Publications by authors named "David E Krummen"

74 Publications

Linking Electrical Drivers With Atrial Cardiomyopathy for the Targeted Treatment of Atrial Fibrillation.

Front Physiol 2020 12;11:570740. Epub 2020 Nov 12.

Division of Cardiology, Department of Medicine, University of California, San Diego, San Diego, CA, United States.

The relationship between atrial fibrillation (AF) and underlying functional and structural abnormalities has received substantial attention in the research literature over the past decade. Significant progress has been made in identifying these changes using non-invasive imaging, voltage mapping, and electrical recordings. Advances in computed tomography and cardiac magnetic resonance imaging can now provide insight regarding the presence and extent of cardiac fibrosis. Additionally, multiple technologies able to identify electrical targets during AF have emerged. However, an organized strategy to employ these resources in the targeted treatment of AF remains elusive. In this work, we will discuss the basis for mechanistic importance of atrial fibrosis and scar as potential sites promoting AF and emerging technologies to identify and target these structural and functional substrates in the electrophysiology laboratory. We also propose an approach to the use of such technologies to serve as a basis for ongoing work in the field.
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http://dx.doi.org/10.3389/fphys.2020.570740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689158PMC
November 2020

Machine Learned Cellular Phenotypes in Cardiomyopathy Predict Sudden Death.

Circ Res 2021 01 10;128(2):172-184. Epub 2020 Nov 10.

Department of Medicine and Cardiovascular Institute (A.J.R., A.S., M.I.A., T.B., P.C., P.J.W., S.M.N.), Stanford University.

Rationale: Susceptibility to VT/VF (ventricular tachycardia/fibrillation) is difficult to predict in patients with ischemic cardiomyopathy either by clinical tools or by attempting to translate cellular mechanisms to the bedside.

Objective: To develop computational phenotypes of patients with ischemic cardiomyopathy, by training then interpreting machine learning of ventricular monophasic action potentials (MAPs) to reveal phenotypes that predict long-term outcomes.

Methods And Results: We recorded 5706 ventricular MAPs in 42 patients with coronary artery disease and left ventricular ejection fraction ≤40% during steady-state pacing. Patients were randomly allocated to independent training and testing cohorts in a 70:30 ratio, repeated K=10-fold. Support vector machines and convolutional neural networks were trained to 2 end points: (1) sustained VT/VF or (2) mortality at 3 years. Support vector machines provided superior classification. For patient-level predictions, we computed personalized MAP scores as the proportion of MAP beats predicting each end point. Patient-level predictions in independent test cohorts yielded c-statistics of 0.90 for sustained VT/VF (95% CI, 0.76-1.00) and 0.91 for mortality (95% CI, 0.83-1.00) and were the most significant multivariate predictors. Interpreting trained support vector machine revealed MAP morphologies that, using in silico modeling, revealed higher L-type calcium current or sodium-calcium exchanger as predominant phenotypes for VT/VF.

Conclusions: Machine learning of action potential recordings in patients revealed novel phenotypes for long-term outcomes in ischemic cardiomyopathy. Such computational phenotypes provide an approach which may reveal cellular mechanisms for clinical outcomes and could be applied to other conditions.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.317345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855939PMC
January 2021

Termination of persistent atrial fibrillation by ablating sites that control large atrial areas.

Europace 2020 06;22(6):897-905

Department of Medicine and Cardiovascular Institute, Stanford University, 780 Welch Road, MC 5773, Stanford, CA 94305, USA.

Aims: Persistent atrial fibrillation (AF) has been explained by multiple mechanisms which, while they conflict, all agree that more disorganized AF is more difficult to treat than organized AF. We hypothesized that persistent AF consists of interacting organized areas which may enlarge, shrink or coalesce, and that patients whose AF areas enlarge by ablation are more likely to respond to therapy.

Methods And Results: We mapped vectorial propagation in persistent AF using wavefront fields (WFF), constructed from raw unipolar electrograms at 64-pole basket catheters, during ablation until termination (Group 1, N = 20 patients) or cardioversion (Group 2, N = 20 patients). Wavefront field mapping of patients (age 61.1 ± 13.2 years, left atrium 47.1 ± 6.9 mm) at baseline showed 4.6 ± 1.0 organized areas, each separated by disorganization. Ablation of sites that led to termination controlled larger organized area than competing sites (44.1 ± 11.1% vs. 22.4 ± 7.0%, P < 0.001). In Group 1, ablation progressively enlarged unablated areas (rising from 32.2 ± 15.7% to 44.1 ± 11.1% of mapped atrium, P < 0.0001). In Group 2, organized areas did not enlarge but contracted during ablation (23.6 ± 6.3% to 15.2 ± 5.6%, P < 0.0001).

Conclusion: Mapping wavefront vectors in persistent AF revealed competing organized areas. Ablation that progressively enlarged remaining areas was acutely successful, and sites where ablation terminated AF were surrounded by large organized areas. Patients in whom large organized areas did not emerge during ablation did not exhibit AF termination. Further studies should define how fibrillatory activity is organized within such areas and whether this approach can guide ablation.
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http://dx.doi.org/10.1093/europace/euaa018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273336PMC
June 2020

Predictors of rate-adaptive pacing in patients implanted with implantable cardioverter-defibrillator and subsequent differential clinical outcomes.

J Interv Card Electrophysiol 2019 Jun 30;55(1):83-91. Epub 2019 Mar 30.

Cardiac Electrophysiology Section, Division of Cardiology, Department of Medicine, University of California, San Diego, 9452 Medical Center Dr., 3rd Fl., Rm 3E-417, La Jolla, CA, 92037, USA.

Purpose: Patients with severe cardiomyopathy often have chronotropic incompetence, which is predominantly managed by activating rate-adaptive pacing in patients implanted with an implantable cardioverter-defibrillator (ICD) capable of atrial pacing. The purpose of this study was to determine predictors of rate-adaptive pacing activation, the cumulative incidence of activation, and the association of rate-adaptive pacing activation with subsequent clinical outcomes in an ICD population.

Methods: The authors evaluated 228 patients implanted with an ICD between 2011 and 2015. Multivariable logistic regression was used to evaluate predictors of rate-adaptive pacing activation. Cox proportional-hazards regression was used to examine associations of rate-adaptive pacing activation and clinical outcomes.

Results: Rate-adaptive pacing was turned on in 38.5% (n = 88) of patients during follow-up. Several statistically significant predictors of rate-adaptive pacing activation were found, particularly previous atrial fibrillation (odds ratio [OR] = 8.27, 95% confidence interval [CI] = 2.96-23.06, p < 0.001), previous myocardial infarction (OR = 4.17, 95% CI = 1.38-12.58, p = 0.01), and non-ischemic cardiomyopathy (OR = 3.83, 95% CI = 1.22-12.00, p = 0.02). In multivariable adjusted analyses, rate-adaptive pacing activation within 30 days of implantation was not associated with the risk of device therapy for tachyarrhythmias (hazard ratio [HR] = 1.52, 95% CI = 0.71-3.28, p = 0.29), atrial fibrillation (HR = 1.42, 95% CI = 0.71-2.87, p = 0.32), HF re-admission (HR = 1.39, 95% CI = 0.80-2.43, p = 0.25), nor all-cause mortality (HR = 2.34, 95% CI = 0.80-6.84, p = 0.12).

Conclusions: During follow-up, more than one in three HF patients implanted with an ICD developed the need for rate-adaptive pacing. Atrial fibrillation, prior myocardial infarction, and non-ischemic cardiomyopathy were statistically significant baseline clinical predictors of rate-adaptive pacing activation. Rate-adaptive pacing activation was not associated with subsequent adverse clinical outcomes.
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http://dx.doi.org/10.1007/s10840-019-00536-9DOI Listing
June 2019

Transient complete heart block following catheter ablation of a left lateral accessory pathway.

J Arrhythm 2019 Feb 3;35(1):155-157. Epub 2018 Nov 3.

Department of Medicine University of California San Diego San Diego California.

A 16-year-old female with symptomatic Wolff-Parkinson-White (WPW) syndrome underwent catheter ablation of a left-sided lateral accessory pathway. The accessory pathway was eliminated with the first ablation lesion; however, the patient immediately developed complete heart block (CHB). At first, complete heart block was thought to be due to ablation of left atrial extension of the AV node, and pacemaker therapy was considered. However, careful ECG analysis revealed that the development of CHB was in fact due to bump injury to the AV node during transseptal catheterization. Conservative management allowed resolution of AV nodal conduction without need for a permanent pacemaker.
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http://dx.doi.org/10.1002/joa3.12138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373828PMC
February 2019

Long-term mode and timing of premature ventricular complex recurrence following successful catheter ablation.

J Interv Card Electrophysiol 2019 Aug 7;55(2):153-160. Epub 2019 Feb 7.

Department of Medicine, Division of Cardiology, University of California San Diego, San Diego, CA, USA.

Purpose: Catheter ablation of premature ventricular contractions (PVCs) is highly successful and has become the hallmark treatment for symptomatic or highly prevalent cases. However, few studies exist that evaluate the outcomes of ablation and likely mechanisms of PVC recurrence beyond 1 year of follow-up.

Methods: This study is a retrospective analysis of patients who underwent catheter ablation for symptomatic PVCs with acute procedural success and had clinical follow-up ≥ 12 months.

Results: Forty-four patients (24 women; age 53.5 ± 4.8 years) following acutely successful PVC ablation with long-term follow-up were studied. At a mean of 36 ± 6 months, overall long-term ablation success was 75% (33/44 patients). Notably, recurrence of the targeted PVC focus was low (6.8%, 3/44 patients); the majority of recurrences were from a new source location (18.2%, 8/44 patients). The time course for targeted versus de novo PVC recurrences was significantly different: recurrence of a PVC similar to the targeted PVC morphology occurred at a mean of 5.0 ± 2.0 months, while recurrence of a PVC different from the index case occurred at a mean of 35.8 ± 17.1 months (p = 0.01). Non-ischemic cardiomyopathy was associated with increased risk of PVC recurrence (odds ratio [OR] 14.50 (95% confidence interval [CI] 1.92-109.33, p = 0.01)) and was a significant negative prognostic factor in multivariate analysis for PVC recurrence survival (hazard ratio [HR] 4.63, 95% CI 1.03-20.74, p = 0.04).

Conclusions: The majority of long-term PVC recurrences occur late in follow-up, at locations remote from the targeted PVC source or sources. Such sites may represent ongoing substrate evolution; additional work is required to determine the precise substrate alterations which promote such arrhythmogenic changes.
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http://dx.doi.org/10.1007/s10840-019-00520-3DOI Listing
August 2019

Successful ventricular fibrillation functional substrate ablation via a single vascular access site.

HeartRhythm Case Rep 2018 May 17;4(5):173-176. Epub 2018 Feb 17.

Department of Medicine, University of California San Diego, La Jolla, California.

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http://dx.doi.org/10.1016/j.hrcr.2017.12.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6003783PMC
May 2018

Interaction of Localized Drivers and Disorganized Activation in Persistent Atrial Fibrillation: Reconciling Putative Mechanisms Using Multiple Mapping Techniques.

Circ Arrhythm Electrophysiol 2018 06;11(6):e005846

Department of Medicine, Stanford University, CA (C.A.B.K., F.S., M.R., P.C., G.M., M.I.A., M.A.S., V.J., J.A.B.Z., T.B., A.J.R., P.J.W., S.M.N.).

Background: Mechanisms for persistent atrial fibrillation (AF) are unclear. We hypothesized that putative AF drivers and disorganized zones may interact dynamically over short time scales. We studied this interaction over prolonged durations, focusing on regions where ablation terminates persistent AF using 2 mapping methods.

Methods: We recruited 55 patients with persistent AF in whom ablation terminated AF prior to pulmonary vein isolation from a multicenter registry. AF was mapped globally using electrograms for 360±45 cycles using (1) a published phase method and (2) a commercial activation/phase method.

Results: Patients were 62.2±9.7 years, 76% male. Sites of AF termination showed rotational/focal patterns by methods 1 and 2 (51/55 vs 55/55; =0.13) in spatially conserved regions, yet fluctuated over time. Time points with no AF driver showed competing drivers elsewhere or disordered waves. Organized regions were detected for 61.6±23.9% and 70.6±20.6% of 1 minute per method (=nonsignificant), confirmed by automatic phase tracking (<0.05). To detect AF drivers with >90% sensitivity, 8 to 32 s of AF recordings were required depending on driver definition.

Conclusions: Sites at which persistent AF terminated by ablation show organized activation that fluctuate over time, because of collision from concurrent organized zones or fibrillatory waves, yet recur in conserved spatial regions. Results were similar by 2 mapping methods. This network of competing mechanisms should be reconciled with existing disorganized or driver mechanisms for AF, to improve clinical mapping and ablation of persistent AF.

Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02997254.
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http://dx.doi.org/10.1161/CIRCEP.117.005846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475887PMC
June 2018

Left Atrial Venous Anatomy: A Map for Future AF Therapies.

JACC Clin Electrophysiol 2017 09 2;3(9):1033-1036. Epub 2017 Aug 2.

Department of Medicine, University of California-San Diego, San Diego, California; Department of Medicine, VA San Diego Healthcare System, San Diego, California.

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http://dx.doi.org/10.1016/j.jacep.2017.04.013DOI Listing
September 2017

Efficient Computational Modeling of Human Ventricular Activation and Its Electrocardiographic Representation: A Sensitivity Study.

Cardiovasc Eng Technol 2018 09 16;9(3):447-467. Epub 2018 Mar 16.

Lawrence Livermore National Laboratory, 7000 East Avenue L-126, Livermore, CA, 94550, USA.

Patient-specific models of the ventricular myocardium, combined with the computational power to run rapid simulations, are approaching the level where they could be used for personalized cardiovascular medicine. A major remaining challenge is determining model parameters from available patient data, especially for models of the Purkinje-myocardial junctions (PMJs): the sites of initial ventricular electrical activation. There are no non-invasive methods for localizing PMJs in patients, and the relationship between the standard clinical ECG and PMJ model parameters is underexplored. Thus, this study aimed to determine the sensitivity of the QRS complex of the ECG to the anatomical location and regional number of PMJs. The QRS complex was simulated using an image-based human torso and biventricular model, and cardiac electrophysiology was simulated using Cardioid. The PMJs were modeled as discrete current injection stimuli, and the location and number of stimuli were varied within initial activation regions based on published experiments. Results indicate that the QRS complex features were most sensitive to the presence or absence of four "seed" stimuli, and adjusting locations of nearby "regional" stimuli provided finer tuning. Decreasing number of regional stimuli by an order of magnitude resulted in virtually no change in the QRS complex. Thus, a minimal 12-stimuli configuration was identified that resulted in physiological excitation, defined by QRS complex feature metrics and ventricular excitation pattern. Overall, the sensitivity results suggest that parameterizing PMJ location, rather than number, be given significantly higher priority in future studies creating personalized ventricular models from patient-derived ECGs.
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http://dx.doi.org/10.1007/s13239-018-0347-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6095770PMC
September 2018

Identification and Characterization of Sites Where Persistent Atrial Fibrillation Is Terminated by Localized Ablation.

Circ Arrhythm Electrophysiol 2018 01;11(1):e005258

From the Department of Cardiovascular Medicine, Stanford University, Palo Alto, CA (J.A.B.Z., M.I.A., T.B., C.A.B.K., P.C.Z., S.P., M.N.V., P.J.W., S.M.N.); Imperial Centre for Cardiac Engineering, Imperial College London, United Kingdom (J.A.B.Z., N.S.P.); Cardiac Electrophysiology, Cedars Sinai Heart Institute, Los Angeles, CA (J.A.B.Z.); Department of Cardiology, University of Colorado, Aurora (W.H.S., R.T.B.); Departments of Medicine (T.B., D.E.K.) and Physics (W.J.R.), University of California San Diego; Faculty of Medicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany (C.A.B.K.); Department of Cardiology, Klinikum Coburg, Germany (S.B., J.B.); and Department of Medicine, Indiana University, Bloomington (J.M.M.).

Background: The mechanisms by which persistent atrial fibrillation (AF) terminates via localized ablation are not well understood. To address the hypothesis that sites where localized ablation terminates persistent AF have characteristics identifiable with activation mapping during AF, we systematically examined activation patterns acquired only in cases of unequivocal termination by ablation.

Methods And Results: We recruited 57 patients with persistent AF undergoing ablation, in whom localized ablation terminated AF to sinus rhythm or organized tachycardia. For each site, we performed an offline analysis of unprocessed unipolar electrograms collected during AF from multipolar basket catheters using the maximum -dV/dt assignment to construct isochronal activation maps for multiple cycles. Additional computational modeling and phase analysis were used to study mechanisms of map variability. At all sites of AF termination, localized repetitive activation patterns were observed. Partial rotational circuits were observed in 26 of 57 (46%) cases, focal patterns in 19 of 57 (33%), and complete rotational activity in 12 of 57 (21%) cases. In computer simulations, incomplete segments of partial rotations coincided with areas of slow conduction characterized by complex, multicomponent electrograms, and variations in assigning activation times at such sites substantially altered mapped mechanisms.

Conclusions: Local activation mapping at sites of termination of persistent AF showed repetitive patterns of rotational or focal activity. In computer simulations, complete rotational activation sequence was observed but was sensitive to assignment of activation timing particularly in segments of slow conduction. The observed phenomena of repetitive localized activation and the mechanism by which local ablation terminates putative AF drivers require further investigation.
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http://dx.doi.org/10.1161/CIRCEP.117.005258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5769709PMC
January 2018

Spatiotemporal Progression of Early Human Ventricular Fibrillation.

JACC Clin Electrophysiol 2017 12 2;3(12):1437-1446. Epub 2017 Aug 2.

Department of Physics, University of California San Diego, San Diego, CA.

Objectives: The objective of this study was to evaluate the spatio-temporal organization and progression of human ventricular fibrillation (VF) in the left (LV) and right (RV) ventricles.

Background: Studies suggest that localized sources contribute to VF maintenance, but the evolution of VF episodes has not been quantified.

Methods: Synchrony between electrograms recorded from 25 patients with induced VF is computed and used to define the Asynchronous Index (ASI), indicating regions which are out-of-step with surrounding tissue. Computer simulations show that ASI can identify the location of VF-maintaining sources, where larger values of ASI correlate with more stable sources.

Results: Automated synchrony analysis shows elevated values of ASI in a majority of self-terminating episodes (LV: 8/9, RV: 7/8) and sustained episodes (LV: 11/11, RV: 12/12). The locations of ASI in sustained episodes co-localize with rotor cores when rotational activity is simultaneously present in phase maps (LV: 8/8, RV: 5/7, p<.05). The distribution of ASI differentiates self-terminating from sustained episodes (mean ASI = 0.60±0.14 and 0.70±0.16, respectively; p=0.01). Across sustained episodes the LV exhibits an increase in ASI with time.

Conclusions: Quantitative analysis identifies localized asynchronous regions that correlate with sources in VF, with sustained episodes evolving to exhibit more stable activation in the LV. This successive increase in stability indicates a stabilizing agent may be responsible for perpetuating fibrillation in a "migrate-and-capture" mechanism in the LV.
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http://dx.doi.org/10.1016/j.jacep.2017.04.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5725953PMC
December 2017

Mechanistic targets for the ablation of atrial fibrillation.

Glob Cardiol Sci Pract 2017 Mar 31;2017(1):e201707. Epub 2017 Mar 31.

Stanford University, Palo Alto, California.

The mechanisms responsible for sustaining atrial fibrillation are a key debate in cardiovascular pathophysiology, and directly influence the approach to therapy including ablation Clinical and basic studies have split AF mechanisms into two basic camps: 'spatially distributed disorganization' and 'localized sources'. Recent data suggest that these mechanisms can also be separated by the method for mapping - with nearly all traditional electrogram analyses showing spatially distributed disorganization and nearly all optical mapping studies showing localized sources We will review this dichotomy in light of these recently identified differences in mapping, and in the context of recent clinical studies in which localized ablation has been shown to impact AF, also lending support to the localized source hypothesis. We will conclude with other concepts on mechanism-based ablation and areas of ongoing research that must be addressed to continue improving our knowledge and treatment of AF.
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http://dx.doi.org/10.21542/gcsp.2017.7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5621726PMC
March 2017

Spatial relationship of sites for atrial fibrillation drivers and atrial tachycardia in patients with both arrhythmias.

Int J Cardiol 2017 Dec 14;248:188-195. Epub 2017 Jul 14.

Stanford University Medical Center, Palo Alto, CA, United States.

Introduction: Atrial fibrillation (AF) often converts to and from atrial tachycardia (AT), but it is undefined if these rhythms are mechanistically related in such patients. We tested the hypothesis that critical sites for AT may be related to regional AF sources in patients with both rhythms, by mapping their locations and response to ablation on transitions to and from AF.

Methods: From 219 patients undergoing spatial mapping of AF prior to ablation at 3 centers, we enrolled 26 patients in whom AF converted to AT by ablation (n=19) or spontaneously (n=7; left atrial size 42±6cm, 38% persistent AF). Both atria were mapped in both rhythms by 64-electrode baskets, traditional activation maps and entrainment.

Results: Each patient had a single mapped AT (17 reentrant, 9 focal) and 3.7±1.7 AF sources. The mapped AT spatially overlapped one AF source in 88% (23/26) of patients, in left (15/23) or right (8/23) atria. AF transitioned to AT by 3 mechanisms: (a) ablation anchoring AF rotor to AT (n=13); (b) residual, unablated AF source producing AT (n=6); (c) spontaneous slowing of AF rotor leaving reentrant AT at this site without any ablation (n=7). Electrogram analysis revealed a lower peak-to-peak voltage at overlapping sites (0.36±0.2mV vs 0.49±0.2mV p=0.03).

Conclusions: Mechanisms responsible for AT and AF may arise in overlapping atrial regions. This mechanistic inter-relationship may reflect structural and/or functional properties in either atrium. Future work should delineate how acceleration of an organized AT may produce AF, and whether such regions can be targeted a priori to prevent AT recurrence post AF ablation.
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http://dx.doi.org/10.1016/j.ijcard.2017.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865446PMC
December 2017

Rotors exhibit greater surface ECG variation during ventricular fibrillation than focal sources due to wavebreak, secondary rotors, and meander.

J Cardiovasc Electrophysiol 2017 Oct 4;28(10):1158-1166. Epub 2017 Aug 4.

Department of Medicine, University of California, San Diego, CA, USA.

Introduction: Ventricular fibrillation is a common life-threatening arrhythmia. The ECG of VF appears chaotic but may allow identification of sustaining mechanisms to guide therapy.

Hypothesis: We hypothesized that rotors and focal sources manifest distinct features on the ECG, and computational modeling may identify mechanisms of such features.

Methods: VF induction was attempted in 31 patients referred for ventricular arrhythmia ablation. Simultaneous surface ECG and intracardiac electrograms were recorded using biventricular basket catheters. Endocardial phase maps were used to mechanistically classify each VF cycle as rotor or focally driven. ECGs were analyzed from patients demonstrating both mechanisms in the primary analysis and from all patients with induced VF in the secondary analysis. The ECG voltage variation during each mechanism was compared. Biventricular computer simulations of VF driven by focal sources or rotors were created and resulting ECGs of each VF mechanism were compared.

Results: Rotor-based VF exhibited greater voltage variation than focal source-based VF in both the primary analysis (n = 8, 110 ± 24% vs. 55 ± 32%, P = 0.02) and the secondary analysis (n = 18, 103 ± 30% vs. 67 ± 34%, P = 0.009). Computational VF simulations also revealed greater voltage variation in rotors compared to focal sources (110 ± 19% vs. 33 ± 16%, P = 0.001), and demonstrated that this variation was due to wavebreak, secondary rotor initiation, and rotor meander.

Conclusion: Clinical and computational studies reveal that quantitative criteria of ECG voltage variation differ significantly between VF-sustaining rotors and focal sources, and provide insight into the mechanisms of such variation. Future studies should prospectively evaluate if these criteria can separate clinical VF mechanisms and guide therapy.
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http://dx.doi.org/10.1111/jce.13283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909714PMC
October 2017

Recurrent Post-Ablation Paroxysmal Atrial Fibrillation Shares Substrates With Persistent Atrial Fibrillation : An 11-Center Study.

JACC Clin Electrophysiol 2017 04;3(4):393-402

Indiana University School of Medicine, Indianapolis, United States.

Introduction: The role of atrial fibrillation (AF) substrates is unclear in patients with paroxysmal AF (PAF) that recurs after pulmonary vein isolation (PVI). We hypothesized that patients with recurrent post-ablation (redo) PAF despite PVI have electrical substrates marked by rotors and focal sources, and structural substrates that resemble persistent AF more than patients with (de novo) PAF at first ablation.

Methods: In 175 patients at 11 centers, we compared AF substrates in both atria using 64 pole-basket catheters and phase mapping, and indices of anatomical remodeling between patients with de novo or redo PAF and first ablation for persistent AF.

Results: Sources were seen in all patients. More patients with de novo PAF (78.0%) had sources near PVs than patients with redo PAF (47.4%, p=0.005) or persistent AF (46.9%, p=0.001). The total number of sources per patient (p=0.444), and number of non-PV sources (p=0.701) were similar between groups, indicating that redo PAF patients had residual non-PV sources after elimination of PV sources by prior PVI. Structurally, left atrial size did not separate de novo from redo PAF (49.5±9.5 vs. 49.0±7.1mm, p=0.956) but was larger in patients with persistent AF (55.2±8.4mm, p=0.001).

Conclusions: Patients with paroxysmal AF despite prior PVI show electrical substrates that resemble persistent AF more closely than patients with paroxysmal AF at first ablation. Notably, these subgroups of paroxysmal AF are indistinguishable by structural indices. These data motivate studies of trigger versus substrate mechanisms for patients with recurrent paroxysmal AF after PVI.
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http://dx.doi.org/10.1016/j.jacep.2016.10.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5458418PMC
April 2017

Spatial relationship of organized rotational and focal sources in human atrial fibrillation to autonomic ganglionated plexi.

Int J Cardiol 2017 Aug 19;240:234-239. Epub 2017 Apr 19.

Department of Cardiology, Athens Euroclinic, Athens, Greece; Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

Background: One approach to improve ablation for atrial fibrillation (AF) is to focus on physiological targets including focal or rotational sources or ganglionic plexi (GP). However, the spatial relationship between these potential mechanisms has never been studied. We tested the hypothesis that rotors and focal sources for AF may co-localize with ganglionated plexi (GP).

Methods: We prospectively identified locations of AF rotors and focal sources, and correlated these to GP sites in 97 consecutive patients (age 59.9±11.4, 73% persistent AF). AF was recorded with 64-pole catheters with activation/phase mapping, and related to anatomic GP sites on electroanatomic maps.

Results: AF sources arose in 96/97 (99%) patients for 2.6±1.4 sources per patient (left atrium: 1.7±0.9 right atrium: 1.1±0.8), each with an area of 2-3cm. On area analyses, the probability of an AF source randomly overlapping a GP area was 26%. Left atrial sources were seen in 94 (97%) patients, in whom ≥1 source co-localized with GP in 75 patients (80%; p<0.05). AF sources were more likely to colocalize with left vs right GPs (p<0.05), and colocalization was more likely in patients with higher CHADS2VASc scores (age>65, diabetes; p<0.05).

Conclusions: This is the first study to demonstrate that clinically detected AF focal and rotational sources in the left atrium often colocalize with regions of autonomic innervation. Studies should define if the role of AF sources differs by their anatomical location.
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http://dx.doi.org/10.1016/j.ijcard.2017.02.152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5856175PMC
August 2017

Electrocardiographic spatial loops indicate organization of atrial fibrillation minutes before ablation-related transitions to atrial tachycardia.

J Electrocardiol 2017 May - Jun;50(3):307-315. Epub 2017 Jan 15.

Stanford University, CA, USA. Electronic address:

Background: During ablation for atrial fibrillation (AF), it is challenging to anticipate transitions to organized tachycardia (AT). Defining indices of this transition may help to understand fibrillatory conduction and help track therapy.

Objective: To determine the timescale over which atrial fibrillation (AF) organizes en route to atrial tachycardia (AT) using the ECG referenced to intracardiac electrograms.

Methods: In 17 AF patients at ablation (58.7±9.6years; 53% persistent AF) we analyzed spatial loops of atrial activity on the ECG and intracardiac electrograms over successive timepoints. Loops were tracked at precisely 15, 10, 5, 3 and 1min prior to defined transitions of AF to AT.

Results: Organizational indices reliably quantified changes from AF to AT. Spatiotemporal AF organization on the ECG was identifiable at least 15min before AT was established (p=0.02).

Conclusions: AF shows anticipatory global organization on the ECG minutes before AT is clinically evident. These results offer a foundation to establish when AF therapy is on an effective path, and for a quantitative classification separating AT from AF.
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http://dx.doi.org/10.1016/j.jelectrocard.2017.01.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5515359PMC
February 2018

Non-invasive, model-based measures of ventricular electrical dyssynchrony for predicting CRT outcomes.

Europace 2016 Dec;18(suppl 4):iv104-iv112

Department of Bioengineering, University of California, 9500 Gilman Drive, La Jolla, San Diego, CA 92093-0412, USA

Aims: Left ventricular activation delay due to left bundle branch block (LBBB) is an important determinant of the severity of dyssynchronous heart failure (DHF). We investigated whether patient-specific computational models constructed from non-invasive measurements can provide measures of baseline dyssynchrony and its reduction after CRT that may explain the degree of long-term reverse ventricular remodelling.

Methods And Results: LV end-systolic volume reduction (ΔESV) measured by 2D trans-thoracic echocardiography in eight patients following 6 months of CRT was significantly (P < 0.05) greater in responders (26 ± 20%, n = 4) than non-responders (11 ± 16%, n = 4). LV reverse remodelling did not correlate with baseline QRS duration or its change after biventricular pacing, but did correlate with baseline LV endocardial activation measured by electroanatomic mapping (R=0.71, P < 0.01). Patient-specific models of LBBB ventricular activation with parameters obtained by matching model-computed vectorcardiograms (VCG) to those derived from standard patient ECGs yielded LV endocardial activation times that correlated well with those measured from endocardial maps (R=0.90). Model-computed 3D LV activation times correlated strongly with the reduction in LVESV (R=0.93, P < 0.001). Computed decreases due to simulated CRT in the time delay between LV septal and lateral activation correlated strongly with ΔESV (R=0.92, P < 0.001). Models also suggested that optimizing VV delays may improve resynchronization by this measure of activation delay.

Conclusions: Patient-specific computational models constructed from non-invasive measurements can compute estimates of LV dyssynchrony and their changes after CRT that may be as good as or better than electroanatomic mapping for predicting long-term reverse remodelling.
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http://dx.doi.org/10.1093/europace/euw356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5225967PMC
December 2016

Determining conduction patterns on a sparse electrode grid: Implications for the analysis of clinical arrhythmias.

Phys Rev E 2016 Nov 9;94(5-1):050401. Epub 2016 Nov 9.

Department of Physics, University of California, San Diego, La Jolla, California 92903, USA.

We present a general method of utilizing bioelectric recordings from a spatially sparse electrode grid to compute a dynamic vector field describing the underlying propagation of electrical activity. This vector field, termed the wave-front flow field, permits quantitative analysis of the magnitude of rotational activity (vorticity) and focal activity (divergence) at each spatial point. We apply this method to signals recorded during arrhythmias in human atria and ventricles using a multipolar contact catheter and show that the flow fields correlate with corresponding activation maps. Further, regions of elevated vorticity and divergence correspond to sites identified as clinically significant rotors and focal sources where therapeutic intervention can be effective. These flow fields can provide quantitative insights into the dynamics of normal and abnormal conduction in humans and could potentially be used to enhance therapies for cardiac arrhythmias.
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http://dx.doi.org/10.1103/PhysRevE.94.050401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161037PMC
November 2016

Compatibility of Radiofrequency Surgical Sponge Detection Technology with Cardiac Implantable Electronic Devices and Temporary Pacemakers.

Pacing Clin Electrophysiol 2016 Nov 6;39(11):1254-1260. Epub 2016 Oct 6.

Divisions of Cardiology and Cardiothoracic Surgery, Department of Medicine and Surgery, Sulpizio Cardiovascular Center, University of California, San Diego School of Medicine, La Jolla, California.

Background: Radiofrequency (RF) technology has improved detection of retained surgical sponges with a reported 100% sensitivity and specificity. However, the potential for interactions of the RF signals emitted by the detection system with cardiac implantable electronic devices (CIEDs) or temporary pacemakers may limit its use in those patients with these devices. This study investigated whether RF detection technology causes interference or clinically significant changes in the programmed settings of implanted pacemakers and defibrillators or temporary epicardial pacemakers.

Methods: Fifty patients who were scheduled either for CIED removal or placement of a temporary epicardial pacemaker (at the time of open heart surgery) were recruited for this study. Device settings and measurements from separate interrogations before and after scanning with the RF detection system were compared. For the temporary pacemakers, we observed for any changes in hemodynamics or signs of pacing interference.

Results: Twenty (40%) pacemakers, 20 (40%) implantable cardioverter defibrillators, and 10 (20%) temporary pacemakers were analyzed in this study. During scanning, no signal interference was detected in any permanent device, and there were no significant changes in programmed settings after scanning with the RF detection system. However, pacing inhibition was detected with temporary pacing systems when programmed to a synchronous mode (DDD).

Conclusions: RF detection technology can be safely used to scan for retained surgical sponges in patients with permanent CIEDs and temporary pacemakers set to asynchronous mode.
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http://dx.doi.org/10.1111/pace.12938DOI Listing
November 2016

Comparative efficacy of stellate ganglion block with bupivacaine vs pulsed radiofrequency in a patient with refractory ventricular arrhythmias.

J Clin Anesth 2016 Jun 15;31:162-5. Epub 2016 Apr 15.

University of California San Diego, San Diego, CA; Veterans Affairs San Diego Healthcare System, San Diego, CA. Electronic address:

There is increasing interest in interventional therapies targeting the cardiac sympathetic nervous system to suppress ventricular arrhythmias. In this case report, we describe an 80-year-old patient with ischemic cardiomyopathy and multiple implantable cardioverter-defibrillator shocks due to refractory ventricular tachycardia and ventricular fibrillation who was unable to continue biweekly stellate ganglion block procedures using bupivacaine 0.25% for suppression of his arrhythmias. He had previously failed antiarrhythmic drug therapy with amiodarone, catheter ablation, and attempted surgical autonomic denervation. He underwent pulsed radiofrequency treatment (3 lesions, 2 minutes each, temperature 42°C, 2-Hz frequency, 20-millisecond pulse width) of the left stellate ganglion resulting in persistent arrhythmia suppression for more than 12 months duration. This represents the first report of a pulsed radiofrequency stellate ganglion lesion providing long-term suppression of ventricular arrhythmias. Further study of this technique in patients with refractory ventricular tachycardia or ventricular fibrillation is warranted.
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http://dx.doi.org/10.1016/j.jclinane.2016.01.026DOI Listing
June 2016

Ventricular fibrillation: triggers, mechanisms and therapies.

Future Cardiol 2016 05 27;12(3):373-90. Epub 2016 Apr 27.

Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.

Ventricular fibrillation (VF) is a common, life-threatening arrhythmia responsible for significant morbidity and mortality. Due to challenges in safely mapping VF, a comprehensive understanding of its mechanisms remains elusive. Recent findings have provided new insights into mechanisms that sustain early VF. Notably, the central role of electrical rotors and catheter-based ablation of VF rotor substrate have been recently reported. In this article, we will review data regarding four stages of VF: initiation, transition, maintenance and evolution. We will discuss the particular mechanisms for each stage and therapies targeting these mechanisms. We also examine inherited arrhythmia syndromes, including the mechanisms and therapies specific to each. We hope that the overview of VF outlined in this work will assist other investigators in designing future therapies to interrupt this life-threatening arrhythmia.
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http://dx.doi.org/10.2217/fca-2016-0001DOI Listing
May 2016

Organized Sources Are Spatially Conserved in Recurrent Compared to Pre-Ablation Atrial Fibrillation: Further Evidence for Non-Random Electrical Substrates.

J Cardiovasc Electrophysiol 2016 06 5;27(6):661-9. Epub 2016 Apr 5.

Stanford University, Palo Alto, California, USA.

Introduction: Recurrent atrial fibrillation (AF) after ablation is associated with reconnection of initially isolated pulmonary vein (PV) trigger sites. Substrates are often targeted in addition to PVI, but it is unclear how substrates progress over time. We studied if substrates in recurrent AF are conserved or have developed de novo from pre-ablation AF.

Methods And Results: Of 137 patients undergoing Focal Impulse and Rotor Mapping (FIRM) at their index procedure for AF, 29 consecutive patients (60 ± 8 years, 79% persistent) recurred and were also mapped at repeat procedure (21 ± 20 months later) using carefully placed 64-pole baskets and RhythmView(TM) (Topera, Menlo Park, CA, USA) to identify AF sources and disorganized zones. Compared to index AF, recurrent AF had a longer cycle length (177 ± 21 vs. 167 ± 19 milliseconds, P = 0.01). All patients (100%) had 1 or more conserved AF rotors between procedures with surrounding disorganization. The number of sources was similar for recurrent AF post-PVI versus index AF (3.2 ± 1.4 vs. 3.1 ± 1.0, P = 0.79), but was lower for recurrent AF after FIRM+PVI versus index AF (4.4 ± 1.4 vs. 2.9 ± 1.7, P = 0.03). Overall, 81% (61/75) of AF sources lay in conserved regions, while 19% (14/75) were detected de novo.

Conclusion: Electrical propagation patterns for recurrent AF after unsuccessful ablation are similar in individual patients to their index AF. These data support temporospatial stability of AF substrates over 1-2 years. Trials should determine the relative benefit of adding substrate mapping and ablation to PVI for recurrent AF.
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http://dx.doi.org/10.1111/jce.12964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5515372PMC
June 2016

Atrial Fibrillation and Heart Failure-- Identification of Patients at Risk.

Authors:
David E Krummen

Circ J 2016 5;80(3):587-9. Epub 2016 Feb 5.

University of California San Diego and VA San Diego Healthcare System.

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http://dx.doi.org/10.1253/circj.CJ-16-0065DOI Listing
August 2016

Multicentre safety of adding Focal Impulse and Rotor Modulation (FIRM) to conventional ablation for atrial fibrillation.

Europace 2017 May;19(5):769-774

Department of Medicine, Stanford University, 780 Welch Road MC-5773, Stanford, Palo Alto, CA 94305, USA.

Aims: Focal Impulse and Rotor Modulation (FIRM) uses 64-electrode basket catheters to identify atrial fibrillation (AF)-sustaining sites for ablation, with promising results in many studies. Accordingly, new basket designs are being tested by several groups. We set out to determine the procedural safety of adding basket mapping and map-guided ablation to conventional pulmonary vein isolation (PVI).

Methods And Results: We collected 30 day procedural safety data in five US centres for consecutive patients undergoing FIRM plus PVI (FIRM-PVI) compared with contemporaneous controls undergoing PVI without FIRM. A total of 625 cases were included in this analysis: 325 FIRM-PVI and 300 PVI-controls. FIRM-PVI patients were more likely than PVI-controls to be male (83% vs. 66%, P < 0.001) and have long-standing persistent AF (26% vs. 13%, P < 0.001) reflecting patients referred for FIRM. Total ablation time was greater for FIRM-PVI (62 ± 22 min) vs. PVI-controls (52 ± 18 min, P = 0.03). The complication rate for FIRM-PVI procedures (4.3%) was similar to controls (4.0%, P = 1) for both major and minor complications; no deaths were reported. The rate of complications potentially attributable to the basket catheter was small and did not differ between basket types (Constellation 2.8% vs. FIRMap 1.8%, P = 0.7) or between cases in which basket catheters were and were not used (P = 0.5). Complication rates did not differ between centres (P = 0.6).

Conclusions: Procedural complications from the use of the basket catheters for AF mapping are low, and thus procedural safety appears similar between FIRM-PVI and PVI-controls in a large multicentre cohort. Future studies are required to determine the optimal approach to maximize the efficacy of FIRM-guided ablation.
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http://dx.doi.org/10.1093/europace/euw377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834113PMC
May 2017

Modifying Ventricular Fibrillation by Targeted Rotor Substrate Ablation: Proof-of-Concept from Experimental Studies to Clinical VF.

J Cardiovasc Electrophysiol 2015 Oct 6;26(10):1117-26. Epub 2015 Sep 6.

Stanford University, Palo Alto, California, USA.

Introduction: Recent work has suggested a role for organized sources in sustaining ventricular fibrillation (VF). We assessed whether ablation of rotor substrate could modulate VF inducibility in canines, and used this proof-of-concept as a foundation to suppress antiarrhythmic drug-refractory clinical VF in a patient with structural heart disease.

Methods And Results: In 9 dogs, we introduced 64-electrode basket catheters into one or both ventricles, used rapid pacing at a recorded induction threshold to initiate VF, and then defibrillated after 18±8 seconds. Endocardial rotor sites were identified from basket recordings using phase mapping, and ablation was performed at nonrotor (sham) locations (7 ± 2 minutes) and then at rotor sites (8 ± 2 minutes, P = 0.10 vs. sham); the induction threshold was remeasured after each. Sham ablation did not alter canine VF induction threshold (preablation 150 ± 16 milliseconds, postablation 144 ± 16 milliseconds, P = 0.54). However, rotor site ablation rendered VF noninducible in 6/9 animals (P = 0.041), and increased VF induction threshold in the remaining 3. Clinical proof-of-concept was performed in a patient with repetitive ICD shocks due to VF refractory to antiarrhythmic drugs. Following biventricular basket insertion, VF was induced and then defibrillated. Mapping identified 4 rotors localized at borderzone tissue, and rotor site ablation (6.3 ± 1.5 minutes/site) rendered VF noninducible. The VF burden fell from 7 ICD shocks in 8 months preablation to zero ICD therapies at 1 year, without antiarrhythmic medications.

Conclusions: Targeted rotor substrate ablation suppressed VF in an experimental model and a patient with refractory VF. Further studies are warranted on the efficacy of VF source modulation.
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http://dx.doi.org/10.1111/jce.12753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4826737PMC
October 2015
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