Showing papers in "Circulation-arrhythmia and Electrophysiology in 2008"

Atrial remodeling and atrial fibrillation: mechanisms and implications.

Abstract: Atrial fibrillation (AF) is the most common arrhythmia in clinical practice It can occur at any age but is very rare in children and becomes extremely common in the elderly, with a prevalence approaching 20% in patients >85 years of age1 AF is associated with a wide range of potential complications and contributes significantly to population morbidity and mortality Present therapeutic approaches to AF have major limitations, including limited efficacy and significant adverse effect liability These limitations have inspired substantial efforts to improve our understanding of the mechanisms underlying AF, with the premise that improved mechanistic insights will lead to innovative and improved therapeutic approaches2 Our understanding of AF pathophysiology has advanced significantly over the past 10 to 15 years through an increased awareness of the role of “atrial remodeling” Any persistent change in atrial structure or function constitutes atrial remodeling Many forms of atrial remodeling promote the occurrence or maintenance of AF by acting on the fundamental arrhythmia mechanisms illustrated in Figure 1 Both rapid ectopic firing and reentry can maintain AF Reentry requires a suitable vulnerable substrate, as well as a trigger that acts on the substrate to initiate reentry Ectopic firing contributes to reentry by providing triggers for reentry induction Atrial remodeling has the potential to increase the likelihood of ectopic or reentrant activity through a multitude of potential mechanisms This article reviews the types of atrial remodeling, their underlying pathophysiology, the molecular basis of their occurrence, and finally, their potential therapeutic significance Figure 1 General schema representing AF mechanisms and the role of remodeling The mechanisms underlying AF are portrayed schematically in Figure 2 AF can be maintained by rapid focal firing, which may itself be regular but result in fibrillatory activity because of wave breakup in portions of the atrium that …

Novel Contact Force Sensor Incorporated in Irrigated Radiofrequency Ablation Catheter Predicts Lesion Size and Incidence of Steam Pop and Thrombus

Abstract: Background— An open-irrigated radiofrequency (RF) ablation catheter was developed to measure contact force (CF). Three optical fibers measure microdeformation of the catheter tip. The purpose of this study was to (1) validate the accuracy of CF sensor (CFS) (bench test); and (2) determine the relationship between CF and tissue temperatures, lesion size, steam pop, and thrombus during RF ablation using a canine thigh muscle preparation. Methods and Results— CFS measurements (total 1409) from 2 catheters in 3 angles (perpendicular, parallel, and 45°) were compared with a certified balance (range, 0 to 50 g). CFS measurements correlated highly ( R 2≥0.988; mean error, ≤1.0 g). In 10 anesthetized dogs, a skin cradle over the thigh muscle was superfused with heparinized blood at 37°C. A 7F catheter with 3.5-mm saline-irrigated electrode and CFS (Endosense) was held perpendicular to the muscle at CF of 2, 10, 20, 30, and 40 g. RF was delivered (n=100) for 60 seconds at 30 or 50 W (irrigation 17 or 30 mL/min). Tissue temperature (3 and 7 mm depths), lesion size, thrombus, and steam pop increased significantly with increasing CF at each RF power. Lesion size was greater with applications of lower power (30 W) and greater CF (30 to 40 g) than at high power (50 W) with lower CF (2 to 10 g). Conclusions— This novel ablation catheter, which accurately measures CF, confirmed CF is a major determinant of RF lesion size. Steam pop and thrombus incidence also increases with CF. CFS in an open-irrigated ablation catheter that may optimize the selection of RF power and application time to maximize lesion formation and reduce the risk of steam pop and thrombus. Received July 10, 2008; accepted October 6, 2008. # CLINICAL PERSPECTIVE {#article-title-2}

Fragmented Wide QRS on a 12-Lead ECG: A Sign of Myocardial Scar and Poor Prognosis

Abstract: Background— Fragmented QRS (duration <120 ms) on a 12-lead ECG represents myocardial scar in patients with coronary artery disease. However, the significance of fragmented QRS has not been defined in the presence of a wide QRS (wQRS; duration ≥120 ms). We postulate that fragmented wQRS (f-wQRS) due to bundle branch block, premature ventricular complexes, or paced rhythms (f-pQRS) signify myocardial scar and higher mortality. Methods and Results— Patients who underwent cardiac evaluation with nuclear stress imaging or cardiac catheterization and had wQRS (bundle branch block, premature ventricular complex, or pQRS) were studied. f-wQRS was defined by the presence of >2 notches on the R wave or the S wave and had to be present in ≥2 contiguous inferior (II, III, aVF), lateral (I, aVL, V6) or anterior (V1 to V5) leads. ECG analyses of 879 patients (age, 66.7±11.4 years; male, 97%; mean follow-up, 29±18 months) with bundle branch block (n=310), premature ventricular complex (n=301), and pQRS (n=268) revealed f-wQRS in 415 (47.2%) patients. Myocardial scar was present in 440 (50%) patients. The sensitivity, specificity, positive predictive value, and negative predictive value of f-wQRS for myocardial scar were 86.8%, 92.5%, 92.0%, and 87.5%, respectively. The sensitivity and specificity for diagnosing myocardial scar were 88.6% and 94.4%, 81.4% and 88.4%, and 89.8% and 95.7% for f-bundle branch block, f-premature ventricular complex, and f-pQRS, respectively. f-wQRS was associated with mortality after adjusting for age, ejection fraction, and diabetes ( P =0.017). Conclusions— f-wQRS on a standard 12-lead ECG is a moderately sensitive and highly specific sign for myocardial scar in patients with known or suspected coronary artery disease. f-wQRS is also an independent predictor of mortality. Received January 3, 2008; accepted July 2, 2008.

Functional effects of KCNE3 mutation and its role in the development of Brugada syndrome.

Abstract: Background— The Brugada syndrome, an inherited syndrome associated with a high incidence of sudden cardiac arrest, has been linked to mutations in 4 different genes, leading to a loss of function in sodium and calcium channel activity. Although the transient outward current ( I to) is thought to play a prominent role in the expression of the syndrome, mutations in I to-related genes have not been identified as yet. Methods and Results— One hundred five probands with the Brugada syndrome were screened for ion channel gene mutations using single-strand conformation polymorphism electrophoresis and direct sequencing. A missense mutation (R99H) in KCNE3 ( MiRP2 ) was detected in 1 proband. The R99H mutation was found 4/4 phenotype-positive and 0/3 phenotype-negative family members. Chinese hamster ovary-K1 cells were cotransfected using wild-type (WT) or mutant KCNE3 and either WT KCND3 or KCNQ1. Whole-cell patch clamp studies were performed after 48 hours. Interactions between Kv4.3 and KCNE3 were analyzed in coimmunoprecipitation experiments in human atrial samples. Cotransfection of R99H- KCNE3 with KCNQ1 produced no alteration in tail current magnitude or kinetics. However, cotransfection of R99H KCNE3 with KCND3 resulted in a significant increase in the I to intensity compared with WT KCNE3 +KCND3. Using tissues isolated from the left atrial appendages of human hearts, we also demonstrate that K v 4.3 and KCNE3 can be coimmunoprecipitated. Conclusions— These results provide definitive evidence for a functional role of KCNE3 in the modulation of I to in the human heart and suggest that mutations in KCNE3 can underlie the development of the Brugada syndrome. Received October 24, 2007; accepted May 5, 2008.

Calcium-Handling Abnormalities Underlying Atrial Arrhythmogenesis and Contractile Dysfunction in Dogs With Congestive Heart Failure

Abstract: Background— Congestive heart failure (CHF) is a common cause of atrial fibrillation. Focal sources of unknown mechanism have been described in CHF-related atrial fibrillation. The authors hypothesized that abnormal calcium (Ca2+) handling contributes to the CHF-related atrial arrhythmogenic substrate. Methods and Results— CHF was induced in dogs by ventricular tachypacing (240 bpm ×2 weeks). Cellular Ca2+-handling properties and expression/phosphorylation status of key Ca2+ handling and myofilament proteins were assessed in control and CHF atria. CHF decreased cell shortening but increased left atrial diastolic intracellular Ca2+ concentration ([Ca2+]i), [Ca2+]i transient amplitude, and sarcoplasmic reticulum (SR) Ca2+ load (caffeine-induced [Ca2+]i release). SR Ca2+ overload was associated with spontaneous Ca2+ transient events and triggered ectopic activity, which was suppressed by the inhibition of SR Ca2+ release (ryanodine) or Na+/Ca2+ exchange. Mechanisms underlying abnormal SR Ca2+ handling were then studied. CHF increased atrial action potential duration and action potential voltage clamp showed that CHF-like action potentials enhance Ca2+i loading. CHF increased calmodulin-dependent protein kinase II phosphorylation of phospholamban by 120%, potentially enhancing SR Ca2+ uptake by reducing phospholamban inhibition of SR Ca2+ ATPase, but it did not affect phosphorylation of SR Ca2+-release channels (RyR2). Total RyR2 and calsequestrin (main SR Ca2+-binding protein) expression were significantly reduced, by 65% and 15%, potentially contributing to SR dysfunction. CHF decreased expression of total and protein kinase A–phosphorylated myosin-binding protein C (a key contractile filament regulator) by 27% and 74%, potentially accounting for decreased contractility despite increased Ca2+ transients. Complex phosphorylation changes were explained by enhanced calmodulin-dependent protein kinase IIδ expression and function and type-1 protein-phosphatase activity but downregulated regulatory protein kinase A subunits. Conclusions— CHF causes profound changes in Ca2+-handling and -regulatory proteins that produce atrial fibrillation–promoting atrial cardiomyocyte Ca2+-handling abnormalities, arrhythmogenic triggered activity, and contractile dysfunction. Received November 22, 2007; accepted February 29, 2008. # CLINICAL PERSPECTIVE {#article-title-2}

Sudden Death and Defibrillators in Transposition of the Great Arteries with Intra-atrial Baffles: A Multicenter Study

Abstract: Background— Transposition of the great arteries with intra-atrial baffle repair is among the congenital heart defects at highest risk of sudden death. Little is known about mechanisms of sudden death and the role of implantable cardioverter defibrillators. Methods and Results— We conducted a multicenter cohort study in patients with transposition of the great arteries to determine actuarial rates of implantable cardioverter defibrillator shocks, identify risk factors, assess underlying arrhythmias, and characterize complications. Overall, 37 patients (age, 28.0±7.6 years; 89.2% male) were enrolled from 7 sites. Implantable cardioverter defibrillators were implanted for primary prevention in 23 (62.1%) patients and secondary prevention in 14 patients (37.8%). Annual rates of appropriate shocks were 0.5% and 6.0% in primary and secondary prevention, respectively ( P =0.0366). Independent predictors were a secondary prevention indication (hazard ratio, 18.0; P =0.0341) and lack of β-blockers (hazard ratio, 16.7; P =0.0301). In patients with appropriate shocks, intracardiac electrograms documented supraventricular tachycardia preceding or coexisting with ventricular tachycardia in 50%. No patient with inducible ventricular tachycardia received an appropriate shock in comparison with 37.5% of noninducible patients ( P =0.0429). Inappropriate shocks occurred in 6.6% per year, more so in patients of lesser weight (hazard ratio, 0.91 per kg; P =0.0168). Additionally, 14 patients (37.8%) experienced complications: 5 (13.5%) acute, 1 (2.7%) late generator related, and 12 (32.4%) late lead related. Conclusion— In patients with transposition of the great arteries, high rates of appropriate shocks are noted in secondary but not primary prevention. Supraventricular arrhythmias may be implicated in the etiology of ventricular tachyarrhythmias; β-blockers seem protective, and inducible ventricular tachycardia does not seem to predict future events. Inappropriate shocks and late lead-related complications are common. Received February 26, 2008; accepted July 23, 2008.

Long-term clinical results of 2 different ablation strategies in patients with paroxysmal and persistent atrial fibrillation.

Abstract: Background— Data regarding the long-term efficacy of atrial fibrillation (AF) ablation are still lacking. Methods and Results— Two hundred four consecutive patients symptomatic for paroxysmal or persistent/permanent AF were randomly assigned to 2 different ablation schemes: pulmonary vein isolation (PVI) and PVI plus left linear lesions (LL). Primary end point was to assess the maintenance of sinus rhythm (SR) after procedures 1 and 2 in the absence of antiarrhythmic drugs in a long-term follow-up of at least 3 years. Paroxysmal AF— With a single procedure at 12-month follow-up, 46% of patients treated with PVI maintained SR, whereas at 3-year follow-up, 29% were in SR; using the “PVI plus LL” at the 12-month follow-up, 57% of patients were in SR, whereas at the 3-year follow-up, 53% remained in SR. After a second procedure, the long-term overall success rate without antiarrhythmic drugs was 62% with PVI and 85% with PVI plus LL. Persistent/Permanent AF— With a single procedure at the 12-month follow-up, 27% of patients treated with PVI were in SR, whereas at the 3-year follow-up, 19% maintained SR; using the PVI plus LL with a single procedure at the 12-month follow-up 45% of patients were in SR, whereas at the 3-year follow-up, 41% remained in SR. After a second procedure, the long-term overall success rate without antiarrhythmic drugs was 39% with PVI and 75% with PVI plus LL. Conclusions— A long-term follow-up of AF ablation shows that short-term results cannot be considered permanent because AF recurrences are still present after the first year especially in patients who have had “PVI” strategy. PVI isolation plus LL is superior to the PVI strategy in maintaining SR without antiarrhythmic drugs after procedures 1 and 2 both in paroxysmal and persistent AF. Received February 25, 2008; accepted August 11, 2008.

Ventricular Tachycardia Originating From the Posterior Papillary Muscle in the Left Ventricle A Distinct Clinical Syndrome

Abstract: Background Several distinct forms of focal ventricular tachycardia (VT) from the left ventricle (LV) have been described. We report a new syndrome of VT arising from the base of the posterior papillary muscle in the LV. Methods and results Among 290 consecutive patients who underwent ablation for VT or symptomatic premature ventricular complexes (PVCs) based on a focal mechanism, 7 patients were found to have an ablation site at the base of the posterior papillary muscle in the LV. All patients had normal LV systolic function and a normal baseline electrocardiogram. The electrocardiogram during VT or PVCs demonstrated a right bundle-branch block and superior-axis QRS morphology in all patients. VT was not inducible by programmed atrial or ventricular stimulation. In 2 patients with sustained VT, overdrive pacing neither terminated VT nor demonstrated any criterion for transient entrainment. Activation mapping localized the earliest site of activation to the base of the posterior papillary muscle in all patients. When Purkinje potentials were recorded at the site of successful ablation, these potentials preceded local ventricular muscle potentials during sinus rhythm. During VT or PVCs, however, the ventricular muscle potential always preceded the Purkinje potentials. After recurrence of VT or PVCs with standard radiofrequency ablation, irrigated ablation was successful in eliminating the arrhythmia in all patients. Over a mean follow-up period of 9 months, all patients have been free of PVCs and VT. Conclusions We present a distinct syndrome of VT arising from the base of the posterior papillary muscle in the LV by a nonreentrant mechanism. Ablation can be challenging, and irrigated ablation may be necessary for long-term success.

Esophageal Injury and Temperature Monitoring During Atrial Fibrillation Ablation

Abstract: Background —It is common practice to empirically limit the radiofrequency (RF) power when ablating the posterior left atrium (LA) during atrial fibrillation (AF) ablation to avoid thermal injury to the esophagus. The objective of this study was to determine whether RF energy delivery limited by luminal esophageal temperature (LET) monitoring is associated with a reduction in esophageal injury compared to a strategy of RF power limitation alone. Methods and Results —Eighty-one consecutive patients undergoing AF ablation followed by esophageal endoscopy (EGD) were included in this observational study. All patients underwent extra-ostial electrical PV isolation using an electro-anatomical mapping system and irrigated RF ablation. All RF applications on the posterior LA were limited to 35 Watts. A commercially available, single-thermocouple esophageal probe was used to monitor LET in a subset of patients (n=67). In these cases, applications were promptly interrupted when LET was ≥38.5°C; further applications were performed at reduced power to obtain a LET <38.5°C. EGD was performed 1-3 days post-procedure. Ablation-related esophageal ulcerations were identified in 9/81 (11%) patients. All patients were asymptomatic. Of these 81 patients, LET monitoring during ablation occurred in 67 (83%) of patients. Esophageal injury was observed more frequently (36% vs. 6%, p< 0.006) in the group without LET monitoring. Conclusions —These data suggest that LET monitoring may be associated with a reduction in esophageal injury compared to power limitation alone.

Atrial Fibrillation Begets Atrial Fibrillation: Autonomic Mechanism for Atrial Electrical Remodeling Induced by Short-term Rapid Atrial Pacing

Abstract: Background— The mechanism(s) for acute changes in electrophysiological properties of the atria during rapid pacing induced atrial fibrillation (AF) is not completely understood. We sought to evaluate the contribution of the intrinsic cardiac autonomic nervous system in acute atrial electrical remodeling and AF induced by 6-hour rapid atrial pacing. Methods and Results— Continuous rapid pacing (1200 bpm, 2× threshold [TH]) was performed at the left atrial appendage. Group 1 (n=7) underwent 6-hour pacing immediately followed by ganglionated plexi (GP) ablation; group 2 (n=7) underwent GP ablation immediately followed by 6-hour pacing; and group 3 (n=4) underwent administration of autonomic blockers, atropine (1 mg/kg), and propranolol (0.6 mg/kg) immediately followed by 6-hour pacing. The effective refractory period (ERP) and window of vulnerability (WOV, in milliseconds), ie, the difference between the longest and the shortest coupling interval of the premature stimulus that induced AF, were measured at 2×TH and 10×TH at the left atrium, right atrium, and pulmonary veins every hour before and after GP ablation or autonomic blockade. In group 1, ERP was markedly shortened in the first 2 hours and then stabilized both at 2×TH and 10×TH; however, WOV was progressively widened throughout the 6-hour period. After GP ablation, ERP was significantly longer than before ablation and AF could not be induced (WOV=0) at either 2×TH or 10×TH. In groups 2 and 3, rapid atrial pacing failed to shorten the ERP. AF could not be induced in 6 of 7 dogs in group 2 and all 4 dogs in group 3 during the 6-hour pacing period. Conclusion— The intrinsic cardiac autonomic nervous system plays a crucial role in the acute stages of atrial electrical remodeling induced by rapid atrial pacing. Received April 3, 2008; accepted June 16, 2008.

Ventricular tachycardia ablation: evolution of patients and procedures over 8 years.

Abstract: Background— Evolving management of coronary artery disease, heart failure, and the use of implantable cardioverter-defibrillators impacts the characteristics of patients with recurrent ventricular tachycardia (VT). We investigated the substrate, procedure, and outcome evolution of all patients referred for VT ablation during the past 8 years. Methods and Results— From 1999 to 2006, 493 consecutive patients (358 male, 57±16 years) underwent 623 VT ablations: 131 had no structural heart disease (SHD), 213 had ischemic cardiomyopathies (ICMP), and 149 had nonischemic cardiomyopathies (NICMP). Although the main substrate is ICMP, the proportion of NICMP has increased from 27% to 35% ( P =0.06) from 1999–2002 to the 2003–2006. The procedure abolished or modified inducible VTs in ≥75% of patients in all groups, but abolition of all monomorphic VTs was achieved in 125 (83%) patients without SHD, 180 (65%) with ICMP, and 99 (51%) with NICMP ( P <0.0001). During a mean follow-up of 3.3±2.4 years, no deaths occurred in patients without SHD, but 75 patients (35%) with ICMP and 26 patients (17%) with NICMP died after a median of 13 months. Multivariate Cox regression analysis found that age, ejection fraction, and need for preprocedural mechanical hemodynamic support predicted mortality. Conclusions— The substrate causing VT in patients requiring ablation is evolving and determines the long-term outcome. In the setting of a normal heart, VT ablation is associated with a low risk of subsequent mortality, with no deaths occurring during a mean follow-up of >3 years. In contrast, in patients with SHD and recurrent VT, VT ablation can be helpful to suppress drug refractory VT, but long-term mortality remains significant. Received January 28, 2008; accepted May 1, 2008.

Chronic atrial fibrillation is a biatrial arrhythmia: data from catheter ablation of chronic atrial fibrillation aiming arrhythmia termination using a sequential ablation approach.

Abstract: Background— Termination of chronic atrial fibrillation (CAF) can be achieved by catheter ablation using a stepwise approach. However, there are limited data on the contribution of the right atrium to the CAF process. Furthermore, the prognostic value of CAF termination remains unclear. Methods and Results— Eighty-eight patients (61±10 years of age) underwent de novo ablation of CAF in 2006 at our institution. The ablation procedure was performed sequentially in the following order: pulmonary vein isolation, defragmentation of the left atrium, coronary sinus, and right atrium. Attempted procedural end point was termination of CAF. Consecutive arrhythmias occurring after AF termination were mapped, and ablation was attempted. AF termination was achieved in 68 (77%) patients: in 37 (55%) patients it occurred in the left atrium, in 18 (26%) patients in the right atrium, and in 13 (19%) patients in the coronary sinus. In 54 patients, at least one redo was performed (total number of procedures: 154). After the first redo, another 30 patients were in sinus rhythm (total 63), 8 patients were in atrial tachycardia (AT), and 17 patients were in AF. Another 11 patients underwent a second redo. After a mean follow-up of 20±4 months, 71 (81%) patients were in sinus rhythm, 1 (1%) patient was in AT, and 16 (18%) patients were in AF. Patients with CAF termination had predominantly ATs as recurrent arrhythmias (83%), whereas those without mainly presented with recurrent CAF (85%). The overall success rate in patients with CAF termination was 95% compared with 5% of patients without CAF termination in 2 procedures (n=12). In almost all redo procedures attributable to AT, at least 1 AT during redo was documented previously. Conclusions— AF termination is a prognostic important end point of catheter ablation for CAF. Termination of AF was achieved in both atria and the coronary sinus, suggesting a biatrial substrate of CAF. Subsequent arrhythmias often recur during follow-up and, therefore, should be targeted for ablation. Received February 11, 2008; accepted September 15, 2008. # CLINICAL PERSPECTIVE {#article-title-2}

The left ventricular ostium: an anatomic concept relevant to idiopathic ventricular arrhythmias.

Abstract: Received June 17, 2008; accepted September 4, 2008. Idiopathic ventricular arrhythmias (VAs) arising from the left ventricle (LV) are often accessible for catheter ablation from the aortic sinuses of Valsalva or adjacent to the mitral annulus (MA).1 The aortic and mitral valves are direct apposition and attach to an elliptical opening at the base of the LV known as the LV ostium.2 The VAs arising from this region are being increasingly recognized as targets for catheter ablation.3–7 This review describes the anatomic features of the LV ostium and the electrocardiographic, electrophysiological, and angiographic characteristics that are relevant to the mapping and ablation of these arrhythmias. The dominant central structure of the heart is the junction of the aorta with the LV. Fundamental for understanding idiopathic VAs arising near the aortic and mitral valves are 2 concepts: first, these arrhythmias arise from the LV ostium (Figure 1); and second, the LV ostium is covered by the aorto-ventricular membrane, a tough fibrous structure which is perforated by the aorta anteriorly and the mitral valve (MV) posteriorly (Figure 2). The anatomic concept of the LV ostium and its covering, the aorto-ventricular membrane, are based on the pioneering work of McAlpine.2 Figure 1. The left ventricular ostium (postero-cranial view). The left panel includes the aortic root with the right coronary sinus (R), left coronary sinus (L), and noncoronary sinus (N). In the right panel, the root of the aorta has been removed to demonstrate the elliptical ostium of the left ventricle (LV) with the junction of the right coronary cusp (RCC), left coronary cusp (LCC), and LV summit demonstrated. APM indicates anterior papillary muscle; LA, left atrium; LAFT, left anterior fibrous trigone; LFT, left fibrous trigone; L-RCC, the junction between the LCC and RCC; PPM, posterior papillary muscle; PSP, postero-superior …

Slow and discontinuous conduction conspire in Brugada syndrome: a right ventricular mapping and stimulation study.

Abstract: Background— Brugada syndrome (BrS) is associated with lethal arrhythmias, which are linked to specific ST-segment changes (type-1 BrS-ECG) and the right ventricle (RV). The pathophysiological basis of the arrhythmias and type-1 BrS-ECG is unresolved. We studied the electrophysiological characteristics of the RV endocardium in BrS. Methods and Results— RV endocardial electroanatomical mapping and stimulation studies were performed in controls (n=12) and BrS patients with a type-1 (BrS-1, n=10) or type-2 BrS-ECG (BrS-2, n=12) during the studies. BrS-1 patients had prominent impairment of RV endocardial impulse propagation when compared with controls, as represented by: (1) prolonged activation-duration during sinus rhythm (86±4 versus 65±3 ms), (2) increased electrogram fractionation (1.36±0.04 versus 1.15±0.01 deflections per electrogram), (3) longer electrogram duration (83±3 versus 63±2 ms), (4) activation delays on premature stimulation (longitudinal: 160±26 versus 86±9 ms; transversal: 112±5 versus 58±6 ms), and (5) abnormal transversal conduction velocity restitution (42±8 versus 18±2 ms increase in delay at shortest coupling intervals). Wider and more fractionated electrograms were also found in BrS-2 patients. Repolarization was not different between groups. Conclusions— BrS-1 and BrS-2 patients are characterized by wide and fractionated electrograms at the RV endocardium. BrS-1 patients display additional conduction slowing during sinus rhythm and premature stimulation along with abnormal transversal conduction velocity restitution. These patients may thus exhibit a substrate for slow and discontinuous conduction caused by abnormal active membrane processes and electric coupling. Our findings support the emerging notion that BrS is not solely attributable to abnormal electrophysiological properties but requires the conspiring effects of conduction slowing and tissue discontinuities. Received May 11, 2008; accepted October 6, 2008.

Esophageal Injury and Temperature Monitoring During Atrial Fibrillation AblationCLINICAL PERSPECTIVE

Abstract: Background— It is common practice to empirically limit the radiofrequency (RF) power when ablating the posterior left atrium during atrial fibrillation ablation to avoid thermal injury to the esophagus. The objective of this study was to determine whether RF energy delivery limited by luminal esophageal temperature (LET) monitoring is associated with a reduction in esophageal injury compared with a strategy of RF power limitation alone. Methods and Results— Eighty-one consecutive patients who underwent atrial fibrillation ablation followed by esophageal endoscopy were included in this observational study. All patients underwent extraostial electric pulmonary vein isolation by using an electroanatomic mapping system and irrigated RF ablation. All RF applications on the posterior left atrium were limited to 35 W. A commercially available, single-thermocouple esophageal probe was used to monitor LET in a subset of patients (n=67). In these cases, applications were promptly interrupted when LET was ≥38.5°C; further applications were performed at reduced power to obtain a LET <38.5°C. Esophageal endoscopy was performed 1 to 3 days after the procedure. Ablation-related esophageal ulcerations were identified in 9 of 81 (11%) patients. All patients were asymptomatic. Of these 81 patients, LET monitoring during ablation occurred in 67 (83%) of patients. Esophageal injury was observed more frequently (36% versus 6%, P <0.006) in the group without LET monitoring. Conclusions— These data suggest that LET monitoring may be associated with a reduction in esophageal injury compared with power limitation alone. Received March 20, 2008; accepted May 30, 2008.

ECG Quantification of Myocardial Scar in Cardiomyopathy Patients with or without Conduction Defects: Correlation with Cardiac Magnetic Resonance and Arrhythmogenesis

Abstract: Background— Myocardial scarring from infarction or nonischemic fibrosis forms an arrhythmogenic substrate. The Selvester QRS score has been extensively validated for estimating myocardial infarction scar size in the absence of ECG confounders, but has not been tested to quantify scar in patients with hypertrophy, bundle branch/fascicular blocks, or nonischemic cardiomyopathy. We assessed the hypotheses that (1) QRS scores (modified for each ECG confounder) correctly identify and quantify scar in ischemic and nonischemic patients when compared with the reference standard of cardiac magnetic resonance using late-gadolinium enhancement, and (2) QRS-estimated scar size predicts inducible sustained monomorphic ventricular tachycardia during electrophysiological testing. Methods and Results— One hundred sixty-two patients with left ventricular ejection fraction ≤35% (95 ischemic, 67 nonischemic) received 12-lead ECG and cardiac magnetic resonance using late-gadolinium enhancement before implantable cardioverter defibrillator placement for primary prevention of sudden cardiac death. QRS scores correctly diagnosed cardiovascular magnetic resonance scar presence with receiver operating characteristics area under the curve of 0.91 and correlation for scar quantification of r =0.74 ( P <0.0001) for all patients. Performance within hypertrophy, conduction defect, and nonischemic subgroups ranged from area under the curve of 0.81 to 0.94 and r =0.60 to 0.80 ( P <0.001 for all). Among the 137 patients undergoing electrophysiological or device testing, each 3-point QRS-score increase (9% left ventricular scarring) was associated with an odds ratio for inducing monomorphic ventricular tachycardia of 2.2 (95% CI, 1.5 to 3.2; P <0.001) for all patients, 1.7 (1.0 to 2.7, P =0.04) for ischemics, and 2.2 (1.0 to 5.0, P =0.05) for nonischemics. Conclusions— QRS scores identify and quantify scar in ischemic and nonischemic cardiomyopathy patients despite ECG confounders. Higher QRS-estimated scar size is associated with increased arrhythmogenesis and warrants further study as a risk-stratifying tool. Received June 12, 2008; accepted October 17, 2008. # CLINICAL PERSPECTIVE {#article-title-2}

alpha-1-syntrophin mutation and the long-QT syndrome: a disease of sodium channel disruption.

Abstract: Background —Long QT syndrome (LQTS) is an inherited disorder associated with sudden cardiac death. The cytoskeletal protein alpha-1-syntrophin (SNTA1) is known to interact with the cardiac sodium channel (hNa v 1.5) and we hypothesized that SNTA1 mutations might cause phenotypical LQTS in patients with genotypically normal hNa v 1.5 by secondarily disturbing sodium channel function. Methods and Results —Mutational analysis of SNTA1 was performed on 39 LQTS patients (QTc ≥ 480ms) with previously negative genetic-screening for the known LQTS-causing genes. We identified a novel A257G- SNTA1 missense mutation, which affects a highly conserved residue, in 3 unrelated LQTS probands but not in 400 ethnic-matched control alleles. Only one of these probands had a preexisting family history of LQTS and sudden death with an additional intronic variant in KCNQ1. Electrophysiological analysis was performed using HEK-293 cells stably expressing hNa v 1.5 and transiently transfected with either wild type (WT) or mutant SNTA1, and in neonatal rat cardiomyocytes transiently expressing with either WT or mutant SNTA1. In both HEK293 cells and neonatal rat cardiomyocytes increased peak sodium currents were noted along with a 10 mV negative shift of the onset and peak of currents of the I-V relationships. In addition, A257G-SNTA1 shifted the steady-state activation ( V h ) leftward by 9.4 mV, while the voltage-dependent inactivation kinetics and the late sodium currents were similar to WT-SNTA1. Conclusion — SNTA1 is a new susceptibility gene for LQTS. A257G- SNTA1 can cause gain-of-function of Na v 1.5 similar to the LQT3.

Ventricular Tachycardia Ablation

Abstract: While catheter ablation (CA) of ventricular arrhythmias (VAs) was in the past often only considered after pharmacological options had been exhausted, substantial progress has occurred and CA is now an option that should be considered early when therapy of recurrent arrhythmia is needed. In patients with VAs without structural heart disease CA is highly successful with a low rate of complications. In patients with heart disease efficacy is determined by the nature of the arrhythmia substrate, most often an area of scar. The current ability of mapping to identify substrate during stable sinus rhythm makes CA an option even when multiple and unstable ventricular tachycardias (VTs) are present. Its major role is in controlling of incessant VT and recurrent symptomatic VT in patients with implanted defibrillators. Continued advances in mapping and ablation methods are anticipated to continue to improve efficacy and safety.

Atrial tachycardia after ablation of persistent atrial fibrillation: identification of the critical isthmus with a combination of multielectrode activation mapping and targeted entrainment mapping.

Abstract: Background— Atrial tachycardia (AT) that develops after ablation of atrial fibrillation often poses a more difficult clinical situation than the index arrhythmia. This study details the use of an impedance-based electroanatomic mapping system (Ensite NavX) in concert with a specialized multielectrode mapping catheter for rapid, high-density atrial mapping. In this study, this activation mapping was combined with entrainment mapping to eliminate ATs developing late after atrial fibrillation ablation. Methods and Results— All study patients developed AT after ablation for atrial fibrillation. The approach to AT ablation consisted of 4 steps: use of a 20-pole penta-array catheter to map the chamber rapidly during the rhythm of interest, analysis of the patterns of atrial activation to identify wave fronts of electric propagation, targeted entrainment at putative channels, and catheter ablation at these “isthmuses.” All ablations were performed with irrigated radiofrequency ablation catheters. Forty-one ATs were identified in 17 patients (2.4±1.6 ATs per patient). Using the multielectrode catheter in conjunction with the Ensite NavX system, we created activation maps of 33 of 41 ATs (81%) (mean cycle length, 284±71 seconds) with a mean of 365±108 points per map and an average mapping time of 8±3 minutes. Of the 33 mapped ATs, 7 terminated either spontaneously or during entrainment maneuvers. Radiofrequency energy was used to attempt ablation of 26 ATs; 25 of 26 of the ATs (96%) were terminated successfully by ablation or catheter pressure. Conclusions— This study demonstrates a strategy for rapidly defining and eliminating the scar-related ATs typically encountered after ablation of atrial fibrillation. Received November 5, 2007; accepted January 29, 2008. # CLINICAL PERSPECTIVE {#article-title-2}

Patient and implanting physician factors associated with mortality and complications after implantable cardioverter-defibrillator implantation, 2002-2005.

Abstract: Background— Little is known about factors that influence survival and complications after implantable cardioverter-defibrillator (ICD) implantation in routine clinical practice. We examined patient and implanting physician factors associated with outcomes of ICD therapy in Medicare beneficiaries from 2002 through 2005. Methods and Results— We limited this analysis to patients aged ≥65 with Medicare fee-for-service coverage who received an ICD between January 2002 and September 2005. The main outcome measures are time to postprocedural complications within 90 days and 1-year mortality. During the study period, 8581 patients had an ICD implanted by 1959 physicians. The number of procedures increased from 1644 in 2002 to 2374 in the first 3 quarters of 2005. The overall complication rate declined from 18.8% in 2002 to 14.2% in 2005 ( P <0.001). Factors independently associated with an increased hazard of complications include chronic lung disease, dementia, renal disease, implantation by a thoracic surgeon, and implantation with removal/replacement. History of congestive heart failure, outpatient implantation, and more recent years of ICD implantation were associated with a lower risk of complications ( P <0.05 for all factors). From 2002 to 2005, we observed a decline in 1-year mortality ( P <0.001). Conclusions— We observed an appreciable increase in the number of ICD implants, which was associated with a significant decrease in the rate of complications and 1-year mortality. We identified factors associated with an increased risk of mortality and postprocedural complications that may support more nuanced treatment decisions than are currently possible. Received March 5, 2008; accepted August 11, 2008.

Molecular and clinical characterization of a novel SCN5A mutation associated with atrioventricular block and dilated cardiomyopathy.

Abstract: Background— Increased susceptibility to dilated cardiomyopathy has been observed in patients carrying mutations in the SCN5A gene, but the underlying mechanism remains unclear. In this study, we identified and characterized, both in vitro and clinically, an SCN5A mutation associated with familial progressive atrioventricular block of adult onset and dilated cardiomyopathy in a Chinese family. Methods and Results— Among 32 family members, 5 were initially diagnosed with atrioventricular block after age 30; 4 were studied, 3 of whom later developed dilated cardiomyopathy. We found a heterozygous single-nucleotide mutation resulting in an amino acid substitution (A1180V) in all studied patients and in 6 other younger unaffected members but not in 200 control chromosomes. When expressed with the β1 subunit, the mutated channels exhibited a −4.5-mV shift of inactivation with slower recovery leading to a rate-dependent Na+ current reduction and a moderate increase in late Na+ current. Clinical study revealed that although QRS duration decreased with increasing heart rate in noncarrier family members, this change was blunted in unaffected carriers whose ECG and heart function were normal. Resting corrected QT interval of unaffected carriers was significantly longer than that of noncarriers, even though it was still within the normal range. Conclusions— A1180V expresses a mild Na+ channel phenotype in vitro and a corresponding clinical phenotype in unaffected mutation carriers, implying that A1180V caused structural heart disease in affected carriers by disturbing Na+ influx and, hence, cellular Na+ homeostasis. The high penetrance of A1180V suggests this phenotype as a high risk factor for dilated cardiomyopathy with preceding atrioventricular block. Received November 6, 2007; accepted March 21, 2008. # CLINICAL PERSPECTIVE {#article-title-2}

Randomized evaluation of right atrial ablation after left atrial ablation of complex fractionated atrial electrograms for long-lasting persistent atrial fibrillation.

Abstract: Background— With electrogram-guided radiofrequency ablation (RFA) of long-lasting persistent atrial fibrillation (AF), the best results have been reported when complex fractionated electrograms (CFAEs) in both the left (LA) and right (RA) atria were targeted. However, many studies have reported excellent outcomes from RFA of long-lasting persistent AF with the use of other ablation strategies that were limited to the LA. The incremental value of RFA of RA CFAEs is yet to be defined. Methods and Results— In 85 patients with long-lasting persistent AF (age=59±10 years), RFA was directed at CFAEs in the LA and coronary sinus until AF terminated (19) or all identified LA CFAEs were eliminated. Sixty-six patients who remained in AF were randomly assigned to cardioversion and no further RFA (n=33) or to RFA of RA CFAEs (n=33). RA sites consisted of the crista terminalis (69%), septum (38%), superior vena cava (28%), coronary sinus ostium (22%), and the base of the appendage (31%). AF terminated in 1 (3%) of 33 patients during RA RFA. At 17±6 months after a single ablation procedure, 74% of the patients in whom AF terminated during LA RFA were in sinus rhythm. Rates of freedom from AF were similar in the patients randomized to no RFA in the RA (24%) and those randomized to RFA of RA CFAEs (30%, P =0.8). The ablation procedure was repeated in 26 patients (31%) for AF (n=22) or atrial flutter (n=4). At 16±7 months after the final procedure, 89% of the patients in whom AF terminated during LA RFA were in sinus rhythm. Among the randomized patients, the proportion of patients who remained in sinus rhythm was similar in patients who did not undergo RFA of RA CFAEs (52%) and those who did (58%, P =0.6). Conclusion— After RFA of CFAEs in the LA and coronary sinus, ablation of CFAEs in the RA provides little or no increment in efficacy among patients with long-lasting persistent AF. Received October 29, 2007; accepted December 24, 2007. # CLINICAL PERSPECTIVE {#article-title-2}

Three-dimensional ultrasound for image-guided mapping and intervention: methods, quantitative validation, and clinical feasibility of a novel multimodality image mapping system.

Abstract: Background— Multiple factors create discrepancies between electroanatomic maps and merged, preacquired computed tomographic images used in guiding atrial fibrillation ablation. Therefore, a Carto-based 3D ultrasound image system (Biosense Webster Inc) was validated in an animal model and tested in 15 atrial fibrillation patients. Methods and Results— Twelve dogs underwent evaluation using a newly developed Carto-based 3D ultrasound system. After fiducial clip markers were percutaneously implanted at critical locations in each cardiac chamber, 3D ultrasound geometries, derived from a family of 2D intracardiac echocardiographic images, were constructed. Point-source error of 3D ultrasound-derived geometries, assessed by actual real-time 2D intracardiac echocardiographic clip sites, was 2.1±1.1 mm for atrial and 2.4±1.2 mm for ventricular sites. These errors were significantly less than the variance on CartoMerge computed tomographic images (atria: 3.3±1.6 mm; ventricles: 4.8±2.0 mm; P< 0.001 for both). Target ablation at each clip, guided only by 3D ultrasound-derived geometry, resulted in lesions within 1.1±1.1 mm of the actual clips. Pulmonary vein ablation guided by 3D ultrasound-derived geometry resulted in circumferential ablative lesions. Mapping in 15 patients produced modestly smaller 3D ultrasound versus electroanatomic map left atrial volumes (98±24 cm3 versus 109±25 cm3, P< 0.05). Three-dimensional ultrasound-guided pulmonary vein isolation and linear ablation in these patients were successfully performed with confirmation of pulmonary vein entrance/exit block. Conclusions— These data demonstrate that 3D ultrasound images seamlessly yield anatomically accurate chamber geometries. Image volumes from the ultrasound system are more accurate than possible with CartoMerge computed tomographic imaging. This clinical study also demonstrates the initial feasibility of this guidance system for ablation in patients with atrial fibrillation. Received September 18, 2007; accepted April 7, 2008. # CLINICAL PERSPECTIVE {#article-title-2}

Altered sympathetic nervous reactivity and norepinephrine transporter expression in patients with postural tachycardia syndrome.

Abstract: Background— Clinical observations in patients with postural tachycardia syndrome (POTS) suggest abnormal sympathetic nervous system activity and a dysfunction of the norepinephrine (NE) transporter (NET). Methods and Results— We examined sympathetic nervous system responses to head-up tilt by combining NE plasma kinetics measurements and muscle sympathetic nerve activity recordings and by quantifying NET protein content in peripheral sympathetic nerves in patients with POTS compared with that in controls. POTS patients had an elevated heart rate during supine rest (81±2 bpm versus 66±2 bpm in healthy subjects [HS], P <0.01). Head-up tilt to 40° induced a greater rise in heart rate in patients with POTS (+24±4 bpm versus +13±2 bpm in HS, P <0.001). During rest in the supine position, muscle sympathetic nerve activity, arterial NE concentration, and whole-body NE spillover to plasma were similar in both groups. Muscle sympathetic nerve activity response to head-up tilt was greater in the POTS group (+29±3 bursts/min in patients with POTS and +13±2 bursts/min in HS, P <0.001), but the NE spillover rise was similar in both groups (51% in the POTS subjects and 50% in the HS). Western blot analysis of NET protein extracted from forearm vein biopsies in patients with POTS and HS demonstrated a decrease in the expression of NET protein in patients with POTS. Conclusion— Patients with POTS exhibit a decrease in NET protein in their peripheral sympathetic nerves. Paradoxically, whole-body NE spillover to plasma during rest in the supine position and in response to head-up tilt is not altered despite excessive nerve firing rate in response to the head-up tilt. Received November 4, 2007; accepted April 11, 2008. # CLINICAL PERSPECTIVE {#article-title-2}

Atrial Septopulmonary Bundle of the Posterior Left Atrium Provides a Substrate for Atrial Fibrillation Initiation in a Model of Vagally Mediated Pulmonary Vein Tachycardia of the Structurally Normal Heart

Abstract: Background— The posterior left atrium (PLA) and pulmonary veins (PVs) have been shown to be critical for atrial fibrillation (AF) initiation However, the detailed mechanisms of reentry and AF initiation by PV impulses are poorly understood We hypothesized that PV impulses trigger reentry and AF by undergoing wavebreaks as a result of sink-to-source mismatch at specific PV-PLA transitions along the septopulmonary bundle, where there are changes in thickness and fiber direction Methods and Results— In 7 Langendorff-perfused sheep hearts AF was initiated by a burst of 6 pulses (CL 80 to 150ms) delivered to the left inferior or right superior PV ostium 100 to 150 ms after the sinus impulse in the presence of 05 μmol/L acetylcholine The exposed septal-PLA endocardial area was mapped with high spatio-temporal resolution (DI-4-ANEPPS, 1000-fr/s) during AF initiation Isochronal maps for each paced beat preceding AF onset were constructed to localize areas of conduction delay and block Phase movies allowed the determination of the wavebreak sites at the onset of AF Thereafter, the PLA myocardial wall thickness was quantified by echocardiography, and the fiber direction in the optical field of view was determined after peeling off the endocardium Finally, isochrone, phase and conduction velocity maps were superimposed on the corresponding anatomic pictures for each of the 28 episodes of AF initiation The longest delays of the paced PV impulses, as well as the first wavebreak, occurred at those boundaries along the septopulmonary bundle that showed sharp changes in fiber direction and the largest and most abrupt increase in myocardial thickness Conclusion— Waves propagating from the PVs into the PLA originating from a simulated PV tachycardia triggered reentry and vagally mediated AF by breaking at boundaries along the septopulmonary bundle where abrupt changes in thickness and fiber direction resulted in sink-to-source mismatch and low safety for propagation Received December 13, 2007; accepted May 30, 2008

Mechanisms and utility of discrete great arterial potentials in the ablation of outflow tract ventricular arrhythmias.

Abstract: Background— Outflow tract ventricular tachycardia originating above the semilunar valves has been reported in a small number of studies. Discrete potentials in the great arteries (above the semilunar valves) have been rarely described in patients undergoing electrophysiology evaluation and radiofrequency ablation for ventricular arrhythmias. The mechanisms of these discrete potentials in the great arteries and the utility of such potentials in guiding radiofrequency ablation are unknown. Methods and Results— Twelve patients with outflow tract ventricular arrhythmia originating above the semilunar valves with discrete arterial potentials were studied. The clinical characteristics, properties of the arterial potentials, electrophysiological evaluation and ablation, and short- and long-term outcomes were reviewed. Of the twelve patients, 8 (67%) were women. The patients’ average age was 41±14 years. The average ejection fraction was 0.52±0.16 (range: 0.16 to 0.75). Contact mapping in the great artery demonstrated discrete near-field electrograms that were separate from far-field ventricular electrograms in all patients (8 above the pulmonary valve and in 4 the aortic valve). One or more of the following electrophysiological characteristics, supportive of an arrhythmogenic substrate, were observed in 10 of 12 patients: (1) A fixed or reproducibly variable pattern of discrete potential–ventricular arrhythmia relationship was present at baseline or during pacing; (2) the discrete potential–ventricular electrogram relationship during sinus rhythm was the reverse of that during the ventricular arrhythmia; (3) during sustained ventricular tachycardia, spontaneous variation of the ventricular (V-V) cycle length was preceded by a similar variation of arterial spike potential–spike potential cycle length; and (4) ablation guided by the discrete arterial potential successfully eliminated the clinical arrhythmia. Ablation was successful in these patients. In the remaining 2 patients, the potentials were believed to be bystanders. Over 10±4 months (range: 5 to 32 months) of follow-up, there have been no recurrences of the premature ventricular complex or ventricular arrhythmia. Conclusions— Discrete potentials are present in the great arteries of a select group of patients with outflow tract ventricular tachycardia originating above the semilunar valves. When an arrhythmogenic relationship can be demonstrated, discrete potentials are useful in guiding ablation within the great vessels, despite significant anatomic complexity. Received November 3, 2007; accepted December 24, 2007. # CLINICAL PERSPECTIVE {#article-title-2}

Ventricular Pump Function and Pacing Physiological and Clinical Integration

Abstract: Optimal cardiac pump function depends on ordered mechanical events that are orchestrated by electrical timing. This electromechanical coupling occurs at multiple anatomic levels: within atria, between atria and ventricles, between ventricles, and especially within the left ventricle (LV). Such disruptions to proper electrical timing result in disordered mechanical events (desynchronization, or “dyssynchrony”), can occur spontaneously or be induced in isolation or in various combinations at any level, and degrade cardiac pump function. These disruptions to normal mechanical ordering occur because of fixed or functional conduction blocks and can be generated by myocardial disease or can be induced by cardiac pacing. The adverse effects of disruption of proper electromechanical coupling at all levels with particular attention to the effects of ventricular conduction delay due to conventional (usually right ventricular apical, RVA) pacing and left bundle-branch block (LBBB) are discussed later. Subsequently, remedies for prevention or treatment are discussed along the same lines. ### Uncoupling at the Atrial Level The right atrium and left atrium are activated nearly simultaneously (within 50 to 80 ms) during sinus rhythm. Preferential sites of interatrial conduction exist at the posterior-superior interatrial septum (Bachmann’s bundle region), fossa ovalis, and coronary sinus ostium.1,2 Significant interatrial conduction delays (up to 200 ms or greater) can occur in myopathic atria. Similar conduction delays can be also be induced, or exacerbated, by right atrial pacing. Delayed left atrial contraction can disrupt optimal left-sided atrioventricular (AV) coupling. Severe atrial decoupling and delayed left atrial contraction reverses the left-sided AV contraction sequence, resulting in atrial transport block.3 This causes increased left atrial pressures, retrograde flow in the pulmonary veins, and counterphysiological neurohormonal responses termed “pseudopacemaker syndrome.”4–6 ### Uncoupling at Atrioventricular Level Optimal AV coupling contributes to ventricular pump function. The normal AV interval results in atrial contraction just before the pre-ejection (isovolumic) period of ventricular contraction that maximizes LV filling (LV …

Therapeutic strategies for long-QT syndrome: does the molecular substrate matter?

Abstract: The discovery of genetic defects underlying long-QT syndrome (LQTS) has allowed to identify important genotype-phenotype correlations that are now being used for risk stratification. The next challenge is to exploit the new information on the pathophysiology of the disease derived from molecular genetics to devise more effective therapies. The successful response of LQT1 patients to β-blockers, the QT-shortening action of sodium channel blockers in at least some LQT3 patients, and the importance of maintaining adequate plasma potassium levels in LQT2 patients clearly demonstrate the importance of selecting therapy in the context of the molecular substrate. The hurdles on the road toward the development of novel therapeutic strategies are represented by the variable expressivity of the disease, the high prevalence of “private” mutations, and the role of genetic and nongenetic factors that act as modifiers of the phenotype. Given the large number of mutations identified and their phenotypic complexity, it is clearly impossible to anticipate a scenario in which each mutation will be managed through a specific therapy. However, the evidence that mutations in the LQTS gene may be clustered based on their electrophysiological profile and on their response to specific drugs may provide the rationale for the development of mutation-specific therapies. In this article, we will review the most relevant genotype-phenotype features of LQTS and the strategies explored to develop novel therapeutic approaches. ### Definition and Prevalence The congenital LQTS is an inherited arrhythmogenic disease characterized by abnormally prolonged QT interval leading to life-threatening arrhythmias in the presence of a structurally normal heart.1 Different clinical variants of LQTS have been identified. Romano Ward syndrome, transmitted as an autosomal dominant trait, is the most common form of LQTS and presents only a cardiac phenotype. Less prevalent variants of LQTS, such as Andersen and Timothy syndromes or the recessive Jervell and Lange-Nielsen syndromes, also present …

Incidence of atrial fibrillation in relation to changing heart rate over time in hypertensive patients: the LIFE study.

Abstract: Background— Onset of atrial fibrillation (AF) has been linked to changes in autonomic tone, with increasing heart rate (HR) immediately before AF onset in some patients suggesting a possible role o ...

Malignant Perinatal Variant of Long-QT Syndrome Caused by a Profoundly Dysfunctional Cardiac Sodium Channel

Abstract: Background— Inherited cardiac arrhythmia susceptibility contributes to sudden death during infancy and may contribute to perinatal and neonatal mortality, but the molecular basis of this risk and the relationship to genetic disorders presenting later in life is unclear. We studied the functional and pharmacological properties of a novel de novo cardiac sodium channel gene ( SCN5A ) mutation associated with an extremely severe perinatal presentation of long-QT syndrome in unrelated probands of different ethnicity. Methods and Results— Two subjects exhibiting severe fetal and perinatal ventricular arrhythmias were screened for SCN5A mutations, and the functional properties of a novel missense mutation (G1631D) were determined by whole-cell patch clamp recording. In vitro electrophysiological studies revealed a profound defect in sodium channel function characterized by ≈10-fold slowing of inactivation, increased persistent current, slowing of recovery from inactivation, and depolarized voltage dependence of activation and inactivation. Single-channel recordings demonstrated increased frequency of late openings, prolonged mean open time, and increased latency to first opening for the mutant. Subjects carrying this mutation responded clinically to the combination of mexiletine with propranolol and survived. Pharmacologically, the mutant exhibited 2-fold greater tonic and use-dependent mexiletine block than wild-type channels. The mutant also exhibited enhanced tonic (2.4-fold) and use-dependent block (≈5-fold) by propranolol, and we observed additive effects of the 2 drugs on the mutant. Conclusions— Our study demonstrates the molecular basis for a malignant perinatal presentation of long-QT syndrome, illustrates novel functional and pharmacological properties of SCN5A -G1631D, which caused the disorder, and reveals therapeutic benefits of propranolol block of mutant sodium channels in this setting. Received April 24, 2008; accepted September 15, 2008. # CLINICAL PERSPECTIVE {#article-title-2}