FREQUENCY COHERENCE MAPPING OF CANINE ATRIAL FIBRILLATION: IMPLICATION FOR ANTI-ARRHYTHMIC DRUG-INDUCED TERMINATION

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1 56 Vol. 5 No. 2 April 2003 FREQUENCY COHERENCE MAPPING OF CANINE ATRIAL FIBRILLATION: IMPLICATION FOR ANTI-ARRHYTHMIC DRUG-INDUCED TERMINATION HAN-WEN TSO', TSAIR KAO', SHIH-AMN CHEN 2, CHING-TAI TAI\ WEI-CHIH HU 3 institute of Biomedical Engineering, National Yang-Ming University, Taipei, Taiwan department of Cardiology, Veterans General Hospital, Taipei, Taiwan department of Biomedical Engineering, Chung Yang University, Chung-Li, Taiwan ABSTRACT The coherence mapping was used in in frequency analysis of of atrial fibrillation (AF). Unipolar electrograms were recorded at at A AF F and during infusion of of anliarrhythmic antiarrhythmic drug, using a 2()-e!ectrode 20-electrode array (electrode spacing is is 3 mm/ mm) placed on the right atrial free wall of of canine. We used magnitudesquared coherence in in frequency (MSCF) maps to to show the frequency distribution during AF. The spectra were limited to to 2-5 Hz for AF signals. We chose each site as a reference and established its MSC spectra with other sites in in the array. Dominant frequency (DF) was defined by maximum power of of spectrum from reference. MSC spectrum was calculated for every point in in the array relative to to the reference site. If If the MSC value of ofdf is is greater than or or equal to to , the frequency at at this site is is set to to DF, otherwise it it is is set to to zero. The majority of of these values was assigned as the DF of of thai that position. The spatial distribution of of DFs was presented as a map. map, MSCF map. The dominant urea area (DA) was chosen from the isochronal maps. We developed the MSCF maps for four episodes; episodes: (I) () normal sinus rhythm; (2/ (2) AF without drug infusion; (3) just before AF termination by drug infusion; (4) sinus rhythm following termination. The results show that MSCF map in in DA just before AF termination has a uniform pattern. The signals in in DA have lower frequencies and longer cycle lengths compared with those in in other areas (P < 0.05). In conclusion, this mapping study of the epicardia! epicardial surface during induced atrial fibrillation in in canine right atrial wall has demonstrated that a dominant area near SA node may have an important role for drug-induced AF termination. Biomed Eng Appl Basis Comin. Comm, 2003 (April); 2003:5: INTRODUCTION Atrial Fibrillation (AF) is characterized by rapid and irregular activation of the atrium. The occurrence of AF increases with age, ischemia stroke, and hypertension. Based on insights from human studies and animal models, the reentrant mechanism is involved in Received: Nov. 27, 2002; Accepted: April 4, 2003 Correspondence: Tsair Kao, Ph.D., Professor Institute of Biomedical Engineering, National Yang-Ming University 55, Sec. 2, Li-Nong St, Peitou, Taipei, Taiwan, tkao@bme.yn.edu.tw the genesis and maintenance of AF. Recently, AF was widely believed to result from asynchronous and incoordinated activation of the atria by multiple wavelets [-3]. Cardiac mapping can be used to show the pathways of wavelets. It is obtained from simultaneous electrical activations in numerous locations of the heart. Analysis of mapping of epicardium has remained primarily through constructing on isochronal or similar time-domain maps [4-6]. Isochronal mapping cannot hold for complex rhythms like fibrillation, which had different type of signals in morphology. Even organized rhythms were still confused by double potentials and artefacts. Other analysis techniques involving transformation into frequency domain have also been used for longer periods of signals to help visualization and analysis. -0-

2 BIOMEDICAL ENGINEERING- APPLICATIONS, BASIS & COMMUNICATIONS 57 NC AP 8 dote SVc 5 dote Fig. Mapping of the canine right atrium free wall (left graph). Using 20 electrodes (right graph) simultaneously to record epicardial electrograms. The interelectrode distance is 3 mm. SVC: superior vena cava, IVC: inferior vena cava, AP: atrial appendage. Magnitude-squared coherence (MSC) function, a frequency domain measurement of phase consistency between two signals, can quantify the levels of various arrhythmias [7]. Coherence maps were used to interpret multiple seconds of mapping data with no need to define activation times and also could reveal characteristics of the spatial organization of complex rhythms [7-9]. Previous studies have described that coherence mapping was calculated from the average of MSC spectrum during 0-50 Hz. The entire map had strong constant phase relationship with reference at organized rhythm. During AF, coherence was lower than that of organized rhythm, and there was a small area of high coherence around the reference. Averaged MSC drops with distance for all rhythms, being most pronounced for fibrillation. MSC mapping may provide a longterm spatial organization of rhythms that can distinguish fibrillatory and nonfibrillatory rhythms. According to the hypothesis about the mechanism of AF, the maintenance of AF depends on the presence of a number of simultaneous reentrant waves. As the minimum size of a reentrant wave is related to the wavelength, the wavelength should be an important determinant of the occurrence of AF [0]. Increasing cycle length should decrease the number of the reentrant waves and enhance atrial organization that may lead to AF termination. In this study, we used MSC function and main-power frequency to make MSCF maps. MSCF map is attained by high coherence at dominant frequency of the reference site. We investigated the characteristics of spatial and temporal organization of complex rhythms by MSCF mapping and cycle length. We also used these two parameters to demonstrate a possible mechanism of AF termination. 2. METHODS 2. Animal Preparation All animal experiments were approved by the Veterans General Hospital, Taipei. Ten open-chest M PF S+AT Fig. 2 Five simultaneously recorded unipolar electrograms. There are four periods : sinus rhythm before AF (SR), AF without antiarrhythmic drug (AF- BD), AF just before drug-induced termination (AF- BT), and sinus rhythm after termination (SR-AT). dogs of either sex weighting 0±5 kg with induced AF by extra-stimulation under continuous infusion of methyl-acetylcholine (0.5µg/kg/min) to sustain AF were studied. After 5 minutes of AF, all dogs received intravenous procainamide (5 mg/kg) to terminate AF. 2.2 Data Acquisition and Preprocessing A spoon-shaped plate consisting of 20 unipolar electrodes that are arranged in a 2-D array (5x 8) was used. These are metallic electrodes with interdistance of 3 mm. The plate was placed on the right atrial wall and was kept in place carefully to obtain signals without motion artifacts. Since some electrodes at the edge of the plate may not have good contact with the atrium, the measurable area in the experiment is about 42 mm x 2 mm, slightly smaller than the electrode array. Recorded signals were connected to a mapping system (Cardiolab 4., Prucka GE, FL, USA). Epicardial recordings were obtained during sinus rhythm before AF (SR), AF without antiarrhythmic drug (AF-BD), AF just before drug-induced termination (AF-BT), and sinus rhythm after termination (SR-AT). A 0 s recording for each period was taken simultaneously from all electrodes. Five simultaneously recorded unipolar epicardial electrograms taken from a dog's right atrium are shown in Figure 2. Every electrogram was appropriately amplified and low-pass filtered ( Hz). The recordings were digitized at a sample rate of KHz. This study analysed recordings retrospectively. Each recording was digitally filtered by using a sixthorder Butterworth bandpass filter (5-50 Hz) because all the power in fibrillatory signals was considered to be limited to this band. Each 0 s recording was divided into five 2 s segments. For each segment, MSC spectrum was calculated for every electrode in the array relative to the reference. A Hamming window and FFT with 50% overlap were used to calculate the spectra. The frequency with maximum power was defined as dominant frequency (DF). --

3 58 Vol. 5 No. 2 April 2003 b 0 4 Hz ti...r DF map 20 DF maps MSCF map Fig. 3 The procedure to obtain the MSCF maps. See text for details. Fig. 4 An example of isochronal map in sinus rhythm is shown. The earliest depolarization area around SA node (dotted square) is denoted as dominant area (DA). Twenty-four electrodes (about 945 cm2) are enclosed by the dotted square. 2.3 MSCF Map Magnitude-squared coherence (MSC) is a measure of the relationship between two different signals in frequency domain. It is defined as: 2 MSC(f)= S^(f)S,y(f) where x(t) and y(t) are two simultaneous time recordings. S,.,, is the cross-power spectrum of x(t) and y(t). S,,, and Syy are the power spectra of x(t) and y(t), respectively. The MSC value is between 0 and. If x(t) and y(t) have high relation, the MSC is near to. If these two signals are uncorrelated, the MSC is equal to O.The ordinary coherence maps are dependent on the Fig. 5 An example of MSCF map for a 2 s recording is shown. Upper 5 maps represent consecutive 0 s of AF signal. Lower 5 maps represent 0 s signal just before AF termination. The dotted square indicates the dominant area (DA). choice of reference location. In this study, we applied MSC and DF for measuring the correlation between signals from different sites in the atrium during AF and after antiarrhythmic drug infusion. The MSCF map was obtained by the procedures described below. A position in the array was selected as the reference site, starting from position (,). For the signal of the reference site (m, n), the power spectrum density was estimated and the frequency with the maximum power was assigned to be the dominant frequency, DF(m, n). MSC spectrum was calculated for every point in the array relative to the reference site. If the MSC value of DF(m, n) is greater than or equal to 0.5, the frequency at this site is set to DF(m, n), otherwise it is set to zero. Hence, for each position there were 20 values, most of them are zeros. The majority of these values was assigned as the DF of that position. This gave the spatial distribution of DFs and was presented as a map, MSCF map. 2.4 Dominate Area We used the traditional method to obtain an isochronal map. An area that including the electrodes with earliest depolarization times was defined as dominant area (DA). The area around SA node is also included in DA. The changes in DFs in the dominant area of MSCF map were illustrated for each episode. 2.5 Statistical Analysis All data are presented as means±d.s. A twotailed student's t-test was used to determine the significance of difference between two periods. A P value of less than 0.05 was considered statistically significant. -2-

4 BIOMEDICAL ENGINEERING- APPLICATIONS, BASIS & COMMUNICATIONS 59 o + SR.SR-AT AF-BD AF-BT Fig. 6 Frequency distribution in DA in four specific periods: during sinus rhythm before AF (SR), AF without antiarrhythmic drug (AF-BD), AF just before drug-induced termination (AF-BT), and sinus rhythm after termination (SR-AT). Frequency band is divided into three bands: band A (2-5 Hz), band B (6-0 Hz), and band C (-5 Hz). 3. RESULTS The frequency range of MSCF maps is 2-5 Hz. Figure 5 shows an example of MSCF maps. Each map summarized 2 s recordings. The upper five maps represent consecutive 0 s of AF electrograms and the lower five maps represent consecutive 0 s electrograms just before AF termination. All maps are colorcoded according to color table as shown. The MSCF maps have shown strong relationship to the frequency changes of AF with antiarrhythmic drug or without. The 5 MSCF maps on top panel have high frequency distribution and irregular patterns. The 5 maps in the bottom panel have almost the same color showing that atrial activity becomes more organized before termination. In order to compare the changes in DFs in the DA before and after drug infusion, three frequency bands were used: band A (2-5 Hz), band B (6-0 Hz), and band C (-5 Hz). In Figure 7, before AF termination (AF-BT), most of DFs (82.5±5%) are in median frequency band (band B). If more than 50% of frequency in DA is in band B, it seems that AF could start to be terminated. Depending on the percentage distribution, frequencies in SR and SR-AT belong to band A, AF- BD to band C, and AF-BT to band B. As expected, during AF without drug infusion, the values of frequency were higher than that of after drug infusion (.0 ± 0.93 Hz vs ± 0.69 Hz, P < 0.0) in DA (Figure 7). At third period (AF-BT), there is clearly different frequency distribution between DA and other area (P < 0.05). For data acquisition in time P<0.00 i p < aooi + I L I other area - " n p<(.05 i n"h SR AF-BD AF-BT SR-AT Fig. 7 Frequency Variations of MSC maps in four periods. Block bar is for DA, white bar is for other area. DA: dominant area, SR: sinus rhythm before AF, AF-BD: AF without antiarrhythmic drug, AF- BT: AF just before drug-induced termination, SR- AT: sinus rhythm after termination. domain, we started at 0 seconds before and after we injected antiarrhythmic drugs. To compare the variation of local cycle lengths during AF, The cycle lengths in DA and another area with the same size were 73.3±8.9 ms and 73.0±8.0 ms, respectively, during AF without drug. After injection of the drug, the cycle length was increased. Just before AF termination, the cycle lengths in DA and other area were.±.7 ms and 95.±5.6 ms, respectively. The difference is significant (P < 0.05). Procainamide made AF termination successfully for all dogs. 4. DISCUSSION Sinus rhythm is an organized rhythm with high MSC between unipolar electrograms from any position and the reference site in the electrode array. The MSCF map is similar for every 2 s data segment. However, The DFs are clustered in clearly distinct regions. The value of the DFs may relate to the cycle length of the activity in that region. During antiarrhythmic drug administration, atrial activity becomes more organized. An increased organization of atrial fibrillation prior to termination was demonstrated. Termination of AF by procainamide is associated with evidence of increased wavelength, i.e., slowed atrial rate. The dominant area including SA node was defined in this study. After the injection of procainamide, frequency in DA was reduced to median frequency (6-0 Hz), and the contraction of myocardium in DA may be synchronized by SA node again. Just before termination, SA node will be controlling atrium into normal rhythm. Increased organization of electrical activation in DA may be the underlying mechanisms of druginduced termination of AF. -3-

5 60 In conclusion, this mapping study of the epicardial surface during induced atrial fibrillation in canine right atrial wall has demonstrated that a dominant area near SA node may have an important role for drug-induced AF termination. ACKNOWLEDGEMENT This study was supported by grant NSC E , National Science Council, Taiwan. REFERENCE. Moe GK, Rheinboldt WC and Abildskov JA: A computer model of atrial fibrillation.am Heart J 964;67:200: Allessie MA, Lammers WJEP, Bonke FIM, Hollen J. Experimental evaluation of Moe 's multiple wavelet hypothesis of atrial fibrillation. In: Zips DP, Jalife J, eds. Cardiac Electrophysiology and Arrhythmias,, San Diego, Calif: Grune &Stratton; 985: Jalife J, Berenfeld 0, Skanes A and Mandapati R: Mechanisms of atrial fibrillation: Mother rotors or multiple daughter wavelets, or both? J Cardiovasc Electrophysiol 998;9:S2-S Konings KTS, Kirchhof CJHJ, Smeets JRLM, Wellens HJJ, Penn OC and Allessie MA: High-density Vol. 5 No. 2 April 2003 mapping of electrically induced atrial fibrillation in humans. Circulation 994;89: Holm M, Johansson R, Olsson B, Brandt J and Li hrs C: A new method for analysis of atrial activation during chronic atrial fibrillation in man. IEEE Trans Biomed Eng 996;43: Berenfeld 0, Mandapati R, Dixit S, Skanes AC,. Chen J, Mansour M and Jalife J: Spatially distributed dominant excitation frequencies reveal hidden organization in atrial fibrillation in the Langendroff-perfused sheep heart. J Cardiovasc Electrophysiol 2000;: Ropella KM, Sahakian AV, Baerman JM and Swiryn S: The coherence spectrum: a quantitative discriminator of fibrillatory and nonfibrillatory cardiac rhythms. Circulation 989; 80: Sih HJ, Sahakian AV, Arentzen CE and Swiryn S: A frequency domain analysis of spatial organization of epicardial maps. IEEE Trans Biomed Eng 995; 42: Lovett EG and Ropella KM: Time-frequency coherence analysis of atrial fibrillation termination during procainamide administration. Annals Biomed Eng 997;25: Allessie MA, Bonke FIM and Schopman FJG: Circus movement in rabbit atrial muscle as a mechanism of tachycardia. The leading circle concept: a new model of circus movement in cardiac tissue without the involvement of an anatomic circle. Circ Res 977;4: