Maria Strom

Connexin Gene Transfer Preserves Conduction Velocity and Prevents Atrial Fibrillation

Background— Several lines of evidence have suggested that maintenance of atrial fibrillation (AF) depends on reentrant mechanisms. Maintenance of reentry necessitates a sufficiently short refractory period and/or delayed conduction, and AF has been associated with both alterations. Fibrosis, cellular dysfunction, and gap junction protein alterations occur in AF and cause conduction delay. We performed this study to test the hypothesis that gap junction protein overexpression would improve conduction and prevent AF. Methods and Results— Thirty Yorkshire swine were randomized into 2 groups (sinus rhythm and AF), and each group into 3 subgroups: sham-operated control, gene therapy with adenovirus expressing connexin (Cx) 40, and gene therapy with adenovirus expressing Cx43 (n=5 per subgroup). All animals had epicardial gene painting; the AF group had burst atrial pacing. All animals underwent terminal study 7 days after gene transfer. Sinus rhythm animals had strong transgene expression but no atrial conduction changes. In AF animals, controls had reduced and lateralized Cx43 expression, and Cx43 gene transfer restored expression and cellular location to sinus rhythm control levels. In the AF group, both Cx40 and Cx43 gene transfer improved conduction and reduced AF relative to controls. Conclusions— Connexin gene therapy preserved atrial conduction and prevented AF.

Comparative Electromechanical and Hemodynamic Effects of Left Ventricular and Biventricular Pacing in Dyssynchronous Heart Failure: Electrical Resynchronization Versus Left–Right Ventricular Interaction

OBJECTIVES The purpose of this study was to enhance understanding of the working mechanism of cardiac resynchronization therapy by comparing animal experimental, clinical, and computational data on the hemodynamic and electromechanical consequences of left ventricular pacing (LVP) and biventricular pacing (BiVP). BACKGROUND It is unclear why LVP and BiVP have comparative positive effects on hemodynamic function of patients with dyssynchronous heart failure. METHODS Hemodynamic response to LVP and BiVP (% change in maximal rate of left ventricular pressure rise [LVdP/dtmax]) was measured in 6 dogs and 24 patients with heart failure and left bundle branch block followed by computer simulations of local myofiber mechanics during LVP and BiVP in the failing heart with left bundle branch block. Pacing-induced changes of electrical activation were measured in dogs using contact mapping and in patients using a noninvasive multielectrode electrocardiographic mapping technique. RESULTS LVP and BiVP similarly increased LVdP/dtmax in dogs and in patients, but only BiVP significantly decreased electrical dyssynchrony. In the simulations, LVP and BiVP increased total ventricular myofiber work to the same extent. While the LVP-induced increase was entirely due to enhanced right ventricular (RV) myofiber work, the BiVP-induced increase was due to enhanced myofiber work of both the left ventricle (LV) and RV. Overall, LVdP/dtmax correlated better with total ventricular myofiber work than with LV or RV myofiber work alone. CONCLUSIONS Animal experimental, clinical, and computational data support the similarity of hemodynamic response to LVP and BiVP, despite differences in electrical dyssynchrony. The simulations provide the novel insight that, through ventricular interaction, the RV myocardium importantly contributes to the improvement in LV pump function induced by cardiac resynchronization therapy.

Cardiac Electrophysiological Substrate Underlying the ECG Phenotype and Electrogram Abnormalities in Brugada Syndrome Patients

Background— Brugada syndrome (BrS) is a highly arrhythmogenic cardiac disorder, associated with an increased incidence of sudden death. Its arrhythmogenic substrate in the intact human heart remains ill-defined. Methods and Results— Using noninvasive ECG imaging, we studied 25 BrS patients to characterize the electrophysiological substrate and 6 patients with right bundle-branch block for comparison. Seven healthy subjects provided control data. Abnormal substrate was observed exclusively in the right ventricular outflow tract with the following properties (in comparison with healthy controls; P<0.005): (1) ST-segment elevation and inverted T wave of unipolar electrograms (2.21±0.67 versus 0 mV); (2) delayed right ventricular outflow tract activation (82±18 versus 37±11 ms); (3) low-amplitude (0.47±0.16 versus 3.74±1.60 mV) and fractionated electrograms, suggesting slow discontinuous conduction; (4) prolonged recovery time (381±30 versus 311±34 ms) and activation-recovery intervals (318±32 versus 241±27 ms), indicating delayed repolarization; (5) steep repolarization gradients (&Dgr;recovery time/&Dgr;x=96±28 versus 7±6 ms/cm, &Dgr;activation-recovery interval/&Dgr;x=105±24 versus 7±5 ms/cm) at right ventricular outflow tract borders. With increased heart rate in 6 BrS patients, reduced ST-segment elevation and increased fractionation were observed. Unlike BrS, right bundle-branch block had delayed activation in the entire right ventricle, without ST-segment elevation, fractionation, or repolarization abnormalities on electrograms. Conclusions— The results indicate that both slow discontinuous conduction and steep dispersion of repolarization are present in the right ventricular outflow tract of BrS patients. ECG imaging could differentiate between BrS and right bundle-branch block.

Validation of novel 3-dimensional electrocardiographic mapping of atrial tachycardias by invasive mapping and ablation: A multicenter study

OBJECTIVES This study prospectively evaluated the role of a novel 3-dimensional, noninvasive, beat-by-beat mapping system, Electrocardiographic Mapping (ECM), in facilitating the diagnosis of atrial tachycardias (AT). BACKGROUND Conventional 12-lead electrocardiogram, a widely used noninvasive tool in clinical arrhythmia practice, has diagnostic limitations. METHODS Various AT (de novo and post-atrial fibrillation ablation) were mapped using ECM followed by standard-of-care electrophysiological mapping and ablation in 52 patients. The ECM consisted of recording body surface electrograms from a 252-electrode-vest placed on the torso combined with computed tomography-scan-based biatrial anatomy (CardioInsight Inc., Cleveland, Ohio). We evaluated the feasibility of this system in defining the mechanism of AT-macro-re-entrant (perimitral, cavotricuspid isthmus-dependent, and roof-dependent circuits) versus centrifugal (focal-source) activation-and the location of arrhythmia in centrifugal AT. The accuracy of the noninvasive diagnosis and detection of ablation targets was evaluated vis-à-vis subsequent invasive mapping and successful ablation. RESULTS Comparison between ECM and electrophysiological diagnosis could be accomplished in 48 patients (48 AT) but was not possible in 4 patients where the AT mechanism changed to another AT (n = 1), atrial fibrillation (n = 1), or sinus rhythm (n = 2) during the electrophysiological procedure. ECM correctly diagnosed AT mechanisms in 44 of 48 (92%) AT: macro-re-entry in 23 of 27; and focal-onset with centrifugal activation in 21 of 21. The region of interest for focal AT perfectly matched in 21 of 21 (100%) AT. The 2:1 ventricular conduction and low-amplitude P waves challenged the diagnosis of 4 of 27 macro-re-entrant (perimitral) AT that can be overcome by injecting atrioventricular node blockers and signal averaging, respectively. CONCLUSIONS This prospective multicenter series shows a high success rate of ECM in accurately diagnosing the mechanism of AT and the location of focal arrhythmia. Intraprocedural use of the system and its application to atrial fibrillation mapping is under way.

Connexin43 Gene Transfer Reduces Ventricular Tachycardia Susceptibility After Myocardial Infarction

OBJECTIVES The aim of this study was to evaluate the links between connexin43 (Cx43) expression, myocardial conduction velocity, and ventricular tachycardia in a model of healed myocardial infarction. BACKGROUND Post-infarction ventricular arrhythmias frequently cause sudden death. Impaired myocardial conduction has previously been linked to ventricular arrhythmias. Altered connexin expression is a potential source of conduction slowing identified in healed scar border tissues. The functional effect of increasing border-zone Cx43 has not been previously evaluated. METHODS Twenty-five Yorkshire pigs underwent anterior infarction by transient left anterior descending coronary artery occlusion, followed by weekly testing for arrhythmia inducibility. Twenty animals with reproducibly inducible sustained monomorphic ventricular tachycardia were randomized 2:1:1 to receive AdCx43, Adβgal, or no gene transfer. One week later, animals underwent follow-up electrophysiologic study and tissue assessment for several functional and molecular measures. RESULTS Animals receiving AdCx43 had less electrogram fractionation and faster conduction velocity in the anterior-septal border zone. Only 40% of AdCx43 animals remained inducible for ventricular tachycardia, while 100% of controls were inducible after gene transfer. AdCx43 animals had 2-fold higher Cx43 protein levels in the anterior-septal infarct border, with similar percents of phosphorylated and intercalated disk-localized Cx43 compared with controls. CONCLUSIONS These data mechanistically link Cx43 expression to slow conduction and arrhythmia susceptibility in the healed scar border zone. Targeted manipulation of Cx43 levels improved conduction velocity and reduced ventricular tachycardia susceptibility. Cx43 gene transfer represents a novel treatment strategy for post-infarction arrhythmias.

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.

Confirmation of novel noninvasive high-density electrocardiographic mapping with electrophysiology study: Implications for therapy

Background—Twelve lead ECGs have limited value in precisely identifying atrial and ventricular activation during arrhythmias, including accessory atrioventricular conduction activation. The aim of this study was to report a single center’s clinical experience validating a novel, noninvasive, whole heart, beat-by-beat, 3-dimensional mapping technology with invasive electrophysiological studies, including ablation, where applicable. Methods and Results—Using an electrocardiographic mapping (ECM) system in 27 patients, 3-dimensional epicardial activation maps were generated from >250 body surface ECGs using heart–torso geometry obtained from computed tomographic images. ECM activation maps were compared with clinical diagnoses, and confirmed with standard invasive electrophysiological studies mapping. (1) In 6 cases of Wolff–Parkinson–White syndrome, ECM accurately identified the ventricular insertion site of an accessory atrioventricular connection. (2) In 10 patients with premature ventricular complexes, ECM accurately identified their ventricular site of origin in 8 patients. In 2 of 10 patients transient premature ventricular complex suppression was observed during ablation at the site predicted by ECM as the earliest. (3) In 10 cases of atrial tachycardia/atrial flutter, ECM accurately identified the chamber of origin in all 10, and distinguished isthmus from nonisthmus dependent atrial flutter. (4) In 1 patient with sustained exercise induced ventricular tachycardia, ECM accurately identified the focal origin in the left ventricular outflow tract. Conclusions—ECM successfully provided valid activation sequence maps obtained noninvasively in a variety of rhythm disorders that correlated well with invasive electrophysiological studies.

Gap junction heterogeneity as mechanism for electrophysiologically distinct properties across the ventricular wall

Gap junctions are critical to maintaining synchronized impulse propagation and repolarization. Heterogeneous expression of the principal ventricular gap junction protein connexin43 (Cx43) is associated with action potential duration (APD) dispersion across the anterior ventricular wall. Little is known about Cx43 expression patterns and their disparate impact on regional electrophysiology throughout the heart. We aimed to determine whether the anterior and posterior regions of the heart are electrophysiologically distinct. Multisegment, high-resolution optical mapping was performed in canine wedge preparations harvested separately from the anterior left ventricle (aLV; n = 8) and posterior left ventricle (pLV; n = 8). Transmural APD dispersion was significantly greater on the aLV than the pLV (45 +/- 13 vs. 26 +/- 8.0 ms; P < 0.05). Conduction velocity dispersion was also significantly higher (P < 0.05) across the aLV (39 +/- 7%) than the pLV (16 +/- 3%). Carbenoxolone perfusion significantly enhanced APD and conduction velocity dispersion on the aLV (by 1.53-fold and 1.36-fold, respectively), but not the pLV (by 1.27-fold and 1.2-fold, respectively), and produced a 4.2-fold increase in susceptibility to inducible arrhythmias in the aLV. Confocal immunofluorescence microscopy revealed significantly (P < 0.05) greater transmural dispersion of Cx43 expression on the aLV (44 +/- 10%) compared with the pLV wall (8.3 +/- 0.7%), suggesting that regional expression of Cx43 expression patterns may account for regional electrophysiological differences. Computer simulations affirmed that localized uncoupling at the epicardial-midmyocardial interface is sufficient to produce APD gradients observed on the aLV. These data demonstrate that the aLV and pLV differ importantly with respect to their electrophysiological properties and Cx43 expression patterns. Furthermore, local underexpression of Cx43 is closely associated with transmural electrophysiological heterogeneity on the aLV. Therefore, regional and transmural heterogeneous Cx43 expression patterns may be an important mechanism underlying arrhythmia susceptibility, particularly in disease states where gap junction expression is altered.

Body Surface Electrocardiographic Mapping for Non-invasive Identification of Arrhythmic Sources

The authors describe a novel three-dimensional, 252-lead electrocardiography (ECG) and computed tomography (CT)-based non-invasive cardiac imaging and mapping modality. This technique images potentials, electrograms and activation sequences (isochrones) on the epicardial surface of the heart. This tool has been investigated in the normal cardiac electrophysiology and various tachyarrhythmic, conduction and anomalous depo-repolarisation disorders. The clinical application of this system includes a wide range of electrical disorders like atrial arrhythmias (premature atrial beat, atrial tachycardia, atrial fibrillation), ventricular arrhythmias (premature ventricular beat, ventricular tachycardia) and ventricular pre-excitation (Wolff-Parkinson-White syndrome). In addition, the system has been used in exploring abnormalities of the His-Purkinje conduction like the bundle branch block and intraventricular conduction disturbance and thereby useful in electrically treating the associated heart failure (cardiac resynchronisation). It has a potential role in furthering our understanding of abnormalities of ventricular action potential (depolarisation [Brugada syndrome and repolarisation], long QT and early repolarisation syndromes) and in evaluating the impact of drugs on His-Purkinje conduction and cardiac action potential.

The Electrophysiological Substrate of Early Repolarization Syndrome: Noninvasive Mapping in Patients

Background The early repolarization (ER) pattern is a common ECG finding. Recent studies established a definitive clinical association between ER and fatal ventricular arrhythmias. However, the arrhythmogenic substrate of ER in the intact human heart has not been characterized. Objectives To map the epicardial electrophysiological (EP) substrate in ER syndrome patients using noninvasive Electrocardiographic Imaging (ECGI), and to characterize substrate properties that support arrhythmogenicity. Methods Twenty-nine ER syndrome patients were enrolled, 17 of which had a malignant syndrome. Characteristics of the abnormal EP substrate were analyzed using data recorded during sinus rhythm. The EP mapping data were analyzed for electrogram morphology, conduction and repolarization. Seven normal subjects provided control data. Results The abnormal EP substrate in ER syndrome patients has the following properties: (1) Abnormal epicardial electrograms characterized by presence of J-waves in localized regions; (2) Absence of conduction abnormalities, including delayed activation, conduction block, or fractionated electrograms; (3) Marked abbreviation of ventricular repolarization in areas with J-waves. The action potential duration (APD) was significantly shorter than normal (196±19 vs. 235±21 ms, p<0.05). Shortening of APD occurred heterogeneously, leading to steep repolarization gradients compared to normal control (45±17 vs.7±5 ms/cm, p<0.05). Premature ventricular contractions (PVCs) were recorded in 2 patients. The PVC sites of origin were closely related to the abnormal EP substrate with J-waves and steep repolarization gradients. Conclusions Early Repolarization is associated with steep repolarization gradients caused by localized shortening of APD. Results suggest association of PVC initiation sites with areas of repolarization abnormalities. Conduction abnormalities were not observed.