This study disclosed the difference in the extent of LV myocardial fibrosis and LA functional remodeling by the simultaneous assessment of LV-ECV and feature tracking LA strain derived from a single CMR study between PAF patients and control subjects. The main findings of this study were: 1) CMR-FT LA strain could identify subtle LA booster pump dysfunction undetectable by conventional active LAEF; 2) LV-ECV was significantly greater in PAF patients than in control subjects, indicating advanced LV myocardial fibrosis; 3) significant correlations were evident between LV-ECV and LA reservoir function and LA conduit function in the PAF group; 4) LV-ECV and LA strain parameters displayed robust reproducibility for both intra- and interobserver classes.
LA remodeling
LA remodeling involves structural and functional changes, and those changes in LA already coexist before the development and persistence of AF.23 Early detection of these changes in individuals is helpful for optimal management of AF in clinical practice. LA dilation reflected by LA structural remodeling is a well-known risk for AF development and stroke.24,25 As expected, our study showed LA volumes were significantly higher in the PAF group than in the control group. Nonetheless, in our cohort, the percentage of LA dilation in PAF was relatively low (26%) and mean LAVmax (43.6 ± 17.6 mL/m2) was within the normal range (26–52 mL/m2).26 Given the complex atrial geometry and thin atrial wall thickness, cardiovascular imaging for noninvasive assessment of LA function is challenging. With the remarkable developments in CMR imaging (excellent spatial resolution to identify heterogeneous atrial wall thickness), complex LA function can now be accurately assessed.12 LA function has been divided into three components:21 reservoir function when the atria store blood in systole, as a conduit when blood flows passively into the LV in early diastole, and as a booster pump when the atria contract in late diastole. In our study, total and passive LAEF (corresponding to reservoir and conduit functions) were decreased in the PAF group as compared to the control group, in line with a previous report.23 However, our study demonstrated that active LAEF (corresponding to booster pump function) did not differ significantly between the PAF and control groups. Whether active LAEF is reduced23 or not27 in PAF patients has remained controversial. In an animal experiment, AF itself induced booster pump dysfunction by causing a tachycardia-induced atrial cardiomyopathy.28 Shin et al. demonstrated that active LAEF was significantly reduced in patients with frequent episodes of AF than in others.29 Alternatively, even in patients with PAF, booster pump function tends to be unaffected when the basic cardiac rhythm is almost sinus rhythm. A potential explanation for similar active LAEF between the PAF and control groups in our study was that the frequency of PAF episodes had been low and the duration of PAF had been short, since we selected PAF patients presenting with sinus rhythm at both outpatient clinic and CMR examinations. LA remodeling in the PAF group might thus be mild and booster pump function assessed by LAEF was preserved in the present study.
Myocardial strain is more sensitive imaging marker to detect early changes of cardiac function than EF, as is the case with incipient disease such as PAF.30 We found that CMR-FT LA strain could identify subtle LA booster pump dysfunction undetectable by conventional active LAEF. A recent study showed LA strain to be the strongest independent predictor of progression to persistent AF in a model including LA diameter, volume, and function.31 In this context, a large registry demonstrated that LA strain and p-wave-to-A’ duration on echocardiographic tissue Doppler imaging was independently associated with stroke risk in a model including CHA2DS2-VASc score, age, and anticoagulant use.32 Moreover, emerging data suggest an independent, inverse association between LA strain measured using CMR and incident heart failure.33 These findings suggested that early detection of LA dysfunction by CMR-FT LA strain in the stage of PAF could help to identify patients at high risk of progression to persistent AF and future cardio-cerebrovascular events.
LV remodeling
The pathogenesis of LV fibrosis in PAF has not been fully elucidated. LV fibrosis may occur secondary to AF as a consequence of rapid ventricular rates or the irregularity of ventricular contraction.34,35 Alternatively, PAF may occur secondary to diastolic dysfunction caused by LV fibrosis as a consequence of primary cardiomyopathy or conditions such as hypertension, diabetes mellitus, obesity, and aging.36,37 A histological study by Frustaci et al. showed that LV endomyocardial biopsy in 14 lone AF patients demonstrated nonspecific necrosis or fibrosis in 60%.38 We have previously demonstrated that ventricular fibrotic changes are more pronounced in AF patients than in subjects with sinus rhythm according to echocardiography-derived integrated backscatter.39 CMR-based myocardial ECV has been regarded as the most robust noninvasive measurement for quantifying myocardial fibrosis.7,8 However, evidence for the association between LV-ECV and AF remains limited.40 Moreover, direct comparisons regarding LV-ECV between PAF and control subjects have not been conducted previously. In this study, CMR-based LV-ECV revealed that myocardial fibrosis in the setting of PAF was more advanced than in control subjects. We also found a significant correlation between LV-ECV and LA volume index in PAF patients. Elevated LV-ECV is reported to be a major contributor to the impaired LV relaxation and stiffness.41 With increased LV stiffness, left atrial pressure rises to maintain adequate ventricular filling, and the increased atrial wall tension leads to subsequent left atrial enlargement. Furthermore, LV-ECV in PAF patients significantly correlated with LA reservoir function and LA conduit function, suggesting a potential link between LV remodeling and LA functional remodeling.
Limitations
This study has some limitations that need to be acknowledged when interpreting the results. First, LV-ECV and LA/LV strain data in our study were derived from a single center and a single vendor. A multicenter, multivendor study is warranted to validate the results of our study. Second, subjects in this study were ineligible for cardiac catheterization including endomyocardial biopsy and pressure study, and histological validation and physiological parameters regarding atrial and ventricular pressure were not obtained. However, a number of studies have shown myocardial ECV as determined by CMR correlated excellently with histological quantification of myocardial fibrosis and association between atrial pressure and atrial remodeling.42 Third, the association of LA strain and electrophysiological parameters was not analyzed. Moreover, the impact of PVI for PAF on LA/LV remodeling was also undetermined, and continued research is required regarding these points. Finally, this study did not address clinical outcomes such as progression to persistent AF or cardio-cerebrovascular events, and further studies are warranted to clarify the relationship between LA/LV remodeling and future cardio-cerebrovascular events.