Longer QTc Research Articles

Abstract P308: Lower Neighborhood Socioeconomic Status is Associated with Higher BNP and Prolonged QTc Intervals among Heart Failure Patients with Preserved Ejection Fraction

Background: Prior studies have shown that high B-type natriuretic peptide (BNP) levels and prolonged QTc intervals are associated with increased mortality, particularly sudden cardiac death, among heart failure (HF) patients. Whether neighborhood socioeconomic status (nSES) impacts BNP or QTc remains unknown. Methods: This study included consecutive patients enrolled from the outpatient clinic of the Northwestern Heart Failure with Preserved Ejection Fraction (HFpEF) Program from June 2007 to November 2010 after hospitalization for HF and followed through May 2011. Patients’ residential addresses were geocoded to identify their census tract of residence. Census 2000 data were used to create a single, summary score of nSES based on residential income, education and employment for each census tract and was divided into tertiles. Outcomes included post-discharge BNP and QTc, obtained within 1 month after HF hospitalization during the outpatient HFpEF clinic visit GEE models were used to examine the association between nSES and BNP and QTc adjusting for age, race, gender, NYHA class, blood pressure, obesity, smoking, glucose, eGFR, and comorbidities. Results: Among the 368 HFpEF patients, 37.0% were female, 50.5% White, avg. age was 64.8 yrs and 45.9% had NYHA class 3+. Higher nSES was significantly associated with lower BNP levels and shorter QTc intervals (Table). The adjusted BNP levels per nSES tertile were 718 pg/mL (±101.4) for the lowest nSES tertile, 508 pg/mL (± 75.3) for the intermediate nSES tertile and 454.2 pg/mL for the highest nSES tertile. Simlarly, QTc interval decreased with increasing tertile of nSES from 464.1 ms (± 5.7) in the lowest nSES tertile to 457.2 ms (± 5.8) and 448.9 ms (± 5.4) for the intermediate and highest tertiles, respectively. Conclusion: Low nSES is associated with increased BNP levels and a longer QTc interval in HFpEF patients. These findings may explain the association of nSES with higher rates of sudden cardiac death and worse outcomes among HF patients in disadvantaged neighborhoods.

Baseline Correction in Parallel Thorough QT Studies

In parallel thorough QT (TQT) studies, it has been speculated that either baseline correction should be omitted, under the assumption that it only adds noise to the data, or a time-averaged baseline instead of a time-matched baseline correction should be considered in order to reduce the study variability. This study characterized the assumptions and implications of different baseline correction approaches in parallel TQT studies submitted for regulatory review. 57 parallel TQT studies conducted between 2002 and 2009 in 5591 healthy volunteers were evaluated. Only moxifloxacin and placebo arms, including their baselines, were considered. The options of using no baseline correction, time-averaged baseline correction, and time-matched baseline correction were examined and compared. QTc values exhibited a diurnal pattern, with longer QTc intervals during sleep preserved when correcting for a time-averaged baseline. Post-dose and baseline QTc values were highly correlated (mean ρ = 0.80, range 0.56-0.98 and mean ρ = 0.79, range 0.50-0.96 in the placebo and moxifloxacin groups, respectively). The variability of raw QTc values was substantially larger than that of baseline-adjusted QTc values. The difference in the point estimate of QTc differences between moxifloxacin and placebo differed by up to ± 4 ms between the time-averaged and the time-matched baseline corrections. Statistical tests indicate that assumptions of time-averaged baseline and no baseline correction are not appropriate. Baseline correction in parallel TQT studies leads to more precise QTc estimates. Because of possible inaccuracy introduced by time-averaged baseline correction, the time-matched baseline correction appears to be preferable for a parallel TQT study to both reduce the intrinsic variability due to circadian patterns and obtain more accurate point estimates.

A case series of chronic haemodialysis patients: mortality, sudden death, and QT interval

A high prevalence of prolonged QT interval duration has been observed among haemodialysis (HD) patients. The aim of this cases series was to describe the association of various risk factors with total mortality and sudden cardiac death (SCD) in this population. One hundred and twenty-two patients undergoing HD, [median: age 71.3 years [interquartile ratio (IQR) 62.9-76.6], HD duration 3.0 years (IQR 1.3-7.8) and 64.8% male], of which 37.7% with ischaemic cardiac disease, 41.8% with dilated cardiomyopathy (DC), 84.4% with hypertension, and 27.1% with diabetes, were studied. Median left ventricular ejection fraction (LVEF) was 60.0% (IQR 52-64) and left ventricular mass index (LVMI) was 147.3 g/m(2) (IQR 128.0-179.9). QT interval duration corrected for heart rate (QTc) was measured by electrocardiogram Holter recording and considered prolonged when longer than 450 ms in men and 460 ms in women. Forty-four patients (36.0%) had a prolonged QTc. Female gender (P < 0.001) and DC (P = 0.018) were associated with a longer QTc, while LVEF (P = 0.012) was inversely related. During the study period (median follow-up 3.9 years), 51 patients died (41.8%), of whom 12 died for SCD. In multivariate analysis age at recruitment [HR = 1.07, 95% confidence interval (CI): 1.03-1.11, P < 0.001], prolonged QTc (HR = 2.16, 95% CI: 1.20-3.91, P = 0.011) and presence of DC (HR = 3.75, 95% CI: 1.01-7.00, P < 0.001) were independently associated with total mortality, while only a prolonged QTc (HR = 8.33, 95% CI: 1.71-40.48, P = 0.009) and increasing LVMI (HR = 1.01, 95% CI: 1.00-1.02, P = 0.022) were associated with SCD. In a case series of HD patients, QTc was associated with total mortality and SCD. Further studies to test this hypothesis in a larger population are necessary.

QT interval prolongation by acute gastrointestinal bleeding in patients with cirrhosis

QT interval prolongation is frequent in cirrhosis, and stressful conditions could further prolong QT. We aimed to test this hypothesis and, if it proved correct, to assess its prognostic meaning. We reviewed the clinical records of 70 consecutive cirrhotic and 40 non-cirrhotic patients with acute gastrointestinal bleeding. All patients had been evaluated before bleeding (T0) and were re-evaluated at the time of bleeding (T1) and 6 weeks afterwards (T2). QT corrected by heart rate (QTc) lengthened at T1, returning towards baseline values at T2 (mean ± SEM; from 415.9 ± 4.3 to 453.4 ± 4.3 to 422.2 ± 5.7 ms, P < 0.001) in cirrhotics; contrariwise, QTc did not change in non-cirrhotic patients. The 6-week mortality was 29.6% among cirrhotic patients, while no control patient died. At T1, patients who died had longer QTc (P = 0.001) and higher model of end-stage liver disease (MELD) score (P < 0.001) than survivors. MELD and QTc independently predicted survival. Their areas under the ROC curve were 0.88 (CI 95% 0.78-0.95) and 0.75 (CI 95% 0.63-0.85) respectively; the best cut-off values were MELD ≥20 and QTc ≥ 460 ms. Based on these factors, the 6-week mortality was: 0% for patients without risk factors, 32.1% for those with one risk factor and 70.6% for those with both (P < 0.001). Acute gastrointestinal bleeding further prolongs QTc in cirrhosis. This abnormality independently predicts bleeding-induced mortality. The combined measurement of QTc interval and MELD can clearly identify three patient strata at increasing risk of bleeding-related mortality, thus improving the decision-making for these patients.

Prevalence of Significant Genetic Variants in Congenital Long QT Syndrome is Largely Underestimated

Congenital long QT syndrome (LQTS) is clinically characterized by the occurrence of syncope due to polymorphic ventricular tachycardia (torsades de pointes), associated to delayed cardiac repolarization that is reflected by a prolongation of the QT interval on the ECG (Webster and Berul, 2008). Thus far, 13 genes coding for ion channel subunits and ion channel regulatory proteins have been found mutated in patients and families with LQTS (Schwartz et al., 2009). The estimated prevalence of LQTS in the general population is reported to be in the range of 1:7000–1:2000 (0.01–0.05%), without any significant ethnical disparity (Roden and Spooner, 1999; Tester et al., 2006; Schwartz et al., 2009). Different research groups from many countries have reported similar data or cited the same sources (Roden and Spooner, 1999; Tester et al., 2006; Schwartz et al., 2009). Recently, two original studies reported a high prevalence of LQTS founder mutations in the Finnish and Norwegian population (Berge et al., 2008; Marjamaa et al., 2009). In Finland, it was concluded that 1 out of 250 individuals (0.4%) carry a LQTS founder mutation (Marjamaa et al., 2009). In Norway, the prevalence of LQTS mutation carriers was estimated to be close to 1%, which is a prevalence that is the highest documented worldwide (Berge et al., 2008). These findings are of clear interest to researchers and clinicians since they may not be only relevant for the Finnish and Norwegian populations, but may also give some important clues about the actual worldwide distribution of genetic variants predisposing to cardiac arrhythmias. In a study looking at variants in KCNQ1 in a subgroup with the longest QTc interval (403–443 ms) from French general population of 100 non-related and non-treated individuals from the DESIR cohort, two new mutations in KCNQ1 were found (Gouas et al., 2004). This study suggests that such low-penetrant variants might be found with 2% frequency within one “healthy” cohort after screening of one only one gene of interest. As it can be seen, there are clear discrepancies in estimations of LQTS mutation prevalence depending on the sources. Long QT syndrome is considered as a Mendelian arrhythmic disorder which is transmitted mainly in an autosomal dominant mode of inheritance (Priori et al., 2008). Thus, one should be able to apply the basic concepts of genetics such as Mendel’s law for families and Hardy–Weinberg equation for population in equilibrium. Hereafter, we analyze and interpret published data and our own results to estimate the prevalence of LQTS using different approaches.

The correlation between ventricular repolarization and clinical severity of spinal cord injuries

Alteration in ventricular repolarization has been reported in patients with spinal cord injuries (SCIs). However, its clinical impact remains unclear. The purpose of this study was to investigate the correlation between SCIs and ventricular repolarization and the associated clinical impact. One hundred forty-four patients with an SCI were retrospectively reviewed and were divided into two groups (SCI level ≤ T6, n = 110; SCI level >T6, n = 34). The electrocardiograms were reviewed during acute phase (at emergency room) and chronic phase (>1 year). There were no differences in the underlying diseases or in ASIA score between the two groups, except there were more patients with tetraplegia among those with an SCI level ≤ T6. For the electrophysiological parameters from the electrocardiograms, the patients with an SCI level ≤ T6 had longer QTc and PR interval than those with an SCI level >T6 during acute phase. In the chronic phase, there were no differences in the electrophysiological parameters between the two groups. Only in patients with an SCI level ≤ T6 did a Kaplan-Meier analysis show that QTc prolongation could predict 30-day mortality after the acute injury. After multivariate Cox regression analysis, only tetraplegia and QTc prolongation were independent predictors of 30-day mortality (odds ratios 7.85 and 34.62, respectively). In patients with an SCI level ≤ T6, the QTc intervals were shorter in the chronic phase than those during the acute phase. QTc interval was associated with the level of acute SCI and predicted the 30-day mortality.

Clinical and Genetic Features of Japanese Patient with Congenital Long QT Syndrome

Backgrounds: Genotype-phenotype aspects in Japanese patients (pts) with congenital long QT syndrome (LQTS) have not been fully elucidated. Methods and Results: Genotyped LQTS patients from Japanese multicenter registry (402 LQT1, 381 LQT2, and 113 LQT3 pts) were investigated. Age at first cardiac event (CE) was significantly lower and corrected QT (QTc) interval was significantly shorter in LQT1 than in LQT2 and LQT3 (13±14, 19±15, 17±20 yo; P=0.0004, 475±46, 489±46, 482±58 ms; P=0.0003). Notched T wave (NTW) was more frequently observed in LQT2 (77%) than in LQT1 (9%) and LQT3 (10%). T wave alternance (TWA) was more frequently found in LQT3 (13%) compared with LQT1 (4%) and LQT2 (6%). Multivariate Cox-regression demonstrated that LQT1 and LQT2 pts with pore-site mutation and LQT3 pts with transmembrane mutation had significantly higher CE rate than those without (HR=1.52, 1.63, and 4.67, respectively). TWA (HR=2.37) in LQT1, longer QTc (HR=1.06 for QTc/10 ms) and NTW (HR=1.51) in LQT2, and longer QTc (HR=1.11), NTW (HR=3.26), and TWA (HR=2.51) in LQT3 were independent risk factors of CE. Conclusions: In addition to mutations located in transmembrane region, some electrocardiographic parameters can be available as predictors of cardiac events in 3 genotypes of Japanese LQTS.

Oxycodone is associated with dose‐dependent QTc prolongation in patients and low‐affinity inhibiting of hERG activity in vitro

During recent years some opioids have been associated with prolonged QT and torsade de pointes (TdP). In vitro testing has shown that most opioids can block the cardiac potassium channels. This indicates that QT prolongation and TdP could be a more general problem associated with the use of these drugs. This study is the first to show that oxycodone dose is associated with QT prolongation and in vitro blockade of hERG channels expressed in HEK293. Neither morphine nor tramadol doses are associated with the QT interval length. During recent years some opioids have been associated with prolonged QT interval and torsade de pointes (TdP). In vitro patch clamp testing has shown that most opioids can block human ether-a-go-go related gene (hERG) channels that are known to underlie cardiac repolarizing I(Kr) current. This indicates that QT prolongation and TdP could be a more general problem associated with the use of these drugs. The aims of this study were to evaluate the association between different opioids and the QTc among patients and measure hERG activity under influence by opioids in vitro. One hundred chronic nonmalignant pain patients treated with methadone, oxycodone, morphine or tramadol were recruited in a cross-sectional study. The QTc was estimated from a 12-lead ECG. To examine hERG activity in the presence of oxycodone, electrophysiological testing was conducted using Xenopus laevis oocytes and HEK293 cells expressing hERG channels. There were no differences in gender distribution or age between the treatment groups. The known association between methadone dose and QTc was confirmed (R(2) = 0.09; P = 0.02). Higher oxycodone dose was also associated with longer QTc (R(2) = 0.21; P = 0.02). A 100 mg higher oxycodone dose was associated with a 10 ms(1/2) (95% CI 2-19) longer QTc. Neither morphine nor tramadol dose was associated with the QTc. Electrophysiological testing revealed low-affinity inhibition of the potassium current through hERG channels expressed in HEK293 cells (IC(50) = 171 microM oxycodone). Among patients treated with methadone or oxycodone, higher doses were associated with longer QTc. Oxycodone is capable of inhibiting hERG channels in vitro.

Relationship between Genetic Variants in Myocardial Sodium and Potassium Channel Genes and QT Interval Duration in Diabetics: The Diabetes Heart Study

Genetic variants in myocardial sodium and potassium channel genes are associated with prolonged QT interval and increased risk of sudden death. It is unclear whether these genetic variants remain relevant in subjects with underlying conditions such as diabetes that are associated with prolonged QT interval. We tested single nucleotide polymorphisms (SNPs) in five candidate genes for association with QT interval in a family-based study of subjects with type 2 diabetes mellitus (T2DM). Thirty-six previously reported SNPs were genotyped in KCNQ1, HERG, SCN5A, KCNE1, and KCNE2 in 901 European Americans from 366 families. The heart rate-corrected (QTc) durations were determined using the Marquette 12SL program. Associations between the QTc interval and the genotypes were evaluated using SOLAR adjusting for age, gender, T2DM status, and body mass index. Within KCNQ1 there was weak evidence for association between the minor allele of IVS12 +14T>C and increased QTc (P = 0.02). The minor allele of rs2236609 in KCNE1 trended toward significance with longer QTc (P = 0.06), while the minor allele of rs1805123 in HERG trended toward significance with shorter QTc (P = 0.07). However, no statistically significant associations were observed between the remaining SNPs and QTc variation. We found weak evidence of association between three previously reported SNPs and QTc interval duration. While it appears as though genetic variants in previously identified candidate genes may be associated with QT duration in subjects with diabetes, the clinical implications of these associations in diabetic subjects at high risk for sudden death remain to be determined.

Effects of a controlled hypoglycaemia test on QTc in adolescents with Type 1 diabetes

Our objective was to test the ventricular repolarization response to a controlled hypoglycaemia test in Type 1 diabetic adolescents, an age group at risk for 'dead in bed syndrome'. We measured QTc, blood glucose level, potassium, heart rate, blood pressure and urinary metanephrine levels in 16 Type 1 diabetic adolescents during an insulin clamp mimicking the transition from mild hyperglycaemia to hypoglycaemia. QTc increased in all patients by 146 +/- 44 ms (mean +/-sd) ranging from 70 to 230 ms. The longest QTc (630 ms) was recorded in the sibling of a diabetic patient found 'dead in bed'. Heart rate and urinary metanephrine levels correlated with QTc (r = 0.60 and 0.79, respectively; P = 0.02 and 0.003). QTc in euglycaemia showed no correlation with hypoglycaemia associated QTc prolongation. The prognostic value of the hypoglycaemia test for the risk of recurrent episodes of QTc prolongation should be evaluated in real-life conditions in large-scale studies of diabetic adolescents.

Abstract 2764: Clinical Phenotype of Japanese LQT3 Form of Congenital Long QT Syndrome by Location of Mutation from Japanese Multicenter Registry

Background: Effects of location of mutation on clinical phenotype in a large scale of patients with LQT3 syndrome are unclear. Methods and Results: Forty-nine patients (male=30, proband=25) with an SCN5A mutation were retrospectively studied from a Japanese multicenter registry and divided into patients with mutations located in the transmembrane (TM) portion and the non-transmembrane (non-TM) portion. Although there was no significant difference in the QTc interval between the two groups (478±78 vs. 508±37ms; p=0.079), both cumulative cardiac event rates and lethal cardiac event (VF and/or aborted cardiac arrest) rates were significantly higher in the TM group (Figure , p=0.006, p=0.007, respectively). By performing the multivariate analysis, longer QTc interval and the TM group was an independent risk factor for cardiac events (QTc≥500ms vs. QTc&lt;500ms; hazard ratio=5.612, p=0.05, TM vs. non-TM; hazard ratio=15.234, p=0.009). Conclusion: In this multicenter study, Japanese LQT3 patients with mutations located in the transmembrane portion were at higher risk for cardiac events.

The QTc interval and its dispersion in patients receiving two atypical antipsychotics

Treatment with atypical antipsychotics may prolong the rate-corrected Q-T interval (QTc) on electrocardiogram and increase the risk of dangerous ventricular arrhythmias. Polytherapy with atypical antipsychotics is becoming common, but the effect of this practice on the QTc has not been explored in detail. Among 364 adults treated with atypical antipsychotics randomly selected from consecutive admissions to a single hospital, electrocardiograms with measurable Q-T intervals in at least six leads were available for 38 of 49 patients receiving polytherapy with two atypical antipsychotics. Daily chlorpromazine equivalent, QTc duration and QTc dispersion were assessed in this group and in 73 closely matched patients receiving atypical antipsychotic monotherapy. The daily chlorpromazine equivalent of atypical antipsychotics was significantly greater in the polytherapy group (525.2 vs. 244.7 mg, P = 0.0003). Polytherapy and monotherapy patients were similar with regard to QTc duration, QTc dispersion and proportion of patients with gender-adjusted QTc prolongation (7.9% vs. 9.6%). The QTc duration had only a modest correlation with the total antipsychotic dose (P = 0.064). The presence of hypokalemia (3.0-3.5 mEq/l) was not associated with longer QTc intervals. The common practice of polytherapy with two atypical antipsychotics does not seem to lead to significant QTc prolongation compared to monotherapy.

Length of the QT interval: determinants and prognostic implications in a population-based prospective study of older men

Objective We examined potential determinants and prognostic value of the corrected QT interval (QTc). Design A total of 4252 British men aged 60 to 79 years had a resting 12-lead electrocardiogram. Potential determinants of the QTc were assessed using multivariable regression. Men were followed up for 7 years. Results A 1 standard deviation increase in QTc (26 milliseconds) was associated with increased all-cause mortality (hazard ratio, 1.13; 95% confidence interval, 1.05-1.22). Longer QTc was associated with increasing age, preexisting coronary heart disease, and a range of drugs. Shorter QTc was present in diabetics and smokers. Corrected QT interval was related inversely with serum potassium and calcium and positively with serum urate, sodium, and systolic blood pressure. The relation of QTc to all-cause mortality was independent of adjustment for these factors. Conclusions Age, preexisting coronary heart disease, certain medications and biochemical factors, and diabetes are independently associated with QTc. Corrected QT interval is an independent predictor of all-cause mortality.

Abstract 3717: Corrected Qt Interval (qtc) Is Prolonged In Metabolic Syndrome Population

Background : Prolonged corrected QT interval (QTc) is a risk factor for cardiovascular disease, recent studies suggested that patients with metabolic syndrome had significantly higher values of QTc, but those studies were conducted in small sample, the result should be verified in large population. Purpose : The study is to evaluate the relationship between QTc and metabolic syndrome in large population and to elucidate the possible pathophysiological mechanism. Methods: The date was collected in a hypertensive survey in rural China, a total of 5467 individuals (men 3667, women 1800), aged from 20 to 80 years, were enrolled. Subjects with history of coronary heart disease, valvular heart disease, stroke, hepatic, renal, thyroid diseases and all kinds of arrhythmia (recorded by 12 lead ECGs) were excluded. Electrocardiogram was recorded and the value of QTc was calculated using Bazett’s equation. All individuals had ultrasonic echocardiograph examination and blood test. Using revised NCEP-ATPIII definition, 2271 individuals were diagnosed with metabolic syndrome, 3128 were non-metabolic syndrome. Results: Both men and women individuals with metabolic syndrome had longer QTc than those with no metabolic syndrome (404.1±30.7ms vs 407.6±31.5 ms, p&lt;0.05; 412.3±32.1 ms vs 417.5 ±32.4ms, p&lt;0.001 respectively). The value of QTc increased with the number of abnormal metabolic parameters. After adjusted age and sex, QTc is negatively correlated to serum potassium concentration and positively correlated with posterior left ventricular wall and intraventricular septum in both men and womem. Conclusion: Metabolic syndrome, even its single component is a risk factor for prolonged QTc. As metabolic syndrome individuals have lower serum potassium concentration and thicker posterior left ventricular wall and intraventricular septum than non-metabolic syndrome individuals, we propose that low serum potassium concentration and myocardial hypertrophy might play important roles in the development of prolonged QTc in metabolic syndrome.

Abstract 2193: Genetically-mediated Torsades De Pointes During Complete Heart Block

Background: Torsades de pointes (TdP) is a well known arrhythmic sequela in congenital and acquired long QT syndromes (LQTS). Less frequently, bradyarrhythmias are associated with QT prolongation and TdP. Although some observations have been made on the predictors of TdP in bradyarrhythmias, there is limited data on cellular mechanisms or genetic predisposition to bradycardia-induced TdP. Methods: In a retrospective case-control study, we identified 11 patients who were referred with CHB and TdP. Comprehensive assessment was performed in these patients, including, history, examination, ECG parameters (baseline, in CHB and pre-TdP) and genetic testing of repolarization related ion channel genes. 33 control patients with CHB and no TdP were selected for comparison of ECG parameters. All patients received either a pacemaker or implantable cardioverter defibrillator, with outpatient follow-up. Results: Four out of 11 patients with CHB and TdP had a genetic mutation identified involving ion channels responsible for cardiac repolarization (36%), involving hERG (n=3) and SCN5A (n=1). The key observations were that Tpeak to Tend interval was significantly longer in patients with a genetic abnormality at baseline, in CHB and pre-TdP (see Table 1 ). Compared to controls, patients who had TdP complicating CHB had significantly longer QTc and Tpeak to Tend intervals in CHB. Conclusion: TdP in the setting of CHB appears to identify patients who have an underlying genetic predisposition to reduced repolarization reserve. In particular, the terminal phase of repolarization (Tpeak to Tend) appears to be a marker for patients who have a cardiac ion channel abnormality. Given these findings, genetic testing should be considered in patients with TdP in the setting of CHB.

Confirmation of associations between ion channel gene SNPs and QTc interval duration in healthy subjects

Population-based association studies have identified several polymorphic variants in genes encoding ion channel subunits associated with the electrocardiographic heart-rate-corrected QT (QTc) length in healthy populations of Caucasian origin (KCNH2 rs1,805,123 (K897 T) and rs3,815,459, SCN5A rs1,805,126 (D1,819D), 1,141-3 C>A, rs1,805,124 (H558R), and IVS24+116 G>A, KCNQ1 rs757,092, KCNE1 IVS2-128 G>A and rs1,805,127 (G38S), and KCNE2 rs2,234,916 (T8A)). However, few of these results have been replicated in independent populations. We tested the association of SNPs KCNQ1 rs757,092, KCNH2 rs3,815,459, SCN5A IVS24+116 G>A, KCNE1 IVS2-128 G>A and KCNE2 rs2,234,916 with QTc length in two groups of 200 subjects presenting the shortest and the longest QTc from a cohort of 2,008 healthy subjects. All polymorphisms were in Hardy-Weinberg equilibrium in both groups. The minor allele SCN5A IVS24+116 A was more frequent in the group of subjects with the shortest QTc, whereas the minor alleles KCNQ1 rs757,092 G and KCNH2 rs3,815,459 A were more frequent in the group with the longest QTc. There was no significant difference for KCNE1 IVS2-128 G>A and KCNE2 rs2,234,916 between the two groups. Haplotype analysis showed a twofold increased risk of QTc lengthening for carriers of the haplotype, combining alleles C and A of the two common KCNE1 SNPs, IVS2-129 C>T (rs2,236,609) and rs1,805,127 (G38S), respectively. In conclusion, our study confirms the reported associations between QTc length and KCNQ1 rs757,092 and KCNH2 rs3,815,459.

Prolonged Ventricular Repolarization Measured by Corrected QT Interval (QTc) in Subclinical Hyperthyroidism

Overt hyperthyroidism and hypothyroidism exert a major effect on cardiac function and on ECG. The influence of subclinical hyperthyroidism on the circulatory system is still under debate. Few studies examined the effect of thyroid hormones on ventricular repolarization measured by corrected QT interval (QTc). Longer QTc is associated with increased risk of arrhythmia and cardiac mortality. The aim of this study was to examine the influence of subclinical hyperthyroidism on ventricular repolarization measured by corrected QTc in a standard 12-lead electrocardiogram. The examined group consisted of thirty-two patients with subclinical hyperthyroidism; the controls were thirty-nine healthy individuals. In the group with subclinical hyperthyroidism, we observed a significant increase in heart rate (80.3 +/- 10.59 vs. 73.7 +/- 11.37 bpm, p < 0.05). The mean corrected QTc was 0.434 +/- 0.0207 seconds and 0.414 +/- 0.0208 in the examined groups and in controls, respectively (p < 0.001). QTc did not correlate with free thyroxin concentrations (p = 0.5084). Corrected QT intervals were significantly longer in patients with subclinical hyperthyroidism.

Risk management and eligibility criteria for QTc assessment in patients with advanced cancer

3047 Background: Emerging regulatory and industry practices (ICH E14, 2004) require the potential for QTc interval prolongation to be characterized in a ‘Thorough QT’ (TQT) study with eligibility restricted based on screening QTc criteria (<430 ms in men, <450 ms in women) derived from non-oncology experience. For patients with advanced cancer who volunteer for Phase 1–2 clinical studies of promising new agents, risk-benefit implications of these and other TQT components have not been well defined. Methods: We surveyed baseline QTc interval in 160 adult patients with advanced malignancy enrolled into two Phase 2 trials with an experimental anticancer agent [97 GIST, 63 renal cell carcinoma; mean age 55.7 years (range 24, 87)]. QTc was measured by the ECG recorder’s automated algorithm on single 12-lead ECG obtained prior to treatment. Results: No significant differences in mean or median QTc were observed for patients aged <65 versus >=65 years. Distribution by gender-specific QTc risk categories showed that 94 men (87.9%) and 49 women (92.5%) had normal QTc (<430 and <450 ms, respectively). Eleven men (10.3%) and 4 women (7.6%) had borderline QTc (430–450 and 450–470 ms, respectively), while 2 men (1.9%) and no women had prolonged QTc (>450 and >470 ms, respectively). No QTc was >500 ms (CTCAE Grade 3). Overall, 17 of 160 patients (10.6%) had baseline QTc above the upper limits of normal. Conclusions: These data are consistent with anecdotal reports that cancer patients may have longer QTc than other segments of the population. Over 10% of our patients would have been excluded from treatment with a promising anticancer agent if eligibility criteria from TQT studies in non-oncology populations were applied. Given risk-benefit considerations and expectations for access to new agents in clinical trials, our data support alternative approaches to eligibility criteria and risk management in studies designed to evaluate QTc prolongation in patients with advanced cancer. No significant financial relationships to disclose.

Lithium concentration correlates with QTc in patients with psychosis

QT prolongation induced by antipsychotics has been reported to be a determinant for the development of torsade de pointes and sudden death. However, the effect of lithium on QT interval has not been fully clarified. The aim of the present study was to elucidate the relationship between serum lithium concentration and QT interval in patients treated with lithium. We examined serum lithium concentrations and electrocardiographic features in 39 inpatients with bipolar affective disorder or schizophrenia. The longest QT interval in the 12 electrocardiographic leads was measured using GE Marquette QT guard System Software, and Bazett formula was used for heart rate correction. The longest QTc was positively correlated with lithium concentration ( r = 0.46, P = .003). Multiple regression analysis revealed that sex (female, P = .037), lower serum K + concentration ( P = .029), and especially, higher serum lithium concentration ( P = .009) were determinants for the prolongation of the QTc.

Dispersion of the corrected QT interval in acute carbon monoxide poisoning

Carbon monoxide (CO) poisoning is known to cause myocardial toxicity and life-threatening arrhythmias. Corrected QT dispersion (QTdc) of the ECG is an indirect measure of heterogeneity of ventricular repolarisation, which may contribute to ventricular arrhythmias. The aim of the study was to evaluate the relationship between the carboxyhemoglobin (COHb) level and QTdc during carbon monoxide poisoning. This study was prospectively performed in 104 patients who diagnosed CO intoxication. Patients were assigned to two groups according to COHb levels 25% (Group II, n = 72). In each ECG lead, the QT interval and QRS duration were measured in the two groups and corrected for heart rate (QTc) using Bazett's formula (QT/RR1/2). QTdc is then the difference between the leads with the shortest and longest QTc intervals. Measurement of QT intervals were calculated at admission and in 24-hour and 48-hour ECGs after admission. Cardiac enzymes were measured at each stage. The myocardial perfusion after exercise and at rest 4 hours after exercise were determined in all patients 1 week after admission. QT, QTc and QTd intervals were not significantly different in both of groups each stage whereas the values of the QTdc after 24 hours were significantly greater than QTdc at admission in Group II but not in Group I. Comparison of QTdc for the two groups demonstrated significant differences after 24 hours (P < 0.05) (Table ​(Table1).1). Plasma creatinine phosphokinase (CPK) and CPK-MB levels at admission, and 24 and 48 hours later in Group II were significantly higher than the other group (P < 0.05). Seven patients in Group I and 23 patients in Group II had an extent of myocardial ischemia on scintigraphy. Table 1 The reduced threshold for arrhythmias in CO poisoning may be due to inhomogeneous repolarization of ventricles, assessed by QTdc. Measuring QTdc for monitoring after CO poisoning may be suggestive of the potential danger of high levels of COHb to cardiac-disabled individuals.