Nicholas S. Peters

Characterization of Left Atrial Activation in the Intact Human Heart

Background—The patterns of activation of the human left atrium (LA), how they relate to atrial myocardial architecture, and their role in arrhythmogenesis remain largely unknown. Methods and Results—Left atrial endocardial activation was mapped in 19 patients with a percutaneous noncontact mapping system. Earliest endocardial breakthrough during sinus rhythm (SR) occurred more frequently in the septal (63%, principally posteroseptal) than anterosuperior (37%) LA and varied little with isoproterenol or high right atrial pacing rate. Regardless of site of breakthrough, LA activation was characterized in all patients by propagation around a variably complete line of functional conduction block, descending on the posterior wall from the roof, passing between the ostia of the superior and then inferior pulmonary veins (PVs) before turning septally, passing below the oval fossa, and merging further anteriorly with the septal mitral annulus. Examination of the myocardial architecture in 10 normal adult postmortem hearts revealed an abrupt change in subendocardial fiber orientation along a line following the same course. During episodes of focal initiation of atrial fibrillation (AF), interaction was observed between wavefronts entering the LA from PVs and this functional line of conduction block that resulted in LA macroreentry or formation of daughter wavefronts. Conclusions—The LA endocardium has complex but characteristic patterns of activation during sinus rhythm, pacing, and AF initiation by PV ectopy that are determined largely by the functional properties of atrial musculature. These findings have important implications for both pacing and ablative strategies for the prevention of initiation of AF.

Experience of robotic catheter ablation in humans using a novel remotely steerable catheter sheath

BackgroundA novel remotely controlled steerable guide catheter has been developed to enable precise manipulation and stable positioning of any eight French (Fr) or smaller electrophysiological catheter within the heart for the purposes of mapping and ablation.ObjectiveTo report our initial experience using this system for remotely performing catheter ablation in humans.MethodsConsecutive patients attending for routine ablation were recruited. Various conventional diagnostic catheters were inserted through the left femoral vein in preparation for treating an accessory pathway (nu2009=u20091), atrial flutter (nu2009=u20092) and atrial fibrillation (nu2009=u20097). The steerable guide catheter was inserted into the right femoral vein through which various irrigated and non-irrigated tip ablation catheters were used. Conventional endpoints of loss of pathway conduction, bidirectional cavotricuspid isthmus block and four pulmonary vein isolation were used to determine acute procedural success.ResultsTen patients underwent remote catheter ablation using conventional and/or 3D non-fluoroscopic mapping technologies. All procedural endpoints were achieved using the robotic control system without manual manipulation of the ablation catheter. There was no major complication. A radiation dosimeter positioned next to the operator 2.7xa0m away from the X-ray source showed negligible exposure despite a mean cumulative dose area product of 7,281.4xa0cGycm2 for all ten ablation procedures.ConclusionsSafe and clinically effective remote navigation of ablation catheters can be achieved using a novel remotely controlled steerable guide catheter in a variety of arrhythmias. The system is compatible with current mapping and ablation technologies Remote navigation substantially reduces radiation exposure to the operator.

Ablation of Persistent Atrial Fibrillation Using Multielectrode Catheters and Duty-Cycled Radiofrequency Energy

OBJECTIVESnThe purpose of this study was to assess the efficacy and safety of a novel, multielectrode, duty-cycled radiofrequency ablation (RFA) system for long-standing persistent atrial fibrillation (AF).nnnBACKGROUNDnRFA for persistent AF remains a lengthy and challenging procedure.nnnMETHODSnIn 5 European centers, 50 patients with long-standing persistent AF underwent RFA. A circular pulmonary vein (PV) ablation catheter was used for PV isolation. Complex fractionated atrial electrograms were targeted at the interatrial septum using a multiarray septal ablation catheter and in the left atrium using a multiarray ablation catheter.nnnRESULTSnDuring a mean total procedure time of 155 +/- 40 min, complete PV isolation and complex fractionated atrial electrogram ablation were achieved in all patients. In 50% of patients, redo ablation was performed using the same strategy and technology. There were no device-related adverse events. At 6 months, a 7-day Holter electrocardiogram showed >80% AF reduction in 40 of 50 patients (80%), and 32 of 50 (64%) were off antiarrhythmic drugs. At 20 +/- 4 months after the last procedure, 31 of 47 patients (66%) had a >80% reduction in AF burden, with 21 patients (45%) free of AF and off antiarrhythmic drugs.nnnCONCLUSIONSnThis initial 50-patient multicenter study demonstrates a 80% short-term and 66% success rate at 20 months, with a low complication rate and a relatively short procedure time in patients with persistent AF using 3 anatomically specific multielectrode ablation catheters and low-energy duty-cycled radiofrequency energy.

Targeted deletion of kcne2 impairs ventricular repolarization via disruption of IK,slow1 and Ito,f

Mutations in human KCNE2, which encodes the MiRP1 potassium channel ancillary subunit, associate with long QT syndrome (LQTS), a defect in ventricular repolarization. The precise cardiac role of MiRP1 remains controversial, in part, because it has marked functional promiscuity in vitro. Here, we disrupted the murine kcne2 gene to define the role of MiRP1 in murine ventricles. kcne2 disruption prolonged ventricular action potential duration (APD), suggestive of reduced repolarization capacity. Accordingly, kcne2 (−/−) ventricles exhibited a 50% reduction in IK,slow1, generated by Kv1.5—a previously unknown partner for MiRP1. Ito,f, generated by Kv4 α subunits, was also diminished, by ~25%. Ventricular MiRP1 protein coimmunoprecipitated with native Kv1.5 and Kv4.2 but not Kv1.4 or Kv4.3. Unexpectedly, kcne2 (−/−) ventricular membrane fractions exhibited 50% less mature Kv1.5 protein than wild type, and disruption of Kv1.5 trafficking to the intercalated discs. Consistent with the reduction in ventricular K+ currents and prolonged ventricular APD, kcne2 deletion lengthened the QTc under sevoflurane anesthesia. Thus, targeted disruption of kcne2 has revealed a novel cardiac partner for MiRP1, a novel role for MiRPs in α subunit targeting in vivo, and a role for MiRP1 in murine ventricular repolarization with parallels to that proposed for the human heart.—Roepke, T. K., Kontogeorgis, A., Ovanez, C., Xu, X., Young, J. B., Purtell, K., Goldstein, P. A., Christini, D. J., Peters, N. S., Akar, F. G., Gutstein, D. E., Lerner, D. J., Abbott, G. W. Targeted deletion of kcne2 impairs ventricular repolarization via disruption of IK,slow1 and Ito,f. FASEB J. 22, 3648–3660 (2008)

Relationship Between Connexins and Atrial Activation During Human Atrial Fibrillation

Introduction: Gap junctional connexin proteins (connexin40 [Cx40], connexin43 [Cx43]) are a determinant of myocardial conduction and are implicated in the development of atrial fibrillation (AF). We hypothesized that atrial activation pattern during AF is related to connexin expression and that this relationship is altered by AF‐induced remodeling in the fibrillating atria of chronic AF.

Characterization of the Electroanatomical Substrate in Human Atrial Fibrillation: The Relationship between Changes in Atrial Volume, Refractoriness, Wavefront Propagation Velocities, and AF Burden

Introduction: Progressive remodeling occurs in experimental models of AF whereby slowing of conduction, shortening of refractoriness, and atrial dilatation are associated with an increased vulnerability to atrial fibrillation (AF). This study investigates the relative changes in atrial geometry and electrophysiology with increasing AF burden in humans.

Spatiotemporal Behavior of High Dominant Frequency During Paroxysmal and Persistent Atrial Fibrillation in the Human Left Atrium

Background— Sites of high dominant frequency (DFpeak) are thought to indicate the location of drivers of atrial fibrillation (AF), but characterization of their spatiotemporal distribution and stability, critical to their relevance as targets for catheter ablation, requires simultaneous global mapping of the left atrium. Methods and Results— Noncontact electrograms recorded simultaneously from 256 left atrial sites during spontaneous AF were analyzed. After subtraction of the ventricular component, fast Fourier transform identified the DF at each site. Focal areas of DFpeak were defined as those having a DF >20% above all neighboring sites. Twenty-four patients with spontaneous AF (11 paroxysmal and 13 persistent) were studied. In paroxysmal AF, sites of DFpeak (mean DF, 11.6±2.9 Hz) were observed in 100% of patients (present during 65% of the mapping period). In contrast, DFpeak was detected in only 31% of patients with persistent AF (P<0.001) and for only 5% of the mapping period (P<0.001). In both groups, locations of DFpeak varied widely in both consecutive and separated segments of AF (&kgr; coefficient range, -0.07–0.22). Activation sequences around sites of DFpeak did not demonstrate centrifugal activation that would be expected from focal drivers. Conclusions— Focal areas of high DF are more frequent in paroxysmal than persistent AF, are spatiotemporally unstable, are not the source of centrifugal activation, and are not, therefore, indicative of fixed drivers of AF. In the absence of spatiotemporal stability, the success of ablation at sites of DFpeak cannot be explained by elimination of fixed drivers.

Adrenergic regulation of a key cardiac potassium channel can contribute to atrial fibrillation: evidence from an IKs transgenic mouse

Inherited gain‐of‐function mutations of genes coding for subunits of the heart slow potassium (IKs) channel can cause familial atrial fibrillation (AF). Here we consider a potentially more prevalent mechanism and hypothesize that β‐adrenergic receptor (β‐AR)‐mediated regulation of the IKs channel, a natural gain‐of‐function pathway, can also lead to AF. Using a transgenic IKs channel mouse model, we studied the role of the channel and its regulation by β‐AR stimulation on atrial arrhythmias. In vivo administration of isoprenaline (isoproterenol) predisposes IKs channel transgenic mice but not wild‐type (WT) littermates that lack IKs to prolonged atrial arrhythmias. Patch‐clamp analysis demonstrated expression and isoprenaline‐mediated regulation of IKs in atrial myocytes from transgenic but not WT littermates. Furthermore, computational modelling revealed that β‐AR stimulation‐dependent accumulation of open IKs channels accounts for the pro‐arrhythmic substrate. Our results provide evidence that β‐AR‐regulated IKs channels can play a role in AF and imply that specific IKs deregulation, perhaps through disruption of the IKs macromolecular complex necessary for β‐AR‐mediated IKs channel regulation, may be a novel therapeutic strategy for treating this most common arrhythmia.

The atrioventricular delay of cardiac resynchronization can be optimized hemodynamically during exercise and predicted from resting measurements.

BACKGROUNDnAtrioventricular (AV) optimization of cardiac resynchronization therapy (CRT) is typically calculated at rest. However, patients often become symptomatic during exercise.nnnOBJECTIVEnIn this study, we use acute noninvasive hemodynamics to optimize the AV delay of CRT during exercise and investigate whether this exercise optimum can be predicted from a three-phase resting model.nnnMETHODSnIn 20 patients with CRT, we adjusted the sensed AV delay while the patient exercised on a treadmill up to a heart rate of 100 bpm to identify the hemodynamically optimal value. Separately, at rest, by pacing with three different configurations and calculating the sensed-paced difference, we calculated an expected value for the exercise optimum.nnnRESULTSnIt was possible to perform AV delay optimization while a patient exercised. The resting three-phase model correlated well with the actual exercise optimal AV delay (r = 0.85, mean difference +/- standard deviation [SD] = 3.7 +/- 17 ms). Simply using measurements made at rest during atrial-sensed pacing showed a poorer correlation with exercise (r = 0.64, mean difference +/- SD = 2.2 +/- 24 ms). The three-phase resting model allows improved exercise hemodynamics to be achieved. Programming according to the three-phase resting model yields an exercise blood pressure of only 0.5 mmHg (+/-1.4 mmHg; P = NS) less than the true exercise optimum, whereas programming the resting sensed optimum yields an exercise blood pressure of 1.4 mmHg (+/-2.2 mmHg, P = .02) less than the true optimum.nnnCONCLUSIONSnUsing acute noninvasive hemodynamics and a protocol of alternations, it is possible to optimize the AV delay of cardiac resynchronization devices even while a patient exercises. In clinical practice, the exercise optimum AV delay could be determined from three phases of resting measurements, without performing exercise.

Localization of the isthmus in reentrant circuits by analysis of electrograms derived from clinical noncontact mapping during sinus rhythm and ventricular tachycardia.

Introduction: New methods for electrogram analysis accurately estimated reentrant circuit isthmus location and shape in a canine model. It was hypothesized that these methods also would locate reentrant circuits causing clinical ventricular tachycardia (VT).