Epistatic effects of potassium channel variation on cardiac repolarization and atrial fibrillation risk

Objectives The aim of this study was to evaluate the role of cardiac K+ channel gene variants in families with atrial fibrillation (AF). Background The K+ channels play a major role in atrial repolarization but single mutations in cardiac K+ channel genes are infrequently present in AF families. The collective effect of background K+ channel variants of varying prevalence and effect size on the atrial substrate for AF is largely unexplored. Methods Genes encoding the major cardiac K+ channels were resequenced in 80 AF probands. Nonsynonymous coding sequence variants identified in AF probands were evaluated in 240 control subjects. Novel variants were characterized using patch-clamp techniques and in silico modeling was performed using the Courtemanche atrial cell model. Results Nineteen nonsynonymous variants in 9 genes were found, including 11 rare variants. Rare variants were more frequent in AF probands (18.8% vs. 4.2%, p < 0.001), and the mean number of variants was greater (0.21 vs. 0.04, p < 0.001). The majority of K+ channel variants individually had modest functional effects. Modeling simulations to evaluate combinations of K+ channel variants of varying population frequency indicated that simultaneous small perturbations of multiple current densities had nonlinear interactions and could result in substantial (>30 ms) shortening or lengthening of action potential duration as well as increased dispersion of repolarization. Conclusions Families with AF show an excess of rare functional K+ channel gene variants of varying phenotypic effect size that may contribute to an atrial arrhythmogenic substrate. Atrial cell modeling is a useful tool to assess epistatic interactions between multiple variants.

Fractional diffusion models of cardiac electrical propagation: Role of structural heterogeneity in dispersion of repolarization

Impulse propagation in biological tissues is known to be modulated by structural heterogeneity. In cardiac muscle, improved understanding on how this heterogeneity influences electrical spread is key to advancing our interpretation of dispersion of repolarization. We propose fractional diffusion models as a novel mathematical description of structurally heterogeneous excitable media, as a means of representing the modulation of the total electric field by the secondary electrical sources associated with tissue inhomogeneities. Our results, analysed against in vivo human recordings and experimental data of different animal species, indicate that structural heterogeneity underlies relevant characteristics of cardiac electrical propagation at tissue level. These include conduction effects on action potential (AP) morphology, the shortening of AP duration along the activation pathway and the progressive modulation by premature beats of spatial patterns of dispersion of repolarization. The proposed approach may also have important implications in other research fields involving excitable complex media.

Electrocardiographic repolarization variables in detecting myocardial infarction and ischemic injury : From body surface potential mapping to a single lead

The aim of the studies was to improve the diagnostic capability of electrocardiography (ECG) in detecting myocardial ischemic injury with a future goal of an automatic screening and monitoring method for ischemic heart disease. The method of choice was body surface potential mapping (BSPM), containing numerous leads, with intention to find the optimal recording sites and optimal ECG variables for ischemia and myocardial infarction (MI) diagnostics. The studies included 144 patients with prior MI, 79 patients with evolving ischemia, 42 patients with left ventricular hypertrophy (LVH), and 84 healthy controls. Study I examined the depolarization wave in prior MI with respect to MI location. Studies II-V examined the depolarization and repolarization waves in prior MI detection with respect to the Minnesota code, Q-wave status, and study V also with respect to MI location. In study VI the depolarization and repolarization variables were examined in 79 patients in the face of evolving myocardial ischemia and ischemic injury. When analyzed from a single lead at any recording site the results revealed superiority of the repolarization variables over the depolarization variables and over the conventional 12-lead ECG methods, both in the detection of prior MI and evolving ischemic injury. The QT integral, covering both depolarization and repolarization, appeared indifferent to the Q-wave status, the time elapsed from MI, or the MI or ischemia location. In the face of evolving ischemic injury the performance of the QT integral was not hampered even by underlying LVH. The examined depolarization and repolarization variables were effective when recorded in a single site, in contrast to the conventional 12-lead ECG criteria. The inverse spatial correlation of the depolarization and depolarization waves in myocardial ischemia and injury could be reduced into the QT integral variable recorded in a single site on the left flank. In conclusion, the QT integral variable, detectable in a single lead, with optimal recording site on the left flank, was able to detect prior MI and evolving ischemic injury more effectively than the conventional ECG markers. The QT integral, in a single-lead or a small number of leads, offers potential for automated screening of ischemic heart disease, acute ischemia monitoring and therapeutic decision-guiding as well as risk stratification.

Ventricular repolarization during cardiovascular autonomic function testing

The autonomic nervous system is an important modulator of ventricular repolarization and arrhythmia vulnerability. This study explored the effects of cardiovascular autonomic function tests on repolarization and its heterogeneity, with a special reference to congenital arrhythmogenic disorders typically associated with stress-induced fatal ventricular arrhythmias. The first part explored the effects of standardized autonomic tests on QT intervals in a 12-lead electrocardiogram and in multichannel magnetocardiography in 10 healthy adults. The second part studied the effects of deep breathing, Valsalva manouvre, mental stress, sustained handgrip and mild exercise on QT intervals in asymptomatic patients with LQT1 subtype of the hereditary long QT syndrome (n=9) and in patients with arrhythmogenic right ventricular dysplasia (ARVD, n=9). Even strong sympathetic activation had no effects on spatial QT interval dispersion in healthy subjects, but deep respiratory efforts and Valsalva influenced it in ways that were opposite in electrocardiographic and magnetocardiographic recordings. LQT1 patients showed blunted QT interval and sinus nodal responses to sympathetic challenge, as well as an exaggerated QT prolongation during the recovery phases. LQT1 patients showed a QT interval recovery overshoot in 2.4 ± 1.7 tests compared with 0.8 ± 0.7 in healthy controls (P = 0.02). Valsalva strain prolonged the T wave peak to T wave end interval only in the LQT1 patients, considered to reflect the arrhythmogenic substrate in this syndrome. ARVD patients showed signs of abnormal repolarization in the right ventricle, modulated by abrupt sympathetic activation. An electrocardiographic marker reflecting interventricular dispersion of repolarization was introduced. It showed that LQT1 patients exhibit a repolarization gradient from the left ventricle towards the right ventricle, significantly larger than in controls. In contrast, ARVD patients showed a repolarization gradient from the right ventricle towards the left. Valsalva strain amplified the repolarization gradient in LQT1 patients whereas it transiently reversed it in patients with ARVD. In conclusion, intrathoracic volume and pressure changes influence regional electrocardiographic and magnetocardiographic QT interval measurements differently. Especially recovery phases of standard cardiovascular autonomic functions tests and Valsalva manoeuvre reveal the abnormal repolarization in asymptomatic LQT1 patients. Both LQT1 and ARVD patients have abnormal interventricular repolarization gradients, modulated by abrupt sympathetic activation. Autonomic testing and in particular the Valsalva manoeuvre are potentially useful in unmasking abnormal repolarization in these syndromes.

Electrocardiographic parameters of ventricular repolarization : modifiers and the prognostic value

Electric activity of the heart consists of repeated cardiomyocyte depolarizations and repolarizations. Abnormalities in repolarization predispose to ventricular arrhythmias. In body surface electrocardiogram, ventricular repolarization generates the T wave. Several electrocardiographic measures have been developed both for clinical and research purposes to detect repolarization abnormalities. The study aim was to investigate modifiers of ventricular repolarization with the focus on the relationship of the left ventricular mass, antihypertensive drugs, and common gene variants, to electrocardiographic repolarization parameters. The prognostic value of repolarization parameters was also assessed. The study subjects originated from a population of more than 200 middle-aged hypertensive men attending the GENRES hypertension study, and from an epidemiological survey, the Health 2000 Study, including more than 6000 participants. Ventricular repolarization was analysed from digital standard 12-lead resting electrocardiograms with two QT-interval based repolarization parameters (QT interval, T-wave peak to T-wave end interval) and with a set of four T-wave morphology parameters. The results showed that in hypertensive men, a linear change in repolarization parameters is present even in the normal range of left ventricular mass, and that even mild left ventricular hypertrophy is associated with potentially adverse electrocardiographic repolarization changes. In addition, treatments with losartan, bisoprolol, amlodipine, and hydrochlorothiazide have divergent short-term effects on repolarization parameters in hypertensive men. Analyses of the general population sample showed that single nucleotide polymorphisms in KCNH2, KCNE1, and NOS1AP genes are associated with changes in QT-interval based repolarization parameters but not consistently with T-wave morphology parameters. T-wave morphology parameters, but not QT interval or T-wave peak to T-wave end interval, provided independent prognostic information on mortality. The prognostic value was specifically related to cardiovascular mortality. The results indicate that, in hypertension, altered ventricular repolarization is already present in mild left ventricular mass increase, and that commonly used antihypertensive drugs may relatively rapidly and treatment-specifically modify electrocardiographic repolarization parameters. Common variants in cardiac ion channel genes and NOS1AP gene may also modify repolarization-related arrhythmia vulnerability. In the general population, T-wave morphology parameters may be useful in the risk assessment of cardiovascular mortality.

Modification of ventricular repolarization in silent long QT syndrome mutation carriers

Congenital long QT syndrome (LQTS) is a familial disorder characterized by ventricular repolarization that makes carriers vulnerable to malignant ventricular tachycardia and sudden cardiac death. The three main subtypes (LQT1, LQT2 and LQT3) constitute 95% of cases. The disorder is characterized by a prolonged QT interval in electrocardiograms (ECG), but a considerable portion are silent carriers presenting normal (QTc < 440 ms) or borderline (QTc < 470 ms) QT interval. Genetic testing is available only for 60-70% of patients. A number of pharmaceutical compounds also affect ventricular repolarization, causing a clinically similar disorder called acquired long QT syndrome. LQTS carriers - who already have impaired ventricular repolarization - are especially vulnerable. In this thesis, asymptomatic genotyped LQTS mutation carriers with non-diagnostic resting ECG were studied. The body surface potential mapping (BSPM) system was utilized for ECG recording, and signals were analyzed with an automated analysis program. QT interval length, and the end part of the T wave, the Tpe interval, was studied during exercise stress testing and an epinephrine bolus test. In the latter, T wave morphology was also analyzed. The effect of cetirizine was studied in LQTS carriers and also with supra- therapeutic dose in healthy volunteers. At rest, LQTS mutation carriers had a slightly longer heart rate adjusted QTc interval than healthy subjects (427 ± 31 ms and 379 ± 26 ms; p<0.001), but significant overlapping existed. LQT2 mutation carriers had a conspicuously long Tpe-interval (113 ± 24 ms; compared to 79 ± 11 ms in LQT1, 81 ± 17 ms in LQT3 and 78 ± 10 ms in controls; p<0.001). In exercise stress tests, LQT1 mutation carriers exhibit a long QT interval at high heart rates and during recovery, whereas LQT2 mutation carriers have a long Tpe interval at the beginning of exercise and at the end of recovery at low heart rates. LQT3 mutation carriers exhibit prominent shortening of both QT and Tpe intervals during exercise. A small epinephrine bolus revealed disturbed repolarization, especially in LQT2 mutation carriers, who developed prolonged Tpe intervals. A higher epinephrine bolus caused abnormal T waves with a different T wave profile in LQTS mutation carriers compared to healthy controls. These effects were seen in LQT3 as well, a group that may easily escape other provocative tests. In the cetirizine test, the QT and Tpe intervals were not prolonged in LQTS mutation carriers or in healthy controls. Subtype-specific findings in exercise test and epinephrine bolus test help to diagnose silent LQTS mutation carriers and to guide subtype-specific treatments. The Tpe interval, which signifies the repolarization process, seems to be a sensitive marker of disturbed repolarization along with the QT interval, which signifies the end of repolarization. This method may be used in studying compounds that are suspected to affect repolarization. Cetirizine did not adversely alter ventricular repolarization and would not be pro-arrhythmic in common LQT1 and LQT2 subtypes when used at its recommended doses.

Nonlinear measures of QT interval series: novel indices of cardiac repolarization lability: MEDqthr and LLEqthr

In this study, we investigated nonlinear measures of chaos of QT interval time series in 28 normal control subjects, 36 patients with panic disorder and 18 patients with major depression in supine and standing postures. We obtained the minimum embedding dimension (MED) and the largest Lyapunov exponent (LLE) of instantaneous heart rate (HR) and QT interval series. MED quantifies the system's complexity and LLE predictability. There was a significantly lower MED and a significantly increased LLE of QT interval time series in patients. Most importantly, nonlinear indices of QT/HR time series, MEDqthr (MED of QT/HR) and LLEqthr (LLE of QT/HR), were highly significantly different between controls and both patient groups in either posture. Results remained the same even after adjusting for age. The increased LLE of QT interval time, series in patients with anxiety and depression is in line with our previous findings of higher QTvi (QT variability index, a log ratio of QT variability corrected for mean QT squared divided by heart rate variability corrected for mean heart rate squared) in these patients, using linear techniques. Increased LLEqthr (LLE of QT/HR) may be a more sensitive tool to study cardiac repolarization and a valuable addition to the time domain measures such as QTvi. This is especially important in light of the finding that LLEqthr correlated poorly and nonsignificantly with QTvi. These findings suggest an increase in relative cardiac sympathetic activity and a decrease in certain aspects of cardiac vagal function in patients with anxiety as well as depression. The lack of correlation between QTvi and LLEqthr suggests that this nonlinear index is a valuable addition to the linear measures. These findings may also help to explain the higher incidence of cardiovascular mortality in patients with anxiety and depressive disorders. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.

Postpacing abnormal repolarization in catecholaminergic polymorphic ventricular tachycardia associated with a mutation in the cardiac ryanodine receptor gene.

BACKGROUND Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an arrhythmogenic disease for which electrophysiological studies (EPS) have shown to be of limited value.OBJECTIVE This study presents a CPVT family in which marked postpacing repolarization abnormalities during EPS were the only consistent phenotypic manifestation of ryanodine receptor (RyR2) mutation carriers.METHODS The study was prompted by the observation of transient marked QT prolongation preceding initiation of ventricular fibrillation during atrial fibrillation in a boy with a family history of sudden cardiac death (SCD). Family members underwent exercise and pharmacologic electrocardiographic testing with epinephrine, adenosine, and flecainide. Noninvasive clinical test results were normal in 10 patients evaluated, except for both epinephrine- and exercise-induced ventricular arrhythmias in 1. EPS included bursts of ventricular pacing and programmed ventricular extrastimulation reproducing short-long sequences. Genetic screening involved direct sequencing of genes involved in long QT syndrome as well as RyR2.RESULTS Six patients demonstrated a marked increase in QT interval only in the first beat after cessation of ventricular pacing and/or extrastimulation. All 6 patients were found to have a heterozygous missense mutation (M4109R) in RyR2. Two of them, presenting with aborted SCD, also had a second missense mutation (I406T- RyR2). Four family members without RyR2 mutations did not display prominent postpacing QT changes.CONCLUSION M4109R- RyR2 is associated with a high incidence of SCD. The contribution of I406T to the clinical phenotype is unclear. In contrast to exercise testing, marked postpacing repolarization changes in a single beat accurately predicted carriers of M4109R- RyR2 in this family.

Global and Regional Ventricular Repolarization Study by Body Surface Potential Mapping in Patients with Left Bundle-Branch Block and Heart Failure Undergoing Cardiac Resynchronization Therapy

Background: The controversial effects promoted by cardiac resynchronization therapy (CRT) on the ventricular repolarization (VR) have motivated VR evaluation by body surface potential mapping (BSPM) in CRT patients. Methods: Fifty-two CRT patients, mean age 58.8 +/- 12.3 years, 31 male, LVEF 27.5 +/- 9.2, NYHA III-IV heart failure with QRS181.5 +/- 14.2 ms, underwent 87-lead BSPM in sinus rhythm (BASELINE) and biventricular pacing (BIV). Measurements of mean and corrected QT intervals and dispersion, mean and corrected T peak end intervals and their dispersion, and JT intervals characterized global and regional (RV, Intermediate, and LV regions) ventricular repolarization response. Results: Global QTm (P < 0.001) and QTcm (P < 0.05) were decreased in BIV; QTm was similar across regions in both modes (P = ns); QTcm values were lower in RV/LV than in Intermediate region in BASELINE and BIV (P < 0.001); only RV/Septum showed a significant difference (P < 0.01) in the BIV mode. QTD values both of BASELINE (P < 0.01) and BIV (P < 0.001) were greater in the Intermediate than in the LV region. CRT effect significantly reduced global/regional QTm and QTcm values. QTD was globally decreased in RV/LV (Intermediate: P = ns). BIV mode significantly reduced global T peak end mean and corrected intervals and their dispersion. JT values were not significant. Conclusions: Ventricular repolarization parameters QTm, QTcm, and QTD global/regional values, as assessed by BSPM, were reduced in patients under CRT with severe HF and LBBB. Greater recovery impairment in the Intermediate region was detected by the smaller variation of its dispersion.

Early repolarization, left ventricular diastolic function, and left atrial size in professional soccer players

Recent data have suggested a relation among long-term endurance sport practice, left atrial remodeling, and atrial fibrillation. We investigated the influence of an increased vagal tone, represented by the early repolarization (ER) pattern, on diastolic function and left atrial size in professional soccer players. Fifty-four consecutive athletes underwent electrocardiography, echocardiography, and exercise testing as part of their preparticipation screening. Athletes were divided into 2 groups according to presence or absence of an ER pattern, defined as a ST-segment elevation at the J-point (STE) > or =0.1 mm in 2 leads. For linear comparisons average STE was calculated. Mean age was 24 +/- 4 years. Twenty-five athletes (46%) showed an ER pattern. Athletes with an ER pattern had a significant lower heart rate (54 +/- 9 vs 62 +/- 11 beats/min, p = 0.024), an increased E/e' ratio (6.1 +/- 1.2 vs 5.1 +/- 1.0, p = 0.002), and larger volumes of the left atrium (25.6 +/- 7.3 vs 21.8 +/- 5.0 ml/m(2), p = 0.031) compared to athletes without an ER pattern. There were no significant differences concerning maximum workload, left ventricular dimensions, and systolic function. Univariate regression analysis revealed significant correlations among age, STE, and left atrial volume. In a stepwise multivariate regression analysis age, STE and e' contributed independently to left atrial size (r = 0.659, p <0.001). In conclusion, athletes with an ER pattern had an increased E/e' ratio, reflecting a higher left atrial filling pressure, contributing to left atrial remodeling over time.

Ajmaline attenuates electrocardiogram characteristics of inferolateral early repolarization

J waves are the hallmark of both inferolateral early repolarization (ER) and Brugada syndrome. While ajmaline, a class 1a antiarrhythmic drug, accentuates the J wave in Brugada syndrome, its effect on ER is unreported.

Role of electrophysiological studies in predicting risk of ventricular arrhythmia in early repolarization syndrome.

BACKGROUND The early repolarization (ER) pattern is associated with an increased risk of arrhythmogenic sudden death. However, strategies for risk stratification of patients with the ER pattern are not fully defined. OBJECTIVES This study sought to determine the role of electrophysiology studies (EPS) in risk stratification of patients with ER syndrome. METHODS In a multicenter study, 81 patients with ER syndrome (age 36 ± 13 years, 60 males) and aborted sudden death due to ventricular fibrillation (VF) were included. EPS were performed following the index VF episode using a standard protocol. Inducibility was defined by the provocation of sustained VF. Patients were followed up by serial implantable cardioverter-defibrillator interrogations. RESULTS Despite a recent history of aborted sudden death, VF was inducible in only 18 of 81 (22%) patients. During follow-up of 7.0 ± 4.9 years, 6 of 18 (33%) patients with inducible VF during EPS experienced VF recurrences, whereas 21 of 63 (33%) patients who were noninducible experienced recurrent VF (p = 0.93). VF storm occurred in 3 patients from the inducible VF group and in 4 patients in the noninducible group. VF inducibility was not associated with maximum J-wave amplitude (VF inducible vs. VF noninducible; 0.23 ± 0.11 mV vs. 0.21 ± 0.11 mV; p = 0.42) or J-wave distribution (inferior, odds ratio [OR]: 0.96 [95% confidence interval (CI): 0.33 to 2.81]; p = 0.95; lateral, OR: 1.57 [95% CI: 0.35 to 7.04]; p = 0.56; inferior and lateral, OR: 0.83 [95% CI: 0.27 to 2.55]; p = 0.74), which have previously been demonstrated to predict outcome in patients with an ER pattern. CONCLUSIONS Our findings indicate that current programmed stimulation protocols do not enhance risk stratification in ER syndrome.

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.