Statins Protect Against Early Stages of Doxorubicin-induced Cardiotoxicity Through the Regulation of Akt Signaling and SERCA2.

Background: Doxorubicin-induced cardiomyopathy (DICM) is one of the complications that can limit treatment for a significant number of cancer patients. In animal models, the administration of statins can prevent the development of DICM. Therefore, the use of statins with anthracyclines potentially could enable cancer patients to complete their chemotherapy without added cardiotoxicity. The precise mechanism mediating the cardioprotection is not well understood. The purpose of this study is to determine the molecular mechanism by which rosuvastatin confers cardioprotection in a mouse model of DICM. Methods: Rosuvastatin was intraperitoneally administered into adult male mice at 100 µg/kg daily for 7 days, followed by a single intraperitoneal doxorubicin injection at 10 mg/kg. Animals continued to receive rosuvastatin daily for an additional 14 days. Cardiac function was assessed by echocardiography. Optical calcium mapping was performed on retrograde Langendorff perfused isolated hearts. Ventricular tissue samples were analyzed by immunofluorescence microscopy, Western blotting, and quantitative polymerase chain reaction. Results: Exposure to doxorubicin resulted in significantly reduced fractional shortening (27.4% ± 1.11% vs 40% ± 5.8% in controls; P < 0.001) and re-expression of the fetal gene program. However, we found no evidence of maladaptive cardiac hypertrophy or adverse ventricular remodeling in mice exposed to this dose of doxorubicin. In contrast, rosuvastatin-doxorubicin-treated mice maintained their cardiac function (39% ± 1.26%; P < 0.001). Mechanistically, the effect of rosuvastatin was associated with activation of Akt and phosphorylation of phospholamban with preserved sarcoplasmic/endoplasmic reticulum Ca2+ transporting 2 (SERCA2)-mediated Ca2+ reuptake. These effects occurred independently of perturbations in ryanodine receptor 2 function. Conclusions: Rosuvastatin counteracts the cardiotoxic effects of doxorubicin by directly targeting sarcoplasmic calcium cycling.

Contexte: La cardiomyopathie induite par la doxorubicine (CMID) est l'une des complications pouvant limiter le traitement d'un nombre considérable de patients atteints de cancer. Dans des modèles animaux, l'administration de statines peut prévenir l'apparition d'une CMID. Ainsi, l'utilisation de statines avec les anthracyclines pourrait vraisemblablement permettre aux patients de compléter leur chimiothérapie en évitant une cardiotoxicité supplémentaire. Le mécanisme précis qui sous-tend cet effet cardioprotecteur n'est pas entièrement élucidé. Cette étude a pour objectif de déterminer dans un modèle murin de CMID le mécanisme moléculaire par lequel la rosuvastatine confère une cardioprotection. Méthodologie: La rosuvastatine a été administrée par voie intrapéritonéale à des souris adultes mâles à une dose de 100 µg/kg par jour pendant sept jours, suivie d'une dose unique de doxorubicine de 10 mg/kg administrée par injection intrapéritonéale. Les animaux poursuivaient ensuite le traitement par la rosuvastatine une fois par jour pendant 14 jours supplémentaires. La fonction cardiaque a été mesurée par échocardiographie. Une cartographie optique du calcium a été réalisée sur des cœurs isolés soumis à une perfusion rétrograde selon la méthode de Langendorff. Des échantillons de tissu ventriculaire ont été analysés par microscopie en immunofluorescence, par buvardage de western et par mesure quantitative de l'amplification en chaîne par polymérase. Résultats: L'exposition à la doxorubicine a entraîné une diminution significative de la fraction de raccourcissement (27,4 % ± 1,11 % vs 40 % ± 5,8 % dans le groupe témoin; p < 0,001) et la réexpression du programme génique fœtal. Toutefois, aucune hypertrophie cardiaque inadaptée ni aucun remodelage ventriculaire indésirable n'ont été observés chez les souris ayant été exposées à la dose de doxorubicine étudiée. En revanche, la fonction cardiaque a été préservée chez les souris traitées par l'association rosuvastatine-doxorubicine (39 % ± 1,26 %; p < 0,001). Sur le plan du mode d'action, l'effet de la rosuvastatine a été associé à une activation de l'Akt et à une phosphorylation du phospholambane, avec préservation du recaptage de Ca2+ médié par la pompe SERCA2 (sarcoplasmic/endoplasmic reticulum Ca 2+ transporting 2). Ces effets sont survenus indépendamment des perturbations de la fonction du récepteur RyR2 (ryanodine receptor 2). Conclusions: La rosuvastatine neutralise les effets cardiotoxiques de la doxorubicine en ciblant directement la circulation sarcoplasmique du calcium.

Reinserting Physiology into Cardiac Mapping Using Omnipolar Electrograms.

Omnipolar electrograms (EGMs) make use of biophysical electric fields that accompany activation along the surface of the myocardium. A grid-like electrode array provides bipolar signals in orthogonal directions to deliver catheter-orientation-independent assessments of cardiac electrophysiology. Studies with myocyte monolayers, isolated animal and human hearts, and anesthetized animals validated the tenets of omnipolar EGMs. The combination of information from omnipolar-based activation vectors and voltages may aid in localizing areas of scar, lesion gaps, wavefront disorganization, and fractionation or collision during arrhythmias. The goal of omnipolar EGMs is to better characterize myocardium through reintroducing electrogram direction related fundamentals of cardiac electrophysiology.

Omnipolarity applied to equi-spaced electrode array for ventricular tachycardia substrate mapping.

AIMS: Bipolar electrogram (BiEGM)-based substrate maps are heavily influenced by direction of a wavefront to the mapping bipole. In this study, we evaluate high-resolution, orientation-independent peak-to-peak voltage (Vpp) maps obtained with an equi-spaced electrode array and omnipolar EGMs (OTEGMs), measure its beat-to-beat consistency, and assess its ability to delineate diseased areas within the myocardium compared against traditional BiEGMs on two orientations: along (AL) and across (AC) array splines. METHODS AND RESULTS: The endocardium of the left ventricle of 10 pigs (three healthy and seven infarcted) were each mapped using an Advisor™ HD grid with a research EnSite Precision™ system. Cardiac magnetic resonance images with late gadolinium enhancement were registered with electroanatomical maps and were used for gross scar delineation. Over healthy areas, OTEGM Vpp values are larger than AL bipoles by 27% and AC bipoles by 26%, and over infarcted areas OTEGM Vpp values are 23% larger than AL bipoles and 27% larger than AC bipoles (P < 0.05). Omnipolar EGM voltage maps were 37% denser than BiEGM maps. In addition, OTEGM Vpp values are more consistent than bipolar Vpps showing less beat-by-beat variation than BiEGM by 39% and 47% over both infarcted and healthy areas, respectively (P < 0.01). Omnipolar EGM better delineate infarcted areas than traditional BiEGMs from both orientations. CONCLUSION: An equi-spaced electrode grid when combined with omnipolar methodology yielded the largest detectable bipolar-like voltage and is void of directional influences, providing reliable voltage assessment within infarcted and non-infarcted regions of the heart.

Information theory to tachycardia therapy: electrogram entropy predicts diastolic microstructure of reentrant ventricular tachycardia.

There is no known strategy to differentiate which multicomponent electrograms in sinus rhythm maintain reentrant ventricular tachycardia (VT). Low entropy in the voltage breakdown of a multicomponent electrogram can localize conditions suitable for reentry but has not been validated against the classic VT activation mapping. We examined whether low entropy in a late and diversely activated ventricular scar region characterizes and differentiates the diastolic path of VT and represents protected tissue channels devoid of side branches. Intraoperative bipolar electrogram (BiEGM) activation and entropy maps were obtained during sinus rhythm in 17 patients with ischemic cardiomyopathy and compared with diastolic activation paths of VT (total of 39 VTs). Mathematical modeling of a zigzag main channel with side branches was also used to further validate structural representation of low entropy in the ventricular scar. A median of one region per patient (range: 1-2 regions) was identified in sinus rhythm, in which BiEGM with the latest mean activation time and adjacent minimum entropy were assembled together in a high-activation dispersion region. These regions accurately recognized diastolic paths of 34 VTs, often to multiple inducible VTs within a single individual arrhythmogenic region. In mathematical modeling, side branching from the main channel had a strong influence on the BiEGM composition along the main channel. The BiEGM obtained from a long unbranched channel had the lowest entropy compared with those with multiple side branches. In conclusion, among a population of multicomponent sinus electrograms, those that demonstrate low entropy and are delayed colocalize to critical long-protected channels of VT. This information is pertinent for planning VT ablation in sinus rhythm. NEW & NOTEWORTHY Entropy is a measure to quantify breakdown in information. Electrograms from a protected tissue channel can only possess a few states in their voltage and thus less information. In contrast, current-load interactions from side branches in unprotected channels introduce a number of dissimilar voltage deflections and thus high information. We compare here a mapping approach based on entropy against a rigorous reference standard of activation mapping during VT and entropy was assessed in sinus rhythm.

Determinants of atrial bipolar voltage: Inter electrode distance and wavefront angle.

BACKGROUND: Local bipolar electrogram (EGM) peak-to-peak voltage (Vpp) is currently used to characterise mapped myocardial substrate. However, how interelectrode distance and angle of wavefront incidence affect bipolar, Vpp values, in the current era of multi-electrode mapping is unknown. OBJECTIVES: To elucidate the effects of tissue and electrode geometry on bipolar Vpp measurements, when mapping healthy versus diseased atrial regions. METHODS: A bidomain model of human atrial tissue was used to quantify the influence on Vpp values of various electrode configurations in healthy tissue, and tissue containing an unexcitable region. The orientation angle and interelectrode spacing of a surface bipole, and thickness and depth of the unexcitable core were serially varied. Results were validated with data obtained from isolated porcine hearts. RESULTS: In healthy tissue, bipolar Vpp values increased with increasing interelectrode spacing and plateaued beyond a spacing of approximately 4 mm. The bipolar Vpp values in healthy tissue were relatively less sensitive to wavefront orientation angle with large interelectrode spacing. In diseased tissue, on the contrary, with increasing interelectrode spacing, bipolar Vpp values increased linearly without a plateau and were more sensitive to orientation angle. The bipolar Vpp values decreased with increasing thickness of the scar, with larger relative decrease in small bipoles than larger ones. Bipolar Vpp values increased with a progressively intramural location of fixed-size scar and became less distinguishable from healthy tissue especially for smaller interelectrode spacings. CONCLUSIONS: The scalable relationship established for interelectrode distances favour an electric-field-based assessment as opposed to traditional Vpp values as a tool for physiologically relevant measurement for mapping catheters with interelectrode spacing up to 4 mm. This will allow for universal assessment of myocardial health across catheters with varied spacing.

Multicenter Study of Ischemic Ventricular Tachycardia Ablation With Decrement-Evoked Potential (DEEP) Mapping With Extra Stimulus.

OBJECTIVES: The authors conducted a multicenter study of decrement-evoked potential (DEEP)-based functional ventricular tachycardia (VT) substrate modification to evaluate if such a mechanistic and physiological strategy is feasible and efficient in clinical practice and provides reduction in the VT burden. BACKGROUND: Only a fraction of the myocardium targeted in current VT substrate modification procedures is involved in the initiation and perpetuation of VT. The physiological basis of the DEEP strategy for identification of areas of initiation and maintenance of VT was recently established. METHODS: We included 20 consecutive patients with ischemic cardiomyopathy. During substrate mapping, fractionated and late potentials (LPs) were tagged, and an extra stimulus was performed to determine which LPs displayed decrement (DEEPs). All patients underwent DEEP-focused ablation: elimination of DEEP + further radiofrequency (RF) if VT was still inducible. Patients were followed during 6 months. RESULTS: Patients were predominantly male (95%), and their mean age was 64.6 ± 17.1 years. Mean left ventricular ejection fraction was 33.4 ± 11.4%. Mean ablation time was 30.6 ± 20.4 min. Specificity of DEEPs to detect the isthmus of VT was better than that of LPs (0.97 [95% confidence interval [CI]: 0.95 to 0.98] vs. 0.82 [95% CI: 0.73 to 0.89]), without significant differences in terms of sensitivity (0.61 [95% CI: 0.52 to 0.69] vs. 0.60 [95% CI: 0.44 to 0.74], respectively). Fifteen of 20 (75%) patients were free of any VT after DEEP-RF at 6 months of follow-up and there was a strong reduction in VT burden compared to 6 months pre-ablation. CONCLUSIONS: In a multicenter prospective study, DEEP substrate mapping identified the functional substrate critical to the VT circuit with high specificity. DEEP-guided VT ablation, by its physiological nature, may enable greater access to focused ablation therapy for patients requiring VT treatment.

Quantifying the determinants of decremental response in critical ventricular tachycardia substrate.

BACKGROUND: Decremental response evoked with extrastimulation (DEEP) is a useful tool for determining diastolic return path of ventricular tachycardia (VT). Though a targeted VT ablation is feasible with this approach, determinants of DEEP response have not been studied OBJECTIVES: To elucidate the effects of clinically relevant factors, specifically, the proximity of the stimulation site to the arrhythmogenic scar, stimulation wave direction, number of channels open in the scar, size of the scar and number of extra stimuli on decrement and entropy of DEEP potentials. METHODS: In a 3-dimensional bi-domain simulation of human ventricular tissue (TNNP cell model), an irregular subendocardial myopathic region was generated. An irregular channel of healthy tissue with five potential entry branches was shaped into the myopathic region. A bipolar electrogram was derived from two electrodes positioned in the centre of the myopathic region. Evoked delays between far-field and local Electrogram (EGM) following an extrastimulus (S1-S2, 500-350 ms) were measured as the stimulation site, channel branches, and inexcitable tissue size were altered. RESULTS: Stimulation adjacent to the inexcitable tissue from the side opposite to the point-of-entry produces longest DEEP delay. The DEEP delay shortens when the stimulation point is farther away from the scar, and it decreases maximally when stimulation is done from a site beside a conduction barrier. Entropy increases with S2 when stimulation site is from farther away. An unprotected channel structure with multiple side-branch openings had shorter DEEP delay compared to a protected channel structure with a paucity of additional side-branch openings and a point-of-entry on the side opposite to the pacing source. Addition of a second shorter extrastimulus did not universally lead to higher DEEP delay CONCLUSIONS: Location and direction of the wavefront in relation to scar entry and size of scar determine the degree of evoked response while the number of extrastimuli has a small additional decremental effect.

The effect of left ventricular pacing on transmural activation delay in myopathic human hearts.

Aims: Left ventricular (LV) epicardial pacing (LVEpiP) in human myopathic hearts does not decrease global epicardial activation delay compared with right ventricular (RV) endocardial pacing (RVEndoP); however, the effect on transmural activation delay has not been evaluated. To characterize the transmural electrical activation delay in human myopathic hearts during RVEndoP and LVEpiP compared with global epicardial activation delay. Methods and results: Explanted hearts from seven patients (5 male, 46 ± 10 years) undergoing cardiac transplantation were Langendorff-perfused and mapped using an epicardial sock electrode array (112 electrodes) and 25 transmural plunge needles (four electrodes, 2 mm spacing), for a total of 100 unipolar transmural electrodes. Electrograms were recorded during LVEpiP and RVEndoP, and epicardial (sock) and transmural (needle) activation times, along with patterns of activation, were compared. There was no difference between the global epicardial activation times (LVEpiP 147 ± 8 ms vs. RVEndoP 156 ± 17 ms, P = 0.46). The mean LV transmural activation time during LVEpiP was significantly shorter than that during RVEndoP (125 ± 44 vs. 172 ± 43 ms, P < 0.001). During LVEpiP, of the transmural layers endo-, mid-myocardium and epicardium, LV endocardial layer was often the earliest compared with other transmural layers. Conclusion: In myopathic human hearts, LVEpiP did not decrease global epicardial activation delays compared with RVEndoP. LV epicardial pacing led to early activation of the LV endocardium, revealing the importance of the LV endocardium even when pacing from the LV epicardium.

Physiological Assessment of Ventricular Myocardial Voltage Using Omnipolar Electrograms.

BACKGROUND: Characterization of myocardial health by bipolar electrograms are critical for ventricular tachycardia therapy. Dependence of bipolar electrograms on electrode orientation may reduce reliability of voltage assessment along the plane of arrhythmic myocardial substrate. Hence, we sought to evaluate voltage assessment from orientation-independent omnipolar electrograms. METHODS AND RESULTS: We mapped the ventricular epicardium of 5 isolated hearts from each species-healthy rabbits, healthy pigs, and diseased humans-under paced conditions. We derived bipolar electrograms and voltage peak-to-peak (Vpps) along 2 bipolar electrode orientations (horizontal and vertical). We derived omnipolar electrograms and Vpps using omnipolar electrogram methodology. Voltage maps were created for both bipoles and omnipole. Electrode orientation affects the bipolar voltage map with an average absolute difference between horizontal and vertical of 0.25±0.18 mV in humans. Vpps provide larger absolute values than horizontal and vertical bipolar Vpps by 1.6 and 1.4 mV, respectively, in humans. Bipolar electrograms with the largest Vpps from either along horizontal or vertical orientation are highly correlated with omnipolar electrograms and with Vpps values (0.97±0.08 and 0.94±0.08, respectively). Vpps values are more consistent than bipoles, in both beat-by-beat (CoV, 0.28±0.19 versus 0.08±0.13 in human hearts) and rhythm changes (0.55±0.21 versus 0.40±0.20 in porcine hearts). CONCLUSIONS: Omnipoles provide physiologically relevant and consistent voltages that are along the maximal bipolar direction on the plane of the myocardium.

Effects of Late Sodium Current Blockade on Ventricular Refibrillation in a Rabbit Model.

BACKGROUND: After defibrillation of initial ventricular fibrillation (VF), it is crucial to prevent refibrillation to ensure successful resuscitation outcomes. Inability of the late Na+ current to inactivate leads to intracellular Ca2+ dysregulation and arrhythmias. Our aim was to determine the effects of ranolazine and GS-967, inhibitors of the late Na+ current, on ventricular refibrillation. METHODS AND RESULTS: Long-duration VF was induced electrically in Langendorff-perfused rabbit hearts (n=22) and terminated with a defibrillator after 6 minutes. Fibrillating hearts were randomized into 3 groups: treatment with ranolazine, GS-967, or nontreated controls. In the treated groups, hearts were perfused with ranolazine or GS-967 at 2 minutes of VF. In control experiments, perfusion solution was supplemented with isotonic saline in lieu of a drug. Inducibility of refibrillation was assessed after initial long-duration VF by attempting to reinduce VF. Sustained refibrillation was successful in fewer ranolazine-treated (29.17%; P=0.005) or GS-967-treated (45.83%, P=0.035) hearts compared with that in nontreated control hearts (84.85%). In GS-967-treated hearts, significantly more spontaneous termination of initial long-duration VF was observed (66.67%; P=0.01). Ca2+ transient duration was reduced in ranolazine-treated hearts compared with that in controls (P=0.05) and also Ca2+ alternans (P=0.03). CONCLUSIONS: Late Na+ current inhibition during long-duration VF reduces the susceptibility to subsequent refibrillation, partially by mitigating dysregulation of intracellular Ca2+. These results suggest the potential therapeutic use of ranolazine and GS-967 and call for further testing in cardiac arrest models.

Effect of spatial resolution and filtering on mapping cardiac fibrillation.

BACKGROUND: Endocardial mapping tools use variable interelectrode resolution, whereas body surface mapping tools use narrow bandpass filtering (BPF) to map fibrillatory mechanisms established by high-resolution optical imaging. OBJECTIVE: The purpose of this study was to study the effect of resolution and BPF on the underlying mechanism being mapped. METHODS: Hearts from 14 healthy New Zealand white rabbits were Langendorff perfused. We studied the effect of spatial resolution and BPF on the location and characterization of rotors by comparing phase singularities detected by high-resolution unfiltered optical maps and of fibrillating myocardium with decimated and filtered maps with simulated electrode spacing of 2, 5, and 8 mm. RESULTS: As we decimated the maps with 2-mm, 5-mm, and 8-mm interelectrode spacing, the mean ( ± SD) number of rotors detected decreased from 10.2 ± 9.6, 1.6 ± 3.2, and 0.2 ± 0.5, respectively. Lowering the resolution led to synthesized pseudo-rotors that may be inappropriately identified. Applying a BPF led to fewer mean phase singularities detected (248 ± 207 vs 333 ± 130; P<.01), giving the appearance of pseudo-spatial stability measured as translation index (with BPF 3.6 ± 0.4 mm vs 4.0 ± 0.5 mm without BPF; P<.01) and pseudo-temporal stability with longer duration (70.0 ± 17.6 ms in BPF maps vs 44.1 ± 6.6 ms in unfiltered maps; P<.001) than true underlying fibrillating myocardium mapped. CONCLUSION: Electrode resolution and BPF of electrograms can result in distortion of the underlying electrophysiology of fibrillation. Newer mapping techniques need to demonstrate sensitivity analysis to quantify the degree of distortion before clinical use to avoid inaccurate electrophysiologic interpretation.

Orientation-Independent Catheter-Based Characterization of Myocardial Activation.

Cardiac electrogram (EGM) signals and electrophysiologic (EP) characteristics derived from them such as amplitude and timing are central to the diagnosis and therapeutic management of arrhythmias. Bipolar EGMs are often used but possess polarity and shape dependence on catheter orientation contributing to uncertainty. OBJECTIVE: We describe a novel method to map cardiac activation that resolves signals into meaningful directions and is insensitive to electrode directional effects. METHODS: Multielectrode catheters that span 2- and 3-D space are used to derive local electric field (E-field) signals. A traveling wave model of local EGM propagation motivates a new "omnipolar" reference frame in which to understand EGM E-field signals and provide bipolar component EGMs aligned with these anatomic and physiologic directions. We validate the basis of this technology and determine its accuracy using a saline tank in which we simulate physiologic propagation. RESULTS: Omnipole signals from healthy tissue are nearly free of catheter orientation effects and are constrained by biophysics to consistent morphologies and thus consistent measured amplitudes and timings. Using a 3-D EP mapping system, traveling wave treatment, and omnipolar technology (OT) E-field loops, we derived a new and nearly instantaneous means to determine conduction velocity and activation direction. CONCLUSION: We describe the basis of OT and validate it with ablation and mapping catheters in a saline tank. Finally, we illustrate OT with signals from live subjects. SIGNIFICANCE: OT's novel approach with signal processing and real-time visualization allows for a newly detailed characterization of myocardial activation that is insensitive to catheter orientation.

Decrement Evoked Potential Mapping: Basis of a Mechanistic Strategy for Ventricular Tachycardia Ablation.

BACKGROUND: Substrate-based mapping for ventricular tachycardia (VT) ablation is hampered by its inability to determine critical sites of the VT circuit. We hypothesized that those potentials, which delay with a decremental extrastimulus (decrement evoked potentials or DEEPs), are more likely to colocalize with the diastolic pathways of VT circuits. METHODS AND RESULTS: DEEPs were identified in intraoperative left ventricular maps from 6 patients with ischemic cardiomyopathy (total 9 VTs) and were compared with late potential (LP) and activation maps of the diastolic pathway for each VT. Mathematical modeling was also used to further validate and elucidate the mechanisms of DEEP mapping. All patients demonstrated regions of DEEPs and LPs. The mean endocardial surface area of these potentials was 18±4% and 21±6%, respectively (P=0.13). The mean sensitivity for identifying the diastolic pathway in VT was 50±23% for DEEPs and 36±32% for LPs (P=0.31). The mean specificity was 43±23% versus 20±8% for DEEP and LP mapping, respectively (P=0.031). The electrograms that displayed the greatest decrement in each case had a sensitivity and specificity for the VT isthmus of 29±10% and 95±1%, respectively. Mathematical modeling studies recapitulated DEEPs at the VT isthmus and demonstrated their role in VT initiation with a critical degree of decrement. CONCLUSIONS: In this preliminary study, DEEP mapping was more specific than LP mapping for identifying the critical targets of VT ablation. The mechanism of DEEPs relates to conduction velocity restitution magnified by zigzag conduction within scar channels.

Tracking rotors with minimal electrodes: modulation index-based strategy.

BACKGROUND: High-frequency periodic sources during cardiac fibrillation can be detected by phase mapping techniques. To enable practical therapeutic options for modulating periodic sources (existing techniques require high density multielectrode arrays and real time simultaneous mapping capability), a method to identify electrogram morphologies colocalizing to rotors that can be implemented on few electrograms needs to be devised. METHOD AND RESULTS: Multichannel ventricular fibrillation electrogram data from 7 isolated human hearts using Langendorff setup and intraoperative clinical data from 2 human hearts were included in the analysis. The spatial locations of rotors were identified using phase maps constructed from 112 electrograms. Electrograms were analyzed for repeating patterns and discriminating signal morphologies around the locations of rotors and nonrotors were identified and quantified. Features were extracted from the unipolar electrogram patterns, which corroborated well with the spatial location of rotors. The results suggest that using the proposed modulation index feature, and as low as 1 sample point in the vicinity of the rotors, an accuracy as high as 86% (P<0.001) was obtained in separating rotor locations versus nonrotor locations. The analysis of bipolar electrogram signatures in the vicinity of the rotor locations suggest that 62.5% of the rotors occur at locations where the bipolar electrogram demonstrates continuous activities during ventricular fibrillation. CONCLUSIONS: Unipolar electrogram extracted modulation index-based detection of rotors is feasible with few electrodes and has greater detection rate than bipolar approach. This strategy may be suitable for nonarray-based single mapping catheter enabled detection of rotors.

Bipolar ablation for deep intra-myocardial circuits: human ex vivo development and in vivo experience.

AIMS: Current conventional ablation strategies for ventricular tachycardia (VT) aim to interrupt reentrant circuits by creating ablation lesions. However, the critical components of reentrant VT circuits may be located at deep intramural sites. We hypothesized that bipolar ablations would create deeper lesions than unipolar ablation in human hearts. METHODS AND RESULTS: Ablation was performed on nine explanted human hearts at the time of transplantation. Following explant, the hearts were perfused by using a Langendorff perfusion setup. For bipolar ablation, the endocardial catheter was connected to the generator as the active electrode and the epicardial catheter as the return electrode. Unipolar ablation was performed at 50 W with irrigation of 25 mL/min, with temperature limit of 50°C. Bipolar ablation was performed with the same settings. Subsequently, in a patient with an incessant septal VT, catheters were positioned on the septum from both the ventricles and radiofrequency was delivered with 40 W. In the explanted hearts, there were a total of nine unipolar ablations and four bipolar ablations. The lesion depth was greater with bipolar ablation, 14.8 vs. 6.1 mm (P < 0.01), but the width was not different (9.8 vs. 7.8 mm). All bipolar lesions achieved transmurality in contrast to the unipolar ablations. In the patient with a septal focus, bipolar ablation resulted in termination of VT with no inducible VTs. CONCLUSION: By using a bipolar ablation technique, we have demonstrated the creation of significantly deeper lesions without increasing the lesion width, compared with standard ablation. Further clinical trials are warranted to detail the risks of this technique.

Electrical remodelling precedes heart failure in an endothelin-1-induced model of cardiomyopathy.

AIMS: Binary transgenic (BT) mice with doxycycline (DOX)-suppressible cardiac-specific overexpression of endothelin-1 (ET-1) exhibit progressive heart failure (HF), QRS prolongation, and death following DOX withdrawal. However, the molecular basis and reversibility of the electrophysiological abnormalities in this model were not known. Here, we assess the mechanisms underlying ET-1-mediated electrical remodelling, and its role in HF. METHODS AND RESULTS: BT vs. non-BT littermate controls were withdrawn from DOX and serially studied with ultrasound biomicroscopy, octapolar catheters, multielectrode epicardial mapping, histopathology, western blot, immunohistochemistry, and qRT-PCR. Abnormalities in ventricular activation and -dV/dt were detected as early as 4 weeks after transgene activation, when the structure and function of the heart remained unaffected. By 8 weeks of ET-1 overexpression, biventricular systolic and diastolic dysfunction, myocardial fibrosis, and cardiomyocyte hypertrophy were observed. Intracardiac and epicardial electrograms revealed prolonged conduction and ventricular activation, reduced -dV/dt, and abnormal atrioventricular nodal function. Within 4 weeks of ET-1 induction, connexin 40 (Cx40) protein and Cx43 mRNA, protein, and phosphorylation levels were reduced by 36, 64, 93, and 69%, respectively; Na(v)1.5 mRNA and protein levels were reduced by 30 and 50%, respectively, as was Na(+) channel conductance. Importantly, the associated electrophysiological abnormalities at this time point were reversible upon suppression of ET-1 overexpression and completely prevented the development of structural and functional remodelling. CONCLUSION: ET-1-mediated electrical remodelling correlates with reduced Cx40, Cx43, and Na(v)1.5 expression and decreased Na(+) channel conductance and precedes HF. The sequence and reversibility of this phenotype suggest that a primary abnormality in electrical remodelling may contribute to the pathogenesis of HF.

Effect of global ischemia and reperfusion during ventricular fibrillation in myopathic human hearts.

The effect of lack of global coronary perfusion on myocardial activation rate, wavebreak, and its temporal progression during human ventricular fibrillation (VF) is not known. We tested the hypothesis that global myocardial ischemia decreases activation rate and spatiotemporal organization during VF in myopathic human hearts, while increasing wavebreak, and that a short duration of reperfusion can restore these spatiotemporal changes to baseline levels. The electrograms were acquired during VF in a human Langendorff model using global mapping consisting of two 112-electrode arrays placed on the epicardium and endocardium simultaneously. We found that global myocardial ischemia results in slowing of the global activation rate (combined endo and epi), from 4.89+/-0.04 Hz. to 3.60+/-0.04 Hz. during the 200 s of global ischemia (no coronary flow) (P<0.01) in eight myopathic hearts. Two minutes of reperfusion contributed to reversal of the slowing with activation rate value increasing close to VF onset (4.72+/-0.04 Hz). In addition, during the period of ischemia, an activation rate gradient between the endocardium (3.76+/-0.06 Hz) and epicardium (3.45+/-0.06 Hz) was observed (P<0.01). There was a concomitant difference in wavebreak index (that provides a normalized parameterization of phase singularities) between the epicardium (11.29+/-2.7) and endocardium (3.25+/-2.7) during the 200 s of ischemia (P=0.02). The activation rate, gradient, and wavebreak changes were reversed by short duration (2 min) of reperfusion. Global myocardial ischemia of 3 min leads to complex spatiotemporal changes during VF in myopathic human hearts; these changes can be reversed by a short duration of reperfusion.

Spatiotemporal frequency analysis of ventricular fibrillation in explanted human hearts.

Ventricular fibrillation (VF) is a medical condition that occurs due to rapid and irregular electrical activity of heart. If undiagnosed or untreated, VF leads to sudden cardiac death. VF has been studied by researchers for over 100 years to elucidate the mechanism that maintains VF, and thus to arrive at therapeutic options. VF is a nonstationary process, and it manifests into variations in the waveform morphology, phase, and frequency dynamics of the surface electrograms. Dominant frequency analysis (DF maps) and phase maps are two widely used complementary approaches in assessing the evolution of VF process. These techniques are applied to electrograms or fluorescence signals obtained with voltage-sensitive dyes. In spite of VF being a nonstationary process, most of the existing literature limits frequency analysis to a segmented, time-averaged spectral analysis, where valuable information on the instantaneous temporal evolution of the spectral characteristics is lost. In order to resolve this issue, in this paper, we present a joint time-frequency approach that is suited for VF analysis and demonstrate the application of instantaneous mean frequency (IMF) in interpreting VF episodes. Human VF sources are rarely anatomically stable and are migratory. Traditional DF techniques fail in tracking this migratory behavior. IMF, on the other hand, can deal with these migratory sources and conduction blocks better than DF approaches. Results of the analysis using the electrograms of 204 VF segments obtained from 13 isolated human hearts (explanted during cardiac transplantation) indicate that in 81% of the VF segments, there were significant changes in the spatiotemporal evolution of the frequency, suggesting that IMF provides better mechanistic insight of these signals. The IMF tool presented in this paper demonstrates potential for applications in tracking frequency patterns, conduction blocks, and arriving at newer therapies to modulate VF.