Robert L. Abraham

Cardiac Potassium Channel Dysfunction in Sudden Infant Death Syndrome

Life-threatening arrhythmias have been suspected as one cause of the sudden infant death syndrome (SIDS), and this hypothesis is supported by the observation that mutations in arrhythmia susceptibility genes occur in 5-10% of cases. However, the functional consequences of cardiac potassium channel gene mutations associated with SIDS and how these alleles might mechanistically predispose to sudden death are unknown. To address these questions, we studied four missense KCNH2 (encoding HERG) variants, one compound KCNH2 genotype, and a missense KCNQ1 mutation all previously identified in Norwegian SIDS cases. Three of the six variants exhibited functional impairments while three were biophysically similar to wild-type channels (KCNH2 variants V279M, R885C, and S1040G). When co-expressed with WT-HERG, R273Q and K897T/R954C generated currents resembling the rapid component of the cardiac delayed rectifier current (I(Kr)) but with significantly diminished amplitude. Action potential modeling demonstrated that this level of functional impairment was sufficient to evoke increased action potential duration and pause-dependent early afterdepolarizations. By contrast, KCNQ1-I274V causes a gain-of-function in I(Ks) characterized by increased current density, faster activation, and slower deactivation leading to accumulation of instantaneous current upon repeated stimulation. Action potential simulations using a Markov model of heterozygous I274V-I(Ks) incorporated into the Luo-Rudy (LRd) ventricular cell model demonstrated marked rate-dependent shortening of action potential duration predicting a short QT phenotype. Our results indicate that certain potassium channel mutations associated with SIDS confer overt functional defects consistent with either LQTS or SQTS, and further emphasize the role of congenital arrhythmia susceptibility in this syndrome.

Clonidine for the Treatment of Supine Hypertension and Pressure Natriuresis in Autonomic Failure

Patients with autonomic failure are disabled by orthostatic hypotension, which can be worsened by the nighttime pressure natriuresis induced by associated supine hypertension. Several pharmacological agents are available that effectively reduce nighttime hypertension, but none of them prevent pressure natriuresis. Because hypertension of autonomic failure can be driven by residual sympathetic tone, we hypothesized that clonidine would be effective in reducing blood pressure (BP) and nocturnal natriuresis. Therefore, we determined the effect of placebo, 0.1 mg clonidine, and 0.1-mg/h nitroglycerin transdermal patch on supine BP, orthostatic hypotension, and pressure natriuresis in 23 patients with primary autonomic failure and supine hypertension. Medications were given at 8:00 pm, and BP was recorded every 2 hours for 12 hours. The maximal decrease in BP was seen 6 to 8 hours after drug administration and was similar to clonidine and nitroglycerin (−29±9 and −30±10 mm Hg, respectively), as was the average fall in BP throughout the night. However, only clonidine effectively reduced nocturnal natriuresis (−0.09 mmol/mg Cr; 95% CI, −0.13 to −0.04; P=0.004), but this was not associated with improvement in morning orthostatic hypotension because of a residual hypotensive effect. The decrease in BP induced by clonidine was modestly but significantly correlated with the magnitude of residual sympathetic tone determined in 10 subjects by the fall in BP induced by ganglionic blockade (r=0.66; P=0.043). These results are consistent with residual sympathetic tone contributing to supine hypertension in autonomic failure, which can be targeted with clonidine to decrease BP and nocturnal natriuresis.

Role of Adenosine and Nitric Oxide on the Mechanisms of Action of Dipyridamole

Background and Purpose— The combination of dipyridamole and aspirin has been shown to be more effective than aspirin alone in the secondary prevention of stroke. Dipyridamole may act by inhibiting adenosine uptake, thus potentiating its actions. Dipyridamole also inhibits cGMP-specific phosphodiesterases (PDE) and, through this mechanism, could potentiate cGMP-mediated actions of nitric oxide. Methods— To define the mechanism of action of dipyridamole, we studied the local vascular effects of adenosine, acetylcholine (NO-mediated dilation), and nitroprusside (cGMP-mediated dilation) in a double-blind study after treatment with dipyridamole/aspirin (200 mg dipyridamole/25 mg aspirin twice a day) or aspirin control for 7 days in 6 normal volunteers. Vasodilators were administered into the brachial artery in the nondominant arm in random order and forearm blood flow (FBF) was measured by venous occlusion plethysmography. Results— Adenosine at a dosage of 125 &mgr;g/min increased FBF from 4.6±0.9 to 29.4±5.3 (539% increase) with dipyridamole/aspirin and from 3.9±0.8 to 12±2.5 mL/100 mL forearm/min (208% increase) with aspirin alone (P=0.007). In contrast, dipyridamole/aspirin did not alter the response to acetylcholine or to nitroprusside. The magnitude of adenosine-induced vasodilation correlated with plasma dipyridamole concentrations (r2=0.6); no correlation was observed with acetylcholine- or nitroprusside-induced vasodilation. Similar potentiation of adenosine, but not acetylcholine or nitroprusside, was observed in 7 additional subjects when adenosine, acetylcholine, and nitroprusside were given in random order before and 2 hours after a single dose of dipyridamole/aspirin. Conclusion— The effects of dipyridamole on resistance vessels are preferentially explained by potentiation of adenosine mechanisms rather than potentiation of nitric oxide or other cGMP-mediated actions.

Electrophysiologic Substrate in Congenital Long QT Syndrome Noninvasive Mapping With Electrocardiographic Imaging (ECGI)

Background— Congenital Long QT syndrome (LQTS) is an arrhythmogenic disorder that causes syncope and sudden death. Although its genetic basis has become well-understood, the mechanisms whereby mutations translate to arrhythmia susceptibility in the in situ human heart have not been fully defined. We used noninvasive ECG imaging to map the cardiac electrophysiological substrate and examine whether LQTS patients display regional heterogeneities in repolarization, a substrate that promotes arrhythmogenesis. Methods and Results— Twenty-five subjects (9 LQT1, 9 LQT2, 5 LQT3, and 2 LQT5) with genotype and phenotype positive LQTS underwent ECG imaging. Seven normal subjects provided control. Epicardial maps of activation, recovery times, activation-recovery intervals, and repolarization dispersion were constructed. Activation was normal in all patients. However, recovery times and activation–recovery intervals were prolonged relative to control, indicating delayed repolarization and abnormally long action potential duration (312±30 ms versus 235±21 ms in control). Activation–recovery interval prolongation was spatially heterogeneous, with repolarization gradients much steeper than control (119±19 ms/cm versus 2.0±2.0 ms/cm). There was variability in steepness and distribution of repolarization gradients between and within LQTS types. Repolarization gradients were steeper in symptomatic patients (130±27 ms/cm in 12 symptomatic patients versus 98±19 ms/cm in 13 asymptomatic patients; P <0.05). Conclusions— LQTS patients display regions with steep repolarization dispersion caused by localized action potential duration prolongation. This defines a substrate for reentrant arrhythmias, not detectable by surface ECG. Steeper dispersion in symptomatic patients suggests a possible role for ECG imaging in risk stratification. # CLINICAL PERSPECTIVE {#article-title-34}Background— Congenital Long QT syndrome (LQTS) is an arrhythmogenic disorder that causes syncope and sudden death. Although its genetic basis has become well-understood, the mechanisms whereby mutations translate to arrhythmia susceptibility in the in situ human heart have not been fully defined. We used noninvasive ECG imaging to map the cardiac electrophysiological substrate and examine whether LQTS patients display regional heterogeneities in repolarization, a substrate that promotes arrhythmogenesis. Methods and Results— Twenty-five subjects (9 LQT1, 9 LQT2, 5 LQT3, and 2 LQT5) with genotype and phenotype positive LQTS underwent ECG imaging. Seven normal subjects provided control. Epicardial maps of activation, recovery times, activation-recovery intervals, and repolarization dispersion were constructed. Activation was normal in all patients. However, recovery times and activation–recovery intervals were prolonged relative to control, indicating delayed repolarization and abnormally long action potential duration (312±30 ms versus 235±21 ms in control). Activation–recovery interval prolongation was spatially heterogeneous, with repolarization gradients much steeper than control (119±19 ms/cm versus 2.0±2.0 ms/cm). There was variability in steepness and distribution of repolarization gradients between and within LQTS types. Repolarization gradients were steeper in symptomatic patients (130±27 ms/cm in 12 symptomatic patients versus 98±19 ms/cm in 13 asymptomatic patients; P<0.05). Conclusions— LQTS patients display regions with steep repolarization dispersion caused by localized action potential duration prolongation. This defines a substrate for reentrant arrhythmias, not detectable by surface ECG. Steeper dispersion in symptomatic patients suggests a possible role for ECG imaging in risk stratification.

Refining repolarization reserve

A body of cellular and molecular studies over the past 15 years has demonstrated that the fundamental molecular lesion in the drug-induced long QT syndrome (LQTS) is block of the repolarizing potassium current IKr, the “rapid” component of the repolarizing potassium current that was initially termed IK.1,2 Further, decreased IKr due to KCNH2 mutations causes type 2 congenital LQTS, one of the commonest forms of this disease.3 Both the congenital and drug-associated form of LQTS present with QT interval prolongation and torsades de pointes, and a striking clinical feature in both is the highly variable nature of the phenotype: not every patient exposed to IKr-blockers develops QT prolongation, let alone exaggerated QT prolongation and arrhythmias, and not every patient with a loss-of-function mutation in KCNH2 displays QT interval prolongation. It was this clinical disconnect and the increasing recognition that normal repolarization represents a complex interaction among multiple components that led in the late 1990s to the formulation of the idea of “repolarization reserve.”4 Recognizing that repolarization is accomplished not just by IK and ICa but by IKr, IKs, ICa-L, ICa-T, INa-L, INCX, and so on, the concept suggests that a reduction in IKr might generate a huge effect in cells, or in patients, in whom other efficient repolarization mechanisms were absent. By contrast, the same reduction in IKr might produce little change in repolarization time in settings in which other mechanisms could readily accomplish normal repolarization. The idea seems appealing, since a PubMed search identifies 209 references to “repolarization reserve” and a Google Scholar search identifies “about 5,480” hits. The term may have acquired some currency because the idea makes intuitive sense to basic and clinical electrophysiologists or perhaps because it has a nice alliterative ring. However, just because it seems to sound good does not make it so, and experimental validation is a next step. One obvious possible contributor to variable repolarization reserve is variability in function of the slow component of repolarizing potassium current, IKs,4 generated in vivo by coexpression of the poreforming subunit encoded by KCNQ1 and the function-modifying subunit KCNE1. Indeed, initial computer simulations indicated that while reducing IKs produces minimal action potential prolongation, the extent to which IKr block prolongs action potentials is strikingly exaggerated when IKs is blocked.5–7 These simulations were then followed by experiments showing that variable IKs function could indeed play a role in modulating response to IKr block.8,9 In addition, modeling state transitions of the KCNQ1 channel underlying IKs revealed a critical role in maintaining normal repolarization (maximizing reserve) only when KCNQ1 was coexpressed with KCNE1; the coexpression allows the channels to rest in “preopen” states and thus contribute maximally to the maintenance of repolarization reserve.10 While these experimental and simulation data support the repolarization reserve concept and a role for IKs, they leave open many questions. What about calcium current or sodium-calcium exchange or late sodium current or inward rectifier current or other currents? How do function-modifying genetic variants (rare mutations or even common polymorphisms) affect the function of individual components of this complex system to modulate repolarization reserve? With modern electrophysiology and genetics, the possibilities become almost infinite, and thus experiments to address these possibilities seem increasingly daunting. In the present issue of Heart Rhythm, Sarkar and Sobie demonstrate how computational modeling of action potentials can be used to address this conundrum.11 They used the TNNP computational model12 of individual ion currents and other components (such as exchangers and intracellular calcium control mechanisms) to reconstruct cardiac action potentials in silico and then asked a simple question: by how much do action potentials prolong when IKr is 70% blocked? However, they did not set out to answer this question in one model but rather in hundreds of models, each one of which was generated by a random change in single-channel conductance, open-channel probability, or voltage dependence of activation or inactivation. That is, each simulation was conducted in an action potential with slightly different repolarization physiology. Gratifyingly enough (at least to those who might accept the concept of repolarization reserve), the extent to which 70% IKr block prolonged action potential varied across simulations. Because the experiment could be conducted in hundreds of different “background” myocyte physiologies, the dependence of action potential prolongation on the multiple characteristics of simulated ion currents and other components of repolarization reserve could be determined. Not surprisingly, the biggest influences on the drug response were the magnitudes of IKr and of IKs, in agreement with the earlier thoughts discussed above. On the other hand, some changes that clearly modulate the extent of action potential prolongation by IKr block are not readily predictable by intuitive approaches but are revealed by the computational simulation. One example is the dramatic effect imposed by a change in IKr gating that shifts the voltage dependence of inactivation in a positive direction: the implication would be that mutations producing such an effect might be silent at baseline but produce dramatic prolongation upon drug exposure. Similarly, increasing calcium channel conductance increased action potential duration (as would be predicted) but reduced the extent to which IKr block prolongs action potential duration. The modeling reveals that this blunted effect reflects a shift in the plateau potential, which thereby inhibits IKs inactivation, making more current available and thus increasing repolarization reserve. The cardiac action potential represents the integrated activity of dozens (or hundreds) of individual components, and simulating the behavior of these individual components can lead to modeled action potential behaviors. Such modeling, however, runs the risk of being merely a sterile exercise unless it informs further physiology or answers questions that are not addressable in any other reasonable fashion. The present study falls squarely into the latter category: the results simply could not have been obtained using conventional animal or even cellular models. The results are of interest themselves because they begin to provide a global quantitative framework for the intuitively appealing concept of repolarization reserve. Many questions remain unanswered, some of which are acknowledged in the paper: How dependent is this upon the specific model? What about individual cell layers in the heart? Are the results different with varying pacing rates, or pauses? What about different degrees of IKr block? Under what conditions does IKr block generate arrhythmias? These are not deficiencies in the present study but rather highlight the way in which computational modeling can go forward to address these issues and ultimately inform experimentalists on the optimal design of physiologic studies. Another clear application of this approach will be to further understand the way in which genetic variants in the individual components of this complex system influence its overall behavior. The present studies have focused on changes in action potential duration as a consequence of IKr block, but there are many other situations in which action potentials are prolonged and associated with arrhythmias: after myocardial infarction, in patients with diabetes, after cardioversion from atrial fibrillation, in heart failure, with subarachnoid hemorrhage, and so on. Understanding the fundamental physiological perturbations in these settings and then understanding how altered repolarization reserve in these settings can promote arrhythmias is another potential application of the present approach. Thus, the lessons that Sarkar and Sobie and others in the field will learn as modeling of this type becomes increasingly integrated into contemporary molecular electrophysiology and genomics should have widespread applicability to many other settings. More generally, they reinforce the idea that as we come to appreciate increasingly biologic complexity using buzzwords like pathways or systems biology, computational modeling will become increasingly indispensible to understand the predictable, and sometimes not so predictable, behaviors of these systems.

Risk factors for bradycardia requiring pacemaker implantation in patients with atrial fibrillation.

Symptomatic bradycardia may complicate atrial fibrillation (AF) and necessitate a permanent pacemaker. Identifying patients at increased risk for symptomatic bradycardia may reduce associated morbidities and health care costs. The aim of this study was to investigate predictors for developing bradycardia requiring a permanent pacemaker in patients with AF. The records of all patients treated for AF or atrial flutter in an academic hospitals emergency department from August 1, 2005, to July 31, 2008, were reviewed. Survival and the presence of a pacemaker as of November 1, 2011, were determined. Cases were defined as patients with pacemakers placed for bradycardia after their AF diagnoses. Patients without pacemakers who were followed constituted the control group. Variables for the logistic regression analysis were identified a priori. A post hoc model was fit adjusting for AF type and atrioventricular nodal blocker use. Of the 362 patients in the cohort, 119 cases had permanent pacemakers implanted for bradycardia after AF diagnosis, and 243 controls were alive without pacemakers. The median follow-up time was 4.5 years (interquartile range 3.8 to 5.4). Odds ratios were determined for age at the time of AF diagnosis (1.02, 95% confidence interval [CI] 1 to 1.04), female gender (1.58, 95% CI 0.95 to 2.63), previous heart failure (2.72, 95% CI 1.47 to 5.01), and African American race (0.33, 95% CI 0.12 to 0.94). The post hoc model identified permanent AF (odds ratio 2.99, 95% CI 1.61 to 5.57) and atrioventricular nodal blocker use (odds ratio 1.43, 95% CI 0.85 to 2.4). In conclusion, in patients with AF, heart failure and permanent AF each nearly triple the odds of developing bradycardia requiring a permanent pacemaker; although not statistically significant, our results suggest that women are more likely and African Americans less likely to develop bradycardia requiring pacemaker implantation.

The AFFORD Clinical Decision Aid to Identify Emergency Department Patients With Atrial Fibrillation at Low Risk for 30-Day Adverse Events

There is wide variation in the management of patients with atrial fibrillation (AF) in the emergency department (ED). We aimed to derive and internally validate the first prospective, ED-based clinical decision aid to identify patients with AF at low risk for 30-day adverse events. We performed a prospective cohort study at a university-affiliated tertiary-care ED. Patients were enrolled from June 9, 2010, to February 28, 2013, and followed for 30 days. We enrolled a convenience sample of patients in ED presenting with symptomatic AF. Candidate predictors were based on ED data available in the first 2 hours. The decision aid was derived using model approximation (preconditioning) followed by strong bootstrap internal validation. We used an ordinal outcome hierarchy defined as the incidence of the most severe adverse event within 30 days of the ED evaluation. Of 497 patients enrolled, stroke and AF-related death occurred in 13 (3%) and 4 (<1%) patients, respectively. The decision aid included the following: age, triage vitals (systolic blood pressure, temperature, respiratory rate, oxygen saturation, supplemental oxygen requirement), medical history (heart failure, home sotalol use, previous percutaneous coronary intervention, electrical cardioversion, cardiac ablation, frequency of AF symptoms), and ED data (2 hours heart rate, chest radiograph results, hemoglobin, creatinine, and brain natriuretic peptide). The decision aids c-statistic in predicting any 30-day adverse event was 0.7 (95% confidence interval 0.65, 0.76). In conclusion, in patients with AF in the ED, Atrial Fibrillation and Flutter Outcome Risk Determination provides the first evidence-based decision aid for identifying patients who are at low risk for 30-day adverse events and candidates for safe discharge.

Repolarization recipes for atrial fibrillation: beyond single channel variants.

Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, represents a major health burden to people and health care systems within the Western world ([1][1]). Given its increasing prevalence with age, coupled with the aging population, the number of Americans affected is expected to

Electrophysiologic Substrate in Congenital Long QT SyndromeCLINICAL PERSPECTIVE

Background— Congenital Long QT syndrome (LQTS) is an arrhythmogenic disorder that causes syncope and sudden death. Although its genetic basis has become well-understood, the mechanisms whereby mutations translate to arrhythmia susceptibility in the in situ human heart have not been fully defined. We used noninvasive ECG imaging to map the cardiac electrophysiological substrate and examine whether LQTS patients display regional heterogeneities in repolarization, a substrate that promotes arrhythmogenesis. Methods and Results— Twenty-five subjects (9 LQT1, 9 LQT2, 5 LQT3, and 2 LQT5) with genotype and phenotype positive LQTS underwent ECG imaging. Seven normal subjects provided control. Epicardial maps of activation, recovery times, activation-recovery intervals, and repolarization dispersion were constructed. Activation was normal in all patients. However, recovery times and activation–recovery intervals were prolonged relative to control, indicating delayed repolarization and abnormally long action potential duration (312±30 ms versus 235±21 ms in control). Activation–recovery interval prolongation was spatially heterogeneous, with repolarization gradients much steeper than control (119±19 ms/cm versus 2.0±2.0 ms/cm). There was variability in steepness and distribution of repolarization gradients between and within LQTS types. Repolarization gradients were steeper in symptomatic patients (130±27 ms/cm in 12 symptomatic patients versus 98±19 ms/cm in 13 asymptomatic patients; P <0.05). Conclusions— LQTS patients display regions with steep repolarization dispersion caused by localized action potential duration prolongation. This defines a substrate for reentrant arrhythmias, not detectable by surface ECG. Steeper dispersion in symptomatic patients suggests a possible role for ECG imaging in risk stratification. # CLINICAL PERSPECTIVE {#article-title-34}Background— Congenital Long QT syndrome (LQTS) is an arrhythmogenic disorder that causes syncope and sudden death. Although its genetic basis has become well-understood, the mechanisms whereby mutations translate to arrhythmia susceptibility in the in situ human heart have not been fully defined. We used noninvasive ECG imaging to map the cardiac electrophysiological substrate and examine whether LQTS patients display regional heterogeneities in repolarization, a substrate that promotes arrhythmogenesis. Methods and Results— Twenty-five subjects (9 LQT1, 9 LQT2, 5 LQT3, and 2 LQT5) with genotype and phenotype positive LQTS underwent ECG imaging. Seven normal subjects provided control. Epicardial maps of activation, recovery times, activation-recovery intervals, and repolarization dispersion were constructed. Activation was normal in all patients. However, recovery times and activation–recovery intervals were prolonged relative to control, indicating delayed repolarization and abnormally long action potential duration (312±30 ms versus 235±21 ms in control). Activation–recovery interval prolongation was spatially heterogeneous, with repolarization gradients much steeper than control (119±19 ms/cm versus 2.0±2.0 ms/cm). There was variability in steepness and distribution of repolarization gradients between and within LQTS types. Repolarization gradients were steeper in symptomatic patients (130±27 ms/cm in 12 symptomatic patients versus 98±19 ms/cm in 13 asymptomatic patients; P<0.05). Conclusions— LQTS patients display regions with steep repolarization dispersion caused by localized action potential duration prolongation. This defines a substrate for reentrant arrhythmias, not detectable by surface ECG. Steeper dispersion in symptomatic patients suggests a possible role for ECG imaging in risk stratification.

Electrophysiologic Substrate in Congenital Long QT SyndromeCLINICAL PERSPECTIVE: Noninvasive Mapping With Electrocardiographic Imaging (ECGI)

Background— Congenital Long QT syndrome (LQTS) is an arrhythmogenic disorder that causes syncope and sudden death. Although its genetic basis has become well-understood, the mechanisms whereby mutations translate to arrhythmia susceptibility in the in situ human heart have not been fully defined. We used noninvasive ECG imaging to map the cardiac electrophysiological substrate and examine whether LQTS patients display regional heterogeneities in repolarization, a substrate that promotes arrhythmogenesis. Methods and Results— Twenty-five subjects (9 LQT1, 9 LQT2, 5 LQT3, and 2 LQT5) with genotype and phenotype positive LQTS underwent ECG imaging. Seven normal subjects provided control. Epicardial maps of activation, recovery times, activation-recovery intervals, and repolarization dispersion were constructed. Activation was normal in all patients. However, recovery times and activation–recovery intervals were prolonged relative to control, indicating delayed repolarization and abnormally long action potential duration (312±30 ms versus 235±21 ms in control). Activation–recovery interval prolongation was spatially heterogeneous, with repolarization gradients much steeper than control (119±19 ms/cm versus 2.0±2.0 ms/cm). There was variability in steepness and distribution of repolarization gradients between and within LQTS types. Repolarization gradients were steeper in symptomatic patients (130±27 ms/cm in 12 symptomatic patients versus 98±19 ms/cm in 13 asymptomatic patients; P <0.05). Conclusions— LQTS patients display regions with steep repolarization dispersion caused by localized action potential duration prolongation. This defines a substrate for reentrant arrhythmias, not detectable by surface ECG. Steeper dispersion in symptomatic patients suggests a possible role for ECG imaging in risk stratification. # CLINICAL PERSPECTIVE {#article-title-34}Background— Congenital Long QT syndrome (LQTS) is an arrhythmogenic disorder that causes syncope and sudden death. Although its genetic basis has become well-understood, the mechanisms whereby mutations translate to arrhythmia susceptibility in the in situ human heart have not been fully defined. We used noninvasive ECG imaging to map the cardiac electrophysiological substrate and examine whether LQTS patients display regional heterogeneities in repolarization, a substrate that promotes arrhythmogenesis. Methods and Results— Twenty-five subjects (9 LQT1, 9 LQT2, 5 LQT3, and 2 LQT5) with genotype and phenotype positive LQTS underwent ECG imaging. Seven normal subjects provided control. Epicardial maps of activation, recovery times, activation-recovery intervals, and repolarization dispersion were constructed. Activation was normal in all patients. However, recovery times and activation–recovery intervals were prolonged relative to control, indicating delayed repolarization and abnormally long action potential duration (312±30 ms versus 235±21 ms in control). Activation–recovery interval prolongation was spatially heterogeneous, with repolarization gradients much steeper than control (119±19 ms/cm versus 2.0±2.0 ms/cm). There was variability in steepness and distribution of repolarization gradients between and within LQTS types. Repolarization gradients were steeper in symptomatic patients (130±27 ms/cm in 12 symptomatic patients versus 98±19 ms/cm in 13 asymptomatic patients; P<0.05). Conclusions— LQTS patients display regions with steep repolarization dispersion caused by localized action potential duration prolongation. This defines a substrate for reentrant arrhythmias, not detectable by surface ECG. Steeper dispersion in symptomatic patients suggests a possible role for ECG imaging in risk stratification.