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Cardiovascular Research 2001 50(2):386-398; doi:10.1016/S0008-6363(01)00263-2
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Copyright © 2001, European Society of Cardiology

Non-invasive testing of acquired long QT syndrome

Evidence for multiple arrhythmogenic substrates

Philippe Chevaliera, Claire Rodriguezb, Laurence Bontempsc, Maryvonne Miqueld, Gilbert Kirkoriana, Robert Roussonb, Franck Potete, Jean-Jacques Schotte, Isabelle Baróe and Paul Touboula,*

aDépartement de Cardiologie et de Soins Intensifs, Hôpital Louis Pradel, Lyon, France
bDépartement de Biochimie, Hôpital Louis Pradel, Lyon, France
cUnité de Médecine Nucléaire, Lyon, France
dINSERM U121, Lyon, France
eINSERM U533 Hôtel-Dieu, Nantes, France

* Corresponding author. Hôpital Louis Pradel, 28 Avenue Doyen Lépine, 69-394 Lyon Cedex 03, France. Tel.: +33-472-357-549; fax: +33-472-357-341

Received 27 September 2000; accepted 31 January 2001


   Abstract
Top
 Abstract
1 Introduction
 2 Genetic testing
 3 QT interval dispersion...
 4 Myocardial sympathetic...
 5 Time--frequency analysis of...
 6 Discussion
 7 Limitations
 8 Conclusions
 References
 
Background: Although well-defined clinically and electrocardiographically, Acquired Long QT Syndrome (LQTS) remains elusive from a pathophysiologic point of view. An increasingly accepted hypothesis is that it represents an attenuated form of Congenital Long QT Syndrome. To test this hypothesis further, we investigated patients with Acquired LQTS, using various investigations that are known to give information in patients with Congenital LQTS. Methods: All the investigations were performed in patients with a history of Acquired Long QT Syndrome, defined by marked transient QT lengthening (QT>600 ms) and/or torsades de pointes. Measurement of the QT interval dispersion, the interlead difference for the QT interval on a 12-lead ECG, was performed in 18 patients and compared with 18 controls, matched for age and sex. To assess sympathetic myocardial innervation, I-123 Meta-iodobenzylguanidine (I-123-MIBG) scintigraphy was performed in 12 patients, together with Thallium scintigraphy, to rule out abnormal myocardial perfusion. Time—frequency analysis of a high-resolution ECG using a wavelet technique, was made for nine patients and compared with 38 healthy controls. Finally, genetic studies were performed prospectively in 16 consecutive patients, to look for HERG, KCNE1, KCNE2 and KCNQ1 mutations. The functional profile of a mutated HERG protein was performed using the patch-clamp technique. Results: Compared with the control group, a significant increase in QT dispersion was observed in the patients with a history of Acquired LQTS (55±15 vs. 33±9 ms, P<0.001). In another group of patients with Acquired LQTS, 123 I-MIBG tomoscintigraphy demonstrated a decrease in the sympathetic myocardial innervation. Time—frequency analysis using wavelet transform, demonstrated an abnormal frequency content within the QRS complexes, in the patients with Acquired LQTS, similar to that found in Congenital LQTS patients. Molecular screening in 16 consecutive patients, identified one patient with a missense mutation on HERG, one of the LQTS genes. Expression of the mutated HERG protein led to altered K+ channel function. Conclusion: Our results suggest that Acquired and Congenital Long QT Syndromes have some common features. They allow the mechanism of the clinical heterogeneity, found in both syndromes, to be understood. Further multi-facet approaches are needed to decipher the complex interplay between the main determinants of these arrhythmogenic diseases.

KEYWORDS Antiarrhythmic agents; ECG; Long QT syndrome; Sudden death; Ventricular arrythmias


   1 Introduction
Top
 Abstract
 1 Introduction
2 Genetic testing
 3 QT interval dispersion...
 4 Myocardial sympathetic...
 5 Time--frequency analysis of...
 6 Discussion
 7 Limitations
 8 Conclusions
 References
 
The clinical and electrocardiographic features of Acquired Long QT Syndrome are stereotypic [1,2]. In a context of marked lengthening of the QT interval, torsades de pointes is said to be ‘pause dependent’, that is that it occurs when there is slowing of the cardiac rhythm. It is often preceded by an extrasystole with long fixed coupling. Finally, this arrhythmia occurs predominantly in women and the triggering factors, which are mostly drug treatment, are well-known [3]. Nevertheless, the very scanty knowledge about the causation of Acquired Long QT Syndrome is insufficient, in view of the potentially serious nature of this disease. In fact, 25 years after clinical identification of torsades de pointes, we still do not know why one patient develops this arrhythmia, whereas another patient with the same drug treatment at the same dose for the same indication, will not suffer from it [4]. A hypothesis, which was made 18 years ago, is that Acquired Long QT Syndrome is a variant of Congenital Long QT Syndrome [5]. Therefore the genetic abnormalities seen in the congenital form should also be present in the acquired form. The difference between the two conditions may be the result of attenuation of the phenotypic expression, which may not be detected on screening with standard investigation techniques. The same could be true for a myocardial innervation abnormality, which has also been found in patients with Congenital Long QT Syndrome [6,7]. The same argument may be valid for an increase in QT interval dispersion or the presence of spectral changes in signal-averaged QRS, found by time—frequency analysis, these being two potential markers of Congenital Long QT Syndrome [8,9].

For 5 years, our objective has been to find a common denominator, which is common to the acquired and congenital forms of Long QT Syndrome. To do this we have applied techniques which have shown abnormalities in patients with Congenital Long QT Syndrome to different populations of patients with Acquired LQTS. This article shows the results of this multi-faceted approach. The details of the rationale, methods and results are shown for each of the examinations we used.


   2 Genetic testing
Top
 Abstract
 1 Introduction
 2 Genetic testing
3 QT interval dispersion...
 4 Myocardial sympathetic...
 5 Time--frequency analysis of...
 6 Discussion
 7 Limitations
 8 Conclusions
 References
 
2.1 Rationale
Data from gene analysis in patients with Acquired Long QT Syndrome are increasing [10–13]. The results are encouraging, and show in some patients, a genetic substrate similar to what has been found in the congenital form of the syndrome. It is not known if all patients have a genetic predisposition. It therefore seems that systematic evaluation of at least the genes that are known to be involved in Congenital LQTS, in patients with drug-induced life-threatening arrhythmias, would be useful.

2.2 Methods
Since January 1998, 16 patients with Acquired LQTS, hospitalized in our intensive care unit, were included in the study. Informed consent was obtained from each patient. There were 12 women and four men. Their mean age was 66±15 years. All of them had either torsades de pointes and/or lengthening of the QTc interval, lasting more than 600 ms. The QT interval returned to normal after correction of the triggering factor. The causes were hypokalemia in two cases, contrast media containing iodine in three cases, atrioventricular block in five cases and drug treatment in the remaining patients (Sotalol in four patients, Amiodarone in two patients).

Genomic DNA was extracted from whole blood using a QIA amp DNA midi blood kit (Quiagen, Hilden, Germany). Polymerase chain reaction (PCR) amplifications of KCNQ1 fragments were performed, essentially as described by Neyroud et al. [14]. Exons 3–5, of HERG were amplified with primers published by Splawski et al. [15] and exons 6–15 with those of Berthet et al. [16]. Single-stranded conformation polymorphism (SSCP) analysis was performed on the PCR products, at 7 and/or 25°C. The PCR products were sequenced using the dye terminator technique on a Perkin Elmer 373 sequencer (Genome Express, Grenoble, France). One hundred chromosomes from unrelated control subjects were screened for mutations.

2.3 Results
Sixteen patients with Acquired Long QT Syndrome were screened for mutations on the KCNQ1, KCNE1, KCNE2 and HERG (exons 3–15) genes. None of the 16 probands presented abnormal conformers, associated with mutations of the KCNE1, KCNE2, and KCNQ1 genes. SSCP analysis of exons 3–15 of HERG showed an aberrant conformer in the PCR-amplified fragment covering exon 5 (Fig. 1). Direct sequencing revealed a heterozygous C->T change at nucleotide 1048 of the published cDNA sequence of HERG [15]. The mutation affected the first base in codon 328, changing an arginine to a cysteine in the N-terminal domain of HERG (R328C HERG). To test if the nucleotide change was a polymorphism, SSCP analysis of exon 5 was performed on 100 normal chromosomes. We found no abnormal conformer in any part of the sample. The patient was a 45-year-old man with no previous medical history. No sudden deaths had occurred in his family. He was hospitalized in our unit for syncopal episodes of recent onset. An ECG on admission to hospital, showed marked QT lengthening and complete atrioventricular block (Fig. 3Go). Torsades de pointes complicating an atrioventricular block was diagnosed. A pacemaker was inserted and since then, he has remained asymptomatic. It is of note that the QT interval was normal during electrical stimulation with a pacemaker.


Figure 1
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  		Fig. 1 A silent mutation in the patient with Acquired LQTS was found on HERG. (A) Single-stranded conformation polymorphism analysis of exon 5 from the HERG gene. The aberrant conformer of this patient with acquired long QT syndrome is indicated by a star. (B) Partial HERG sequence of this patient, heterozygous for a C->T (=N) change at nucleotide 1048 of exon 5.

 

Figure 2
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  		Fig. 2 Effects of R328C mutation on HERG channel activity in transfected COS-7. (A) Tail current density measured at –60 mV after a depolarization to 10 mV for 500 ms (holding potential: –80 mV) measured in cells transfected with 0.4 µg/ml pSI-WT HERG (WT HERG), 0.4 µg/ml pSI-R328C HERG or 0.4 µg/ml pSI-WT HERG plus 0.4 µg/ml pSI-R328C HERG (WT HERG+G328C HERG). (B) Superimposed current traces in transfected cells. Inset: voltage protocol. (C) Tail current density versus prepulse potential. Statistical significance: *P<0.05; **P<0.01; ***P<0.001.

 

Figure 3
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  		Fig. 3 ECGs from a patient with complete atrioventricular block and marked lengthening of the QT interval (A). A silent mutation on HERG was found. An ECG from the same patient after a pacemaker had been inserted (B). Note that the QT interval returned to normal.

 
2.3.1 Functional expression
In order to evaluate the functional characteristics that may correlate to the attenuated phenotype of this acquired LQTS, we investigated the consequences of R328C mutation on the HERG channel activity. The HERG R328C mutation was introduced in WT HERG cDNA (a kind gift from S. Kupershmidt, D. Snyders and D. Roden, Nashville, TN, USA) subcloned into the mammalian expression vector pSI (Promega) using the Strategene QuickChangeTM Site-Directed Mutagenesis Kit according to the manufacture guidelines. The pSI-R328C HERG construct was sequenced before expression studies. COS-7 cells (ATCC, Rockville, MD, USA) were cultured and transfected as previously described [17,18]. Whole-cell currents were recorded as indicated elsewhere in Cl–-free solutions at 37°C [19]. Patch-clamp measurements are presented as mean±S.E.M. Student's t-test and two-way ANOVA analysis were used when appropriate.

COS-7 cells transfected with 0.4 µg/ml pSI-R328C HERG exhibited a strongly reduced voltage-activated K+ current (n = 14, Fig. 2A) compared to the K+ current recorded in cells expressing pSI-WT HERG (0.4 µg/ml; n = 23). Since R328C HERG carriers also express the WT form of HERG, we evaluated the effects of co-expression of WT and R328C HERG on K+ current (0.4 µg/ml of each plasmid). As illustrated in Fig. 2A, the K+ current was decreased, despite the increase of total plasmid concentration, revealing a partial dominant-negative activity of the mutated HERG protein. The dominant-negative activity was observed at each tested potential (Fig. 2B and C).


   3 QT interval dispersion on a 12-lead ECG
Top
 Abstract
 1 Introduction
 2 Genetic testing
 3 QT interval dispersion...
4 Myocardial sympathetic...
 5 Time--frequency analysis of...
 6 Discussion
 7 Limitations
 8 Conclusions
 References
 
3.1 Rationale
An increase in ventricular repolarization dispersion is thought to be a marker of arrhythmogenicity [20,21]. It is believed that heterogeneity in myocardial electrical recovery can be evaluated in individuals, by measurement of the interlead difference in the QT interval, with a 12-lead ECG. Day et al. were the first ones to demonstrate that an increase in QT interval dispersion was present in patients with Congenital LQTS [22]. This was later confirmed by Linker et al. [23]. Priori et al. provided further evidence that effective treatment with beta-blockers, produced a decrease in QT interval dispersion in Congenital Long QT Syndrome [9]. To our knowledge, no studies have investigated whether an increase in QT dispersion is present in patients, who are not taking any treatment, and who have a history of iatrogenic torsades de pointes. We therefore analysed a group of 18 patients, who had suffered from drug-induced life-threatening arrhythmias.

3.2 Methods
Standard 12-lead ECGs were recorded at 25 mm/s, during treatment and after withdrawal of treatment. All of the ECGs were interpreted by two observers, who were unaware of which ECGs related to the patients, and which were from the controls. The QT interval was defined as the interval from the onset of the QRS complex to the end of the T wave, which was defined as the return to the TP baseline. Analysis of variance and the student unpaired t-test were used to compare the patients and the controls, and to calculate the precordial QT dispersion (Max QT in leads V1 through V6 minus Min QT in leads V1 through V6), as a measure of regional variability in the ventricular repolarization times. QTc was calculated using Bazett's formula. A group of 18 controls matched for age and sex, was also analysed.

3.3 Results
There were 16 women and two men with a mean age of 64±11 years. All of the patients had QTc interval lengthening immediately before torsades de pointes had occurred (QTc=650±110 ms). Underlying cardiac disease was present in 14 cases. Torsades de pointes occurred in 13 patients during treatment with class I a or 3 drugs. Antibiotics were involved in two cases and an antihistamine in three cases. After drug withdrawal, the QTc interval returned to normal (450±4 ms vs. 435±7 ms, NS). However, precordial dispersion was significantly higher than in the control group (55±15 vs. 33±9 ms, P<0.005). Blinded intra-observer reproducibility of the QT measurements was evaluated, giving a Spearman correlation coefficient of 0.90 (P = 0.001).


   4 Myocardial sympathetic heterogeneity
Top
 Abstract
 1 Introduction
 2 Genetic testing
 3 QT interval dispersion...
 4 Myocardial sympathetic...
5 Time--frequency analysis of...
 6 Discussion
 7 Limitations
 8 Conclusions
 References
 
4.1 Rationale
A regional disparity in the myocardial sympathetic innervation was found in patients with Congenital Long QT Syndrome, using I-123-meta-iodo-benzylguanidine scintigraphy (I-123-MIBG) [6,7]. However, there are few studies suggesting autonomic regulation of drug-induced torsades de pointes. For example, Charpentier et al., demonstrated that in Cesium-intoxicated Purkinje fibers, beta-adrenergic stimulation increased the early after-depolarization magnitude and the occurrence of triggered activity [24]. In a preliminary study, we showed abnormal innervation to be present in seven patients with Acquired LQTS compared to five healthy controls, using planar I-123-MIBG scintigraphy [25]. In this study, the Heart/Mediastinum activity ratio was calculated using an anterior view, 4 h after injection of the isotope. In this way, we were able to demonstrate that patients with Acquired Long QT Syndrome had a reduction in sympathetic innervation (Fig. 5Go). MIBG scintigraphy was then performed in other patients, this time using a tomographic technique, to confirm and give details about the extent of the abnormalities observed.


Figure 4
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  		Fig. 4 I-123-MIBG tomography in a patient with a history of Acquired LQTS. A four-step color scale was chosen (relative fixation compared with the point of maximum fixation): red for 75–100% of maximum fixation, yellow for 50–75% of maximum fixation, green for 25–50%, blue for 0–25%. To avoid activation of the adrenergic system between the two stages of imaging, the patients remained lying down. Note that the defect appears in yellow and shows a 50% to 75% loss of myocardial sympathetic innervation. The postero-inferior localization also predominates in the other patients. Note that Thallium scintigraphy was normal.

 

Figure 5
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  		Fig. 5 Planar I-123-MIBG scintigraphy in patients with (A) normal myocardial fixation, (B) transplanted heart with absence of fixation, (C) Acquired LQTS with heterogeneous fixation.

 
4.2 Methods
Twelve patients from two University hospitals, who suffered from Acquired Long QT Syndrome, were studied. Seven of them were excluded because of incomplete investigations. Four of the remaining five patients were women. Their mean age was 67±9 years. Acquired Long QT Syndrome was due to antiarrhythmic drugs in four patients and antihistamines in one patient. No patients were taking beta-blockers or tricyclic antidepressants at the time of the scintigraphy. To rule out ischemic heart disease, a Thallium scintigraphy was performed before the I-123-MIBG examination. Planar images were obtained in anterior oblique projections, after 15 min of rest, following an injection of 111 MBq of Thallium-201. Tomographic images were started immediately afterwards, using a gamma-camera with 180° rotation, 32 projections, 30 s/step and a 64x64 matrix.

4.3 Results
All of the patients with Acquired LQTS had uneven fixation of MIBG at 15 min and at 4 h. This abnormality was observed on the 2D projection images of the small axis slices, as non-heterogeneity of the colors (Fig. 4). In one patient, a defect in myocardial perfusion was found on Thallium scintigraphy. With the semi-quantitative ‘bull's eye’ method, which examines 16 segments, there were between six and 10 pathological segments in four patients, 4 h after the MIBG injection. These abnormalities predominated in the postero-inferior part of the left ventricle. The patient who had an abnormal Thallium scintigraphy, had more pathological segments with I-123-MIBG than on Thallium scintigraphy (10 and five segments, respectively). For all the other patients, more pathological segments were seen on MIBG at 4 h than at 15 min.


   5 Time—frequency analysis of signal-averaged ECG
Top
 Abstract
 1 Introduction
 2 Genetic testing
 3 QT interval dispersion...
 4 Myocardial sympathetic...
 5 Time--frequency analysis of...
6 Discussion
 7 Limitations
 8 Conclusions
 References
 
5.1 Rationale
Although it is known that the ventricular repolarization process starts within the QRS, conventional non-invasive techniques do not allow proper signal analysis to be made within this interval. None of the non-invasive conventional techniques provide relevant information about the start of repolarization. As information within the QRS remains elusive, there is a clear need for tools capable of investigating the beginning of the QRS accurately. Using wavelet transform, a new time—frequency technique, we recently identified abnormal intra-QRS signals in patients with myocardial infarction and ventricular tachycardia [26]. Thanks to the availability of this new signal processing technique, which extracts relevant information from the QRS, and in view of evidence of abnormal ventricular repolarization in Acquired LQTS patients, we decided to analyze their HR-ECGs using the wavelet technique. We found that frequency analysis of HR-ECG recordings provided significant information about the frequency content within the QRS, in patients with Congenital Long QT Syndrome [8]. Since the original publication, the population has been enlarged and more importantly, we have confirmed the results in genotyped patients. Fig. 6A represents the results of this new series of 23 patients with Congenital Long QT Syndrome, compared with 38 healthy controls. The most significant wavelets extracted were localized at the onset of QRS, probably indicating abnormalities right at the beginning of the repolarization process.


Figure 6
Figure 6
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  		Fig. 6 Three-dimensional mapping of the time scale representation of patients with Congenital (A) and Acquired (B) Long QT Syndromes onto the P value axis, with reference to a study population of 38 healthy subjects. Dark colors indicate increased energy and light colors indicate depressed activity. Note that both populations have abnormal frequency components right at the onset of QRS.

 
With this in mind, using the wavelet technique, we hypothesized that patients with Acquired Long QT Syndrome may have the same pattern of time—frequency abnormalities, as patients with the congenital form of the syndrome.

5.2 Methods
We compared the wavelet transform (WT) of the HR-ECGs of nine patients with ALQTS, with that of 38 normal volunteers. Recordings were made with bipolar pseudo-orthogonal X, Y, and Z leads, using an ART-1200 EPX (Arrhythmia Research Technology, Austin, TX, USA) high-resolution signal-averaging system. Conventional time—domain analysis was performed using the ART version 3·00 analysis software, following Simson's method [27]. Non-orthogonal Morlet WTs were computed from the onset of the QRS complex (onQRS) to onQRS+150 ms, with unfiltered X, Y and Z leads, and a magnitude vector lead (VM). The localization of the abnormal time—frequency components of the HR-ECGs, characterizing the patients with ALQTS, was found using a method based on the standard ANOVA technique [28,29]. This approach allowed stratification of the magnitude of the wavelet transforms into distinguishing features, by comparing the means of the wavelet coefficients of the Acquired LQTS population, with the corresponding means of the control population. In this way, we obtained a three-dimensional statistical map in the time—frequency and P-value spaces, to provide discriminating power for each of the wavelets.

5.3 Results
The mean age of the patient population was 67±24 years. Torsades de pointes was caused by hypokaliemia in one case, antiarrhythmic drugs in five cases (Sotalol in four cases and Amiodarone in one case), antibiotics in two cases and an antihistamine in one case. The QT interval became normal, after the patients had stopped these drugs. Late potentials, defined by time—domain analysis, were present in three patients. Time—domain analysis of the HR-ECGs indicated a significant increase in the QRS duration of the patients with Acquired LQTS, when compared with the controls (92.8±10 vs. 108.4±14 ms). Three-dimensional mapping presented in Fig. 6B, displays two abnormal time—frequency areas in the HR-ECGs of the Acquired LQTS patients, one within the QRS complex and the other in the ST-T segment. The intra-QRS abnormalities were similar to what has been found in Congenital LQTS patients, the most significant wavelets (P<0.001) being localized in the Z and VM leads. For the VM lead, the scales were 7 and 8 between –2 and +8 ms. The frequency locations were low and medium (40–125 Hz). Importantly, when the wavelet coefficients of the Acquired and Congenital LQTS patients were compared, no differences were noted in the QRS complexes. These findings further suggest that the common abnormalities that we found in the two groups of patients have pathological significance.


   6 Discussion
Top
 Abstract
 1 Introduction
 2 Genetic testing
 3 QT interval dispersion...
 4 Myocardial sympathetic...
 5 Time--frequency analysis of...
 6 Discussion
7 Limitations
 8 Conclusions
 References
 
6.1 Genetic studies
In our prospective series of 16 patients who were hospitalized for Acquired Long QT Syndrome, only one patient had a genetic abnormality of the types reported in Congenital Long QT Syndrome. More than 10 years ago, Moss and Schwartz first suggested that some cases of Acquired LQTS may in fact represent an attenuated form of Congenital LQTS [5]. Since then, genetic abnormalities have been shown in patients with a normal QT interval under normal conditions, but for whom certain drugs may cause dangerous lengthening of ventricular polarization [30,31]. Only a minority of patients with complete heart-block developed torsades de pointes. Our finding provides an understanding of the mechanism involved, since patients with atrioventricular block-related torsades de pointes may have abnormal repolarization responses to bradycardia [32]. This finding is in keeping with the fact that patients with Congenital Long QT Syndrome that are carriers of HERG mutations, are generally known to have bradycardia-related clinical events [33]. To our knowledge the R328C missense mutation in the N-terminal domain of HERG, has not previously been identified. Mutations in the C-terminal part of KCNQ1 and HERG have already been described, and were associated with less malignant clinical symptoms than mutations occurring in the pore region [16,34]. The present report gives further evidence that a subset of HERG mutations leads to a partial dominant-negative activity of HERG protein that alters HERG channel function. Partial reduction of IKr can be correlated with an attenuated clinical phenotype.

The concept of repolarization reserve [4] implies that a defect in the repolarization current of genetic origin exists. Reduction in this current as a result of an environmental factor (drugs, toxic substances, ischemia...) may unmask latent vulnerability. Using a dog model of atrioventricular block to study torsades de pointes, Volgers et al. demonstrated down-regulation of the Ikr current in the right ventricular myocardium [35]. We could therefore speculate that in our patient, the silent HERG mutation and a probable decrease in the Ikr current caused by the atrioventricular block, may have acted together to precipitate Acquired LQTS.

6.2 QT interval dispersion
The present study provides evidence for the presence of an increase in the QT interval dispersion in patients with Acquired LQTS, before any treatment had been started. This finding suggests that these patients have a greater non-heterogeneity of repolarization, that may contribute to their susceptibility to pro-arrhythmias. It remains to be proved if the magnitude of the increased ventricular repolarization dispersion underlies the magnitude of the sensitivity to torsades de pointes, in a given individual. QT prolongation alone is not sufficient to cause torsades de pointes. In fact, it appears to be the first stage before other features occur. Dispersion of electrical activation is certainly one of them. In a dog model of acquired torsades de pointes, Voss et al. found that enhanced dispersion of ventricular repolarization was necessary to induce polymorphic tachycardias, together with early after depolarization and QT prolongation [36]. It should be noted than non-heterogeneous electrophysiologic properties have been found in animal models of left ventricular hypertrophy [37], and in humans, this abnormality is known to be associated with an increased risk of torsades de pointes [38]. It has also been demonstrated that the pro-arrhythmic potential of D-Sotalol is proportional to this drug's concentration and experimentally, the highest dispersion is obtained with the highest concentration of D-Sotalol [39]. However, it appears that the cardiac side effects of Quinidine are independent of its dosage and of its action on electrical ventricular heterogeneity [40]. As stated earlier, this latter fact indicates that other predisposing factors exist, other than an increased dispersion of ventricular repolarization, to explain drug-induced torsades de pointes.

Hii et al. found that in patients treated with class Ic drugs, the development of torsades de pointes was preceded by increased QT interval dispersion [41]. Automated measurement with digital recordings should enhance the predictive accuracy of this potential marker of the arrhythmogenic risk [42].

6.3 Sympathetic myocardial innervation
The results of the present study suggest that the myocardial sympathetic innervation is abnormal in patients with previous Acquired Long QT Syndrome. In fact in their study, Gohl et al. reported that Congenital LQTS patients had a non-heterogeneous scintigraphic pattern for sympathetic innervation, with a decreased uptake of I-123-MIBG being detected in the postero-inferior wall of the left ventricle, like in our Acquired LQTS patients [7]. Much clinical and experimental evidence has proved that ventricular electrical stability may be threatened by an imbalance in the autonomic nervous system [43]. As for Congenital LQTS patients, it was suggested in 1971 that they may have lower than normal right cardiac sympathetic activity [44]. Indeed, left stellectomy has been shown to be quite effective in some patients who are resistant to medical therapy.

The mechanism by which sympathetic denervation may make drug-induced torsades de pointes more likely to occur, remains speculative. Liu QY et al. [45] demonstrated that sympathetic innervation was able to modulate K+ repolarization currents in rat epicardial myocytes. Using a dog model, Shimizu et al. recently found that an Iks blocker, Chromanolol 293B, induced torsades de pointes, only after beta-adrenergic stimulation [46]. The authors attributed this result to an increase in the transmural dispersion of the ventricular depolarization, by sympathetic stimulation. Thus, all these studies suggest a correlation between dispersion of the electrical activity and sympathetic denervation.

6.4 Wavelet analysis of HR-ECG
In the present study we demonstrated that discrimination between Acquired LQTS and normal patients, was possible by analysis of an HR-ECG with an orthogonal wavelet transform. The differences between LQTS patients and healthy subjects appeared only with time—frequency analysis, and not with standard time—domain analysis. It should be noted that the differences in QRS duration between the study group and the Long QT Syndrome patients accounted for the time—frequency changes observed at the end of the QRS. Fig. 6B highlights an increase in the low and medium frequency potentials at the onset of the QRS complex, that suggests a possible abnormality at the beginning of repolarization. This pattern of frequency content resembles that which we found in patients with Congenital Long QT Syndrome (Fig. 6A). Thus, wavelet analysis has allowed us to identify a common electrophysiologic substrate for both syndromes.

The mechanism underlying the abnormal frequency components early in the QRS complex, still need to be worked out. It is tempting to compare these abnormalities with those found by Schwartz et al., by echocardiography in patients with Congenital Long QT Syndrome [47]. They showed that ventricular wall contractility was abnormal, but that this was corrected with Verapamil. In dog experiments, right stellectomy has allowed this abnormal contractility of the posterior left ventricle to be produced. The authors deduced that these abnormalities were due to late after depolarization.


   7 Limitations
Top
 Abstract
 1 Introduction
 2 Genetic testing
 3 QT interval dispersion...
 4 Myocardial sympathetic...
 5 Time--frequency analysis of...
 6 Discussion
 7 Limitations
8 Conclusions
 References
 
The patient populations investigated differed according to the technique used. This is because over the 5 years studied, our approach was modified in line with the different methods that were available at the time. A 12-lead ECG was the first investigation to be examined retrospectively, because it is easy to perform. It should be noted that since the ECGs were recorded at 25 mm/s, interpretation of the results was made more difficult, although the control group should limit this problem. Not all of patients had an ECG-HA recording after the arrhythmic episode, because it is uncommon to prescribe this in patients with AQTLS. I-123-MIBG tomoscintigraphy was limited to just five patients, because this examination takes a long time when combined with Thallium scintigraphy, any treatment that may interfere with myocardial catecholamine uptake has to be stopped, and it is contra-indicated if there is coronary heart disease. Despite this, abnormal innervation was found in seven patients, included in another study, who were tested with planar scintigraphy. Finally, we also consider that the incidence of Acquired Long QT Syndrome has decreased over the last few years. This would certainly be thanks to better knowledge and more widely publicized information, about the drugs which are potentially responsible. All of these factors make the recruitment of an homogenous population of AQTLS patients a difficult task. Nevertheless, despite the small population size, statistical significance was reached for all of the results we obtained. These investigations were performed prospectively in order to improve our interpretation and to establish a cut-off value, which may help a quantitative diagnostic test to be developed. Ideally, further studies should include patients that have undergone all the investigations performed in this study.


   8 Conclusions
Top
 Abstract
 1 Introduction
 2 Genetic testing
 3 QT interval dispersion...
 4 Myocardial sympathetic...
 5 Time--frequency analysis of...
 6 Discussion
 7 Limitations
 8 Conclusions
References
 
Our results suggest that there are multiple links between the acquired and congenital forms of Long QT Syndrome. It appears that Acquired Long QT Syndrome can not be explained by a single abnormality, but rather by a complex interplay of different substrates. It is probable that the exact contribution of each of the defects or factors, varies from one individual to another. The respective changes over time that accompany aging, may also contribute by variably altering the arrhythmogenic setting. Efforts should therefore be directed towards an integrated approach which brings electrophysiologic, imaging and genetic techniques together, to allow the Long QT Syndromes to be better understood. This strategy will hopefully improve non-invasive quantification of the risk of developing of drug-induced life-threatening arrhythmias.

Times for primary review 22 days.


   Acknowledgements
 
We thank Patricia Charpentier (Laennec TeK, Nantes, France) and Christine Goutaland (Laboratoire de Biochimie, Lyon, France) for technical assistance.


   References
Top
 Abstract
 1 Introduction
 2 Genetic testing
 3 QT interval dispersion...
 4 Myocardial sympathetic...
 5 Time--frequency analysis of...
 6 Discussion
 7 Limitations
 8 Conclusions
 References
 

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