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    • Different ideas however emerged in the

    2019-05-16

    Different ideas, however, emerged in the 1960s and 1970s in the minds of computational biologists interested in the theory of wave propagation in excitable media. Based on chemical [17] and numerical experiments, [18] scientists in the Soviet Union and the USA began to suggest that fibrillation was not random, but spatio-temporally well organized and maintained by the formation of spiral waves spinning around functional organizing centers called “rotors.” Subsequently, the use of optical mapping technology in the early 1990s allowed for the demonstration that a small number of rotors (i.e., 1 or 2) were capable of maintaining fibrillation in the atria or ventricles; [19,20] this led to the “mother rotor” hypothesis of AF [21]. Over the last 10 years, several clinical studies have focused on testing whether rotors are the underlying mechanism of AF through inference by the use of dominant frequency mapping [22–24]. Very recently, Narayan et al. [25] developed a phase-mapping approach that enabled them to visualize the dynamics of rotors on the atria of patients through the use of a multiple electrode, basket catheter system. Our work over the last 2 years has focused on the demonstration that electrical activity during sheep persistent AF is organized by a few “scroll waves,” 3-dimensional (3-D) waves of excitation emitted by rotors that span from the endocardium to the epicardium within the highest dominant frequency domain [26].
    Optical/electrode mapping in isolated sheep hearts Since the 1990s, extensive high-resolution optical mapping of the electrical activity during AF in the isolated heart has been an important source of information regarding AF dynamics and its mechanisms [27,28]. To investigate the dynamics of AF, our laboratory selected the sheep heart since its size and electrophysiological properties are similar to those of humans [29,30]. Briefly, our experimental procedures were as follows. The hearts were excised and immediately attached to a Langendorff-apparatus. Unless otherwise stated, after a purchase NMS-873 injection of 5 to 10mL Di-4-ANEPPS (10mg/mL), 2 charge-coupled device (CCD) cameras focused on the epicardium of the left atrial appendage (LAA) and the right atrial appendage (RAA) recorded fluorescence changes, each from an area of ∼3cm2 at 500–1000frames/s to obtain 5-s movies (80×80 pixels). In the simultaneous endocardium–epicardium mapping project, a third CCD camera is connected to a cardio-endoscope introduced in the left atrium by the transseptal route and is synchronized with the other 2 cameras [26,31,32]. Dominant frequency (DF) maps are obtained for each optical movie after applying a Fast Fourier Transformation of the fluorescence signal recorded at each pixel. To analyze rotor dynamics quantitatively, we also constructed phase movies after a phase analysis according to that originally described by Gray et al. [33] but modified as to be based upon Hilbert transformation as in the report by Warren et al. [34]. Bipolar electrodes were positioned on the left and right atrial appendages, on the left atrial roof, inside the coronary sinus and on the left superior pulmonary vein (LSPV), left inferior pulmonary vein (LIPV), right superior pulmonary vein (RSPV), and right inferior pulmonary vein (RIPV). During AF, bipolar electrograms were acquired at a sample rate of 200 points per s. Segments of 4096 points (approximately 20s) were analyzed with Fast Fourier transformation as previously reported, [35] and the highest dominant frequency location (DFmax) was determined.
    3-D scroll waves as mechanisms of AF The analysis of the general characteristics of reentrant activity by means of optical mapping is usually achieved in 2 dimensions, i.e., spiral wave reentry. However, accurate understanding of the mechanisms of reentry in the whole heart requires knowledge of the manner in which electrical waves propagate in 3-D, as the myocardial wall thickness is not insignificant. Therefore, ideally, it would be important to elucidate the dynamics of votex-like reentrant activity, i.e., scroll waves spanning the thickness of the atrial wall. While new approaches such as laminar optical tomography are enabling investigators to visualize more deeply into the myocardial wall, [36] most recordings of fibrillatory wave propagation to date have been performed from the epicardium or the endocardium. Hence, the experimental knowledge regarding scroll waves in the heart remains very limited, despite significant progress in the theory and computer modeling of 3-D votex-like reentrant activity [37,38].