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Different features of ventricular arrhythmias and the RR-interval dynamics in atrial fibrillation related to the patient’s clinical characteristics: An analysis using RR-interval plotting
Journal of Electrocardiology Vol. 37 No. 3 2004
Different Features of Ventricular Arrhythmias and the RR-Interval Dynamics in Atrial Fibrillation Related to the Patient’s Clinical Characteristics: An Analysis using RR-Interval Plotting
Akiko Suyama Chishaki, MD, PhD,* Fang-Jie Li, MD,† Akira Takeshita, MD, PhD,† and Hiroaki Chishaki, MD‡
Abstract: The clinical features of ventricular arrhythmia and RR-interval dynamics in AF-patients remain unresolved. We successively plotted points on an X–Y plain as (X, Y) ⫽ (RRn, RRn ⫹ 1) from the consecutive RR-intervals of Holter ECGs. Eighty of 175 AF-patients were thus diagnosed to have ventricular arrhythmia based on the different plotting patterns between ventricular premature contractions (VPCs) and aberrations. Different characteristics of the RR-interval dynamics before VPCs were observed such as fixed or variable coupling, and a regular or irregular RR-interval sequence. Malignant arrhythmias occurred more frequently in AF-patients with variable coupling VPCs and/or an irregular RR-interval sequence before VPCs than in those with the fixed coupling VPCs and/or the regular RR-interval sequence before VPCs. The RR-interval plotting method enabled us to distinguish different types of VPCs which were related to the clinical characteristics of the AF-patients. Key words: Ventricular arrhythmia, atrial fibrillation, RR-interval plotting.
Atrial fibrillation (AF) is the most common cardiac arrhythmia and it is becoming more prevalent in the elderly. Hemodynamic impairment and thromboembolic events result in significant morbidity and mortality in patients with AF (1– 4).
Recently, the guidelines for the management of patients with AF were proposed by the ACC/AHA/ ESC committee based on a comprehensive review of literature from 1980 to 2000 (5). However, these guidelines made no recommendations regarding the management of ventricular arrhythmia associated with AF. On the other hand, there is considerable evidence that the presence of ventricular premature complexes (VPCs) can predict mortality after acute myocardial infarction or other heart diseases (6 –9). In these investigations, however, the subjects were mainly patients with an ordinary sinus rhythm, and patients with AF were usually excluded from such study populations. The main reason for this is because a definite diagnosis of
From the *School of Health Sciences, Faculty of Medicine, Kyushu University; †Research Institute of Angiocardiology and Cardiovascular Clinic, Kyushu University, Medical School; ‡St. Mary’s Hospital, Tsufukuhonmachi, Kurume-city, Fukuoka, Japan. Reprint requests: Akiko Suyama Chishaki, MD, PhD, School of Health Sciences, Faculty of Medicine, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka-city, Fukuoka, 812-8582, Japan; e-mail: [email protected]. © 2004 Elsevier Inc. All rights reserved. 0022-0736/04/3703-0009$30.00/0 doi:10.1016/j.electrocard.2004.04.007
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208 Journal of Electrocardiology Vol. 37 No. 3 July 2004 wide QRS complexes in AF, such as aberrant ventricular conductions or VPCs, is not always easy from surface electrocardiograms (ECGs) (10,11). In our previous studies, we introduced a non-invasive method, namely RR-interval plotting, which allowed us to differentiate aberrant ventricular conductions and VPCs in AF (12,13). Furthermore, this method also enables us to visually analyze the characteristics of VPCs in AF. The most prominent characteristics of AF are beat-to-beat irregularity of RR-intervals. We hypothesized that the RR-interval dynamics in AF may thus be somehow related to the occurrence of VPCs. Therefore, the aims of this study were to elucidate the different characteristics of ventricular arrhythmias in AF based on the RR-interval dynamics before VPCs using the RR-interval plotting. In addition, the significance of such different features of ventricular arrhythmias was studied regarding the clinical characteristics of AF-patients with VPCs.
Methods Subjects We retrospectively analyzed the Holter ECGs of 175 consecutive AF-patients who were treated at Kyushu University Hospital between 1990 and 2001. Tapes were analyzed using the RR- interval plotting method according to the principle mentioned below. As a result, 80 AF-patients were found to have frequent VPCs of more than 50/hr, and the number of VPCs was sufficient to make a clear plotting pattern. These patients consisted of 50 with valvular heart diseases (VHD), 11 with ischemic heart diseases (IHD, 8 with an old myocardial infarction and 3 with angina), 10 with dilated cardiomyopathies (CM), 5 with congenital heart diseases (CHD), 2 with hypertensive heart diseases (HHD), 1 with left atrial myxoma and 1 with lone AF. Fifty patients with VHD included 27 rheumatic (22: mitral and 5: aortic) and 23 non-rheumatic valvular heart disease patients (10: mitral valve prolapse and 13: degenerative). The mean age (⫾SD) was 59 ⫾ 12 years and 27 females were included. We examined all patients by echocardiograms and chest X-rays. Furthermore, we interviewed the patients and determined the New York Heart Association (NYHA) functional classification. Forty-eight patients who were taking digitalis showed serum levels within the normal therapeutic range (1.4 ⫾ 0.2 ng/mL) and none had any clinical
evidence of toxicity. We used the first Holter ECG recording for our analysis among the series of recordings for each patient to avoid any influence due to other anti-arrhythmic drugs. We followed these patients for 2.6 ⫾ 1.5years on average (1.0⬃4.6 years) to observe the prognosis. ECG Recordings and the Principle of Plotting RR-interval Plottings Holter ECGs were recorded for 24 hours with portable tape recorders (model SM50, Fukuda Denshi, Japan) and the tapes were then played back with an automatic cardioscanner (model DMW9000H, Fukuda Denshi, Japan). The analysis was manually conducted to determine the different waveforms. We modified the scanner so that the RR-interval and waveform signals, which corresponded to the different waveforms, could be downloaded to a personal computer (NEC PCLC700J34DL, Nihon Denshi, Japan) and then stored the data on a disk for off-line analysis. From the stored data, we obtained an RR-interval plotting according to the previously described principle (12– 14). Briefly, regarding Fig 1, the first pair of RRintervals (R, R) between normal QRS complexes in panel A give the point labeled X1 in panel B. The point X1 is defined as the preceding point since it is the point just before the occurrence of a wide QRS complex. The next point X2 derived from the next pair of RR- intervals (R, S) is defined as a coupling point of the wide QRS complex since the RRinterval S is a coupling interval of the wide QRS complex. The next point from (S, L) shifts up to X3 in the X–Y plain and the point from (L, R) shifts down to X4 as well. Panel C shows an example of an RR-interval plotting of the sinus rhythm associated with VPCs. Panel D shows an example of an RR-interval plotting of AF. In AF, the RR-intervals were irregular and limited by the shortest RRintervals, and therefore, the dots fanned out along the X- and Y-axes. As previously reported, the curvilinear envelope of the normal AF distribution along the X- axis shown in Fig 1D (dotted line) reasonably represents the functional refractory period of the atrioventricular node, since the Y-value of the envelope indicates the shortest attainable RR-interval as a function of the preceding cycle length (12,13). Diagnosis of aberrant ventricular conduction and VPC on the RR-interval plotting A diagnosis of aberrant ventricular conductions and VPCs in AF has been also described in our
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Fig. 1. Principle of the RR-interval plotting. (A) An ECG of sinus rhythm with a VPC. (B) The schematic illustration of the principle. (C) An example of the RR-interval plotting of sinus rhythm with VPCs. (D) An example of AF. A dotted curve represents the refractory period of the AV node. A detailed explanation is given in the text.
previous study (12). Briefly, in reference to Fig 2, panel A shows the distribution of normal AF points and only the coupling points of wide QRS complexes. For purposes of simplicity, the points from (S, L) and (L, R) described in Fig 1B were not shown in the RR-interval plotting of AF. Panel B shows the curvilinear distribution of coupling points of aberrant conductions. On the other hand, in panel C, the coupling points of VPCs were linearly distributed without any relationship to the envelope along the X-axis of the normal AF points. Since aberrations occur when the refractory period of either bundle is longer than that of the atrioventricular node, the distribution of the coupling points of aberrant conductions in the RR-interval plotting overlaps with the curvilinear area between the refractory curve of the atrioventricular node (a dotted line in Fig 2D) and that of either blocked bundle branch (a solid line in Fig 2D). Generally,
the coupling points of the VPCs either show a linear distribution clearly below the envelope of AF or form a scattered band partially overlapping in the area of normal AF distribution according to the variability of the coupling intervals of VPCs. Using these different distributions of the coupling points, we can diagnose the wide QRS complexes in AF as either VPCs or as aberrant ventricular conductions. Upstream RR-interval Dynamics before VPCs Variability in the Coupling Points along the Y-axis (the first upstream RR-interval). As shown in the lower panel of Fig 3, we measured the variability of the coupling points along the Y-axis as twice the standard deviations of the mean Y-values of the coupling points (Yv), ie, the coupling interval of all VPCs for 24 hours. From the Yv value, we
Fig. 2. Differentiation of VPCs and aberrant conductions. (A) the RR-interval plotting of all normal AF points and coupling points of aberration and VPCs. The points of (B) and (C) are only the coupling points of the aberrant conductions and VPCs, respectively. (D) the principle of diagnosing aberrant conductions using RR-interval plotting.
210 Journal of Electrocardiology Vol. 37 No. 3 July 2004 Variability in the Coupling Points along the X-axis (the second upstream RR-interval). In the same way, we used twice the standard deviations of the mean X-values of the coupling points (Xv) as the index for the distribution of the coupling points along the X-axis. If the occurrence of VPCs is limited to the specific preceding RR-intervals, then the Xv must be smaller than the distribution of the normal AF points along the X-axis (Xa). We quantified the relationship of the occurrence of VPCs to the preceding RR-intervals as the ratio of the Xv to Xa, i.e., Xv/Xa (percentage). The small value of Xv/Xa means that the occurrence of VPCs is limited to the specific preceding RR-intervals. If the ratio of Xv/Xa was equal to or smaller than 74% (a mean value of Xv/Xa), we considered the occurrence of the VPCs to have close relationship to the preceding RR-intervals. Thirty-five satisfied the criterion (the related group) while 45 did not (the non-related group). Variability of the Preceding Points (the second and third upstream RR-intervals). Furthermore, we studied the preceding points of the VPCs to examine any variations of the second and third upstream RR-intervals before the occurrence of VPCs. The preceding points were plotted on a different plain from that of normal AF points in order to visually recognize the sequence between 2 RR-intervals of the preceding points. The plottings of the preceding points were obtained separately for different morphologies of VPCs in cases with multiform VPCs. Statistical Analysis
Fig. 3. Definitions of the coupling points, preceding points, and indices for the RR- interval dynamics. In an ECG of AF with a VPC (E3), the point from (N2, V3) is the coupling point and the point from (N1, N2) is the preceding point for the VPC. The upper plotting shows the points of normally conducted AF beats. Xa is twice the standard deviation of the mean X-value of these points. In the lower plot, the mean value (------) and twice the standard deviation (Yv) of the coupling intervals of the VPCs are shown. Xv is twice the standard deviation of the mean X-value of the coupling points. The relationship to the preceding RRinterval is represented by the ratio Xv to Xa, i.e., Xv/Xa (percentage, %).
The data were shown as the mean and ⫾SD. For a comparison of the mean values between the unmatched data of two groups, we used Student’s t-test. The equality of variance of each group was confirmed by the F-test. Comparisons between proportions were made by Fisher’s exact test. The time to the onset of the events was analyzed by means of the Kaplan- Meier survival curves. A P value of less than .05 was considered to be significant.
Results Typical Examples of RR-interval Plottings
divided the total of 80 AF patients with VPCs into 2 groups, ie, the fixed coupling group (Yv value ⫽ 0.2 or ⬍0.2 s, n ⫽ 43) and the variable coupling group (Yv value ⬎ 0.2 s, n ⫽ 37).
Figure 4 shows four typical examples of the RR-interval plottings of AF with VPCs which are classified based on the different variability of the
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Fig. 4. Different patterns of an RR-interval plotting of AF with VPCs. The 2 panels on the left (A) show the plottings without any relationship to the preceding RR-interval and 2 panels on the right (B) are examples of those with a preceding R-interval relationship. The upper plots in each panel show the normal AF points and lower plots indicate the coupling points of VPCs. The upper panels in both A and B show an example of the fixed coupling interval and the lower panels indicate the variable coupling interval. The details are described in the text.
coupling points along the X- and Y-axes. In each plotting, the normally conducted AF points and coupling points of VPCs are plotted separately in the upper and lower panels. The upper two plottings are examples of the imperceptible variability of the coupling points as seen by thin linear distributions of the coupling points. The lower two plottings show the most variable distributions. In the 2 cases on the left side of Fig 4, the distribution of the
coupling points along the X-axis approximately coincided with that of the normal AF points. Therefore, these VPCs had no specific relationship to the preceding RR-interval regarding the occurrence of VPCs. On the other hand, in 2 cases on the right side of Fig 4, the coupling points showed only a limited distribution along the X-axis compared to the normal AF distributions along the X-axis. Namely, the occurrence of VPCs in these cases
212 Journal of Electrocardiology Vol. 37 No. 3 July 2004 tended to be related to the preceding RR- intervals. The upper plotting in Fig 4B showed an example of two different coupling points corresponding to two different forms of VPCs. The distribution of VPCs with shorter coupling intervals (around 0.50 s) showed a wider distribution along the X-axis than that of longer coupling intervals (around 0.68 s). This means that the longer coupling VPCs tend to occur after the specific preceding RR-intervals. The VPCs in the lower panel showed a relationship to the shorter preceding RR-intervals from 0.4 to 0.96 s. Upstream RR-interval Dynamics before VPCs Variability of the Coupling Points along the Y-axis. One patient had both fixed and variable coupling VPCs, but the variable VPCs only rarely occurred, and therefore this case was included in the fixed group. The waveforms of the VPCs were monomorphic in the fixed coupling group, except for 4 patients. These 4 cases had the polymorphic VPCs with separately distributed different coupling points (the upper panel of Fig 4B). In the variable coupling group, 10 had monomorphic VPCs and 27 had polymorphic ones. We quantitatively analyzed the coupling points of the most frequent type of VPCs in the cases with polymorphic VPCs. The average Yv values were 0.27 ⫾ 0.23 s in all patients, 0.32 ⫾ 0.13 sec in the variable coupling group, and 0.16 ⫾ 0.04 sec in the fixed coupling group. Variability in the Coupling Points along the X-axis. The averages of Xv/Xa were 74 ⫾ 15% in all patients, 59 ⫾ 7% in the related group, and 85 ⫾ 10% in the non-related group. In the related group, roughly three types were observed, ie, 55% of the VPCs occurred at the shorter preceding RR-intervals of the normal AF distribution (Fig 4B, plot c in the lower panel), 20% at the intermediate RR-intervals (Fig 4B, plot a in the upper plotting), and 25% at from intermediate to longer RR-intervals (Fig 4B, plot b in the upper plotting). Variability of the Preceding Points. The upper panel of Fig 5 shows the points from all RRintervals of the normally conducted AF beats, and only the preceding points of VPCs were plotted on the lower panel. As shown in Fig 5, we obtained two different patterns of the preceding points, namely a partial type (panel A) and a diffuse type (panel B). In 29 of the 30 cases with the partial type, the preceding points deviated to the left side of the normal AF distribution as shown in Fig 5A. This means that the X- and Y-values of the preceding
points were relatively short and long, respectively. This sequence in the partial type was similar to that of the Ashman phenomenon which is known as a mechanism of aberrant conduction. Another pattern for the partial type was a gathered type in the area of short RR-intervals, but this was found in only 1 case (Figure not shown). On the other hand, the diffuse type of the preceding points was observed in 50 patients, and this meant that any combination of upstream 2 RR-intervals could induce the VPCs. In the diffuse type, 35 were variable coupling VPCs and 15 were fixed coupling ones, while the partial type included only 2 patients with variable coupling VPCs and 28 were fixed coupling VPCs. The variable coupling VPCs had a significantly higher association with the diffuse type than with the partial type, and the fixed coupling VPCs were significantly related to the partial type (P ⬍.001). Clinical Characteristics in Each Group The clinical characteristics of the patients in the 3 categories are presented in Table 1. There was no significant difference in relation to age and gender between the 2 groups in the 3 categories. Comparisons Between the Fixed and Variable Coupling Groups. The incidences of ischemic heart diseases and cardiomyopathy were significantly different between the fixed and the variable coupling groups (P ⬍.05). Comparisons Between the Related and Non-related Groups. Differences in the basal heart diseases were not significantly different between the related and the non-related groups. Comparisons Between the Partial and Diffuse Groups. The diffuse type (n ⫽ 50, 63%) was more frequently found than the partial type (n ⫽ 30, 37%) in the AF population (P ⬍.01). In addition, cardiomyopathy was more dominant in the diffuse type than in the partial type (P ⬍.01). Cardiac Function of Each Group We compared the echocardiographic indices, CTR, and NYHA functional classification in two groups of the 3 categories aforementioned, as well. Comparisons Between the Fixed and Variable Coupling Groups. As shown in Table 2, the mean values of the left ventricular diastolic diameters (LVDDs, P ⬍.05) and the systolic diameters (LVDSs, P ⬍.01) were significantly greater in the
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Fig. 5. Two types of plottings of the preceding points. The upper panels only show the plots for the normal AF beats. The lower plots show the preceding points. (A) The partial type of the plottings of the preceding points where the preceding points of the VPCs deviated to the left side of the normal AF distribution. (B) The diffuse type of the plottings of the preceding points where the preceding points in the diffuse type are scattered in the normal AF area.
variable group than in the fixed group. The average ejection fraction (EF) significantly decreased (P ⬍.05) in the variable group in comparison to the fixed group. The mean CTR was also larger in the variable group than in the fixed group (P ⬍.0001).
The NYHA functional class was significantly higher (P ⬍.001) in the variable group than in the fixed group. The differences in the left atrial dimension (LAD) and the left ventricular wall thickness (IVST, PWT) were not significant between the 2 groups.
Table 1. Clinical Characteristics of the Different VPC Groups Coupling Point Coupling Interval
Patient number Female sex, n Mean Age (y) Basal heart disease VHD IHD CM CHD HHD LA myxoma None
Preceding Interval
Preceding Point
Fixed
Variable
Related
Non-related
Partial
Diffuse
43 17 61 ⫾ 12
37 10 57 ⫾ 10
35 11 59 ⫾ 12
45 16 59 ⫾ 11
30 12 60 ⫾ 12
50† 15 61 ⫾ 12
25 10 1 3 2 1 1
25 1* 9* 2 0 0 0
25 3 4 1 0 1 1
25 8 6 4 2 0 0
24 3 0 1 0 1 1
26 8 10† 4 2 0 0
VHD, valvular heart disease; IHD, ischemic heart disease; CM, cardiomyopathy; HHD, hypertensive heart disease; CHD, congenital heart disease; LA Myxoma, left atrial myxoma. *P ⬍ .05, †P ⬍ .01
214 Journal of Electrocardiology Vol. 37 No. 3 July 2004 Table 2. Echo Cardiographic Indices, CTR, and NYHA Class in the Different VPC Groups Coupling point Coupling Interval
Echocardiogram LVDD (mm) LVDS EF (%) LAD IVST PWT CTR (%) NYHA I II III IV
Preceding Interval
Preceding Point
Fixed
Variable
Related
Non-related
Partial
Diffuse
54 ⫾ 10 39 ⫾ 9 62 ⫾ 14 48 ⫾ 17 11 ⫾ 2 11 ⫾ 2 58 ⫾ 6
78 ⫾ 11* 44 ⫾ 12† 54 ⫾ 19* 52 ⫾ 12 11 ⫾ 4 12 ⫾ 4 65 ⫾ 8‡
57 ⫾ 11 51 ⫾ 16 60 ⫾ 19 60 ⫾ 19 10 ⫾ 2 11 ⫾ 2 64 ⫾ 9
55 ⫾ 10 49 ⫾ 14 57 ⫾ 16 57 ⫾ 16 12 ⫾ 3 12 ⫾ 3 60 ⫾ 6
55 ⫾ 13 32 ⫾ 14 66 ⫾ 17 45 ⫾ 12 12 ⫾ 2 11 ⫾ 3 60 ⫾ 6
74 ⫾ 14* 48 ⫾ 15† 51 ⫾ 18* 50 ⫾ 16 11 ⫾ 3 12 ⫾ 3 65 ⫾ 8
1 (2.3) 34 (79.0) 8 (18.6) 0
0 6 (16.2) 29 (78.4) 2 (5.4)
1 (2.9) 16 (45.7) 17 (48.6) 1 (2.9)
0 24 (53.3) 20 (44.4) 1 (2.2)
1 (3.3) 26 (86.7) 3 (10) 0
0 14 (28.0) 34 (68.0) 2 (4.0)
LVDD: left ventricular end-diastolic diameter, LVDS: left ventricular end-systolic diameter, LAD: left atrial diameter, EF: ejection fraction, IVST: interventricular septal thickness, PWT: posterior wall thickness, CTR: cardiothoracic ratio, NYHA: New York Heart Association functional classification. Values are the mean ⫾ SD or n (%). *P ⬍.05, †P ⬍ .01. ‡P ⬍ .0001.
Comparisons Between the Related and Non-related Groups. No echocardiographic index, CTR and NYHA functional classification were significantly different between the 2 groups. Comparisons Between the Partial and Diffuse Groups. Similar differences between the fixed and variable groups were observed in these two groups. The mean values of the LVDDs (P ⬍.05) and the LVDSs (P ⬍.01) were significantly greater in the diffuse group than in the partial group. The ejection fraction was significantly lower in the diffuse group than in the partial group (P ⬍.05). The CTR tended to be greater in the diffuse group than in the partial group, but the difference was not statistically significant. The NYHA functional classification was significantly higher in the diffuse group than in the partial group (P ⬍.001).
The Kaplan-Meier estimates of the probability of the remaining free of events are shown in Fig 6. The cardiac events significantly increased in both the variable coupling group (P ⬍.03) and in the diffuse group (p ⬍0.05). The basic heart diseases of the patients with these events were CM (4 patients, 40% of CM), IHD (2 patients, 18% of IHD), VHD (6 patients, 12% of VHD), and CHD (1 patient, 20% of CHD).
Discussion In our previous study, we established the criteria for making a different diagnosis of aberrant conduction and VPC in AF. In this study, we analyzed the AF patients with VPCs to confirm the clinical usefulness of this method.
Prognosis of Each Group Fixed and Variable Coupling During the 2.6 ⫾ 1.5 year long follow-up period, 10 events (27%) occurred in the variable coupling group, while only 3 events (7%) were observed in the fixed coupling group. The ten events in the variable group included 3 sudden cardiac deaths, 5 episodes of sustained ventricular tachycardia, and 2 episodes of congestive heart failure (CHF). Among the 3 events in the fixed group, 1 episode was sustained VT and 2 episodes were CHF. Between the 2 groups of the preceding points, there were cardiac events of 11 (22%) in the diffuse group and 2 (7%) in the partial group. The eleven events in the diffuse group included 3 sudden cardiac deaths, 6 episodes of sustained VT, and 2 episodes of CHF.
Anan et al. previously described the variable patterns of VPCs with sinus rhythm using RRinterval plotting (14); ie, the fixed coupling intervals of VPCs demonstrated a narrow distribution parallel to the X-axis and the variable coupling intervals showed a vertical distribution between the shortest coupling interval of ventricular refractoriness and the longest coupling interval of the basic sinus rhythm. Our study clarified that VPCs with AF also had variable patterns in the coupling intervals as seen in the previous study in sinus rhythm. We defined the fixed coupling as less than a 0.2 s variation in the coupling intervals through 24
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The cardiac function was worse in the variable coupling group than in the fixed one. Ino-Oka et al. reported a similar result to ours in the VPC-patients with sinus rhythm (17). This might suggest that the substrates for the multiple re-entry circuits and the various conduction delays existing in the impaired hearts could result in the variable coupling intervals. However, Surawicz and MacDonald reported that the patients with VPCs of variable coupling intervals were not necessarily associated with organic heart diseases (15). There are still conflicting reports regarding the relationship between the cardiac function and the variability of coupling intervals of VPCs. Preceding Heart Rate Relationship In sinus rhythm, some VPCs often occur only in sinus tachycardia or bradycardia. We could also observe that some cases showed a weak relationship with the preceding RR- interval in the occurrence of VPCs. However, the RR-intervals before the occurrence of VPCs were irregular in AF, and therefore, it was difficult to determine the effect of stable and constant preceding RR-intervals on the occurrence of VPCs. This might be one of the reasons why there was no significant difference in the clinical features between the related and nonrelated groups. Fig. 6. The event free ratios in the 2 groups of the coupling points and preceding points. The Kaplan-Meier estimates of the probability of the patients remaining free of any events such as sustained ventricular tachycardia, sudden cardiac death, and CHF. The variable group and the diffuse group were found to more likely develop these events.
hours. This value was longer than those of earlier studies in sinus rhythm (15,16). They arbitrarily determined the coupling intervals of fixed coupling VPCs to be less than 0.08⬇0.12 s. Differences in the basic cardiac rhythms, the analyzed periods and the analyzed number of VPCs between the earlier studies and ours might have influenced the criteria of variability of coupling intervals, since the more the basic cycle length changed in the longer recording period, the more the coupling intervals varied. Furthermore, the RR- intervals in AF changed more even during short periods than those in sinus rhythm, and this increased the variability of the coupling intervals of VPCs. For these reasons, our relatively longer criterion for the fixed coupling than that used in previous studies seemed to be appropriate for our purposes.
Variability of the Preceding Points Gomes et al. emphasized that the short-long sequence of RR-intervals produced a dispersion of the refractoriness in arrhythmic substrates and resulted to initiate the complex ventricular arrhythmia (18). Furthermore, they pointed out that the dispersion of the refractory period induced by the “Ashman sequence” also plays an important role in the induction of VT in the sinus rhythm. This sequence is originally known as the mechanism of induction of aberrant conductions. The preceding points of the partial group demonstrated the “Ashman sequence” before the occurrence of VPCs. This sequential change of RR-intervals is also known to induce ‘torsades de pointes’ in familiar long QT syndrome (19). In AF, the RR- intervals and the RR-interval sequences are both irregular. Consequently the dispersion of the refractory period might increase more dramatically in AF than in the sinus rhythm. In our 175 patients with AF, frequent ventricular arrhythmias occurred in 80 patients (45.7%). The incidence of ventricular arrhythmias in our study population was substantially higher
216 Journal of Electrocardiology Vol. 37 No. 3 July 2004 than that in the study subjects with an ordinary sinus rhythm (6 –9,20). First, this might be derived from the circumstances that all of our AF patients except one had from moderate to severe underlying heart diseases. Second, AF itself might induce VPCs more easily than sinus rhythm due to the dispersion of the refractoriness induced by its irregular pulses. In the maintained cardiac function, the electrical dispersion of ventricular refractoriness could thus be primarily induced by the preceding RR-sequence of a short-long cycle (the partial type). On the other hand, in an impaired heart, there might be many other electrical instabilities and anatomical substrates than the Ashman sequence, which is known to be an important factor to induce VPCs in the maintained cardiac function. Therefore, the shortlong preceding RR- sequence was not necessarily observed before the occurrence of VPCs in patients with an impaired cardiac function. However, further study is needed before any definitive conclusions can be made. Various VPCs and Prognosis Arrhythmia related deaths and impaired cardiac function were associated more significantly with the VPCs showing the variable coupling intervals and/or the diffuse plotting patterns of the preceding points than in those with the fixed coupling intervals and/or the partial patterns of the preceding points. Furthermore, the preponderance of the dilated cardiomyopathy in the variable coupling and the diffuse groups might be related to the higher occurrences of the cardiac episodes in both groups. However, in order to develop a prognostic index, we need not only to analyze many other factors such as the addition of any antiarrhythmic drugs, AF rates, estimated functional refractory periods of the AV node, the occurrence of nonsustained VT and the density of PVCs, but also to accumulate more cases. Since the aim of this study was primarily to distinguish the different types of VPCs even in AF and then to clarify the influence of the RRinterval dynamics in AF on the occurrence of VPCs, such a prognostic study is also planned as part of our future research.
Limitation We studied the characteristics of VPCs in AF using RR-interval plotting and investigated the relationship between different types of VPCs and the clinical characteristics. There were, however, some
limitations in our study. Firstly, an automatic diagnosis of arrhythmia in the RR-interval plotting is arbitrary, however, we have yet to find an optimal method to perform this more accurately. We will continue to try to develop a more accurate method. Secondly, we could not distill the parasystole from the VPCs with variable coupling by RR-interval plotting as we could do for the sinus rhythm (14). More basic electrophysiological studies are thus called for confirming the mechanisms of arrhythmias. Finally, we need to accumulate more cases to better identify the precise relationship between the different characteristics of VPCs and the clinical features.
Conclusion In line with the findings of our previous study on the sinus rhythm (14), we classified various types of VPCs in AF using RR-interval plottings. This method clarified that the occurrence of VPCs was related to the RR-interval dynamics of AF. This irregularity of the RR-intervals might be a critical factor in the induction of malignant ventricular arrhythmia in AF. Furthermore, the different types of VPCs were related to the different clinical characteristics and prognoses of the patients. It is therefore important to elucidate the detailed mechanisms regarding ventricular arrhythmias in AFpatients and also establish an optimal treatment regimen. To achieve this goal, the RR-interval plotting method is considered to be a clinically useful tool.
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16.
among ventricular dysfunction and mortality in the two years after myocardial infarction. Circulation 69:250, 1984 Maron BJ, Savage DD, Wolfson JK: Prognostic significance of 24 hour ambulatory electrocardiographic monitoring in patients with hypertrophic cardiomyopathy: a prospective study. Am J Cardiol 48:252, 1981 Klingfield PMD, Levy D, Devereux RB: Arrhythmias and sudden death in mitral valve prolapse. Am Heart J 113:1298, 1987 Gatzoulis MA, Balaji S, Webber SA: Risk factors for arrhythmia and sudden cardiac death late after repair of tetralogy of Fallot: a multicentre study. Lancet 356:975, 2000 Denker ST, Gilbert CJ, Shenasa M: An electrocardiographic-electrophysiologic correlation of aberrant ventricular conduction in man. J Electrocardiol 16: 269, 1983 Gulamhusein S, Yee R, Ko PT: Electrocardiographic criteria for differentiating aberrancy and ventricular extrasystole in chronic atrial fibrillation: Validation by intracardiac recordings. J Electrocardiol 18:41, 1985 Chishaki-Suyama A, Sunagawa K, Sugimachi M: Differentiation between aberrant ventricular conduction and VE in atrial fibrillation using RR- interval scattergram. Circulation 88:2307, 1993 Chishaki SA, Sunagawa K, Hayashida K: Identification of the rate-dependent functional refractory period of the atrioventricular node in simulated arterial fibrillation. Am Heart J 121:820, 1991 Anan T, Sunagawa K, Araki H: Arrhythmia analysis by successive RR- plotting. J Electrocardiol 23:243, 1990 Surawicz B, MacDonald MG: Ventricular ectopic beats with fixed and variable coupling, incidence, clinical significance and factors influencing the coupling interval. Am J Cardiol 13:198, 1964 Michelson EL, Morganroth J, Spear JF: Fixed coupling: different mechanisms revealed by exerciseinduced changes in cycle length. Circulation 58: 1002, 1978
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17. Ino-Oka E, Yoshikata S, Shimizu Y: The relationship between the coupling interval and preceding RR interval of ventricular premature contractions recorded by 24 hours ambulatory ECG, Iwa T (ed): Cardiac Arrhythmias-current topics Amsterdam, Exepta Medica, 1986, p 318 18. Gomes JA, Alexopoulos D, Winters SL: The role of silent ischemia, the arrhythmic substrate and the short-long sequence in the genesis of sudden cardiac death. JACC 14:1618, 1989 19. Shimizu W, Tanaka K, Suenaga K: Bradycardiadependent early afterdepolarization in a patient with QTU prolongation and torsade de pointes in association with marked bradycardia and hypokalemia. Pacing Clin Electrophysiol 14:1105, 1991 20. Bikkina M, Larson MG, Levy D: Prognostic implication ventricular arrhythmias: the Framingham Heart Study. Ann Intern Med 117:990, 1992
Appendix Yv ⫽ 2 ⫻ SDy SDy ⫽
冑冘共y ⫺ y¯ 兲
2
i
⫻ fny/ny
yi ⫽ y-values of all coupling points, y : the mean value of yi, fny: frequency, ny: total number of yi Xv ⫽ 2 ⫻ SDx SDx ⫽
冑冘共x ⫺ x¯ 兲
2
i
⫻ fnx/nx
xi ⫽ x-values of all coupling points, x : the mean value of xi, fnx: frequency, nx: total number of xi Xa ⫽ 2 ⫻ SDxa SDxa ⫽
冑冘共x
ai
⫺ x¯ a兲2 ⫻ fnxa/nxa
xai ⫽ x-values of all AF points, x a: the mean value of xai, fnxa: frequency, nxa: total number of xai
Different Features of Ventricular Arrhythmias and the RR-Interval Dynamics in Atrial Fibrillation Related to the Patient’s Clinical Characteristics: An Analysis using RR-Interval Plotting
Akiko Suyama Chishaki, MD, PhD,* Fang-Jie Li, MD,† Akira Takeshita, MD, PhD,† and Hiroaki Chishaki, MD‡
Abstract: The clinical features of ventricular arrhythmia and RR-interval dynamics in AF-patients remain unresolved. We successively plotted points on an X–Y plain as (X, Y) ⫽ (RRn, RRn ⫹ 1) from the consecutive RR-intervals of Holter ECGs. Eighty of 175 AF-patients were thus diagnosed to have ventricular arrhythmia based on the different plotting patterns between ventricular premature contractions (VPCs) and aberrations. Different characteristics of the RR-interval dynamics before VPCs were observed such as fixed or variable coupling, and a regular or irregular RR-interval sequence. Malignant arrhythmias occurred more frequently in AF-patients with variable coupling VPCs and/or an irregular RR-interval sequence before VPCs than in those with the fixed coupling VPCs and/or the regular RR-interval sequence before VPCs. The RR-interval plotting method enabled us to distinguish different types of VPCs which were related to the clinical characteristics of the AF-patients. Key words: Ventricular arrhythmia, atrial fibrillation, RR-interval plotting.
Atrial fibrillation (AF) is the most common cardiac arrhythmia and it is becoming more prevalent in the elderly. Hemodynamic impairment and thromboembolic events result in significant morbidity and mortality in patients with AF (1– 4).
Recently, the guidelines for the management of patients with AF were proposed by the ACC/AHA/ ESC committee based on a comprehensive review of literature from 1980 to 2000 (5). However, these guidelines made no recommendations regarding the management of ventricular arrhythmia associated with AF. On the other hand, there is considerable evidence that the presence of ventricular premature complexes (VPCs) can predict mortality after acute myocardial infarction or other heart diseases (6 –9). In these investigations, however, the subjects were mainly patients with an ordinary sinus rhythm, and patients with AF were usually excluded from such study populations. The main reason for this is because a definite diagnosis of
From the *School of Health Sciences, Faculty of Medicine, Kyushu University; †Research Institute of Angiocardiology and Cardiovascular Clinic, Kyushu University, Medical School; ‡St. Mary’s Hospital, Tsufukuhonmachi, Kurume-city, Fukuoka, Japan. Reprint requests: Akiko Suyama Chishaki, MD, PhD, School of Health Sciences, Faculty of Medicine, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka-city, Fukuoka, 812-8582, Japan; e-mail: [email protected]. © 2004 Elsevier Inc. All rights reserved. 0022-0736/04/3703-0009$30.00/0 doi:10.1016/j.electrocard.2004.04.007
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208 Journal of Electrocardiology Vol. 37 No. 3 July 2004 wide QRS complexes in AF, such as aberrant ventricular conductions or VPCs, is not always easy from surface electrocardiograms (ECGs) (10,11). In our previous studies, we introduced a non-invasive method, namely RR-interval plotting, which allowed us to differentiate aberrant ventricular conductions and VPCs in AF (12,13). Furthermore, this method also enables us to visually analyze the characteristics of VPCs in AF. The most prominent characteristics of AF are beat-to-beat irregularity of RR-intervals. We hypothesized that the RR-interval dynamics in AF may thus be somehow related to the occurrence of VPCs. Therefore, the aims of this study were to elucidate the different characteristics of ventricular arrhythmias in AF based on the RR-interval dynamics before VPCs using the RR-interval plotting. In addition, the significance of such different features of ventricular arrhythmias was studied regarding the clinical characteristics of AF-patients with VPCs.
Methods Subjects We retrospectively analyzed the Holter ECGs of 175 consecutive AF-patients who were treated at Kyushu University Hospital between 1990 and 2001. Tapes were analyzed using the RR- interval plotting method according to the principle mentioned below. As a result, 80 AF-patients were found to have frequent VPCs of more than 50/hr, and the number of VPCs was sufficient to make a clear plotting pattern. These patients consisted of 50 with valvular heart diseases (VHD), 11 with ischemic heart diseases (IHD, 8 with an old myocardial infarction and 3 with angina), 10 with dilated cardiomyopathies (CM), 5 with congenital heart diseases (CHD), 2 with hypertensive heart diseases (HHD), 1 with left atrial myxoma and 1 with lone AF. Fifty patients with VHD included 27 rheumatic (22: mitral and 5: aortic) and 23 non-rheumatic valvular heart disease patients (10: mitral valve prolapse and 13: degenerative). The mean age (⫾SD) was 59 ⫾ 12 years and 27 females were included. We examined all patients by echocardiograms and chest X-rays. Furthermore, we interviewed the patients and determined the New York Heart Association (NYHA) functional classification. Forty-eight patients who were taking digitalis showed serum levels within the normal therapeutic range (1.4 ⫾ 0.2 ng/mL) and none had any clinical
evidence of toxicity. We used the first Holter ECG recording for our analysis among the series of recordings for each patient to avoid any influence due to other anti-arrhythmic drugs. We followed these patients for 2.6 ⫾ 1.5years on average (1.0⬃4.6 years) to observe the prognosis. ECG Recordings and the Principle of Plotting RR-interval Plottings Holter ECGs were recorded for 24 hours with portable tape recorders (model SM50, Fukuda Denshi, Japan) and the tapes were then played back with an automatic cardioscanner (model DMW9000H, Fukuda Denshi, Japan). The analysis was manually conducted to determine the different waveforms. We modified the scanner so that the RR-interval and waveform signals, which corresponded to the different waveforms, could be downloaded to a personal computer (NEC PCLC700J34DL, Nihon Denshi, Japan) and then stored the data on a disk for off-line analysis. From the stored data, we obtained an RR-interval plotting according to the previously described principle (12– 14). Briefly, regarding Fig 1, the first pair of RRintervals (R, R) between normal QRS complexes in panel A give the point labeled X1 in panel B. The point X1 is defined as the preceding point since it is the point just before the occurrence of a wide QRS complex. The next point X2 derived from the next pair of RR- intervals (R, S) is defined as a coupling point of the wide QRS complex since the RRinterval S is a coupling interval of the wide QRS complex. The next point from (S, L) shifts up to X3 in the X–Y plain and the point from (L, R) shifts down to X4 as well. Panel C shows an example of an RR-interval plotting of the sinus rhythm associated with VPCs. Panel D shows an example of an RR-interval plotting of AF. In AF, the RR-intervals were irregular and limited by the shortest RRintervals, and therefore, the dots fanned out along the X- and Y-axes. As previously reported, the curvilinear envelope of the normal AF distribution along the X- axis shown in Fig 1D (dotted line) reasonably represents the functional refractory period of the atrioventricular node, since the Y-value of the envelope indicates the shortest attainable RR-interval as a function of the preceding cycle length (12,13). Diagnosis of aberrant ventricular conduction and VPC on the RR-interval plotting A diagnosis of aberrant ventricular conductions and VPCs in AF has been also described in our
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Fig. 1. Principle of the RR-interval plotting. (A) An ECG of sinus rhythm with a VPC. (B) The schematic illustration of the principle. (C) An example of the RR-interval plotting of sinus rhythm with VPCs. (D) An example of AF. A dotted curve represents the refractory period of the AV node. A detailed explanation is given in the text.
previous study (12). Briefly, in reference to Fig 2, panel A shows the distribution of normal AF points and only the coupling points of wide QRS complexes. For purposes of simplicity, the points from (S, L) and (L, R) described in Fig 1B were not shown in the RR-interval plotting of AF. Panel B shows the curvilinear distribution of coupling points of aberrant conductions. On the other hand, in panel C, the coupling points of VPCs were linearly distributed without any relationship to the envelope along the X-axis of the normal AF points. Since aberrations occur when the refractory period of either bundle is longer than that of the atrioventricular node, the distribution of the coupling points of aberrant conductions in the RR-interval plotting overlaps with the curvilinear area between the refractory curve of the atrioventricular node (a dotted line in Fig 2D) and that of either blocked bundle branch (a solid line in Fig 2D). Generally,
the coupling points of the VPCs either show a linear distribution clearly below the envelope of AF or form a scattered band partially overlapping in the area of normal AF distribution according to the variability of the coupling intervals of VPCs. Using these different distributions of the coupling points, we can diagnose the wide QRS complexes in AF as either VPCs or as aberrant ventricular conductions. Upstream RR-interval Dynamics before VPCs Variability in the Coupling Points along the Y-axis (the first upstream RR-interval). As shown in the lower panel of Fig 3, we measured the variability of the coupling points along the Y-axis as twice the standard deviations of the mean Y-values of the coupling points (Yv), ie, the coupling interval of all VPCs for 24 hours. From the Yv value, we
Fig. 2. Differentiation of VPCs and aberrant conductions. (A) the RR-interval plotting of all normal AF points and coupling points of aberration and VPCs. The points of (B) and (C) are only the coupling points of the aberrant conductions and VPCs, respectively. (D) the principle of diagnosing aberrant conductions using RR-interval plotting.
210 Journal of Electrocardiology Vol. 37 No. 3 July 2004 Variability in the Coupling Points along the X-axis (the second upstream RR-interval). In the same way, we used twice the standard deviations of the mean X-values of the coupling points (Xv) as the index for the distribution of the coupling points along the X-axis. If the occurrence of VPCs is limited to the specific preceding RR-intervals, then the Xv must be smaller than the distribution of the normal AF points along the X-axis (Xa). We quantified the relationship of the occurrence of VPCs to the preceding RR-intervals as the ratio of the Xv to Xa, i.e., Xv/Xa (percentage). The small value of Xv/Xa means that the occurrence of VPCs is limited to the specific preceding RR-intervals. If the ratio of Xv/Xa was equal to or smaller than 74% (a mean value of Xv/Xa), we considered the occurrence of the VPCs to have close relationship to the preceding RR-intervals. Thirty-five satisfied the criterion (the related group) while 45 did not (the non-related group). Variability of the Preceding Points (the second and third upstream RR-intervals). Furthermore, we studied the preceding points of the VPCs to examine any variations of the second and third upstream RR-intervals before the occurrence of VPCs. The preceding points were plotted on a different plain from that of normal AF points in order to visually recognize the sequence between 2 RR-intervals of the preceding points. The plottings of the preceding points were obtained separately for different morphologies of VPCs in cases with multiform VPCs. Statistical Analysis
Fig. 3. Definitions of the coupling points, preceding points, and indices for the RR- interval dynamics. In an ECG of AF with a VPC (E3), the point from (N2, V3) is the coupling point and the point from (N1, N2) is the preceding point for the VPC. The upper plotting shows the points of normally conducted AF beats. Xa is twice the standard deviation of the mean X-value of these points. In the lower plot, the mean value (------) and twice the standard deviation (Yv) of the coupling intervals of the VPCs are shown. Xv is twice the standard deviation of the mean X-value of the coupling points. The relationship to the preceding RRinterval is represented by the ratio Xv to Xa, i.e., Xv/Xa (percentage, %).
The data were shown as the mean and ⫾SD. For a comparison of the mean values between the unmatched data of two groups, we used Student’s t-test. The equality of variance of each group was confirmed by the F-test. Comparisons between proportions were made by Fisher’s exact test. The time to the onset of the events was analyzed by means of the Kaplan- Meier survival curves. A P value of less than .05 was considered to be significant.
Results Typical Examples of RR-interval Plottings
divided the total of 80 AF patients with VPCs into 2 groups, ie, the fixed coupling group (Yv value ⫽ 0.2 or ⬍0.2 s, n ⫽ 43) and the variable coupling group (Yv value ⬎ 0.2 s, n ⫽ 37).
Figure 4 shows four typical examples of the RR-interval plottings of AF with VPCs which are classified based on the different variability of the
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Fig. 4. Different patterns of an RR-interval plotting of AF with VPCs. The 2 panels on the left (A) show the plottings without any relationship to the preceding RR-interval and 2 panels on the right (B) are examples of those with a preceding R-interval relationship. The upper plots in each panel show the normal AF points and lower plots indicate the coupling points of VPCs. The upper panels in both A and B show an example of the fixed coupling interval and the lower panels indicate the variable coupling interval. The details are described in the text.
coupling points along the X- and Y-axes. In each plotting, the normally conducted AF points and coupling points of VPCs are plotted separately in the upper and lower panels. The upper two plottings are examples of the imperceptible variability of the coupling points as seen by thin linear distributions of the coupling points. The lower two plottings show the most variable distributions. In the 2 cases on the left side of Fig 4, the distribution of the
coupling points along the X-axis approximately coincided with that of the normal AF points. Therefore, these VPCs had no specific relationship to the preceding RR-interval regarding the occurrence of VPCs. On the other hand, in 2 cases on the right side of Fig 4, the coupling points showed only a limited distribution along the X-axis compared to the normal AF distributions along the X-axis. Namely, the occurrence of VPCs in these cases
212 Journal of Electrocardiology Vol. 37 No. 3 July 2004 tended to be related to the preceding RR- intervals. The upper plotting in Fig 4B showed an example of two different coupling points corresponding to two different forms of VPCs. The distribution of VPCs with shorter coupling intervals (around 0.50 s) showed a wider distribution along the X-axis than that of longer coupling intervals (around 0.68 s). This means that the longer coupling VPCs tend to occur after the specific preceding RR-intervals. The VPCs in the lower panel showed a relationship to the shorter preceding RR-intervals from 0.4 to 0.96 s. Upstream RR-interval Dynamics before VPCs Variability of the Coupling Points along the Y-axis. One patient had both fixed and variable coupling VPCs, but the variable VPCs only rarely occurred, and therefore this case was included in the fixed group. The waveforms of the VPCs were monomorphic in the fixed coupling group, except for 4 patients. These 4 cases had the polymorphic VPCs with separately distributed different coupling points (the upper panel of Fig 4B). In the variable coupling group, 10 had monomorphic VPCs and 27 had polymorphic ones. We quantitatively analyzed the coupling points of the most frequent type of VPCs in the cases with polymorphic VPCs. The average Yv values were 0.27 ⫾ 0.23 s in all patients, 0.32 ⫾ 0.13 sec in the variable coupling group, and 0.16 ⫾ 0.04 sec in the fixed coupling group. Variability in the Coupling Points along the X-axis. The averages of Xv/Xa were 74 ⫾ 15% in all patients, 59 ⫾ 7% in the related group, and 85 ⫾ 10% in the non-related group. In the related group, roughly three types were observed, ie, 55% of the VPCs occurred at the shorter preceding RR-intervals of the normal AF distribution (Fig 4B, plot c in the lower panel), 20% at the intermediate RR-intervals (Fig 4B, plot a in the upper plotting), and 25% at from intermediate to longer RR-intervals (Fig 4B, plot b in the upper plotting). Variability of the Preceding Points. The upper panel of Fig 5 shows the points from all RRintervals of the normally conducted AF beats, and only the preceding points of VPCs were plotted on the lower panel. As shown in Fig 5, we obtained two different patterns of the preceding points, namely a partial type (panel A) and a diffuse type (panel B). In 29 of the 30 cases with the partial type, the preceding points deviated to the left side of the normal AF distribution as shown in Fig 5A. This means that the X- and Y-values of the preceding
points were relatively short and long, respectively. This sequence in the partial type was similar to that of the Ashman phenomenon which is known as a mechanism of aberrant conduction. Another pattern for the partial type was a gathered type in the area of short RR-intervals, but this was found in only 1 case (Figure not shown). On the other hand, the diffuse type of the preceding points was observed in 50 patients, and this meant that any combination of upstream 2 RR-intervals could induce the VPCs. In the diffuse type, 35 were variable coupling VPCs and 15 were fixed coupling ones, while the partial type included only 2 patients with variable coupling VPCs and 28 were fixed coupling VPCs. The variable coupling VPCs had a significantly higher association with the diffuse type than with the partial type, and the fixed coupling VPCs were significantly related to the partial type (P ⬍.001). Clinical Characteristics in Each Group The clinical characteristics of the patients in the 3 categories are presented in Table 1. There was no significant difference in relation to age and gender between the 2 groups in the 3 categories. Comparisons Between the Fixed and Variable Coupling Groups. The incidences of ischemic heart diseases and cardiomyopathy were significantly different between the fixed and the variable coupling groups (P ⬍.05). Comparisons Between the Related and Non-related Groups. Differences in the basal heart diseases were not significantly different between the related and the non-related groups. Comparisons Between the Partial and Diffuse Groups. The diffuse type (n ⫽ 50, 63%) was more frequently found than the partial type (n ⫽ 30, 37%) in the AF population (P ⬍.01). In addition, cardiomyopathy was more dominant in the diffuse type than in the partial type (P ⬍.01). Cardiac Function of Each Group We compared the echocardiographic indices, CTR, and NYHA functional classification in two groups of the 3 categories aforementioned, as well. Comparisons Between the Fixed and Variable Coupling Groups. As shown in Table 2, the mean values of the left ventricular diastolic diameters (LVDDs, P ⬍.05) and the systolic diameters (LVDSs, P ⬍.01) were significantly greater in the
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Fig. 5. Two types of plottings of the preceding points. The upper panels only show the plots for the normal AF beats. The lower plots show the preceding points. (A) The partial type of the plottings of the preceding points where the preceding points of the VPCs deviated to the left side of the normal AF distribution. (B) The diffuse type of the plottings of the preceding points where the preceding points in the diffuse type are scattered in the normal AF area.
variable group than in the fixed group. The average ejection fraction (EF) significantly decreased (P ⬍.05) in the variable group in comparison to the fixed group. The mean CTR was also larger in the variable group than in the fixed group (P ⬍.0001).
The NYHA functional class was significantly higher (P ⬍.001) in the variable group than in the fixed group. The differences in the left atrial dimension (LAD) and the left ventricular wall thickness (IVST, PWT) were not significant between the 2 groups.
Table 1. Clinical Characteristics of the Different VPC Groups Coupling Point Coupling Interval
Patient number Female sex, n Mean Age (y) Basal heart disease VHD IHD CM CHD HHD LA myxoma None
Preceding Interval
Preceding Point
Fixed
Variable
Related
Non-related
Partial
Diffuse
43 17 61 ⫾ 12
37 10 57 ⫾ 10
35 11 59 ⫾ 12
45 16 59 ⫾ 11
30 12 60 ⫾ 12
50† 15 61 ⫾ 12
25 10 1 3 2 1 1
25 1* 9* 2 0 0 0
25 3 4 1 0 1 1
25 8 6 4 2 0 0
24 3 0 1 0 1 1
26 8 10† 4 2 0 0
VHD, valvular heart disease; IHD, ischemic heart disease; CM, cardiomyopathy; HHD, hypertensive heart disease; CHD, congenital heart disease; LA Myxoma, left atrial myxoma. *P ⬍ .05, †P ⬍ .01
214 Journal of Electrocardiology Vol. 37 No. 3 July 2004 Table 2. Echo Cardiographic Indices, CTR, and NYHA Class in the Different VPC Groups Coupling point Coupling Interval
Echocardiogram LVDD (mm) LVDS EF (%) LAD IVST PWT CTR (%) NYHA I II III IV
Preceding Interval
Preceding Point
Fixed
Variable
Related
Non-related
Partial
Diffuse
54 ⫾ 10 39 ⫾ 9 62 ⫾ 14 48 ⫾ 17 11 ⫾ 2 11 ⫾ 2 58 ⫾ 6
78 ⫾ 11* 44 ⫾ 12† 54 ⫾ 19* 52 ⫾ 12 11 ⫾ 4 12 ⫾ 4 65 ⫾ 8‡
57 ⫾ 11 51 ⫾ 16 60 ⫾ 19 60 ⫾ 19 10 ⫾ 2 11 ⫾ 2 64 ⫾ 9
55 ⫾ 10 49 ⫾ 14 57 ⫾ 16 57 ⫾ 16 12 ⫾ 3 12 ⫾ 3 60 ⫾ 6
55 ⫾ 13 32 ⫾ 14 66 ⫾ 17 45 ⫾ 12 12 ⫾ 2 11 ⫾ 3 60 ⫾ 6
74 ⫾ 14* 48 ⫾ 15† 51 ⫾ 18* 50 ⫾ 16 11 ⫾ 3 12 ⫾ 3 65 ⫾ 8
1 (2.3) 34 (79.0) 8 (18.6) 0
0 6 (16.2) 29 (78.4) 2 (5.4)
1 (2.9) 16 (45.7) 17 (48.6) 1 (2.9)
0 24 (53.3) 20 (44.4) 1 (2.2)
1 (3.3) 26 (86.7) 3 (10) 0
0 14 (28.0) 34 (68.0) 2 (4.0)
LVDD: left ventricular end-diastolic diameter, LVDS: left ventricular end-systolic diameter, LAD: left atrial diameter, EF: ejection fraction, IVST: interventricular septal thickness, PWT: posterior wall thickness, CTR: cardiothoracic ratio, NYHA: New York Heart Association functional classification. Values are the mean ⫾ SD or n (%). *P ⬍.05, †P ⬍ .01. ‡P ⬍ .0001.
Comparisons Between the Related and Non-related Groups. No echocardiographic index, CTR and NYHA functional classification were significantly different between the 2 groups. Comparisons Between the Partial and Diffuse Groups. Similar differences between the fixed and variable groups were observed in these two groups. The mean values of the LVDDs (P ⬍.05) and the LVDSs (P ⬍.01) were significantly greater in the diffuse group than in the partial group. The ejection fraction was significantly lower in the diffuse group than in the partial group (P ⬍.05). The CTR tended to be greater in the diffuse group than in the partial group, but the difference was not statistically significant. The NYHA functional classification was significantly higher in the diffuse group than in the partial group (P ⬍.001).
The Kaplan-Meier estimates of the probability of the remaining free of events are shown in Fig 6. The cardiac events significantly increased in both the variable coupling group (P ⬍.03) and in the diffuse group (p ⬍0.05). The basic heart diseases of the patients with these events were CM (4 patients, 40% of CM), IHD (2 patients, 18% of IHD), VHD (6 patients, 12% of VHD), and CHD (1 patient, 20% of CHD).
Discussion In our previous study, we established the criteria for making a different diagnosis of aberrant conduction and VPC in AF. In this study, we analyzed the AF patients with VPCs to confirm the clinical usefulness of this method.
Prognosis of Each Group Fixed and Variable Coupling During the 2.6 ⫾ 1.5 year long follow-up period, 10 events (27%) occurred in the variable coupling group, while only 3 events (7%) were observed in the fixed coupling group. The ten events in the variable group included 3 sudden cardiac deaths, 5 episodes of sustained ventricular tachycardia, and 2 episodes of congestive heart failure (CHF). Among the 3 events in the fixed group, 1 episode was sustained VT and 2 episodes were CHF. Between the 2 groups of the preceding points, there were cardiac events of 11 (22%) in the diffuse group and 2 (7%) in the partial group. The eleven events in the diffuse group included 3 sudden cardiac deaths, 6 episodes of sustained VT, and 2 episodes of CHF.
Anan et al. previously described the variable patterns of VPCs with sinus rhythm using RRinterval plotting (14); ie, the fixed coupling intervals of VPCs demonstrated a narrow distribution parallel to the X-axis and the variable coupling intervals showed a vertical distribution between the shortest coupling interval of ventricular refractoriness and the longest coupling interval of the basic sinus rhythm. Our study clarified that VPCs with AF also had variable patterns in the coupling intervals as seen in the previous study in sinus rhythm. We defined the fixed coupling as less than a 0.2 s variation in the coupling intervals through 24
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The cardiac function was worse in the variable coupling group than in the fixed one. Ino-Oka et al. reported a similar result to ours in the VPC-patients with sinus rhythm (17). This might suggest that the substrates for the multiple re-entry circuits and the various conduction delays existing in the impaired hearts could result in the variable coupling intervals. However, Surawicz and MacDonald reported that the patients with VPCs of variable coupling intervals were not necessarily associated with organic heart diseases (15). There are still conflicting reports regarding the relationship between the cardiac function and the variability of coupling intervals of VPCs. Preceding Heart Rate Relationship In sinus rhythm, some VPCs often occur only in sinus tachycardia or bradycardia. We could also observe that some cases showed a weak relationship with the preceding RR- interval in the occurrence of VPCs. However, the RR-intervals before the occurrence of VPCs were irregular in AF, and therefore, it was difficult to determine the effect of stable and constant preceding RR-intervals on the occurrence of VPCs. This might be one of the reasons why there was no significant difference in the clinical features between the related and nonrelated groups. Fig. 6. The event free ratios in the 2 groups of the coupling points and preceding points. The Kaplan-Meier estimates of the probability of the patients remaining free of any events such as sustained ventricular tachycardia, sudden cardiac death, and CHF. The variable group and the diffuse group were found to more likely develop these events.
hours. This value was longer than those of earlier studies in sinus rhythm (15,16). They arbitrarily determined the coupling intervals of fixed coupling VPCs to be less than 0.08⬇0.12 s. Differences in the basic cardiac rhythms, the analyzed periods and the analyzed number of VPCs between the earlier studies and ours might have influenced the criteria of variability of coupling intervals, since the more the basic cycle length changed in the longer recording period, the more the coupling intervals varied. Furthermore, the RR- intervals in AF changed more even during short periods than those in sinus rhythm, and this increased the variability of the coupling intervals of VPCs. For these reasons, our relatively longer criterion for the fixed coupling than that used in previous studies seemed to be appropriate for our purposes.
Variability of the Preceding Points Gomes et al. emphasized that the short-long sequence of RR-intervals produced a dispersion of the refractoriness in arrhythmic substrates and resulted to initiate the complex ventricular arrhythmia (18). Furthermore, they pointed out that the dispersion of the refractory period induced by the “Ashman sequence” also plays an important role in the induction of VT in the sinus rhythm. This sequence is originally known as the mechanism of induction of aberrant conductions. The preceding points of the partial group demonstrated the “Ashman sequence” before the occurrence of VPCs. This sequential change of RR-intervals is also known to induce ‘torsades de pointes’ in familiar long QT syndrome (19). In AF, the RR- intervals and the RR-interval sequences are both irregular. Consequently the dispersion of the refractory period might increase more dramatically in AF than in the sinus rhythm. In our 175 patients with AF, frequent ventricular arrhythmias occurred in 80 patients (45.7%). The incidence of ventricular arrhythmias in our study population was substantially higher
216 Journal of Electrocardiology Vol. 37 No. 3 July 2004 than that in the study subjects with an ordinary sinus rhythm (6 –9,20). First, this might be derived from the circumstances that all of our AF patients except one had from moderate to severe underlying heart diseases. Second, AF itself might induce VPCs more easily than sinus rhythm due to the dispersion of the refractoriness induced by its irregular pulses. In the maintained cardiac function, the electrical dispersion of ventricular refractoriness could thus be primarily induced by the preceding RR-sequence of a short-long cycle (the partial type). On the other hand, in an impaired heart, there might be many other electrical instabilities and anatomical substrates than the Ashman sequence, which is known to be an important factor to induce VPCs in the maintained cardiac function. Therefore, the shortlong preceding RR- sequence was not necessarily observed before the occurrence of VPCs in patients with an impaired cardiac function. However, further study is needed before any definitive conclusions can be made. Various VPCs and Prognosis Arrhythmia related deaths and impaired cardiac function were associated more significantly with the VPCs showing the variable coupling intervals and/or the diffuse plotting patterns of the preceding points than in those with the fixed coupling intervals and/or the partial patterns of the preceding points. Furthermore, the preponderance of the dilated cardiomyopathy in the variable coupling and the diffuse groups might be related to the higher occurrences of the cardiac episodes in both groups. However, in order to develop a prognostic index, we need not only to analyze many other factors such as the addition of any antiarrhythmic drugs, AF rates, estimated functional refractory periods of the AV node, the occurrence of nonsustained VT and the density of PVCs, but also to accumulate more cases. Since the aim of this study was primarily to distinguish the different types of VPCs even in AF and then to clarify the influence of the RRinterval dynamics in AF on the occurrence of VPCs, such a prognostic study is also planned as part of our future research.
Limitation We studied the characteristics of VPCs in AF using RR-interval plotting and investigated the relationship between different types of VPCs and the clinical characteristics. There were, however, some
limitations in our study. Firstly, an automatic diagnosis of arrhythmia in the RR-interval plotting is arbitrary, however, we have yet to find an optimal method to perform this more accurately. We will continue to try to develop a more accurate method. Secondly, we could not distill the parasystole from the VPCs with variable coupling by RR-interval plotting as we could do for the sinus rhythm (14). More basic electrophysiological studies are thus called for confirming the mechanisms of arrhythmias. Finally, we need to accumulate more cases to better identify the precise relationship between the different characteristics of VPCs and the clinical features.
Conclusion In line with the findings of our previous study on the sinus rhythm (14), we classified various types of VPCs in AF using RR-interval plottings. This method clarified that the occurrence of VPCs was related to the RR-interval dynamics of AF. This irregularity of the RR-intervals might be a critical factor in the induction of malignant ventricular arrhythmia in AF. Furthermore, the different types of VPCs were related to the different clinical characteristics and prognoses of the patients. It is therefore important to elucidate the detailed mechanisms regarding ventricular arrhythmias in AFpatients and also establish an optimal treatment regimen. To achieve this goal, the RR-interval plotting method is considered to be a clinically useful tool.
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Appendix Yv ⫽ 2 ⫻ SDy SDy ⫽
冑冘共y ⫺ y¯ 兲
2
i
⫻ fny/ny
yi ⫽ y-values of all coupling points, y : the mean value of yi, fny: frequency, ny: total number of yi Xv ⫽ 2 ⫻ SDx SDx ⫽
冑冘共x ⫺ x¯ 兲
2
i
⫻ fnx/nx
xi ⫽ x-values of all coupling points, x : the mean value of xi, fnx: frequency, nx: total number of xi Xa ⫽ 2 ⫻ SDxa SDxa ⫽
冑冘共x
ai
⫺ x¯ a兲2 ⫻ fnxa/nxa
xai ⫽ x-values of all AF points, x a: the mean value of xai, fnxa: frequency, nxa: total number of xai