Tachycardia Torsade De Pointes Research Articles

Safe electrophysiologic profile of the neprilysin-inhibitor sacubitril in combination with different antiarrhythmic drugs

Abstract Background Observational clinical data suggest a direct effect of sacubitril on cardiac electrophysiology. However, data concerning the impact of combination of sacubitril with antiarrhythmic drug therapy is sparse. Purpose We aimed at characterizing the electrophysiologic effects of a combination therapy of sacubitril with the class III-drug sotalol and the class IB-agent mexiletine in a sensitive, experimental whole-heart model. Methods and results 25 isolated rabbit hearts were retrogradely perfused. Hearts were treated with mexiletine (25 μM, 13 hearts) or sotalol (100 μM, 12 hearts) after generating baseline data. Eight endo- and epicardial monophasic action potentials and ECG recordings demonstrated an abbreviation of action potential duration (APD90, −21 ms, p<0.01) and no significant changes of QT interval (+10ms, p=ns) after administration of mexiletine. Spatial dispersion of repolarization (SDR) remained stable after mexiletine treatment (+6 ms, p=ns) whereas effective refractory periods (ERP) were significantly prolonged (+80 ms, p<0.01). Sotalol prolonged cardiac repolarization (APD90: +1 ms, p=ns; QT: +24 ms, p<0.01) and amplified spatial dispersion (+19 ms, p<0.01) without changing ERP (+8 ms, p=ns). Additional treatment with sacubitril (5 μM) led to a significant reduction of APD90 (−12 ms, p<0.01), QT interval (−20 ms, p<0.01) and ERP (−23 ms, p<0.01) in the presence of a stable SDR (−4 ms, p=ns) in the mexiletine group. In the sotalol group, additional administration of sacubitril abbreviated APD90 (−9 ms, p<0.05) and QT interval (−13 ms, p<0.01) and reduced ERP (−18 ms, p<0.01) without affecting SDR (−3 ms, p=ns). Ventricular vulnerability was assessed by a predefined pacing protocol employing premature extra stimuli and burst stimulation. After lowering the potassium concentration, 30 episodes of torsade de pointes tachycardia were observed after sotalol treatment (vs. 0 episodes under baseline, p<0.05). Additional sacubitril treatment significantly suppressed torsade de pointes tachycardia (8 episodes, p<0.05) in the sotalol-group. No proarrhythmic effect was observed after mexiletine treatment (8 episodes vs. 3 episodes under baseline conditions, p=ns). Additional sacubitril treatment did not increase ventricular vulnerability (32 episods, p=ns). Conclusion Sacubitril in combination with antiarrhythmic drugs demonstrates a safe electrophysiologic profile. In class IB- and class III-pretreated hearts, sacubitril abbreviates cardiac repolarization duration and effective refractory periods without changing spatial dispersion of repolarization. Thereby, sacubitril reduces the occurrence of torsade de pointes-tachycardia in antiarrhythmic pretreated hearts. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Deutsche Stiftung für Herzforschung (to G.F.)

Arrhythmias related to antipsychotics and antidepressants: an analysis of the summaries of product characteristics of original products approved in Germany

PurposeMost psychiatric drugs, such as antidepressants (AD) and antipsychotics (AP), may cause cardiac adverse events (CAE). We used summaries of product characteristics (SmPC) for assessing the likelihood of AD and AP to cause CAE.MethodsWe identified all original medicinal products (OMP) of AD and AP approved in Germany. We searched for their SmPCs using the online services of PharmaNet.Bund, Gelbe liste®, Rote Liste®, Fachinfo-Service®, and via manufacturer contact. We extracted frequencies of reported CAE (QT prolongation, Torsade de Pointes tachycardia, and ventricular arrhythmia) and performed a risk assessment.ResultsWe obtained the SmPCs of 24 AD and 26 AP identified as OMP. Comparably high reported frequencies regarding QT prolongation were found for Invega® (paliperidone), Serdolect® (sertindole) (≥ 1/100 and < 1/10), and Zoloft® (sertraline) (≥ 1/10.000 and < 1/1000); regarding Torsade de Pointes tachycardia were found for Serdolect® (≥ 1/1000 to < 1/100), Zoloft®, and Trevilor® (venlafaxine) (≥ 1/10.000 and < 1/1000); regarding ventricular tachycardia for Solian® (amisulpride), Xomolix® (droperidol), Zyprexa® (olanzapine), and Trevilor® (≥ 1/10.000 and < 1/1000).ConclusionThe risk and frequency of CAE, as reported in the SmPCs, varied significantly among substances and between groups. There are more reports for AP than AD. The AP with the most frequently reported CAE (QT prolongation and Torsade de Pointes tachycardia) was Serdolect®; for AD, Zoloft® (QT prolongation, Torsade de Pointes tachycardia) and Trevilor® (Torsade de Pointes tachycardia and ventricular tachycardia) carried a higher cardiac risk.

Fragmented endocardial signals and early afterdepolarizations during torsades de pointes tachycardia.

Bradycardia-induced torsade de pointes (TdP) tachycardia in patients with spontaneous high-degree atrioventricular block (AVB) is common. The aim of this study was to analyze endocardial recordings during TdP in spontaneous high-degree AVB in humans to better understand the electrophysiological mechanisms underlying this phenomenon. The study group consisted of 5 patients with typical episodes of TdP during spontaneous high-degree AVB. A standard (USCI) temporary bipolar endocardial catheter positioned at the apex of the right ventricle (RV) and bipolar chest leads from two precordial leads V1 and V4 were used to record the tracings during TdP. The presence of a wide spectrum of fragmentations was noted on endocardial electrograms (EGMs), which were invisible on the surface electrocardiogram (ECG) tracing. Endocardial signals indicated that TdP started in the proximity of the RV apex, since the local EGM began prior to the QRS complex on the surface ECG. Early afterdepolarizations (EADs) were observed in 2 out of 5 cases confirming a common opinion about the mechanism of TdP. However, this phenomenon was not observed in 3 other patients suggesting that the arrhythmia was the result of a different mechanism originating in proximity to the RV apex. This work demonstrated early endocardial signals in the RV apex during TdP associated with high-degree AVB in humans, and exhibits a spectrum of fragmented signals in this area occurring on a single or multiple beats. These fragmentations indicate areas of poor conduction and various degrees of intramyocardial block, and therefore a new mechanism of TdP tachycardia in some patients with spontaneous high-degree AVB.

How to Prescribe Drugs With an Identified Proarrhythmic Liability.

This is an article in the Journal of Clinical Pharmacology's Core Entrustable Professional Activities in Clinical Pharmacology series that discusses drug-induced proarrhythmia and is offered as a teaching aid for medical students and residents. Drugs from diverse pharmacological classes can lead to multiple types of arrhythmias including the polymorphic ventricular tachycardia torsades de pointes (TdP). Although typically occurring in self-limiting bursts with or without associated symptoms, which can range from mild lightheadedness and palpitations to syncope and seizures, TdP can also occasionally progress to ventricular fibrillation and sudden cardiac death. To provide patients with the optimal therapeutic benefits of potentially proarrhythmic drugs, prescribers are responsible for obtaining a good understanding of the compound's benefit-risk properties and perform a judicious assessment of the patient's clinical characteristics and individual risk factors. Dose adjustments and/or additional monitoring of electrocardiograms and electrolyte balances may be appropriate in some cases. This article explains the pharmacological mechanism of action of drug-induced proarrhythmia associated with compounds that prolong the repolarization period, illustrates how this liability is conveyed in a drug's prescribing information (label), details the clinical characteristics of patients most susceptible to this type of proarrhythmia, and describes interventions that can be made if TdP occurs. Three clinical vignettes are provided at the end of the article to highlight the relevance of the preceding discussions.

Clinical characterization of men with long QT syndrome and torsades de pointes associated with hypogonadism: A review and pharmacovigilance study

Long QT syndrome (LQTS) can cause the potentially fatal ventricular tachycardia torsades de pointes (TdP). QT interval corrected for heart rate (QTc) is shorter in men than in women, with testosterone contributing to shorten QTc. We recently described male hypogonadism as a reversible risk factor for acquired LQTS and TdP, but the clinical characteristics of such patients have not been characterized. To describe the clinical characteristics of men with acquired LQTS or TdP associated with hypogonadism caused by endocrine conditions or androgen deprivation therapy (ADT), and to evaluate the relationship between testosterone concentrations and electrocardiographic changes. We searched MEDLINE (to 04 January 2019) and the French pharmacovigilance database (to 09 August 2018) to identify male cases of acquired LQTS and TdP associated with endocrine hypogonadism or ADT; their narratives were gathered from reporting collaborators. We identified seven cases of TdP (one fatal) with endocrine hypogonadism, abnormally long QTc and morphologically abnormal T-wave notches. After reversion of low testosterone concentrations in the surviving patients (N=6), QTc shortened, T-wave morphology normalized and there was no TdP recurrence. Among these cases, none had mutation in the LQTS genes, three men required testosterone and three had reversible hypogonadism after resolution of a concurrent acute severe illness. We found an additional 27 reports of men with LQTS (N=6), TdP (N=9; 2/9 fatal) or sudden death (N=12; 10/12 fatal) suspected to be induced or favoured by ADT (24/27 for prostate cancer). Generally, after ADT withdrawal, QTc shortened and no TdP recurred. We propose seeking for hypogonadism caused by endocrine conditions or ADT in men presenting with TdP. Caution is warranted when ADT is used in situations at risk of TdP. Testosterone may be useful to treat or prevent TdP.

Clinical pharmacists' opportunities to reduce inappropriate prescription of QT-prolonging medications: calls to action.

All biologically active agents carry the potential to lead to adverse reactions in certain individuals, including serious cardiac adverse reactions. Since 2005, there has been an international regulatory landscape governing the investigation of a new drug's propensity to lead to the polymorphic ventricular tachycardia Torsades de Pointes (Torsades), a rare but potentially fatal occurrence. When a regulatory agency considers it appropriate, warning information is placed in a medicine's patient information leaflet (label) concerning drug-induced QT interval prolongation, a phenomenon associated with Torsades. In busy hospital settings, however, prescribers, including cardiologists, make injudicious prescribing decisions that put patients at risk. The science of cardiac safety, including the clinical trials that generate the information about QT prolongation in patient information leaflets, is frequently not part of the curriculum at Schools of Pharmacy. Given that medication-induced cardiotoxicity is extremely serious, we advocate that schools integrate the science of cardiac safety into existing therapeutics/therapeutic medication monitoring courses. Given their expert knowledge of pharmacology, pharmacists working as part of a hospital's clinical team would then be even better placed to review prescribing decisions concerning medications that prolong the QT interval, and alert prescribers in cases where reassessing their decisions seems prudent. National pharmacy societies or other pertinent professional societies could create practice guidelines to support graduates once employed as clinical pharmacists. Clinical pharmacists are well placed to be influential arbiters of safer prescribing decisions. Cardiac safety education during their pharmacy training and practice guideline support from professional societies during their careers can optimize this role.

Life-threatening cardiac arrhythmias due to drug-induced QT prolongation : A retrospective study over 6 years from a medical intensive care unit.

Long QT syndrome (LQTS) can lead to ventricular arrhythmia, especially torsade de pointes (TdP) tachycardia and/or ventricular tachycardia (VT). The aim of this study is to characterize patients with life-threatening cardiac arrhythmias associated with drug-induced LQTS and to identify risk factors of distinct presenting arrhythmias. In this retrospective study, we present 33 consecutive cases of life-threatening cardiac arrhythmias associated with drug-induced long QT, which were direct admitted as emergency to a medical intensive care unit (MICU) during an observational time of 6 years. Of 33 identified cases, 55 % presented with TdP with the need of resuscitation and 45 % showed nonsustained VT, respectively. In the total cohort the mean corrected QT interval (QTc) was 532 ± 29ms, with 530 ± 31ms (n = 14) in men and 533 ± 28ms (n = 19) in women (p = 0.80), respectively. Cardiac drugs with QTc interval prolonging effect were reported in 24 % of cases, and the other 76 % involved noncardiac medications. Although hypokalemia is the most common risk factor for drug-induced malignant arrhythmias, a QTc interval of at least 500ms seems to be the major determinant of the risk of drug-induced proarrhythmias. Interestingly, patients with TdP exhibit more bradycardia as such with VT. This is the first study of patients with drug-induced life-threatening cardiac arrhythmias who were admitted as a case of emergency to a MICU. Physicians should be aware of drug-induced LQTS and be able to identify patients at risk and avoid specific drugs in such patients.

Sudden cardiac death in CKD patients.

The risk of sudden cardiac death (SCD) is high in chronic kidney disease patients, and it increases with the progression of kidney function deterioration. The most common causes of SDC are the following: ventricular tachycardia, ventricular tachyarrhythmia, tachycardia torsade de pointes, sustained ventricular fibrillation and bradyarrhythmia. Dialysis influences cardiovascular system and results in hemodynamic disturbances as well as electrolyte shifts altering myocardial electrophysiology. Studies suggest that this procedure exerts both detrimental (poor volume control can exacerbate hypertension and left ventricle hypertrophy) and beneficial effects (associated with fluid removal and subsequent decrease in left ventricle stretch). Dialysis-related vulnerability to serious arrhythmias is the result of sudden shifts in fluid status and electrolytes, particularly potassium, which alter the physiological milieu. Also Ca(2+) ions, in which concentration alters during dialysis, are of key importance in the contraction of vascular smooth muscle cells and cardiac myocytes, thus exerting significant effects on hemodynamics. Due to the fact that SCD occurs with similar frequency in peritoneal dialysis and in hemodialysis patients, it seems that end-stage renal disease factors are more important than the specific ones associated with dialysis type. The results of randomized trials suggested that hemodialysis patients may not derive the same benefit of cardiovascular disease therapy including beta-blockers, calcium channel blockers and angiotensin-converting enzyme inhibitors as the general population with normal kidney function. Noninvasive tests used to stratify SCD risk in HD patients have poor positive value, and thus, combining tests including HRV, baroreceptor sensitivity and effectiveness index as well as its function indices and heart rate turbulence should be implemented. There are only few large randomized placebo-controlled trials assessing the influence of cardioprotective medications or implantable cardioverter defibrillator (ICD) implantation in dialysis patients on life quality and survival, and their results are sometimes contradictory. The decision concerning treatment and/or ICD implantation in this group of patients should be made on the basis of careful assessment of individual risk factors. Moreover, due to the high hazard of cardiovascular mortality including SCD in dialysis patients, physicians should concentrate on the early selection of high-risk patients, monitoring them and introduction of preventive measures.

Torsade de Pointes Tachycardia in a Patient on Dronedarone Therapy

Dronedarone is a promising, relatively new antiarrhythmic agent characterized by structural similarities to amiodarone but without amiodarone's severe organ toxicity. The proarrhythmic potential of dronedarone, however, is of increasing concern. We describe a 76-year-old woman who had been receiving dronedarone 400mg twice/day to prevent recurrent atrial tachycardia with rapid ventricular response. Several months later, she came to the emergency department with decompensated congestive heart failure and episodes of atrial tachycardia; digoxin 0.5mg and furosemide 40mg were administered intravenously. Thereafter nonsustained torsade de pointes (TdP) tachycardia occurred. She was transferred to the intensive care unit where a dose of amiodarone 150mg was administered intravenously by mistake. Thereafter, the patient showed sustained TdP necessitating cardiac resuscitation. Dronedarone was discontinued, and digoxin and amiodarone were not administered again. Under dronedarone a relevant QT prolongation was documented that was additionally augmented after concomitant treatment with digoxin and amiodarone. Use of the Naranjo adverse drug reaction probability scale indicated a probable adverse drug reaction to dronedarone (score of 7). To our knowledge, this is the first case report of a patient who experienced TdP tachycardias while receiving dronedarone therapy in connection with a worsening of heart failure and possible drug interactions with digoxin and amiodarone. Clinicians should be aware of this potential adverse drug reaction and perform repeated heart rate-corrected QT (QTc) interval measurements as well as screening for congestive heart failure in patients receiving dronedarone therapy.

Torsade de pointes caused by gluten sensitive enteropathy leading to multiplex endocrine failure: case report

Abstact A 55 year-old man was brought to the emergency room because of hypotension, fatigue, fever and pain in the left shoulder. Glucose, sodium and potassium levels were normal in the blood. ECG showed 65/min sinus rhythm with negative T waves in the precordial leads. Blood pressure was 70/50 mm Hg. Suddenly torsade de pointes ventricular tachycardia (TdP) occurred,which was converted to sinus rhythm with 300 mg amiodarone. Coronarography showed no significant stenosis on epicardial coronaries. During the intervention, supraventricular tacyhcardia occurred for 30 s and disappeared after 150 mg amiodarone, ECGs showed no PQ prolongation, 76/min sinus rhythm and diffuse T-wave depression. Echocardiography found EF 38%, anterior, inferior, septal akinesis. On the 4th and 7th day of observation 35/min bradycardia occurred with junctional and ventricular extrasystole requiring defibrillation with 200 J. TSH measurement suggested hypothyroidism (TSH: 13.89 mIU/), severe hypocalcaemia suggested hypoparathyroidism. Serum total calcium level was: 1.82 mM/l, PTH: 1.5 pM/ l. Low serum hydrocortisone value revealed adrenal insufficiency. As the suggested diagnosis was polyglandular autoimmune syndrome, we performed autoimmune screening and found anti-transglutaminase antibodies. However, further autoimmune screening showed no sign for other autoimmune disesases. Gluten-free diet, hydrocortisone, levothyroxine, calcium, vitamin D3, and testosterone supplementation started, ICD was implanted. TdP never occurred again. Last results showed normal Ca, TSH, fT3, fT4 values, mildly lower testosterone, suppressed ACTH and mildly elevated cortisol levels. Conclusion: We found gluten-enteropathy caused persistent polyglandular endocrine failure leading to torsade de pointes tachycardia requiring reanimation and ICD implantation without having autoimmune origin.

Practice and challenges of thorough QT studies

The drug-induced Torsade de Pointes (TdP) tachycardia is a known regulatory problem which led to the concept of the so-called thorough QT (TQT) studies now required for practically every new pharmaceutical compound. This review summarizes the concept of the TQT studies, their statistical evaluation, and related pharmacodynamic /pharmacokinetic modeling. The review also lists suggestions of how to make TQT studies more efficient and how to improve the interpretation of clinical data obtained during drug development to identify drugs prone to TdP induction more effectively.

Fetal Long QT Syndrome Manifested as Atrioventricular Block and Ventricular Tachycardia: A Case Report and a Review of the Literature

Fetal onset of congenital long QT syndrome (LQTS) is a rare manifestation, and prenatal diagnosis is difficult. This report describes a boy who presented with both atrioventricular (AV) block and ventricular tachycardia during the antenatal period. The early postnatal electrocardiogram showed prolongation of the QT interval and AV block, subsequently leading to a polymorphic ventricular tachycardia torsade de pointes. This unique feature of congenital LQTS has a poor outcome, but the boy was successfully treated with beta-blockers and implantation of an automated cardioverter-defibrillator. The intrauterine manifestation of fetal AV block and ventricular tachycardia should raise a high suspicion of congenital LQTS, and the strong association with a malignant clinical course should warrant special evaluation. The literature on the prenatal diagnosis, fetal therapy, and neonatal outcome of this condition also are reviewed.

Assessing QT Interval Prolongation and its Associated Risks with Antipsychotics

Several antipsychotics are associated with the ventricular tachycardia torsade de pointes (TdP), which may lead to sudden cardiac death (SCD), because of their inhibition of the cardiac delayed potassium rectifier channel. This inhibition extends the repolarization process of the ventricles of the heart, illustrated as a prolongation of the QT interval on a surface ECG. SCD in individuals receiving antipsychotics has an incidence of approximately 15 cases per 10,000 years of drug exposure but the exact association with TdP remains unknown because the diagnosis of TdP is uncertain. Most patients manifesting antipsychotic-associated TdP and subsequently SCD have well established risk factors for SCD, i.e. older age, female gender, hypokalaemia and cardiovascular disease. QT interval prolongation is the most widely used surrogate marker for assessing the risk of TdP but it is considered somewhat imprecise, partly because QT interval changes are subject to measurement error. In particular, drug-induced T-wave changes (e.g. flattening of the T-wave) may complicate the measurement of the QT interval. Furthermore, the QT interval depends on the heart rate and a corrected QT (QTc) interval is often used to compensate for this. Several correction formulas have been suggested, with Bazett's formula the most widely used. However, Bazett's formula overcorrects at a heart rate above 80 beats per minute and, therefore, Fridericia's formula is considered more appropriate to use in these cases. Several other surrogate markers for TdP have been developed but none of them is clinically implemented yet and QT interval prolongation is still considered the most valid surrogate marker. Although automated QT interval determination may offer some assistance, QT interval determination is best performed by a cardiologist skilled in its measurement. A QT interval >500 ms markedly increases the risk for TdP and SCD, and should lead to discontinuation of the offending drug and, if present, correction of underlying electrolyte disturbances, particularly serum potassium and magnesium derangements. Before prescribing antipsychotics that may increase the QTc interval, the clinician should ask about family and personal history of SCD, presyncope, syncope and cardiac arrhythmias, and recommend cardiology consultation if history is positive.

Cardiac Arrest Caused by Torsades de Pointes Tachycardia after Successful Atrial Flutter Radiofrequency Catheter Ablation

A 66-year-old woman underwent successful radiofrequency catheter ablation for long-lasting, drug refractory fast atrial flutter. Two days later she had a cardiac arrest due to torsades de pointes (TdP) tachycardia attributed to relative sinus bradycardia and QT interval prolongation. After successful resuscitation further episodes of TdP occurred, which were treated with temporary pacing. Because of concomitant systolic dysfunction due to ischemic and valvular heart disease she was finally treated with an implantable defibrillator. In conclusion we strongly advise prolonged monitoring for 2 or more days for patients with structural heart disease following successful catheter ablation for long lasting tachyarrhythmias.

Cardiac Arrest Caused by Torsades de Pointes Tachycardia after Successful Atrial Flutter Radiofrequency Catheter Ablation

Cardiac Arrest Caused by Torsades de Pointes Tachycardia after Successful Atrial Flutter Radiofrequency Catheter Ablation

Antiarrhythmic effect of I Kr activation in a cellular model of LQT3

Long QT syndrome type 3 (LQT3) is an inherited cardiac disorder caused by gain-of-function mutations in the cardiac voltage-gated sodium channel, Na(v)1.5. LQT3 is associated with the polymorphic ventricular tachycardia torsades de pointes (TdP), which can lead to syncope and sudden cardiac death. The sea anemone toxin ATX-II has been shown to inhibit the inactivation of Na(v)1.5, thereby closely mimicking the underlying cause of LQT3 in patients. The hypothesis for this study was that activation of the I(Kr) current could counteract the proarrhythmic effects of ATX-II. Two different activators of I(Kr), NS3623 and mallotoxin (MTX), were used in patch clamp studies of ventricular cardiac myocytes acutely isolated from guinea pig to test the effects of selective I(Kr) activation alone and in the presence of ATX-II. Action potentials were elicited at 1 Hz by current injection and the cells were kept at 32 degrees C to 35 degrees C. NS3623 significantly shortened action potential duration at 90% repolarization (APD(90)) compared with controls in a dose-dependent manner. Furthermore, it reduced triangulation, which is potentially antiarrhythmic. Application of ATX-II (10 nM) was proarrhythmic, causing a profound increase of APD(90) as well as early afterdepolarizations and increased beat-to-beat variability. Two independent I(Kr) activators attenuated the proarrhythmic effects of ATX-II. NS3623 did not affect the late sodium current (I(NaL)) in the presence of ATX-II. Thus, the antiarrhythmic effect of NS3623 is likely to be caused by selective I(Kr) activation. The present data show the antiarrhythmic potential of selective I(Kr) activation in a cellular model of the LQT3 syndrome.

Long QT syndrome

Long QT syndrome (LQTS) is caused by malfunction of cardiac ion channels impairing ventricular repolarization. This predisposes to the development of the polymorphic ventricular tachycardia torsade de pointes (‘twisting of the points’) (Fig. 1). This may either revert spontaneously back to sinus rhythm causing syncope or degenerate to ventricular fibrillation causing sudden death. LQTS can be congenital, in which there are mutations in the genes encoding for the cardiac ion channels, or acquired in which malfunction of the ion channels is caused by drugs or metabolic abnormalities. It is likely that many of those with acquired LQTS have a genetic basis in which common polymorphisms cause subtle alterations in the cardiac ion channels responsible for repolarization. The increase in sympathetic tone associated with the stress of anaesthesia and surgery can provoke torsade de pointes in those with LQTS, and some drugs used during anaesthesia can prolong the QT interval.

Genetics of acquired long QT syndrome

The QT interval is the electrocardiographic manifestation of ventricular repolarization, is variable under physiologic conditions, and is measurably prolonged by many drugs. Rarely, however, individuals with normal base-line intervals may display exaggerated QT interval prolongation, and the potentially fatal polymorphic ventricular tachycardia torsade de pointes, with drugs or other environmental stressors such as heart block or heart failure. This review summarizes the molecular and cellular mechanisms underlying this acquired or drug-induced form of long QT syndrome, describes approaches to the analysis of a role for DNA variants in the mediation of individual susceptibility, and proposes that these concepts may be generalizable to common acquired arrhythmias.

Effects of clinically available drugs on the repolarization process of the heart assessed by the in vivo canine models

The proarrhythmic effects of class III antiarrhythmic agents and non-cardiovascular drugs, which have been shown to prolong QT interval, were assessed using two types of in vivo canine models. First, electrophysiological effects of dofetilide, nifekalant, amiodarone, cisapride, astemizole, sulpiride, haloperidol, and sparfloxacin were assessed using halothane-anesthetized dogs. Each drug prolonged the monophasic action potential (MAP) duration and effective refractory period (ERP) at clinically recommended daily doses. The extent of increase was greater in the refractoriness than in the repolarization only for amiodarone, indicating abbreviation of the terminal repolarization period. The reverse was true for the other drugs. Next, torsadogenic action of sematilide, nifekalant, amiodarone, cisapride, terfenadine, sulpiride, and sparfloxacin was assessed using chronic complete atrioventricular block dogs with Holter ECG monitoring in the conscious state. Oral administration of 1-10 times higher doses than the clinically relevant doses of the drugs induced polymorphic ventricular tachycardia torsades de pointes (TdP), except for amiodarone. These results indicate that the prolongation and backward shift of the terminal repolarization period may be closely related to the drug-induced TdP and suggest that these in vivo models can be used to screen proarrhythmic potential of new drugs.

Familial and acquired long qt syndrome and the cardiac rapid delayed rectifier potassium current.

1. Long QT syndrome (LQTS) is a cardiac disorder characterized by syncope, seizures and sudden death; it can be congenital, idiopathic, or iatrogenic. 2. Long QT syndrome is so-named because of the connection observed between the distinctive polymorphic ventricular tachycardia torsade de pointes and prolongation of the QT interval of the electrocardiogram, reflecting abnormally slowed ventricular action potential (AP) repolarization. Acquired LQTS has many similar clinical features to congenital LQTS, but typically affects older individuals and is often associated with specific pharmacological agents. 3. A growing number of drugs associated with QT prolongation and its concomitant risks of arrhythmia and sudden death have been shown to block the 'rapid' cardiac delayed rectifier potassium current (IKr) or cloned channels encoded by the human ether-a-go-go-related gene (HERG; the gene believed to encode native IKr). Because IKr plays an important role in ventricular AP repolarization, its inhibition would be expected to result in prolongation of both the AP and QT interval of the electrocardiogram. 4. The drugs that produce acquired LQTS are structurally heterogeneous, including anti-arrhythmics, such as quinidine, non-sedating antihistamines, such as terfenadine, and psychiatric drugs, such as haloperidol. In addition to heterogeneity in their structure, the electrophysiological characteristics of HERG/IKr inhibition differ between agents. 5. Here, clinical observations are associated with cellular data to correlate acquired LQTS with the IKr/HERG potassium (K+) channel. One strategy for developing improved compounds in those drug classes that are currently associated with LQTS could be to design drug structures that preserve clinical efficacy but are modified to avoid pharmacological interactions with IKr. Until such time, awareness of the QT-prolongation risk of particular agents is important for the clinician.