Low Dose Amitriptyline-Induced Electrical Storm Unmasking a Novel SCN5A and KCNQ1 Compound Genotype: Insights from Family Cascade Screening.

Solifenacin, an antimuscarinic drug, has been widely used for the treatment of overactive bladder (OAB), but severe cardiac adverse effects have not been reported. An 81-year-old woman was prescribed solifenacin 5 mg day−1 for OAB. Two weeks later she developed the first syncope. Nine days after the first syncope she developed recurrent syncope, and electrocardiogram monitoring showed marked QT prolongation and torsade de pointes (TdP). Concomitant drugs remained unchanged. Serum electrolytes and hepatic function were normal. Calculated creatinine clearance was mildly decreased. We considered that the loss of consciousness was associated with solifenacin. Although intravenous magnesium sulphate could not terminate the recurrence of TdP, increasing the pacing rate prevented further attacks of TdP. Solifenacin might be a possible cause of QT prolongation and TdP. Solifenacin is a newer bladder-selective antimuscarinic drug for the treatment of OAB [1]. Although terodiline, an older antimuscarinic drug for OAB, has been reported to predispose to QT prolongation and TdP and was withdrawn from the market in the early 1990s [2–4], solifenacin has not been reported to have severe cardiac adverse effects [1]. An 81-year-old woman was admitted to the division of orthopaedics with dislocation of hip joint and infection of decubitus. One year before admission she had undergone total hip arthroplasty. Her past medical history included hypertension and pacemaker implantation for sick sinus syndrome. Her medication included amlodipine, but not any over-the-counter drugs or herbals. Electrocardiogram (ECG) on admission showed sinus rhythm with normal QT interval (QT400 ms/QTc360 ms) (Figure 1a). Solifenacin 5 mg day−1 was started for OAB after admission. Her infection was initially treated with intravenous cefazolin, but was changed to intravenous teicoplanin because of methicillin-resistant Staphylococcus aureus infection. Two weeks later she suddenly developed loss of consciousness, but she spontaneously regained full consciousness. Figure 1 ECG monitoring. (a) Sinus rhythm with normal QT interval on admission. (b) Marked QT prolongation after the first syncope. (c) Typical episode of torsade de pointes 9 days after the first syncope Although ECG was not recorded during the episode, ECG monitoring showed QT prolongation (QT600 ms/QTc581 ms) after regaining consciousness (Figure 1b). Nine days after the first syncope she developed recurrent loss of consciousness and ECG monitoring showed TdP (Figure 1c). She was resuscitated with a single DC shock. She was immediately transferred to the division of cardiology. ECG monitoring showed QT prolongation (QT600 ms) and recurrent TdP. Serum electrolytes and hepatic function were normal. Calculated creatinine clearance was 60 ml min−1. We considered that solifenacin was closely related to syncope and TdP. We stopped solifenacin. Intravenous magnesium sulphate could not terminate recurrent episodes of TdP. The pacing rate was increased 60 to 90 beats min−1 to shorten the QT interval, resulting in a QT interval of 600 to 500 ms (QTc 408 ms). There were no further attacks of TdP. Electrocardiographic abnormalities resolved a few days after solifenacin was discontinued. The high bladder selectivity of solifenacin might be expected to reduce adverse effects [1], which include dry mouth, constipation and blurred vision, but severe cardiac adverse effects have not been reported [1]. Known risk factors for drug-induced TdP are female sex, hypokalaemia, hypomagnesaemia, bradycardia, simultaneous administration of inhibitor compounds, and genetic factors [4–6]. Serum electrolytes, especially potassium and magnesium, were normal. Age and mild renal dysfunction had no clinically relevant effects on the pharmacokinetics of solifenacin [1]. The main metabolic pathway of solifenacin is CYP3A4 [1]. Although hepatic dysfunction decreased clearance of solifenacin [1], hepatic function was also normal. Anti-infective agents that were administered intravenously did not include CYP3A4 inhibitors such as erythromycin [4–6]. She had no other structural heart diseases, nor any family history of sudden death. Concomitant drugs remained unchanged. Amlodipine would not have interacted with solifenacin because of little influence of first-pass effect by CYP3A4 at therapeutic dose [7]. Marked QT prolongation and TdP were considered to be related to solifenacin. Intravenous magnesium sulphate, the first-choice treatment of drug-induced TdP [6], was not effective. Recurrence of TdP was prevented after the QT interval was shortened by increasing the pacing rate. We did not investigate her genetic factors and plasma drug concentration. Although the mechanism is not fully understood, the start of solifenacin might have influenced the outcome in our elderly female patient. To our knowledge, this is the first reported case of QT prolongation and TdP associated with solifenacin.

Torsades de pointes related to transient marked QT prolongation following successful emergent percutaneous coronary intervention for acute coronary syndrome

The epinephrine infusion test (EIT) typically induces marked QT prolongation in LQT1, but not LQT3, while the efficacy of β-blocker therapy is established in LQT1, but not LQT3. We encountered an LQT3 family, with an SCN5A V1667I mutation, that exhibited epinephrine-induced marked QT prolongation. Wild-type (WT) or V1667I-SCN5A was transiently expressed into tsA-201 cells, and whole-cell sodium currents (INa ) were recorded using patch-clamp techniques. To mimic the effects of epinephrine, INa was recorded after the application of protein kinase A (PKA) activator, 8-CPT-cAMP (200 μM), for 10 minutes. The peak density of V1667I-INa was significantly larger than WT-INa (WT: 469 ± 48 pA/pF, n = 20; V1667I: 690 ± 62 pA/pF, n = 19, P < .01). The steady-state activation (SSA) and fast inactivation rate of V1667I-INa were comparable to WT-INa . V1667I-INa displayed a significant depolarizing shift in steady-state inactivation (SSI) in comparison to WT-INa (V1/2 -WT: -88.1 ± 0.8 mV, n = 17; V1667I: -82.5 ± 1.1 mV, n = 17, P < .01), which increases window currents. Tetrodotoxin (30 μM)-sensitive persistent V1667I-INa was comparable to WT-INa . However, the ramp pulse protocol (RPP) displayed an increased hump in V1667I-INa in comparison to WT-INa . Although 8-CPT-cAMP shifted SSA to hyperpolarizing potentials in WT-INa and V1667I-INa to the same extent, it shifted SSI to hyperpolarizing potentials much less in V1667I-INa than in WT-INa (V1/2 -WT: -92.7 ± 1.3 mV, n = 6; V1667I: -85.3 ± 1.6 mV, n = 6, P < .01). Concordantly, the RPP displayed an increased hump in V1667I-INa , but not in WT-INa . We demonstrated an increase of V1667I-INa by PKA activation, which may provide a rationale for the efficacy of β-blocker therapy in some cases of LQT3.

Background: Patients with acute coronary syndrome (ACS) complicated by heart failure with reduced ejection fraction (HFrEF) are at increased risk for malignant ventricular arrhythmias due to ischemia-related electrical instability and impaired repolarization reserve (Al-Khatib et al., 2018, Wellens et al., 2014). Loop diuretics are frequently required for the management of congestion; however, furosemide-induced renal potassium and magnesium wasting may produce an acquired electrolyte phenotype resembling Bartter or Gitelman syndromes (Seyberth and Schlingmann, 2011, Colussi et al., 1992). In the proarrhythmic milieu of ACS and HFrEF, this disturbance can precipitate QT prolongation and torsades de pointes (TdP) (Al-Khatib et al., 2018, Wellens et al., 2014, Roden, 2004). Case Summary: We report three patients with ACS and HFrEF who developed severe hypokalemia and hypomagnesemia during furosemide therapy, resulting in marked QT prolongation and TdP. All patients were successfully treated with prompt rhythm stabilization, intravenous magnesium, aggressive potassium repletion, withdrawal or modification of precipitating factors, and heart-rate augmentation when required (Al-Khatib et al., 2018, Roden, 2004, Tzivoni et al., 1988). No patient experienced arrhythmia recurrence after correction of electrolyte abnormalities. Conclusion: In patients with ACS and HFrEF, the occurrence of TdP should prompt immediate evaluation for diuretic-induced electrolyte depletion representing a reversible acquired pseudo–Bartter/Gitelman syndrome. Early recognition and targeted correction are lifesaving and may prevent unnecessary long-term device therapy (Al-Khatib et al., 2018, Wellens et al., 2014, Roden, 2004).

Hyperglycemia and subsequent torsades de pointes with marked QT prolongation during refeeding

Atrial fibrillation (AF) is the most common cause of tachycardia-induced cardiomyopathy (TIC). A 75-year-old woman was referred to our hospital for catheter ablation for persistent AF. On admission, transthoracic echocardiography (TTE) revealed diffuse left ventricular (LV) hypokinesis, which was suspected to be due to TIC. Catheter ablation was performed on the fifth day of hospitalization, and Torsade de Pointes (TdP) appeared on the sixth day. The serum concentration of bepridil and potassium was below the reference level. An electrocardiogram revealed marked QT prolongation, giant-negative T waves, and T-wave alternans on the seventh day of hospitalization. Cardiac magnetic resonance imaging with no contrast indicated diffuse mild LV hypokinesis, mild prolonged native T1, and no evidence of myocardial edema at T2. Coronary angiography revealed normal coronary arteries, and the ergonovine stress test results were negative. The results for five long QT syndrome susceptibility genes, including the three major genes, were negative. Subsequently, QT prolongation, giant-negative T waves, and LV dysfunction improved without treatment. This case report highlights the importance of risk management for AF patients with TIC scheduled for catheter ablation and carefully evaluating the risks of QT prolongation. Moreover, patients with TIC can experience marked QT prolongation and TdP during the perioperative period of catheter ablation. Therefore, caution should be required.

The hereditary long QT syndrome (LQTS) is an important cause of polymorphous ventricular tachycardia (torsades de pointes) and sudden cardiac death in otherwise young and healthy individuals. Clinically, this condition is caused by delayed ventricular repolarization and manifests as an abnormally prolonged QT interval on the electrocardiogram (ECG). The most common subtypes of LQTS are LQT1, LQT2, and LQT3 (1-10). This article is protected by copyright. All rights reserved.

Patients with LQTS (long QT syndrome) with a mutation in a cardiac ion channel gene, leading to mild-to-moderate channel dysfunction, may manifest marked QT prolongation or torsade de pointes only upon an additional stressor. A 59-year-old woman had marked QT prolongation and repeated torsade de pointes 3 months after initiation of probucol, a cholesterol-lowering drug. We identified a single base substitution in the HERG gene by genetic analysis. This novel missense mutation is predicted to cause an amino acid substitution of Met(124)-->Thr (M124T) in the N-terminus. Three other relatives with this mutation also had QT prolongation and one of them had a prolonged QT interval and torsade de pointes accompanied by syncope after taking probucol. We expressed wild-type HERG and HERG with M124T in Xenopus oocytes and characterized the electrophysiological properties of these HERG channels and the action of probucol on the channels. Injection of the M124T mutant cRNA into Xenopus oocytes resulted in expression of functional channels with markedly smaller amplitude. In both HERG channels, probucol decreased the amplitude of the HERG tail current, decelerated the rate of channel activation, accelerated the rate of channel deactivation and shifted the reversal potential to a more positive value. The electrophysiological study indicated that QT lengthening and cardiac arrhythmia in the two present patients were due to inhibition of I(Kr) (rapidly activating delayed rectifier K(+) current) by probucol, in addition to the significant suppression of HERG current in HERG channels with the M124T mutation.

A Reversible ECG Signature of Hypothermia.

Marked QT Prolongation and Torsades de Pointes Secondary to Acute Ischemia in an Elderly Man Taking Dofetilide for Atrial Fibrillation: A Cautionary Tale

Incidence and clinical features of the quinidine-associated long QT syndrome: Implications for patient care

Marked sinus bradycardia and QT prolongation in a diabetic patient with severe hypoglycemia

To use dynamic electrocardiographic (ECG) techniques to study the influence of heart rate on dofetilide-induced QT prolongation among healthy volunteers. The extent to which heart rate modulates QT prolongation induced by the new class III antiarrhythmic drug dofetilide is a matter of debate. Ten healthy volunteers underwent two 24-hour ECG recordings, one in the absence of dofetilide and the other after a single oral dose of 0.5 mg dofetilide. Two 4-hour periods were defined during the second recording: Dh, which corresponded to stable high concentration of the drug, and D1, which corresponded to low concentration of the drug. Corresponding baseline recording periods, Ch and C1, matched by time with Dh and D1 were selected from the control ECG recording in the absence of dofetilide. QT versus R-R relations were compared in the presence and absence of dofetilide. The QT versus R-R relation slope was used as an index of the rate dependence QT prolongation. Rate-independent changes in QT duration were also analyzed. During Dh, dofetilide induced a mean 12% lengthening of ventricular repolarization. Dynamic ECG analysis showed that this prolongation increased as R-R cycles became longer, a phenomenon known as reverse rate dependence. However, QT prolongation persisted at the shortest (600 ms) R-R cycle length that could be analyzed. During D1, dynamic ECG analysis showed a persistent, although small, effect of dofetilide on both QT prolongation (3%) and reverse rate dependence of this effect. Dofetilide prolongs QT duration, and this class III effect is influenced by heart rate. Although dofetilide-induced QT prolongation decreases when the R-R cycle shortens, this reverse rate dependence is only partial because marked QT prolongation persists at an R-R cycle of 600 ms. The results of our study indicated that dynamic ECG techniques can be useful in detection of subtle, drug-induced changes in the duration of ventricular repolarization.

Management of QT prolongation induced by anti-cancer drugs: Target therapy and old agents. Different algorithms for different drugs

Effect of atropine on QT prolongation and torsade de pointes induced by intracoronary acetylcholine in the long QT syndrome