Atrial fibrosis (amount and distribution)
Left atrial (LA) late gadolinium enhancement (LGE) on cardiovascular magnetic resonance (CMR) imaging is indicative of fibrosis and has been correlated with reduced LA function, increased LA volume, and poor procedural outcomes in cohorts with atrial fibrillation (AF) . Previous studies had assessed left atrial fibrosis using DE-MRI. However, these studies were done in non-valvular AF patients [7, 11]. To the best of our knowledge, our study is the first one to study atrial fibrosis regarding its amount and distribution in patients with rheumatic MVD using DE-MRI.
Amount of fibrosis
Among the most consistently described structural abnormalities associated with AF is the development of atrial fibrosis . Atrial fibrosis is the process in which collagen and extracellular matrix are deposited within the atria, often resulting in heterogeneous conduction and impaired contraction. It has been described in a range of conditions including aging [14, 15], heart failure [16, 17], valve disease , hypertension [19, 20], and myocardial infarction (MI) .
In our study, the presence of atrial fibrosis was more in patients with AF than those in sinus rhythm. Patients with AF showed more severe fibrosis. The amount of atrial fibrosis increases with age, duration of symptoms, and progression of mitral stenosis and LA enlargement. The burden of atrial fibrosis increases across the spectrum of AF. The amount of atrial fibrosis was the best predictor of AF. Using stepwise multivariate regression analysis, atrial fibrosis is still keeping its statistical significant as the best independent predictor of AF.
Previous studies have observed the association between atrial fibrosis and AF in both animal models [17, 22, 23] and humans [24, 25]. However, in general, most of these studies have been performed in vitro or on explanted tissues, with limited clinical application.
Platonov et al.  found a twofold to threefold increase in the amount of inflammatory cell count and fibrosis by histopathological examination in a patient with AF compared to a control group. These findings were more prevalent and extensive with permanent compared to paroxysmal AF patients.
Swartz et al.  found that atrial fibrosis was more in patients who developed post-operative AF compared to those remaining in the sinus rhythm in patients going for open-heart surgery without prior history of AF.
Distribution of atrial fibrosis
Among the atrial walls studied (septal, anterior and posterior left atrial walls, and right atrial wall), the posterior left atrial wall is the most frequently affected site in all patients (56.6%) and in both sinus and AF sub-groups (26.7% and 86.7%, respectively). This could be explained to the regional propensities for inflammatory reaction in rheumatic fever (MacCallum patch) [7, 24].
Platonov et al.  took atrial tissue samples from different locations: crista terminalis at right atrium lateral wall, Bachmann’s bundle, superior portion of the interatrial groove, posterior left atrial wall at superior pulmonary vein level, centrally between pulmonary vein ostia, and at inferior pulmonary veins level. They found that the only site-specific, time-dependent change was in the LA at the level of inferior PV. The explanation was that in addition to the possible regional propensities for fibrotic reaction, the characteristics of cardiac motion may play a role. The fulcrum of atrial movement is the site of attachment of the pericardium around the atria-PV junction and may explain relatively accelerated evidence of tissue damage at some sites more than the others.
Oaks et al.  demonstrated that not only the extent but also the locations of LA enhancement appear to be important predictors of ablation success. Patients who suffered recurrent AF showed enhancement in all portions of the LA, whereas patients who responded successfully to ablation showed enhancement limited primarily to the posterior wall and septum.
Atrial fibrosis and atrial fibrillation: a cause and effect relationship?
Atrial fibrosis and AF have been shown to occur concurrently, but it is unclear whether there is a direct cause and effect relationship or whether these events occur as a consequence of independent pathologic changes in the heart .
A number of studies have been performed to establish whether fibrosis always accompanies AF. Clinically, histological analyses of atrial biopsy samples from patients with lone AF revealed that 25% of these patients exhibited no hallmarks of atrial fibrosis . In human lone AF, it has been shown that long-term assessment of patients diagnosed with AF, which had normal-sized atria upon diagnosis, does lead to structural remodeling of the atria causing atrial enlargement and dilatation over a subsequent period of 20 months .
Animal models of chronic atrial fibrosis, which utilized chronic rapid ventricular pacing or over-expression of transforming growth factor-β1 (TGF-β1), have an associated increase in atrial fibrosis with increased AF inducibility [23, 30].
In our study, most of the patients (n = 40, 66.6%) showed atrial fibrosis that could be explained by the underlying rheumatic MVD (essentially a chronic inflammatory disease). All patients in the AF group showed atrial fibrosis. The presence of atria fibrosis in one-third of the patients in the sinus rhythm group suggests a cause rather than an effect relationship. Furthermore, atrial fibrosis was the best predictor of AF. On the other hand, AF was not a significant predictor of atrial fibrosis. Consistent with these data, ROC analysis showed that atrial fibrosis showed the largest area under the curve (AUC = 0.9) for prediction of AF with more than mild atrial fibrosis could predict AF with a sensitivity of 100% and specificity of 66%. In addition, ROC analysis using left atrial diameter could predict atrial fibrosis at a smaller size than AF (4.55 vs. 4.65 cm) that suggests that atrial fibrosis precedes atrial fibrillation at least in this cohort of patients with rheumatic heart disease. So, we can conclude that atrial fibrosis is the cause of AF in patients with rheumatic MVD.
Relation between atrial size and atrial fibrillation/fibrosis
Left atrial (LA) enlargement has been proposed as a barometer of diastolic burden and a predictor of common cardiovascular outcomes such as atrial fibrillation, stroke, congestive heart failure, and cardiovascular death.
Prospective data from the large population-based studies have established a relationship between M-mode antero-posterior LA diameter and the risk of developing AF [31, 32]. In the Framingham study, a 5-mm incremental increase in the antero-posterior LA diameter was associated with a 39% increased risk for subsequent development of AF . In the Cardiovascular Health Study, subjects in sinus rhythm with an antero-posterior LA diameter > 5.0 cm had approximately four times the risk of developing AF during the subsequent period of surveillance . LA volume has been shown to predict AF in patients with cardiomyopathy  and first-diagnosed non-valvular AF in a random sample of elderly Olmsted County residents who had undergone investigation with a clinically indicated echocardiogram .
In our study, LA size was larger in patients with AF than those in sinus rhythm and the LA size differs significantly across the spectrum of AF.
In our study, minimal increase in LA diameter and size were associated with increased odds of developing AF, as a 1-mm incremental increase in LA diameter was associated with 49% increase in the odds of developing AF and a 1-ml incremental increase in LA volume was associated with 32% increase in the odds of developing AF.
LA diameter ≥ 4.65 cm could predict AF with a sensitivity and specificity of 80% and 84%, respectively. LA volume ≥ 72.5 ml could predict AF with a sensitivity and specificity of 83% and 74%, respectively. This smaller threshold to predict AF compared to the Cardiovascular Health Study  could also be explained by the rheumatic etiology of AF.
Knackstedt et al.  conducted a study using dogs and induced CHF using rapid ventricular stimulation followed by rapid atrial stimulation to induce AF. They found that atrial fibrillation/CHF leads to significant atrial fibrosis and dilation. They concluded that increased echocardiographic size correlates to the degree of atrial fibrosis and may be used as a simple clinical marker for atrial fibrosis. The fibrosis accompanying atrial dilatation may also explain why LA size, as determined by echocardiography, is a strong predictor of cardioversion success.
In our study, the LA size was larger in patients with atrial fibrosis than those without atrial fibrosis. Among clinical and echocardiographic variables, LA diameter had the greatest correlation with LA fibrosis (r = 0.74, P < 0.001). LA diameter ≥ 5.05 cm can predict severe atrial fibrosis with a sensitivity and specificity of 93% and 94%, respectively. Taking these data together, we can conclude that LA can be used as a simple marker of atrial fibrosis and may guide the success of AF ablation in patients with rheumatic MVD.
Relation between mitral valve area and atrial fibrillation/fibrosis
To the best of our knowledge, our study is the first one to study the relation between mitral valve area and atrial fibrillation/fibrosis using DE MRI.
We found that the mitral valve area was smaller in patients with AF than those in the sinus rhythm. The mitral valve area differs significantly across the spectrum of AF and could differentiate between the three different types of AF. A 1-mm incremental decrease in mitral valve area is associated with 2.71 times increase in the risk of developing AF.
Mitral valve area ≤ 1.25 cm2 can predict atrial fibrosis with a sensitivity and specificity of 95% and 73%. The mitral valve area was the best independent predictor for the presence of atrial fibrosis.
Mitral valve area/LA size and atrial fibrosis
The mitral valve area showed better sensitivity and specificity for the prediction of the presence of atrial fibrosis. On the other hand, LA diameter showed better sensitivity and specificity for the prediction of severe atrial fibrosis.
Taken these data together, we can conclude that mitral valve area is a simple marker for early atrial fibrosis while LA size is a simple marker for severe atrial fibrosis. This could be explained by the natural history of rheumatic MVD where LA enlargement develops secondary to valve distortion and the subsequent progressive hemodynamic load and structural remodeling.