A new paradigm for predicting risk of Torsades de Pointes during drug development: Commentary on: "Improved prediction of drug-induced Torsades de Pointes through simulations of dynamics and machine learning algorithms".

Drug-induced long QT syndrome (diLQTS) is a clinical entity in which administration of a drug produces marked prolongation of the QT interval on the ECG. DiLQTS places a patient at risk of developing Torsades de Pointes (TdP), a malignant polymorphic ventricular tachycardia associated with arrhythmic sudden cardiac death (SCD). In addition to diLQTS, other clinical risk factors for TdP include female gender, bradycardia, electrolyte disturbances, recent conversion to normal (sinus) rhythm, and congenital LQTS.

Sympathetic activation enhances QT prolongation by quinidine.

INTRODUCTION: Salt restriction results in endogenous sympathetic activation, and we previously showed that plasma concentrations of quinidine measured after oral drug administration are increased during a low-salt diet. However, it is not known whether, independent of effects on plasma concentration, the extent to which quinidine prolongs the QT interval also is modulated by changes in endogenous sympathetic activity. METHODS AND RESULTS: In these studies, we evaluated quinidine concentration-QT relations during low-salt (10 mEq/day for 8 days) and high-salt (400 mEq/day for 8 days) diets, with or without beta blockade in normal volunteers. In the absence of beta blockade, the concentration producing a fixed (15%) increase in QTc was significantly lower with salt restriction: 1.2 +/- 0.4 microg/mL (low salt) versus 2.2 +/- 0.4 microg/mL (high salt) (P < 0.01). With beta blockade, this difference was abolished: 1.9 +/- 0.3 microg/mL (low salt + beta blockade) versus 2.1 +/- 0.3 microg/mL (high salt + beta blockade). QT morphologic abnormalities including bifid T waves and U waves were abolished with beta-adrenergic blockade. CONCLUSION: Sympathetic activation by a low-salt diet not only modulates drug disposition but also increases sensitivity to drug-induced QT prolongation.

Localization of the origin of arrhythmias for ablation: from Electrocardiography to advanced endocardial mapping systems.

Radiofrequency catheter ablation techniques have had a dramatic impact on the treatment of a variety of cardiac arrhythmias. However, catheter ablation of complex arrhythmias, such as intra-atrial reentry, ventricular tachycardias, and atrial fibrillation, continues to pose a major challenge. This stems from limitations of fluoroscopy and conventional catheter-based mapping techniques that limit the accurate anatomic localization of complex arrhythmogenic substrates. In this article, ECG features of complex arrhythmias are reviewed, which may facilitate the planning of an ablation procedure. The physical principles of the newly available catheter-based endocardial mapping techniques and their clinical applicability for treatment of complex arrhythmias are discussed. The role of intracardiac echocardiography to facilitate mapping and ablation is reviewed.

Localized aortic dissection: unusual features by transesophageal echocardiography.

Transesophageal echocardiography relies on the presence of an undulating intimal flap for the diagnosis of aortic dissection. Furthermore, to distinguish true dissection from echo artifacts, the flap has to be identified in more than one view, and it must have a motion independent of the aortic wall. We describe the transesophageal echocardiography appearance of a localized aortic dissection with atypical features for an intimal flap. Awareness of this unusual echocardiographic appearance of an intimal flap will avoid misdiagnosis of the potentially serious acute aortic dissection.

Exaggerated QT prolongation after cardioversion of atrial fibrillation.

OBJECTIVES: The purpose of this study was to test the hypothesis that the extent of drug-induced QT prolongation by dofetilide is greater in sinus rhythm (SR) after cardioversion compared with during atrial fibrillation (AF). BACKGROUND: Anecdotes suggest that when action potential-prolonging antiarrhythmic drugs are used for AF, excessive QT prolongation and torsades de pointes (TdP) often occur shortly after sinus rhythm is restored. METHODS: QT was measured in nine patients with AF who received two identical infusions of dofetilide: 1) before elective direct current cardioversion and 2) within 24 h of restoration of SR. RESULTS: During AF, dofetilide did not prolong QT (baseline: 368 +/- 48 ms vs. drug: 391 +/- 60, p = NS) whereas during SR, QT was prolonged from 405 +/- 55 to 470 +/- 67 ms (p < 0.01). In four patients (group I), the SR dofetilide infusion was terminated early because QT prolonged to >500 ms, and one patient developed asymptomatic nonsustained TdP. The remaining five patients (group II) received the entire dose during SR. Although deltaQT was greater in group I during SR (91 +/- 22 vs. 45 +/- 25 ms, p < 0.05), plasma dofetilide concentrations during SR were similar in the two groups (2.72 +/- 0.96 vs. 2.77 +/- 0.25 ng/ml), and in AF (2.76 +/- 1.22 ng/ml). DeltaQT in SR correlated inversely with baseline SR heart rate (r = -0.69, p < 0.05), and QT dispersion developing during the infusion (r = 0.79, p < 0.01). CONCLUSIONS: Shortly after restoration of SR, there was increased sensitivity to QT prolongation by this I(Kr)-specific blocker. Slower heart rates after cardioversion and QT dispersion during treatment appear to be important predictors of this response.

Modulation of effect of dietary salt on prehepatic first-pass metabolism: effects of beta-blockade and intravenous salt loading.

We previously demonstrated that increased dietary salt markedly decreases plasma quinidine concentrations shortly after p.o. dosing, without an effect on the drug's terminal elimination half-life or concentrations after i.v. administration. These findings suggest an effect of dietary salt on intestinal metabolism or transport of the drug. Because one effect of salt loading is sympathetic inhibition, we examined the effect of beta-adrenoceptor blockade on salt-related changes in quinidine disposition. Furthermore, we examined whether the action of salt is local or systemic by determining the effect of salt loading by the i.v. route. To assess the effect of beta-blockade, quinidine disposition was studied in eight normal volunteers after a single p.o. dose of quinidine; data were obtained after 1 week on a high-salt diet (400 mEq/day) and 1 week on a low-salt diet (10 mEq/day) during chronic nadolol and compared with those previously obtained in the same subjects without the beta-blocker. beta-Blockade had no effect on oral clearance during the high-salt diet [0.28 +/- 0.1 (quinidine + nadolol) versus 0.30 +/- 0.2 liters/h/kg (quinidine alone)] but increased clearance on the low-salt diet from 0.23 +/- 0.1 to 0.29 +/- 0.1 liters/h/kg (p <. 05). For the i.v. salt study, the disposition of single p.o. and single i.v. doses of quinidine was determined on two occasions in eight subjects: once during a low-salt diet (10 mEq/day) and once during the same diet, supplemented by 400 mEq/day NaCl i.v. for 8 days. In contrast to our findings after p.o. salt loading, i.v. salt loading did not alter the pharmacokinetics of p.o. quinidine. Taken together, these data implicate a local alteration of drug-metabolizing activity and/or drug transport in the intestinal mucosa as the major effect of dietary salt on the disposition of p.o. quinidine and further suggest that beta-adrenergic activation by a low-salt diet is one component of a signaling pathway whereby intestinal drug disposition is suppressed, resulting in increased oral bioavailability.

QT dispersion is reduced after valve replacement in patients with aortic stenosis.

OBJECTIVE: To investigate whether QT dispersion is a reliable index of the severity of aortic stenosis and left ventricular hypertrophy in the setting of aortic stenosis. DESIGN: A retrospective analysis of the results of echocardiography and electrocardiography before and after aortic valve replacement. SETTING: Tertiary centre. PATIENTS: 36 men (30 white and six black) with symptomatic aortic stenosis requiring valve replacement. RESULTS: All patients had significant aortic stenosis (mean (SD) aortic valve area 0.68 (0.18) cm2) and evidence of left ventricular hypertrophy (left ventricular mass index (LVMI): 267 (90) g/m2). Before aortic valve replacement, QT dispersion was correlated with mean aortic valve area and LVMI (r = 0.697, p < 0.001, and r = 0.59, p < 2.4 x 10(-6), respectively). QT dispersion and QT corrected for heart rate dispersion decreased from 133 (54) to 71 (33) ms and from 151 (64) to 94 (76) ms, respectively (p < 0.001 for both). LVMI regressed after aortic valve replacement to 190 (79) g/m2, p < 0.01. CONCLUSIONS: QT dispersion is increased in association with LVMI in patients with significant symptomatic aortic stenosis. Aortic valve replacement reduces QT dispersion and LVMI. QT dispersion could be a useful indicator of risk and risk reduction in patients with significant symptomatic aortic stenosis.

Modulation by dietary salt of verapamil disposition in humans.

BACKGROUND: The intestine is an increasingly well-recognized site of first-pass drug metabolism. In this study, we determined the influence of dietary salt on the steady-state disposition of verapamil, a drug that undergoes extensive first-pass metabolism. METHODS AND RESULTS: Eight normal volunteers received 120 mg of racemic verapamil orally twice a day for 21 days. The disposition kinetics of verapamil enantiomers were determined after coadministration of intravenous deuterated verapamil with the morning oral dose on days 7, 14, and 21. Each study day was preceded by 7 days on a fixed-salt diet: in 5 subjects, the initial study was conducted during a low-salt (10 mEq/d) diet, the second study during a high-salt (400 mEq/d) diet, and the third during a low-salt diet, whereas in the other 3 subjects, the sequence of diets was reversed. Plasma concentrations of both unlabeled enantiomers (ie, from oral therapy) were significantly (P<0.05) lower during the high-salt phase (eg, mean area under the time-concentration curve [0 to 12 hours] for S-verapamil: 7765+/-2591 ng. min. mL-1 [high salt] versus 12 514+/-3527 ng. min. mL-1 [low salt], P<0.05). Peak plasma concentrations were significantly lower and the extent of PR interval prolongation significantly blunted with the high-salt diet. In contrast, data with labeled drug (ie, reflecting the intravenous route) were nearly identical for the 2 diets. CONCLUSIONS: These data indicate that a clinically important component of presystemic drug disposition occurs at the prehepatic (presumably intestinal) level and is sensitive to dietary salt.

Dietary salt increases first-pass elimination of oral quinidine.

BACKGROUND: Some cytochrome P450 (CYP) enzymes, including CYP3A, are expressed not only in the liver but also in the intestine; the latter may therefore be an important site of drug disposition. Animal data suggests that dietary salt modulates expression of renal CYPs. We therefore hypothesized that intestinal CYP3A may be similarly modulated by dietary salt. METHODS: The effect of changes in dietary salt on the disposition of two CYP3A substrates, quinidine (administered orally and intravenously) and 14C-erythromycin (administered intravenously) were determined after normal volunteers were given high-salt (400 mEq/day) and low-salt (10 mEq/day) diets for 7 to 10 days each. RESULTS: Plasma concentrations after oral quinidine were significantly lower during the high-salt phase, with the difference between the two treatments attributable to changes within the first 1 to 4 hours after administration. For example, the area under the plasma concentration-time curve for the first hour after drug administration was 0.56 +/- 0.38 microgram.hr/ml for the high-salt diet compared with 1.57 +/- 0.60 micrograms.hr/ml for the low-salt diet (p < 0.05). Similarly, the peak plasma concentration (Cmax) achieved was lower and the time to reach Cmax was later for the high-salt diet (p < 0.05). In contrast, the terminal phase elimination half-lives were similar for the two diets, and no differences in disposition were found with the intravenous drug. The erythromycin breath test was unaffected by the dietary treatments. CONCLUSIONS: These results indicate an effect of dietary salt on the presystemic disposition of orally administered quinidine. Although the mechanism(s) of CYP3A activity modulation is unknown, this finding may be important in determining drug availability in conditions associated with abnormal salt homeostasis.

Diagnosing left ventricular dysfunction after myocardial infarction: the Dundee algorithm.

Large-scale trials of angiotensin converting enzyme (ACE) inhibitors after acute myocardial infarction (AMI) suggest that the benefits are greatest in patients with left ventricular (LV) dysfunction. However, early evaluation of LV function in all patients after AMI by current methods can be difficult due to a lack of resources and skilled personnel. Thus a clinical algorithm that could be used at the bedside to reliably identify patients with a left ventricular ejection fraction (LVEF) < or = 40% would be helpful as an occasional alternative to echocardiography. We have devised such an algorithm based on the presence of one of: (i) clinical signs of heart failure; (ii) an index Q-wave anterior myocardial infarction; (iii) lack of thrombolytic therapy when there is a history of two or more previous myocardial infarctions and a CK rise > 1000 U/l. We tested this new algorithm prospectively in the coronary care units of two hospitals (one UK and one USA). In the UK centre, the sensitivity and specificity of the algorithm at identifying patients with a LVEF < or = 40% were 82% and 72%, respectively. In the US centre, the sensitivity of the algorithm was 91% and the specificity 78% at identifying patients with LV dysfunction. We have validated a simple clinical algorithm which can be used at the bedside for identifying patients who would benefit from an ACE inhibitor after AMI.

Prediction of late cardiac events by dipyridamole thallium scintigraphy in patients with intermittent claudication and occult coronary artery disease.

Concomitant coronary artery disease often occurs in patients with peripheral vascular disease, but it may be asymptomatic. Despite being asymptomatic, cardiovascular events are the main source of morbidity and mortality in this group of patients. Dipyridamole thallium scintigraphy has been shown to be of prognostic value in patients with peripheral vascular disease and symptomatic coronary artery disease, but its effect on the long-term outcome in the asymptomatic group of patients is less defined. Eighty-four consecutive patients with peripheral vascular disease and no symptoms of coronary artery disease were therefore evaluated by clinical assessment, dipyridamole thallium imaging, radionuclide ventriculography, and cardiac catheterization and followed for a mean of 66 months. Abnormal perfusion patterns were found on thallium scintigraphy in 48 patients (57%); fixed, mixed, and reversible defects were present in 14 (17%), 11 (13%), and 23 (27%) patients, respectively. Significant coronary artery disease was present in 52 patients (69%) and mean left ventricular ejection fraction was 44%. During the follow-up period, 23 patients had a cardiac event (nonfatal myocardial infarction or cardiac death). Univariate analysis of 15 clinical, scintigraphic, radionuclide, and angiographic variables revealed that age, angiographic extent of coronary artery disease, and an abnormal thallium scan were significant predictors of subsequent cardiac events. Multivariate stepwise logistic regression analyses selected fixed and mixed thallium defects and diffuse coronary artery disease as the only significant independent predictors of outcome. Thus, the present study shows the value of dipyridamole thallium scintigraphy as a valuable prognostic indicator for long-term event-free survival in a cohort of patients with peripheral vascular disease and no history or symptoms of coronary artery disease.

Acute psychosis associated with abrupt withdrawal of carbamazepine following intoxication.

Carbamazepine is regularly used in the treatment of trigeminal neuralgia. Although exacerbation of psychosis has been described following abrupt discontinuation of carbamazepine in chronic schizophrenics, a withdrawal syndrome has not been reported previously in patients treated for trigeminal neuralgia. The case presented here suggests that abrupt withdrawal of toxic concentrations of carbamazepine may precipitate a withdrawal reaction, which is manifest some days after discontinuation of the drug. Therefore it may be advisable to withdraw therapy slowly in these situations.

Diagnostic value of B-type natriuretic peptide concentrations in patients with acute myocardial infarction.

Although elevations of plasma atrial natriuretic peptide (ANP) concentrations have been shown to have prognostic significance in patients after acute myocardial infarction (AMI), the relation between plasma levels of B-type natriuretic peptide (BNP) and cardiovascular mortality remains unknown. To test the prognostic value of plasma ANP and BNP after AMI, plasma concentrations were measured a mean of 3 days after infarction in 75 patients. During a median follow-up of 19.7 months, 14 patients (18.4%) died of cardiovascular causes. On univariate analysis, plasma ANP and BNP, Killip class, modified Peel index, left ventricular ejection fraction, and presence of left ventricular failure were all associated with cardiovascular mortality. In contrast, plasma ANP was the only variable that correlated with the development of symptomatic heart failure and hospitalization. For the combined end point of cardiovascular mortality, symptomatic heart failure, and hospitalization, plasma neurohormones were the only variables of predictive value. By stepwise regression analysis, plasma BNP was the only significant independent predictor of cardiovascular mortality (p = 0.001), whereas plasma ANP identified patients at risk of symptomatic heart failure and hospitalization (p = 0.002 and 0.019, respectively). This study indicates that plasma BNP measured after AMI is a powerful neurohormonal predictor of subsequent cardiovascular mortality, whereas plasma ANP correlates better with the development of symptomatic heart failure and hospitalization. Routine measurement of both of these peptides in the period immediately after an AMI may provide a simple means of risk stratification with different information gained from each peptide.

Epinephrine-induced changes in serum potassium and cardiac repolarization and effects of pretreatment with propranolol and diltiazem.

Although increases in serum epinephrine are known to cause hypokalemia, the epinephrine dosages and concentrations at which this effect occurs, and the electrocardiographic consequences, have not been evaluated. Because epinephrine infusion is now being used to provoke arrhythmias in some patients, we have determined the physiologic effects of a range of dosages of epinephrine. The effects of pretreatment with propranolol and diltiazem on these indexes of epinephrine effect were also evaluated. Epinephrine dose ranging started at 10 ng/kg/min, with doubling of the dose every 10 minutes until a predetermined end point was reached. At the end of each dosage level, serum electrolytes, catecholamines, and an electrocardiogram were recorded. Whereas even the lowest dosage of epinephrine significantly increased heart rate, serum glucose levels increased and serum potassium decreased only when dosages of 160 to 320 ng/kg/min were administered. Plasma concentrations of epinephrine at these dosages were mean +/- SD 1,328 +/- 902 pg/ml, comparable to those observed in these subjects during maximal exercise (1,003 +/- 527 pg/ml). The major electrocardiographic effect of epinephrine infusion was a dose-related increase in QTc, but pretreatment with propranolol blunted this effect and tended to shorten QTc. At an epinephrine dose of 40 ng/kg/min, QTc prolongation persisted and was inhibited by diltiazem. These data suggest that the major electrocardiographic effect of epinephrine infusion is mediated by increased calcium current. At dosages > 80 ng/kg/min, plasma epinephrine concentrations are comparable to those observed with severe stress, and hypokalemia is common. The use of epinephrine as an electrophysiologic provoker at dosages > 80 ng/kg/min results in both a direct effect, as well as an indirect effect due to hypokalemia.

Sensitivity and specificity of QTc dispersion for identification of risk of cardiac death in patients with peripheral vascular disease.

OBJECTIVE: To determine whether QTc dispersion, which is easily obtained from a standard electrocardiogram, can predict those patients with peripheral vascular disease who will subsequently suffer a cardiac death, despite having no cardiac symptoms or signs. DESIGN: Patients with peripheral vascular disease were followed up for five years after they had had coronary angiography, radionuclide ventriculography, and their QTc dispersion calculated from their 12 lead electrocardiogram. SUBJECTS: 49 such patients were then divided into three groups: survivors (34), cardiac death (12), and non-cardiac death (3). MAIN OUTCOME MEASURE: Survival. RESULTS: The mean (SD; range) ejection fractions were similar in all three groups: survivors 45.9 (11.0; 27.0-52.0), cardiac death 44.0 (7.90; 28.5-59.0), and non-cardiac death 45.3 (4.55; 39.0-50.0). QTc dispersion was significantly prolonged in the cardiac death group compared with in the survivors (86.3(23.9; 41.0-139) v 56.5 (25.4; 25.0-164); P = 0.002). A QTc dispersion > or = 60 ms had a 92% sensitivity and 81% specificity in predicting cardiac death, QTc dispersion in patients with diffuse coronary artery disease was significantly (P < 0.05) greater than in those with no disease or disease affecting one, two, or three vessels. CONCLUSIONS: There is a strong link between QTc dispersion and cardiac death in patients with peripheral vascular disease. QTc dispersion may therefore be a cheap and non-invasive way of assessing the risk of cardiac death in patients with peripheral vascular disease.

Loss of quinidine gluconate injection in a polyvinyl chloride infusion system.

The effect of a polyvinyl chloride (PVC) i.v. administration system on the availability of quinidine gluconate was studied. Quinidine gluconate diluted in 5% dextrose injection was administered intravenously to five healthy volunteers via conventional PVC infusion sets, and the subjects received oral quinidine sulfate two days later. The mean +/- S.D. oral bioavailability of quinidine was, unexpectedly, greater than 100% (147 +/- 44%). To test the possibility that this occurred because of reduced delivery of i.v. quinidine, the percentage of drug delivered via two systems was evaluated in simulation studies, one involving a conventional PVC administration set and the other a glass syringe attached to shorter PVC tubing and a winged i.v. catheter. Spectrophotometric analysis revealed a 5-7% reduction in absorbance associated with loss of quinidine in the PVC infusion bag and a further 34-38% reduction in absorbance attributable to quinidine loss in the PVC tubing. However, with the winged i.v. catheter system the loss was reduced to less than 3%. More than 40% of a dose of quinidine gluconate was lost when the drug was administered with a conventional PVC i.v. administration set. Drug loss was reduced by using a winged i.v. catheter and shorter tubing.