QT Interval Prolongation Research Articles

Prevalence and characteristics of the catecholamine induced QT prolongation syndrome

Abstract Background We have recently described large families of idiopathic ventricular fibrillation characterised by catecholamine-induced QT interval prolongation (CIQTP). The patient presented with a normal QT duration at rest but an abnormal QT prolongation during a mental stress test (MST). Objective The aim of this study was to investigate the role of this new syndrome in inherited arrhythmic diseases. Methods Consecutive patients and their relatives, identified after unexplained familial sudden cardiac death or sudden cardiac arrest, were enrolled in the study in the presence of: - no other diagnosis after cardiac ultrasound, stress test, pharmacological test with adrenaline and ajmaline. - positive MST defined by a prolongation of the QT interval (>-11ms) during MST (as previously published). Results 134 families with unexplained SCD were examined. CIQTP was diagnosed in 15 families, representing a prevalence of 11.2%. Family screening of these 15 families identified a total of 43 individuals. Seven (16%) had symptoms prior to diagnosis, including sudden cardiac arrest in one. At baseline, the QTc interval was measured at 440+/-23 ms. MST increased the QTc interval by 49+/-33 ms. The identification of QT interval prolongation was less important in the exercise test (delta QTc 17+/-52 ms at 4 minutes after exercise) and the epinephrine test (delta QTc 19+/-36 at 1 minute according to the Krahn protocol). Treatment with beta-blockers was initiated in 19 patients (44%) on the basis of symptoms and major prolongation of the QT interval during the MST. After a mean follow-up of 7+/-2 years, only one patient developed ventricular fibrillation. This episode occurred during a short period when he was no observant for the treatment. Since then, there has been no recurrence of the arrhythmia on beta-blocker therapy. All other patients, including those who were previously symptomatic remained symptom-free on treatment. Conclusion CIQTP may explain a significant part of sudden cardiac arrest or syncope in young patients. Conventional screening using ECG, exercise test and epinephrine challenge may not be able to unmask CIQTP. Then MST may be systematically proposed for the screening of patient and their family. In CIQTP patients beta blocker therapy appears to be highly efficient to prevent symptoms.

SLC4A3 anion exchanger mutations associated to sudden death : short or long QT syndrome?

Abstract Introduction SLC4A3 gene codes for an (Cl-/HCO3-) exchanger present on the surface of cardiomyocytes (AE3 channel) is involved in maintaining the physiological acid-base gradient of the cardiomyocyte at rest. Loss of function of the SLC4A3 gene leading to an increase in intracellular pH has. been reported to be responsible for short QT syndrome (SQT). Methods The aim of our study was to characterize the genotype-phenotype relationships of SLC4A3 mutations identified in the French databases (Paris, Nantes and Lyon) in patients with sudden death. Through systematic exome sequencing we identified 3 new SLC4A3 variants in 3 families with a history of sudden death in two universitary hospitals. Results Family 1. The c.3209G>C variant (p.Gly1070Ala) in the SLC4A3 gene was identified in a 7-yo boy with VF at sleep but admitted in encephalic death. EKG showed short QT (QTc 280ms). Clinical examination, blood tests, TTE and autopsy were normal. There was no family history of sudden death. His mother had EKG evidence of SQT and was carrier the SLC4A3 mutation. She was implanted with an ICD. His two older brothers and the rest of the family had no mutation or pathological ECG and were asymptomatic. Family 2. The c.1027C>T (p.Arg343Cys) mutation in the SLC4A3 gene was identified in a 29-year-old man who presented with sudden death at sleep (VF). Clinical examination, blood tests, TTE and autopsy were normal. A maternal uncle died suddenly while sleeping. His two brothers (30 and 27 yo) are both carriers of the SLC4A3 mutation and exhibit SQT (QTc 320 and 330 ms respectively). TEE, Holter monitoring and stress test were normal in both. Both brothers were treated with hydroquinidine. Over a 2-year follow-up they had no symptom nor AF. Family 3. The c.1022C>G (p.Thr341Arg) mutation was identified in the SLC4A3 gene in a 54-yoman who presented with VF during shower but admitted in encephalic death. There was no family history of sudden death. Clinical examination, blood tests and echocardiography as well as coronary angiogram were normal. The initial ECG showed a prolonged QT interval (QTc 520 ms). QTc decreased to 480 ms in the 48 following hours. His parents and his sister as well as his 18 yo daughter have normal QTc values. We are awaiting the genetic results. Conclusion Loss-of-activity-mutation in the cardiac chloride-bicarbonate exchanger AE3 has been recently reported to cause short QT syndrome but it seems that in rare cases it may also be responsible for LQTS. Further patients are needed to confirm these data. In order to understand the underlying electrophysiological mechanisms, we plan to characterize the cellular impact of these new mutations through IPS.

Characteristics associated with prevalent atrial fibrillation and risk profile for future atrial fibrillation among those in sinus rhythm in an elderly population in the ELSA Brasil Study

Abstract Background Atrial fibrillation (AF) is an arrhythmia that can lead to limiting symptoms and increases the risk of stroke and heart failure (HF). Purpose To evaluate the association of clinical, electrocardiographic, and echocardiographic parameters with prevalent AF or flutter (AFF), and the risk profile for future AFF according to Charge-AF and EHR scores in an elderly population. Methods The ELSA-Brasil is a prospective cohort study designed to investigate cardiovascular disease and diabetes in 15,105 men and women, civil servants from universities or research institutions in six cities of Brazil. We included all participants in ELSA-Brasil aged 60 and over whose diagnosis of AFF could be assessed and had echocardiography performed at the study's baseline. From the initial sample with participants ≥ 60 years (n = 3,263), 400 participants were excluded due to missing data about AFF, and 775 who did not have echocardiographic studies. Results There were 88 (4.2%) participants with AFF at baseline among the 2,088 (65 ± 4.1 years; 53% women) included in this analysis. Those with AFF were older (66.8 ± 4.4 vs 65 ± 4.0 y-o) and had a higher prevalence of HF (16% vs 3.1%), previous myocardial infarction (14.8% vs 3.8%), left bundle branch block (LBBB: 4.6% vs 0,9%), prolonged QT interval (7.9% vs 2.0%), supraventricular extrasystoles (4.6% vs 1.2%), and sinus bradycardia (11.3% vs 2.9%). AFF individuals also presented larger left atrial volume index - LA (33.3 mL/m2 versus 27 mL/m2), left ventricular end-diastolic diameter (4,63 ± 0,6 cm versus 4,47 ± 0,4 cm) and lower left ventricular ejection fraction (LVEF: 63.6 ± 9.1% vs 67.4 ± 6.4%) that non-AFF (all p-values <0.05). In multivariable analysis, prevalent HF, LBBB, larger LA, and lower LVEF were independently associated with the presence of AFF. Among those in sinus rhythm at study baseline, both risk models showed that most individuals in our sample were at low risk. In the Charge-AF, 63% of individuals were identified as presenting low risk (<2.5%), and 12% of the sample was categorized as high risk, with a risk of five-year AFF greater than 5%. Similarly, in the EHR, 67% of participants were classified as low risk, and 13% were considered high risk. Conclusion We found that AFF was present in 4.2% of the subset of older participants in a cohort composed of free-living individuals in Brazil. The presence of AFF was associated with HF history, altered cardiac electrical activity, LA dilation, and worse LV systolic function. Among those with sinus rhythm, 12-13% were considered at high risk of developing AFF (> 5% in five years) based on two clinical scores. Clinical surveillance and monitoring of electrocardiography and echocardiography parameters may help the early identification of risk factors for AFF.

A novel formula to assess the QT interval in ventricular paced rhythm

Abstract Background QT interval measurement in the presence of right ventricular pacing (RVP) represents a clinical challenge due to altered ventricular activation resulting in a prolonged QT-interval. The aim of this study is to compare the QT interval in patients before and after ventricular pacing to develop a new formula for QT interval assessment in patients with RVP. Methods and results All patients presenting to our pacemaker clinic with single- or dual chamber device were included in this prospective observational study. Inclusion criteria were no permanent right ventricular stimulation, an intrinsic QRS interval of <120 ms, and ventricular rate >35 bpm and <150 bpm. Three 12-lead electrocardiograms were recorded for each patient: during intrinsic rhythm and 2 following an atrial paced and a ventricular paced QRS at the same rate. The intrinsic QRS and QT time/JT time (QTi/JTi) were measured during intrinsic and subsequent RVP. To obtain the formula, all measurements were performed on 100 patients (mean age 74 ± 11.3, male 33%) (RV apical lead 30% and non-apical lead 70%). Based on our measurements, a new formula QT (non-paced) = 139.23 + 0.55 xQT (paced) was derived. A population of 482 individuals (mean age 75.5±13.2 years (SD), 64% male) with permanent RV pacing were used as a validation group. The intrinsic QRS and QT time were measured during SR and subsequent RVP. To assess the relationship between the predicted QT with RVP and the measured QT without RVP, linear correlations analyses were performed. Our formula had a strong correlation with the irrespective QT without RVP (r=0.50) Conclusion We proposed a new simple formula to accurately estimate QT during RVP. This formula can be easily utilized in clinical practice. Figure 1: MAD characteristic value via plots stands for Median Absolute Difference (i.e. by how many ms the prediction is estimated on average). Figure 2: "Forest Plot" illustrates the correlation coefficients in the form of a forest plot. The dot r represents r and the bars the 95% confidence intervalsMAD characteristic value via plots standForest Plot" illustrates the correlation

Circulating metabolites associate with the QT interval in individuals without prevalent cardiovascular disease

Abstract Background Patients with metabolic syndrome have a higher prevalence of heart-rate corrected QT (QTc) interval prolongation. Despite this the effect of circulating metabolites on the QTc is largely unknown and limited to small studies. Purpose To test for association of circulating metabolites with the QTc interval in the UK Biobank study. Methods Participants were identified from the UK Biobank with same day plasma metabolite profiling and electrocardiograms. All 249 metabolites measured underwent quality control and log transformation to account for rightward skew and zero values. 149 metabolites with inter-correlations >0.7 were excluded. Participants taking QTc-prolonging medication or with a history of ischaemic heart disease or heart failure up to 6 months after the visit, were excluded. Participants were allocated to a training group (N=21,610) or an independent test group (N=5,304), if samples were obtained at recruitment or at a second visit, respectively. In the training group, each metabolite was tested separately for association with the QTc in linear regression analyses, adjusted for clinical covariates (age, sex, fasting time, body mass index (BMI), systolic blood pressure (SBP), smoking status, diabetes, lipid-lowering drug use and dietary factors). Significant metabolites (P<5x10-4) underwent validation in the test group. Sex-stratified analyses were also performed. In the training group, variables in two models underwent regularisation by LASSO regression (10-fold cross-validation) to reduce multicollinearity and downweigh less important variables; 1) clinical variables, 2) clinical variables and validated metabolites. Coefficients were used for QTc prediction in the test group. Significance between the models was evaluated by fisher’s transformation of R-squared statistics. Results In the per metabolite multivariate analysis, 56 metabolites were associated with the QTc interval. 19 metabolites validated in the test group. For 14 of these, absolute effect sizes were >5ms when comparing individuals in the top decile of the metabolite distribution verses the bottom (Figure 1), including the ketone body 3-hydroxybutyrate (9ms), and omega-6 fatty acid to total fatty acid ratio (7.2ms). For associations in males and females separately, significant effect size differences (P<0.05) were observed for 9 metabolites (Figure 2). In the training group, the combined LASSO model selected 17 (of 19) metabolites along with age, sex, SBP and BMI. In the test group, this model R-squared was 0.115 compared with 0.081 for clinical covariates alone, representing a significant 41.9% increase in QTc variation explained (P=0.002). Conclusions This study demonstrates clinically relevant metabolite associations with the QTc in individuals without cardiovascular disease and explain a significant proportion of QTc variation. Further investigation is warranted to test for direct effects on cardiac electrophysiology and proarrhythmic potential.Validated metabolitesSignificant sex differences

The endocannabinoid ARA-S facilitates the activation of cardiac Kv7.1/KCNE1 channels from different species

ABSTRACT The endogenous endocannabinoid-like compound N-arachidonoyl-L-serine (ARA-S) facilitates activation of the human Kv7.1/KCNE1 channel and shortens a prolonged action potential duration and QT interval in guinea pig hearts. Hence, ARA-S is interesting to study further in cardiac models to explore the functional impact of such Kv7.1/KCNE1-mediated effects. To guide which animal models would be suitable for assessing ARA-S effects, and to aid interpretation of findings in different experimental models, it is useful to know whether Kv7.1/KCNE1 channels from relevant species respond similarly to ARA-S. To this end, we used the two-electrode voltage clamp technique to compare the effects of ARA-S on Kv7.1/KCNE1 channels from guinea pig, rabbit, and human Kv7.1/KCNE1, when expressed in Xenopus laevis oocytes. We found that the activation of Kv7.1/KCNE1 channels from all tested species was facilitated by ARA-S, seen as a concentration-dependent shift in the voltage-dependence of channel opening and increase in current amplitude and conductance over a broad voltage range. The rabbit channel displayed quantitatively similar effects as the human channel, whereas the guinea pig channel responded with more prominent increase in current amplitude and maximal conductance. This study suggests that rabbit and guinea pig models are both suitable for studying ARA-S effects mediated via Kv7.1/KCNE1.

Donepezil and Memantine-Induced Second-Degree Atrioventricular Block: A Case Report

Donepezil and memantine are second-generation antipsychotics widely used in the management of mild to moderate Alzheimer’s disease. These drugs are highly selective for the central nervous system, targeting different neural pathways to mitigate cognitive decline. Donepezil is a reversible and specific acetylcholinesterase inhibitor, while memantine is an NMDA receptor antagonist which modulates glutamatergic activity. Although these medications are safe, they are associated with adverse effects, and cardiovascular complications are rare. The reported cardiac adverse drug reactions include bradycardia, atrioventricular block, and prolonged QT interval. We are reporting a case of an 81-year-old male patient with schizophrenia, Alzheimer’s disease and bilateral sensorineural deafness receiving oral donepezil and memantine presented with second-degree atrioventricular block. The patient’s atrioventricular block recovered completely in 2 to 3 weeks after the discontinuation of donepezil-memantine and with a short course of sympathomimetic drugs.

Elevated Plasma Atherogenic and Triglyceride-Glucose Indices: Markers of Cardiovascular Risk in Transfusion-Dependent Thalassemia

Background Transfusion-dependent thalassemia (TDT) is an autosomal recessive disorder characterized by defective hemoglobin synthesis, leading to severe complications such as iron overload and multi-organ dysfunction. This study aims to elucidate the distinctive clinical and biochemical profiles of TDT patients compared to healthy controls, with an emphasis on cardiovascular risk assessment using novel markers such as the Plasma Atherogenic Index (PAI) and Triglyceride-Glucose (TyG) index. Methods This cross-sectional study included 32 TDT patients and 36 healthy controls, matched for age and gender. Comprehensive demographic, laboratory, and imaging data were collected and analyzed. TDT patients were further stratified based on cardiac involvement and ferritin levels. Key assessments included hemoglobin levels, liver enzymes, lipid profiles, and cardiac imaging. The PAI and TyG index were calculated to evaluate cardiovascular risks. Statistical analyses were performed using SPSS 27.0, employing Student’s t-test, Mann–Whitney U test, and Pearson chi-square test as appropriate. Results No significant differences in basic demographic parameters were observed between groups; however, TDT patients exhibited significant clinical and laboratory differences. Notably, these patients had lower hemoglobin levels, higher platelet counts, elevated liver enzymes (ALT and AST), and markedly increased ferritin levels. Lipid profiles were significantly altered, with lower levels of total cholesterol, HDL, and LDL but elevated triglycerides. Importantly, the PAI was significantly higher in TDT patients, suggesting an increased atherosclerotic risk. Subgroup analysis revealed that patients with cardiac involvement had worse metabolic profiles, higher TyG indices, and prolonged QT intervals, indicating heightened cardiovascular risk. As the iron burden increases, the TyG index and PAI may lose their sensitivity in distinguishing between varying levels of iron overload, suggesting that their effectiveness plateaus beyond a certain threshold of iron accumulation. Conclusion TDT patients show significant hematological and metabolic deviations, including elevated cardiovascular risk markers like PAI and TyG index. As iron burden increases, these markers lose discriminative power, and cardiac involvement escalates rapidly once a critical iron threshold is surpassed, as supported by studies showing a non-linear relationship between iron load and cardiac complications. Comprehensive cardiovascular risk assessment and tailored management are essential for these patients. Future studies should focus on tracking cardiovascular risk progression and the effects of targeted interventions.

Pseudo-Hyperaldosteronism Arising from Licorice Cough Syrup Self-Ingestion: A Case Report

Background: Licorice (glycyrrhiza glabra) cough syrup intoxication is manifested with refractory hypokalemia, hypertension, and metabolic alkalosis. The transformation of glycyrrhiza glabra metabolic into glycyrrhetic acid after ingestion further inhibits the 11-β-hydroxysteroid dehydrogenase-2 enzyme, impeding the conversion of cortisol into cortisone. The accumulation of cortisol can also stimulate mineralocorticoid receptors, which leads to a pseudo-hyperaldosteronism-like effect. Case Presentation: We report a 60-year-old male patient with licorice intoxication due to the chronic consumption of licorice cough syrup. He exhibited a transient seizure lasting approximately one minute. Initially, hypokalemia (potassium level was 2.0 mmol/L), metabolic alkalosis, and QT interval prolongation with premature ventricular complexes were demonstrated on his electrocardiogram. Despite the administration of both intravenous and oral potassium supplements over two days, there was no significant improvement in hypokalemia. Spironolactone, an aldosterone receptor antagonist, was administered in addition to ongoing potassium supplementation from the 3rd day. This intervention led to a rapid normalization of hypokalemia in one day. The patient was ultimately discharged on the 6th day without any subsequent complications. Conclusions: The licorice-induced chronic intoxication, which led to pseudo-hyperaldosteronism and refractory hypokalemia, was successfully managed with aggressive potassium supplementation and spironolactone treatment.

Leukotriene B4 is elevated in diabetes and promotes ventricular arrhythmogenesis in guinea pig.

Diabetes (DM) patients have an increased risk (~50%) for sudden cardiac death (SCD), mostly as a result of ventricular arrhythmias. The molecular mechanisms involved remain partially defined. The potent proinflammatory lipid mediator leukotriene (LT) B4, is pathologically elevated in DM compared to nondiabetic patients, resulting in increased LTB4 accumulation in heart, leading to an increased risk for life-threatening proarrhythmic signatures. We used electrophysiology, immunofluorescence, and confocal microscopy approaches to evaluate LTB4 cellular effects in guinea pig heart and ventricular myocytes. We have observed that LTB4 is increased in multiple mouse models (C57BL/6 J/Lepob/ob and PANIC-ATTAC) of DM, promotes profound cellular arrhythmogenesis (spontaneous beats and early after depolarizations, EADs), and severely depresses the rapidly activating delayed rectifier K current (hERG1/IKr) density in HEK293 cells and guinea pig ventricular myocytes. We have further found that guinea pigs challenged with LTB4 displayed a significantly prolonged QT interval, and that this can be prevented with LTB4R inhibition, suggesting that preventing such LTB4R effects may be therapeutically beneficial in DM. Our data suggests that a further elucidation of LTB4 vulnerable substrates, and how this leads to ventricular arrhythmias, is likely to lead to continued improvements in management options, and the development of new therapies for prevention of SCD in DM patients.

Association between QT prolongation and cardiovascular mortality in cancer patients

BackgroundCancer patients’ vulnerability to QT prolongation contradicts certain anti-cancer drug usage. Until now, the QT prolongation’s impact on CV mortality in cancer patients remains unclear, potentially biasing therapeutic decisions.MethodsThis retrospective observational cohort included adult cancer patients with an electrocardiogram (ECG) performed in a tertiary hospital in Taiwan. The first performed ECGs after cancer diagnosis (n = 59,568) were analyzed. The corrected QT intervals by Bazett (QTcB), Fridericia (QTcFri), and Framingham (QTcFra) formulae were used to predict the 90-day and one-year CV mortality according to the Taiwan death registry.ResultsThe AUC of QTcB (90 days: 0.70, 1 year: 0.68) for predicting CV mortality was better than QTcFri and QTcFra (90 days: 0.63 and 0.50, 1 year: 0.65 and 0.56). Using the restricted cubic spline regression model adjusted by age and comorbidities, QTcB increased a significant but trivial risk of CV mortality at 90 days (hazard ratio, 1.007, P = 0.02) and one year (1.006, P < 0.01). Compared to those with QTcB < 500ms, the patients with QTcB ≥ 500ms were older and had more comorbidities and mortalities within one year. The incidence of sudden death and ventricular arrhythmias was only 0.2%. After adjusting for comorbidities, QTcB was neither associated with 90-day nor one-year CV mortality. In the patients already with QTcB ≥ 500ms, the patients receiving the unexpected uses of QT-prolonging drugs were not associated with higher one-year CV mortality than those without (P = 0.14).ConclusionsRather than a prolonged QT interval per se, comorbidities contributed to CV mortality and irreversible outcomes in cancer patients.

Adverse events associated with azithromycin and clarithromycin in adults aged ≥65: a disproportionality analysis of the FDA Adverse Event Reporting System (FAERS) database

ABSTRACT Background Azithromycin and clarithromycin are commonly used to treat community-acquired pneumonia in adults aged ≥ 65, such as mycoplasma pneumonia. This study aims to evaluate adverse events (AEs) associated with azithromycin and clarithromycin in this age group by analyzing the FDA Adverse Event Reporting System (FAERS), providing insights for clinical use and management of AEs in this population. Research design and methods We retrieved reports of AEs related to azithromycin and clarithromycin from the FAERS database. Disproportionality analysis was conducted using the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-Gamma Poisson Shrinkage (MGPS) to identify AEs associated with azithromycin and clarithromycin in adults aged ≥ 65. Results A total of 2,019 adverse event reports were retrieved for azithromycin, and 2,392 for clarithromycin. Off-label use (n = 349) and drug interactions (n = 487) were the most reported AEs in adults aged ≥ 65 for azithromycin and clarithromycin, respectively. Prolonged QT interval showed the strongest signal among AEs for azithromycin in this age group. Drug interaction-related medication errors had the strongest signal for clarithromycin. Seven signals not explicitly included in the azithromycin package insert were identified in adults aged ≥ 65. Fourteen signals not explicitly included in the clarithromycin package insert were identified. Conclusions Among adults aged ≥ 65, cardiac-related adverse events are more closely associated with azithromycin than with clarithromycin. Conversely, AEs related to drug interactions and psychiatric symptoms are more associated with clarithromycin. Additionally, clinicians should be vigilant regarding AEs not specified in the package inserts. The findings of this study may help optimize the selection of azithromycin and clarithromycin based on patient circumstances and assist clinicians in focusing on relevant AEs for early intervention.

Idiopathic Prolonged Long QT Interval Leading to Sudden Cardiac Arrest in an Adolescent

Idiopathic Prolonged Long QT Interval Leading to Sudden Cardiac Arrest in an Adolescent

Torsades de Pointes electrical storm in children with KCNH2 mutations

Congenital long QT syndrome (LQTS) is a genetic heart disorder, which may lead to life-threatening arrhythmias, especially in children. Here, we reported two children who were initially misdiagnosed with epilepsy and experienced Torsades de Pointes (TdP) cardiac electrical storm (ES). Through whole exome sequencing (WES), we identified two Potassium voltage-gated channel subfamily H member 2 (KCHN2) mutations (c.1841 C > T and c.1838 C > T) respectively in a 6-year-old boy and a 13-year-old girl. Clinical data indicated that the QT interval was significantly prolonged, the T-wave pattern of chest V5-V6 leads and limb leads were inverted. Our study suggests that patients with epilepsy, especially those refractory epilepsy with atypical features, need comprehensive evaluation of cardiovascular function. KCNH2 mutation in pore region, QT interval prolongation and T wave inversion are high risk factors for ES. For LQT2 patients with ES, Nadolol and left cardiac sympathetic denervation are indicated, sometimes with an ICD.

Potential drug-drug interactions and associated factors among hospitalized pediatric patients in Adigrat general hospital, Tigrai, north Ethiopia: a retrospective cross-sectional study

BackgroundDrug-drug interactions (DDIs) are associated with increased or decreased adverse effects and decreased or decreased therapeutic effects. Hospitalized pediatric patients are exposed to a number of potential DDIs (pDDIs). There are limited studies on pDDIs among pediatric patients in Ethiopia. This study was aimed to evaluate the pDDIs and associated factors among hospitalized pediatric patients in Adigrat general hospital, Tigrai, northern Ethiopia.MethodsA retrospective cross-sectional study was carried out among hospitalized pediatric patients in Adigrat general hospital from 01 July 2020 to 31 August 2020. A simple random sampling technique was used to select medical charts. Micromedex 2.0 database was used to screen pDDIs. Data was analyzed using statistical package for social science version 21 and a P-value of ≤ 0.05 was considered statistically significant.ResultsOf the total 146 patients studied, 100 (68.5%) were exposed for at least one pDDI. A total of 158 pDDIs consisting of 33 distinct interacting drug pairs were identified. About 19.3% of the patients had at least one major pDDI, 6.7% at least one moderate and 68.9% at least one minor pDDIs. On the other hand, 63.3% of the total pDDIs were minor and 25.9% major while 3. 8% were contraindicated pDDIs with 15.2% fair and 81.6% good level of documentation. The overall mean duration of pDDIs exposure was about 4.9 (1-23) days. The frequently occurring potential clinical consequences of pDDIs comprised increased risk of QT-interval prolongation (10.1%), theophylline toxicity (5.1%), antiepileptic toxicity (5.1%) and formation of ceftriaxone calcium precipitates (3.8%). Infant/toddler age group (adjusted odds ratio [AOR] = 31.961, 95% CI: 1.117-914.528), number of diseases (AOR = 0.255, 95% CI: 0.069-0.939) and polypharmacy (AOR = 0.276, 95% CI: 0.091-0.838) were associated with pDDIs exposures.ConclusionsA large number of pediatric patients were exposed to a various pDDIs. Age, number of diseases and polypharmacy predicted for the occurrence of pDDIs. Besides, the major severity pDDIs encounted frequently in the current study can potentially lead to a life threatening cardio-vascular toxicicty from QT-interval prolongation. Clinicians should be vigilant to pDDIs to prevent potential clinical consequences of pDDIs. Moreover, computerized drug interaction screening and clincal pharmacy services should be practiced to improve patients’ safety.

The Impact of QT-Prolonging Medications and Drug-Drug Interactions on QTc Interval Prolongation in Hospitalized Patients: A Case-Crossover Study.

Researchers have studied potential corrected QT interval (QTc) prolongation from drug-drug interactions (DDIs), raising unresolved questions about their real-world impact. This retrospective case-crossover study investigated the effects of QT-prolonging drugs and DDIs on QTc prolongation in hospitalized patients aged 45 years and above. The cohort comprised patients who had multiple hospitalizations and developed QTc prolongation (QTc > 500 ms or an increase of >60 ms from baseline) at least 24 hours after admission between 2011 and 2019. Conditional logistic regression compared drug exposure between hospitalizations with QTc prolongation (case window) and those without (reference window). Among 2,276 patients (mean age 71; 43.8% female), the use of QT-prolonging drugs significantly increased the risk of QTc prolongation (odds ratio: 2.42 (95% confidence interval: 1.95-3.02)). The risk was higher with drugs of "known risks" (OR: 3.78 (2.91-4.90)) and "conditional risk" (OR: 2.08 (1.65-2.62)). DDIs, particularly involving multiple "known risk" drugs (OR: 7.86 (4.96-12.45)), strong cytochrome P450 enzyme inhibitors (OR: 5.57 (2.75-11.30)), or the concurrent use of ≥4 QT-prolonging drugs with any risk (OR: 5.28 (3.96-7.03)) substantially increased the risk. Cautious prescribing for patients with multiple risk factors is important to minimize the likelihood of QTc prolongation. However, when considering enhanced monitoring or drug choices, it is crucial to carefully evaluate the overall risk of QT prolongation against the benefits of treatment to ensure optimal patient care.

Nigella sativa oil attenuates inflammation and oxidative stress in experimental myocardial infarction.

A growing interest in using Nigella sativa oil (NSO) in the prevention or treatment of several cardiovascular diseases has prompted this study. The research aims to investigate the effect of NSO on cardiac damage prevention after long-term administration in induced myocardial infarction (MI) in rats. NSO was analyzed for its fatty acids composition using gas chromatography-mass spectrometry (GC-MS) analysis and administered in rats before and after isoproterenol (45mg/kg body weight) induced myocardial infarction. The following parameters were assessed: electrocardiograms, histopathological examination, serum biochemical aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatine kinase-myocardial band (CK-MB), serum and heart inflammation (tumor necrosis factor-alpha (TNF), interleukin 1 beta (IL-1b), and interleukin 6 (IL-6)), and tissue oxidative stress (total antioxidant capacity (TAC), total oxidative stress (TOS), nitric oxide (NO), malondialdehyde (MDA), and the total thiols (THIOL)). Linoleic acid (C18:2n-6) and oleic acid (C18:1n-9) were approximately 89% of total fatty acids while palmitic acid (C16:0) was 6.10%. Administration of NSO for 28 days helped in preventing QT and QTc interval prolongation and reduced heart rate (HR), after MI induction. The histological assessment showed improvement in myofibrillary degeneration and necrosis and also better reduced inflammatory process in the groups treated with NSO. In serum, pro-inflammatory cytokines IL-1b and IL-6 were downregulated in chronic conditions (for IL-1b, NSO vs. control was 86.09vs 150.39 pg/mL, and for IL-6 NSO vs. control was 78.00 vs. 184.98 pg/ml). In the heart tissue, the downregulation was observed only for TNF in both acute and chronic conditions (acute NSO vs. control was 132.37 vs. 207.63 pg/mL, and chronic NSO vs. control was 135.83 vs. 183.29 pg/ml). The pro-oxidant parameters TOS, NO, MDA, and OSI, were reduced in the groups treated with NSO only after 14 days of treatment, suggesting that the NSO antioxidant effect is time-dependent. NSO administration might have a favourable impact on the regulation of oxidative stress and inflammation processes after MI induction in rats, and it is worth considering its administration as an adjuvant treatment.

6966 A Rhythmic Life-Threatening Enigma Unveiled: KCNH2 Mutation-Associated Torsades de Points Unmasking Primary Hyperaldosteronism in Cardiological Realm

Abstract Disclosure: S. Dejprapasorn: None. N. Nopparatana: None. S. Soonthornpun: None. R. Leelawattana: None. N. Kietsiriroje: None. S. Limumpornpetch: None. T. Nilmoje: None. W. Lohawijarn: None. T. Wongsuttipakorn: None. P. Choochuen: None. P. Limumpornpetch: None. Introduction: Primary hyperaldosteronism (PA) is characterized by hypertension and hypokalemia. However, its ability to masquerade life-threatening Torsades de Pointes makes it an unusual and dismissed diagnosis, revealing the link between PA and serious arrythmia. Clinical Case A 30-year-old female experienced three episodes of palpitations, followed by syncope. Upon admission, her blood pressure was 147/87 mmHg. ECG showed prolonged QT intervals with potassium level was 2.6 mmol/L (3.5-5.0 mmol/L). Continuous cardiac monitoring captured Torsades de Pointes. Despite potassium replacement, long QT still persisted. Pathogenic variant, c.2592+1G&amp;gt;A, within KCNH2 was discovered. Aldosterone concentration showed 69.65 ng/dL (9.70-62.60 ng/dL) and plasma renin activity was 0.12 ng/mL/h (1.50-5.70 ng/mL/h). Aldosterone-to-renin ratio was 580. Aldosterone post 4-h saline infusion test was 31.71 ng/dL which were consistent with PA. Adrenal unenhanced CT scan identified bilateral adrenal nodules (right 1.3 cm, left 1.1 cm). After receiving a cardioverter-defibrillator and spironolactone, the patient has had no palpitations, and their potassium level has remained normal. Clinical lessons: PA rarely presents ventricular arrhythmia. KCNH2 mutation may link between long QT syndrome (LQTS) and PA arises. LQTS type 2 is attributable to KCNH2 mutations, impacting potassium channel subunits crucial for adjusting currents during sympathetic activation. This is essential for shortening the QT interval with increasing heart rate. KCNH2 mutations disrupt this process, prolonging the QT interval and heightening the risk of arrhythmias. Aldosterone synthesis relies on calcium signaling triggered by potassium currents. Adrenal cortex hosts approximately 90 potassium channels genes, including KCNJ5 and KCNH2. Mutations in gene can disrupt the calcium signaling cascade, leading to excessive aldosterone production. While KCNJ5 mutation is well-documented in PA, the potential correlation between KCNH2 mutations and a similar mechanism remains unexplored in clinical reports to date. This case highlights the importance of a thorough comprehension of genetic cause contributing to pathogenesis of PA with complex clinical presentations. Presentation: 6/1/2024

Design, synthesis and biological evaluation of arylpropylamine derivatives as potential multi-target antidepressants

In this study, a series of novel arylpropylamine derivatives were designed, synthesized and evaluated as potential multi-target antidepressants. Among them, compound (R)-13j displayed unique pharmacological features, exhibiting excellent inhibitory potency against serotonin and noradrenaline transporters (SERT/NET) and high affinity for 5-HT2A/2C receptor, and showing low affinity for histamine H1, adrenergic α1 receptors and hERG channels (to reduce QT interval prolongation). Molecular docking studies provided a rational binding model of (R)-13j in complex with SERT and 5-HT2A/2C receptor. In animal models, compound (R)-13j dose-dependently reduced the immobility time in the tail suspension test (TST) and the forced swimming test (FST) in mice, with higher efficacy when compared to duloxetine, and showed no stimulatory effect on the locomotor activity. Moreover, compound (R)-13j significantly shortened the immobility time in the ACTH-induced rat model of treatment-resistant depression (TRD). Furthermore, compound (R)-13j also exhibited a higher threshold for acute toxicity than duloxetine. In addition, compound (R)-13j possessed a favorable pharmacokinetic profile in mice. Taken together, compound (R)-13j may constitute a novel class of drugs for the treatment of depression.

5074 Licorice Root Supplement As A Cause Of Hypokalemic Hypertension

Abstract Disclosure: G. Gill: None. S.M. Harman: None. L.A. Robles: None. A 67-year-old female Veteran presented to an emergency room with a one-day history of high blood pressure, chest tightness, and exertional dyspnea. Her blood pressure was 162/90 mm Hg, pulse regular at 71 BPM, and pain level 5/10. She had a history of hypertension, stable on hydrochlorothiazide alone, hyperlipidemia, anxiety, and depression. Physical exam was benign. EKG revealed normal sinus rhythm at 60 BPM, normal axis, a prolonged QT interval of 510 ms, and no ST changes. Lab evaluation showed a low potassium of 2.4 mEq/L, sodium 145 mEq/L. Other lab measurements (CBC, liver function tests and cardiac enzymes) were within laboratory reference ranges. Medications included topiramate for migraine and over-the-counter supplements for constipation, “thyroid health,” and a topical “testosterone booster” prescribed by a non-allopathic practitioner. Her hypokalemia was attributed to hydrochlorothiazide and topiramate and both were discontinued. She was started on nifedipine for blood pressure control and 40 mEq/day of potassium for hypokalemia. Within 2 weeks of discharge, she presented again with elevated blood pressure and a plasma potassium of 4.0 mMol/L. Further history revealed that her constipation supplement consisted of licorice root (glycyrrhiza glabra) extract 900 mg per capsule, of which she took 3 to 4 capsules daily. The patient was advised to discontinue all supplements. Thyroid function tests were within normal limits. Due to a suspicion of hyperaldosteronism, the ED physician requested an abdominal CT scan which showed a 1 cm, -17.5 Hounsfield unit, right adrenal nodule. Also consistent with hyperaldosteronism, plasma renin activity (PRA) was suppressed at 0.07 ng/mL/hr. However, a serum aldosterone level was less than 1 ng/dL. Her 24-hour urinary metanephrines were normal and a 24-hour urine free cortisol was 31.6 mcg/dL. Morning plasma cortisol was 5.1 mcg/dL. A tentative diagnosis of licorice-induced hyperaldosteronism was made and the patient was treated with a taper of spironolactone. After discontinuing spironolactone, blood pressure was 116/70mmHg and serum potassium was 4.5 mMol/L with a PRA of 0.66 ng/mL/hr and serum aldosterone of &amp;lt;5.0 ng/dL. The syndrome of factitious hyperaldosteronism due to licorice consumption has been well described. The mechanism, inhibition of renal (type 2) 11-beta-hydroxysteroid dehydrogenase by glycyrrhizic acid, allowing cortisol to exercise its considerable mineralocorticoid action, is well understood. Most prior reports have been in patients habitually consuming licorice candy, usually imported, since conventional licorice sold in the U.S. is artificially flavored. Our report illustrates the importance of obtaining a history of use of over-the-counter supplements and assessing their ingredients and the fact that presence of an adrenal nodule and a low PRA does not always indicate endogenous hyperaldosteronism. Presentation: 6/2/2024