Could successful cryoballoon ablation of paroxysmal atrial fibrillation prevent progressive left atrial remodeling?

Patients

36 consecutive patients with recurrent, symptomatic, nonvalvular PAF were enrolled in the study between June 2008 and July 2009. All had failed to respond antiarrhythmic (propafenone, or amiodarone, or sotalol) or beta blocker therapy. They underwent their first catheter ablation by the cryoballoon technique.

The study was carried out in compliance with the Helsinki Declaration and was approved by the Regional and Institutional Scientific and Research Ethics Committee of the Semmelweis University Budapest (reference number: TUKEB 70/2008). All patients gave written informed consent before participating in the study.

Cryoballoon ablation

As described in our previous report [17], all patients were treated with a double lumen cryoballoon (Arctic front, Cryocath, Montreal, Quebec), after local anaesthesia and under conscious sedation using boluses of midazolam and fentanyl. At first a decapolar electrophysiological catheter (Bard Electrophysiology Inc., Lowell, MA, USA) was placed in the coronary sinus through the right jugular vein, and a diagnostic quadripolar electrophysiological catheter was introduced through the right femoral vein and positioned in the right ventricle. An intracardiac echocardiography catheter (Acunave, Acuson, Mountain View, CA, USA) was introduced through the left femoral vein and positioned in the right atrium, in order to ensure safe transseptal approach. After the intracardiac echocardiography-guided single posterior transseptal puncture, a circular mapping catheter (Lasso catheter, PV Orbiter, Bard) was advanced and positioned in the antrum of each pulmonary vein to record the presence of pulmonary vein potentials. After registration, the 8 F sheath was exchanged for a 14 F steerable sheath, and the mapping catheter was exchanged for a 28 mm balloon catheter and positioned over an exchange wire to occlude the ostium of each pulmonary vein. At least two 5-minute cryo applications per vein were given to each vein, during using continuous phrenic nerve stimulation when freezing the ostium of the right superior pulmonary vein.

Study protocol

Antiarrhythmic drugs were stopped 5 half-lives before the ablation, and were not continued afterwards. Oral anticoagulation was before and after ablation, according to the CHADS2-score based on the valid guideline [18].

Comprehensive transthoracic echocardiographic examinations were performed in all patients during sinus rhythm before, and 3, 6 and 12 months after cryoballoon catheter ablation. Transoesophageal echocardiography was performed in all patients before catheter ablation, to exclude left atrial and left atrial appendage thrombus. Transthoracic and transoesophageal echocardiography were performed within 24 hours of each other.

After the ablation, follow-up examinations at 1, 3, 6 and 12 months included clinical history and examination, ECG and 24-hour Holter ECG. A 10-day transtelephonic ECG was performed before the 3-month, 6-month and 12-month follow-up visits.

Definition of success

Based on the definition of the Expert Consensus Statement on Catheter and Surgical Ablation of Atrial Fibrillation [4], cryoballoon catheter ablation was considered to be clinically successful, if after the initial 3-month blanking period--a time interval during which success is not evaluated--recurrent atrial arrhythmia was not recognized on clinical, or ECG or Holter ECG, or transtelephonic ECG examinations.

In order to evaluate the effect of all episodes of recurrent arrhythmia, recurrences in the blanking period were also taken into account for the final analysis. So the patients were divided into recurrent and arrhythmia-free (AF-free) groups. The recurrent group was defined as patients with recurrent atrial arrhythmia at any time during the follow-up.

Echocardiography

Transthoracic echocardiography was performed with a General Electric Vivid S6 machine (General Electric, Milwaukee, WI, USA).

Left ventricular (LV) global systolic function was assessed by ejection fraction (EF) evaluated by the modified biplane Simpson's rule. LV longitudinal systolic function was assessed by septal and lateral systolic velocities of the mitral annulus (Sa_sept, Sa_lat) using pulsed-wave tissue Doppler echocardiography (TDE).

In order to evaluate LA remodeling LA size and LA function were evaluated before and after ablation. LA volumes were calculated by two-dimensional echocardiography by the biplane area-length method. Maximal LA volume (LAV_max) was obtained at left ventricular end-systole, just before mitral valve opening. Minimal LA volume (LAV_min) was determined at left ventricular end-diastole. LA areas (A₁, A₂) and superoinferior longitudinal diameters were measured from apical 4- and 2-chamber views. LA volumes were calculated by the following formula [19]: LAV = 8/3π*A₁*A₂/L = 0.85*A₁*A₂/L, where L is the shorter superoinferior diameter of the LA. LA volume index (LAVI) was calculated by dividing maximal LA volume by the body surface area (calculated by the Dubois formula, using body height and weight).

The evaluation of LA function by echocardiography is not standardized; different methods have been used to assess LA function in research and in clinical practice [20, 21]. The left atrium serves multiple functions, acts as a reservoir during left ventricular systole; as a conduit for blood transiting from the pulmonary veins to the LV during early diastole and as an active contractile pump that augments LV ventricular filling in late diastole.

In the present study four TTE methods were used in the assessment of LA function.

More recent methods of evaluating LA function, such as colour-coded tissue-Doppler based strain and strain-rate and two-dimensional speckle-tracking based strain and strain rate were not available in our institute during the study period.

In the detailed evaluation of left ventricular diastolic dysfunction, we used the methods described in recent recommendations [22, 23]. Septal and lateral early diastolic velocities of the mitral annulus (Ea_sept, Ea_lat) were measured by TDE, which characterize left ventricular relaxation. In the assessment of mean left ventricular filling pressure E/Ea ratios were calculated, using both the lateral, septal and average Ea velocity. Early (E) and late diastolic (A) velocities of mitral inflow, and deceleration time (DT) were measured by pulsed wave Doppler echocardiography, and E/A ratio was calculated. Systolic (S) and diastolic (D) velocities of pulmonary venous flow were measured and S/D ratio was also calculated.

Statistical analysis

Data are shown as mean ± standard deviation (SD) (95% confidence interval). Unpaired t-test was used to compare means of continuous variables between unrelated groups. Chi-square analysis was used to compare patient group characteristics with discrete variables. Paired-sample Student's t-test was used to evaluate changes in echocardiographic parameters of LA size and function and of LV diastolic function during the follow-up period within groups. A p < 0.05 was considered statistically significant for all calculations. Statistical analysis was performed using SPSS (Statistical Software for Social Sciences) version 13.0.

Procedural outcome

The clinical success rate, as it was defined previously with no recurrence after the 3-month blanking period [4], was 23 out of 36 patients (64%). Repeat ablation had not been performed during the first year follow-up.

15 patients were totally free of arrhythmias throughout the first 12 months of follow-up (the AF-free group). The other 21 patients (the recurrent group) experienced some recurrence of atrial arrhythmias. Only early (within 3 months after treatment) recurrence in 8, only between 3 and 12 months after treatment recurrence in 4, both early and 3 to 12 months recurrences in 9 patients were detected.

Baseline characteristics

Follow-up results

Left atrial size

In the recurrent group, at 12 months after ablation, the minimal left atrial volume (38 ± 19 to 44 ± 20 ml; p < 0.05), the maximal left atrial volume (73 ± 23 to 81 ± 24 ml; p < 0.05), LAVI (35 ± 10 to 39 ± 11 ml/m²; p = 0.01) and the maximal left atrial longitudinal diameter (55 ± 5 to 59 ± 6 mm; p < 0.01) had all increased (Figure 1). In contrast, after successful cryoballoon ablation, LA size had not increased (Table 2).

	Recurrent				AF-free
	Baseline	3	6	12	Baseline	3	6	12
LAV min (ml)	38 ± 19	41 ± 16	43 ± 18	44 ± 20a	30 ± 12	32 ± 13	30 ± 11	32 ± 11
LAV max (ml)	73 ± 23	78 ± 29	78 ± 23	81 ± 24a	67 ± 20	70 ± 20	67 ± 19	69 ± 15
LAVI (ml/m 2 )	35 ± 10	38 ± 13	38+10	39 ± 11a	33 ± 9	35 ± 8	33 ± 8	34 ± 7
LAD max (mm)	55 ± 5	56 ± 6	58 ± 6	59 ± 6b	54 ± 6	55 ± 5	56 ± 4	56 ± 5
LAFF (%)	36 ± 7	35 ± 8	34 ± 6	33 ± 8a	34 ± 7	35 ± 11	38+11	32 ± 8
Aa sept (cm/s)	8.8 ± 1.8	8.3 ± 2.1	8.6 ± 1.8	8.8 ± 2.2	9.7 ± 2.1	10.3 ± 3.1c	10.4 ± 1.7c	9.7 ± 2.1
Aa lat (cm/s)	9.8 ± 2.1	10.1 ± 3.4	10.2 ± 2.7	10.2 ± 2.7	10.7 ± 2.7	10.7 ± 2.2	11.5 ± 2.1	10.8 ± 3.1
LAEF (%)	48 ± 11	47 ± 13	45 ± 10	47 ± 11	55 ± 8c	55 ± 8c	56 ± 8d	55 ± 9c
PVSF (%)	58 ± 9	55 ± 8	55 ± 9	50 ± 10a	60 ± 7	56 ± 9	61 ± 9	60 ± 10
Ea sept (cm/s)	8.1 ± 1.9	8.8 ± 1.6	8.9 ± 1.9	7.7 ± 1	8.8 ± 2.8	9 ± 2.5	8.6 ± 2.3	8.8 ± 2.3
Ea lat (cm/s)	11.2 ± 2.4	12 ± 2.5	12 ± 2.8	11.3 ± 1.6	10.9 ± 3.2	11.6 ± 3.5	11.6 ± 3.6	11.7 ± 3.1
E/Ea avg	7.2 ± 1.8	7.3 ± 2.	8 ± 2.6	8.5 ± 2.3b	7.3 ± 2.1	7.4 ± 2	7 ± 1.5	7.4 ± 2.4

^a: p < 0.05, baseline to 12 months;

^b: p < 0.01, baseline to 12 months;

^c: p < 0.05, recurrent vs AF-free at the same follow-up visit;

^d: p < 0.01, recurrent vs AF-free at the same follow-up visit.

Abbreviations:

Aal _at ; late diastolic velocity measured by pulsed-wave tissue Doppler echocardiography at the lateral mitral annulus

Aa _sept ; late diastolic velocity measured by pulsed-wave tissue Doppler echocardiography at the septal mitral annulus

E; early diastolic velocity of mitral pulsed wave Doppler inflow

Ea _avg ; average value of septal and lateral early diastolic velocities measured by pulsed-wave tissue Doppler echocardiography

Ea _lat ; early diastolic velocity measured by pulsed-wave tissue Doppler echocardiography at the lateral mitral annulus

Ea _sept ; early diastolic velocity measured by pulsed-wave tissue Doppler echocardiography at the septal mitral annulus

LAD _max ; maximal left atrial longitudinal diameter

LAEF; left atrial total emptying fraction

LAFF; left atrial filling fraction

LAVI; left atrial volume index

LAV _max ; left atrial maximal volume

LAV _min ; left atrial minimal volume

PVSF; systolic fraction of pulmonary venous flow

Left atrial function

In the recurrent group, at 12 months after ablation, the left atrial reservoir function as assessed by the systolic fraction of pulmonary venous flow (58 ± 9 to 50 ± 10%; p = 0.01) and LA pump function assessed by left atrial filling fraction (36 ± 7 to 33 ± 8%; p = 0.03) had decreased (Figure 2). Left atrial total emptying fraction, which is a parameter of LA reservoir function, did not change significantly during the follow-up; however, it was significantly lower at all follow-up visits in the recurrent group (Figure 3).

In contrast, after successful cryoballoon ablation, LA function had not declined (Table 2).

Left ventricular diastolic function

Lateral and septal early diastolic velocities did not change significantly during the follow-up (Table 2). Whereas, E/Eaaverage, which was used to assess the mean LV filling pressure, was increased at one year from baseline values (7.2 ± 1.8 to 8.5 ± 2.3; p = 0.005) (Figure 4).

Left atrial size before ablation

In the present study, left atrial size before cryoballoon ablation did not affect the success rate; there was no difference in LA size before ablation between AF- free and recurrent group of patients. These results are similar to a study by Rodrigues et al. [26] in which PAF patients underwent radiofrequency catheter ablation and the LA volume before ablation was not different between the successful and unsuccessful groups. However, in some other studies LA enlargement before treatment, detected by different imaging modalities has been identified as a risk factor for AF recurrence after radiofrequency catheter ablation [13, 27–30].

Left atrial structural remodeling

We found that at one year after unsuccessful cryoballoon catheter ablation left atrial size had increased. In contrast, successful ablation had prevented progressive LA dilatation. The meta-analysis of 17 studies by Jeevanantham et al. [14] confirmed that in patients who had successful radiofrequency catheter ablation of paroxysmal and/or persistent atrial fibrillation LA diameter and volume decreased, which is described as LA structural reverse remodeling. After unsuccessful ablation, LA size did not change or non-significantly increased.

In patients with PAF, LA structural reverse remodeling has not always been observed even after successful catheter ablation. Beukema et al. [8] found that at six months left atrial anteroposterior and superoinferior diameters had decreased in patients who remained in sinus rhythm. Donal et al. [31] investigated 31 lone PAF patients after successful RF ablation, and at 1 year also found a reduced mean left atrial anteroposterior diameter and LA volume index. Reant et al. observed that LA area had decreased in lone PAF patients 11 months after successful RF ablation; but LA area had also decreased after unsuccessful ablation [6]. Rodrigues [26] et al. observed that after radiofrequency catheter ablation of PAF, there was no significant change of the LA maximal volume 8 ± 2 months after ablation, either in the successful, or in the unsuccessfully treated groups. In their study the prevalence of hypertension was 39%. In our study the high prevalence of associated hypertension (80%), which is a well-known determinant of left atrial size, and the limited sample size (AF-free group: N = 15), probably contributed to the lack of reverse remodeling. Another potential explanation could be that the left atrium of the AF-free patients might have been remodeled to such an extent during the years in which they had paroxysmal atrial fibrillation (3.8 ± 3.3 years), that the one-year follow-up period was not long enough for significant reverse remodeling which could be recognised by two-dimensional transthoracic echocardiography, especially in such a small sample (AF-free group: N = 15).

Left atrial functional remodeling

Left ventricular diastolic function before and after ablation

Left ventricular diastolic function did not affect the success rate in the present study; no difference was found between the groups regarding LV diastolic function at baseline.

We did not demonstrate any change in Ea velocities during the one-year follow-up in the recurrent, or in the AF-free group, similarly to the study of patients with successful PAF ablation by Donal et al. [31]. However, in the studies by Reant et al. [6, 7] Ea was found to increase following successful radiofrequency catheter ablation in PAF patients during a 11-month follow-up.

In our study the E/Eaaverage was increased at one year after cryoballoon catheter ablation in the recurrent group. E/Ea ratio was shown to decrease [6, 7] or did not change [31] in other studies after successful radiofrequency catheter ablation in PAF patients