Frequency of QTc Interval Prolongation in Children and Adults with Williams Syndrome.

QTc prolongation (≥ 460 ms), according to Bazett formula (QTcB), has been identified to be increased in Williams syndrome (WS) and suggested as a potential cause of increased risk of sudden cardiac death. The Bazett formula tends to overestimate QTc in higher heart rates. We performed a retrospective chart review of WS patients with ≥ 1 electrocardiogram (EKG) with sinus rhythm, no evidence of bundle branch blocks, and measurable intervals. A total of 280 EKGs from 147 patients with WS were analyzed and 123 EKGs from 123 controls. The QTc was calculated using Bazett formula. The average QTcB for individuals with WS and controls was 444 ± 24 ms and 417 ± 26 ms, respectively (p < 0.001). In our WS cohort 34.4% had at least 1 EKG with a QTcB ≥ 460 ms. The mean heart rate (HR) from patients with WS was significantly higher than controls (96 bpm vs 76 bpm, p < 0.001). Linear regression showed that HR contributed 27% to QTcB prolongation in the patients with WS. Patients with WS have a mean QTcB in the normal range but higher than controls, and a higher than expected frequency of QTc ≥ 460 ms compared to the general population. HR is also higher in WS and contributes modestly to the WS QTcB prolongation. Future studies are needed to assess if these findings contribute risk to sudden cardiac death but in the interim we recommend routine EKG testing, especially when starting QTc prolonging medications.

QT correction using Bazett's formula remains preferable in long QT syndrome type 1 and 2.

BACKGROUND: The heart rate (HR) corrected QT interval (QTc) is crucial for diagnosis and risk stratification in the long QT syndrome (LQTS). Although its use has been questioned in some contexts, Bazett's formula has been applied in most diagnostic and prognostic studies in LQTS patients. However, studies on which formula eliminates the inverse relation between QT and HR are lacking in LQTS patients. We therefore determined which QT correction formula is most appropriate in LQTS patients including the effect of beta blocker therapy and an evaluation of the agreement of the formulae when applying specific QTc limits for diagnostic and prognostic purposes. METHODS: Automated measurements from routine 12-lead ECGs from 200 genetically confirmed LQTS patients from two Swedish regions were included (167 LQT1, 33 LQT2). QT correction was performed using the Bazett, Framingham, Fridericia, and Hodges formulae. Linear regression was used to compare the formulae in all patients, and before and after the initiation of beta blocking therapy in a subgroup (n = 44). Concordance analysis was performed for QTc ≥ 480 ms (diagnosis) and ≥500 ms (prognosis). RESULTS: The median age was 32 years (range 0.1-78), 123 (62%) were female and 52 (26%) were children ≤16 years. Bazett's formula was the only method resulting in a QTc without relation with HR. Initiation of beta blocking therapy did not alter the result. Concordance analyses showed clinically significant differences (Cohen's kappa 0.629-0.469) for diagnosis and prognosis in individual patients. CONCLUSION: Bazett's formula remains preferable for diagnosis and prognosis in LQT1 and 2 patients.

Problems with Bazett QTc correction in paediatric screening of prolonged QTc interval.

BACKGROUND: Bazett formula is frequently used in paediatric screening for the long QT syndrome (LQTS) and proposals exist that using standing rather than supine electrocardiograms (ECG) improves the sensitivity of LQTS diagnosis. Nevertheless, compared to adults, children have higher heart rates (especially during postural provocations) and Bazett correction is also known to lead to artificially prolonged QTc values at increased heart rates. This study assessed the incidence of erroneously increased QTc values in normal children without QT abnormalities. METHODS: Continuous 12-lead ECGs were recorded in 332 healthy children (166 girls) aged 10.7 ± 2.6 years while they performed postural manoeuvring consisting of episodes (in the following order) of supine, sitting, standing, supine, standing, sitting, and supine positions, each lasting 10 min. Detailed analyses of QT/RR profiles confirmed the absence of prolonged individually corrected QTc interval in each child. Heart rate and QT intervals were measured in 10-s ECG segments and in each segment, QTc intervals were obtained using Bazett, Fridericia, and Framingham formulas. In each child, the heart rates and QTc values obtained during supine, sitting and standing positions were averaged. QTc durations by the three formulas were classified to < 440 ms, 440-460 ms, 460-480 ms, and > 480 ms. RESULTS: At supine position, averaged heart rate was 77.5 ± 10.5 beat per minute (bpm) and Bazett, Fridericia and Framingham QTc intervals were 425.3 ± 15.8, 407.8 ± 13.9, and 408.2 ± 13.1 ms, respectively. At sitting and standing, averaged heart rate increased to 90.9 ± 10.1 and 100.9 ± 10.5 bpm, respectively. While Fridericia and Framingham formulas showed only minimal QTc changes, Bazett correction led to QTc increases to 435 ± 15.1 and 444.9 ± 15.9 ms at sitting and standing, respectively. At sitting, Bazett correction identified 51, 4, and 0 children as having the QTc intervals 440-460, 460-480, and > 480 ms, respectively. At sitting, these numbers increased to 118, 11, and 1, while on standing these numbers were 151, 45, and 5, respectively. Irrespective of the postural position, Fridericia and Framingham formulas identified only a small number (< 7) of children with QT interval between 440 and 460 ms and no children with longer QTc. CONCLUSION: During screening for LQTS in children, the use of Bazett formula leads to a high number of false positive cases especially if the heart rates are increased (e.g. by postural manoeuvring). The use of Fridericia formula can be recommended to replace the Bazett correction not only for adult but also for paediatric ECGs.

Preoperative QTc Interval is Not Associated With Intraoperative Cardiac Events or Mortality in Liver Transplantation Patients.

OBJECTIVES: The primary objective of this study was to determine whether liver transplantation recipients with preoperative prolonged corrected (QTc) intervals have a higher incidence of intraoperative cardiac events and/or postoperative mortality compared with their peers with normal QTc intervals. DESIGN: This was a retrospective cohort study. SETTING: Single academic hospital in New York, NY. PARTICIPANTS: Patients undergoing liver transplantation between 2007 and 2016. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Data relating to all liver transplantation recipients with preoperative electrocardiograms were queried from an institutional anesthesia data warehouse and electronic medical records. Primary outcomes were a composite outcome of intraoperative cardiac events and postoperative mortality. Patients with a prolonged QTc interval (>450 ms for men, >470 ms for women) did not demonstrate an association with intraoperative cardiac events, 30- or 90-day mortality, in-hospital mortality, or overall mortality compared with recipients in the normal QTc interval group. A prolonged QTc was found to be associated with increased anesthesia time, surgical time, length of hospital stay, and incidence of fresh frozen plasma and platelets transfusion. CONCLUSIONS: Prolonged QTc interval is not associated with an increased incidence of intraoperative cardiac events or mortality in liver transplantation recipients. The demonstrated correlation among QTc length and Model for End-stage Liver Disease score, blood component requirements, surgical and anesthetic times, and hospital length of stay likely represents the association between QTc length and severity of liver disease.

QT Assessment in Early Drug Development: The Long and the Short of It.

The QT interval occupies a pivotal role in drug development as a surface biomarker of ventricular repolarization. The electrophysiologic substrate for QT prolongation coupled with reports of non-cardiac drugs producing lethal arrhythmias captured worldwide attention from government regulators eventuating in a series of guidance documents that require virtually all new chemical compounds to undergo rigorous preclinical and clinical testing to profile their QT liability. While prolongation or shortening of the QT interval may herald the appearance of serious cardiac arrhythmias, the positive predictive value of an abnormal QT measurement for these arrhythmias is modest, especially in the absence of confounding clinical features or a congenital predisposition that increases the risk of syncope and sudden death. Consequently, there has been a paradigm shift to assess a compound's cardiac risk of arrhythmias centered on a mechanistic approach to arrhythmogenesis rather than focusing solely on the QT interval. This entails both robust preclinical and clinical assays along with the emergence of concentration QT modeling as a primary analysis tool to determine whether delayed ventricular repolarization is present. The purpose of this review is to provide a comprehensive understanding of the QT interval and highlight its central role in early drug development.

Reproducibility of corrected QT interval in pediatric genotyped long QT syndrome.

Reproducibility of corrected QT interval (QTc), especially QTc after exercise, has not been thoroughly investigated. We reviewed charts of pediatric patients who underwent treadmill-exercise stress testing without medication multiple times within 1 year. In patients with long-QT syndrome (LQTS; n = 22), the discrepancy in QTc between two treadmill exercise stress tests using Fridericia's formula was 14 ± 12 ms at rest, 13 ± 12 ms 4 min after exercise, with a maximum of 14 ± 12 ms after exercise. There was no statistically significant difference in QTc between the two tests. Intraclass correlation coefficients (ICC) were 0.84, 0.85, and 0.85, respectively. In controls (n = 13), the discrepancy in QTc was 18 ± 12 ms at rest, 14 ± 7 ms 4 min after exercise, with a maximum of 14 ± 9 ms after exercise. There was no significant difference in QTc between the two tests. ICC were 0.78, 0.80, and 0.80, respectively. QTc calculated using Bazett's formula also showed high reproducibility. Reproducibility of QTc in children is high at rest and after exercise.

Prevalence and predictors of false positive QTc prolongation by the automated measurement.

Background: Corrected QT (QTc) is an important electrocardiographic (ECG) interval. Physicians rely on automated QTc provided by ECG machines while the manual method is the recommended method. We sought to assess the prevalence and predictors of false positive QTc prolongation by the automated measurement. Methods and results: Consecutive ECGs were retrieved from the ECG database at King Khaled University Hospital. Manual QT was measured by a trained physician using the tangent method and was corrected for heart rate and QRS duration. Automated QTc measurement was recorded by the ECG machine. "Long QT (LQT)" was defined as QTc≥470 ms for males and ≥480 for females. False positive LQT was defined as LQT by automated QTc but not manual QTc. Pre-determined factors were included in a multivariate logistic regression to assess predictors of false positive LQT. A total of 567 ECGs were included in this study. Automated QTc was longer than manual QTc (440 ms [±35] vs. 417 ms [±35], respectively) which resulted in a high negative predictive value (NPV) (99%) and a low positive predictive value (PPV) (32%). Male gender and abnormal rhythm were found to be independently associated with false positive LQT (OR = 1.9 [95% 1.1-3.5], p = 0.03 and OR = 3.1 [95% 1.2-8.3], p = 0.02; respectively). Conclusion: Automated QTc measurement is unreliable for detecting long QT, necessitating manual verification and further research to enhance its accuracy.

Comparison of methods for correcting QT interval in athletes and young people: A systematic review.

Screening elite athletes for conditions associated with sudden cardiac death is recommended by numerous international guidelines. Current athlete electrocardiogram interpretation criteria recommend the Bazett formula (QTcB) for correcting QT interval. However, other formulae may perform better at lower and higher heart rates (HR). This review aimed to examine the literature on various QT correction methods in athletes and young people aged 14-35 years and determine the most accurate method of calculating QTc in this population. A systematic review of MEDLINE, EMBASE, Scopus, and SportDiscus was performed. Papers comparing at least two different methods of QT interval correction in athletes or young people were included. Quality and risk of bias were assessed using a standardized tool. The search strategy identified 545 papers, of which 10 met the criteria and were included. Nine of these studies concluded that QTcB was least reliable for removing the effect of HR and was inaccurate at both high (>90 beats per min [BPM]) and low (<60 BPM) HRs. No studies supported the use of QTcB in athletes and young people. Alternative QT correction algorithms such as Fridericia (QTcF) produce more accurate correction of QT interval at HRs seen in athletes and young people. QTcB is less accurate at lower and higher HRs. QTcF has been shown to be more accurate in these HR ranges and may be preferred to QTcB for QTc calculation in athletes and young people. However, accurate QTc reference values for discrete HRs using alternative algorithms are not well established and require further research.

A Case of Bradycardia-Induced Torsades De Pointes in a Patient Presenting to the Emergency Room With Cardiac Arrest.

Torsades de pointes (TdP) is a less common type of ventricular tachycardia (VT) characterized by polymorphic VT of changing amplitude and characteristic twists around the isoelectric baseline. It is almost always associated with QT interval prolongation. Unless immediately intervened, it can lead to ventricular fibrillation followed by cardiac arrest. We report a case of a patient with bradycardia-induced TdP who presented to the emergency room with cardiac arrest.

Marked QTc Reduction Immediately Following Direct Current Cardioversion of Atrial Fibrillation: Clinical Implications and Mechanisms.

BACKGROUND: The QTc in sinus rhythm (SR) following direct current cardioversion (DCCV) of atrial fibrillation (AF) is commonly used as a baseline QTc for patients who require initiation of antiarrhythmic drugs for rhythm control. Inaccurate baseline QTc may cause drug-induced torsades de pointes. OBJECTIVES: This study sought to assess time-dependent QTc changes following DCCV. METHODS: We prospectively assessed QTc changes with Bazett's QTc and Fridericia's QTc formulas in 65 patients following conversion of AF to SR. Among these 65 patients, 48 underwent DCCV and 17 spontaneously converted to SR. RESULTS: There was a large and statistically significant decrease in QTc in SR immediately following DCCV in 40 patients, which occurred with an abrupt reduction in heart rate postcardioversion. This finding excluded 8 patients with ventricular-paced QRS. The mean decrease from QTc in AF was 70.7 ± 37.2 milliseconds in the QTc interval for heart rate using Bazett's formula and 33.8 ± 17.9 milliseconds in the QTc interval for heart rate using Fridericia's formula at 1-minute post-DCCV. In 17 patients with spontaneous conversion from AF to SR, the QTc reduction was comparable to those in patients with DCCV. The QTc increased with time and reached a steady state at 5 minutes following conversion. Initiation of Class III drugs based on the "shortened" baseline QTc following DCCV was associated with drug-induced torsades de pointes. CONCLUSIONS: In patients with AF following conversion, regardless spontaneous or DCCV, the QTc shortened significantly with decreases in heart rate, likely via the mechanism of time-dependent rate adaption of ventricular repolarization. A steady-state QTc at 5-minutes following DCCV should be used as real baseline for guidance of pharmacotherapy in patients with AF.

Estimation of cardiac QTc intervals in people prescribed antipsychotics: a comparison of correction factors.

Background: A prolonged electrocardiogram (ECG) QT interval is associated with cardiac events and increased mortality. Antipsychotics can prolong the QT interval. The QT interval requires correction (QTc) for heart rate using a formula or QT-nomogram. The QT and QTc can be calculated automatically by the ECG machine or manually; however, machine-measured QT(c) intervals may be inaccurate. Objective: We aimed to investigate the mean QTc and proportion of prolonged QTc intervals in people taking antipsychotic medicines. Methods: We conducted an observational retrospective chart review and data analysis of all consecutive patients taking antipsychotics, with an ECG record, admitted to the psychiatric unit of a large tertiary hospital in Brisbane, Australia, between 1 January 2017 and 30 January 2019. We investigated the mean QTc of people taking antipsychotics to determine differences using (a) machine versus manual QT interval measurement and (b) QTc correction formulae (Bazett, Fridericia, Framingham, Hodges and Rautaharju) and the QT-nomogram. We also determined the number of people with a prolonged QTc using different methods and compared rates of prolonged QTc with antipsychotic monotherapy and polypharmacy. Results: Of 920 included people, the mean (±SD) machine-measured, Bazett-corrected QT interval (recorded from the ECG) was 435 ms (±27), significantly longer (p < 0.001) than the mean manually measured corrected QT intervals with Fridericia 394 ms (±24), Framingham 395 ms (±22), Hodges 398 ms (±22) and Rautaharju 400 ms (±24) formulae. There were significantly more people with a prolonged QTc using machine-measured QT and the Bazett formula (12.0%, 110/920) when compared with manually measured QT and the Fridericia formula (2.2%, 20/920) or QT-nomogram (0.7%, 6/920). Rates of QTc prolongation did not differ between people taking antipsychotic polypharmacy compared with monotherapy. Conclusion: Machine-measured QTc using the Bazett formula overestimates the QTc interval length and number of people with a prolonged QTc, compared with other formulae and the QT-nomogram. We recommend manually measuring the QT and correcting with the Fridericia formula or QT-nomogram prior to modifying antipsychotic therapies.

The Effect of Hypothermia and Osmotic Shock on the Electrocardiogram of Adult Zebrafish.

The use of zebrafish to explore cardiac physiology has been widely adopted within the scientific community. Whether this animal model can be used to determine drug cardiac toxicity via electrocardiogram (ECG) analysis is still an ongoing question. Several reports indicate that the recording configuration severely affects the ECG waveforms and its derived-parameters, emphasizing the need for improved characterization. To address this problem, we recorded ECGs from adult zebrafish hearts in three different configurations (unexposed heart, exposed heart, and extracted heart) to identify the most reliable method to explore ECG recordings at baseline and in response to commonly used clinical therapies. We found that the exposed heart configuration provided the most reliable and reproducible ECG recordings of waveforms and intervals. We were unable to determine T wave morphology in unexposed hearts. In extracted hearts, ECG intervals were lengthened and P waves were unstable. However, in the exposed heart configuration, we were able to reliably record ECGs and subsequently establish the QT-RR relationship (Holzgrefe correction) in response to changes in heart rate.

Diagnostic accuracy of the 12-lead electrocardiogram in the first 48 hours of life for newborns of a parent with congenital long QT syndrome.

BACKGROUND: Long QT syndrome (LQTS) is an autosomal dominant disorder characterized by a prolonged QT interval. Electrocardiographic (ECG) screening in the first 48 hours of life may be misleading, even in newborns with a genotype-positive LQTS parent. OBJECTIVE: The purpose of this study was to determine the ECG's diagnostic accuracy in the first 48 hours of life for neonates born to a parent with LQTS. METHODS: We conducted a retrospective review of all neonates born at Mayo Clinic to a parent with ≥1 pathogenic variant in a LQTS-causative gene who had least 1 ECG in the first 48 hours and genetic test results were available. The sensitivity and specificity of the diagnostic ECG were calculated using Bazett's heart rate-corrected QT (QTc) thresholds of 440, 450, 460, and 470 ms. RESULTS: Overall, 74 newborns (36 females [49%]) were included (mean QTc interval on the first ECG 489 ± 54 ms; 50 [68%] LQTS genotype-positive). The mean QTc interval in the first 48 hours for neonates that ultimately were genotype-positive was greater (506 ± 52 ms) than that for genotype-negative neonates (455 ± 41 ms) (P = .0004). When using a recommended threshold QTc interval of ≥440 ms, 6 of 50 genotype-positive neonates (12%) were missed (underdiagnosed) and 17 of 24 genotype-negative neonates (71%) were overdiagnosed (sensitivity 88%; specificity 29%). CONCLUSION: The newborn ECG should not be used in isolation to make the diagnosis of LQTS since it will result in many misclassifications. Genetic testing must be initiated before discharge, and proper anticipatory guidance is vital while awaiting test results.

A Practical Method for QTc Interval Measurement.

Objective The various formulae used for QT correction by heart rate (HR) require the execution of operations with the aid of calculators or applications. This study aimed to evaluate the performance of a simple rule for QTc estimation, comparing the measurements obtained with those provided by the commonly used equations of Bazett, Fridericia, Framingham, and Hodges. Methods We used the database of a previous observational study, which analyzed patients prospectively with acute pulmonary edema admitted in an emergency service. One hundred four patients were included for QTc assessment, of whom 86 patients underwent two ECG: one ECG <24h and other >24h after admission. Thus, a total of 190 ECGs were analyzed by two observers that manually measured QT and HR. QTc was obtained using the known formulae and the proposed equations: QTc = QT+2 (FC-60) for HR ≤ 90 bpm and QTc=QT+2(FC-60)-10 for HR>90 bpm. Results Bland-Altman plots show good agreement between the simple rule and Hodges equation, with a mean difference of -3,4, SD of 4.96 and 95% limits of agreement from -9,9 to 3.2. There was not a good agreement between the simple method and the other formulae. Conclusion The proposed method has good agreement with the measures of QTc by the equation of Hodges in the HR range of 40 to 130bpm in acutely ill patients. Our method may be a plausible option for quick QT correction in these subjects.

Significance of prolonged QTc in acute exacerbations of COPD requiring hospitalization.

Background: A prolonged QT interval is associated with increased risk of Torsade de Pointes and cardiovascular death. The prevalence and clinical relevance of QT prolongation in acute exacerbations of COPD (AECOPD), with high risk for cardiac morbidity and mortality, is currently unclear. Methods: A dual cross-sectional study strategy was therefore designed. A retrospective study evaluated 140 patients with an AECOPD requiring hospitalization, half of which had prolonged QTc on the admission ECG. Univariate and multivariate analyses were conducted to determine associated factors; Kaplan-Meier and Cox regression analyses to assess prognostic significance. A prospective study evaluated 180 pulmonary patients with acute respiratory problems requiring hospitalization, to determine whether a prolonged QTc at admission represents an AECOPD-specific finding and to investigate the change in QTc-duration during hospitalization. Results: Retrospectively, hypokalemia, cardiac troponin T and conductance abnormalities on ECG were significantly and independently associated with QTc prolongation. A prolonged QTc was associated with increased all-cause mortality (HR 2.698 (95% CI 1.032-7.055), p=0.043), however, this association was no longer significant when corrected for age, FEV1 and cardiac troponin T. Prospectively, QTc prolongation was observed in 1/3 of the patients diagnosed with either an AECOPD, lung cancer, pulmonary infection or miscellaneous acute pulmonary disease, and was not more prevalent in AECOPD. The QTc-duration decreased significantly during hospitalization in patients with and without COPD. Conclusion: A prolonged QTc is a marker of underlying cardiovascular disease during an AECOPD. It is not COPD-specific, but a common finding during the acute phase of a pulmonary disease requiring urgent hospital admission.

QT Interval Shortening After Bariatric Surgery Depends on the Applied Heart Rate Correction Equation.

BACKGROUND: A shortening of electrocardiographic QT interval has been observed in obese subjects after weight loss, but previous results may have been biased by inappropriate heart rate (HR) correction. METHODS: Electrocardiography (ECG) recordings of 49 (35 females) severely obese patients before and 12 months after Roux-en-Y gastric bypass (RYGB) surgery were analysed. QT interval (QTc) was calculated by using four different equations, i.e. Bazett, Fridericia, Framingham and Hodges. RESULTS: Irrespectively of the used correction formula, QTc interval length was reduced after the surgery (QTcBazett -31 ± 18 ms; QTcFridericia -12 ± 15 ms; QTcFramingham -14 ± 15 ms; QTcHodges -9 ± 15 ms; all Ps < 0.001), but QTcBazett reduction was significantly greater than the reduction in QTc calculated upon the other three equations (all Ps < 0.001). Moreover, changes in QTcBazett (P < 0.001) but not in QTcFridericia, QTcFramingham and QTcHodges (all Ps > 0.05) were significantly correlated with concurrent changes in HR. Multivariate regression analyses revealed a significant independent association of serum insulin levels with QTcFridericia, QTcFramingham and QTcHodges values (all Ps < 0.05) preoperatively, whilst changes in QTc interval length after the surgery were not consistently associated to concurrent changes in metabolic traits. CONCLUSIONS: Our data show that the extent of weight loss-associated QTc interval shortening largely depends on the applied HR correction equation and appears to be overestimated when the most popular Bazett's equation is used.

Human Electrical Muscular Incapacitation and Effects on QTc Interval.

Human Electrical Muscular Incapacitation (HEMI) is used to subdue combative individuals. Changes in cardiac electrical activity have been proposed as the cause of death in a small fraction of these individuals. The current study sought to determine whether changes in QTc interval occur after HEMI exposure. Twenty-four participants had EKG readings before a 5-second HEMI exposure and within 30 min after exposure. All subject EKGs were read by a data-blinded cardiac electrophysiologist who calculated a QT corrected (QTc) interval. QTc interval was calculated using Bazett method. QTc prolongation was defined as >430 ms and a threshold of 30 ms for identifying QTc lengthening. Five participants experienced QTc prolongation and six had QTc lengthening. One participant developed QTc prolongation exceeding 500 ms, which carries a risk of developing multifocal ventricular tachycardia. These results suggest that HEMI exposure may cause EKG changes with a risk of ventricular tachycardia.