Magnetocardiographic turbulence analysis in patients with the long QT syndrome

Magnetocardiographic turbulence analysis in patients with the long QT syndrome

Journal of Electrocardiology Vol. 30 Supplement Magnetocardiographic Turbulence Analysis in Patients With the Long QT Syndrome Lothar Schmitz, MD,* ...

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Journal of Electrocardiology Vol. 30 Supplement

Magnetocardiographic Turbulence Analysis in Patients With the Long QT Syndrome

Lothar Schmitz, MD,* Konrad Czerski, PhD,J- Konrad Brockmeier, MD,* Rahul Agrawal, MD,~- Uwe Steinhoff, MSc,$ Lutz Trahms, PhD,$ and Michael Oeff, MD~-

Congenital long QT syndrome (LQTS) is a disease characterized by syncopal attacks, prolonged QT interval in the surface electrocardiogram (ECG), and familial occurrence. Although rare, LQTS represents a main cause of sudden unexpected death in children and young adults. Two forms of the disease are usually distinguished, the R o m a n o - W a r d syndrome, with dominant inheritance, and the autosomal recessive Jervell and Lange-Nielsen syndrome, which is associated with congenital deafness. In the R o m a n o - W a r d syndrome, four genes located on chromosomes 3 (SCN5A), 7 (HERG), I1 (KVLQT1), and 21 (minK) have been identified as carrying mutations that cause potassium or sodium channel dysfunction in the ventricular myocardium (1-4). Recently, a defective gene has also been identified in the Jervell and Lange-Nielsen cardioauditory syndrome (JLNS); this gene is located in the region of 1 lp15.5, where the KVLQT1 gene maps (5). For most patients with inherited LQTS, the existence of a defective m e m b r a n e channel function can be assumed. Two hypotheses for LQTS have been proposed. One suggested that a predominance of left sympathetic innervation caused abnormal cardiac repolarization and arrhythmias. This hypothesis was supported by the finding that arrhythmias could be induced in dogs by removal of the right stellate ganglion (6). In addition, most patients with LQTS can be treated successfully by beta-adrenergic blocking agents and by left stellate ganglionectomy (7). The second hypothesis for LQT-related arrhythmias suggested that mutations in cardiac-specific ion channel genes cause delayed myocellular repolarization, which could promote reactivation of L-type calcium channels, resulting in secondary depolarization. These afterdepolarizations are very likely the mechanism for the initiation of

ventricular tachycardias of the torsade de pointes type in patients. This hypothesis is supported by the observation that pharmacologic block of potassium channels can induce QT prolongation and arrhythmias in humans and in animal models (8). The discovery that one form of LQTS results from mutations in a cardiac potassium channel gene supported the myocellular hypothesis. The voltagegated sodium channel SCN5A is responsible for the initial upstroke of the action potential in the ECG. By expression of recombinant h u m a n heart sodium channels in Xenopus [aevis oocytes, m u t a n t channels showed a sustained inward current during membrane depolarization. Singlechannel recordings indicated that m u t a n t channels fluctuate between normal and noninactivating gating modes (9). Persistent inward sodium current explains prolongation of cardiac action potentials and provides a molecular mechanism for the chromosome 3-1inked form of the LQTS. In a recent animal study, the electrophysiologic mechanism of ventricular arrhythmias in the acquired LQTS could be demonstrated in vivo by experimental pharmacologic slowing of the sodium channel (I0). By measuring the activation-recovery interval through microelectrodes inserted transmurally into canine myocardium, it was possible to demonstrate a bradycardia-dependent progressive dispersion of the transmural activation-recovery intervals during pacing at different cycle lengths. At any paced cycle length, the greatest prolongation of activation-recovery intervals occurred at midmyocardial zones, whereas in the subendocardial and subepicardial regions there was much less prolongation. This type of dispersion on a microsphere level has not been detected by noninvasive electrocardiography. From the physical point of view, electrical heart activity can be described as a low-dimensional chaotic system, the dynamics of which are variable (eg, in the study of heart rate variability). However, we can additionally expect a significant spatial beat-to-beat variability, especially in LQTS, in which large regional dispersion of action potentials and electrical conductivity is observed, the investigation of spatiotemporal variability can provide important diagnostic information. An ideal tool for the study of such effects is multichan-

From the *Department of Pediatric Cardiology, ½"rchow-Klinikum of the Humboldt-University of Berlin, -pDepartrnent of Cardiology and Pneumology, Klinikum Benjamin Franklin, Free University of Berlin, and ~:Physikalisch-TechnischeBundesanstalt, Berlin, Germany. Reprint requests: Dr. L. Schmitz, Department of Pediatric Cardiology, Zentrum f/Jr Fdnder- und Jugendmedizin, VirchowFdinikum der Humboldt-Universit~t zu Berlin, Augustenburger Platz I, D-13353 Berlin, Germany. 01998 Churchill Livingstone® 0022-07361300S-003955.00/0

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Journal of Electrocardiology Vol. 30 Supplement

neI magnetocardiography. It offers the possibility of measuring the instantaneous distributions of magnetic fields arising directly from currents produced by depolarization and repolarization of the myocardial tissue. By solving the inverse problem, the current source can be localized. In the simplest case, we can apply an equivalent current dipole model to obtain parameterization of the integral electrical activity of the heart in the time and space domains. Thus, beat-to-beat variability of the heart rate can be described in terms of beat-to-beat variability of the equivalent current dipole. The aim of our study was to describe magnetocardiographically the fluctuations of instantaneous equivalent current dipoles throughout the entire cardiac cycle, in both the time and the space domain. We compared healthy normal subjects and patients with LQTS before and during medication with beta-adrenergic blocking agents in order to test the hypothesis that magnetocardiographic (MCG) can provide new information about temporospatial dispersion of the myoelectrical activity of the heart.

Materials and Methods Magnetocardiographic Measurements The MCG measurements were performed with two different multichannel superconducting q u a n t u m interference device (SQUID) systems developed by the Physikalisch-Technische Bundesanstalt (PTB) and operated in magnetically shielded rooms. The first facility (11) operates with 37 independent SQUID magnetometer units with a white noise level of 5 iT Hz -~/2. The second facility (12), located at the Klinikum Benjamin Franklin (Free University of Berlin), is a 49-channel first-order gradiometer system with a white noise level better than 2.5 fT Hz -]/2. Both sensors measure the z component of the magnetic field in a plane parallel to the anterior chest wall of the subject at a distance of about 3 cm. Simultaneously to magnetic signals, a three-lead vector ECG was recorded. Acquisition time was 100 seconds, and the sampling rate was 1 kl-Iz. Hardware bandpass filtering at 0.016-250 Hz for the 37channel system and 0.16-250 Hz for the 49-channeI system was applied for both magnetic and electric channels.

Spatiotemporal Turbulence Analysis by Magnetocardiography Magnetocardiographic mapping allows three-dimensional analysis of the electrical activity in the myocardium by solving the inverse problem. In our approach, we apply the model of an equivalent current dipole in a half-space volume conductor to determine the time-dependent location and stretch of the current source, according to

g= No 7 x ~

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(t)

where if, ~, and g are the magnetic flux density, the equivalent current dipole, and the location vector, respectively. Consequently, by solving the above equation, we can describe the dipolar component of ff by a few parameters (Jx, Jy, Rx, Ry, and Rz in our case). The ~ and ~ vectors are calculated for every time point of a measurement. In order to study beat-to-beat variability, we define an absolute time scale for each heart beat by means of R point triggering and calculate the m e a n values of the J and vectors as well as their standard deviations from

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where N is the number of heart beats involved in the analysis. Diagrams of current dipole amplitude I~1 obtained from a healthy subject and from three LQTS patients are presented in Figures 1 to 4. Raw data were checked for quality and irregular signals. In case of ventricular premature beats, the irregular cycle and at least two normal cycles preceding and following the irregular signal were excluded. In order to exclude effects caused by excessive heart rate variability, out of the remaining heart cycles those not exceeding the mean -+ 5 % of cycle length were chosen for further evaluation. In the next step, we constructed for every time instant a vector distribution consisting of N Ji(t) vectors. An example of such a distribution corresponding to the T wave m a x i m u m is shown in Figure 5. By means of the scalar and vector product, the current dipole vectors can be decomposed relative to the vector ~i-~o into two normal components, radial and tangential. These two vector components form new variables, temled Source (S) and Circulation (~), respectively, which are defined as follows N

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Patients and Controls

Two young patients with LQTS had two to four syncope attacks during physical and mental stress before confirmation of the diagnosis. The girl (E.J.) was 9 years old and the boy (H.A.) 12 years old at that time. Both were treated with beta-adrenergic blocking agents (propranolol and atenolol) and followed up in our outpatient department,

and both remained free of symptoms since initiation of therapy. The mother of E.J. has a prolonged QTc interval of 0.49 seconds in the resting ECG but never had symptoms other than common fainting during adolescence. The family of H.A. is completely free of prolonged QTc on the mother's side; the father is not available for investigation. There are no reported unexpected sudden deaths in either family history. A 6-year-old girl with JLNS has congenital deafness and has had multiple attacks of syncope since 3 years before initiation of therapy. With propranolol, 4.5 mg/kg body weight, she has been free of symptoms for 1 year. Her 4-year-old brother has a QTc of 0.49 seconds, is free of symptoms, and has no hearing loss. Both parents are free of symptoms and have normal QTc

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Fig. 5. (Left) Frontal plane instantaneous equivalent current dipole distribution of N consecutive cardiac cycles at peak of the T wave. (Middle) Tangential (circulation) component of the same current dipole distribution. (Right) Radial (source) component of the same current dipole distribution. The origin of the coordinate system corresponds to the mean location for the instant.

intervals. The parents are third cousins. No other cases of deafness have been reported in the family. Eight healthy control subjects had normal 12-lead ECGs, normal bicycle stress tests, normal echocardiographic findings, and no history of cardiac symptoms. The patients and healthy normal subjects (or their parents) gave their written informed consent to the investigations. The study was approved by the ethics committee of the Free University of Berlin.

Results Control Group All subjects had normal QTc intervals and QT dispersion (Table 1). In the MCG, the Circulation component of the current dipole during the QRS complex (CQRs) was in any case substantially higher than the Circulation compon e n t during the T wave (ST) (Fig. 1). Consequently, the ratio C T / C Q R S became low at a level of 0.29 _+ 0.2I. During the ST segment, Circulation was never at the same level as or higher than during the T wave.

Long QT Syndrome Both patients had prolonged QTc intervals before treatment which shortened by about 5% under medication.

Maximal QT dispersion in the precordial leads was greater than normal and shortened in one patient (H.A.) but was prolonged in the other patient, who had received betaadrenergic blocking therapy (Table I). In the MCG, CQRs and CT were abnormal before treatment in both patients. The ratio of both Circulation periods was completely inverted, with high Circulation during late repolarization compared with relatively low CQRs (Figs. 2 and 3). After medication with beta-adrenergic blocking agents, there was an increase in CQRs and a decrease in CT, so that the ratio CT/CQRs moved toward normal values. In the patient E.J., a persistent low-power Circulation component was detectable throughout the ST-segment and persisted under medication (Fig. 3).

Jervell and Lange-Nielsen Syndrome In JLNS, QTc shortened by 8% and QT dispersion did not change significantly with medication (Table 1). The ratio of high Circulation during the QRS complex and low Circulation during the T wave was not affected in this patient. However, the absolute value of CQRs was lower than all observed values in the control group, CT was twice the highest value found in the control group, and the CT/CQRs ratio was abnormally high, with values between those of the control group and those of untreated LQTS patients. There was practically no effect of the CT/CQRs ratio on beta-adrenergic block despite elimination of symptoms (Fig. 4).

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Journal of Electrocardiology Vol, 30 Supplement Table 1. Magnetocardiographic Turbulence Analysis Indices and ECG Markers in Patients With Long QT Syndrome and in Healthy Control Subjects

Index/Marker

Control Group (n = 8)

LQTS (n = 2)

LQTS + Beta-Blocker (n = 2)

JLNS (n = 1)

JLNS + Beta-Blocker (n = 1)

CQ~s (mA.m)

38 -+ 27

9.5 28

18 86

19.5

24.5

Cr (mA-m)

7.8 +_ 7

21.5 42.5

13 16

14

14

0.29 ± 0.2

2.3 1.5 70 68 0.56 0.53 105 75 10 12

CT/CQRs Heart rate (beats/min)

68 +--9

QTc (s)

0.4 ± 0.01

QT dispersion (ms)

25.5 -+ 14

Age (y)

25.6 -+ 8.6

0.72 0.19 71 63 0.49 0.51 90 80 14 16

0.72 58 0.64

0.57 64 0.59

95

88

6

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C, circulation component of the current dipole; T, during T wave duration; QRS, during QRS complex duration; LQTS, Romano Ward syndrome; JLNS, JervelI and Lange-Nielsen syndrome.

Discussion These are preliminary results of a study undertaken to develop suitable algorithms for MCG evaluation in patients with inherited LQTS. For better understanding of our findings, we designed the study to combine MCG investigations with molecular genetic studies in the families of our index patients to learn more about the electrophysiologic consequences of membrane channel defects in the myocardium. No results from the molecular genetic studies are available at this time, but we hope that in the future such results will add more evidence for the interpretation of our magnetocardiographic data. In our analysis, we used the integral information obtained with a multichannel SQUID system over a period of 100 seconds. This approach in the time and spatial domains goes beyond a descriptive observation of magnetic field and equivalent current dipole changes. By decomposition of the instantaneous current dipole field into its radial and tangential components, which we called Source and Circulation, respectively, we were able to describe the beat-to-beat variation of temporospatial patterns of myocardial electrical activity throughout the cardiac cycle. The applied algorithm is by definition insensitive to uncorrelated spatial dipole distributions (eg, remote artifacts). E n h a n c e m e n t of instantaneous Circulation corresponds to the simultaneous shift of polarization in both location and amplitude. The fact that all symptomatic patients with LQTS have abnormally high Circulation during late repolarization possibly relates to the in vivo experiments of El-Sherif et aL in dogs, in which they confirmed the hypothesis that transmural dispersion of activation to recovery time exists in pharmacologically induced LQTS (10). As transmural dispersion of activation to recovery time in a spatial dimension also means close coexistence of membranes at

different polarization levels, the existence of myocardial currents in the terminal portion of the repolarization phase can be assumed. The a m o u n t of dispersion would correlate first with the time interval in which currents persist at a cellular level. If this pathophysiologic condition did n o t vary b e t w e e n h e a r t beats or if variations were stochastic, neither the Source nor the Circulation component of the magnetocardiographically measured equivalent current dipole would be abnormally increased. Not only is repolarization in LQTS inhomogeneous between the myocyte layers of the ventricular walls, but there is additional evidence of inhomogeneities of adrenergic innervation in distinct parts of the ventricular myocardium (13). The pathophysiologic background of our findings may be discussed in this context. Either beat-tobeat variation in the a m o u n t of transmural action potential dispersion or beat-to-beat variation of action potential propagation in the temporal or spatial dimension would explain our results. Interestingly, in one LQTS patient, abnormally high Circulation could also be detected during the ST-segment, which means that electrophysiologic dysfunction in LQTS may not be restricted to late repolarization. The fact that Circulation during that part of the cardiac cycle did not change after medical treatment is reminiscent of the findings of Tobe et al., who reported on a bradycardia-dependent LQTS family, in which late potentials also persisted after normalization of QTc (14). High Circulation during the QRS complex in healthy normal subjects can be explained by the directing forces of the specialized conduction system, which propagates a rapid and widespread depolarization front at different locations simultaneously, but in an organized and directed way. At peak and in the early downstroke of the QRS complex, w h e n in most of the subjects maximal Circulation is encountered, considerable polarization differences

Turbulence in Long QT Syndrome certainly exist in the depolarization wave front. This physiologic p h e n o m e n o n would fit the finding that beat-tobeat differences in a relatively small time w i n d o w within the QRS complex are more the rule than the exception. W h y Circulation during depolarization of the ventricles is lower in LQTS patients than in healthy normal subjects and w h y it increases after beta-adrenergic blocking therapy remain unexplained. In the JLNS patient, the absolute values of Circulation during repolarization did not change after reinitiation of beta-adrenergic blocking therapy. However, the ratio of Circulation in the QRS complex and the T wave changed by 25% in the same direction as it did in R o m a n o - W a r d syndrome patients. This indicates that normalization of Circulation variability during repolarization may not be the hallmark of successful medical therapy in all forms of LQTS. In conclusion, we could demonstrate that abnormal beat-to-beat variability of the tangential component of the equivalent current dipole during repolarization of the ventricular myocardium was consistently present in LQTS patients with JLNS. In Romano Ward syndrome but not in JLNS, successful medical treatment was related to normalization of this parameter. There is no doubt that the inverse problem can be solved by using either electrical body surface mapping or multichannel MCG. In our view, magnetocardiography has advantages in the measurem e n t procedure, which is fast and free of skin contact, and is therefore well tolerated even by pediatric patients. In long-term follow-up evaluation, the reproducibility of MCG data could turn out to be superior to ECG data because of the absolute geometric stability of the sensor arrangement in the measurement device. Furthermore, MCG studies in a greater n u m b e r of patients will be needed to determine w h e t h e r the short time variability of circulation during repolarization is a valuable clinical tool for the diagnosis and follow-up evaluation of LQTS patients.

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syndrome loci map to chromosomes 3 and 7 with evidence for further heterogeneity. Nat Genet 8:141, 1994 Keating M, Atkinson D, Dunn C et al: Linkage of a cardiac arrhythmia, the long QT syndrome, and the Harvey ras-1 gene. Science 252:704, 1991 Sanguinetti MC, Curran ME, Zou A et ah Coassembly of K(v)LQT1 and m i n k (IsK) proteins to form cardiac I(Ks) potassium channel. Nature 384:80, 1996 Neyroud N, Tesson E Denjoy I e t ah A novel mutation in the potassium channel gene KVLQTI causes the Jervell and Lange-Nielsen cardioauditory syndrome. Nat Genet 15:186, 1997 Schwartz PJ, Verrier RL, Lown B: Effect of stellectomy and vagotomy on ventricular refractoriness in dogs. Circ Res 40:536, 1977 Schwartz PJ, Locati EH, Moss AJ et al: Left cardiac sympathetic denervation in the therapy of congenital long QT syndrome: a worldwide report. Circulation 84:503, 1991 Hii J, Wyse D, Gillis A e t al: Precordial QT interval dispersion as a marker of torsade de pointes. Disparate effects of class Ia antiarrhythmic drugs and amiodarone. Circulation 86:1376, 1992 Bennett PB, Yazawa K, Makita N, George ALJ: Molecular mechanism for an inherited cardiac arrhythmia. Nature 376:683, 1995 E1-Sherif N, Caref EB, Yin H, Restivo M: The electrophysiological mechanism of ventricular arrhythmias in the long QT syndrome. Circ Res 79:474, 1996 Koch H, Cantor R, Drung D et al: A 37 channel dc SQUID magnetometer system. IEEE Trans Magn 27:2793, 1991 Drung D: The PTB 83-SQUID system for biomagnetic applications in a clinic. IEEE Trans Appl Supercond 5:1, 1995 GohI K, Feistel H, WeikI A et al: Congenital myocardial sympathetic dysinnervation (CMSD)--a structural defect of idiopathic long QT syndrome. PACE Pacing Clin Electrophysiol 14:1544, 1991 Tobe TJ, de Langen CD, Bink-Boelkens MT et al: Late potentials in a bradycardia dependent long QT syndrome associated with sudden death during sleep. J Am Coll Cardiol 19:541, 1992