Interplay between natriuretic peptides and left atrial mechanics and the relation to recurrence of atrial fibrillation following catheter ablation

This was a substudy of the randomized, double-blinded, placebo-controlled AMIO-CAT trial (Clinicaltrials.gov ID: NCT00826826) which sought to investigate whether short-term amiodarone treatment reduced AF recurrence following catheter ablation. A detailed description of the trial has previously been outlined [11].

This substudy only included participants from Rigshospitalet (n = 124), one of two centers that participated in the main trial, as only this institution performed natriuretic peptide measurements as part of the study. These patients were enrolled from February 2009 to July 2013. Of the 124 patients enrolled at Rigshospitalet, 19 did not have natriuretic measurements performed, 3 were excluded as they had a creatinine > 150 µmol/L, 2 patients did not have Holter monitoring performed at 6-month follow-up, and 1 patient did not have any echocardiographic measures of the LA available, leaving 99 patients for final inclusion.

The study complied with the Helsinki Declaration, was approved by a regional scientific ethics committee, the Danish Data Protection Agency, the Danish Medicines Agency and informed consent was obtained from all participants.

The endpoint was late AF recurrence defined as documented atrial tachyarrhythmia > 30 s after a 3-month blanking period. Patients had 72-h Holter monitoring performed at 6 months for rhythm monitoring.

Patients had venous blood samples drawn at study inclusion, prior to ablation. N-terminal pro B-type natriuretic peptide (NT-proBNP) was measured on the automated Modular P platform (limit of detection ≥ 5.9 pmol/L). Mid-regional pro atrial natriuretic peptide (MR-proANP) was measured on the automated Kryptor Plus platform (Thermo Fisher, Hennigsdorf, Germany) after the plasma had been stored at − 80 °C. The intra-assay coefficient of variation according to the manufacturer is < 2.5% when the concentration is within the relevant range of 20 to 1000 pmol/L (limit of detection ≥ 2.1 pmol/L, and limit of quantitation ≥ 4.5 pmol/L).

Detailed description of the echocardiographic analyses have previously been described [12]. All patients had a transthoracic echocardiogram (Philips iE 33, Netherlands) performed prior to catheter ablation (0–90 days before). Echocardiographic measurements were performed using Xcelera quantification software (Philips Healthcare), with the exception of speckle tracking which was performed with Epsilon Imaging vendor-independent software (EchoInsight® software revision 2.2.0.x).

Left ventricular systolic function was evaluated by the left ventricular ejection fraction (LVEF) measured by the Simpson’s biplane method. LA volumes were measured by the biplane area-length method at end-systole and end-diastole. They were indexed to body surface area to provide the left atrial volume index (LAVi) and left atrial end-diastolic volume index (LAEDVi), respectively. The LA expansion index (LAi) was calculated as the fractional difference between these two volumes (LAVi − LAEDVi)/LAEDVi.

LA speckle tracking was performed by manual delineation along the endocardial border in the apical 4- and 2-chamber views after which the software generated a region of interest to cover the LA wall. The software subsequently provided corresponding strain values, including the peak LA reservoir strain. LA speckle tracking was feasible in 94% of these patients.

LAVi, LAi, and LA reservoir strain all represent measures of the reservoir/distension function of the LA [13].

Baseline characteristics are listed for the entire population and according to the outcome of AF recurrence. Differences between groups were tested by Student’s t-test for Gaussian distributed continuous variables and with Mann–Whitney U test for non-Gaussian distributed continuous. Categorical variables were compared by Chi²-test and Fisher’s exact test as appropriate. All continuous variables are expressed as mean values ± standard deviation, continuous non-parametric variables are presented by the median (IQR) and categorical variables as total numbers with percentages. Logistic regression was used to assess the risk of AF recurrence according to changes in natriuretic peptides. The natriuretic peptides were log-transformed for these analyses. Log-transformation was done in a log(1.10) approach that allowed for assessment of change in risk according to 10% changes in natriuretic peptide concentration. Multivariable adjustment was made for age, gender, LVEF, and randomization group. Test for effect modification was performed to assess whether randomization group (amiodarone treatment vs. placebo) modified the associations between natriuretic peptides and AF recurrence. Similarly, tests for interaction were performed for measures of LA distension (LA reservoir strain, LAi, and LAVi) to assess for any effect modification on the association between natriuretic peptides and AF recurrence.

A restricted cubic spline curve based on Poisson regression was created to visualize the continuous association between MR-proANP (untransformed) and risk of AF recurrence. The number of knots were chosen based on the lowest Akaike information criterion.

Kaplan–Meier curves were created to visualize the risk of AF recurrence at follow-up stratified by MR-proANP value (above vs. below the population median value of 116 pmol/L) in the patients with preserved LA strain.

For all analyses, a p-value ≤ 0.05 in two-tailed tests was considered statistically significant. STATA Statistics/Data analysis SE 15.1 (StataCorp, Texas, USA) was used for statistical analysis. Kaplan–Meier curves were created with R Studio (v. 3.6.0).

As 30–50% of patients develop AF recurrence following first catheter ablation [3], there is a continued need for optimizing the selection of patients to identify those who will not benefit at all from ablation treatment—to prevent unnecessary procedures—as well as those who will likely need re-ablation and therefore require close monitoring following their first ablation. A meta-analysis from Jiang et al. has previously established that plasma ANP can predict AF recurrence following catheter ablation [4]. This meta-analysis included six studies with a collective population of 298 patients and 113 recurrences. However, the studies were heterogeneous in design and included AF recurrence within the 3-month blanking period, during which AF events are generally not considered failure of catheter ablation [14]. When only considering studies with AF recurrence outside the blanking period, plasma ANP was not predictive of AF recurrence. The lack of predictive ability of plasma ANP has since been confirmed by Nakanishi [9], and similar results have been observed for other ANP precursors [15, 16]. Overall, the findings consistently show that ANP is not predictive of significant AF recurrence and stresses a need for exploring other ways to use ANP instead. So far, studies investigating the predictive value of natriuretic peptides have primarily operated under the assumption that increasing natriuretic peptide concentration translates into increased AF recurrence risk in a linear fashion. However, Daniels et al. outlined another way of considering the association between natriuretic peptide concentration and AF risk by linking the endocrine function to the atrial viability [10]. In patients without atrial fibrosis, a low natriuretic peptide concentration represents a healthy atrium and a high concentration of natriuretic peptide reflects pathology. In patients with extensive atrial fibrosis the interpretation of natriuretic peptide concentration is more complicated as a low natriuretic peptide concentration may indicate an endocrine burnout due to degenerative changes [17, 18], and a low ANP concentration has indeed previously been shown to predict AF recurrence following cardioversion [19]. On the other hand, a high concentration in part reflects ongoing disease state but also that the atrium is healthy enough to produce a secretory response. This complex response in natriuretic peptide secretion with progressive mechanical dysfunction may explain why increasing atrial natriuretic peptide concentration failed to predict AF recurrence in patients with low LA strain. The reason why LA strain, as opposed to the other measures of LA distension, modified the association between natriuretic peptides and AF may be explained by the fact it is a direct measure of atrial tissue function. By extension, LA strain has been shown to be closely linked to atrial fibrosis [20], and may be therefore be used as a surrogate measure of atrial fibrosis.