Atrial fibrillation (AF) has been widely recognized as a modern-day disease epidemic (1- 2). Although AF ablation has been a major advance, offering a new spectrum of treatment options for symptomatic patients, high recurrence rates have significantly tempered initial optimism (2- 3). Another alarmingly frequent conglomerate of common disorders is the metabolic syndrome (MS), estimated to affect up to 21% to 24% of the adult U.S. population (4- 7).

In this issue of the Journal, Mohanty et al. (1) report their findings from a well-conceived, large, prospective study (1,496 consecutive patients with AF) undergoing AF ablation. The investigators report a higher recurrence rate of AF after ablation in the patients with MS. Moreover, the difference in observed recurrence depended on AF type (nonparoxysmal AF) (1).

Before we assess the impact of this important study on how we risk-stratify patients for AF ablation benefit and improved outcomes, we need to consider the impact of these findings on our understanding of what causes AF, why ablation fails, and why the MS should matter at all.

The cause of AF remains poorly understood. Substrate abnormalities that promote re-entry were once considered the only mechanism of AF (8), but with the recent demonstration of “focal” sources of AF, a more comprehensive hypothesis for AF origin is acknowledged.

This lack of disease mechanism understanding, however, has not prevented the explosion in the past decade of AF ablation procedures (9). However, not obtaining optimal success is the rule rather than the exception with AF ablation, and we now recognize that for future improvement, a better understanding of the pathogenesis of AF is necessary. Mohanty et al. (1) provide unique insights into AF pathogenesis by exploring the relationship of AF with MS.

Two of the independent factors predicting AF recurrence after ablation were C-reactive protein and white blood cell count. Cause and effect with regard to C-reactive protein has been unclear, with 1 study showing that C-reactive protein levels decrease after successful ablation, implying that inflammation is a result of the arrhythmia. The present study (1), however, found that pre-ablation markers of inflammation predicted recurrence, suggesting cause not only for AF but for ablation failure. This finding highlights a conundrum with AF ablation. The more we ablate, the more likely we are to eliminate AF triggers and modify substrate, but the associated inflammatory response may be arrhythmogenic, at least in the short term.

Hypertension, an integral component of MS, is a well-known risk factor for developing AF. Chronic blood pressure elevation is associated with atrial myocyte hypertrophy, myolysis, conduction abnormalities, and increased AF, even without changes in refractoriness (10).

DM and insulin resistance have established adverse effects on myocardium and arterial stiffness. A direct electrophysiological consequence of DM is not established (6- 7). However, in 1 study, DM was an independent predictor of very late recurrence after AF ablation (3,6- 7).

A complex and multifactorial link between obesity and AF likely exists. Elevated plasma volume, neurohormonal activation, and electrical instability (11), along with oxidative stress and inflammation, serve to increase the likelihood of AF. In addition, noncardiac associations such as autonomic dysfunction and sleep apnea (12- 13) may increase atrial arrhythmogenicity in obese patients.

The propensity to create structural abnormalities and electrical instability for MS appears more than additive of what has been observed for its individual components (7,14). This suggests that a common underlying condition that requires the multiple components of MS increases AF likelihood. Two such candidate conditions are diastolic dysfunction and increased left atrial size (6).

Although earlier studies showed an association between the occurrence of MS and AF, Mohanty et al. (1) have shown that ablation fails more commonly when MS is present. For ablation success, both initiating triggers and arrhythmogenic substrate need to be addressed. In this study, the excess of recurrence of AF after ablation was exclusively limited to the population with nonparoxysmal AF. In this population, it is likely that negative structural remodeling is the key arrhythmogenic process. Given the extensive cellular and whole atrial changes associated with the components of MS, we learn from this study that atrial arrhythmogenic substrate is a moving target. Because in most patients, MS is an ongoing state, substrate changes possibly continue to occur, and a 1-time ablation-based “substrate modification” may be insufficient. It is also possible that we simply do not yet know how to modify arrhythmogenic substrate (15).

However, in other similar recent studies relating MS to ablation failure (14), paroxysmal AF had a higher rate of recurrence in patients with MS. The differences between these and the Mohanty et al. (1) reports are unclear, but in the present study, there was an aggressive approach to eliminate triggers (up to 30 μg isoproterenol and non–pulmonary vein trigger elimination). On the basis of this assumption of difference, perhaps we learn that trigger elimination, even if in a 1-time procedure, can be effective despite an ongoing primary arrhythmia-provoking process.

If what we have learned from this informative study (1) is that substrate abnormalities may be progressive and we do not have a uniformly effective method to treat structural arrhythmogenic substrate in patients with AF, can we hope for a true disease-modifying effect with ablation in the future? If AF is simply a symptom of an underlying process related to the components of MS and possibly diastolic dysfunction, how can we address AF in a permanent fashion without changing the underlying process? The paracardiac autonomic nervous system lies in close physical proximity to the pulmonary vein ostia and has been investigated as a potential target for AF ablation (16- 17). Present approaches pioneered by Scherlag et al. (16) involve atrial ablation to target these epicardial ganglia. However, the enhanced inflammatory response with myocardial ablation along with proarrhythmic macrore-entry may offset gains. Given the decreased incidence of AF in denervated hearts after transplantation (18), perhaps approaches similar to these need to be developed to render AF less likely to recur regardless of an ongoing provocatory substrate? Knowing that we cannot halt the underlying process, can we make the atria immune to fibrillation?