Association of left ventricular late gadolinium enhancement with left atrial low voltage areas in patients with atrial fibrillation

Abstract

Aims

Presence of late gadolinium enhancement (LGE) is related to adverse cardiovascular outcome. Many patients suffering from atrial fibrillation (AF) undergo cardiovascular magnetic resonance (CMR) imaging prior to ablation. Since quantification of atrial fibrosis still lacks reproducibility, we sought to investigate risk factors for the presence of left ventricular (LV)-LGE and a possible correlation between ventricular fibrosis as defined by positive LGE and pathological atrial voltage maps evaluated by 3D mapping systems.

Methods and results

Between May 2015 and January 2017, 241 patients with AF (73% persistent AF, 71% male, mean age 62.8 ± 10.1 years, Redo procedure in 24%, AF history 4.5 ± 5.2 years) underwent CMR including LV LGE prior to pulmonary vein (PV) isolation at Heart Center Leipzig. Depending on CMR results, two groups were separated: ‘LV-LGE negative’ (Group A, n = 197, 82%) and ‘LV-LGE positive’ (Group B, n = 44, 18%). To identify low voltage areas (LVA), a 3D electro-anatomic map was created during PV isolation.

Multivariate analysis revealed male gender [odds ratio (OR) 7.6, 95% confidence interval (95% CI) 2.4–23.9, P = 0.001] and an increased CHA₂DS₂VASc Score (OR 1.6, 95% CI 1.2–2.2, P = 0.004) as significantly associated with LV-LGE. Impaired left ventricular ejection fraction, LV dilatation, larger LA size and, enlarged septum diameter occurred significantly more often in the ‘LGE positive’ group. Low voltage areas were detected in 83 patients overall (34%): Group A: n = 64/197 (33%), Group B: n = 19/44 (43%) (P = 0.177).

Conclusion

Male gender and high CHA₂DS₂VASc Score are significantly associated with presence of LV-LGE, but LV-LGE is not associated with left atrial LVA.

Introduction

Presence of left ventricular (LV) late gadolinium enhancement (LGE) is related to adverse cardiovascular outcome in general.^1,2 Catheter ablation has become a cornerstone in atrial fibrillation (AF) treatment and a growing number of patients undergo cardiovascular magnetic resonance (CMR) imaging prior to pulmonary vein (PV) isolation, with protocols often including a LV-LGE scan. Investigations in AF patients have demonstrated that absence of LV-LGE is related to LV recovery and reduction in mortality and heart failure after successful catheter ablation.³ Furthermore, it has been revealed that left atrial (LA) structural remodelling favours development of AF^4,5 and, consequently, presence of atrial fibrosis is associated with AF recurrence.^6,7 Left atrial structural remodelling can be detected by positive LA-LGE prior to catheter ablation which also has been shown to lead to higher AF recurrence rates.⁸ However, these findings remain controversial, especially as quantification of atrial fibrosis still lacks reproducibility. Left atrial-late gadolinium enhancement is more technically demanding than LV-LGE due to the thin LA wall thickness; therefore, analysis remains operator-dependent, time-consuming, and consequently expensive. Another option to detect and quantify LA fibrosis is given by pathological 3D atrial voltage maps during catheter ablation.⁹ It is still unknown if the presence of LV scar in LGE CMR is associated with LA low voltage areas (LVA). The aim of this study was to investigate this possible correlation.

Methods

Study population

Consecutive patients with AF who underwent CMR imaging including LV-LGE prior to AF catheter ablation were retrospectively analysed. Indication for additional LGE scans was given by the attending physician. Patients with suspected structural heart diseases, known coronary artery disease or ischaemic cardiomyopathy, impaired left ventricular ejection fraction (LVEF), and symptoms of angina were considered for further diagnostic investigation. Type of AF (paroxysmal or persistent) was defined according to current European Guidelines.¹⁰ Depending on the CMR results, two groups were created: ‘LV-LGE negative’ and ‘LV-LGE positive’.

Moreover, a subgroup analysis was performed, in which patients with ischaemic cardiomyopathy were excluded.

Cardiovascular magnetic resonance protocol

Cardiovascular magnetic resonance imaging was performed using a 1.5-T scanner system (Philips Ingenia, Best, The Netherlands). For cine imaging, steady-state free procession (SSFP) were used during repetitive end-expiratory breath holding. All cardiac standard geometries were acquired (2-, 3-, and 4-chamber views and multiple, gapless short-axis slices covering the entire left ventricle). Contrast-enhanced 3D angiography was done to evaluate LA and PV anatomy. Subsequently, LV-LGE imaging was carried out 10–15 min after contrast agent administration (gadolinium-DTPA, 0.2 mmol/kg body weight) using an inversion-prepared 3D spoiled gradient echo sequence with an individually adapted inversion delay. Late gadolinium enhancement positive areas were defined according to the ‘full width at half maximum’ criterion, which uses half the maximal signal within the scars as the threshold.¹¹ Left ventricular late gadolinium enhancement was classified in four categories based on percentage of LV myocardial mass (I: <5%, II: 5–9%, III: 10–19%, IV: ≥20%, Figure 1).

Catheter ablation

Left atrial catheter ablation was performed as previously described under deep conscious sedation and monitoring of vital signs and oesophageal temperature.⁹ Diagnostic multipolar catheters were placed in the coronary sinus and right ventricular apex as reference signals. A trans-septal puncture was performed by using a steerable sheath (Agilis, St. Jude Medical). For isolation of the PV, circumferential application of radiofrequency energy was performed at the antrum of the PV. In some cases, additional linear lesions were placed if any stable atrial tachycardia was inducible, including substrate modification in atrial scar areas, if appropriate.^9,12 Bidirectional conduction block was confirmed as procedural Endpoint for PV-encircling lesions and additional ablation lines.

3D electro-anatomical mapping

Before PV isolation a 3D electro-anatomical voltage map was performed in sinus rhythm in all patients using CARTO 3 (Biosense Webster, Diamond Bar, CA, USA), NavX (St. Jude Medical, St. Paul, MN, USA), or Rhythmia^TM system. Only in those patients with failed electrical cardioversions we started with PV isolation followed by cardioversion and voltage analysis. Mapping was performed using a decapolar circular mapping catheter (Inquiry Optima or Reflexion Spiral; St. Jude Medical or Lasso; Biosense-Webster). In anatomy where sufficient contact was difficult to achieve, voltage was obtained using the 4-mm ablation catheter (Thermocool and Smarttouch, Biosense Webster; Diamond Bar, CA, USA or TactiCath and Flexability SE, St. Jude Medical, St. Paul, MN, USA). Interpolation threshold value was defined as 10 mm for surface colour projection. In case LVAs were detected, the ablation or multipolar circular catheter was used to create a high-density map of these regions to delineate the abnormal areas. Normal tissue was defined as >0.5 mV and signals <0.5 mV as LVAs. According to their surface area as a percentage of the entire LA surface, LVAs were classified in four categories as previously described [I: ‘minimal’ (< 10%), II: ‘mild’ (10–20%), III: ‘moderate’ (21–30%), IV: ‘severe’ (> 30%), Figure 2].¹³

Statistical analysis

Continuous data are presented as mean ± SD, whereas categorical data are presented as numbers and percentages. Differences between study groups were compared using student t-tests and χ²-tests. To reveal predictors of LV-LGE, multivariable binary logistic regression including univariate-analysed variables with a P-value <0.1 was used. Therefore, CMR results regarding LV-LGE are defined as the dependent variable. A P-value <0.05 was defined as statistically significant. To demonstrate a possible association between LV-LGE and LA fibrosis, a Spearman correlation analysis was performed. All statistical analyses were executed with SPSS 23.0 package (SPSS Inc. Chicago, IL, USA).

Results

Baseline characteristics

Between May 2015 and January 2017, a total of 241 patients who underwent CMR including LV-LGE prior to AF catheter ablation at Heart Center Leipzig were enrolled. Among all included individuals, 197 patients (82%) were classified as ‘LV-LGE negative’ (subgroup A) and 44 (18%) patients were ‘LV-LGE positive’ (subgroup B). Clinical baseline characteristics of the population (n = 241) and the two subgroups are shown in Table 1. There were no significant differences in age, AF history, type of AF, or medication (Table 2). Furthermore, risk factors such as diabetes, hypertension, and obesity were not significantly associated with presence of LV-LGE. Male gender, high CHA₂DS₂VASc Score, and presence of coronary artery disease were found more frequently in patients with LV-LGE. The ‘LV-LGE positive’ group consisted of 22 patients with history of ischaemic cardiomyopathy and 22 patients with non-ischaemic cardiomyopathy. Furthermore, there was no significant difference in procedural data between the two groups, as shown in Table 3.

There was a significant difference in the presence of LVAs in patients with persistent AF (73/177, 41%) compared to patients with paroxysmal AF (10/64, 16%) (P < 0.001). Moreover, there was no significant difference in the extent of LVAs between ‘LV-LGE negative’ (2.08 ± 0.91) compared to the ‘LV-LGE positive’ group (1.89 ± 0.74) (P = 0.4).

Presence of left ventricular late gadolinium enhancement

Table 4 summarizes the results of the univariate and multivariate regression analysis. Presence of coronary artery disease and sleep apnoea syndrome were significantly associated with positive LV-LGE in univariate analysis only.

Multivariate analysis revealed male gender (OR 7.6, 95% CI 2.4–23.9, P = 0.001) and higher CHA₂DS₂VASc Score (OR 1.6, 95% CI 1.2–2.2, P = 0.004) as significantly associated with the presence of positive LV-LGE in AF ablation patients.

In the subgroup analysis, we could not find any significant predictors for LV-LGE.

Cardiovascular magnetic resonance parameters

Cardiovascular magnetic resonance parameters are shown in Table 5. Impaired LVEF (P = 0.001), LV dilatation (P = 0.001), larger LA size (P = 0.003), and larger septum diameter (P ≤ 0.001) were seen more frequently in the ‘LV-LGE positive’ group. No differences between the two groups were observed with regard to right atrial size or LV stroke volume.

Association of left ventricular late gadolinium enhancement and left atrial fibrosis

Low voltage areas < 0.5 mV during mapping were detected in 83 patients (34%): Group A: n = 64 (33%) and Group B: n = 19 (43%). LV-LGE was not associated with left atrial LVAs (P = 0.177). Furthermore, Spearman correlation analysis, which included patients with positive LV-LGE and the presence of LVAs, demonstrated no relation between these two parameters (r = 0.249, P = 0.305, Figure 3).

The subgroup analysis could reveal a significant association between LV-LGE and left atrial fibrosis (P = 0.039) in patient with non-ischaemic cardiomyopathy.

Discussion

In this study, a possible association of LV-LGE with LA mapping in patients with AF was analysed. According to our results, male gender and high CHA₂DS₂VASc Score are associated with the presence of LV-LGE scar. There was no correlation between LV-LGE and LA LVAs.

Previous studies have demonstrated that LA fibrosis plays an important role in the development of AF and also predicts recurrence after rhythm control therapy.^4,8,13 Non-paroxysmal patients have higher AF recurrence rates after catheter ablation than those with paroxysmal AF, which has led to a rise in use of individual substrate modification as an approach for these patients. This has shown to be more effective in preventing AF recurrence.^14,15 A similar situation exists with the presence of LV scar. Permanent AF is more frequently associated with LV fibrosis than paroxysmal AF.¹⁶ In our study population, no difference was found between paroxysmal and persistent AF in terms of LV-LGE. Shantsila et al.¹⁶ have shown that LV fibrosis was not associated with atrial stiffness, which is in line with our findings.

Clinical predictors of LV-LGE in AF patients prior to catheter ablation were previously analysed by Nance et al.¹⁷ They described age and congestive heart failure as significant predictors. Our baseline characteristics did not differ in terms of age. But we did find that an increased CHA₂DS₂VASc Score is significantly associated with the presence of LV-LGE, which included patients older than 65 years. In contrast to our results, Nance et al. could not find any significant difference in LVEF between patients with positive and negative LV-LGE. A possible explanation could be our very selected study population.

Furthermore, positive LV-LGE may have clinical implications since a higher CHA₂DS₂VASc Score is known to be associated with higher complication rates and impaired outcomes.¹⁸ Suksaranjit et al.¹⁹ determined prognostic implications in these patients. Patients with a history of coronary artery disease, myocardial infarction, and hypertrophic or dilated cardiomyopathy were excluded from the analysis. CHA₂DS₂VASc Score and positive LV-LGE were significantly associated with higher rates of major adverse cardiac and cerebrovascular events. In addition, they examined the impact of positive LV-LGE on AF recurrence after successful catheter ablation.²⁰ In this trial, only patients without previous ablation procedures or myocardial infarction were analysed. In their investigation, patients with presence of LV-LGE suffered more often from AF recurrence (69% vs. 38%) in comparison to the LV-LGE negative group. They disclosed male gender and CHA₂DS₂VASc Score as predictors in univariate analyse only. Additionally, LV-LGE has a prognostic value as a predictor of mortality in AF patients, as demonstrated by Neilan et al.²¹ The mortality rate per patient year was significantly increased in the LV-LGE positive group (8% vs. 2%).

Therefore, we should take caution in patients with presence of LV-LGE to prevent AF recurrence, which could lead to heart failure or other adverse cardiovascular events. According to the results of our subgroup analysis, the association between positive LV-LGE and presence of LVAs in non-ischaemic cardiomyopathy patients could indicate that in some of these patients a general ‘fibrotic affection’ of the heart is present, e.g. after myocarditis. This needs to be evaluated in larger cohorts in the future.

However, it is still not well understood if AF causes LV fibrosis or vice versa. Furthermore, an association between LV fibrosis and LA fibrosis is not yet described with certainty, but based on our investigation, we transferred that there is no correlation between LV-LGE and LA LVAs. Consequently, patients presenting for AF catheter ablation should not be excluded from this procedure due to presence of ventricular scar as detected by CMR imaging.

Study limitations

This study is limited by its retrospective character. Furthermore, there was no standard protocol. Redo procedure patients did not receive CMR scans routinely if any imaging modality (CT or MRI) from within the previous years was available. It should be noted that the majority of patients did not obtain LV-LGE scans before catheter ablation and could therefore not be taken into consideration for our investigation. Left ventricular late gadolinium enhancement scan was only performed if the attending physician deemed it necessary, such as due to known coronary artery disease or impaired LV-function in echocardiography. We have to consider that the positive LV-LGE group may appear less healthy because of this selection bias. Moreover, some patients with implantable cardioverter defibrillators or pacemakers received CT scans instead of CMR to evaluate PV und LA anatomy, and consequently, we may have missed additional patients with LV-LGE scar.

In this study only patients were considered who underwent a rhythm control therapy with catheter ablation. Therefore, our findings cannot be transferred to all AF patients—in particular long standing persistent AF patients. Finally, a Holter monitoring was not performed during follow-up. Consequently, we cannot provide predictors of AF recurrence in this cohort.

Conclusion

Male gender and high CHA₂DS₂VASc Score are significantly associated with presence of LV-LGE, but LV-LGE is not associated with left atrial LVAs.

Conflict of interest: P.S. has received modest lecture fees by Biosense Webster and Abbott. P.S. is member of the advisory board of Abbott. P.S. received research funding by Abbott. G.H.: research funding by Abbott. The other authors have no conflict of interest.

References