In this study, we systematically investigated a series of patients with primary scar-related LAMRT. The main findings of this study are as follows:(1). We found that arrhythmogenic substrates of LAMRT were the spontaneous scars of LAAW. (2). The critical isthmus is usually located between the LAAW scar and the anterior MV or RPV. (3). A novel finding of this study is that the LVA of LAAW has a consistently between the LA and the aorta or LA and pulmonary artery contiguous area. (4). Moreover, the combination of gender and age can effectively predict this particular type of MRAT. CA linear lesions between the scar of the LAAW and the MV or RSPV seem to be an effective and safe therapy for this arrhythmia.
Arrhythmogenic Substrates and Reentry Circuits
In this study, the arrhythmogenic substrates of this unusual type of MRAT were revealed by high-density mapping. The LVA and spontaneous scar were consistently presented and located in LAAW. The predominantly observed mechanism of MRAT could be related to a central anterior scar that appears to form an isthmus between the scar of LAAW and the MV or RPV. The CV in the isthmus was the slowest than that in other parts of the heart. On the whole, the isthmus showed the following obvious characteristics such as abnormal local electrogram duration, low signal voltage, fractionation, and conduction slowing, which is critical for stabilizing such circuits.
Previous Studies of Pathogenesis of the LA Scarring
In this study, low voltage was found in all patients and only in the LAAW, which was unexpected and impressive. Fukamizu, S.et al described 6 patients with LAMRT originating from the spontaneous scars of LAAW[10]. Schaeffer, B.et al described 15 patients who had LAMRT and no history of LA ablation or cardiac surgery. The LVA of LAAW were predominantly related to 8 patients by formation of the isthmus between the LVA and the MV[12]. The above study is very similar to our studies. Kishima, H.et al demonstrated that the existence of LVA of LAAW was associated with higher LA stifness index[13]. Nakatani, Y.et al demonstrated that a thin LA wall is an independent predictor of LVA in patients with paroxysmal AF[14], but in the study that the septal wall was thinner than all other walls, so the septal wall LVA was more extensive than the LVAs of roof, posterior, and bottom walls. The results are not consistent with what we found which focuses on LAAW. A recently reported phenomenon called “fibrotic atrial cardiomyopathy (ACM)” which was responsible for some of the atrial arrhythmias, including AF, atrial tachycardia, or sick sinus syndrome[15]. However, in our study, all the bi-atrial voltage mapping shows a LVA only in the LAAW, which contributed to the MRAT substrates, whereas the right atrium voltage map was normal. At the same time, during our follow-up after ablation, none of the patients showed sick sinus syndrome except for 2 patients with recurrence, so this explanation is also hard to convince. For 2 patients with recurrent atrial tachycardia, it was considered that only the isthmus was ablated, and the ablation line was not extended to the RPV, so the recurrent tachycardia may be around the RPV.
Our Study of Pathogenesis of the LA Scarring
Why is LVA only present in the LAAW? Hori Y et al reported that external structures have an LA anatomical contact area, where there were frequent sites of LVA and fractionated electrograms in patients [16]. Pak et al.demonstrated that the LAAW corresponds to the LVA in the contiguous aorta-LA area around the MV in the 11–12 o’clock direction [17]. Our study has shown different findings. We also found that the LVA is not only partially consistent with the aorta, but also partially consistent with the pulmonary artery by merging enhanced CT and Carto3 mapping. As from the CT images, the scar of LAAW could represent areas of direct contact regions from the aorta or/and the pulmonary artery. However, to the best of our knowledge, no other report has described the anatomic associations of the LVZ of the LAAW in patients with scar-related LAMRT. Scarring around the anterior wall of the MV(area 1) is due to at the MV–aorta junction, the LA is continuous through the subaortic curtain with the musculature of the anterior mitral leaflet. This region can generate abnormal electrical activity[18], but the exact mechanism of voltage reduction in the contiguous aorta-LA or pulmonary artery-LA area is unclear. Age, gender, hypertension, pulmonary hypertension and left atrial enlargement may contribute to the formation of LAAW scar. The morphologic enlargement of the LAAW is more extensive in the setting of LA dilation[19]. We also found that MRAT patients were mostly older female with a long history of hypertension and mild to moderate pulmonary hypertension in addition to left atrial dilatation, which can cause dilation of the aorta, pulmonary artery, which can lead to closer contact between them and its contact against the constantly pulsating aorta and pulmonary artery may result in a LVA on LAAW. Although we found no significant difference in aortic and pulmonary artery diameters between the study group and control group. Chronic hypertension can lead to impaired left ventricular diastolic function, resulting in increased left ventricular pressure, which increases left atrial pressure and volume, more often encountered in women with AF than in men. Aging has been shown to be associated with regional conduction slowing and structural changes that include areas of low voltage [20]. In post-menopausal women, the increased sympathetic tone[21,22], the pronounced decrease in oestrogen [23], the increase in epicardial fat and metabolic syndrome[24] and increased diastolic dysfunction [25-27] may contribute to the formation of atrial fibrosis.As women age, their atrial functional decay is more severe [28]. However, the detailed relationship between sex, age, the external structures and arrhythmogenic substrates is still unclear and requires further investigation.
Clinical implications for future therapies and research
Although the typical MRAT (CTI-dependent flutter) is most common in patients, the LAMRT mostly occurs in elderly female patients with hypertension or pulmonary hypertension for many years. If clinically encountered with chronic hypertension and pulmonary hypertension elderly female MRAT patients without any prior cardiac interventions, we should first consider this type of MRAT. The tachycardia could be eliminated with 1–9 RF by selecting the critical isthmus with low signal amplitude, long-duration, and fractionated electrograms in the majority of LAMRT. The critical isthmus is usually located between the LAAW scar and the anterior MV or RPV, which is clinical guiding significance for novices or electrophysiologists who are unable to perform high-density mapping. During CA for AF, if a LVA is found on the LAAW of the patient with no history of MRAT, the ablation line should be routinely performed between an LVA and an anatomic obstacle (the MV or/and RPV) to prevent this type of MRAT. Our results describe that the scar formation is related to sex, age, and external structures. Based on the mechanistic findings discussed above, several therapeutic strategies might prevent the disease. In terms of medications to control high blood pressure, antifibrotic drugs (such as angiotensin receptor blockers or spironolactone) might be beneficial, because the women demonstrate more pronounced fibrotic remodelling. Similarly, in postmenopausal women, epicardial adipocyte infiltration and consecutive pro-inflammatory signalling suggest that complementing classical antiarrhythmic therapy and anti-inflammatory therapy may be beneficial for older women. Microvascular disease and diastolic dysfunction are more common in women than in men, suggesting that these drugs that affect these commitments may be particularly effective in women when added to classic antiarrhythmic therapy.
Study Limitations
This study has several limitations: (1) The patients included in this retrospective study were a highly selected group referred for CA, and the number of patients was also limited. (2) It is found that the LVA is anatomically consistent with the aorta or pulmonary artery, the detailed relationship between the external structures and arrhythmogenic substrates is still unclear and requires further investigation,which need more detailed mechanistic studies. (3) Voltage maps were acquired during MRAT mapping, we did not perform additional voltage mapping in sinus rhythm. (4) Are these patients most elderly female, because our sample size is insufficient, or are elderly females at high risk? We need to expand the sample size and find out what's special about it.