Changes in autonomic activity and ventricular repolarization

Journal of Electrocardiology Vol. 32 Supplement 1999

Changes in Autonomic Activity and Ventricular Repolarization Vladimir Shusterman, MD, PhD, Anna Beigel, BS, S. Ismail Shah, PhD, Benhur Aysin, MS, Raul Weiss, MD, Venkateshwar K. Gottipaty, MD, PhD, David Schwartzman, MD, and Kelley P. Anderson, MD

Abstract: An increase in sympathetic activity, manifested by shortening of RR

intervals (RRi) and changes in RRi variability, precedes and possibly triggers ventricular tachyarrhythmias (VTAs) by altering repolarization. We examined the effects of autonomic activity on the projection of repolarization as detected by body surface potential maps (BSPMs). We recorded 32 lead/192-point BSPMs during passive h e a d - u p tilt, tilt + infusion of isoproterenol, rapid atrial pacing, and atrial pacing + infusion of isoproterenol. Changes in QT; recovery time; activation-recovery interval (ARi); T-wave amplitude; and QT, QRST, and ST integrals and their dispersion were analyzed. Autonomic effects on sinus node were inferred from the Fourier transform-derived low and high frequency powers of RRi variability. Patients were divided into those with (SHD) and without structural heart disease (NSHD). Heart rate increased, whereas QT interval and ARi declined with tilt in both groups. RRi variability indices of sympathetic activity increased in NSHD but did not change in SHD. T-wave amplitudes declined in NSHD but did not change in SHD, suggesting altered responsiveness of ventricular repolarization to autonomic stimulation. Tilt and rapid atrial pacing during infusion of isoproterenol resulted in a paradoxical increase in T-wave amplitudes in some patients, similar to that observed before the onset of spontaneous arrhythmias. We conclude that altering autonomic activity by head-up tilt and/or infusion of sympathomitactic agents results in significant changes in the body surface projection of cardiac repolarization, which differ in patients with SHD from those without SHD. Similar paradoxical changes in the T-wave amplitude have been observed before the onset of spontaneous VTA, suggesting that abnormal response of repolarization to autonomic stimulation predisposes to arrhythmogenesis. K e y w o r d s : autonomic activity, ventricular repolarization, body surface potential mapping.

From the Cardiac Electrophysiology Program, Cardiovascular Institute, University of Pittsburgh Health System, Pittsburgh, Pennsylvania.

Presented in part in abstract form at the Computers in Cardiology in Cleveland, Ohio, 1998. This research was supported in part by the National Heart Lung and Blood Institute, Bethesda, MD (HL52338, K.P.A.), by a grant from the AHA-Southwestern Pennsylvania Affiliate (V.S.), a grant from the Competitive Medical Research Fund of the University of Pittsburgh Medical Center (V.S.), and a grant from Guidant Corporation of St. Paul, MN (K.P.A.). Reprint requests: Vladimir Shusterman, MD, PhD, Cardiac Electrophysiology Program, CVI/UPHS, Presbyterian University Hospital, Rm B535, 200 Lothrop Street, Pittsburgh, PA 15213-2582. Copyright © 1999 by Churchill Livingstone ®

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Spontaneous ventricular tachyarrhythmias (VTAs) are often preceded by a rise in heart rate, suggesting a rise in sympathetic activity or withdrawal of vagal activity (1-5). Patients at risk for malignant VTA often have prominent alterations of autonomic nervous system function, and prognosis is improved by measures that counteract adrenergic activity. However, in most patients, VTAs are not reliably reproduced by catecholamine infusions, anticholinergic agents, or other forms of physical or pharmacological stress. VTAs appearing similar to spontaneous rhythms can be reproduced in some patients by electrical stimulation, but the induction protocol usually requires multiple closely coupled extrastimuli (4). This contrasts with many witnessed or recorded reports that indicate that VTAs are usually not preceded by dramatic signs, symptoms, or hemodynamic disturbances and rarely is there ECG evidence of myocardial ischemia or multiple closely coupled premature beats (1-5). The failure to reproduce spontaneous VTA suggests that a combination of factors contributes to arrhythmogenesis. To further delineate the contribution of autonomic nervous system activity to arrhythmia onset, several laboratories have applied time and frequency domain analysis to the heart rate variability (HRV) signal. Initial results were inconsistent because of inadequate statistical power, diversity of applied methods, and the complexity of the analyzed series (1-3). Using a relatively large data set, our group demonstrated changes in frequency domain components of the HRV signal that were consistent with increased sympathetic activity before the onset of VTA but with no evidence of a decline in parasympathetic activity (5). It is recognized, however, that the correspondence between HRV frequency components and specific facets of autonomic function is imperfect (6). Nevertheless, the observed changes were sensitive indicators of VTA initiation. On the other hand, a preliminary analysis has demonstrated that the observed changes were nonspecific; they were found to occur at other times in the 24-hour recordings. This suggested that the rise in sympathetic tone alone was insufficient to initiate VTA, providing still more evidence that numerous factors participate in arrhythmogenesis. Changes in repolarization play a crucial role in arrhythmogenesis, and autonomic activity is known to alter repolarization. Therefore, alterations in ventricular repolarization might provide the link that explains the relationships between the autonomic perturbations and arrhythmogenesis. In this study, we examined ventricular repolarization and autonomic activity during maneuvers

that elicit changes in autonomic tone and compared them with the changes that precede spontaneous VTA. Head-up tilt, atrial pacing, and infusion of sympathomimetic agents were used to mimic alterations in autonomic tone that precede spontaneous VTA.

Methods Study Patients We studied 54 patients who underwent head-up tilt testing. The protocol was approved by the Institutional Review Board, and all patients gave their informed consent. The patients were divided into those with (SHD) (group I: 18 patients) and without structural heart disease (NSHD) (group II: 36 patients). All patients underwent clinical and echocardiographic examination. Clinical characteristics of the patients are presented in Table 1. Patients from group I were older than patients from group II (6i _+ 18 y and 43 _+ 16 y, P = .0008). There were nonsignificant trends towards lower incidence of syncope and higher proportion of females in group II.

Study Protocol H e a d - U p Tilt Test. After l0 minutes in the supine position, patients were tilted to 70 ° for 45 minutes, then returned to the supine position. A t r i a l Pacing. Atrial pacing was performed at 600-, 500-, and 400-ms cycle lengths before and during isoproterenol infusion adjusted to heart rate

Table 1. Clinical Characteristics of the Study Patients

Number Age Sex (female) Syncope CHF CAD DC EF

Group I

G r o u p II

18 + 18 y (50%) t (33%) (11%) (33%) (22%) _+ 18%

36 43 _+ 16 23 (64%) 2 (6%) 0 0 0

61 9 6 2 6 4 45

P* .0008 .41 .83

Overall 49 32 14 2 6 4

54 _+ 18 (59%) (26%) (4%) (11%) (7%)

*P indicates significance of t h e differences b e t w e e n group I a n d group II. tpercentages are in p a r e n t h e s e s except w h e r e indicated, a n d reflect missing data for s o m e variables. CHF, congestive heart failure; CAD, coronary artery disease; MI, myocardial infarction; DC, dilated cardiomyopathy; EF, election fraction.

Autonomic Activity and Repolarization

increase of 2 5 % greater.

or

100 bpm, w h i c h e v e r was

Data Acquisition and Signal Processing. Body surface potential m a p s (BSPMs) w e r e recorded at 1-kHz sampling f r e q u e n c y with a 32-lead acquisition system (CVRTI, University of Utah, Salt Lake City, UT). The 20-second recordings w e r e perf o r m e d in the supine position (at 3 a n d 6 minutes), at 70 ° tilt (at 5, 10, 15, a n d 20 minutes), a n d after r e t u r n to the supine position (at 3 a n d 6 minutes). Baseline drift was corrected using a special 2-step approach. At the first step, an adaptive high-pass filter was applied to the signal in accordance w i t h the a m p l i t u d e and f r e q u e n c y of the baseline drift. This p r o c e d u r e r e m o v e d m o s t of the baseline w a n der with m i n i m a l distortion of the QRST complexes. At the second step, the R peaks and the baseline segments b e t w e e n the offset of T w a v e and the onset of P w a v e w e r e detected. Linear interpolation and subtraction of the electrocardiographic (ECG) segments b e t w e e n the baseline segments provided accurate and robust baseline estimation. After correction of the baseline wander, the 32 signals w e r e t r a n s f o r m e d into 192-site B SPM using the m e t h o d described by Lux et al. (7). QRS complexes w e r e detected, and an average QRST complex was constructed f r o m the 20-second ECG in each lead. QT Interval (QTi). M e a s u r e m e n t of the end of the T w a v e is technically difficult because of the slowchanging n a t u r e of the T wave, a n d the possible overlap of T, U, a n d P waves. Therefore, we developed software that incorporates several techniques to ensure consistency and reliability of the results. The initial a p p r o x i m a t i o n of the T-wave offset is based on the w o r k of Lepeshkin and Surawicz (8). A t a n g e n t f r o m the point of m a x i m u m absolute slope following the p e a k of the T w a v e is c o m p u t e d and extrapolated to the isoelectric line. The crossing point of the tangent a n d the isoelectric line is m a r k e d as the end of the T wave. The resulting fiducial points a n d the w a v e f o r m s are displayed to allow correction of obvious errors. This m e t h o d was f o u n d to correlate strongly (r = 0.98) with m a n u a l m e a s u r e m e n t s ; h o w e v e r , it does not allow m e a s u r ing the changes in the final portion of the T wave, b e t w e e n the point of the m a x i m u m derivative and the end of the T wave. Recent e x p e r i m e n t a l studies s h o w e d that the shape of the T w a v e represents regional dispersion of repolarization across the ventricular wall and m a y be a valuable index for assessment of a r r h y t h m o g e n i c risk (9). To find the location of exact T - w a v e end, a short, RR interval

•

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(RRi)-adjusted time w i n d o w is defined in vicinity of the initial estimate of the T-wave offset. Termination of the T w a v e is d e t e r m i n e d in this w i n d o w as a point w h e r e the amplitude and its filtered first and second derivatives cross preselected thresholds. Because the m o r p h o l o g y of the T w a v e f o r m and the a m o u n t of noise vary, the thresholds are recursively adapted for each QRST complex. Because there is controversy over the correction of QTi for varying heart rate, separate analyses w e r e p e r f o r m e d for b o t h QTi and the corrected QTi (QTc). The QTcs w e r e calculated in each lead using the Bazett's formula and averaged over 192 leads.

Activation-Recovery Interval (ARi). ARis in the m y o cardium or at the cardiac surface h a v e b e e n s h o w n to correlate with refractory period m e a s u r e m e n t s a n d t r a n s m e m b r a n e action potential durations and their changes resulting f r o m cycle length changes, drugs, ischemia, and catecholamines ( 10-12). ARis at the b o d y surface h a v e b e e n used to d e m o n s t r a t e electrophysiologic r e m o d e l i n g (13). Activation time (AT) is defined as time of m i n i m u m slope during the QRS, a n d recovery time (RT) is defined as the time of m a x i m u m (positive) slope n e a r the p e a k of the T wave: ARI = RT - AT in each lead.

T-Wave Amplitude (TWA). TWA was d e t e r m i n e d by an a u t o m a t i c p r o c e d u r e that searches for the local m a x i m u m in the time w i n d o w starting at 60 ms after the R peak. The duration of the time w i n d o w is adjusted according to the length of the previous RR interval. In the case of a biphasic T wave, the amplitude of the largest absolute deflection (positive or negative) is used as an estimate of TWA. TWA was identified using custom software, and the m e a n TWA was d e t e r m i n e d by averaging TWA in 192 leads. In addition, the interlead dispersion of TWA was calculated as the difference bet w e e n its m a x i m a l and m i n i m a l values. QRST-Area Integral (QRSTI). Theoretical a n d exp e r i m e n t a l evidence d o c u m e n t that QRSTI reflects local disparity of repolarization (14). QRSTI changes v e r y little with gross changes in activation sequence, e v e n in the presence of conduction abnormalities, providing a m e a s u r e of repolarization disparity. QRSTIs w e r e calculated by integrating the baseline corrected ECG over the QT duration. T-Wave Area Integral (TWO: Alterations in different segments of the T w a v e reflect the changes in different layers of the cardiac wall and t r a n s m u r a l dispersion of repolarization (9). To e x a m i n e the changes in different parts of the T-wave area, w e calculated the interval b e t w e e n Tpeak and Tend, w h i c h can serve as an index of t r a n s m u r a l disper-

188

Journal of Electrocardiology Vol. 32 Supplement 1999

100

sion of repolarization (15). In addition, the integrals b e t w e e n the onset and the p e a k of the T wave, the p e a k a n d the offset of the T wave, a n d the onset a n d the offset of the T w a v e w e r e calculated.

Heart Rate Variability Analysis. Holter m o n i t o r i n g was p e r f o r m e d during the test to obtain the continuous RR-time series. ECG data w e r e digitized at 400 Hz. QRS complexes w e r e detected and classified on a commercial system (Burdick, Inc., Milton, WI) using custom software and verified by a cardiologist. Intervals b e t w e e n n o r m a l QRS complexes w e r e extracted, a n d a regularly spaced time series was sampled at f r e q u e n c y 2 Hz using a "boxcar" low-pass filter (16). After subtracting the m e a n f r o m the time series, p o w e r spectral analysis of HRV was p e r f o r m e d in 5-minute, n o n o v e r l a p p i n g data segments using fast Fourier t r a n s f o r m a n d a Hanning w i n d o w . Zero padding was applied to e n h a n c e the o u t c o m e f r e q u e n c y resolution. P o w e r was integrated o v e r each f r e q u e n c y range: high (HFP): 0.15 to 0.4 Hz; low (LFP): 0.04 to 0.15 Hz; total (TP): 0.01 to 0.4 Hz, and the ratio of LFP/HFP was calculated. These values w e r e used to assess changes in the a u t o n o m i c n e r v o u s system activity elicited by 70 ° tilt. In the case of substantial deviation f r o m n o r m a l distribution, n o n p a r a m e t r i c F r i e d m a n analysis of variance (ANOVA) was applied to test the significance of changes in the variables over time. If the distribution was linear, we used ANOVA for repeated m e a s u r e m e n t s . Different groups of patients w e r e c o m p a r e d using M a n n - W h i t n e y U-test.

Results Changes in Repolarization and RRi Variability During H e a d - U p Tilt Heart rates (HRs) w e r e similar during the test in the two groups (Fig. 1). HR increased with tilt in group I (77 _+ 15 to 87 + 17 beats/min, P < .00001) and group II (73 + 16 to 91 + 22 beats/min, P < .0001). TP and LFP did not change in either g r o u p during the test. The HFP decreased, w h e r e a s the ratio of LFPIHFP increased with tilt in group II (HFP: 5.68 _+ 0.72 a n d 4.62 ± 1.29, P = .024; HFP/LFP: 4.44 _+ 6.65 and 7.41 __ 7.21, P = .00002) but did not change in group I (HFP: 3.25 -+ 1.38 and 2.63 _+ 1.41, P = .33; LFP/HFP: 2.39 + 1.63 and 2.95 + 2.05, P = .59) (Fig. 2). QTi and ARi dropped with tilt in b o t h groups (Table 2). T-wave a m p l i t u d e dropped with tilt in group II but did not change in group I (Fig. 3).

•

GroupI

96

92

88 84 ~

80

0

z

76

72 68

s

1"70-5' T70-10' 1"70-15' 1"70-20'

S

Fig. 1. Changes in heart rate during head-up tilt.

Changes in Repolarization During Atrial Pacing Rapid atrial pacing c a u s e d a decrease in T - w a v e a m p l i t u d e , as s h o w n in Fig. 4B. H o w e v e r , infusion of i s o p r o t e r e n o l a n d pacing p r o d u c e d a paradoxical increase in T - w a v e a m p l i t u d e a n d its i n t e r l e a d dispersion in s o m e p a t i e n t s (Fig. 4D). This p a r a d o x i c a l increase in T - w a v e a m p l i t u d e r e s e m b l e d c h a n g e s t h a t w e r e o b s e r v e d b e f o r e the o n s e t of s p o n t a n e o u s v e n t r i c u l a r t a c h y c a r d i a (Fig. 5).

Discussion The m a i n finding of this s t u d y w a s the dissociation b e t w e e n s h o r t e n i n g of RRi a n d QTi a n d u n c h a n g i n g a m p l i t u d e of the T w a v e in r e s p o n s e to m a n e u v e r s t h a t alter a u t o n o m i c t o n e in patients w i t h structural h e a r t disease. By contrast, b o t h the QTi a n d the TWA d e c r e a s e d d u r i n g tilt in NSHD subjects, suggesting t h a t this p a t t e r n r e p r e s e n t s a n o r m a l r e a c t i o n to a u t o n o m i c perturbations. Several factors could account for the observed dissociation in patients with SliD. First, these patients w e r e older w h i c h could account for a w e a k e r repolarization response to the a u t o n o m i c stimulation (17). Second, structural abnormalities in the cardiac tissue could lead to partial uncoupling bet w e e n the s y m p a t h e t i c terminals and cardiac cells. Finally, chronic e n h a n c e m e n t of s y m p a t h e t i c activity could cause d o w n r e g u l a t i o n of adrenergic receptors or diminished response to n e u r o h o r m o n a l influences (18,19). However, despite the differences in age a n d structural disease, the m a g n i t u d e of increase in heart rate was similar in the 2 groups.

Autonomic Activity and Repolarization 10

•

Group I

u. ..J

1"70-5'

T70-10'

1"70-15' "1"70-20'

Shusterman et al.

189

the RR variability, suggesting similarity between their mediating systems and functional responses. The tilt evoked a drop in the HFP and dramatic changes in the ratio of HFP/LFP that were associated with repolarization changes in normal subjects. However, none of these variables changed significantly in patients with SliD. Changes in RR variability, which represent response of the sinus node to autonomic perturbations, are relatively well studied. By contrast, data regarding the interplay between the reactions of sinus node and ventricular repolarization are scarce. Our results suggest an independent value of the T-wave amplitude and duration as an indicator of dynamic repolarization abnormalities that is not invariably coupled to changes in RRi or QTi (15). Induction of VTA in experimental preparations usually requires early coupled extrastimuli that initiate a undirectional block, which in turn produces reentry (21). However, cellular and tissue models do not reproduce dynamic, hemodynamic, neuroendocrine, and other influences that may trigger arrhythmias. VTAs that appear similar to those that occur in patients can be created in animal models, but initiation often requires provocation with intense electrical stimuli or myocardial ischemia. During electrophysiologic study, VTA can be induced in some patients, but the induction protocol usually requires multiple closely coupled extrastimuli, whereas spontaneous VTAs are rarely initiated by multiple closely coupled premature beats (22-24). Furthermore, there are often subtle differences between the characteristics of induced and recorded rhythms (24). Recently, we identified complex perturbations in the cardiac cycles during several hours before the onset of VTA that accurately predicted the timing of the arrhythmia (24). In contrast, we failed to find any dramatic changes in RR intervals, short-longshort sequences, or early coupled extrasystoles immediately before the onset of VTA (25). This suggests that accumulation of the repolarization changes in response to complex perturbations in RR

-'1"-

L u. 3:

S

•

S

Fig. 2. Changes in the ratio of low/high frequency power during head-up tilt.

This does not support major abnormalities in the central nervous system or responsiveness of the sinus node as the cause of the observed differences between the 2 groups. The RRi variability indices of sympathetic tone increased in NSHD but did not change in SHD, which suggests some differences in neurohormonal influences in the 2 groups. Nevertheless, despite these differences, the QTi and ARi shortened in both groups. Therefore, the different behaviors of repolarization indices in the 2 groups most likely represent altered reaction of ventricular repolarization to autonomic stimulation in patients with structural heart disease. Furthermore, paradoxical increases in T-wave amplitude were also observed during infusion of sympathomimetic agents and rapid atrial pacing in patients with structural heart disease, confirming other evidence regarding altered repolarization responses to autonomic stimulation. Similar increases in the T-wave amplitude were also registered on Holter ECGs before the onset of spontaneous VTA (20). This evidence suggests that an index representing the relationship between the duration and magnitude or repolarization changes may be useful for identifying proarrhythmic abnormalities. Notwithstanding, these reactions of repolarization were correlated with the spectral changes in

Table 2. Changes in Repolarization During Head-up Tilt Group I

QTi ARi TWA

Group II

Supine

Tilt

P*

Supine

Tilt

P*

410 ± 46 261 ± 39 .070 ± .068

382 -- 61 241 ± 48 .063 ± .077

< .0001 .0002 .32

417 -± 52 269 ± 45 .084 ± .11

369 --_ 48 242 ± 41 .40 ± .074

<.0001 <.0001 .04

*P indicates significance of the differences b e t w e e n s upi ne a n d tilt positions in e a c h group. QTi, QT interval; ARi, a c t i v a t i o n - r e c o v e r y interval; TWA, T-wave a m p l i t u d e .

190 Journal of Electrocardiology Vol. 32 Supplement 1999 intervals and a u t o n o m i c tone rather t h a n triggering extrasystoles or short-long-short sequences are responsible for the arrhythmogenesis in patients with SHD (24). Satoh and Zipes reported that transient tachycardia superimposed on bradycardia produced a long-lasting (3-hour) increase in the duration of repolarization. Transient tachycardia was also associated with a greater incidence of early afterdepolarization and increased t e n d e n c y for VTA than the heart exposed only to bradycardia after cesium administration (26). Confirmation has been demonstrated by action potential prolongation in midmyocardial myocytes from the same model (27) and by ventricular effective refractory period measurements in patients (27). This study provides additional evidence regarding cumulative changes in repolarization and its dispersion during autonomic stimulation, rapid pacing, and administration of isoproterenol in patients with SHD.

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Baseline after pacing We observed a dynamic dissociation b e t w e e n reactions of the duration and the magnitude of the repolarization changes in response to a u t o n o m i c stimulation. This abnormal responsiveness of ventricular repolarization to a u t o n o m i c activity led to cumulative repolarization changes that were similar to those that occurred preceding the onset of spontaneous events and could result in nonuniformities of electrophysiologic properties that increase vulnerability to ventricular arrhythmias. Analysis of the exact mechanism of this p h e n o m e n o n merits further investigation.

EEZ 0.5

0

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800

Pacing at 150 bpm + isoproterenol

800

1200

Fig. 4. (Top panel) Interlead dispersion of the T-wave amplitude (TWA) at baseline (1,2), after 3 minutes of pacing at 120 bpm (3), after 3 minutes of pacing at 150 bpm (4), sinus rhythm after the pacing (5), after isoproterenol infusion (6), and after 3 minutes of pacing at 150 bpm + isoproterenol (7). Pronounced changes in TWA and its interlead dispersion occurred at the time of rapid atrial pacing and infusion of isoproterenol. (Lower panels) Serial unipolar BSPM recordings (lead 11). Pronounced increase in the T-wave amplitude and the ratio of T/R amplitudes occurred at the time of rapid atrial pacing and infusion of isoproterenol.

Autonomic Activity and Repolarization

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18.

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