Relationship between left atrial tissue structural remodelling detected using late gadolinium enhancement MRI and left ventricular hypertrophy in patients with atrial fibrillation

Abstract

Aims

Therapeutic effectiveness of ablation of atrial fibrillation (AF) is related to cardiovascular comorbidities. We studied the relationship between left ventricular hypertrophy (LVH) and left atrial tissue structural remodelling (LA-SRM), in patients presenting for AF ablation.

Methods and results

We identified 404 AF patients who received a late gadolinium enhancement magnetic resonance imaging (LGE-MRI) prior to catheter ablation. Left ventricular hypertrophy was defined as LV mass index >116 g/m² in men and >104 g/m² in women. One hundred and twenty-two patients were classified as the LVH group and 282 as the non-LVH group. We stratified patients into four stages based on their degree of LA-SRM (minimal, <5% fibrosis; mild, >5–20%; moderate, >20–35%; and extensive, >35%). All patients underwent catheter ablation with pulmonary vein isolation and posterior wall and septal debulking. The procedural outcome was monitored over a 1-year follow-up period. The mean LA-SRM was significantly higher in patients with LVH (19.4 ± 13.2%) than in non-LVH patients (15.3 ± 9.8%; P< 0.01). Patients with LVH generally had extensive LA-SRM (moderate and extensive stages; 38.5% of LVH group) as compared with non-LVH patients (23.1% of non-LVH group; P < 0.01). A Cox regression analysis showed that patients with LVH also had significantly higher AF recurrence rates than non-LVH patients (43.2 vs. 28%; P = 0.008) during the 1-year follow-up period post-ablation.

Conclusion

Patients with LVH tend to have a significantly greater degree of LA-SRM, when compared with patients without LVH. Moreover, LA-SRM is a predictor for procedural success in patients undergoing AF ablation procedure.

Introduction

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, estimated to affect more than 6 million Americans presently and projected to nearly triple by the year 2050.¹ Previous studies have demonstrated that AF is associated with fibrosis and structural remodelling (SRM) in the left atrium (LA) that contributes to persistence and sustainability of the arrhythmia.^2–5 However, fibrosis in the LA occurs in a variety of settings including heart failure, mitral valve disease, and myocardial ischaemia.^6–8

Left ventricular hypertrophy (LVH) is a common comorbidity in patients with AF.^9,10 Both AF and LVH have been shown to be associated with tissue SRM.^2–5,11 Left ventricular hypertrophy causes LV filling pressure to rise, and the stress exerted on the LA wall coupled with increase in LA pressure leads to LA wall stretch and LA dilatation, promoting LA remodelling and subsequent AF. Coexistence of LVH with AF may create a large atrial substrate for AF and lead to increased failing rates following catheter ablation.

Late gadolinium enhancement magnetic resonance imaging (LGE-MRI) is a non-invasive method that has been shown to assess the degree of LA-SRM, or fibrosis, in patients with AF.¹² Late gadolinium enhancement MRI-detected fibrosis has been shown to predict procedural outcome in patients undergoing the AF ablation procedure.^12,13 While the relationship of LVH and AF has been investigated, LA tissue SRM in patients with and without LVH has not been demonstrated using LGE-MRI.

In this study, we examined the hypothesis that the severity of clinical impact of AF in a patient with LVH may be reflected in part by the degree of LA-SRM. Using LGE-MRI, we quantified the extent of LA fibrosis in AF patients with and without LVH. Moreover, we sought to compare the outcome following catheter ablation in patients with and without LVH in relationship to atrial fibrosis.

Methods

In this retrospective study using our IRB-approved AF database, we screened 467 consecutive AF patients presenting for catheter ablation at the University of Utah between October 2007 and May 2010. All patients underwent LGE-MRI prior to ablation. Sixty-three patients with inadequate MRI quality were excluded and finally 404 patients were included in the study. Patient information gathered for the purpose of the study was de-identified prior to the analysis in compliance with the HIPAA regulations. All patients underwent LGE-MRI evaluation before ablation to assess the extent of LA-SRM.

Magnetic resonance image acquisition

All MRI studies were performed on a 1.5 or 3 T clinical MR scanner (Siemens Medical Solutions) using phased-array receiver coils. Each scan was acquired ∼15 min after contrast agent injection (0.1 mmol/kg; Multihance, Bracco Diagnostic Inc.) using a three-dimensional (3D) inversion recovery, respiration navigated, electrocardiogram (ECG)-gated, gradient echo pulse sequence. Typical acquisition parameters were free breathing using navigator gating, a transverse imaging volume with voxel size = 1.25 × 1.25 × 2.5 mm (reconstructed to 0.625 × 0.625 × 1.25 mm), and inversion time (TI) = 270–320 ms. The other imaging parameters were optimized for respective field strength of scanner to improve fibrosis visibility and simultaneously keep scan duration acceptable for patients (<15 min) while maintaining comparable accuracy with similar imaging protocols. For scans performed on 1.5 T scanner: repetition time (TR) = 5.4 ms, echo time (TE) = 2.3 ms, and flip angle = 20°. For scans performed on 3 T scanner: TR = 3.1 ms, TE = 1.4 ms, and flip angle = 14°. Typical scan time for the LGE-MRI study on 1.5/3 T scanner was 8–12/5–9 min depending on subject heart rate and respiration pattern.

Late gadolinium enhancement magnetic resonance imaging assessment of pre-ablation structural remodelling

Left atrial wall volumes were manually segmented by expert observers from LGE-MRI images using Corview image processing software (MARREK Inc.).¹⁴ Quantification of LA remodelling was obtained using the methods previously described.¹² Briefly, to delineate regions of fibrosis in pre-ablation LGE-MRI images, we defined enhancement through an intensity threshold that was determined by expert inspection. A custom transfer function allowed the operator to define gradations of enhancements, while suppressing blood and normal tissue with a transfer function. Patients were then assigned to one of the four groups (Utah stages I–IV) based on the percentage of LA wall enhancement. Utah I (minimal) was defined as ≤5% LA-SRM, Utah II (mild) as >5% and ≤20%, Utah III (moderate) as >20% and ≤35%, and Utah IV (extensive) as >35% (Figure 1).¹³

Definition of left ventricular hypertrophy and interatrial septum thickness analysis

Left ventricular mass was calculated using M-mode records taken on parasternal long-axis images according to the formula: LV mass = 0.8 × 1.04 [(interventricular septum thickness at diastole + posterior wall thickness at diastole + LV diastolic diameter)³ − (LV diastolic diameter)³] × 0.6 g (corrected American Society of Echocardiography cube method).¹⁵ Left ventricular hypertrophy was diagnosed when LV mass index (LV mass corrected for body surface) was >116 g/m² in men and >104 g/m² in women.¹⁶ Interatrial septum thickness (IAST) was assessed off-line from the standard four-chamber long-axis cine images using dedicated commercially available Osirix software. Interatrial septum thickness measurements were made during both end-systole and end-diastole. IAST thickness was measured at exactly one centimeter inferior to the fossa ovalis along the interatrial septum (i.e. primary atrial septum), which is considered to be the thickest part of the interatrial septum and contains a bilaminate muscle structure between endocardial surfaces (Figure 2).¹⁷ The entire tissue was included as visualized using LGE-MRI to measure thickness and did not delineate fat from the myocardium.

Atrial fibrillation ablation procedure

The comprehensive details of the pulmonary vein isolation (PVI) ablation procedure, in addition to posterior wall and septal debulking, have been described elsewhere.¹⁸ In brief, the LA was accessed through two transseptal punctures under intracardiac echo guidance using a phased array catheter (Acunav, Siemens Medical Solutions USA, Inc.). A 10-pole circular mapping catheter (Lasso, Biosense Webster) and a 3.5 mm Thermocool ablation catheter (Biosense Webster) were advanced into the LA for mapping and ablation. A 14-pole catheter (Biosense Webster) was used to record right atrial and coronary sinus electrograms and was also utilized as the reference catheter for 3D electroanatomical mapping with CARTO (Biosense Webster). Radiofrequency (RF) energy was delivered with 50 W at a catheter tip temperature of 50°C for no longer than 5 s, guided by electrogram abolition recorded on the Lasso catheter. Ablation lesions were placed in a circular fashion in the PV antral region until electrical isolation of the PVs was achieved. Additional lesions were placed, dependent on the degree of LA-SRM or fibrosis, along the LA posterior wall and septum. Procedural endpoint was lack of AF inducibility with high-dose isoproterenol and coronary sinus burst pacing at 200 ms, in addition to abolition of PV conduction.

Follow-up and definition of recurrence

A post-ablation blanking period was observed for 3 months. All patients were seen in the clinic at 3 months following ablation and followed-up at 3-month intervals thereafter. Each patient received a 12-lead ECG and an 8-day Holter monitor for detection of arrhythmia recurrence post-blanking. Additional ECG recordings were obtained as suggested by the patients' reported symptoms. Recurrence was defined as any atrial arrhythmia sustained for longer than 30 s without AAD treatment following the 3-month blanking period, as suggested by the Heart Rhythm Society consensus statement.¹⁹

Statistical analysis

Normal continuous variables are presented as mean ± standard deviations. A two-sample t-test and one-way analysis of variance were used to test for statistical significance and adjusted using a Tukey–Kramer correction for multiple comparisons. Categorical variables are presented as number and percentage of total. Pearson's χ² or Fisher's exact tests were used to assess for statistical significance. Recurrence was analysed in a time-to-event univariate and multivariate Cox regression model. Differences were considered significant at a P value of < 0.05.

Results

The study population reported here includes 404 patients (260 men: mean age 65 ± 12 years). One hundred and twenty-two patients (95 men; 65.4 ± 11.3 years) were included in the LVH group; whereas, 282 patients (165 men; 64.8 ± 12.3 years) were categorized into the non-LVH group. Table 1 summarizes baseline characteristics of the two groups. Patients with LVH had a higher prevalence of diabetes, hypertension, and coronary artery disease, and were predominantly male (P < 0.01 for all). There was no statistically significant difference between the two groups based on age, prevalence of congestive heart failure, smoking, and stroke (P = 0.67,0.24,0.84, and 0.27, respectively). Persistent AF was significantly higher in patients with LVH, while paroxysmal AF was more common in patients with non-LVH (P = 0.002).

The pre-ablation LA fibrosis was significantly higher in patients with LVH than the non-LVH group (19.4 ± 13.2 vs. 15.3 ± 9.8%; P < 0.01; Figure 3A). The distribution of patients with LVH and without LVH across the four Utah Stages is provided in Figure 3B. Left ventricular hypertrophy patients were found to more often have moderate-to-extensive SRM (Utah III + Utah IV) than non-LVH patients (38.5 vs. 23.1%; P < 0.01). As shown in Table 2, stepwise linear regression analysis revealed that presence of LVH was an independent determinant of LA-SRM (coefficient = 3.03; P = 0.015).

Pre-ablation left ventricular ejection fraction (LVEF) was 52.2 ± 11.6% in the LVH group and 55.7 ± 10.3% in the non-LVH group (P = 0.02). Average LA diameter was 46.7 ± 5.2 mm for patients with LVH and 43.8 ± 4.8 mm for patients without LVH (P < 0.01).

Correlation between interventricular and interatrial septal thickness

Out of the 404 patients in this study, 33 were excluded due to suboptimal interatrial septum MRI, leaving 371 patients for IAST analysis. Nine patients appeared to have lipomatous hypertrophy of interatrial septum according to MRI findings. Patients with LVH had a statistically significant thicker IAST in end-systole than non-LVH patients (7.7 ± 1.4 vs. 6.9 ± 1.2 mm; P < 0.001). A similar statistically significant difference in end-diastolic IAST was noted between patients with and without LVH (6.1 ± 1.1 vs. 5.6 ± 1 mm, respectively; P < 0.001; Figure 4). Linear regression analysis revealed a significant relationship between interventricular septum thickness and IAST measured during systole and diastole (P < 0.001 for both).

Clinical outcome after ablation

After a mean follow-up period of 332 ± 115 days after ablation, recurrence data for 47 patients could not be reconciled (11 patients in the LVH group and 36 patients in the non-LVH group). Out of the 357 patients with recurrence data, 178 had paroxysmal and 179 patients had persistent AF. Of the 111 patients in the LVH group 63 patients (56.8%) remained free from AF recurrence, whereas of the 246 patients in the non-LVH group 177 patients (72%) remained in stable sinus rhythm. In univariate analysis, LVH was found to be a predictor of recurrence with a hazard ratio of 1.64 (95% confidence interval 1.14–2.38; P = 0.008). A Kaplan–Meier curve shows the difference in long-term recurrence-free days after ablation in the two groups (Figure 5). The procedural success rate in patients with LVH across the Utah stages is as follows: patients in Utah stage I had a outcome success rate of 75%, 65.6% (Utah II), 58.6% (Utah III), and 7.1% (Utah IV), while the outcome success rates in patients in the non-LVH group were 88.9, 76, 61.7, and 35.7%, respectively.

A total of 79 patients (67.5%) of 117 recurrences underwent a repeat procedure. Of these patients, 32 (41%) were in the LVH group and 47 (59%) in the non-LVH group. The amount of fibrosis was significantly higher in patients who experienced a recurrence post-ablation (21.8 ± 14.7 vs. 14.4 ± 8.5%; P < 0.001), independent of AF type.

In multivariate analysis including patient age, AF type, LA-SRM, LVH, LA diameter, diabetes, hypertension, gender, history of stroke, cardiomyopathy, and coronary artery disease, the pre-ablation stage of LA fibrosis was the strongest predictor of recurrence (hazard ratio, 1.77; P < 0.001) followed by increase in LA diameter (hazard ratio, 1.04; P = 0.039). Presence of LVH and AF type (persistent AF) were also associated with recurrence but they did not reach statistical significance (P = 0.087 and 0.09, respectively). The results of the regression analysis are summarized in Table 3.

Discussion

In the present study, we found that the degree of LA-SRM detected using LGE-MRI was higher in AF patients with LVH when compared with AF patients without LVH. We also demonstrated that LA-SRM, in addition to LVH, predicted AF ablation procedural outcome.

Atrial fibrosis in patients with left ventricular hypertrophy

Atrial fibrillation and LVH have been shown to be associated with tissue SRM.^2–5,11 Several studies, which have evaluated atrial SRM in patients with AF and LVH, have used LA diameter and LA volume as the indicator of atrial SRM and have demonstrated a positive correlation between LVH and atrial SRM.^20,21 These studies were limited by non-availability of tools to characterize and directly examine the LA substrate in AF patients with and without LVH. Medi et al.²² recently demonstrated an increase in right atrial SRM in patients with LVH using electroanatomic mapping. Patients with LVH displayed more areas of low voltage and conduction slowing in the LA, which are known indicators of SRM; however, all AF patients were excluded from the study and the SRM evaluations were conducted in sinus rhythm. Our study is the first to demonstrate an increase in LA tissue SRM or fibrosis in patients with AF and LVH using LGE-MRI.

Heart failure and ischaemia have been reported to increase in atrial fibrosis in human and animal models.^6,8 Ohtani et al.⁶ showed that the percentage of atrial fibrosis was significantly correlated to LVEF in autopsied hearts with a history of myocardial infarction. Similarly, in our study, LVH patients commonly had coronary artery disease, lower LVEF, and higher atrial fibrosis when compared with patients without LVH. Likewise, Sinno et al.⁸ confirmed with canine model that atrial ischaemia leads in atrial fibrosis.

Shorter durations of AF lead to low SRM in the LA.^2,3,23 Consistent with these studies, a majority of patients in the non-LVH group had paroxysmal AF and less SRM. On the contrary, a majority of patients with LVH had significantly more fibrosis and persistent AF.

Atrial fibrillation ablation outcome in patients with left ventricular hypertrophy

Long-term success rates following catheter ablation of AF are variable and reported to be between 29 and 86%.^24,25 The comorbidities accompanying AF may play a crucial role in determining the procedural success rates. The results from our study similarly suggest that LVH may additionally play a key role in determining outcome success since patients with LVH experienced a significantly higher recurrence rate than non-LVH patients. Multiple studies demonstrated that pre-ablation left atrial fibrosis is one of the strongest predictors of recurrence postablation.^12,13 In the present study too, patients with significantly higher fibrosis (belonging to Utah stages III and IV) experienced more recurrences and were more often found to have LVH. In clinical practice, quantification of SRM and assessment of LVH may be used to better inform patients about the expected outcomes of catheter ablation, which can beneficially impact how patients are referred to ablation therapy.

Rotter et al.²⁶ have demonstrated that presence of LV hypertrophy significantly increases the likelihood of inducibility of sustained AF after PVI. Inducibility of AF is correlated with an increased incidence of recurrent AF during follow-up.²⁷ Our study confirms this result; patients with LVH have higher recurrence not only during the short term, but also over a long-term follow-up period.

The type of AF (paroxysmal vs. persistent) has been widely recognized as a predictor of freedom from AF during follow-up, with persistent AF patients commonly experiencing more recurrence episodes.^28,29 In our study, patients with LVH more often had persistent AF suggesting that persistent AF could be an additional factor leading to poor procedural outcome success.

Furthermore, this study has also indicated that AF patients with LVH have thicker interatrial septum compared with patients without LVH. To the best of our knowledge, this is the first study to demonstrate a higher interatrial septal thickness in AF patients with LVH. The increased IAST may also be a significant contributor to increased recurrences post-ablation, since ablating these patients with the standard intensity and duration of RF energy might be inadequate to create transmural lesions.

Limitations

The number of patients across the Utah stages is unbalanced (only five patients in Utah I with LVH), so a more balanced sample size across the Utah stages would potentially allow for more robust comparison between these groups. In addition, the MRI operator selection of a wrong inversion time, the presence of respiratory navigator artifacts, and other MRI noise factors may lead to an inappropriate detection and quantification of fibrosis. Such effects seemed to be minimal in this study because all included LGE-MRIs were analysable for segmentation and quantification. The threshold for delayed enhancement identification was determined for each patient individually, so they cannot be compared. Although we tried to make a standardized measurement for assessment of IAST, anatomical variations (such as elongation of the aorta) and perivascular fat of the aortic root can cause incorrect measurements. However, the anatomic variations occur relatively infrequently and this had limited effect on the results.

Conclusion

Atrial fibrillation patients with LVH have more extensive fibrosis in the LA compared with patients without LVH. Extensive fibrosis in these patients is also related to increased recurrences following catheter ablation. Hence, this should be considered to provide accurate pre-procedural counselling as well as to guide patient selection for catheter ablation.

Conflict of interest: none declared.

References