Severe QT Prolongation Research Articles

Efficacy of intraperitoneal calcium for hungry bone syndrome following parathyroidectomy: A case report

A man with hyperparathyroidism secondary to kidney failure on peritoneal dialysis underwent a parathyroidectomy with half-gland reimplantation complicated by severe hungry bone syndrome resulting in severe hypocalcaemia, hypotension and QT prolongation on ECG. He was initially managed with oral calcium and intravenous (IV) calcium chloride. Despite standard supportive treatment, attempts to wean IV therapy were unsuccessful. We report the novel use of intraperitoneal calcium to facilitate the weaning of IV calcium and discharge from hospital. A subsequent peritoneal membrane adequacy study did not demonstrate loss of peritoneal membrane adequacy.

Haloperidol- and quetiapine-induced severe QT prolongation

Haloperidol- and quetiapine-induced severe QT prolongation

Incidences, risk factors, and clinical correlates of severe QT prolongation after the use of quetiapine or haloperidol

BackgroundCase reports suggest that quetiapine or haloperidol use is associated with severe QT prolongation (SQTP) and torsades de pointes. ObjectiveThe purpose of this study was to examine the incidences, risk factors, and outcomes of SQTP in quetiapine and haloperidol users. MethodsThis study accessed electronic medical records from a multicenter health-care hospital system in Taiwan and included patients who received quetiapine or haloperidol therapy and had both baseline and follow-up electrocardiograms. SQTP was defined as a posttreatment corrected QT (QTc) interval exceeding 500 ms or an increase in QTc interval of >60 ms compared with the baseline value. We analyzed the risk factors and outcomes of SQTP using multivariate logistic regression. ResultsMean increases in QTc interval were +8.3 ± 51.8 and +8.9 ± 44.0 ms after the administration of quetiapine (n = 8832) and haloperidol (n = 2341). Among these users, 1149 (13.0%) and 333 (14.2%) developed SQTP, respectively. Common risk factors for SQTP included old age, heart failure, hypokalemia, amiodarone use, and baseline QTc interval. SQTP in quetiapine users was significantly associated with ventricular arrhythmias (odds ratio 2.84; 95% confidence interval 1.95–4.13) and sudden cardiac death (odds ratio 2.29; 95% confidence interval 1.44–3.66). ConclusionMore than 10% of patients receiving quetiapine or haloperidol therapy developed SQTP, and many of them were exposed to risk factors for SQTP. SQTP in quetiapine users was significantly associated with increased risks of ventricular arrhythmias and sudden cardiac death. Clinicians should be vigilant for ventricular arrhythmias in quetiapine users who have risk factors for SQTP.

PO-455617-3 NOVEL PRECISION GENETIC APPROACH IMPROVES DIAGNOSIS AND RISK STRATIFICATION IN LONG QT SYNDROME TYPE 5

Type 5 long QT syndrome (LQT5) is a subtype of long QT syndrome caused by loss of function variants in KCNE1 encoding a key potassium channel function-modifying subunit. LQT5 cases are rare and incompletely penetrant, so it has been controversial whether KCNE1 variants are disease-causing or risk-modifying. We identified 9 local LQT5 probands carrying the D76N KCNE1 variant, the most common variant implicated in LQT5. To test the hypothesis that these probands shared a recent common ancestor and to identify other potential D76N carriers in BioVU, our biobank that links electronic health records to DNA data. We used dense genomic arrays and identity-by-descent (IBD)-based genotype inference to identify shared chromosomal segments in the 9 probands and 3 first-degree relatives, and across BioVU. We determined penetrance (QTc > 490 msec) and the relationship of penetrance to a 1.1 million SNP QT interval polygenic risk score (PRS) in all mutation carriers. IBD analysis identified large (>1 cM) shared chromosomal segments across 8 of the 9 probands, indicating a shared common ancestor approximately 4-5 generations ago. Interrogation of array data in 69,879 European ancestry subjects in BioVU identified a further 26 subjects sharing the same large chromosomal segment, and sequencing confirmed D76N carrier status in 22 subjects, all previously undiagnosed. One BioVU subject had a history of sotalol-induced Torsades de Pointes. We found that among the 34 D76N carriers, QT intervals were prolonged compared to >32,000 BioVU controls free of heart disease or QT prolonging drugs, and that penetrance for QTc>490 was 44%. Among carriers, the QTc PRS was associated with severe QT prolongation. Detection of large shared chromosomal segments around KCNE1 enabled us to define a local founder event, identify previously undiagnosed carriers, demonstrate the contribution of polygenic risk to monogenic disease penetrance, and to further establish LQT5 as a primary arrhythmia disorder. The analysis of distant relatedness is a promising new approach to identify undiagnosed cases of genetic diseases.

ECG monitoring in STREAM Stage 1: can we identify those at increased risk of QT prolongation?

BACKGROUND: STREAM (Standardised Treatment Regimen of Anti-tuberculosis Drugs for Patients with Multidrug-resistant Tuberculosis) Stage 1 was a randomised trial of a Short (9-month) regimen for rifampicin-resistant TB (RR-TB). QT or QTcF prolongation ≥500 ms occurred in 31 (11%) of 282 Short regimen participants. The frequent ECG monitoring employed might be challenging for treatment programmes. This analysis aimed to determine whether those at higher risk of severe QT prolongation could be identified early for more targeted monitoring.METHODS: Data from the first month of treatment were used to investigate whether participants were at risk of developing QT/QTcF ≥500 ms. QTcF increases from baseline at different time points were examined. Absolute QTcF measurements were categorised in 5 ms increments at each time-point. The most discriminating time points and QTcF cut-offs were combined to optimise sensitivity and specificity.RESULTS: Absolute QTcF values were more discriminating than magnitude of increase from baseline. More participants who developed QT/QTcF ≥500 ms had a QTcF of respectively ≥425 ms and ≥430 ms at 4 h and Week 3 (P < 0.05) than those who did not. By combining QTcF values ≥425 ms at 4 h and ≥430 ms at Week 3, we identified high-risk participants with 97% sensitivity and 99% negative predictive value.CONCLUSION: Reduced ECG monitoring may be possible for many Short regimen participants.

Hydroxychloroquine with or without Macrolide and Standard of Care versus Standard of Care Alone for COVID-19 Cases: A Systematic Review and Meta-Analysis

Background: The specific treatment has not yet been approved for the therapy of COVID-19 pandemic. In this review, we aimed at assessing the role of hydroxychloroquine with/without macrolide in terms of efficacy and adverse effects against the standard of care (SOC).&#x0D; Methods: PubMed, Medline, Google Scholar, Cochrane Library, and Clinicaltrials.gov were searched for the quantitative and qualitative synthesis of 13 studies using PRISMA guidelines. Assessment of heterogeneity was done using I-squared (I2) test and fixed/random effect analysis was done to determine the odds/risk ratio among selected studies.&#x0D; Results: Our study demonstrated no significant differences in improvement for virological cure (RR 0.95, 0.67-1.34), whereas a significant relationship was there in radiological progression (RR 1.40, 1.03-1.91) between the two arms. There are 1.52 times the odds of intubation during treatment (CI 0.61-3.77), 1.08 times the risk of mortality (CI 0.65-1.79), and about 2.21 times increased risk of development of adverse effect (OR 2.21, 0.95-5.17). Among randomized controlled trials, the treatment group has 3.5 times (OR 3.48, 1.64-7.42) higher risk of developing adverse effects. There is 2.5 times the likelihood of severe arrhythmias and QT prolongation (OR 2.49, 1.67-3.70) on the treatment arm compared to control.&#x0D; Conclusions: Hydroxychloroquine with/without macrolide demonstrated no beneficial effect in viral clearance and survival rates while showed significant relation in radiological improvement compared to SOC. The increased risk of intubation, overall side effects, and cardiac complications like arrhythmias and QT prolongation suggests utilizing such treatment to be judged with clinical relevance and proper monitoring.

Anesthetic management of a patient with severe aortic regurgitation undergoing reoperation for ascending aorta false aneurysm using hypothermia: prevention of ventricular fibrillation by nifekalant

BackgroundTo prevent cardiac collapse and to protect cerebral function, hypothermic cardiopulmonary bypass is established before resternotomy. However, ventricular fibrillation under hypothermia facilitates left ventricular distension, which causes irreversible myocardial damage when the patient has aortic regurgitation. We report a case of successful management in preventing ventricular fibrillation under hypothermia by using nifekalant.Case presentationA 56-year-old male, who had been performed a David operation, was scheduled for a Bentall operation for a pseudo aortic aneurysm with severe aortic regurgitation. After inducing anesthesia, we administered intravenous nifekalant and a vent tube was inserted into the left ventricle under one-lung ventilation. Extracorporeal circulation was established and resternotomy started after cooling to 27 °C. Although severe bradycardia and QT prolongation were observed, ventricular fibrillation did not occur until aortic cross-clamping.ConclusionCombining maintaining cerebral perfusion and avoiding left ventricle distension during hypothermia was successfully managed with nifekalant in our redo cardiac patient with aortic regurgitation.

Phase 3b Study Assessing the Safety and Efficacy of Midostaurin in Younger and Older Patients with Newly Diagnosed, FLT3-Mutated Acute Myeloid Leukemia (AML) Who Are Eligible for 7+3 or 5+2 Chemotherapy

Phase 3b Study Assessing the Safety and Efficacy of Midostaurin in Younger and Older Patients with Newly Diagnosed, FLT3-Mutated Acute Myeloid Leukemia (AML) Who Are Eligible for 7+3 or 5+2 Chemotherapy

Drug-specific risk of severe QT prolongation following acute drug overdose

Background: Severe QT prolongation (SQTP) has been identified as a strong predictor of adverse cardiovascular events in acute drug overdose, but drug-specific causes of SQTP in the setting of acute drug overdose remain unclear. We aimed to perform the most definitive study to date describing drug-specific risk of SQTP following acute drug overdose.Methods: This was a prospective multicenter cohort study at >50 hospital sites across the US using the ToxIC Registry between 2015 and 2018. Inclusion criteria were adults (≥18 years) receiving medical toxicology consultation for acute drug overdose. The primary outcome was SQTP, which was defined using the computer automated Bazett QT correction (QTc) on the ECG with the previously validated cut point of 500 milliseconds. Mean difference in QTc was also calculated for specific drugs. Drugs associated with SQTP were analyzed using multivariable logistic regression to control for known confounders of QT risk (age, sex, race, cardiac disease).Results: From 25,303 patients screened, 6473 met inclusion criteria with SQTP occurring in 825 (13%). Drugs associated with increased adjusted odds of SQTP included Class III antidysrhythmics (sotalol), sodium channel blockers (amitriptyline, diphenhydramine, doxepin, imipramine, nortriptyline), antidepressants (bupropion, citalopram, escitalopram, trazodone), antipsychotics (haloperidol, quetiapine), and the antiemetic serotonin antagonist ondansetron.Conclusions: This large US cohort describes drug-specific risk of SQTP following acute drug overdose. Healthcare providers caring for acute drug overdoses from any of these implicated drugs should pay close attention to cardiac monitoring for occurrence of SQTP.

Employment of old options to control novel coronavirus: Pros and Cons

Since late December 2019, humans have been under danger due to an outbreak of a coronavirus (SARS-CoV-2) disease COVID-19. Worldwide uncontrolled occurrences (16,812,755 cases out of which 662,095 died as on 30th July 2020) of COVID-19, challenge to public health infrastructures and becoming a grave threat to the population. The condition is becoming worse as the disease is transmitting through a vast number of asymptomatic and pre-symptomatic cases. While the World is finding expedited approvals for the development of a vaccine, which is time-dependent, being preventative and not possibly a cure, physicians are considering several age-old immunotherapeutic techniques– the Convalescent plasma (CP) therapy and antimalarial drug, hydroxychloroquine (HCQ) could be therapeutic options against COVID-19 infection. CP therapy involves the use of passive immunization where the administration of antibodies from a given donor to a susceptible person to initiate the development of immunity to the recipient against SARS-COV-2 is initiated. For the CP therapy to be effective, an adequate amount of antibody has to be administered to the recipient from the donor at the very early stages of the COVID-19 disease. CP therapy for COVID-19 may be beneficial for prophylactic as well as for treatment purposes. But, people may experience any inadvertent untoward effects including immunological reactions and blood-borne pathogenic infections related to blood transfusion. Furthermore, the use of CP therapy may cause antibody-dependent enhancement (ADE) or immune enhancement as a result of infectivity and virulence of the pathogen. As employment of the ADE mechanism may be one of the reasons behind the high severity of SARS-CoV-2 among the older population. On the other hand, HCQ has diverse modes of action, like alteration of the acidic environment inside lysosome, late endosomes, restriction further with endocytosis, exosome release, phagolysosomal fusion in systematically and subsequently inhibition of cytokine storm in the host cell. But, a study report from Brazil warns that the high-dose group patients had more severe QT prolongation (syndrome of heart rhythm disorder, causes arrhythmias) and tendency near higher lethality compared to the low dose. At the time of their reporting, the overall fatality rate across both arms of the study was 13.5%. They are indicating that the percentage of fatality rate was overlapping with the patients, not taking HCQ. One of the sums of diverse mechanisms might work against viral infections and help prevent more deaths. Overall, in this situation of unavailability of specific medication, the CP therapy and HCQ treatment might act as an immediate saviour for society from the pandemic.

A safety evaluation of bedaquiline for the treatment of multi-drug resistant tuberculosis

ABSTRACTIntroduction: Outcomes of treatment for resistant tuberculosis are poor, with long treatment duration and poor tolerability. Bedaquiline is a novel anti-mycobacterial drug, which has a very long terminal elimination half-life. Bedaquiline was approved in 2012 for drug-resistant tuberculosis following improved time to culture conversion and cure rates in a phase 2b study; but mortality was higher in the bedaquiline arm, resulting in a black box warning despite the fact that almost all deaths occurred after bedaquiline was stopped.Areas covered: The authors review safety data of bedaquiline used for rifampicin-resistant tuberculosis from the phase 2 studies, and from case series and observational cohorts. The authors focus on QT interval prolongation, hepatotoxicity, and mortality.Expert opinion: Bedaquiline markedly reduced mortality and improved treatment success in observational studies, resulting in bedaquiline being strongly recommended for rifampicin-resistant tuberculosis by the World Health Organization. In the phase 2 studies participants randomised to bedaquiline had higher rates of liver enzyme elevation and modest QT interval prolongation. Severe QT prolongation was an infrequent cause of bedaquiline interruption despite the frequent use of concomitant drugs that also prolong the QT interval. While awaiting results of phase 3 randomised controlled trials, tuberculosis treatment programmes should strengthen pharmacovigilance.

Adverse drug reactions in South African patients receiving bedaquiline-containing tuberculosis treatment: an evaluation of spontaneously reported cases

BackgroundBedaquiline was recently introduced into World Health Organization (WHO)-recommended regimens for treatment of drug resistant tuberculosis. There is limited data on the long-term safety of bedaquiline. Because bedaquiline prolongs the QT interval, there are concerns regarding cardiovascular safety. The Western Cape Province in South Africa has an established pharmacovigilance programme: a targeted spontaneous reporting system which solicits reports of suspected adverse drug reactions (ADRs) in patients with HIV-1 and/or tuberculosis infection. Since 2015, bedaquiline has been included in the treatment regimens recommended for resistant tuberculosis in South Africa. We describe ADRs in patients on bedaquiline-containing tuberculosis treatment that were reported to the Western Cape Pharmacovigilance programme.MethodsWe reviewed reports of suspected ADRs and deaths received between March 2015 and June 2016 involving patients receiving bedaquiline-containing tuberculosis treatment. A multidisciplinary panel assessed causality, and categorised suspected ADRs using World Health Organisation-Uppsala Monitoring Centre system categories. “Confirmed ADRs” included all ADRs categorised as definite, probable or possible. Preventability was assessed using Schumock and Thornton criteria. Where a confirmed ADR occurred in a patient who died, the panel categorised the extent to which the ADR contributed to the patient’s death as follows: major contributor, contributor or non-contributor.ResultsThirty-five suspected ADRs were reported in 32 patients, including 13 deaths. There were 30 confirmed ADRs, of which 23 were classified as “possible” and seven as “probable”. Bedaquiline was implicated in 22 confirmed ADRs in 22 patients. The most common confirmed ADR in patients receiving bedaquiline was QT prolongation (8 cases, 7 of which were severe). A fatal arrhythmia was suspected in 4 sudden deaths. These 4 patients were all taking bedaquiline together with other QT-prolonging drugs. There were 8 non-bedaquiline-associated ADRs, of which 7 contributed to deaths.ConclusionsConfirmed ADRs in patients receiving bedaquiline reflect the known safety profile of bedaquiline. Quantifying the incidence and clinical consequences of severe QT-prolongation in patients receiving bedaquiline-containing regimens is a research priority to inform recommendations for patient monitoring in treatment programmes for drug resistant tuberculosis. Pharmacovigilance systems within tuberculosis treatment programmes should be supported and encouraged, to provide ongoing monitoring of treatment-limiting drug toxicity.

Development of a predictive model for drug-associated QT prolongation in the inpatient setting using electronic health record data.

We aimed to construct a dynamic model for predicting severe QT interval prolongation in hospitalized patients using inpatient electronic health record (EHR) data. A retrospective cohort consisting of all adults admitted to 2 large hospitals from January 2012 through October 2013 was established. Thirty-five risk factors for severe QT prolongation (defined as a Bazett's formula-corrected QT interval [QTc] of ≥500 msec or a QTc increase of ≥60 msec from baseline) were operationalized for automated EHR retrieval; upon univariate analyses, 26 factors were retained in models for predicting the 24-hour risk of QT events on hospital day 1 (the Day 1 model) and on hospital days 2-5 (the Days 2-5 model). A total of 1,672 QT prolongation events occurred over 165,847 days of risk exposure during the study period. C statistics were 0.828 for the Day 1 model and 0.813 for the Days 2-5 model. Patients in the upper 50th percentile of calculated risk scores experienced 755 of 799 QT events (94%) allocated in the Day 1 model and 804 of 873 QT events (92%) allocated in the Days 2-5 model. Among patients in the 90th percentile, the Day 1 and Days 2-5 models captured 351 of 799 (44%) and 362 of 873 (41%) QT events, respectively. The risk models derived from EHR data for all admitted patients had good predictive validity. All risk factors were operationalized from discrete EHR fields to allow full automation for real-time identification of high-risk patients. Further research to test the models in other health systems and evaluate their effectiveness on outcomes and patient care in clinical practice is recommended.

A REALLY LONG QT: VENTRICULAR TACHYCARDIA STORM POST TAKOTSUBO CARDIOMYOPATHY

Takotsubo cardiomyopathy (TTS) is associated with QT prolongation. Torsade de pointe (TdP) has been increasingly reported in TTS cases with severe QT prolongation. A 66 year old female presented with recurrent polymorphic ventricular tachycardia (figure 1K) and severely prolonged QTc 728 ms (figure

Risk Evaluation of Azithromycin-Induced QT Prolongation in Real-World Practice.

Background Azithromycin exposure has been reported to increase the risk of QT prolongation and cardiovascular death. However, findings on the association between azithromycin and cardiovascular death are controversial, and azithromycin is still used in actual practice. Additionally, quantitative assessments of risk have not been performed, including the risk of QT prolongation when patients are exposed to azithromycin in a real-world clinical setting. Therefore, in this study, we aimed to evaluate the risk of exposure to azithromycin on QT prolongation in a real-world clinical setting using a 21-year medical history database of a tertiary medical institution. Methods We analyzed the electrocardiogram results and relevant electronic health records of 402,607 subjects in a tertiary teaching hospital in Korea from 1996 to 2015. To evaluate the risk of QT prolongation of azithromycin, we conducted a case-control analysis using amoxicillin for comparison. Multiple logistic regression analysis was performed to correct for age, sex, accompanying drugs, and disease. Results The odds ratio (OR) for QT prolongation (QTc>450 ms in male and >460 ms in female) on azithromycin exposure was 1.40 (95% confidence interval [CI], 1.23-1.59), and the OR for severe QT prolongation (QTc>500 ms) was 1.43 (95% CI, 1.13-1.82). On the other hand, the ORs on exposure to amoxicillin were 1.06 (95% CI, 0.97-1.15) and 0.88 (95% CI, 0.70-1.09). In a subgroup analysis, the risk of QT prolongation in patients aged between 60 and 80 years was significantly higher when they are exposed to azithromycin. Conclusions The risk of QT prolongation was increased when patients, particularly the elderly aged 60-79 years, were exposed to azithromycin. Therefore, clinicians should pay exercise caution using azithromycin or consider using other antibiotics, such as amoxicillin, instead of azithromycin.

Novel long QT syndrome-associated missense mutation, L762F, in CACNA1C-encoded L-type calcium channel imparts a slower inactivation tau and increased sustained and window current

BackgroundMutations in the CACNA1C-encoded L-type calcium channel have been associated with Timothy syndrome (TS) with severe QT prolongation, syndactyly, facial dysmorphisms, developmental delay, and sudden death. Recently, patients hosting CACNA1C mutations with only long QT syndrome (LQTS) have been described. We sought to identify novel variants in CACNA1C associated with either TS or LQTS, and to determine the impact of the mutation on channel function. Methods/resultsTwo probands were identified with mutations in CACNA1C, one with a TS-associated mutation, G406R, and a second with genotype-negative LQTS. Illumina HiSeq 2000 whole exome sequencing on the genotype-negative LQTS proband revealed a novel variant, CACNA1C-L762F, that co-segregated within a multi-generational family. The missense mutation localized to the DII/DIII intracellular interlinker segment of the channel in a highly conserved region in close proximity to the 6th transmembrane segment of domain II (DIIS6). Whole cell patch clamp of heterologously expressed CACNA1C-L762F in TSA201 cells demonstrated slower inactivation tau and increased sustained and window current. Comprehensive review and topological mapping of all described CACNA1C mutations revealed TS-specific hotspots localizing to the cytoplasmic aspect of 6th transmembrane segment of respective domains. Probands hosting TS mutations were associated with elevated QTc, higher prevalence of 2:1 AV block, and a younger age at presentation compared to LQTS. ConclusionsThe CACNA1C-L762F mutation is associated with development of LQTS through slower channel inactivation and increased sustained and window current. TS-associated mutations localize to specific areas of CACNA1C and are associated with a younger age at presentation, higher QTc, and 2:1 AV block than isolated LQTS-associated mutations.

Human Induced Pluripotent Stem Cells-Derived Cardiomyocytes Carrying CALM1-F142l Mutation Recapitulate LQTS Phenotype in Vitro

Background: Calmodulin (CaM), a small essential Ca2+ binding protein, is encoded by 3 genes, namely CALM1, CALM2, CALM3, and exerts its modulatory role depending on intracellular Ca2+ concentration changes. In the heart, CaM mutations in these genes led to recurrent cardiac arrest in infants associated with severe QT prolongation (LQTS-CaM).Aims: To explore how the heterozygous CALM1-F142L mutation can support the reported extremely severe cardiac phenotype. To maintain the correct allele balance we studied the functional consequences of this mutation by using patient-specific human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs).Methods: Skin fibroblast of a patient carrying CALM1-F142L mutation were reprogrammed to iPSC and differentiated into CMs; control individuals were 2 unrelated healthy donors without history of cardiac disease. We focus our attention on ICaL biophysics, electrical activity and intracellular Ca2+ dynamics. To make the iPSC-CMs a more reliable model to investigate mechanisms underlying cardiac arrhythmia, in-silico IK1 was injected with a Dynamic-Clamp approach.Results: CALM1-F142L mutation induced impaired Ca2+-dependent inactivation (CDI) and incomplete inactivation of ICaL, thus causing increased Ca2+ influx and consequent action potential prolongation. Therapeutic concentration of verapamil markedly shortened QT in mutated cells. F142L iPSC-CMs failed to adapt to high pacing rates, pointing this as a likely arrhythmogenic mechanism for the mutation. Intracellular Ca2+ handling was instead marginally affected by the mutation. Indeed, sarcoplasmic reticulum (SR) Ca2+content and Ca2+ induced Ca2+ release (CICR)-gain were not affected by the mutation.Conclusions: LQTS-F142L CaM mutation is highly arrhythmogenic mainly because of impaired ICaL CDI; accordingly, its pathogenicity might be limited by the therapeutic use of Ca2+ channel blockers like verapamil.

Sepsis-Induced Takotsubo Cardiomyopathy Leading to Torsades de Pointes.

Background. Takotsubo cardiomyopathy (TCM) is sudden and reversible myocardial dysfunction often attributable to physical or emotional triggers. Case Report. We describe a 51-year-old man presented to emergency department with sepsis from urinary tract infection (UTI). He was placed on cefepime for UTI and non-ST-elevation myocardial infarction protocol given elevated troponins with chest pain. Subsequently, patient was pulseless with torsades de pointes (TdP) and then converted to sinus rhythm with cardioversion. An echocardiogram revealed low ejection fraction with hypokinesis of the apical wall. Over 48 hours, the patient was extubated and stable on 3 L/min nasal cannula. He underwent a cardiac catheterization to evaluate coronary artery disease (CAD) and was found to have mild nonobstructive CAD with no further findings. Conclusion. TCM is a rare disorder presenting with symptoms similar to acute coronary syndrome. Though traditionally elicited by physical and emotional triggers leading to transient left ventricular dysfunction, our case suggests that it may also be triggered by a urinary tract infection and lead to severe QT prolongation and a malignant ventricular arrhythmia in TdP.

Abstract 9741: A Novel Mutation Identified in a Large Multi-Generational Family With Long QT Syndrome Reveals Distinct, Disease-Specific Mutation Hot Spots within the CACNA1C- Encoded L-type Calcium Channel

Background: Mutations in the CACNA1C-encoded L-type calcium channel have been associated with Timothy Syndrome (TS) with severe QT prolongation, cardiac hypertrophy, syndactyly, facial dysmorphisms, developmental delay, and sudden death by impaired channel inactivation and increase peak current. Recently, a small number of patients with CACNA1C mutations with only long QT syndrome (LQTS) have been described. Objective: To explore whether CACNA1C mutations associated with TS were mechanistically and clinically distinct from CACNA1C-mediated LQTS. Methods/Results: Illumina HiSeq 2000 platform-based whole exome sequencing with variant alignment using HGSC Mercury analysis and Atlas2 revealed a novel variant CACNA1C-L762F that co-segregated with affected patients of a large, multi-generational family with LQTS and sudden death. The proband presented at 3 years of age with out-of-hospital cardiac arrest and demonstrated QTc of 530. The mutation localized to the DII/DIII intracellular linker domain of the channel in a highly conserved region in close proximity to the 6th DI transmembrane domain. Whole cell patch clamp of heterologously expressed CACNA1C-L762F in TSA201 cells demonstrated slower inactivation tau and increased late current indicating its gain-of-function cellular electrophysiological phenotype. Comprehensive review and topological mapping of all described CACNA1C mutations associated with TS or LQTS revealed disease-specific hotspots. TS-associated mutations localized to cytoplasmic aspects of transmembrane domains while LQTS-associated mutations localized to cytoplasmic N- and C-terminal domains and linker regions. Probands hosting TS mutations demonstrated markedly prolonged QTc values compared to LQTS (618 vs 486 ms, p&lt;0.001) and were younger at presentation (2.7 vs 20.1 years, p&lt;0.002). Supporting these associations, the L762F mutation localized closer to the CACNA1C transmembrane domain than any other LQTS mutation and are associated with a QTc and age of diagnosis reflective of TS-associated mutations. Conclusions: The CACNA1C-L762F mutation is associated with biochemical and clinical features which highlight a molecular and clinical distinction between TS- and LQTS-associated CACNA1C mutations.

Unusual retrospective prenatal findings in a male newborn with Timothy syndrome type 1

Timothy syndrome 1 (TS1) is a multisystem disorder characterized by severe QT prolongation and potentially lethal ventricular arrhythmias in the first years of life, plus other cardiac and extracardiac manifestations caused by mutation in the CACNA1C gene, a CaV1.2 L-type calcium channel. Here, we report retrospectively an unusual fetal presentation on a second patient with TS1 with fetal hydrops due to a congenital AV block and its postnatal diagnosis by a marked prolongation of the corrected QTc interval of 570 ms and a missense mutation, p.Gly406Arg, in exon 8A of CACNA1C gene. The observed manifestations in our patient during fetal period indicate a severe form and they were probably exacerbated by the maternal use of amitriptyline during the first 4 months of pregnancy. Unfortunately, he died at 3 months-old due a ventricular tachycardia and fibrillation related to a septic event. Although difficult to diagnose, possibly most fetuses with TS1 have symptoms of long QT syndrome. Despite the fatal outcome for our patient, an early diagnosis of TS may help to prevent life-threatening events or early death in future patients, especially in developing countries where availability of therapies such as cardioverter defibrillator are very limited, or require time for its funding.