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Ventricular gradient variability
Journal of Electrocardiology Vol. 28 No. 3 1995
Ventricular Gradient Variability N e w ECG M e t h o d for Detection of Ischemic Heart Disease
Shigeo Horinaka, Masanori
MD, Hideo Yamamoto, Takada, MD, Tomoyuki
Masafumi
Onoda,
MD, Teizou Tabuchi, MD, Akabane,
MD, and Shigeru
MD,
Yagi, M D
Abstract: The usefulness of ventricular gradient variability for detecting the
presence of ischemic heart disease was evaluated in 38 patients with coronary artery disease (group 1), 21 patients with chest pain and no coronary artery disease (group 2), and 33 healthy control subjects. The ventricular gradient of each consecutive heartbeat at rest over a 22-second interval was calculated using a microcomputer. The SD and coefficient of variation for azimuth, elevation, and magnitude were used as indices of ventricular gradient variability. The SD and coefficient of variation of both the magnitude and elevation of ventricular gradient in group 1 were significantly greater than those of the other two groups (P < .01, respectively). When the normal upper limit was defined as 2SD above the mean value in the control group, a comparison between the findings for group 1 and group 2 revealed that the coefficient of variation of magnitude of the ventricular gradient was the most sensitive (82%) and specific (91%) index for coronary artery disease (chi-square test, P < .001). This study suggests that the variability in the magnitude of the ventricular gradient is a reliable index of ischemic heart disease. K e y words: ischemic heart disease, X, Y, Z scalar electrocardiograms, ventricular gradient variability.
Exercise electrocardiography, exercise echocardiography, and the nuclear medicine test h a v e b e e n reported as simple, safe, and noninvasive techniques useful for the diagnosis of ischemic heart disease. I-4 Alternans of the ST-segment h a v e b e e n reported in
acute myocardial ischemia, including patients with variant angina, 5,6 and during percutaneous translum i n a l coronary angioplasty. 7,8 Recently, we studied b e a t - t o - b e a t variability of the spatial QRST angle of consecutive heartbeats m e a s u r e d in Frank lead X, Y, Z scalar electrocardiograms (ECGs) recorded at rest f r o m patients with ischemic heart disease. Variability of the spatial QRST angle in patients with effort angina pectoris was higher t h a n in healthy subjects, and variability in the T vector was greater t h a n that in the QRS vector. Sensitivity of this index for ischemic heart disease, however, was
From the Department of Medicine, Division of Hypertension and Cardio-renal Disease, Dokkyo University School of Medicine, Mibu, Tochigi, Japan. Reprint requests: Shigeo Horinaka, MD, Department of Medicine, Division of Hypertension and Cardio-renal Disease, Dokkyo University School of Medicine, 880 Kitakobayashi, Mibu, Tochigi, 321-02, Japan.
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low (Horinaka S, unpublished data). Theoretically, the ventricular gradient, first described by Wilson et al., 9 is determined by the local excitability of the ventricular myocardium, particularly by differences in the local variations in the duration of the excited state. Thus, the ventricular gradient does not seem to be dependent on the ventricular excitatory process. 1° Ashman et al. 1M4 extensively reviewed the ventricular gradient concept. The ventricular gradient is a vector with magnitude, azimuth, and elevation obtained by addition of the QRS and T vectors. 9,~s It can be determined for the frontal plane alone or for a three-dimensional space, le As an expression of the time course of ventricular repolarization, the ventricular gradient quantitatively determines whether ST-T abnormalities are secondary (abnormalities in ventricular depolarization) or primary (independent of ventricular depolarization). That is, ST-T abnormalities reflect secondary as well as primary changes, but the ventricular gradient is only affected by primary changes. It may identity repolarization abnormalities even wh en the ST-T complex is normal. This study was performed to determine w h e t h e r patients with ischemic heart disease have greater beat-to-beat variability in the ventricular gradient than normal subjects.
Materials and Methods Patient Selection The subjects of this study were 59 patients and 33 healthy volunteers (control group) referred to Dokkyo University Hospital between April 1991 and March 1993. All patients presented with angina-like pain that was evaluated by cardiologists. Patients with ST-segment shift greater than 0.5 mm in 12-lead standard ECGs recorded at rest that were suggestive of myocardial ischemia were excluded from this study. Patients with cardiomyopathy, valvular heart disease, hypertension, myocardial infarction, or arrhythmia were also excluded from the study. Based on coronary angiographic results, patients were categorized into either the coronary artery disease (group 1) or the no coronary artery disease (group 2) group. Patients in group 1 exhibited at least 75% organic stenosis of a major coronary artery on coronary angiography after intracoronary injection of a nitrate drug. Group 1 was composed of 38 patients (29 men and 9 women; mean age, 54 + 9 years), including 23 patients with single-vessel disease and 15 patients with multiple-vessel disease. Group 2 comprised 21 patients (11 men and
10 women; mean age, 48 + 12 years) in w h o m no significant organic stenosis of the coronary artery was observed, and for w hom the acetylcholineloading test produced negative results. Acetylcholine chloride (Daiichi Seiyaku, Tokyo, Japan) was dissolved in 5 mL 0.9% saline in incremental doses of 25, 50, and 100 ~tg and injected into the left coronary" artery. Left coronary angiographic examination was perlormed w h e n ST-segment changes and/or chest pain occurred, or 1 to 3 minutes after each injection. Acetylcholine in incremental doses of 25 and 50 ~tg was injected into the right coronary artery and a right coronary arteriogram was performed in the m anner described above. If coronary spasm was not induced by these procedures, the acetylcholine-ioading test was defined as negative. 17'Is Twenty-seven patients in group 1 had histories consistent with typical chest pain that was accepted as a symptom of angina pectoris and 11 patients had histories of atypical chest pain. In contrast, 17 patients in group 2 had histories of atypical chest pain and only 4 patients had histories ot typical chest pain. Atypical chest pain was defined as chest pain that was either unresponsive to nitroglycerin or atypical for angina in terms of location, duration, quality, and relation to exertion or emotion, or both. 19 Nine patients in group 1 and five patients in group 2 had nonspecific ST-segment or minor T wave abnormalities at rest. The healthy control group consisted of 33 subjects (22 m en and 11 women; mean age, 55 + 11 years) with normal physical examinations, chest radiographs, and ECGs.
Analysis of Alteration of Ventricular Gradient After a 24-hour medication wash-out period, Frank lead X, Y, Z scalar ECGs were recorded with the patients at rest in the supine position without chest pain. The ECGs were recorded for 10 minutes with a data recorder (Sony FC-14, Tokyo, Japan) using a vectorcardiograph (Fukuda Denshi VC-3G, Tokyo, Japan). The samples were inputted to a microcomputer (NEC PC-9801 BA, Tokyo, Japan) via an A/D transducer at a rate of 1,000 samples per second over a 22-second period, reflecting the limit ot the computer memory. The trigger voltage was one quarter of the reference QRS complex value, and the correlation of ten different points before and after the trigger point for each beat to those of the other beats was calculated. Beats with a correlation coefficient less than .990 were excluded. The first derivative waveform was computed from the
Ventricular Gradient Variability • magnitude of the instantaneous spatial vector produced from the averaged X, Y, Z scalar ECGs for a 22-second period, which was displayed on the c o m p u t e r monitor. The time at which the first derivative of the QRS wave exceeded a threshold set to twice the noise level in the PQ-segments was defined as the starting point of the QRS complex (0 level). The endpoint of the T wave was also defined as the point arriving at the 0 level of the first derivative of the T wave in the TP-segments. The QRS complex, ST-segment, and T wave integrals were used to calculate the ventricular gradient for each heartbeat as previously described. ~5 The magnitude, azimuth, and elevation of the ventricular gradient were obtained, and the m e a n and SD of these values for all heartbeats in the 22-second interval were determined. The SD and coefficient of variation (SD/mean x 100) 2°,21 of these three measurements were used as indices of beat-to-beat ventricular gradient variability. The n o r m a l range of the SD and coefficient of variation of magnitude, azimuth, and elevation of the ventricular gradient was defined as m e a n _+2SD of the respective values in the control group. Any value that deviated from this range was considered abnormal. The m e a n heart rate was 65 beats/rain in the control group, 64 beats/min in group 1, and 69 beats/min in group 2, indicating no significant difference among the three groups during the m e a s u r e m e n t s of the ventricular gradient.
Changes in the R-R Interval Changes in heart rate were expressed as the SD of the R-R intervals.
Control
Ventricular Gradient M a g n i t u d e = 77.80=1=3.24 u V s e c Azimuth Elevation
= -9.15+3.00 ° = 48.20~=2.77 °
Horinaka et al.
179
Reproducibility Analysis Reproducibility of the values of the ventricular gradient was evaluated by comparing two sets of data recorded 10 minutes apart from 10 subjects in each group.
Statistical Analysis All calculated data are expressed as m e a n 4- SD. O n e - w a y analysis of variance followed by Tukey's analysis was performed to determine the statistical significance of differences a m o n g the three groups of subjects. The chi-square test was used for comparison of discrete variables. The correlation coefficient was calculated for paired data. Statistical significance was accepted at the 95% confidence level.
Results Alteration of Ventricular Gradients The ventricular gradients of the QRST complexes recorded from one control subject and one patient with coronary artery disease are s h o w n in Figure 1. During the 22-second recording period, the SD of azimuth, elevation, and magnitude of the ventricular gradient were greater in the patient with coronary artery disease t h a n in the control subject (Table 1). The SD of the azimuth, elevation, and magnitude of the ventricular gradient were significantly greater in group 1 t h a n in group 2 or the healthy control group (Y < .01); there was no significant difference b e t w e e n the SD of the latter two
CoronaryArtery Disease
Ventricular Gradient M a g n i t u d e = 62.44~=6.80 ]uVsec Azimuth = -5.26=~4.39 ° Elevation = 46.84±4.76 °
Fig. 1. Superimposed ventricular gradients of each heartbeat in the 22-second interval in one control subject and one patient with coronary artery disease.
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g r o u p s . The c o e t f i c i e n t ol v a r i a t i o n of t h e e l e v a t i o n and magnitude were significantly greater in group 1 t h a n i n g r o u p 2 or t h e h e a l t h y c o n t r o l g r o u p (P < . 0 I , r e s p e c t i v e l y ) . No s i g n i f i c a n t d i f f e r e n c e s in t h e c o e f f i c i e n t of v a r i a t i o n of t h e a z i m u t h e x i s t e d among the three groups.
R-R Interval Variability T h e SD of t h e R-R i n t e r v a l s w a s 33 + 10 m s in t h e c o n t r o l g r o u p , 22 + 17 m s in g r o u p 1, a n d 22 + 9 m s i n g r o u p 2. T h e SD of t h e R - R i n t e r v a l in t h e control group was significantly greater than those in g r o u p s 1 a n d 2 (P < .05).
Sensitivity and Specificity Reproducibility The d a t a in g r o u p s 1 a n d 2 w e r e c o m p a r e d w i t h c o n t r o l g r o u p d a t a to d e t e r m i n e t h e s e n s i t i v i t y a n d specificity of e a c h i n d e x for c o r o n a r y a r t e r y disease. The coefficient of v a r i a t i o n of t h e m a g n i t u d e of t h e v e n t r i c u l a r g r a d i e n t w a s f o u n d to b e t h e b e s t i n d e x , as s h o w n in F i g u r e 2. I n 31 of t h e 38 p a t i e n t s i n g r o u p i, this i n d e x w a s h i g h e r t h a n t h e u p p e r l i m i t ( 7 . 3 3 % ) in t h e c o n t r o l g r o u p ; t h u s , t h e s e n s i t i v i t y w a s 8 2 % . I n 19 of t h e 21 p a t i e n t s in g r o u p 2, it w a s w i t h i n t h e n o r m a l r a n g e ; t h e specificity w a s 9 1 % ( c h i - s q u a r e test, P < .001).
Comparison in the Coefficient of Variation of the Magnitude of the Ventricular Gradient Between Typical and Atypical Chest Pain in Group 1 T h e coefficient of v a r i a t i o n of t h e m a g n i t u d e of t h e v e n t r i c u l a r g r a d i e n t in 23 of t h e 27 p a t i e n t s ( 8 5 % ) w i t h t y p i c a l c h e s t p a i n a n d in 8 of t h e 1 1 patients (73%) with atypical chest pain was higher t h a n t h e u p p e r l i m i t of n o r m a l r a n g e . No significant difference was found between typical and atypical c h e s t p a i n g r o u p s ( c h i - s q u a r e test).
There was a significant correlation between pairs of m e a s u r e m e n t s of t h e coefficient of v a r i a t i o n of t h e m a g n i t u d e of t h e v e n t r i c u l a r g r a d i e n t i n r e c o r d i n g s o b t a i n e d 10 m i n u t e s a p a r t in 10 s u b j e c t s in e a c h g r o u p (r = .94, P < .001).
Discussion The v e n t r i c u l a r g r a d i e n t h a s r a r e l y b e e n u s e d clinically b e c a u s e of difficulty i n m e a s u r i n g it a c c u r a t e l y a n d t h e b r o a d r a n g e of n o r m a l v a l u e s , h o w ever, a d v a n c e s i n c o m p u t e r t e c h n o l o g y h a v e enabled more accurate and simpler measurement. T h e v e n t r i c u l a r g r a d i e n t , w h i c h w a s first d e s c r i b e d b y W i l s o n et al., 9 reflects n o n u n i f o r m i t y in ventricular action potential durations. A u t e n r i e t h et al. 22 l a t e r d e m o n s t r a t e d t h a t t h e v e n t r i c u l a r g r a d i e n t w a s r e l a t e d to r e g i o n a l d i f f e r e n c e s in monophasic action potential durations. T h e o r e t i c a l a n d clinical r e p o r t s h a v e d o c u m e n t e d t h a t t h e v e n t r i c u l a r g r a d i e n t is i n d e p e n d e n t of t h e a c t i v a t i o n sequence./°'23
Table 1. M e a n Value, SD, and Coefficient of Variation of Azimuth, Elevation, and M a g n i t u d e of the Ventricular Gradient in the Three Study Groups Healthy Control Subjects (n = 33) Mean Azimuth (degrees) Elevation (degrees) Magnitude (btVs) SD Azimuth (degrees) ' Elevation (degrees) Magnitude (btVs) CV Azimuth (%) Elevation (%) Magnitude (%)
-18.56 _+ I9.32 54.88 ± 9.23 I09.23 ± 25.06
Patients in Group 1 (n = 38) -23.21 ± 39.03 59.90 _+ 19.43 73.6I ± 30.61"].
Patients in Group 2 (n = 21) -16.84 ± 13.35 52.95 _+8.66 97.20 _+29.61
3.60 _+ 1.42 2.80 ± 0.98 5.70 ± 1.25
6.84 ± 4.48*-{ 5.61 ± 2.91" t 7.16 ± 2.26*]-
3.52 _+ 1.40 3.10 ± 0.83 5.6I _+ 1.16
24.80 ± 35.11 4.98 ± 2.21 5.13 ± 1.10
39.58 ± 48.07 9.86 ± 5.06*]10.94 ± 4.97*]-
40.28 ± 54.78 6.04 k 2.18 (1.00 ± 1.15
The data are presented as mean + SD. Group 1, coronary artery disease; group 2, no coronary artery disease; mean, mean value of all the original values; SD, standard deviation of all the original values; CV, coefficient of variation (SD/mean × 100). *P < .01 vs control group. ].P < .01 vs group 2.
Ventricular Gradient Variability •
(%)
30]
Horinakaet al
181
in group l cannot be explained by R-R interval variability.
Myocardial Ischemia at Rest
~mean _+SD 25• 0
20-
E
"I
15-
Z
0 >
o
10 •
• 00@ •
Control
.!|}!i[ .|.T
QO
~
Group 1
00
Group 2
Fig. 2. Distribution of the coefficients of variation of the magnitude of the ventricular gradient in patients with coronary artery disease, no coronary artery disease, and in normal subjects. *P < .01 vs control group, tP < .0I vs group 2. CV, coefficient of variation; group I, coronary artery disease; group 2, no coronary artery disease.
To our knowledge, studies of the beat-to-beat variability in the ventricular gradient h a v e not b e e n previously reported. Myocardial ischemia is a wellk n o w n cause of changes in the ventricular gradient, but other factors can also affect the action potential in each area of the ventride. In healthy individuals, changes in the ventricular gradient can result from complex effects of changes in the R-R interval, a u t o n o m i c nervous functions, respiration, and electrolyte balance. 24 Changes in the R-R intervals might have a m a r k e d effect on the beat-to-beat variability in the ventricular gradient. Changes in the R-R interval in patients with ischemic heart disease, however, are less p r o n o u n c e d t h a n those in n o r m a l individuals. 25,26 Our results support this finding. The changes in the R-R intervals in g r o u p 1 were smaller t h a n those in the control group. Therefore, the high coefficient of variation of the magnitude of the ventricular gradient found
It has been reported that impaired left ventricular diastolic function and regional diastolic async h r o n y are evident at rest in m a n y patients with coronary artery disease in the absence of regional systolic wall m o t i o n abnormalities or previous myocardial infarctions. 27'2s Moreover, B o n o w et al. 29,~° demonstrated that regional diastolic abnormalities at rest improved after successful percutaneous transluminal coronary angioplasty. These observations m a y support the existence of myocardial ischemia in patients with coronary artery stenosis at rest. The American Heart Association Committee Report 31 defined 80% reduction of vessel diameter as significant on the basis of a study& Other investigators n o t e d that sequential arterial stenosis and longer lesions also resulted in reduced blood flow. 33'34This study revealed that 30 of the 38 patients in group 1 had a 9 1 - 9 9 % reduction in the diameter of the angina-related coronary artery, and the remaining 8 patients had a 7 5 - 9 0 % reduction. It is likely that patients in group 1 also had myocardial ischemia at rest, because the severity of their c o r o n a r y stenosis was c o m p a r a b l e to that of patients in other reports.
Ventricular Gradient in Myocardial Ischemia In an in situ experiment by Drily and Lab 35 using a porcine heart, alternans in the monophasic action potential duration in ischemic areas occurred spontaneously. Clinically, it is possible that the a k e m a n s in action potential duration in certain ischemic states of the m y o c a r d i u m m a y affect the ventricular gradient, even at rest, w h e n there is severe coronary artery stenosis. In other words, the high coefficient of variation of the m a g n i t u d e of the ventricular gradient m a y be caused by certain ischemic states of the ventricular m y o c a r d i u m at rest. Instability of the repolarization phase of action potentials due to ischemia is a possible mechanism, although a causal relation is difficult to prove from body surface ECG recordings.
Body Surface ECG in Myocardial Ischemia ST-segment changes on 12-1ead ECG have been suggested to be an index of myocardial ischemia. 36
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Journal of Electrocardiology Vol. 28 No. 3 July 1995
Khuri et a l . , 37 however, experimentally d e m o n strated ST-segment change appearing first in the inner layer of the ventricular m y o c a r d i u m with a coronary constriction, a l t h o u g h epicardial and body surface ECGs did not change. Watanabe et al. reported similar results. 38 The discrepancy in STsegment change b e t w e e n inner layer and b o d y surface ECGs m a y reflect an inability of the b o d y surface electrode to detect ischemic changes in some regions of the ventricular m y o c a r d i u m .
ischemia or the location of the ischemic lesion. F u r t h e r studies are necessary to elucidate the effects ot collateral circulation in the coronary artery on the ventricular gradient. In addition, studies are n e e d e d on patients w i t h (1) ST-segment shifts greater t h a n 0.5 m m in 12-lead ECGs at rest, (2) a b n o r m a l intraventricular conduction disturbances, and (3) other forms of h e a r t disease.
Conclusion QRS and ST-T Integrals We also calculated the coefficients of variation of the m a g n i t u d e of the ST-T integrals that reflect the repolarization phase of action potentials a n d of the QRS integrals in each group. The coefficient of variation of the m a g n i t u d e of the ST-T integral in group 1 (i4.27 + 9.47%) was significantly greater t h a n those of the control group (7.44 _+ 3.19%) and group 2 (7.41 + 2.44%) (P < .01). In contrast, there w e r e no significant differences a m o n g the QRS integrals of the three groups. The sensitivity and specificity of the coefficient of variation of the magnitude of the ST-T integrals in group 1 w e r e 4 0 % and 95%, respectively. A possible explanation of this low sensitivity is that the ST-T integral is d e p e n d e n t on the ventricular excitatory process (secondary change), as well as on variations in the action p o t e n t i a l d u r a t i o n ( p r i m a r y change), w h e r e a s the ventricular gradient is only d e p e n d e n t on the p r i m a r y change.
Other Findings In this study, the m a g n i t u d e of the ventricular gradient itself was significantly smaller in group 1 t h a n in the control group (Table 1). Only the patients with values 2SD b e l o w the m e a n are considered to h a v e a b n o r m a l values, and the sensitivity of this index was 29% (11 of 38 patients). Moreover, no significant differences in elevation or a z i m u t h existed b e t w e e n the two groups. These results indicate that diagnoses using values obtained f r o m the ventricular gradient are not reliable.
Study Limitations C a n n o n et al. 39'4° d e m o n s t r a t e d that small-vessel disease might be present in some patients with normal angiographic findings. We could not, however, evaluate these patients in this study, w h i c h considered coronary stenosis, but not the severity of
This study suggests that the coefficient of variation of the m a g n i t u d e of the ventricular gradient is a useful index for the diagnosis of ischemic heart disease. This index should be helpful in analyzing exercise test results as well as responses to treatment.
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Ventricular Gradient Variability N e w ECG M e t h o d for Detection of Ischemic Heart Disease
Shigeo Horinaka, Masanori
MD, Hideo Yamamoto, Takada, MD, Tomoyuki
Masafumi
Onoda,
MD, Teizou Tabuchi, MD, Akabane,
MD, and Shigeru
MD,
Yagi, M D
Abstract: The usefulness of ventricular gradient variability for detecting the
presence of ischemic heart disease was evaluated in 38 patients with coronary artery disease (group 1), 21 patients with chest pain and no coronary artery disease (group 2), and 33 healthy control subjects. The ventricular gradient of each consecutive heartbeat at rest over a 22-second interval was calculated using a microcomputer. The SD and coefficient of variation for azimuth, elevation, and magnitude were used as indices of ventricular gradient variability. The SD and coefficient of variation of both the magnitude and elevation of ventricular gradient in group 1 were significantly greater than those of the other two groups (P < .01, respectively). When the normal upper limit was defined as 2SD above the mean value in the control group, a comparison between the findings for group 1 and group 2 revealed that the coefficient of variation of magnitude of the ventricular gradient was the most sensitive (82%) and specific (91%) index for coronary artery disease (chi-square test, P < .001). This study suggests that the variability in the magnitude of the ventricular gradient is a reliable index of ischemic heart disease. K e y words: ischemic heart disease, X, Y, Z scalar electrocardiograms, ventricular gradient variability.
Exercise electrocardiography, exercise echocardiography, and the nuclear medicine test h a v e b e e n reported as simple, safe, and noninvasive techniques useful for the diagnosis of ischemic heart disease. I-4 Alternans of the ST-segment h a v e b e e n reported in
acute myocardial ischemia, including patients with variant angina, 5,6 and during percutaneous translum i n a l coronary angioplasty. 7,8 Recently, we studied b e a t - t o - b e a t variability of the spatial QRST angle of consecutive heartbeats m e a s u r e d in Frank lead X, Y, Z scalar electrocardiograms (ECGs) recorded at rest f r o m patients with ischemic heart disease. Variability of the spatial QRST angle in patients with effort angina pectoris was higher t h a n in healthy subjects, and variability in the T vector was greater t h a n that in the QRS vector. Sensitivity of this index for ischemic heart disease, however, was
From the Department of Medicine, Division of Hypertension and Cardio-renal Disease, Dokkyo University School of Medicine, Mibu, Tochigi, Japan. Reprint requests: Shigeo Horinaka, MD, Department of Medicine, Division of Hypertension and Cardio-renal Disease, Dokkyo University School of Medicine, 880 Kitakobayashi, Mibu, Tochigi, 321-02, Japan.
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low (Horinaka S, unpublished data). Theoretically, the ventricular gradient, first described by Wilson et al., 9 is determined by the local excitability of the ventricular myocardium, particularly by differences in the local variations in the duration of the excited state. Thus, the ventricular gradient does not seem to be dependent on the ventricular excitatory process. 1° Ashman et al. 1M4 extensively reviewed the ventricular gradient concept. The ventricular gradient is a vector with magnitude, azimuth, and elevation obtained by addition of the QRS and T vectors. 9,~s It can be determined for the frontal plane alone or for a three-dimensional space, le As an expression of the time course of ventricular repolarization, the ventricular gradient quantitatively determines whether ST-T abnormalities are secondary (abnormalities in ventricular depolarization) or primary (independent of ventricular depolarization). That is, ST-T abnormalities reflect secondary as well as primary changes, but the ventricular gradient is only affected by primary changes. It may identity repolarization abnormalities even wh en the ST-T complex is normal. This study was performed to determine w h e t h e r patients with ischemic heart disease have greater beat-to-beat variability in the ventricular gradient than normal subjects.
Materials and Methods Patient Selection The subjects of this study were 59 patients and 33 healthy volunteers (control group) referred to Dokkyo University Hospital between April 1991 and March 1993. All patients presented with angina-like pain that was evaluated by cardiologists. Patients with ST-segment shift greater than 0.5 mm in 12-lead standard ECGs recorded at rest that were suggestive of myocardial ischemia were excluded from this study. Patients with cardiomyopathy, valvular heart disease, hypertension, myocardial infarction, or arrhythmia were also excluded from the study. Based on coronary angiographic results, patients were categorized into either the coronary artery disease (group 1) or the no coronary artery disease (group 2) group. Patients in group 1 exhibited at least 75% organic stenosis of a major coronary artery on coronary angiography after intracoronary injection of a nitrate drug. Group 1 was composed of 38 patients (29 men and 9 women; mean age, 54 + 9 years), including 23 patients with single-vessel disease and 15 patients with multiple-vessel disease. Group 2 comprised 21 patients (11 men and
10 women; mean age, 48 + 12 years) in w h o m no significant organic stenosis of the coronary artery was observed, and for w hom the acetylcholineloading test produced negative results. Acetylcholine chloride (Daiichi Seiyaku, Tokyo, Japan) was dissolved in 5 mL 0.9% saline in incremental doses of 25, 50, and 100 ~tg and injected into the left coronary" artery. Left coronary angiographic examination was perlormed w h e n ST-segment changes and/or chest pain occurred, or 1 to 3 minutes after each injection. Acetylcholine in incremental doses of 25 and 50 ~tg was injected into the right coronary artery and a right coronary arteriogram was performed in the m anner described above. If coronary spasm was not induced by these procedures, the acetylcholine-ioading test was defined as negative. 17'Is Twenty-seven patients in group 1 had histories consistent with typical chest pain that was accepted as a symptom of angina pectoris and 11 patients had histories of atypical chest pain. In contrast, 17 patients in group 2 had histories of atypical chest pain and only 4 patients had histories ot typical chest pain. Atypical chest pain was defined as chest pain that was either unresponsive to nitroglycerin or atypical for angina in terms of location, duration, quality, and relation to exertion or emotion, or both. 19 Nine patients in group 1 and five patients in group 2 had nonspecific ST-segment or minor T wave abnormalities at rest. The healthy control group consisted of 33 subjects (22 m en and 11 women; mean age, 55 + 11 years) with normal physical examinations, chest radiographs, and ECGs.
Analysis of Alteration of Ventricular Gradient After a 24-hour medication wash-out period, Frank lead X, Y, Z scalar ECGs were recorded with the patients at rest in the supine position without chest pain. The ECGs were recorded for 10 minutes with a data recorder (Sony FC-14, Tokyo, Japan) using a vectorcardiograph (Fukuda Denshi VC-3G, Tokyo, Japan). The samples were inputted to a microcomputer (NEC PC-9801 BA, Tokyo, Japan) via an A/D transducer at a rate of 1,000 samples per second over a 22-second period, reflecting the limit ot the computer memory. The trigger voltage was one quarter of the reference QRS complex value, and the correlation of ten different points before and after the trigger point for each beat to those of the other beats was calculated. Beats with a correlation coefficient less than .990 were excluded. The first derivative waveform was computed from the
Ventricular Gradient Variability • magnitude of the instantaneous spatial vector produced from the averaged X, Y, Z scalar ECGs for a 22-second period, which was displayed on the c o m p u t e r monitor. The time at which the first derivative of the QRS wave exceeded a threshold set to twice the noise level in the PQ-segments was defined as the starting point of the QRS complex (0 level). The endpoint of the T wave was also defined as the point arriving at the 0 level of the first derivative of the T wave in the TP-segments. The QRS complex, ST-segment, and T wave integrals were used to calculate the ventricular gradient for each heartbeat as previously described. ~5 The magnitude, azimuth, and elevation of the ventricular gradient were obtained, and the m e a n and SD of these values for all heartbeats in the 22-second interval were determined. The SD and coefficient of variation (SD/mean x 100) 2°,21 of these three measurements were used as indices of beat-to-beat ventricular gradient variability. The n o r m a l range of the SD and coefficient of variation of magnitude, azimuth, and elevation of the ventricular gradient was defined as m e a n _+2SD of the respective values in the control group. Any value that deviated from this range was considered abnormal. The m e a n heart rate was 65 beats/rain in the control group, 64 beats/min in group 1, and 69 beats/min in group 2, indicating no significant difference among the three groups during the m e a s u r e m e n t s of the ventricular gradient.
Changes in the R-R Interval Changes in heart rate were expressed as the SD of the R-R intervals.
Control
Ventricular Gradient M a g n i t u d e = 77.80=1=3.24 u V s e c Azimuth Elevation
= -9.15+3.00 ° = 48.20~=2.77 °
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Reproducibility Analysis Reproducibility of the values of the ventricular gradient was evaluated by comparing two sets of data recorded 10 minutes apart from 10 subjects in each group.
Statistical Analysis All calculated data are expressed as m e a n 4- SD. O n e - w a y analysis of variance followed by Tukey's analysis was performed to determine the statistical significance of differences a m o n g the three groups of subjects. The chi-square test was used for comparison of discrete variables. The correlation coefficient was calculated for paired data. Statistical significance was accepted at the 95% confidence level.
Results Alteration of Ventricular Gradients The ventricular gradients of the QRST complexes recorded from one control subject and one patient with coronary artery disease are s h o w n in Figure 1. During the 22-second recording period, the SD of azimuth, elevation, and magnitude of the ventricular gradient were greater in the patient with coronary artery disease t h a n in the control subject (Table 1). The SD of the azimuth, elevation, and magnitude of the ventricular gradient were significantly greater in group 1 t h a n in group 2 or the healthy control group (Y < .01); there was no significant difference b e t w e e n the SD of the latter two
CoronaryArtery Disease
Ventricular Gradient M a g n i t u d e = 62.44~=6.80 ]uVsec Azimuth = -5.26=~4.39 ° Elevation = 46.84±4.76 °
Fig. 1. Superimposed ventricular gradients of each heartbeat in the 22-second interval in one control subject and one patient with coronary artery disease.
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g r o u p s . The c o e t f i c i e n t ol v a r i a t i o n of t h e e l e v a t i o n and magnitude were significantly greater in group 1 t h a n i n g r o u p 2 or t h e h e a l t h y c o n t r o l g r o u p (P < . 0 I , r e s p e c t i v e l y ) . No s i g n i f i c a n t d i f f e r e n c e s in t h e c o e f f i c i e n t of v a r i a t i o n of t h e a z i m u t h e x i s t e d among the three groups.
R-R Interval Variability T h e SD of t h e R-R i n t e r v a l s w a s 33 + 10 m s in t h e c o n t r o l g r o u p , 22 + 17 m s in g r o u p 1, a n d 22 + 9 m s i n g r o u p 2. T h e SD of t h e R - R i n t e r v a l in t h e control group was significantly greater than those in g r o u p s 1 a n d 2 (P < .05).
Sensitivity and Specificity Reproducibility The d a t a in g r o u p s 1 a n d 2 w e r e c o m p a r e d w i t h c o n t r o l g r o u p d a t a to d e t e r m i n e t h e s e n s i t i v i t y a n d specificity of e a c h i n d e x for c o r o n a r y a r t e r y disease. The coefficient of v a r i a t i o n of t h e m a g n i t u d e of t h e v e n t r i c u l a r g r a d i e n t w a s f o u n d to b e t h e b e s t i n d e x , as s h o w n in F i g u r e 2. I n 31 of t h e 38 p a t i e n t s i n g r o u p i, this i n d e x w a s h i g h e r t h a n t h e u p p e r l i m i t ( 7 . 3 3 % ) in t h e c o n t r o l g r o u p ; t h u s , t h e s e n s i t i v i t y w a s 8 2 % . I n 19 of t h e 21 p a t i e n t s in g r o u p 2, it w a s w i t h i n t h e n o r m a l r a n g e ; t h e specificity w a s 9 1 % ( c h i - s q u a r e test, P < .001).
Comparison in the Coefficient of Variation of the Magnitude of the Ventricular Gradient Between Typical and Atypical Chest Pain in Group 1 T h e coefficient of v a r i a t i o n of t h e m a g n i t u d e of t h e v e n t r i c u l a r g r a d i e n t in 23 of t h e 27 p a t i e n t s ( 8 5 % ) w i t h t y p i c a l c h e s t p a i n a n d in 8 of t h e 1 1 patients (73%) with atypical chest pain was higher t h a n t h e u p p e r l i m i t of n o r m a l r a n g e . No significant difference was found between typical and atypical c h e s t p a i n g r o u p s ( c h i - s q u a r e test).
There was a significant correlation between pairs of m e a s u r e m e n t s of t h e coefficient of v a r i a t i o n of t h e m a g n i t u d e of t h e v e n t r i c u l a r g r a d i e n t i n r e c o r d i n g s o b t a i n e d 10 m i n u t e s a p a r t in 10 s u b j e c t s in e a c h g r o u p (r = .94, P < .001).
Discussion The v e n t r i c u l a r g r a d i e n t h a s r a r e l y b e e n u s e d clinically b e c a u s e of difficulty i n m e a s u r i n g it a c c u r a t e l y a n d t h e b r o a d r a n g e of n o r m a l v a l u e s , h o w ever, a d v a n c e s i n c o m p u t e r t e c h n o l o g y h a v e enabled more accurate and simpler measurement. T h e v e n t r i c u l a r g r a d i e n t , w h i c h w a s first d e s c r i b e d b y W i l s o n et al., 9 reflects n o n u n i f o r m i t y in ventricular action potential durations. A u t e n r i e t h et al. 22 l a t e r d e m o n s t r a t e d t h a t t h e v e n t r i c u l a r g r a d i e n t w a s r e l a t e d to r e g i o n a l d i f f e r e n c e s in monophasic action potential durations. T h e o r e t i c a l a n d clinical r e p o r t s h a v e d o c u m e n t e d t h a t t h e v e n t r i c u l a r g r a d i e n t is i n d e p e n d e n t of t h e a c t i v a t i o n sequence./°'23
Table 1. M e a n Value, SD, and Coefficient of Variation of Azimuth, Elevation, and M a g n i t u d e of the Ventricular Gradient in the Three Study Groups Healthy Control Subjects (n = 33) Mean Azimuth (degrees) Elevation (degrees) Magnitude (btVs) SD Azimuth (degrees) ' Elevation (degrees) Magnitude (btVs) CV Azimuth (%) Elevation (%) Magnitude (%)
-18.56 _+ I9.32 54.88 ± 9.23 I09.23 ± 25.06
Patients in Group 1 (n = 38) -23.21 ± 39.03 59.90 _+ 19.43 73.6I ± 30.61"].
Patients in Group 2 (n = 21) -16.84 ± 13.35 52.95 _+8.66 97.20 _+29.61
3.60 _+ 1.42 2.80 ± 0.98 5.70 ± 1.25
6.84 ± 4.48*-{ 5.61 ± 2.91" t 7.16 ± 2.26*]-
3.52 _+ 1.40 3.10 ± 0.83 5.6I _+ 1.16
24.80 ± 35.11 4.98 ± 2.21 5.13 ± 1.10
39.58 ± 48.07 9.86 ± 5.06*]10.94 ± 4.97*]-
40.28 ± 54.78 6.04 k 2.18 (1.00 ± 1.15
The data are presented as mean + SD. Group 1, coronary artery disease; group 2, no coronary artery disease; mean, mean value of all the original values; SD, standard deviation of all the original values; CV, coefficient of variation (SD/mean × 100). *P < .01 vs control group. ].P < .01 vs group 2.
Ventricular Gradient Variability •
(%)
30]
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in group l cannot be explained by R-R interval variability.
Myocardial Ischemia at Rest
~mean _+SD 25• 0
20-
E
"I
15-
Z
0 >
o
10 •
• 00@ •
Control
.!|}!i[ .|.T
QO
~
Group 1
00
Group 2
Fig. 2. Distribution of the coefficients of variation of the magnitude of the ventricular gradient in patients with coronary artery disease, no coronary artery disease, and in normal subjects. *P < .01 vs control group, tP < .0I vs group 2. CV, coefficient of variation; group I, coronary artery disease; group 2, no coronary artery disease.
To our knowledge, studies of the beat-to-beat variability in the ventricular gradient h a v e not b e e n previously reported. Myocardial ischemia is a wellk n o w n cause of changes in the ventricular gradient, but other factors can also affect the action potential in each area of the ventride. In healthy individuals, changes in the ventricular gradient can result from complex effects of changes in the R-R interval, a u t o n o m i c nervous functions, respiration, and electrolyte balance. 24 Changes in the R-R intervals might have a m a r k e d effect on the beat-to-beat variability in the ventricular gradient. Changes in the R-R interval in patients with ischemic heart disease, however, are less p r o n o u n c e d t h a n those in n o r m a l individuals. 25,26 Our results support this finding. The changes in the R-R intervals in g r o u p 1 were smaller t h a n those in the control group. Therefore, the high coefficient of variation of the magnitude of the ventricular gradient found
It has been reported that impaired left ventricular diastolic function and regional diastolic async h r o n y are evident at rest in m a n y patients with coronary artery disease in the absence of regional systolic wall m o t i o n abnormalities or previous myocardial infarctions. 27'2s Moreover, B o n o w et al. 29,~° demonstrated that regional diastolic abnormalities at rest improved after successful percutaneous transluminal coronary angioplasty. These observations m a y support the existence of myocardial ischemia in patients with coronary artery stenosis at rest. The American Heart Association Committee Report 31 defined 80% reduction of vessel diameter as significant on the basis of a study& Other investigators n o t e d that sequential arterial stenosis and longer lesions also resulted in reduced blood flow. 33'34This study revealed that 30 of the 38 patients in group 1 had a 9 1 - 9 9 % reduction in the diameter of the angina-related coronary artery, and the remaining 8 patients had a 7 5 - 9 0 % reduction. It is likely that patients in group 1 also had myocardial ischemia at rest, because the severity of their c o r o n a r y stenosis was c o m p a r a b l e to that of patients in other reports.
Ventricular Gradient in Myocardial Ischemia In an in situ experiment by Drily and Lab 35 using a porcine heart, alternans in the monophasic action potential duration in ischemic areas occurred spontaneously. Clinically, it is possible that the a k e m a n s in action potential duration in certain ischemic states of the m y o c a r d i u m m a y affect the ventricular gradient, even at rest, w h e n there is severe coronary artery stenosis. In other words, the high coefficient of variation of the m a g n i t u d e of the ventricular gradient m a y be caused by certain ischemic states of the ventricular m y o c a r d i u m at rest. Instability of the repolarization phase of action potentials due to ischemia is a possible mechanism, although a causal relation is difficult to prove from body surface ECG recordings.
Body Surface ECG in Myocardial Ischemia ST-segment changes on 12-1ead ECG have been suggested to be an index of myocardial ischemia. 36
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Khuri et a l . , 37 however, experimentally d e m o n strated ST-segment change appearing first in the inner layer of the ventricular m y o c a r d i u m with a coronary constriction, a l t h o u g h epicardial and body surface ECGs did not change. Watanabe et al. reported similar results. 38 The discrepancy in STsegment change b e t w e e n inner layer and b o d y surface ECGs m a y reflect an inability of the b o d y surface electrode to detect ischemic changes in some regions of the ventricular m y o c a r d i u m .
ischemia or the location of the ischemic lesion. F u r t h e r studies are necessary to elucidate the effects ot collateral circulation in the coronary artery on the ventricular gradient. In addition, studies are n e e d e d on patients w i t h (1) ST-segment shifts greater t h a n 0.5 m m in 12-lead ECGs at rest, (2) a b n o r m a l intraventricular conduction disturbances, and (3) other forms of h e a r t disease.
Conclusion QRS and ST-T Integrals We also calculated the coefficients of variation of the m a g n i t u d e of the ST-T integrals that reflect the repolarization phase of action potentials a n d of the QRS integrals in each group. The coefficient of variation of the m a g n i t u d e of the ST-T integral in group 1 (i4.27 + 9.47%) was significantly greater t h a n those of the control group (7.44 _+ 3.19%) and group 2 (7.41 + 2.44%) (P < .01). In contrast, there w e r e no significant differences a m o n g the QRS integrals of the three groups. The sensitivity and specificity of the coefficient of variation of the magnitude of the ST-T integrals in group 1 w e r e 4 0 % and 95%, respectively. A possible explanation of this low sensitivity is that the ST-T integral is d e p e n d e n t on the ventricular excitatory process (secondary change), as well as on variations in the action p o t e n t i a l d u r a t i o n ( p r i m a r y change), w h e r e a s the ventricular gradient is only d e p e n d e n t on the p r i m a r y change.
Other Findings In this study, the m a g n i t u d e of the ventricular gradient itself was significantly smaller in group 1 t h a n in the control group (Table 1). Only the patients with values 2SD b e l o w the m e a n are considered to h a v e a b n o r m a l values, and the sensitivity of this index was 29% (11 of 38 patients). Moreover, no significant differences in elevation or a z i m u t h existed b e t w e e n the two groups. These results indicate that diagnoses using values obtained f r o m the ventricular gradient are not reliable.
Study Limitations C a n n o n et al. 39'4° d e m o n s t r a t e d that small-vessel disease might be present in some patients with normal angiographic findings. We could not, however, evaluate these patients in this study, w h i c h considered coronary stenosis, but not the severity of
This study suggests that the coefficient of variation of the m a g n i t u d e of the ventricular gradient is a useful index for the diagnosis of ischemic heart disease. This index should be helpful in analyzing exercise test results as well as responses to treatment.
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