Biventricular hypertrophy in dogs with chronic AV block: effects of cyclosporin A on morphology and electrophysiology.
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Chronic atrioventricular (AV) block (CAVB) and biventricular hypertrophy in dogs increase susceptibility to drug-induced polymorphic ventricular tachycardia (PVT). In various rodent models, cyclosporin A (CsA) prevented hypertrophy. A similar effect in the CAVB model would allow us to determine whether hypertrophy represents an epiphenomenon, the cause of electrophysiological changes, and/or the anatomic substrate for PVTs. Upon AV node ablation, 6 dogs were studied acutely (AAVB), 25 dogs were kept for 6 (6W) and 12 wk (12W), receiving no treatment [CTL-CAVB-6W (n=6) and CTL-CAVB-12W (n=7)] or a daily oral dose of 10-20 mg/kg CsA directly (n=6, CsA-CAVB-6W) or 6 wk after radio-frequency ablation (n=6, CsA-CAVB-12W). For the final study, dogs were anesthetized, and 60 needles were inserted into both ventricles and connected to a multiplexer mapping system. Local effective refractory periods (ERPs) were determined at 56 +/- 22 randomly selected sites (extrastimulus technique, basic cycle length=800 ms). Arrhythmias within 30 min after application of almokalant (0.34 micromol/kg iv) were registered. The hearts were then excised to obtain the heart weight-body weight index (HBWI). Compared with AAVB, CTL-CAVB-6W and CTL-CAVB-12W showed increased HBWI and ERP associated with PVT inducibility in none of six AAVB dogs, four of six CTL-CAVB-6W dogs, and one of seven CTL-CAVB-12W dogs. Compared with CTL-CAVB-6W and CTL-CAVB-12W, CsA-CAVB-6W and CsA-CAVB-12W partially prevented hypertrophy or led to a regression of hypertrophy without reducing ERP prolongation. Despite ERP prolongation, PVTs were no longer inducible with CsA treatment. Thus prolongation of refractoriness seems to provide the trigger, but hypertrophy provides the essential substrate for the induction of PVTs in this model. (+info)
Channelling the Emperor: what really killed Napoleon?
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Arsenic was present in Napoleon's hair before he arrived on Saint Helena and the findings at necropsy are consistent only with the diagnosis of ulcerating, regionally invasive, gastric carcinoma. The question of whether Napoleon died of, or merely with, arsenic poisoning is illuminated by developments in the treatment of promyelocytic leukaemia. Arsenic trioxide induces remission in many, but treatment can be complicated by QT prolongation, torsades de pointes and sudden death. At clinically relevant concentrations, arsenic blocks both I(Kr) and I(ks) channels and, at the same time, activates I(K-ATP) channels. The balance of these forces is easily disrupted, and QT prolongation is worsened by hypokalaemia. Napoleon was chronically treated with tartar emetic for gastrointestinal symptoms, and the day before he died he was given a huge dose of calomel (mercurous chloride) as a purgative. Both treatments would have caused potassium wastage. In addition, the Emperor was being treated with a decoction containing 'bark'-presumably 'Jesuit's bark'. The quinine in Jesuit's bark is another cause of QT prolongation. It is likely that the immediate cause of the Emperor's death was torsades de pointes, brought on by chronic exposure to arsenic and a medication error. (+info)
Voriconazole-induced QT interval prolongation and ventricular tachycardia: a non-concentration-dependent adverse effect.
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A 15-year-old patient with acute lymphoblastic leukemia and Fusarium infection was treated with voriconazole. She developed asymptomatic bradycardia, QT interval prolongation, and nonsustained, polymorphic ventricular tachycardia, which recurred upon rechallenge with the drug. Voriconazole levels and metabolism were within expected normal values. This non-concentration-dependent, voriconazole-associated ventricular tachycardia mandates cardiac rhythm monitoring during voriconazole treatment. (+info)
Increased short-term variability of repolarization predicts d-sotalol-induced torsades de pointes in dogs.
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BACKGROUND: Identification of patients at risk for drug-induced torsades de pointes arrhythmia (TdP) is difficult. Increased temporal lability of repolarization has been suggested as being valuable to predict proarrhythmia. The predictive value of different repolarization parameters, including beat-to-beat variability of repolarization (BVR), was compared in this serial investigation in dogs with chronic AV block. METHODS AND RESULTS: In anesthetized dogs with electrically remodeled hearts, the dose-dependent difference in drug-induced TdP (d-sotalol, 2 and 4 mg/kg IV over 5 minutes, 25% and 75% TdP, respectively) could not be accounted for by prolongation of QT(c) (410+/-37 to 475+/-60 versus 415+/-47 to 484+/-52 ms, respectively). BVR was quantified by Poincare plots at baseline and immediately before onset of d-sotalol-induced extrasystolic activity. TdP occurrence was associated with an increase in short-term variability (STV) of the left ventricular monophasic action potential duration (3.5+/-1.5 to 5.5+/-1.6 versus 3.0+/-0.7 to 8.6+/-3.8 ms, respectively), which was reversible when TdP was abolished by I(K,ATP) activation. The absence of TdP despite QT(c) prolongation after chronic amiodarone treatment could also be explained by an unchanged STV. In experiments with isolated ventricular myocytes, STV increased after I(Kr) block and was highest in cells that subsequently showed early afterdepolarizations. CONCLUSIONS: Proarrhythmia is not related to differences in prolongation of repolarization but corresponds to BVR, here quantified as STV of the left ventricle. STV could be a new parameter to predict drug-induced TdP in patients. (+info)
Classification and mechanism of Torsade de Pointes initiation in patients with congenital long QT syndrome.
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AIMS: To examine the initiating mode of Torsade de Pointes (TdP) in patients with congenital long QT syndrome (LQTS). METHODS AND RESULTS: We evaluated 111 episodes of TdP recorded on the electrocardiograms of 24 patients with congenital LQTS, and clarified the initiating mode, the three consecutive preceding RR intervals defined as C(2), C(1), and C(0), the timing of initiating premature ventricular contraction (PVC) and the cycle length (CL) of TdP. Three different initiating patterns were observed: (1) a "short-long-short" sequence (SLS) pattern (23 patients, 72 TdP, 65%) defined as one or more short-long cardiac cycles followed by an initiating short-coupled PVC (C(1)>C(2) and C(0)), (2) an "increased sinus rate" (ISR) pattern (8 patients, 28 TdP, 25%) defined as a gradual increase in sinus rate with or without T-wave alternans (C(2)>/=C(1)>/=C(0)), and (3) a "changed depolarization" (CD) pattern (5 patients, 11 TdP, 10%) defined as a sudden long-coupled PVC or fusion beat followed by short-coupled PVC. The C(0) was shorter in ISR than SLS and CD (mean C(0): 488 vs. 587 and 603 ms, respectively; P<0.05). Therefore, the initiating PVC appeared near the T-wave peak of the last beat before onset in ISR, while it occurred after the T-wave peak in SLS and CD. The CL of TdP was shorter in ISR than in SLS (256 vs. 295 ms, P<0.05). CONCLUSIONS: Our data show the existence of three predominant initiating modes of TdP in patients with congenital LQTS and suggests a differential mechanism of initiation of TdP for each mode. (+info)
Molecular and clinical determinants of drug-induced long QT syndrome: an iatrogenic channelopathy.
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More than 70 drugs present on the Swiss market can cause drug-induced long QT syndrome (LQTS), which is associated with torsades de pointes (TdP) arrhythmias, potentially leading to sudden cardiac death. Basic and clinical investigations performed during the last decade have helped a better understanding of the mechanisms and risk factors of this serious public health problem. In their vast majority, QT interval prolonging drugs block the human ERG (hERG) channel involved in the repolarisation phase of the cardiac action potential, and thus lengthen the QT interval. Beside the well-known QT interval prolonging action of class IA, IC and III anti-arrhythmic drugs, many antibiotics, neurotropic, antifungal, and antimalarial drugs are also able to cause drug-induced LQTS. Reviewing the literature indicates that the risk of QT interval prolongation and TdP is increased in females, in patients with organic heart diseases and hypokalaemia. Furthermore in a few cases, genetic factors have also been reported. However thus far, no genetic test is available to detect at-risk patients, and in consequence, drug prescribers are still relying only on the clinical history and findings to perform an evaluation of the risk. Treatment of drug-induced LQTS and TdP includes identifying and withdrawing the culprit drug(s), infusing magnesium and, in resistant cases acceleration of the heart rate. In this review article we provide a list of QT interval prolonging drugs adapted to the pharmaceuticals found on the Swiss market that can be used as a check-list for drug prescribers and at-risk patients. (+info)
Cellular and ionic mechanism for drug-induced long QT syndrome and effectiveness of verapamil.
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OBJECTIVES: We examined the cellular and ionic mechanism for QT prolongation and subsequent Torsade de Pointes (TdP) and the effect of verapamil under conditions mimicking KCNQ1 (I(Ks) gene) defect linked to acquired long QT syndrome (LQTS). BACKGROUND: Agents with an I(Kr)-blocking effect often induce marked QT prolongation in patients with acquired LQTS. Previous reports demonstrated a relationship between subclinical mutations in cardiac K+ channel genes and a risk of drug-induced TdP. METHODS: Transmembrane action potentials from epicardial (EPI), midmyocardial (M), and endocardial (ENDO) cells were simultaneously recorded, together with a transmural electrocardiogram, at a basic cycle length of 2,000 ms in arterially perfused feline left ventricular preparations. RESULTS: The I(Kr) block (E-4031: 1 micromol/l) under control conditions (n = 5) prolonged the QT interval but neither increased transmural dispersion of repolarization (TDR) nor induced arrhythmias. However, the I(Kr) blocker under conditions with I(Ks) suppression by chromanol 293B 10 micromol/l mimicking the KCNQ1 defect (n = 10) preferentially prolonged action potential duration (APD) in EPI rather than M or ENDO, thereby dramatically increasing the QT interval and TDR. Spontaneous or epinephrine-induced early afterdepolarizations (EADs) were observed in EPI, and subsequent TdP occurred only under both I(Ks) and I(Kr) suppression. Verapamil (0.1 to 5.0 micromol/l) dose-dependently abbreviated APD in EPI more than in M and ENDO, thereby significantly decreasing the QT interval, TDR, and suppressing EADs and TdP. CONCLUSIONS: Subclinical I(Ks) dysfunction could be a risk of drug-induced TdP. Verapamil is effective in decreasing the QT interval and TDR and in suppressing EADs, thus preventing TdP in the model of acquired LQTS. (+info)
Prediction of the risk of Torsade de Pointes using the model of isolated canine Purkinje fibres.
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Torsade de Pointes (TdP) is a well-described major risk associated with various kinds of drugs. However, prediction of this risk is still uncertain both in preclinical and clinical trials. We tested 45 reference compounds on the model of isolated canine Purkinje fibres. Of them, 22 are clearly associated and/or labelled with a risk of TdP, and 13 others are drugs with published clinical evidence of QT prolongation, with only one or two exceptional cases of TdP. The 10 remaining drugs are without reports of TdP and QT prolongation. The relevance of different indicators such as APD(90) increase, reverse use dependency, action potential triangulation or effect on V(max) was evaluated by comparison with available clinical data. Finally, a complex algorithm called TDPscreen and based on two subalgorithms corresponding to particular electrophysiological patterns was defined. This latter algorithm enabled a clear separation of drugs into three groups: (A) drugs with numerous or several reports (>2 cases) of TdP, (B) drugs causing QT prolongation and/or TdP only, the latter at a very low frequency (< or =2 cases), (C) drugs without reports of TdP or QT prolongation. The use of such an algorithm combined with a database accrued from reference compounds with available clinical data is suggested as a basis for testing new candidate drugs in the early stages of development for proarrhythmic risk prediction. (+info)