Impact of epicardial ablation of concomitant atrial fibrillation on atrial natriuretic peptide levels and atrial function in 6 months follow-up: does preoperative ANP level predict outcome of ablation?

Atrial fibrillation (AF) is the most common supraventricular cardiac arrhythmia, which affects approximately 6–10.2 million people in Europe, 2.2 million Americans and its prevalence increases with age [1, 2]. Affected patients have a five times bigger stroke risk and twice the risk of death. AF reduces left ventricular (LV) function, diminishes exercise tolerance, cognitive capacity, impairs quality of life (QoL) as well as elevates atrial natriuretic peptide (ANP) secretion [3–5]. In cardiac surgery AF is associated with increased risk of perioperative death and decreased short- and long-term survival [6].

AF is classified as paroxysmal (Pa; self terminating within 7 days or cardioverted ≤48 hours), persistent (Pe; sustained >7 days or cardioverted after 48 hours but prior to 7 days), longstanding persistent (LsPe; continuous >1 year) and permanent (continuous >1 year, presence of AF is accepted and the therapy does not affect the restoration of sinus rhythm by any means) [7].

Current guidelines recommend concomitant surgical ablation in patients with AF who undergo cardiac surgery [1, 7]. The procedure consists of formation of electrical conduction blocks by scalpel like in classic Cox-maze procedure (CMP) or an alternative source of energy such as high intensity focused ultrasound (HIFU), radiofrequency (RF), cryoablation, microwave and laser. The aim is to isolate trigger foci and inhibit macro-reentry circuits, essential in pathogenesis of AF. HIFU allows epicardial ablation on beating heart and its safety and efficacy is well-known [8–12]. The primary goal of ablation is to restore the active function of the atria, to improve cardiac hemodynamics and reduce the risk of embolism. The success of surgical ablation depends on type and duration of AF and left atrium (LA) size [13, 14]. Patients with LsPe AF have the most enlarged atria and show generally the poorest outcome after ablation [11, 12].

Yoshihara et al. revealed that atrial natriuretic peptide (ANP) might be a potential predictive marker of heart rhythm after ablation by maze procedure [15]. ANP belongs to the group of natriuretic homeostatic peptides. It increases diuresis and natriuresis, stimulates vasodilatation, inhibits the renin-angiotensin-aldosteron system (RAAS), the sympathetic nervous system and regulates water balance. ANP is synthesized in atrial myocytes and the key stimulus for its secretion in AF is the stretch of atrial wall (rather than atrial pressure) [16].

Classic CMP has been reported to cause a dramatic decrease of ANP levels for at least 7 days after procedure, leading to post-operative severe fluid retention, oedema and recurrent pleural effusion [17]. To our knowledge, the effect of HIFU on post-operative plasma ANP levels has not yet been studied. The biochemical predictors of cardiac rhythm after epicardial ablation are not yet known. The aims of our prospective study were: (1) to evaluate whether preoperative ANP level might have a predictive value for the success rate of epicardial HIFU ablation (2) to estimate the recovery of atrial mechanical function following epicardial HIFU ablation and their impact on alteration of endocrine secretion in 6 moths follow-up (3) to analyze the effect of epicardial HIFU ablation of concomitant AF on atrial endocrine secretion based on serial postoperative ANP levels.

Our study is the first - to our knowledge - to evaluate the relationship between a biochemical marker, echocardiographic characteristics and heart rhythm in 6 months follow-up after epicardial HIFU ablation in patients with concomitant AF undergoing cardiac surgery. Our results indicate among patients with LsPe AF significantly higher baseline ANP levels in individuals with successful conversion to SR at 6 months follow-up after HIFU ablation compared to patients, who remained in AF despite ablation, suggesting that plasma ANP levels may be a noninvasive biochemical predictor of success after HIFU ablation.

In addition, in LsPe AF, which revealed the lowest conversion rate to SR among all types of AF [8] (in our population 56% of SR after 6 months), patients with baseline ANP levels > 7.5 nmol/l had high success rate of SR restoration (80.0% after 6 months). In contrast in patients with baseline ANP levels < 7.5 nmol/l, the success rate was significantly lower (20.0% after 6 months, p < 0.005). A similar relationship between preoperative ANP levels and effectiveness of ablation by maze procedure was also presented by Yoshihara et al. [15]. Sato et al. showed a strong association between ANP-to-BNP ratio and rhythm after the maze procedure in patients with mitral valve disease [19]. Furthermore our results indicate that among preoperative parameters only baseline plasma ANP levels are independent predictors of cardiac rhythm after HIFU ablation in patients with LsPe AF. Numerous studies reported that the patients with successful SR restoration after classic maze procedure had significantly smaller LAD as determined by preoperative echocardiography, than those who remained in AF [19–21]. In our study, preoperative LAD with cut-off at 50 mm was a dependent predictor of success after ablation, which is consistent with previous reports [11, 12]. In addition, we demonstrate that the patients with LsPe AF those remained in AF despite HIFU ablation had not only larger left atrial size (LAD >50 mm and LA area >29 cm²) but also showed significantly lower preoperative plasma ANP levels, compared to those who successfully converted to SR at 6 months. Furthermore our study indicates that baseline plasma ANP levels in LsPe AF are more useful for predicting the outcome of HIFU ablation than conventional echocardiographic characteristics, such as LAD and LA area.

We discovered an increase of plasma ANP level after epicardial HIFU ablation, which is contrary to other studies which described dramatically decreased ANP levels after classic maze procedure (CMP) [17]. Decreased ANP levels are the main cause for acute postoperative fluid retention with pulmonary oedema and symptomatic pleural effusion observed in 12-36% of patients after CMP. On the other hand, higher ANP levels are assumed to improve kidney function and prevent renal insufficiency after cardiac surgery [21], have beneficial impact on pulmonary pressure reduction [22] and protect against ischemia and reperfusion injury [23]. It is believed that amputation of both atrial appendages in the original Cox-maze procedure is a major cause of postoperative ANP decrease [17]. Therefore, according to Yoshihara et al. preservation of RAA in the modified maze procedure effectively protects against postoperative decrease of ANP and it has beneficial impact on the postoperative course [21]. Hypothetically, an elevated ANP level after HIFU ablation may have a beneficial effect on postoperative course, but this question requires further investigations. In our study we amputated RAA in 100% and LAA in 21.4% of cases, therefore the increased ANP levels on POD 1 must be associated with other factors than preservation of atrial auricles. Since increased ANP levels from POD 7 to 3 months in follow-up were also observed in the control group with SR, we suspect that immediate postoperative ANP increase is rather a reaction to surgical trauma, perioperative higher volume load and atrial stretch. Other studies revealed also similar increase of ANP levels observed on POD 1 and 2 after CABG [24]. Surprisingly, cardiopulmonary bypass and its duration did not influence plasma ANP levels significantly [25]. Among patients with AF, we observed a significant increase in postoperative ANP levels only in the ablation group, but not in the control group without ablation. We might hypothesize that higher ANP concentrations could also be derived from necrotizing wall injury due to ablation. Nevertheless, among the individuals who did not undergo HIFU ablation, we observed that patients in the SR control group had a much greater increase in ANP levels on POD 1 than patients in the AF control group without ablation, (83% vs 24% increase from baseline level). This might suggest an impaired capability of the atria to release ANP, when they are fibrillating. Systemic ANP level depends not only on atrial stretching secondary to hemodynamic changes, but also on structural state and remodeling of atria. Previous study suggested that plasma ANP levels in patients with AF reflected degenerative changes and inversely correlated with the level of LA fibrosis [15]. Probably because the degenerative changes are most expressed in LsPe AF, only in these patients preoperative plasma ANP levels were independent predictors of cardiac rhythm after ablation in the present study. While patients with Pa and Pe AF with intermittent burden of atrial wall-stretch are heterogeneous as for factors stimulating ANP release. It might explain, why in our population we found the lowest basal plasma ANP levels in the SR control group, increased in patients with paroxysmal and persistent and highest in patients with longstanding persistent AF. This data partially confirmed the findings by Cao, which showed elevated plasma ANP levels in paroxysmal and persistent AF compared to SR group [5].

We present the impact of HIFU ablation on atrial hemodynamic active function, using echocardiographic characteristics such as AFF and velocity of A-wave in 6 months follow-up. The most important purpose of surgical AF treatment is restoration of coordinated atrial contraction and their transport function resulting in improved cardiac hemodynamics, reduced risk of thromboembolism and stroke [26]. In patients, who had converted to SR at 6 months follow-up we observed active contractility of both atria in 80.8% of patients, of the left atrium in 84.6% and of the right atrium in 88.5%. Previous studies had shown lower rates of recovery of LA contractility in follow-up after ablation despite stable SR, both in only left atrial ablation (70% for cryoablation) [27] and in biatrial ablation (63% for modified radiofrequency Maze procedure) [28] or in CMP (73%) [29]. However, there is no data in the literature on atrial contractility after ablation using HIFU. We found significant increase of both AFF and A wave velocity of the left atrium in 6-months follow-up. These findings support the assumption that left “atrial stunning” after epicardial HIFU ablation last about 6 months and anticoagulation is necessary throughout this time. We found no correlation between recovery of LA contractility and ANP level alteration (Figure 6). We suspect that the described decreased ANP levels associated with SR restoration and recovery of atrial contractility [30, 31] are masked by additional ANP release due to surgical trauma, necrosis in ablated tissue or higher volume overload in the early postoperative period.

68.4% of our entire study population achieved restoration of SR within 6 months. This corresponds with studies published recently (62-66% conversion rate) [11, 12]. However, our success rate was lower than the first reports on HIFU-ablation (83.2%-85%) [8, 10]. We explain this by a lower percentage of individuals with Pa AF in our study population (11.9%) compared to the study of Groh et al. (33.3%) [10] and lower proportion of patients with concomitant mitral valve surgery (23.8%) in comparison to the study conducted by Ninet et al. (44.6%) [8]. It is well-known that the success rate of ablation is significantly higher in individuals with Pa AF compared to those with LsPe and permanent AF, and correction of mitral valve disease have a beneficial effect on SR restoration [26]. We did not perform any positive selection of patients regarding predictors of successful ablation. In reality every patient with AF, who required surgical treatment of underlying heart disease, has undergone concomitant ablation. This may result in the higher proportion of LsPe and lower of Pa AF in our study.

Epicardial approach allows surgeons to replicate mini-maze lesions on beating heart. It requires controlled propagation of energy without risk of heart and collateral structures damage or coagulates formation in circulating blood. For this reason only the systems based on RF, microwave and HIFU are suitable, whereas laser and cryoablation can be used exclusively from endocardial. Thickness of left atrial wall and epicardial fat layer [32] and the “heat-sink effect” of circulating blood volume are the main factors reducing transmurality and thereby outcome of epicardial methods. Effectiveness of epicardial ablations in restoring of SR by the same lines concept are comparable and ranged between 62.2-65% for microwave [33], 62-85% for HIFU [9, 12] and 67,5-82% for RF [34, 35] at different follow-up periods. Following the acquisition of Guidant company, production of Flex 4 and 10 sole devices using microwave was stopped. Presently, the SJM company closed for business reasons the branch of Epicor production in order to focus on new market of transcatheter aortic valves technologies. As a consequence actually only RF remains on the market for epicardial approach.

(1) Our results indicate that preoperative ANP levels may be a new biochemical predictor of successful surgical HIFU ablation in patients with concomitant LsPe AF. (2) Surgical HIFU ablation of concomitant AF causes a significantly improvement of atrial mechanical function and gradual increase of AFF and did not associate with alteration of atrial endocrine secretion at 6 months follow-up. (3) Our results indicate that epicardial HIFU causes an increased secretion of plasma ANP on POD 1. Since drop of ANP after maze ablation is the main cause of severe fluid retention, an ANP increase after HIFU might have a beneficial impact on postoperative course; however, further study is required to resolve this question.