In our study, we found that AF patients who have suffered an ischemic stroke have significantly higher levels of LA fibrosis as quantified by DE-MRI. In addition, we demonstrated that this LA fibrosis, as a variable of structural atrial remodeling, could be a valuable tool for clinicians to use in conjunction with the CHADS2 index for anticoagulation risk stratification. Further prospective studies are needed; nevertheless, this study provides plausible evidence that LA substrate analysis is an independent risk factor and could possibly be used in addition to standard clinical variables. This could potentially lead to an improvement in the current risk stratification schemes, enhancing our understanding of risks leading to thromboembolic events in AF patients.
It is important to note that prior stroke was not used as a risk factor, but was rather evaluated more akin to an outcome variable in our cross-sectional study, though it should be noted that MRI was performed after the stroke occurred. Furthermore, significant statistical anomalies in our sample, such as a 3 times higher stroke rate in women, correspond to the analysis of population being evaluated for refractory AF who undergo ablations and cannot be universalized with consideration to selection bias. It is believed that women with AF are evaluated later than men with AF are, having the inclination to have more severe phenotypes of AF and have a larger degree of fibrosis (17
index is the most accepted, validated risk stratification model; nonetheless, a recent analysis of the current risk stratification schemes by Fang et al. (8
) demonstrated its poor ability to predict strokes. In addition, the CHADS2
scheme has been shown to have a poor predictive power for moderate-risk patients, who compose the majority of patients stricken with AF (9
). Prior investigators have speculated that additional independent risk factors for AF-related thromboembolism are not included in current risk schemes (8
). This has led researchers to evaluate various biomarkers as potential risk factors, including inflammatory and plasma markers for endothelial dysfunction (10
). So far, these additional markers have not been shown to improve the predictive power of the current models.
A systematic review of clinical studies demonstrates that prior stroke, advanced age, hypertension, and diabetes are the only consistent independent risk factors for stroke in AF patients (23
). It is important to note that most clinical studies lack rigorous characterization and direct examination of the LA substrate and individual tissue characteristics in AF patients with a history of stroke. Structural and functional parameters in AF patients have largely been based on echocardiographic analysis of left ventricular function and LA size (24
). Animal models have shown that an increased atrial size is associated with a higher degree of interstitial fibrosis resulting in increased collagen and glycogen deposition within the LA wall (26
). Fatema et al. (28
) evaluated the role of LA volume index as a biomarker for stroke and reported that LA volume enlargement was present in a majority of patients (75%) with first-ever ischemic strokes. This study is consistent with our findings in demonstrating a correlation between LA structural remodeling and ischemic strokes. Of note, it is recognized that most emboli arise from the LA appendage in AF, so the relation and this associated mechanism between LA appendage function and the overall fibrosis in the LA is presumed and not delineated in this study.
Patient age is a consistent, independent risk factor in all studies and is associated with an incremental risk increase for stroke of 1.5% per decade (23
). At the present time, it is not entirely clear how aging relates to the underlying pathophysiology related to thromboembolism. Although higher stroke rates may partly be explained by the coexistence of other independent risk factors in the elderly (23
), it may also be due to LA structural changes that occur over time, especially within the AF population. Goldman et al. (29
) demonstrated that advancing age is independently associated with reduction of LA appendage velocities. Myocardial fibrosis has been shown to increase with age (30
), and aging has been shown to be associated with increased LA enlargement and wall thickness (31
). Similarly, this study confirms that, although not a linear relationship, elderly AF patients have increased LA enhancement seen on DE-MRI as compared with their younger AF patients. Our data correlating high levels of LA fibrosis and stroke demonstrates the adverse relationship seen in progressive LA substrate remodeling. Therefore, the structural remodeling process accentuated in the elderly may lead to LA substrate and or functional changes resulting in a greater tendency for thromboembolism.
The main limitation of this study was that DE-MRI was not performed at the time of stroke; the time to MRI after the stroke was almost 2 years. We know that LA enhancement as a determinant of fibrosis is a dynamic marker and the level of structural remodeling does not specifically coincide with the time of stroke. It is important to note that the association between structural remodeling and stroke could represent a reverse causality interaction considering that our study results are derived from retrospective data. However, the strength of association among the various stages of LA fibrosis in relationship to the risk factors and stroke is supportive and supports a comprehensive prospective evaluation.
It is also of value to note that the greatest predictive strength of this novel index is evident when applied in conjunction to the standard clinical variables. Therefore, the use of MRI-based LA structural remodeling as a single marker for stroke is not recommended. Also, inclusion of all clinical predictors into the multivariate analysis may have led to model overfitting.