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Objective: The association between common electrocardiogram (ECG) markers and Alzheimer's disease has been scarcely investigated, and it is unknown if ECG markers can improve risk prediction. Thus, we aimed to examine the association between common ECG markers and Alzheimer's disease in a large population., Methods: We studied the association between ECG markers and Alzheimer's disease using Cox models with adjustment for age, sex, and comorbidities using a large primary care population of patients aged 60 years or more., Results: We followed 172,236 subjects for a median of 7.5 years. Increased PR interval (hazard ratio for PR > 188 ms: 0.76 [95% confidence interval: 0.69-0.83, p < 0.001) and increased QTc interval (hazard ratio for QTc = [426;439]: 0.90 [0.83-0.98], p = 0.02) were associated with a decreased rate of Alzheimer's disease. A positive Sokolow-Lyon index >35 mm (1.22 [1.13-1.33], p < 0.001) and increased T-wave amplitude >4.1 mm (1.15 [1.04-1.27]) were associated with an increased rate of Alzheimer's disease. Upon addition of ECG markers to a reference model, 10-year prediction area under the receiver-operator characteristics curve (AUC) improved by 0.39 [0.06-0.67] %-points. The 10-year absolute risk of Alzheimer's disease was 6.5% and 5.2% for an 82-year old female and a male, respectively, with a favorable ECG, and 12% and 9.2%, respectively, with an unfavorable ECG, almost twice as high., Conclusions: We identified several common ECG markers which were associated with Alzheimer's disease, and which improved risk prediction for Alzheimer's disease., Competing Interests: Declaration of Competing Interest A.G.H. is an employee of Acesion Pharma. J.B·N is employed by Regeneron Pharmaceuticals, Inc. The remaining authors have no conflict of interests to declare., (Copyright © 2023. Published by Elsevier B.V.)

Background: The assessment of symptom-rhythm correlation (SRC) in patients with persistent atrial fibrillation (AF) is challenging. Therefore, we performed a novel mobile app-based approach to assess SRC in persistent AF., Methods: Consecutive persistent AF patients planned for electrical cardioversion (ECV) used a mobile app to record a 60-s photoplethysmogram (PPG) and report symptoms once daily and in case of symptoms for four weeks prior and three weeks after ECV. Within each patient, SRC was quantified by the SRC-index defined as the sum of symptomatic AF recordings and asymptomatic non-AF recordings divided by the sum of all recordings., Results: Of 88 patients (33% women, age 68 ± 9 years) included, 78% reported any symptoms during recordings. The overall SRC-index was 0.61 (0.44-0.79). The study population was divided into SRC-index tertiles: low (<0.47), medium (0.47-0.73) and high (≥0.73). Patients within the low (vs high) SRC-index tertile had more often heart failure and diabetes mellitus (both 24.1% vs 6.9%). Extrasystoles occurred in 19% of all symptomatic non-AF PPG recordings. Within each patient, PPG recordings with the highest (vs lowest) tertile of pulse rates conferred an increased risk for symptomatic AF recordings (odds ratio [OR] 1.26, 95% coincidence interval [CI] 1.04-1.52) and symptomatic non-AF recordings (OR 2.93, 95% CI 2.16-3.97). Pulse variability was not associated with reported symptoms., Conclusions: In patients with persistent AF, SRC is relatively low. Pulse rate is the main determinant of reported symptoms. Further studies are required to verify whether integrating mobile app-based SRC assessment in current workflows can improve AF management., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Electrocardiographic T-wave morphology is used in drug safety studies as an adjunct to the QT c interval, but few measurements of T-wave morphology can be interpreted in clinical practice. Morphology combination score (MCS) is a combination of T-wave flatness/peakedness, asymmetry, and notching, enabling easy visual assessment of T-wave morphology. We aimed to test the association between T-wave morphology, quantified by MCS, and mortality., Methods: We included electrocardiograms recorded in 2001-2011 from 342,294 primary care patients. Using Cox regression, we evaluated the association between MCS, cardiovascular death, and all-cause mortality, adjusting for heart rate, QT c , QT-prolonging drugs, diabetes, ischemic heart disease, hypertension, and congestive heart failure., Results: 270,039 individuals (44% men, median age 55 [inter-quartile range: 42-67 years]) were included and followed for a median of 9.3 years, during which time 13,489 (5.0%) died from cardiovascular causes and 50,481 (18.7%) from any cause. High values of MCS (i.e. asymmetric, flattened, and/or notched T waves) were associated with an adjusted mortality Hazard Ratio of 1.75 (95% CI 1.62-1.89) and 1.61 (1.43-1.92) for women and men, respectively. Low values of MCS (i.e. peaked and symmetric T waves) were associated with a Hazard Ratio of 1.18 (1.08-1.28) and 1.71 (1.48-1.98) for women and men, respectively., Conclusions: In a large primary care population, we found that T-wave asymmetry, flatness, and notching provided prognostic information on mortality independent of heart rate, QTc, and baseline comorbidities., Competing Interests: Declaration of Competing Interest J.K.K. and C.G. are co-inventors of a patent regarding T-wave morphology. A.G.H. is an employee of Acesion Pharma. The remaining authors have nothing to declare., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: In patients with long QT syndrome (LQTS), swimming and loud noises have been identified as genotype-specific arrhythmic triggers in LQTS type 1 (LQTS1) and LQTS type 2 (LQTS2), respectively., Objective: The purpose of this study was to compare LQTS group responses to arrhythmic triggers., Methods: LQTS1 and LQTS2 patients were included. Before and after beta-blocker intake, electrocardiograms were recorded as participants (1) were exposed to a loud noise of ∼100 dB; and (2) had their face immersed into cold water., Results: Twenty-three patients (9 LQTS1, 14 LQTS2) participated. In response to noise, LQTS groups showed similarly increased heart rate, but LQTS2 patients had corrected QT interval (Fridericia formula) (QTcF) prolonged significantly more than LQTS1 patients (37 ± 8 ms vs 15 ± 6 ms; P = .02). After intake of beta-blocker, QTcF prolongation in LQTS2 patients was significantly blunted and similar to that of LQTS1 patients (P = .90). In response to simulated diving, LQTS groups experienced a heart rate drop of ∼28 bpm, which shortened QTcF similarly in both groups. After intake of beta-blockers, heart rate dropped to 28 ± 2 bpm in LQTS1 patients and 20 ± 3 bpm in LQTS2, resulting in a slower heart rate in LQTS1 compared with LQTS2 (P = .01). In response, QTcF shortened similarly in LQTS1 and LQTS2 patients (57 ± 9 ms vs 36 ± 7 ms; P = .10)., Conclusion: When exposed to noise, LQTS2 patients had QTc prolonged significantly more than did LQTS1 patients. Importantly, beta-blockers reduced noise-induced QTc prolongation in LQTS2 patients, thus demonstrating the protective effect of beta-blockers. In response to simulated diving, LQTS groups responded similarly, but a slower heart rate was observed in LQTS1 patients during simulated diving after beta-blocker intake., (Copyright © 2020 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Purpose: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate., Methods: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants., Results: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 × 10 -18 ) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 × 10 -13 ). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency., Conclusion: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing.

Background: Both hypoglycemia and severe hyperglycemia constitute known risk factors for cardiac repolarization changes potentially leading to malignant arrhythmias. Patients with loss of function mutations in KCNQ1 are characterized by long QT syndrome (LQTS) and may be at increased risk for glucose-induced repolarization disturbances., Objective: The purpose of this study was to test the hypothesis that KCNQ1 LQTS patients are at particular risk for cardiac repolarization changes during the relative hyperglycemia that occurs after an oral glucose load., Methods: Fourteen KCNQ1 LQTS patients and 28 control participants matched for gender, body mass index, and age underwent a 3-hour oral 75-g glucose tolerance test with ECGs obtained at 7 time points. Fridericia corrected QT interval (QTcF), Bazett corrected QT interval (QTcB), and the Morphology Combination Score (MCS) were calculated., Results: QTc and MCS increased in both groups. MCS remained elevated until 150 minutes after glucose ingestion, and the maximal change from baseline was larger among KCNQ1 LQTS patients compared with control subjects (0.28 ± 0.27 vs 0.15 ± 0.13; P <.05)., Conclusion: Relative hyperglycemia induced by ingestion of 75-g glucose caused cardiac repolarization disturbances that were more severe in KCNQ1 LQTS patients compared with control subjects., (Copyright © 2017 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Purpose: We investigated whether Brugada syndrome (BrS)-associated variants identified in the general population have an effect on J-point elevation as well as whether carriers of BrS variants were more prone to experience syncope and malignant ventricular arrhythmia and had increased mortality compared with noncarriers., Methods: All BrS-associated variants were identified using the Human Gene Mutation Database (HGMD). Individuals were randomly selected from a general population study using whole-exome sequencing data (n = 870) and genotype array data (n = 6,161) and screened for BrS-associated variants. Electrocardiograms (ECG) were analyzed electronically, and data on syncope, ventricular arrhythmias, and mortality were obtained from administrative health-care registries., Results: In HGMD, 382 BrS-associated genetic variants were identified. Of these, 28 variants were identified in the study cohort. None of the carriers presented with type 1 BrS ECG pattern. Mean J-point elevation in V1 and V2 were within normal guideline limits for carriers and noncarriers. There was no difference in syncope susceptibility (carriers 8/624; noncarriers 98/5,562; P = 0.51), ventricular arrhythmia (carriers 4/620; noncarriers 9/5,524; P = 0.24), or overall mortality (hazard ratio 0.93, 95% CI 0.63-1.4)., Conclusions: Our data indicate that a significant number of BrS-associated variants are not the monogenic cause of BrS.Genet Med advance online publication 06 October 2016.

Objectives: Quantitative measurements of cardiac repolarization, defined as the electrocardiographic QT interval, have important diagnostic implications in humans, as irregularities can trigger potentially fatal ventricular tachyarrhythmia. In both humans and horses, cardiac repolarization is influenced to some extent by heart rate, age, body weight (BW), sex, autonomic tone, and environment. In horses, there is substantial inter-breed variation in size and training, and the aims of this study were therefore to determine the best model describing the QT to RR relationship in breeds of various athletic horses and to test for differences in the QT interval., Animals: Ten Icelandic horses, 10 Arabian horses, 10 Thoroughbreds, 10 Standardbreds, six Coldblood trotters, 10 Warmbloods (dressage) and 10 Warmbloods (show jumping). All horses were geldings., Methods: QT intervals were measured from resting to peak exercise level and plotted against RR intervals. Data points were fitted with relevant regression models, and the effect of breed, BW, and estimated exercise intensity was examined., Results: For all breeds in this study, the QT interval was best described as a function of RR by the piecewise linear regression model. The breed of horse had a significant effect on the model. There was no systematic effect of BW or estimated exercise intensity, but a high inter-horse variability was observed., Conclusions: The equine QT interval should preferably be corrected for heart rate according to breed. In addition, the results indicate that equine studies of the QT interval must be designed to eliminate the influence of a large inter-horse variation., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: In long QT syndrome type 1 (LQT1), the location and type of mutations have been shown to affect the clinical outcome. Although haploinsufficiency, including stop-codon and frameshift mutations, has been associated with a lower risk of cardiac events in patients with LQT1, nonsense mutations have been presumed functionally equivalent., Objective: The purpose of this study was to evaluate clinical differences between patients with nonsense mutations., Methods: The study sample comprised 1090 patients with genetically confirmed mutations. Patients were categorized into 5 groups, depending on mutation type and location: missense not located in the high-risk cytoplasmic loop (c-loop) (n = 698), which is used as reference; missense c-loop (n = 192); stop-codon (n = 67); frameshift (n = 39); and others (n = 94). The primary outcome was a composite end point of syncope, aborted cardiac arrest, and long QT syndrome-related death (cardiac events). Outcomes were evaluated using the multivariate Cox proportional hazards regression analysis. Standard patch clamp techniques were used., Results: Compared to patients with missense non-c-loop mutations, the risk of cardiac events was reduced significantly in patients with stop-codon mutations (hazard ratio [HR] 0.57; 95% confidence interval [CI] 0.34-0.96; P = .035), but not in patients with frameshift mutations (HR 1.01; 95% CI 0.58-1.77; P = .97). Our data suggest that currents of the most common stop-codon mutant channel (Q530X) were larger than those of haploinsufficient channels (wild type: 42 ± 6 pA/pF, n = 20; Q530X+wild type: 79 ± 14 pA/pF, n = 20; P < .05) and voltage dependence of activation was altered., Conclusion: Stop-codon mutations are associated with a lower risk of cardiac events in patients with LQT1, while frameshift mutations are associated with the same risk as the majority of the missense mutations. Our data indicate functional differences between these previously considered equivalent mutation subtypes., (Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

The QT interval is the most widely used surrogate marker for predicting TdP; however, several alternative surrogate markers, such as Tpeak-Tend (TpTe) and a quantitative T-wave morphology combination score (MCS) have emerged. This study investigated the cardiac effects of sertindole and quetiapine using the QTc interval and newer surrogate markers. Data were derived from a 12 week randomized double-blind study comparing flexible dosage of sertindole 12-20mg and quetiapine 400-600mg in patients with schizophrenia. ECGs were recorded digitally at baseline and after 3, 6 and 12 weeks. Between group effects were compared by using a mixed effect model, whereas assessment within group was compared by using a paired t-test. Treatment with sertindole was associated with QTcF and QTcB interval prolongation and an increase in MCS, T-wave asymmetry, T-wave flatness and TpTe. The mean increase in QTcF from baseline to last observation was 12.1ms for sertindole (p<0.001) and -0.5ms for quetiapine (p=0.8). Quetiapine caused no increase in MCS, T-wave asymmetry, T-wave flatness or TpTe compared to baseline. In the categorical analysis, there were 11 patients (9.6%) receiving quetiapine who experienced more than 20ms QTcF prolongation compared with 36 patients (33.3%) in the sertindole group. Sertindole (12-20mg) was associated with moderate QTc prolongation and worsening of T-wave morphology in a study population of patients with schizophrenia. Although, quetiapine (400-600mg) did not show worsening of repolarization measures some individual patients did experience significant worsening of repolarization. Clinical Trials NCT00654706., (Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.)

Objectives: Irregularities in cardiac repolarization are known to predispose for arrhythmias and sudden cardiac death in humans. The QT interval is a quantitative measurement of repolarization, and clinically, the QTc (QT interval corrected for heart rate) and Tpeak to Tend intervals (TpTe) are used as repolarization markers. To support the use of these markers in horses, we sought to describe the possible influence of the environment, time of day, day-to-day effects, T wave conformation, age, body weight (BW), and horse-to-horse variation on repolarization measurements., Animals: 12 Warmblood geldings, age 10.8 ± 4.8 years., Methods: Holter ECGs were performed on days 0, 7 and 14. Measures of RR, QT, QTp, QTc and TpTe intervals and T wave conformation were obtained each hour during the recordings. An ANCOVA analysis was performed to estimate diurnal variation and the sources of variation affecting these intervals., Results: Differences between individual horses were the largest source of repolarization variability although the environment had a significant effect on repolarization as well. Diurnal variation affected both the RR interval and the repolarization markers. The QT, QTc and TpTe intervals were prolonged on day 0. Biphasic T waves shortened the TpTe interval approximately 10 ms. Age and BW did not appear to affect repolarization., Conclusions: Equine repolarization markers exhibit significant variation. Factors affecting repolarization measurements include horse-to-horse variation, diurnal variation, the environment, and T wave conformation. These factors must be considered if markers of equine repolarization are used diagnostically., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Long QT syndrome type 13 (LQT13) is caused by loss-of-function mutation in the KCNJ5-encoded cardiac G-protein-coupled inward rectifier potassium channel subtype 4 protein. The electrocardiographic (ECG) features of LQT13 are not described yet., Objective: To describe for the first time in detail the phenotype-genotype relationship of the ECG and clinical features in patients with LQT13., Methods: The 12-lead ECGs, 24-hour Holter recordings, and clinical information from KCNJ5-G387R mutation carriers of a fourth-generation Han Chinese family with LQT13 and a group of healthy Chinese individuals were analyzed., Results: Compared with the analysis of the healthy group (n = 8), age- and sex-matched pair analysis revealed that the mutation carriers (n = 8) had ventricular repolarization abnormality results in the prolongation of corrected QT and QTpeak intervals (P < .01); greater combined measure of repolarization morphology (T-wave morphology combination score) based on asymmetry, flatness, and notch (P < .01); and reduced low frequency/high frequency ratio of heart rate variability (P < .01) as a reflection of cardiac autonomic imbalance. Mean heart rate, time domain parameters of heart rate variability, time interval from T-wave peak to T-wave end, and T-wave amplitude were similar., Conclusions: This study demonstrates for the first time the ECG features of patients with LQT13. Our data suggest that QTpeak intervals and T-wave morphology combination score may be the better parameters than the corrected QT interval to predict the phenotype-genotype relationship in patients with LQT13., (© 2013 Heart Rhythm Society. All rights reserved.)

Objectives: Cardiac repolarization, measured as QT and Tpeak to Tend (TpTe) intervals on the ECG, is important, as irregularities caused by diseases, ventricular hypertrophy, drugs and genetic defects can trigger arrhythmias which predispose human patients to syncope and sudden cardiac death. In horses, repolarization is not well described and therefore QT analysis cannot yet be used diagnostically. Therefore, we sought to describe reference values for the normal QT and TpTe intervals in Standardbreds and to determine the best method for heart rate (HR) correction., Animals: 30 Standardbreds., Methods: QT and TpTe intervals were measured during rest and exercise and plotted against HR converted to Rpeak to Rpeak interval (RR). Data were fitted with relevant regression models. Intra- and inter-observer agreement was assessed using Bland-Altman analyses., Results: Data were best described by a piecewise linear model (r(2) > 0.97). Average prediction error of this model was smaller than for both Bazett and Fridericia corrections. Coefficient of repeatability of intra- and inter-observer variability was 8.76 ms and 5.64 ms respectively and coefficient of variation was 1.77% and 2.76% respectively. TpTe increased with RR in stallions., Conclusions: The QT interval in Standardbred horses shortens with decreasing RR interval (increasing HR) as in humans, but in a markedly different order as it clearly follows a piecewise linear model. The equine QT interval can be measured easily and there is small intra- and inter-observer variability. This model of the equine QT interval provides clinicians with a method that could support a diagnosis of repolarization disturbances in horses., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Low baroreflex sensitivity (BRS) indicates poor prognosis after acute myocardial infarction. Noninvasive BRS assessment is complicated by nonstationarities and noise in electrocardiogram and pressure signals. Phase-rectified signal averaging is a novel signal processing technology overcoming these problems., Objective: To prospectively validate a BRS measure (baroreflex sensitivity assessed by means of phase-rectified signal averaging [BRS(PRSA)]) based on this technology., Methods: Nine hundred forty-one consecutive acute myocardial infarction survivors aged 80 years or younger in sinus rhythm were prospectively enrolled at 2 German university hospitals. All patients underwent 30-minute recordings of electrocardiogram and arterial blood pressures (Portapres; TNO-TPD Biomedical Instrumentation, Amsterdam, Netherlands) within the first 2 weeks after myocardial infarction. BRS(PRSA) was prospectively dichotomized at 1.58 ms/mm Hg. Primary end point was all-cause mortality at 5 years. Multivariable analyses included Global Registry of Acute Coronary Events score (dichotomized at ≥120), sex, BRS(PRSA), left ventricular ejection fraction (dichotomized at ≤35%), and diabetes mellitus. BRS(PRSA) was compared with 3 standard noninvasive BRS measures, that is, the sequence method, the transfer function method, and the correlation method., Results: During follow-up, 72 patients (7.7%) died. BRS(PRSA) stratified the study population into a high-risk group of 405 patients (≤1.58 ms/mm Hg) with an estimated 5-year mortality of 14.2% and a low-risk group of 536 patients (>1.58 ms/mm Hg) with a 5-year mortality of 2.8% (P <.0001). On multivariable analysis, BRS(PRSA) ≤ 1.58 ms/mm Hg was associated with a hazard ratio of 3.1 (confidence interval 1.7-5.6; P = .001). Predictive power of BRS(PRSA) ≤ 1.58 ms/mm Hg was particularly strong in patients with a Global Registry of Acute Coronary Events score of ≥120 or with a left ventricular ejection fraction of ≤35%., Conclusion: BRS(PRSA) is a powerful and independent predictor of mortality in postinfarction patients especially when assessed in patients with a Global Registry of Acute Coronary Events score of ≥120 or a left ventricular ejection fraction of ≤35%., (Copyright © 2012 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Various parameters based on QTc and T-wave morphology have been shown to be useful discriminators for drug induced I(Kr)-blocking. Using different classification methods this study compares the potential of these two features for identifying abnormal repolarization on the ECG. A group of healthy volunteers and LQT2 carriers were used to train classification algorithms using measures of T-wave morphology and QTc. The ability to correctly classify a third group of test subjects before and after receiving d,l-sotalol was evaluated using classification rules derived from training. As a single electrocardiographic feature, T-wave morphology separates normal from abnormal repolarization better than QTc. It is further indicated that nonlinear boundaries can provide stronger classifiers than a linear boundaries. Whether this is true in general with other ECG markers and other data sets is uncertain because the approach has not been tested in this setting., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Study Objective: To evaluate the sensitivity and specificity of various predictors of hypotension during onset of spinal anesthesia in elderly patients., Design: Prospective study., Setting: 32 ASA physical status I, II, and III patients, aged >or=60 years, scheduled for elective lower limb surgery with spinal anesthesia., Interventions: Patients received spinal anesthesia with 10-17.5 mg of bupivacaine. No prophylactic ephedrine or fluid preloading was used., Measurements: A 5-minute baseline was recorded and during onset of spinal anesthesia, hemodynamic changes were measured every 10 seconds from the radial artery pressure curve. Data collection ended when patients were ready for surgery, or if ephedrine was given to increase mean arterial pressure., Main Results: 21 patients had hypotension. Baseline blood pressure variability low-frequency band power (BPV LF) >8 mmHg(2) and near-infrared spectroscopy (NIRS) reduction >or=5% had high sensitivity (0.73 and 0.90, respectively) and specificity (0.78 and 0.64, respectively), and were significantly associated with the development of hypotension., Conclusions: Only NIRS and BPV LF could significantly predict hypotension among the elderly.

Mutations in one of the ion channels shaping the cardiac action potential can lead to action potential prolongation. However, only in a minority of cardiac arrest cases mutations in the known arrhythmia-related genes can be identified. In two patients with arrhythmia and cardiac arrest, we identified the point mutations P91L and E33V in the KCNA5 gene encoding the Kv1.5 potassium channel that has not previously been associated with arrhythmia. We functionally characterized the mutations in HEK293 cells. The mutated channels behaved similarly to the wild-type with respect to biophysical characteristics and drug sensitivity. Both patients also carried a D85N polymorphism in KCNE1, which was neither found to influence the Kv1.5 nor the Kv7.1 channel activity. We conclude that although the two N-terminal Kv1.5 mutations did not show any apparent electrophysiological phenotype, it is possible that they may influence other cellular mechanisms responsible for proper electrical behaviour of native cardiomyocytes.

Background: QT dynamics parameters are used only in sinus rhythm. However, because many patients with paroxysmal atrial fibrillation undergo antiarrhythmic treatment that changes QT, developing methods for measuring QT dynamics during atrial fibrillation is important., Objectives: The purpose of this study was to evaluate whether QT dynamics in atrial fibrillation can be measured more reliably if additional RR intervals are included in the QT calculation., Methods: QT and RR intervals were measured in 15 patients with atrial fibrillation and sinus rhythm on the same 24-hour Holter recording. Full QT adaptation is not instantaneous but lags behind over several beats. To correct for this lag, we adapted a weighted average method using five successive RR intervals. Linear regression was performed on (QT, RR) and (QT, RR(modified)) pairs. Variability ratio (standard deviation of all QT intervals/standard deviation of all RR intervals) and modified variability ratio (standard deviation of all QT intervals/modified standard deviation of all RR intervals) were calculated., Results: QT-RR slope was reduced in atrial fibrillation compared with sinus rhythm (0.076 +/- 0.009 vs 0.113 +/- 0.0013, P = .0005). When correcting for lag, using the QT-RR(modified) slope, the slope in atrial fibrillation became similar to the slope in sinus rhythm (0.126 +/- 0.013 vs 0.126 +/- 0.013, P = .9547). The variability ratio was reduced in atrial fibrillation compared with sinus rhythm (0.175 +/- 0.017 vs 0.240 +/- 0.031, P = .009), but when correcting for the lag, the modified variability ratio was similar in atrial fibrillation and sinus rhythm (0.262 +/- 0.029 vs 0.267 +/- 0.038, P = .80)., Conclusion: The results of this study demonstrate that QT dynamics can be measured reliably in atrial fibrillation using 24-hour Holter recordings.

Background: Ventricular extrasystoles are characterized by a fixed coupling interval to the last QRST complex preceding it., Objectives: We hypothesized that this QRST complex differed from QRST complexes of other sinus beats not followed by ventricular extrasystoles. Further, we investigated whether phase 2 reentry, demonstrated in animal experiments to initiate ventricular extrasystoles, ventricular tachycardia, and ventricular fibrillation, also plays a role in humans., Methods: We examined 18 patients with ventricular extrasystoles and/or ventricular tachycardia by signal averaging of the ECG (group A) or by single-beat analysis of intracardiac electrograms (group B). Group A consisted of six patients without structural heart disease and one patient with the Brugada syndrome. Six of the seven patients had right ventricular outflow tract ventricular extrasystoles. Group B consisted of 11 patients undergoing radiofrequency ablation. Eight of the 11 patients had right ventricular outflow tract extrasystoles., Results: In six of the seven patients in group A, we demonstrated significant ST-elevation and/or T-wave changes in the sinus beat preceding ventricular extrasystoles compared with the second last sinus beat in one or more of the three orthogonal leads X, Y, and Z. In 9 of the 11 patients in group B, single-beat analysis of unipolar and bipolar electrograms recorded close to successful ablation sites demonstrated similar changes, that is, ST-elevation (median peak voltage gradient 150 muV, range 0-1,700) and T-wave changes in the sinus beat prior to ventricular ectopy. In addition, J-point elevation was demonstrated in several cases. In total, significant changes were demonstrated in 15 of the 18 patients studied (83%)., Conclusion: J-point elevation, ST-elevation, and T-wave changes documented in the last sinus beat prior to ventricular extrasystoles are in agreement with phase 2 reentry, suggesting that this may be the responsible mechanism for ventricular extrasystoles and ventricular tachycardia/fibrillation. The phenomenon has been demonstrated in only animal experiments to date.

Objectives: The purpose of this study was to compare measures of repolarization dynamics (QT dynamics) with other Holter risk predictors, left ventricular systolic function, and demographic characteristics to establish whether QT dynamics add independent information on risk stratification after myocardial infarction (MI). A novel QT dynamics parameter, the QT/RR variability ratio (VR), was introduced in this study., Background: Abnormal repolarization contributes to arrhythmogenesis, and quantification of QT dynamics may have prognostic value after MI., Methods: A 24-hour Holter recording was performed in 481 consecutive MI patients. Recordings from 311 patients were included in the analysis. QT/RR slope and intercept, mean and standard deviation of all QT, QTc, and RR intervals, and VR (defined as the ratio between the standard deviation of all QT intervals and the standard deviation of all RR interval) were calculated. Ventricular premature beats and ventricular tachycardia were counted., Results: During 3-year follow-up, 70 deaths from all causes occurred. All parameters except mean of all QT intervals and standard deviation of all QTc intervals univariately predicted all-cause mortality. In multivariate Cox analysis, only VR per 0.1 (hazard ratio [HR]: 1.9 [1.5-2.4]), left ventricular ejection fraction per 5% (HR: 1.2 [1.1-1.3]), ventricular premature beats per 10 beats/hour (HR: 1.03 [1.002-1.06]), and age per 10 years (HR: 1.6 [1.3-2.0]) independently predicted all-cause mortality., Conclusions: Measures of QT dynamics univariately predicted total mortality. VR, left ventricular ejection fraction, ventricular premature beats, and age made up the optimal Cox model for risk stratification after MI. VR seems to be a promising risk factor for identifying sudden arrhythmic death.

Objectives: The aim of this study was to develop an objective method to distinguish between HERG and KvLQT1 genotypes on the surface ECG., Background: The two most prevalent genes affected in long QT syndrome (LQTS) are KvLQT1 (KCNQ1) and HERG (KCNH2), which are mutated in >90% of patients with a reported LQTS genotype. It is known that T waves have lower amplitude and more notches in HERG patients than T waves in KvLQT1 patients, but this semiquantitative method lacks the discriminative power to be used in a clinical setting. We developed a simple mathematical method that allowed us to quantify T wave shape in LQTS mutations for clinical use., Methods: ECGs from 24 HERG patients, 13 KvLQT1 LQTS patients, and 13 healthy relatives were examined. The repolarizing integral (RI) was constructed from the T wave. The resulting RI is sigmoid and was modeled using the Hill equation as (RI(t) = V(max)*[t(n)/[K(m)(n) + t(n)]]). V(max) is equivalent to the total T wave area, K(m) is the time when 50% of the T wave area is reached, and n is a measure of the slope of the sigmoid RI., Results: The RI correlated nearly perfectly to the fitted sigmoid, r = 0.99. In lead V(2), V(max) was larger in KvLQT1 (0.148 +/- 0.021) (mean +/- SE) compared to HERG (0.080 +/- 0.012) and controls (0.067 +/- 0.021). The Hill coefficient n of the RI discriminated perfectly between HERG (2.00 +/- 0.11) and KvLQT1 (4.11 +/- 0.15)., Conclusions: RI allows distinguishing between HERG and KvLQT1 mutations based solely on the T wave morphology in the present LQTS population.

Background: Long QT syndrome [LQTS] is a congenital cardiac disease characterised by prolonged QTC-time, syncopes and sudden cardiac death. LQTS is caused by mutations in genes coding for ion channels involved in the action potential. KCNE5 codes for a novel beta-subunit of the ion channel conducting the delayed rectifier repolarizing current IKs. As KCNE5 is expressed in the human heart and suppresses the IKs current in heterologous systems, it is a candidate gene that may be mutated in LQTS families where no causative mutations in known LQTS associated genes have been found. We examined whether this was the case., Methods: Genomic DNA from LQTS patients [n=88] and normal controls [n=90] was screened for mutations in KCNE5 by endonuclease-enhanced single strand conformation polymorphism analysis [EE-SSCP], and DNA sequencing of aberrant conformers. Mutations in other LQTS associated ion channels were excluded by SSCP., Results: No mutations were found in the coding region of the KCNE5 gene in LQTS patients. One polymorphism, a T-to-C transition at nucleotide 97, causing an amino acid polymorphism P33S, was present in 16 persons, nine heterozygotes and seven homozygotes. The T-allele frequency was 0.13 in LQTS patients and 0.10 in controls., (Copyright 2004 Elsevier B.V.)

Congenital long QT syndrome (LQTS) is characterised by prolongation of the QT interval on ECG and cardiac arrhythmias, syncopes and sudden death. A rapid and reliable genetic diagnosis of the disease may be of great importance for diagnosis and treatment of LQTS. Mutations in the KVLQT1 gene, encoding a potassium-channel subunit of importance for the depolarisation of cardiac myocytes, is believed to be associated with 50% of all LQTS cases. Our data confirms that KvLQT1 isoform 1 is encoded by 16 exons, and not 15, as reported previously. We have used genomic DNA sequences to design intronic PCR primers for amplification of 15 exons of KVLQT1 and optimised a non-radioactive single stranded conformation polymorphism/heteroduplex (SSCP/HD) method for detection of mutations in KVLQT1. The sensitivity of the method was 100% when it was tested on 15 in vitro constructed mutants. By multiplexing the PCR amplification of KVLQT1, it is possible to cover all 15 exons in four PCR reactions.