Heart rate variability as a predictor of successful catheter-guided pulmonary vein isolation for atrial fibrillation

Catheter-based ablation methods are a powerful tool to achieve long-term rhythm control when treating AF. However, not all patients seem to benefit equally from the procedure, as approximately one third of them suffer from recurrences within 1 year. To date, there is still a lack of viable characteristics to identify this group, which could benefit from a different follow-up-treatment. With our study, we demonstrate that low rMSSD values a few days after the ablation can independently predict AF recurrence. This relationship is strongest for CB2 and therefore better suited to predict recurrence after CB2 than after RF. When regarding only the mostly superseded CB1, this association is the weakest and insignificant.

As reported by Pandya et al. [7], in our data too recurrence-free survival was improved by CB2 (p = 0.057) compared to CB1, falling just short of significance. Likewise, as stated by the most recent guidelines [1], we also found CB2 to be noninferior to RF regarding efficiency, thus confirming the validity of our dataset.

Before we identified rMSSD as a predictor for recurrence, we first examined the differences in mean HRV between the recurrence and non-recurrence group, finding that suffering from AF recurrence is associated with significantly higher HRV after CB2 (except for SDANN). This led us to attempt to identify specific cut-offs for differentiating between groups with either high or low risk for recurrence, which we found for all HRV parameters. Thus, our next step was to compare them and find the most applicable: rMSSD, as confirmed by the first Cox regression and validated as an independent predictor by the second analysis. Our earlier results also suggested that the calculated cut-off for rMSSD might show different predictive capabilities depending on the ablation method. Therefore, instead of only using the whole population as basis for our cut-off calculation, we recalculated the best cut-off for every ablation method, confirming our hypothesis that rMSSD is best suited to evaluate recurrence risk after CB2.

Several studies in the past have demonstrated a relation between low HRV after ablation and lower recurrence risk. However, the HRV parameters that have been found to be predictive for AF recurrence differ to some extent between those studies. Wang et al. reported significantly reduced SDNN and rMSSD for the non-recurrence group, but unlike us determined SDNN as the sole independent predictor [8]. Two other studies identified only frequency-domain HRV parameters as independent predictors for recurrence [9, 10] and Zhu et al. found rMSSD, pNN50, and high-frequency components (HF) as independent predictors for AF recurrence [11]. These three studies, however, only included patients who received RF, which could explain some of the differences compared to our study given we included also the first two generations of cryoballoon ablation. We found only one study including patients treated with CB2, which observed significantly reduced rMSSD, HF, and low-frequency components after ablation only in the non-recurrence group but measured not until 3 months after the procedure [12]. Oswald et al. did not find a relation between AF recurrence and attenuated HRV but they used only CB1, and agreed with our estimation that HRV is not suited to predict recurrence for this superseded method [13]. To the best of our knowledge, this is the first study to examine the relationship between HRV and AF recurrence for more than 300 patients while at the same time including patients after CB1, CB2, and RF. Thus, while comparing well with the aforementioned studies in confirming the existence of said relationship with a larger sample, we also add novelty regarding the notion that the strength of this relation might depend on the ablation method.

Taking into consideration that rMSSD “is the primary time-domain measure used to estimate vagally-mediated changes reflected in HRV” [14], our finding of rMSSD as the sole independent predictor for recurrence is consistent with the hypothesized vagal withdrawal happening during ablation. Pappone et al. were among the first to report a link between HRV attenuation and AF recurrence. They mapped parasympathetic innervation around the pulmonary veins and proposed the addition of complete vagal denervation to PVI after they found it to significantly reduce AF recurrence [15], thus identifying a new potential target site for ablation. The intrinsic part of the extensive autonomous innervation of the heart is made of ganglionated plexi (GP), which are located mainly in fat pads around the pulmonary vein ostia [4]. While it has been shown that adjunctive ablation of these GP can increase the success rate of pulmonary vein ablation [4], this technique is not well established. It has been demonstrated that PVI alone attenuates HRV [12, 13] and a more recent study observed vagal responses and HRV attenuation in a similar fashion for both PVI and PVI with GP ablation [16], suggesting that PVI alone might produce GP damage to at least some degree. With the knowledge that the origin and maintenance of AF are partly attributed to a disbalance in the ANS [3], this could explain why HRV could be a useful predictor for AF recurrence.

Concerning our conclusion that HRV is better suited to predict recurrence after CB2 than after RF, we hypothesized that this could be due to the circumstance that ablation via cryoballoon increases myocardium-specific enzymes more strongly after the ablation and causes wider lesions than RF [17], suggesting that CB2 creates more extensive lesions and thus modulates/destroys more GP. The same mechanism could explain why for CB1, HRV is not as applicable for predicting AF recurrence: only four vs. six cryosource emission holes as used with CB2 result in a smaller cooling surface area [18] and potentially in fewer destroyed GP.

Apart from confirming rMSSD as an independent predictor for AF recurrence, our Cox regression also suggests that suffering from heart failure increases the risk for recurrence, which is mostly consistent with previous findings [19]. However, suffering from coronary disease or hypertension seems to be a protective factor in our study, which stands in contrast to previous findings [20]. There are multiple possible explanations for this discrepancy: Firstly, Hiraya et al. reported a lower risk of recurrence for patients with coronary disease who underwent percutaneous coronary intervention [20] and we did not document how many of our patients with coronary disease might have profited from that measure. Secondly, since our co-occurrence of coronary disease and heart failure (see Tables 4 and 5 in supplementary data) is far lower than described in the literature [21] and our study was conducted retrospectively, it may be that one or both comorbidities were poorly documented. The third approach to an explanation also applies to hypertension being a protective factor, because it suggests that patients suffering from one of both conditions might profit from a more extensive antiarrhythmic drug treatment. The percentage of patients with coronary disease/hypertension receiving beta-blockers is significantly higher than the percentage of patients with beta-blockers without those conditions (see Tables 6 and 7 in supplementary data). However, our multivariate Cox-regression analysis could not detect a significantly decreased risk for recurrence for patients taking beta-blockers and on the contrary the trend pointed toward an increased risk for this group. A future prospective study would not have to rely on proper documentation in the past and could thus circumvent part of these issues.