Naturally occurring torsades de pointes and QT interval prolongation in a domestic cat.

A 10-year-old male American Shorthair cat was presented after a witnessed syncopal event. A Holter monitor demonstrated a long QT interval and revealed a rhythm characteristic of torsades de pointes (TdP) coincident with a bout of syncope. On subsequent Holter monitor recordings, sotalol did not prolong the QT interval further and did not reduce the severity of the underlying ventricular tachyarrhythmias, but no TdP was identified. When another syncopal event occurred, sotalol was discontinued, and oral amiodarone and magnesium were started. This resulted in improvement in the ventricular tachyarrhythmia. No syncopal events occurred in the ensuing 3 months, but the cat died of an unrelated disease shortly after. This is the first report of naturally occurring torsades de pointes in a domestic cat.

An Analysis of the Relationship Between Preclinical and Clinical QT Interval-Related Data.

There has been significant focus on drug-induced QT interval prolongation caused by block of the human ether-a-go-go-related gene (hERG)-encoded potassium channel. Regulatory guidance has been implemented to assess QT interval prolongation risk: preclinical guidance requires a candidate drug's potency as a hERG channel blocker to be defined and also its effect on QT interval in a non-rodent species; clinical guidance requires a "Thorough QT Study" during development, although some QT prolonging compounds are identified earlier via a Phase I study. Clinical, heart rate-corrected QT interval (QTc) data on 24 compounds (13 positives; 11 negatives) were compared with their effect on dog QTc and the concentration of compound causing 50% inhibition (IC50) of hERG current. Concordance was assessed by calculating sensitivity and specificity across a range of decision thresholds, thus yielding receiver operating characteristic curves of sensitivity versus (1-specificity). The area under the curve of ROC curves (for which 0.5 and 1 indicate chance and perfect concordance, respectively) was used to summarize concordance. Three aspects of preclinical data were compared with the clinical outcome (receiver operating characteristic area under the curve values shown in brackets): absolute hERG IC50 (0.78); safety margin between hERG IC50 and clinical peak free plasma exposure (0.80); safety margin between QTc effects in dogs and clinical peak free plasma exposure (0.81). Positive and negative predictive values of absolute hERG IC50 indicated that from an early drug discovery perspective, low potency compounds can be progressed on the basis of a low risk of causing a QTc increase.

Cardiopulmonary Effects of Laparoscopic Ovariectomy of Variable Duration in Cats.

OBJECTIVE: To evaluate the cardiopulmonary effects of low-pressure (6 mmHg) peritoneal insufflation of varying duration in healthy cats during ovariectomy (OVE). STUDY DESIGN: Prospective, randomized study. ANIMALS: Female cats (n = 24). METHODS: After anesthesia induction, cats had short (Short LAP; n = 8) or long duration (Long LAP; n = 8) laparoscopic ovariectomy, or Open OVE (Open; n = 8) for comparison. Hemodynamic and pulmonary measurements were recorded after induction of anesthesia (T0), 5 minutes after abdominal insufflation had reached 6 mmHg of pressure (T1), after the 2nd ovary had been resected (T2), after abdominal decompression (T3), and at the end of anesthesia, after abdominal closure (T4). Hemodynamic and pulmonary variables were compared between groups. RESULTS: Low-pressure abdominal insufflation caused cardiopulmonary changes in cats. At T1 and T2, Long LAP and Short LAP caused a significant change in PvCO2 and RC when compared with Open. During T3, RC was lower only in Long LAP. At T2, there was decrease in SV, but not CO for Long LAP when compared with Open. CONCLUSIONS: Duration of insufflation was associated with worsening of negative cardiopulmonary effects; however, these effects were reversible and resolved by the end of the procedure.

Left thoracotomy surgical approach for chronic instrumentation in dogs and monkeys providing high-quality electrocardiogram signals.

INTRODUCTION: Assessment of cardiovascular parameters, including the electrocardiogram (ECG) is required by the regulatory guidelines. In safety pharmacology studies, this is typically done using chronically implanted radiotelemetry devices in non-rodent species. METHODS: We compared ECG signal quality from ten male beagle dogs and 10 male cynomolgus monkeys with telemetry transmitters implanted using two surgical approaches: i) epicardial ECG lead placement via single incision, left side thoracotomy or ii) subcutaneous ECG lead placement via laparotomy. In addition, epicardial leads and semi-automated scoring were used in combination to detect changes in ECG values caused by moxifloxacin. Telemetry-instrumented male beagle dogs (n=8) and male cynomolgus monkeys (n=8) were given moxifloxacin at 10, 30, or 100 mg/kg (dogs) and 10, 50, or 175 mg/kg (monkeys) as a single dose by oral gavage. RESULTS: ECG signals were of excellent quality with epicardial lead placement, and human activity in the room did not significantly alter signal quality. Administration of moxifloxacin was associated with prolongation of QTc interval, in both dogs and monkeys in a dose-dependent pattern. Dogs given 30 mg/kg and 100 mg/kg, the maximum QTcf interval prolongations were 22 ms (+9%, 8 h postdose) and 60 ms (+24%, 15 h postdose). In monkeys given 50 and 175 mg/kg, the QTcb interval was significantly prolonged from 1 to 6h postdose, and QTcb interval prolongation persisted in monkeys given 175 mg/kg through 19 h postdose. In monkeys given 175 mg/kg, the maximum QTcb interval prolongation was 43 ms (+12.9%, 16 h postdose). DISCUSSION: The present study demonstrated that placing leads directly on the epicardium drastically diminishes signal disruption due to room disturbances and subsequent animal excitement. This novel surgical model demonstrated adequate sensitivity to detect changes in ECG parameters, specifically QTc interval prolongation in both the dog and monkey.

Uni- or bi-ventricular hypertrophy and susceptibility to drug-induced torsades de pointes.

INTRODUCTION: Cardiac hypertrophy is an independent risk factor for torsades de pointes (TdP), a polymorphic ventricular tachycardia that is often drug-induced, that may evolve into ventricular fibrillation and sudden death. Therefore this study was designed to determine if right (RVH), left (LVH), or biventricular (BVH) hypertrophy increases susceptibility to drug-induced TdP. METHODS: Rabbits were separated into 4 groups: control or RVH, LVH, BVH (studied 8weeks after banding of one or both great arteries). ECGs were recorded continuously under anesthesia after baseline and after rabbits received escalating doses of torsadogens (dofetilide, clofilium and terfenadine) or non-torsadogens (cilobradine, diltiazem and vehicle). The following parameters were measured [RR, PQ, QRS and QT] or calculated [QTc (F), short term variability of QT interval]. RESULTS: Generally, torsadogenicity for the compounds tested was dofetilide>clofilium>terfenadine, and there was no TdP following cilobradine, diltiazem or vehicle. In general the susceptibility to TdP was RVH>BVH>LVH>control. Rabbits with RVH developed TdP much more prevalently than for those with either LVH or BVH (p<0.05). At the low dose of dofetilide, LVH was actually protective. CONCLUSION: Rabbits with any form of hypertrophy develop prolongation of QT, QTc and increased QT instability. Rabbits with any form of hypertrophy are more prone to arrhythmia than normals in response to known torsadogens.

Evaluation of QT interval using a linear model in individual cynomolgus monkeys.

INTRODUCTION: The cynomolgus monkey, one of a number of primate species phylogenetically close to humans, is commonly used in cardiovascular research, but a method for determination of the RR interval-corrected QT interval in this species needs greater consideration. The objectives of this study were to determine a method for evaluating QT interval in cynomolgus monkeys individually, disregarding RR interval change artifacts, and to investigate prerequisite information for this method. METHODS: The physiological QT-RR relationship for practical evaluation of QT interval was recorded and analyzed by 24-hour telemetric ECG monitoring. A linear model for log-transformed QT and RR intervals was used to correct the QT interval from RR interval change artifacts for each animal. Sample size was also estimated based on the simulation results. RESULTS: Histograms showed that both QT and RR intervals had a right-heavy tail distribution. QT interval corrected individually by the linear model formula showed smaller within-animal variability than QTb and QTf, which were corrected by Bazett's formula and Fridericia's formula. The simulation results showed that the individual correction factor, beta(i), could be reliably estimated when at least 24 pairs of QT-RR baseline data were available. DISCUSSION: As with humans, QT interval in cynomolgus monkeys varies widely between individuals. Therefore, a method for correcting QT interval individually should be considered, whenever extensive untreated data are available.

Molecular genetics of sudden cardiac death in small animals - a review.

Sudden cardiac death in small animals is uncommon but often occurs due to cardiac conduction defects or myocardial diseases. Primary cardiac conduction defects are mainly caused by mutations in genes involved in impulse conduction processes (e.g., gap-junction genes and transcription factors) or repolarisation processes (e.g., ion-channel genes), whereas primary cardiomyopathies are mainly caused by defective force generation or force transmission due to gene mutations in either sarcomeric or cytoskeleton proteins. Although over 50 genes have been identified in humans directly or indirectly related to sudden cardiac death, no genetic aetiologies have been identified in small animals. Sudden cardiac deaths have been also reported in German Shepherds and Boxers. A better understanding of molecular genetic aetiologies for sudden cardiac death will be required for future study toward unveiling aetiology in sudden cardiac death in small animals.

QT interval measurement in the dog: chest leads versus limb leads.

INTRODUCTION: An accurate measurement of the QT interval is dependent on the accurate identification of the end of the T wave. Although chest leads have been recommended in dog toxicology studies, their use has not been widely put into practice, as shown by a recent survey on methodology for ECG collection in the pharmaceutical industry. Therefore, there is little published data on dog QT measurement from chest leads. METHODS: Electrocardiograms (ECGs) were taken from 100 beagle dogs (50 males, 50 females), with the dogs restrained in a sling. On the day of recording, measurements were performed at time zero and 1 h later. Recordings were repeated 7 to 10 days later. QT interval measurements were taken simultaneously from Lead II and the chest Lead CV5RL. Heart rate was taken from Lead II. Statistical analyses included the calculation of a QT correction formula, comparison of the mean values and variability of QT and QTc measurements from Leads II and CV5RL, the comparison of T-wave polarity from both leads, and a power analysis for QT and QTc. RESULTS: The T wave was positive in almost all dogs (99/100) in the Lead CV5RL at all measurement periods, while it was either positive or negative in Lead II (64-75/100), and the incidence of positive T wave varied between measurement periods. The QT interval was significantly shorter (194+/-11 to 197+/-12 vs. 197+/-13 to 200+/-12 ms) when measured from the CV5RL lead at all recording periods and in both sexes. In addition, the standard deviation for QT measurement within each individual ECG record demonstrates less intra-animal variation when QT is measured from Lead CV5RL compared with Lead II (3.8 vs. 13.2 ms). The linear regression between QT and heart rate was improved when QT measurements were taken from CV5RL, as shown by the percentage of variability R2. DISCUSSION: Estimates of the sample sizes showed that fewer animals would be required to detect a change at both the high and the mid-doses when using the chest Lead CV5RL. Using Lead II, we are able to detect within-animal changes of 10% in either QT or QTc; with Lead CV5RL, we are able to detect 10% change in QT and 5% change in QTc.

How to measure electrocardiographic QT interval in the anaesthetized rabbit.

Many drugs prolong QT or QU intervals [QT(U)] in the electrocardiogram (ECG), and this may be associated with the generation of drug-induced torsades de pointes. Therefore, it is essential to assess the ability of the newly developed drugs to prolong QT(U) interval. For this purpose, both in vivo and in vitro rabbit models are frequently used. However, it is very difficult to locate the end of the QT(U) interval in most rabbit ECGs when repolarisation is delayed, as the shape of the T and U waves may be deformed. In addition, as the heart rate of the rabbit is very high, the T (or U) wave may overlap the P wave or even the QRS complex of the following sinoatrial beat. In these circumstances, application of the "extrapolation method" makes it possible to determine the length of the QT(U) interval. This article describes the extrapolation method, shows ECG examples of typical T and U waves in the anaesthetized rabbit, and makes an attempt to provide a useful guide for researchers to measure reliably and reproducibly the duration of the QT(U) interval in rabbit studies.

Structural and functional basis for the long QT syndrome: relevance to veterinary patients.

Long QT syndrome (LQTS) is a condition characterized by prolongation of ventricular repolarization and is manifested clinically by lengthening of the QT interval on the surface ECG. Whereas inherited forms of LQTS associated with mutations in the genes that encode ion channel proteins are identified only in humans, the acquired form of LQTS occurs in humans and companion animal species. Often, acquired LQTS is associated with drug-induced block of the cardiac K+ current designated I(Kr). However, not all drugs that induce potentially fatal ventricular arrhythmias antagonize I(Kr), and not all drugs that block I(Kr), are associated with ventricular arrhythmias. In clinical practice, the extent of QT interval prolongation and risk of ventricular arrhythmia associated with antagonism of I(Kr) are modulated by pharmacokinetic and pharmacodynamic variables. Veterinarians can influence some of the potential risk factors (eg, drug dosage, route of drug administration, presence or absence of concurrent drug therapy, and patient electrolyte status) but not all (eg, patient gender/genetic background). Veterinarians need to be aware of the potential for acquired LQTS during therapy with drugs identified as blockers of HERG channels and I(Kr).

Investigation of QT-interval dispersion in the electrocardiogram of 81 dogs.

QT-interval dispersion (QT dispersion) is a marker of the inhomogeneity of ventricular repolarisation. In human beings an increase in QT dispersion has been linked to sudden death and arrhythmias in several cardiac diseases. In dogs it has yet to be evaluated, and this study aimed to establish a normal reference range for QT dispersion and to assess the effects of cardiac disease upon it. Ten-lead ECGS were recorded from 81 dogs at two hospitals; satisfactory traces were obtained from 68 dogs, 32 of them normal and 36 with cardiac disease. The mean (sd) QT dispersion was 20.8 (18.2 ms) and the mean heart rate-corrected QT dispersion was 26.1 (23.6 ms). There was no significant effect of cardiac disease. The accuracy of the results may be questioned owing to the identification of several potential errors in the measurements.

Hemodynamic and electrophysiologic effects of ontazolast in dogs.

OBJECTIVE: To determine whether QT interval is prolonged or sudden death is caused by ventricular fibrillation resulting from torsades de pointes and to identify hemodynamic effects of ontazolast. ANIMALS: 28 Beagles. PROCEDURE: Physiologic variables were measured for 2 hours in conscious dogs given ontazolast (0, 1, or 3 mg/kg of body weight, IV) and for 1 hour in anesthetized dogs given cumulative doses of ontazolast (0, 1, 3, 6, or 8 mg/kg, IV). RESULTS: Ontazolast prolonged QT interval and QT interval corrected for heart rate (QTc) at doses of 6 mg/kg in anesthetized dogs. At 8 mg/kg, both variables remained prolonged but tended to decrease. In conscious dogs, ontazolast increased QT interval and QTc 15 minutes after administration, but both variables returned to reference ranges by 60 minutes. In conscious dogs, ontazolast increased maximum rate of increase of left ventricular pressure and maximal velocity of fiber shortening, indicators of inotropy, and increased tau, indicating a decreased rate of relaxation. One conscious dog receiving 3 mg/kg developed nonfatal torsades de pointes, but another conscious dog developed ventricular fibrillation. Two anesthetized dogs receiving 6 mg/kg developed early afterdepolarizations, and all dogs developed secondary components in theirT waves. CONCLUSION AND CLINICAL RELEVANCE: Ontazolast possesses potent class-III antiarrhythmic properties and induces prolongation of QTc in a dose-dependent fashion. Because there was a clear dose-dependent prolongation of QT interval in all instances, ontazolast may serve as a positive-control compound for studying other compounds that are believed to prolong the QT interval.