Exercise-induced torsades de pointes as an unusual presentation of cardiac sarcoidosis: A case report and review of literature

BACKGROUND Sarcoidosis is a rare multisystem disease characterized histologically by noncaseating granuloma formation in the affected organ.While cardiac sarcoidosis is found on autopsy in up to 25%of sarcoidosis cases,it is still underdiagnosed and is associated with a poor prognosis.Although the etiology of sarcoidosis remains unclear,an antigen triggered exaggerated immune response has been hypothesized.Early detection and prompt management of cardiac sarcoidosis remains pivotal.CASE SUMMARY A 60-year-old female,with pulmonary sarcoidosis in remission,presented to the cardiology outpatient clinic for evaluation of weeks-long dyspnea on moderate exertion(New York Heart Association class II)that was relieved by rest.Submaximal exercise stress test showed multifocal ventricular extrasystoles,followed by a self-limiting torsades de pointes.Cardiac magnetic resonance imaging showed nondilated and normotrophic left ventricle with basoseptal and mid-septal dyskinesis.The magnetic resonance imaging-derived left ventricular ejection fraction was 45%.Delayed enhancement showed patchy transmural fibrosis of the septum and hyperenhancement of the papillary muscles,all in favor of extensive cardiac involvement of sarcoidosis.A double-chamber implantable cardiac defibrillator was implanted,and methylprednisolone(12 mg/d)and methotrexate(12.5 mg/wk)treatment was initiated.Follow-up and implantable cardiac defibrillator interrogation showed episodes of asymptomatic nonsustained ventricular tachycardia and an asymptomatic episode of nonsustained ventricular tachycardia ending by the first antitachycardia pacing run.CONCLUSION Along an extensive review of the literature,this unusual case report highlights the importance of early detection of cardiac involvement of sarcoidosis,in order to avoid potential complications and increase survival.

Torsades de pointes episode in a woman with high-grade fever and inflammatory activation: A case report

BACKGROUND QT interval prolongation can induce torsades de pointes(TdP),a potentially fatal ventricular arrhythmia.Recently,an increasing number of non-cardiac drugs have been found to cause QT prolongation and/or TdP onset.Moreover,recent findings have demonstrated the key roles of systemic inflammatory activation and fever in promoting long-QT syndrome(LQTS)and TdP development.CASE SUMMARY A 30-year-old woman was admitted with a moderate to high-grade episodic fever for two weeks.The patient was administered with multiple antibiotics after hospitalization but still had repeating fever and markedly elevated C-reactive protein.Once after a high fever,the patient suddenly lost consciousness,and electrocardiogram(ECG)showed transient TdP onset after frequent premature ventricular contraction.The patient recovered sinus rhythm and consciousness spontaneously,and post-TdP ECG revealed a prolonged QTc interval of 560 ms.The patient’s clinical manifestations and unresponsiveness to the antibiotics led to the final diagnosis of adult-onset Still’s disease(AOSD).There was no evidence of cardiac involvement.After the AOSD diagnosis,discontinuation of antibiotics and immediate initiation of intravenous dexamethasone administration resulted in the normal temperature and QTc interval.The genetic analysis identified that the patient and her father had heterozygous mutations in KCNH2(c.1370C>T)and AKAP9(c.7725A>C).During the 2-year follow-up period,the patient had no recurrence of any arrhythmia and maintained normal QTc interval.CONCLUSION This case study highlights the risk of systemic inflammatory activation and antibiotic-induced TdP/LQTS onset.Genetic analysis should be considered to identify individuals at high risk of developing TdP.

Modulations of the fast inactivation current of I_(kr) by extracellular potassium in guinea pig ventricular myocytes──Investigation of the development mechanism of acquired LQT and torsade de points

Acquired long QT syndromes and torsade de points often occur with underlying hypokalemia andbradycardia. With its fast inactivation property, the rapid activating component (Ikr) of the delayed rectifierpotassium current (IK) plays an important role in maintaining normal QT intervals. In this study, we evaluated the effects of different extracellular potassium ([K].) on the fast inactivation current of Ikr in guinea pigventricular myocytes. The results showed that [K]. had strong effects on the fast inactivation current ; thelower [K].(1, 3 mmol/L) significantly decreased the inactivation outward current (P＜0. 05); while higher[K]. (8, 10, 20 mmol/L) slightly increased the inactivation current (P>0. 05). These results may be of greatclinical significance. The lower [K]. decreased Ikr inactivation current, which may help to explain why acquired long QT syndromes and torsade de points often occur in the lower [K]. The correction of hypokalemia can increase the inactivation current, therefore, it is critical in the treatment of acquired long QTsyndromes and torsade de points.

Experimental study on the mechanism of sex difference in the risk of torsade de pointes

Background Torsade de pointes (TdP) is a form of polymorphic ventricular tachycardia featuring prolonged QT intervals. Female gender is associated with an increased risk of TdP. However, the causes of the sex difference in risk are poorly understood. Recently, transmural dispersion of repolarization (TDR) has been implicated in the genesis of TdP. Consequently, we compared TdP incidence and TDR between male and female rabbit hearts in order to investigate the mechanism of sex difference in TdP risk in rabbits in vitro. Methods By means of monophasic action potential recording techniques, the monophasic action potential of the epicardium, midmyocardium, and endocardium were simultaneously recorded using specially designed plunge-needle electrodes placed across the left ventricular free wall of both female (n=8) and male (n=8) rabbit hearts purfused by the Langendorff method. TdP was induced by bradycardia, d-sotalol, and low-K +, Mg 2+ Tyrode solution. Results TDR measurements in all three myocardial layers of male and female rabbit hearts were (18±2) ms and (21±2) ms, respectively (n=8, P>0.05). After perfusion with d-sotalol, the 90% monophasic action potential duration was prolonged in both male and femlae rabbits. TDR in male and female rabbit hearts increased to (29±2) ms and (61±2) ms, respectively, a difference that is significant. Eight female rabbit hearts had early afterdepolarization and 7 of them developed TdP. Seven male rabbit hearts had early after depolarization, but only one of these hearts developed TdP.Conclusion Greater TDR may play an important role in the higher incidence of TdP in female rabbit hearts.

Drugs to be avoided in patients with long QT syndrome:Focus on the anaesthesiological management

Long QT syndrome incidence is increasing in general population.A careful pre-,peri-and post-operative management is needed for patients with this syndrome because of the risk of Torsades de Pointes and malignant arrhythmias.The available data regarding prevention of lethal Torsades de Pointes during anesthesia in patients with long QT syndrome is scant and conflicting:only case reports and small case series with different outcomes have been published.Actually,there are no definitive guidelines on pre-,peri-and post-operative anesthetic management of congenital long QT syndrome.Our review focuses on anesthetic recommendations for patients diagnosed with congenital long QT syndrome furnishing some key points for preoperative optimization,intraoperative anesthetic agents and postoperative care plan,which could be the best for patients with c-long QT syndrome who undergo surgery.

Beat-to-Beat Variability in Field Potential Duration in Human Embryonic Stem Cell-Derived Cardiomyocyte Clusters for Assessment of Arrhythmogenic Risk, and a Case Study of Its Application

We established a QT interval assessment system that uses human embryonic stem cell-derived cardiomyocyte clusters (hES-CMCs) in which the field potential duration (FPD) or corrected FPD (FPDc) was measured as an indicator of drug-induced QT interval prolongation. To investigate the applicability of the hES-CMC system to drug safety assessment, we investigated short-term variability in FPDc (STVFPDc) (beat rate rhythmicity) as a marker of torsadogenic risk. We investigated the FPDc and STVFPDc of hES-CMCs treated with hERG channel blockers (E-4031 or cisapride) or with our proprietary compounds X, Y, and Z. We also evaluated the electrocardiograms and hemodynamics of dogs treated with compound X, Y, or Z. The torsadogenic hERG channel blockers increased STVFPDc and prolonged FPDc. Compounds X, Y, and Z had hERG inhibitory activity. Compound X prolonged FPDc with increased STVFPDc, whereas compounds Y and Z tended to shorten FPDc in the hES-CMC system. In the in vivo canine study, compound X prolonged corrected QT (QTc), and compounds Y and Z tended to shorten QTc, showing a good correlation with the results in hES-CMCs. These findings suggest that combined assessment of FPDc and STVFPDc in the hES-CMC system increases the predictability of torsadogenic risk.

Importance of cardiological evaluation for first seizures

This paper reports two cases of long QT syndrome(LQTS) which presented with seizures as their initial feature. Case 1, AB was seen in emergency department with post-partum seizure, discharged and re-presentedfollowing cardiac arrest associated with LQTS. Case 2, CD presented initially with tonic-clonic seizure and because of experience with AB, CD was assessed for LQTS which was subsequently confirmed. The legal medicine experience re Dobler v Halverson, which involved a young boy with LQTS, who suffered cardiac arrest without prior diagnosis of LQTS, has reinforced the requirement to seriously consider LQTS as an aetiological factor in first seizure presentations.

KN-93, A CaMKⅡ Inhibitor, Suppresses Ventricular Arrhythmia Induced by LQT2 Without Decreasing TDR

Summary： Abnormal enhanced transmural dispersion of repolarization （TDR） plays an important role in the maintaining of the severe ventricular arrhythmias such as torsades de pointes （TDP） which can be induced in long-QT （LQT） syndrome. Taking advantage of an in vitro rabbit model of LQT2, we de- tected the effects of KN-93, a CaM-dependent kinase （CaMK） II inhibitor on repolarization heteroge- neity of ventricular myocardium. Using the monophasic action potential recording technique, the action potentials of epicardium and endocardium were recorded in rabbit cardiac wedge infused with hypo- kalemic, hypomagnesaemic Tyrode＇s solution. At a basic length （BCL） of 2000 ms, LQT2 model was successfully mimicked with the perfusion of 0.5 μmol/L E-4031, QT intervals and the interval from the peak of T wave to the end of T wave （Tp-e） were prolonged, and Tp-e/QT increased. Besides, TDR was increased and the occurrence rate of arrhythmias like EAD, R-on-T extrasystole, and TDP increased under the above condition. Pretreatment with KN-93 （0.5μmol/L） could inhibit EAD, R-on-T extrasys- tole, and TDP induced by E-4031 without affecting QT interval, Tp-e, and Tp-e/QT. This study demon- strated KN-93, a CaMK II inhibitor, can inhibit EADs which are the triggers of TDP, resulting in the suppression of TDP induced by LQT2 without affecting TDR.

Survey concerning internal medicine physicians and prolonged QT interval:Knowledge and treatment practices

Prolongation of the QT interval is associated with adverse cardiac events specifically Torsades de pointes(TdP).There are multiple mediations that have a known,possible,or conditional risk for prolonged QT interval,but general practitioners’knowledge of these medications is unknown.We conducted a survey to assess internal medicine(IM)providers’knowledge of risk factors and medications associated with prolonged QT as well as provider experience and comfort when treating patients with prolonged QT.A 17-question,anonymous survey was constructed in 2019 and distributed to IM providers and residents at a tertiary care center.Questions included demographic information,6 Likert-scale questions gauging provider experience with prolonged QT,and 10 multiple choice clinical vignettes to assess clinical knowledge.Data was analyzed descriptively.Knowledge was assessed via clinical vignettes and compared by level of training.Forty-one responses were received out of a total of 87 possible respondents(47.1%response rate).About 70%of respondents see patients with acquired prolonged QT once monthly or more.95%rarely see congenital prolonged QT.When presented with QTc drug issues,73%of providers seldom or sometimes consulted pharmacy,but about half used online resources.The average correct score on the clinical vignettes was 5.59/10,with the highest scores seen in attending physicians in their first five years of practice(6.96/10).Our survey suggests that IM providers commonly encounter QT prolonging drugs.Educational efforts to improve knowledge of drug and patient risk factors for TdP may be needed.

Relevance of long QT syndrome in clinical neurology

Long QT syndrome(LQTS) is a cardiac conduction disorder that predisposes patients at potentially fatal cardiac events. Inherited conditions and acquired factors contribute to LQTS. A number of frequently prescribed CNS-active drugs prolong the QT interval. The clinical neurologist may encounter LQTS when initiating a pharmacotherapy or when increasing the dosage of drugs. The clinical neurologist may also encounter LQTS during the diagnostic work-up of patients with unexplained loss of consciousness, because LQTS may present as convulsive syncope. Some studies report an association of LQTS and stroke. Awareness of LQTS may help to recognize and prevent potentially fatal cardiac events associated with LQTS. This concise article highlights the clinically most relevant aspects of LQTS in the field of neurology.

Blocking effects of erythromycin on the rapid activating component(I_(kr)) of the delayed rectifier potassium current (I_k) in guinea pig ventricular myocytes ──Direct measurement of the fast inactivation current

Intravenous or oral administrations of erythromycin in humans have been reported to induce excessive prolongation of QT interval and even cause polymorphic ventricular tachycardia and torsade de points. Inthis study, we evaluated the effects of erythromycin on Ik, through direct measurement of the fast inactivationcurrent by using a two-pulses protocol. The results showed that erythrornycin 100 μmol/L restrained the fastinactivation current (P<0. 05), and its effects were both dose--dependent and voltage-dependent. As a result. the time course of erythromycin on the inactivation current was slow and washout was difficult. Our results expectedly may explain the reason why erythromycin slows the repolarization of action potential,lengthens QT interval, and causes torsade de points in humans.