Risk Of Serious Ventricular Arrhythmias Research Articles

MTORC1 is a key regulator that mediates OGD- and TGFβ1-induced myofibroblast transformation and chondroitin-4-sulfate expression in cardiac fibroblasts.

Ischemia-reperfusion infarct-derived chondroitin sulfate proteoglycans (CSPGs) are important for sustaining denervation of the infarct. Sympathetic denervation within the heart after myocardial infarction (MI) predicts the probability of a higher risk for serious ventricular arrhythmias. Chondroitin-4-sulfate (C4S) is the predominant chondroitin sulfate component in the heart. However, the mechanisms that induce CSPG expression in fibroblasts following MI remain to be elucidated. The present study found that oxygen-glucose deprivation (OGD) and TGFβ1 stimulation induced myofibroblast transformation and C4S synthesis in vitro by using reverse transcription-quantitative PCR, western blotting and immunofluorescence. MTT assay was used to detect cell viability following OGD or OGD + TGF lotreatment. Using the PI3K inhibitor ZSTK474, the Akt inhibitor MK2206, or the mTOR inhibitor AZD8055, it was observed that OGD and TGFβ1 stimulation induced myofibroblast transformation and that C4S synthesis was mTOR-dependent, whereas the upstream canonical PI3K/Akt axis was dispensable by using western blotting and immunofluorescence. siRNA knockdown of Smad3, Raptor, or Rictor, indicated that mTORC1 was critical for promoting OGD- and TGFβ1-induced myofibroblast transformation and C4S synthesis by using western blotting and immunofluorescence. This response, may be mediated via cooperation between canonical Smad3 and mTORC1 signaling. These data suggested that inhibiting myofibroblast transformation may reduce C4S synthesis. Target mTORC1 may provide additional insight into the regeneration of sympathetic nerves and the reduction of fibrosis after MI at the cellular level. These findings may contribute to the understanding of the mechanism by which C4S overproduction in the hearts of patients with MI is associated with myocardial fibrosis.

PONV management in patients with QTc prolongation on the EKG.

Postoperative nausea and vomiting (PONV) is a commonly encountered problem in surgical practice. It delays discharge from the post-anesthesia care unit, requires additional resources to treat, and may increase the morbidity in some patients. Many effective drugs are available to treat or prevent PONV, however many of these drugs have the potential to prolong the QTc on the electrocardiogram (EKG) and increase the risk of serious ventricular arrhythmias, in particular, torsade de pointes. The QTc prolongation may be a manifestation of a genetic mutation resulting in abnormal myocyte repolarization or it may be acquired and associated with the use of various medications, electrolyte disorders, and physiological conditions. Patients predisposed to QTc prolongation presenting for surgery constitute a challenging group, since many drugs commonly used for PONV management will put them at risk for perioperative serious arrhythmias. This is an important topic, and our mini-review is an attempt to highlight the problem, summarize the existing experience, and generate recommendations for safe management of PONV for patients, who are at increased risk of QTc prolongation and arrhythmias. Focused prospective studies will help to find definitive answers to the discussed problems and challenges and develop specific guidelines for clinical application.

Risk of Serious Ventricular Arrhythmia in Users of Gastrointestinal Medications: A Retrospective Cohort Study in China.

Clinical data have demonstrated prolongation of the QTc interval associated with domperidone use. The risk of serious ventricular arrhythmias (SVA) in clinical practice in China has not been investigated. The incidence of SVA and all-cause cardiac arrest associated with medications for gastrointestinal disorders in China was assessed in a retrospective cohort study using information from electronic medical record databases from the Xijing and Guangzhou general hospitals. Inpatients and outpatients with at least one prescription for domperidone, mosapride/itopride, metoclopramide, a proton pump inhibitor (PPI), or histamineH2 receptor antagonist were identified in the hospital databases from January 1, 2009 to December 31, 2014. The inpatient exposure cohorts included 66,282 inpatients at Xijing and 23,643 inpatients at Guangzhou hospitals. There were 67 cases of SVA and two cases of SVA at the respective hospitals during the study period. Three cases (all at Xijing) occurred in patients prescribed domperidone (incidence rate 2.9/100person-years (PYs), 95% CI 0.9-9.0) compared to 1.3/100PYs (95% CI 0.2-8.9) for mosapride/itopride and 5.6/100PYs (95% CI 4.4-7.2) for PPIs. The hazard ratio adjusted for age, sex, and co-morbidities for SVA in patients prescribed domperidone compared to PPIs was 0.79 (95% CI 0.25-2.56). There were 44 cases of all-cause cardiac arrest at Xijing and 21 at Guangzhou hospital. Three patients had received domperidone and all had underlying cardiovascular diseases. SVA and cardiac arrest are very rare events in patients prescribed medications for gastrointestinal disorders in China. We found no evidence that domperidone carried a higher risk of SVA compared to other gastrointestinal medications.

Cardiorespiratory Fitness and the Risk of Serious Ventricular Arrhythmias: A Prospective Cohort Study

Cardiorespiratory fitness (CRF) is an established risk factor for cardiovascular disease outcomes. However, the relationship of CRF with risk of ventricular arrhythmias (VAs) is unknown. We aimed to assess the prospective association of CRF with the risk of serious VAs. Cardiorespiratory fitness, as measured by maximal oxygen uptake, was assessed using a respiratory gas exchange analyzer in 2299 middle-aged men in the Kuopio Ischemic Heart Disease prospective cohort. We corrected for within-person variability in CRF levels using data from repeated measurements 11 years apart. During median follow-up of 25.3 years (interquartile range, 18.7-27.2 years), 73 serious VAs were recorded. The age-adjusted regression dilution ratio of CRF was 0.58 (95% CI, 0.53-0.64). In analysis adjusted for age, the hazard ratio (HR) for serious VAs per 1-SD increase in CRF was 0.64 (95% CI, 0.49-0.84). The association persisted on additional adjustment for body mass index, systolic blood pressure, history of hypertension, prevalent coronary heart disease, smoking, history of diabetes, cholesterol level, alcohol consumption, and physical activity (HR, 0.67; 95% CI, 0.51-0.88). The corresponding adjusted HRs (95% CIs) were 0.29 (0.14-0.59) and 0.32 (0.15-0.65), respectively, comparing the top vs bottom tertiles. The associations were stronger on correction for regression dilution bias, remained consistent on exclusion of men with a history of coronary heart disease, and did not vary importantly in several relevant clinical subgroups. Cardiorespiratory fitness is inversely associated with future risk of serious VAs, independently of several cardiovascular disease risk factors. Further research is needed to assess the causal relevance of these findings.

Association of oral ciprofloxacin, levofloxacin, ofloxacin and moxifloxacin with the risk of serious ventricular arrhythmia: a nationwide cohort study in Korea

ObjectiveTo evaluate whether oral ciprofloxacin, levofloxacin, ofloxacin and moxifloxacin increase the risk of ventricular arrhythmia in Korea’s general population.DesignPopulation-based cohort study using administrative claims data on a national scale in...

QTc interval evaluation in patients receiving anticancer drugs: Preliminary results of a retrospective study.

e19605 Background: Most anticancer therapies (ACT) may prolong the QT interval, increasing the risk of serious ventricular arrhythmias and sudden death. Moreover, oncologic patients are considered at increased risk of life-threatening arrhythmias because of additional predisposing risk factors, such as electrolytes abnormalities, starvation and concomitant medications. Most data, however, have been derived from clinical trials in which patients with a baseline long QT have systematically been excluded. Therefore, information on the true incidence of a baseline long QT interval and its possible prolongation during ATC in clinical practice are still lacking Methods: We retrospectively evaluated the hospital records of 646 unselected patients (69% women) undergoing at least two electrocardiograms (EKG), before and during ACT, including anthracyclines and alchylating agents in 65% of cases. QT interval was corrected for heart rate (QTc) using the Bazett's formula. A QTc value >450 msec was defined as prolonged. We considered the following cardiac events during a mean follow-up of 47±37 months: sudden death, non sustained ventricular tachycardia (NSTV), sustained ventricular tachycardia including torsade de point, and syncope. Results: In 203 (31%) patients we found a prolonged QTc (median value 470 [interquartile range: 460-490] msec). In 87 of them the QTc was already prolonged at baseline (470 [460-480] msec); in 116 patients, it increased during ACT (from 420 [400-440] to 480 [460-500] msec), with an increase exceeding 60 msec in 57 cases (49%). A single episode of NSVT was documented, preceded by an EKG showing a normal QTc. Patients with prolonged QTc were more frequently males (43% vs. 32%; p<0.01), older (57±13 vs. 50±14 years; p<0.001), and more frequently with a history of cardiovascular disease (29% vs. 20%; p<0.01). Notably, also in patients who did not reach a value >450 msec, the QTc significantly increased during ACT (from 410 [390-430] to 420 [400-440] msec; p<0.01). Conclusions: A long QTc is frequently observed in oncologic patients, receiving or not ACT. Both a baseline long QTc and its prolongation during ACT, however, do not seem associated with the occurrence of life-threatening arrhythmias.

Risk of serious ventricular arrhythmia and sudden cardiac death in a cohort of users of domperidone: a nested case‐control study

Limited information from spontaneous reports and results of two case-control studies raised concern about the cardiotoxicity of oral domperidone therapy. This case-control study nested in a retrospective cohort evaluated the combined risk of serious ventricular arrhythmia (SVA) and sudden cardiac death (SCD) in users of domperidone compared with users of proton pump inhibitors (PPIs), or non-users of these medications. A cohort of users of domperidone or a PPI from 1990 to 2005 was identified from existing electronic databases of Saskatchewan Health. Possible cases of SVA/SCD were identified using hospital discharge and vital statistics codes. SVA cases were validated by cardiologist review of abstracted hospital medical charts. Up to four controls were matched to each case by index date, year of birth, sex, and diabetes status. The odds ratio (OR) of current domperidone exposure relative to non-use or to current PPI exposure was estimated and adjusted for possible confounding variables using conditional logistic regression. From 83 212 individuals in the exposure cohort we identified 1608 cases, 49 SVA and 1559 SCD (mean age 79.4 years, females 52.9%, diabetes 22.3%) and 6428 matched controls. The adjusted OR for SVA/SCD with current domperidone use compared with non-use was (1.59, 95%CI: 1.28-1.98), or compared with current PPI use was (1.44, 95%CI: 1.12-1.86). In stratified analyses adjusted ORs were numerically higher in males, older subjects, and non-diabetics. The increased risk of SVA/SCD for current domperidone users remained after adjustment for multiple covariates. The risk may vary among subgroups of exposed individuals.

Abstract B212: QTc study of picoplatin with emphasis on pharmacodynamics of cardiac repolarization

Abstract Introduction: Clinical studies have demonstrated that picoplatin (Pico), a new-generation platinum analogue designed to overcome platinum resistance, has activity when administered IV in solid tumors patients (pts); over 1,100 pts have received pico. The primary toxicity is hematological. Clinically significant nephro-, oto-, or neurotoxicity has rarely been observed (&amp;lt;1% grade 3 and 0% grade 4), even in platinum-pretreated patients. Pico (150 mg/m2) Q3W is currently being studied in a Phase 3 trial as 2nd-line monotherapy for SCLC. Pico is also being studied in Phase 2 trials in combination with other chemotherapy drugs for colorectal and prostate cancers. In preclinical studies in dogs, pico had no effect on cardiovascular function, including the QT interval. In clinical trials to date, drug-related serious ventricular arrhythmias have not been observed. The purpose of this study was to assess cardiac effects of Pico in patients with advanced solid tumors. Methods: The effect of pico on the QT/QTc interval as measured by the ECG was evaluated. The correlation between the QTcF interval and platinum concentration in plasma and plasma ultrafiltrate (PUF) was evaluated. ECG was recorded continuously with a Holter monitor. Triplicate 20 second ECG readings were extracted at 3 times before (baseline reference) and at 8 times in the 24 hrs after pico administration in Cycle 1. Triplicate 12-lead ECGs were obtained at the end of the pico infusion in subsequent cycles. Blood samples were collected before study drug administration and immediately after each ECG timepoint in Cycle 1 for pharmacokinetic analysis. The primary endpoint was the Fredericia corrected QT (QTcF). Time-averaged and time point analyses for QTcF were performed. Heart rate, PR, QRS, QT, QTcB (Bazett's) and morphological changes were also evaluated. Results: 45 pts (28 women and 17 men), age 44–79 years (median = 60) received 150 mg/m2 pico as a 1-hr IV infusion. The time-averaged mean change from baseline of QTcF duration during Cycle 1 was +2.2 ms, which is considered a nonsignificant increase. At each time point in Cycle 1 and in subsequent cycles, there were only minimal changes from baseline in QTcF duration. Other ECG changes from baseline were unremarkable: ST depression was noted in 9% of pts at baseline and new T-wave changes in 7% of pts in Cycle 1. Mean ± SD Cmax in plasma and PUF were 5566 ± 1079 ng/mL and 4034 ± 674 ng/mL, respectively. The change in QTcF vs. platinum concentration in plasma or PUF showed a Cmax effect of 5–6 ms with an upper confidence interval of 8–9 ms, suggesting no clear effect of picoplatin on QTcF. Conclusions: Pico had no effect on the QTcF interval or any other ECG parameter, supporting the clinical data showing that Pico does not increase the risk of serious ventricular arrhythmias. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B212.

Development of a program for repolarization parameters of research and clinical interest using the Matlab platform

Introduction: Lux et al (J Electrocardiol, 2006;39:S161-S164) described the use of the root mean square (RMS) electrocardiogram signal to obtain several useful parameters of ventricular repolarization. Two parameters, the RMS Rto T-peak interval (RT; a surrogate for the mean ventricular action potential duration) and the RMS T-width (TW; a measure of the dispersion of ventricular repolarization times), are known to relate to the risk of serious ventricular arrhythmias. Software for these analyses is apparently not now available for Windows or Linus/Unix operating systems. Accordingly, we developed software using the Matlab platform for measuring these 2 (and other) parameters of research and clinical interest. Method: We used 5-minute electrocardiogram traces recorded at 1000 samples/s and 5 μV LSB sensitivity (Hodges and Mortara. J Electrocardiol, 1999(Suppl);32:55-59) as test data for development. The RMS signal from 8 leads (I, II, V1-V6) was used to identify each QRS complex, using slope detection. T-wave peak was identified as the zero-crossing point of the first derivative of the RMS signal in an “expected” T-wave area. The expected Twave area was estimated based on the R-R interval between current and successive beats. The preceding diastolic interval (DI; defined as R wave to previous T-peak) was computed by using the identified R and T peaks. We then plotted DI against RT, as done by Segerson et al (Heart Rhythm, 2008;5:208-214) to see if our plots were qualitatively similar to those of Segerson et al. We also compared on a beat-to-beat basis our results on a given file with the results of the criterion standard Macintosh software of Lux et al on the same file. Results: The RT versus DI plots with data identified by our program for both normal subjects and post-myocardial infraction patients were qualitatively similar to the plots published by Segerson et al. The beat-to-beat comparisons with the program of Lux et al showed good agreement; a complete quantitative analysis will be completed by the time of abstract presentation.

Atypical antipsychotic drugs and the risk of sudden cardiac death.

Users of typical antipsychotic drugs have an increased risk of serious ventricular arrhythmias and sudden cardiac death. However, less is known regarding the cardiac safety of the atypical antipsychotic drugs, which have largely replaced the older agents in clinical practice. We calculated the adjusted incidence of sudden cardiac death among current users of antipsychotic drugs in a retrospective cohort study of Medicaid enrollees in Tennessee. The primary analysis included 44,218 and 46,089 baseline users of single typical and atypical drugs, respectively, and 186,600 matched nonusers of antipsychotic drugs. To assess residual confounding related to factors associated with the use of antipsychotic drugs, we performed a secondary analysis of users of antipsychotic drugs who had no baseline diagnosis of schizophrenia or related psychoses and with whom nonusers were matched according to propensity score (i.e., the predicted probability that they would be users of antipsychotic drugs). Current users of typical and of atypical antipsychotic drugs had higher rates of sudden cardiac death than did nonusers of antipsychotic drugs, with adjusted incidence-rate ratios of 1.99 (95% confidence interval [CI], 1.68 to 2.34) and 2.26 (95% CI, 1.88 to 2.72), respectively. The incidence-rate ratio for users of atypical antipsychotic drugs as compared with users of typical antipsychotic drugs was 1.14 (95% CI, 0.93 to 1.39). Former users of antipsychotic drugs had no significantly increased risk (incidence-rate ratio, 1.13; 95% CI, 0.98 to 1.30). For both classes of drugs, the risk for current users increased significantly with an increasing dose. Among users of typical antipsychotic drugs, the incidence-rate ratios increased from 1.31 (95% CI, 0.97 to 1.77) for those taking low doses to 2.42 (95% CI, 1.91 to 3.06) for those taking high doses (P<0.001). Among users of atypical agents, the incidence-rate ratios increased from 1.59 (95% CI, 1 .03 to 2.46) for those taking low doses to 2.86 (95% CI, 2.25 to 3.65) for those taking high doses (P=0.01). The findings were similar in the cohort that was matched for propensity score. Current users of typical and of atypical antipsychotic drugs had a similar, dose-related increased risk of sudden cardiac death.

Psychological Reaction to Potential Malfunctioning of Implantable Defibrillators

Psychological problems following implantable cardioverter defibrillators (ICD) implantation are diverse and include increased levels of anxiety. Anxiety may even rise further when possible malfunctioning of an ICD is announced, with a higher risk of serious ventricular arrhythmias and death as a consequence. Following the public statement of Medtronic, all patients in the Netherlands with the specific Medtronic ICD were contacted for extra device evaluation. The aim of this exploratory study was to determine whether the proportion of ICD patients with high levels of anxiety would increase after this extra device evaluation. Patients were recruited from an ongoing prospective study on psychological effects of ICD implantation. Thirty-three patients completed the State subscale of the State-Trait Anxiety Inventory (STAI) before and after extra device evaluation. The STAI can identify patients with high levels of anxiety. A high level of anxiety was experienced by two patients (6.1%) at baseline and eight patients (24.2%) at follow-up (P=0.031). Hence, ICD patients were significantly more likely to experience high levels of anxiety following the public statement of potential malfunctioning of their device. A public statement regarding device safety may increase levels of anxiety among ICD patients. Given the potential triggering effect of high levels of anxiety on arrhythmias, psychological support may be considered for some of the ICD patients after such public statement.

Predicting Cardiac Arrhythmias and Sudden Death in Diabetic Users of Proarrhythmic Drugs

In diabetic patients, the corrected QT (QTc) interval is relatively long (1). In accordance with the concept of “reduced repolarization reserve” (2), a subsequent increase in QTc interval by proarrhythmic drugs may lead to cardiac arrhythmias and sudden death. Recently, it was shown that patients with diabetes are at increased risk of drug-induced arrhythmias (3). We developed a decision tool to predict the risk of serious ventricular arrhythmias and sudden death among diabetic users of nonantiarrhythmic proarrhythmic drugs. A cohort study among 61,280 diabetic patients using nonantiarrhythmic proarrhythmic medication (amitriptyline, astemizole, chloroquine, chlorpromazine, cisapride, clarithromycin, clomipramine, cotrimoxazole, diphenhydramine/dimenhydrinate, domperidone, doxepine, droperidol, erythromycin, grepafloxacin, halofantrine, haloperidol, indapamide, ketanserin, lidoflazine, mianserine, pentamidine, pimozide, probucol, promethazine, protriptyline, sulfamethoxazole, sultopride, tacrolimus, terfenadine, terodiline, thioridazine, trimethoprim, and zimeldine) (4) in the General Practice Research Database (1987–2001) was performed. This database contains computerized medical records of ∼650 general practices, including ∼6.5% of the population of England and Wales. Diabetic patients were followed from the 1st day of prescription of any nonantiarrhythmic proarrhythmic drug. Follow-up was censored when the duration of (one of) the prescription(s) had elapsed, when the study outcome occurred, in case of death, upon exit from the study population, or at the end of the study period, whichever of these events came first. The combined study outcome included ventricular tachycardia, ventricular fibrillation and flutter, cardiac arrest, and sudden death. …

QT dispersion and myocardial viability in patients after acute myocardial infarction

Background: In recent years QT dispersion (QTd) in post-infarct patients was estimated in many studies, but still little is known about its association with the presence of dysfunctional but viable myocardium. Aim: We investigated the relation between dispersion of QT interval and myocardial viability in patients after acute myocardial infarction (AMI). Material and methods: In 52 patients (mean age 67.2±11.7) treated thrombolitycally because of AMI 12-lead ECG and low dose–high dose dobutamine echocardiography was performed on 14th day after treatment. QTd and regional myocardial contractility were estimated three times: at baseline, low dose dobutamine (LDD) (10–15 μg/kg per min) and high dose dobutamine (HDD) infusion (up to 40 μg/kg per min). Results: Patients with viable myocardium had lower baseline QTd than patients with only necrosis in infarct zone. Significant increase in QTd was shown during LDD and HDD both in patients with and without myocardial viability. During infusion of HDD QTd was significantly higher in patients with myocardial ischemia. The greatest percentage increase of QTd at HDD was shown in patients with biphasic response to dobutamine infusion i.e. with myocardial viability evidenced at LDD and myocardial ischemia at HDD. Conclusion: Patients with preserved myocardial viability had lower QTd values compared to those with similar left ventricular dysfunction but caused only by post-infarction necrosis. Ischemia evoked on 14th day after AMI was accompanied by greater increase in QTd in patients with myocardial viability in infarct region than in patients without. It may be one of the reasons of greater risk of serious ventricular arrhythmias in such patients during myocardial ischemia.

Impaired left ventricular function is associated with increased recovery time dispersion in patients with previous myocardial infarction

Left ventricular (LV) dysfunction after myocardial infarction is associated with higher risk of serious ventricular arrhythmias and sudden death. We suspected that heterogeneity in ventricular repolarization contributes to these arrhythmias. To quantify this heterogeneity, we measured the recovery time (the interval between QRS onset and the time of maximum dV/dt in the ST-T segment) using an 87-lead body surface mapping electrocardiogram and estimated recovery time dispersion (the difference between maximum recovery time and minimum recovery time) in each lead. Differences between 110 patients with previous myocardial infarction and 31 healthy controls were compared. Recovery time dispersion [medians (25th, 75th percentiles)] was greatest in patients with a dilated LV {169 ms (154, 201) vs. 155 ms (137, 172), P < .005}, impaired ejection fraction {173 ms (155, 202) vs. 152 ms (138, 165), P < .0005} and LV dyskinesis {175 ms (159, 201) vs. 155 ms (137, 161), P < .0005}. This study suggests that LV dysfunction associated with myocardial infarction leads to heterogeneous ventricular repolarization and may provide the electrical substrate for ventricular arrhythmias.

Pharmacotherapeutic approaches for decompensated heart failure: a role for the calcium sensitiser, levosimendan?

Although no universal definition exists, decompensated heart failure may be regarded as either a worsening of chronic heart failure or new-onset heart failure precipitated by an acute incident. Haemodynamic management of patients hospitalised with decompensated heart failure may include the administration of diuretics, vasodilators and positive inotropic agents. Until recently, these latter agents constituted the only drug class to produce a direct increase in stroke volume via enhanced myocardial contractility. However, despite their short-term benefits, the clinical utility of inotropic agents is compromised by their potentially deleterious effects on calcium handling and oxygen consumption, resulting in an increased risk of serious ventricular arrhythmias and death. In contrast, calcium sensitisers enhance cardiac performance without affecting calcium movement and, therefore, are potentially associated with a reduced risk of rhythmic disturbances. These agents constitute a heterogeneous group of compounds with different affinities for calcium sensitisation. Levosimendan is a potent calcium sensitiser with vasodilating properties that has been shown to provide symptomatic and haemodynamic improvement with no increase in oxygen consumption. Calcium sensitisation is therefore emerging as a promising treatment approach in this challenging therapeutic area.

Serious ventricular arrhythmias among users of cisapride and other QT-prolonging agents in the United States.

To evaluate the risk of serious ventricular arrhythmia (SVA) with cisapride use in the United States. The study population included 28,078 patients under the age of 65 years who received cisapride between 1993 and 1998 with no history of antiarrhythmia treatment. Each follow-up day was classified according to use of cisapride and other factors. Outcomes of SVAs were identified using medical claims records and National Death Index search, and confirmed by medical record review. Rates of events were calculated for time on and off cisapride. Poisson regression analysis was used to calculate adjusted rate ratios. There were 23 cases of SVAs; 10 during periods of cisapride use and 13 during periods of non-use. The adjusted rate ratio comparing SVA events in cisapride use time to non-use time was 1.60 (95% CI: 0.67-3.82), and that identified for the other QT-prolonging drugs was 1.60 (95% CI: 0.65-3.98). The evidence for an increased risk of SVAs associated with cisapride was equivocal after taking observation time on and off cisapride into account, and adjusting for risk factors, though we cannot exclude the possibility of a 3.8-fold increased risk. Overall, the plausible risks of cisapride were similar to those of other QT-prolonging drugs.

Antipsychotic linked to sudden unexplained death in psychiatric patients

N research supports earlier evidence that the antipsychotic drug thioridazine may increase the risk of sudden death by delaying ventricular repolarisation and causing torsades de pointes, British researchers report. In 2000, UK and US regulatory agencies issued warnings about the drug, which had been shown to prolong the QTc interval in a dose-related manner. Simon H L Thomas (University of Newcastle upon Tyne, Newcastle, UK) and colleagues investigated sudden, unexplained deaths that took place among in-patients at five psychiatric hospitals in northeast England. There were 1350 deaths in 12 years. Of those, 77 deaths met the criteria for “probable” and 27 for “confirmed” sudden, unexplained death. 69 cases were each matched to two controls, one of which had the same primary diagnosis as the case patient. Sudden, unexplained deaths were associated with hypertension, ischaemic heart disease, and thioridazine treatment (adjusted odds ratio for thioridazine 5·3, p=0·004; Br J Psych 2002; 180: 515–22). The primary cause of thioridazine-related deaths seemed to be torsades de pointes, although a dose-response effect with high-dose or low-dose thioridazine was not observed. Other antipsychotics used by the patients studied were not significantly associated with sudden unexplained death, the researchers found. “Although the effect is rare, thioridazine seems to be more potent than the majority of other drugs that affect cardiac repolarisation, and this may be linked to sudden cardiac death”, Thomas told The Lancet. “Unless there’s a good reason for a patient to continue on thioridazine, it’s appropriate that other antipsychotic drugs be considered”, he advises. However, he points out that a number of other antipsychotic drugs, such as pimozide, sertindol, and droperidol, may also have this effect. In a related editorial, Wayne A Ray (Vanderbilt University, Nashville, TN, USA) notes that the study did not have sufficient power to demonstrate that thioridazine was associated with greater risk than the other specific drugs. But he suggests that it would be “prudent to assume that all available antipsychotics have the potential to increase the risk of serious ventricular arrhythmias and thus sudden cardiac death”.

Management After Myocardial Infarction.

Individuals who survive an acute myocardial infarction (MI) have up to a ninefold greater risk of cardiovascular morbidity and mortality compared with the general population. The modification of traditional coronary risk factors, including hypertension, hyperlipidemia, tobacco use, and diabetes mellitus, constitutes one of the cornerstones of management after acute MI. Therapies aimed at reversing the pathophysiologic disorders that lead to endothelial dysfunction, thrombosis, and atherosclerotic plaque instability may improve the prognosis for patients after acute MI. Aggressive risk stratification diagnostic testing can identify patients at the highest risk for adverse events. Prior to hospital discharge, patients should have an evaluation of left ventricular systolic function, an assessment for the risk for residual myocardial ischemia, and a clinical assessment of the risk for serious ventricular arrhythmias. An array of pharmaceutical agents is available for the secondary prevention of MI, including antiplatelet agents, beta-blockers, angiotensin-converting enzyme inhibitors, and statins.

Inhibition of repolarizing ionic currents by drugs

Every pharmacological substance that prolongs cardiac repolarization produces a risk of serious ventricular arrhythmias leading eventually to sudden death. Numerous non-cardiovascular drugs already in the market have been associated with altered cardiac repolarization and proarrhythmic eects. Because this side e ect is serious (albeit infrequent), every new chemical entity intended for human use should be screened during the preclinical stages of its pharmaceutical development. Various in vitro and in vivo models have been established to accomplish this screen. Standard procedures are now available to prevent that drugs non-intentionally aecting cardiac repolarization will be developed and launched in the future.

VALUE AND LIMITATIONS OF NONINVASIVE ASSESSMENT OF SYNCOPE

The noninvasive assessment of patients who present with syncope is based on a thorough, complete history and physical examination. The history requires close attention to precipitating events and the description of the spell. Often, patients are poor historians with regard to symptoms leading up to and following the episode of syncope. Therefore, it is important to interview individuals who observed the spell to improve the accuracy of the history and sort out whether or not the spell was due to cardiogenic syncope, vasodepressor syncope, or a neurologic disorder. Carotid sinus massage is a useful procedure that can be performed during the routine physical examination, identifying patients who are at increased risk for carotid sinus syncope because of hypersensitivity of the carotid sinus. The clinician must be careful to attribute the clinical syncope to carotid sinus hypersensitivity only when the spell induced at the time of carotid massage reproduces the clinical spell. Routine laboratory tests are commonly performed, although the blood tests rarely yield information to confirm the cause of syncope. The routine ECG is often helpful identifying abnormalities of rhythm, conduction, or morphology that give a clue as to the cause for the patient's syncope. The most helpful aspect of ECG recording is to obtain a recording during an episode of syncope when exact correlation can be made between the ECG findings and the patient's symptoms. Recording the ECG during the spell can be achieved using 24-hour ambulatory monitoring, an event recorder, or a memory loop recorder. Twenty-four-hour ambulatory monitoring is useful in patients who have frequent spells that would be expected to be recorded during 1 or 2 days of monitoring. These individuals need to have a non-life-threatening spell and therefore be safe to evaluate as an outpatient. The event recorder and loop memory recorder have proved extremely helpful in evaluating spells that occur too infrequently to be recorded by 24-hour or 48-hour ambulatory monitoring. The nature of these recording devices does require that the patient or a companion be able to activate the monitor at the time of symptoms. If a patient experiences syncope but is unable to activate the device, the important information as to what the rhythm was doing at the time of symptoms is lost. The implantable loop recorder should prove to be uniquely advantageous by allowing extended ECG recording with the device activated by the patient or companion recording 20 minutes before and 4 minutes after device activation. Signal-averaged electrocardiography is most helpful in assessing patients with ischemic heart disease with a substrate capable of supporting a reentrant ventricular arrhythmia. This test should be used in combination with other historical or laboratory predictors of arrhythmic events such as history of myocardial infarction or abnormal ventricular function assessed by echocardiography. In this setting, the signal-averaged ECG helps to identify patients at increased risk for ventricular tachycardia as the cause of syncope who thus may benefit from electrophysiologic testing.