Catheter ablation of postinfarction reentrant ventricular tachycardia (VT) has received renewed interest owing to the increased availability of high-resolution electroanatomic mapping systems that can describe the VT circuits in greater detail, and the emergence and need to target noninvasive external beam radioablation. These recent advancements provide optimism for improving the clinical outcome of VT ablation in patients with postinfarction and potentially other scar-related VTs. The combination of analyses gleaned from studies in swine and canine models of postinfarction reentrant VT, and in human studies, suggests the existence of common electroanatomic properties for reentrant VT circuits. Characterizing these properties may be useful for increasing the specificity of substrate mapping techniques and for noninvasive identification to guide ablation. Herein, we describe properties of reentrant VT circuits that may assist in elucidating the mechanisms of onset and maintenance, as well as a means to localize and delineate optimal catheter ablation targets.

Background: The optimal method to identify the arrhythmogenic substrate of scar-related ventricular tachycardia (VT) is unknown. Sites of activation slowing during sinus rhythm (SR) often colocalize with the VT circuit. However, the utility and limitations of such approach for guiding ablation are unknown. Methods: We conducted a multicenter study in patients with infarct-related VT. The left ventricular (LV) was mapped during activation from 3 directions: SR (or atrial pacing), right ventricular, and LV pacing at 600 ms. Ablation was applied selectively to the cumulative area of slow activation, defined as the sum of all regions with activation times of ≥40 ms per 10 mm. Hemodynamically tolerated VTs were mapped with activation or entrainment. The primary outcome was a composite of appropriate implanted cardioverter-defibrillator therapies and cardiovascular death. Results: In 85 patients, the LV was mapped during activation from 2.4±0.6 directions. The direction of LV activation influenced the location and magnitude of activation slowing. The spatial overlap of activation slowing between SR and right ventricular pacing was 84.2±7.1%, between SR and LV pacing was 61.4±8.8%, and between right ventricular and LV pacing was 71.3±9.6% ( P <0.05 between all comparisons). Mapping during SR identified only 66.2±8.2% of the entire area of activation slowing and 58% critical isthmus sites. Activation from other directions by right ventricular and LV stimulation unmasked an additional 33% of slowly conducting zones and 25% critical isthmus sites. The area of maximal activation slowing often corresponded to the site where the wavefront first interacted with the infarct. During a follow-up period of 3.6 years, the primary end point occurred in 14 out of 85 (16.5%) patients. Conclusions: The spatial distribution of activation slowing is dependent on the direction of LV activation with the area of maximal slowing corresponding to the site where the wavefront first interacts with the infarct. This data may have implications for VT substrate mapping strategies.

Hein Wellens died on June 9, 2020. His passing marks the loss of a giant among the founders of clinical electrophysiology. Rather than document his many seminal contributions to the origin and continued development of this field of medicine, I would like to briefly reminisce about my own relationship with Hein that began in 1976 and that has lasted my whole lifetime.

HomeCirculation ResearchVol. 127, No. 12The Interaction Between Na+ and Ca2+ Inward Currents in Cardiac Propagation Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessEditorialPDF/EPUBThe Interaction Between Na+ and Ca2+ Inward Currents in Cardiac Propagation Andre G. Kleber, Andrew L. Wit Andre G. KleberAndre G. Kleber Correspondence to: Andre G. Kleber, MD, Department of Pathology, Harvard Medical School, Beth Israel Deaconess Medical Center, Finard 207, 330 Brookline Ave, Boston, MA 02215. Email E-mail Address: [email protected] https://orcid.org/0000-0002-3233-2005 Department of Pathology, Harvard Medical School, Boston, MA (A.G.K.). , Andrew L. WitAndrew L. Wit Department of Pathology, Harvard Medical School, Boston, MA (A.G.K.). Originally published3 Dec 2020https://doi.org/10.1161/CIRCRESAHA.120.318316Circulation Research. 2020;127:1549–1551This article is a commentary on the followingIonic Mechanisms of Impulse Propagation Failure in the FHF2-Deficient HeartArticle, see p 1536The discovery of a slow Ca2+ inward current in the heart by Reuter in 19671 was a milestone in the understanding of cardiac electrical activity. This current was shown to be the missing link between cardiac excitation and contraction (excitation contraction-coupling). Before this discovery, many of the major ion currents producing the cardiac action potential had already been defined, and the underlying cause of propagation in cardiac muscle was attributed to the inward Na+ current, INa.2 However, since both the Na+ and Ca2+ currents correspond to inward movement of electrical charge, and consequently, depolarize cells, the question of whether and how these currents might interact to contribute to the propagation of the cardiac impulse became a major topic in cardiac electrophysiology.The realization that there were 2 major inward currents helped answer an important question on the minds of cardiac electrophysiologists for more than half a century since it was postulated that slow conduction and unidirectional conduction block were the foundation of pathological changes causing reentry and reentrant arrhythmias.3 Accompanying the quest for answers was the demonstration that the slow Ca2+ current can assume a major role in maintaining conduction when Na+ channels are inactivated by membrane depolarization. Cranefield4 showed that under certain conditions, the inward L-type Ca2+ current could maintain phase 0 of the action potential, which they called the slow response,4 and cause slow conduction and unidirectional block, that could lead to reentry in very small circuits.5Subsequently, a second role for Ca2+ current was shown by Shaw and Rudy6 who described a role for L-type Ca2+ current in maintaining conduction across gap junction connections even when depressed Na+ current is still mostly responsible for propagation. The role of Ca2+ current to maintain propagation in conditions of inhibited Na+ current was also confirmed in engineered strands of rat ventricular myocytes.7In the current issue of Circulation Research, Park et al8 define the mechanism of cardiac propagation in hearts with genetic deletion of FHF2 (fibroblast growth factor homologous factor 2) which inactivates Na+ channels, where they attribute a major role to Ca2+ current because of an increased sensitivity to calcium channel blockade.FHF2 belongs to a family of FHFs that bind to the cytoplasmic tails of voltage-gated sodium channels and modulate channel gating properties and trafficking.9A main effect on gating of Nav1.5 channels consists in the shift of the voltage dependence from inactivation to more negative membrane potentials, a finding confirmed by theoretical simulation in Park et al.8 This means that a significant proportion of Nav1.5 channels will be in an inactivated state and not contribute to inward current, when excitation is elicited from a normal resting membrane potential, despite normal channel expression. As a further message, the article highlights the role of L-type Ca2+ current playing the role as a substitute of INa to depolarize the membrane and promote electrical propagation.In the experimental part of their work, Park et al8 show that genetic ablation of FHF2 leads, as expected, to a decrease in electrical propagation velocity both in longitudinal and transverse direction, whereby the decrease in transverse direction is more expressed (decrease of the anisotropy ratio). As a further finding, the authors show an increased sensitivity of electrical propagation and early block formation upon inhibition of Ca2+ inward current in hearts with genetic ablation of Fhf2, a phenomenon that is absent in wild-type hearts. The theoretical part of the work also highlights the interdependence of inward Na+ current, Ca2+ inward current, and cell-to-cell coupling in the propagation process.While the shift in the inactivation curve of Nav1.5 with genetic deletion of FHF2 has an impact on channel behavior and action potential generation at normal resting potentials, the observed changes have a counterpart in diseased states associated with a depolarization of the resting membrane and elevated extracellular [K+]o, conditions typically occurring in acute myocardial ischemia and being associated with ventricular tachycardia and ventricular fibrillation.10The results of Park et al8 warrant additional points of discussion. Whereas the theoretical work in this publication involves a linear strand of cells, the dimensionality and discontinuous structure of cardiac tissue have an important impact on the interplay between the depolarizing ionic currents and cell-to-cell coupling. Normal ventricular myocardium exhibits a complex structure. In ventricle, turning muscle layers are bridged by small muscle bundles thereby producing an inherently discontinuous structure. These discontinuities are significantly enlarged in presence of an infarct scar.11 Age is a further factor leading to discontinuous tissue structure characterized by small connective tissue septa interspersed between and oriented longitudinally to myocardial fiber bundles.12 Functionally, discontinuous structures are characterized by so-called source-to-load or source-to-sink mismatch. During propagation of the electrical impulse the source producing the excitatory current is—depending on the direction of excitation spread—either smaller or larger than the sink where this current will produce excitation to push propagation forward. Numerous experimental and theoretical work has described the biophysical principles underlying conduction slowing and unidirectional propagation block (for references see Kleber and Rudy13). In discontinuous tissue, the interaction between depolarizing ion currents, cell-to-cell coupling, which is specifically addressed in Park et al,8 within the discontinuous microstructure of the cellular network is crucial for successful propagation in the normal state and formation of unidirectional block in pathological states.As a main difference, inward movements of Na+ and Ca2+ during the action potential upstroke occur at different speeds. The Nav1.5 channel system is a fast system, peak flow of INa occurring about 1 ms after activation. By contrast, peak Ca2+ inward flow through L-type Ca2+ channels is observed after ≥5 ms, characterizing the L-type Ca2+ channel as a slow system. In case a structural discontinuity or decreased cell-to-cell coupling (both representing resistive obstacles) produces localized delays in action potential transfer, the slow system is required for depolarization of cells beyond the obstacle because the fast system will already be partially inactivated at the time the downstream cells are excited. In normal hearts, this interdependence between the kinetics of depolarizing ion channels and cell-to-cell coupling is likely to be relevant for the propagation through the atrioventricular node, where slow propagation is attributed to reduced cell-to-cell coupling and inward Ca2+ current responsible for the depolarizing charge movement.A second aspect concerns the expression patterns of ion current in the various species used in experimental work. Small rodents have a relatively large expression of L-type Ca2+ channels. Consequently, inhibition of Nav1.5 channels by tetrodotoxin leaves linear propagation intact albeit at a much lower velocity.7 However, in large mammals such as pigs, this does not seem to be the case under normal conditions. Depolarizing Langendorff-perfused porcine hearts with elevated extracellular K+ produced propagation block at 11 mmol/L [K+]o.14 This type of propagation—termed slow response after earlier work by Wit, Hoffman, and Cranefield4,5,15—would only appear at [K+]o levels in presence of 2.5×10−5 mol/L epinephrine, a drug activating Ca2+ channels. This indicates that the importance of the role L-type Ca2+ current as a driver of propagation should be discussed with caution and include the species-dependent ion channel expression patterns.There are some additional points to consider.While the studies are carefully done and are consistent with the Shaw-Rudy theoretical paper6 showing the importance of ICaL in maintaining conduction when INa is reduced, the importance of the results to the genesis of clinical cardiac arrhythmias require additional evidence. Although the use of knockout mice to understand the importance of a gene or protein in an electrophysiological process is a tried and true procedure, it does not demonstrate the importance of that gene or protein in a human heart with an arrhythmia unless the absence of that gene or protein is documented. At the present time, there are limited data showing the absence of the FHF2 gene for any of the cardiac pathological conditions mentioned, such as Brugada syndrome or ischemic heart disease.The authors state: “These results not only validate the findings of the original Shaw–Rudy model but also identify FHF2 as the principal modulator of INa availability that ensures propagation safety.” However, many pathological conditions involving reduced Na+ channel availability do not seem to involve FHF2; depolarization of the resting potential that results in voltage-dependent inactivation of INa without documented changes in FHF2 are important in acute ischemia and more long-standing ischemic conditions, as described above.The importance of the L-type Ca2+ current to maintain conduction in many clinical conditions of depressed conduction is unproven. It appears that verapamil is not an effective antiarrhythmic drug for many clinical atrial and ventricular arrhythmias that involve slow activation, conduction block, and reentry (including Brugada syndrome) while being highly effective against arrhythmias involving the atrioventricular node where the role of the L-type calcium current is a certainty.Sources of FundingThis work was supported by the National Institutes of Health grant R01HL136463.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Sources of Funding and Disclosures, see page 1551.Correspondence to: Andre G. Kleber, MD, Department of Pathology, Harvard Medical School, Beth Israel Deaconess Medical Center, Finard 207, 330 Brookline Ave, Boston, MA 02215. Email [email protected]harvard.eduReferences1. Reuter H. The dependence of slow inward current in Purkinje fibres on the extracellular calcium-concentration.J Physiol. 1967; 192:479–492. doi: 10.1113/jphysiol.1967.sp008310CrossrefMedlineGoogle Scholar2. Weidmann S. Heart: electrophysiology.Annu Rev Physiol. 1974; 36:155–169. doi: 10.1146/annurev.ph.36.030174.001103CrossrefMedlineGoogle Scholar3. Schmitt FO, Erlanger J. Directional differences in the conduction of the cardiac impulse through heart muscle and their possible relationship to extrasystolic and fibrillatory contractions.Am J Physiol. 1928; 87:326–347.CrossrefGoogle Scholar4. Cranefield PF. The Conduction of the Cardiac Impulse. New York: Mt. Kisko; 1975.Google Scholar5. Wit AL, Cranefield PF, Hoffman BF. Slow conduction and reentry in the ventricular conducting system. II. Single and sustained circus movement in networks of canine and bovine Purkinje fibers.Circ Res. 1972; 30:11–22. doi: 10.1161/01.res.30.1.11LinkGoogle Scholar6. Shaw RM, Rudy Y. Ionic mechanisms of propagation in cardiac tissue. Roles of the sodium and L-type calcium currents during reduced excitability and decreased gap junction coupling.Circ Res. 1997; 81:727–741. doi: 10.1161/01.res.81.5.727CrossrefMedlineGoogle Scholar7. Rohr S, Kucera JP, Kléber AG. Slow conduction in cardiac tissue, I: effects of a reduction of excitability versus a reduction of electrical coupling on microconduction.Circ Res. 1998; 83:781–794. doi: 10.1161/01.res.83.8.781CrossrefMedlineGoogle Scholar8. Park DS, Shekhar A, Santucci J, et al.. Ionic mechanisms of impulse propagation failure in the FHF2-deficient heart.Circ Res. 2020; 127:1536–1548. doi: 10.1161/CIRCRESAHA.120.317349LinkGoogle Scholar9. Goldfarb M. Voltage-gated sodium channel-associated proteins and alternative mechanisms of inactivation and block.Cell Mol Life Sci. 2012; 69:1067–1076. doi: 10.1007/s00018-011-0832-1CrossrefMedlineGoogle Scholar10. Janse MJ, Wit AL. Electrophysiological mechanisms of ventricular arrhythmias resulting from myocardial ischemia and infarction.Physiol Rev. 1989; 69:1049–1169. doi: 10.1152/physrev.1989.69.4.1049CrossrefMedlineGoogle Scholar11. Rutherford SL, Trew ML, Sands GB, LeGrice IJ, Smaill BH. High-resolution 3-dimensional reconstruction of the infarct border zone: impact of structural remodeling on electrical activation.Circ Res. 2012; 111:301–311. doi: 10.1161/CIRCRESAHA.111.260943LinkGoogle Scholar12. Spach MS, Miller WT, Dolber PC, Kootsey JM, Sommer JR, Mosher CE. The functional role of structural complexities in the propagation of depolarization in the atrium of the dog. Cardiac conduction disturbances due to discontinuities of effective axial resistivity.Circ Res. 1982; 50:175–191. doi: 10.1161/01.res.50.2.175LinkGoogle Scholar13. Kléber AG, Rudy Y. Basic mechanisms of cardiac impulse propagation and associated arrhythmias.Physiol Rev. 2004; 84:431–488. doi: 10.1152/physrev.00025.2003CrossrefMedlineGoogle Scholar14. Kleber AG, Janse MJ, Wilms-Schopmann FJ, Wilde AA, Coronel R. Changes in conduction velocity during acute ischemia in ventricular myocardium of the isolated porcine heart.Circulation. 1986; 73:189–198. doi: 10.1161/01.cir.73.1.189LinkGoogle Scholar15. Wit AL, Hoffman BF, Cranefield PF. Slow conduction, reentry, and the mechanism of ventricular arrhythmias in myocardial infarction.Bull N Y Acad Med. 1971; 47:1233–1234.MedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesIonic Mechanisms of Impulse Propagation Failure in the FHF2-Deficient HeartDavid S. Park, et al. Circulation Research. 2020;127:1536-1548 December 4, 2020Vol 127, Issue 12Article InformationMetrics Download: 139 © 2020 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.120.318316PMID: 33270548 Originally publishedDecember 3, 2020 Keywordsheartgap junctionsfibroblast growth factorsverapamilEditorialskineticsPDF download

Determining optimal treatment strategies for complex arrhythmogenesis in AF is confounded by the lack of consensus regarding the mechanisms causing AF. Studies report different mechanisms for AF, ranging from hierarchical drivers to anarchical multiple activation wavelets. Differences in the assessment of AF mechanisms are likely due to AF being recorded across diverse models using different investigational tools, spatial scales and clinical populations. The authors review different AF mechanisms, including anatomical and functional re-entry, hierarchical drivers and anarchical multiple wavelets. They then describe different cardiac mapping techniques and analysis tools, including activation mapping, phase mapping and fibrosis identification. They explain and review different data challenges, including differences between recording devices in spatial and temporal resolutions, spatial coverage and recording surface, and report clinical outcomes using different data modalities. They suggest future research directions for investigating the mechanisms underlying human AF.

BackgroundTo validate the predictability of reentrant circuit isthmus locations without ventricular tachycardia (VT) induction during high-definition mapping, we used computer methods to analyse sinus rhythm activation in experiments where isthmus location was subsequently verified by mapping reentrant VT circuits.MethodIn 21 experiments using a canine postinfarction model, bipolar electrograms were obtained from 196-312 recordings with 4mm spacing in the epicardial border zone during sinus rhythm and during VT. From computerized electrical activation maps of the reentrant circuit, areas of conduction block were determined and the isthmus was localized. A linear regression was computed at three different locations about the reentry isthmus using sinus rhythm electrogram activation data. From the regression analysis, the uniformity, a measure of the constancy at which the wavefront propagates, and the activation gradient, a measure that may approximate wavefront speed, were computed. The purpose was to test the hypothesis that the isthmus locates in a region of slow uniform activation bounded by areas of electrical discontinuity.ResultsBased on the regression parameters, sinus rhythm activation along the isthmus near its exit proceeded uniformly (mean r2= 0.95±0.05) and with a low magnitude gradient (mean 0.37±0.10mm/ms). Perpendicular to the isthmus long-axis across its boundaries, the activation wavefront propagated much less uniformly (mean r2= 0.76±0.24) although of similar gradient (mean 0.38±0.23mm/ms). In the opposite direction from the exit, at the isthmus entrance, there was also less uniformity (mean r2= 0.80±0.22) but a larger magnitude gradient (mean 0.50±0.25mm/ms). A theoretical ablation line drawn perpendicular to the last sinus rhythm activation site along the isthmus long-axis was predicted to prevent VT reinduction. Anatomical conduction block occurred in 7/21 experiments, but comprised only small portions of the isthmus lateral boundaries; thus detection of sinus rhythm conduction block alone was insufficient to entirely define the VT isthmus.ConclusionsUniform activation with a low magnitude gradient during sinus rhythm is present at the VT isthmus exit location but there is less uniformity across the isthmus lateral boundaries and at isthmus entrance locations. These factors may be useful to verify any proposed VT isthmus location, reducing the need for VT induction to ablate the isthmus. Measured computerized values similar to those determined herein could therefore be assistive to sharpen specificity when applying sinus rhythm mapping to localize EP catheter ablation sites.

To most cellular and clinical electrophysiologists studying arrhythmias today, the origin and development of their disciplines are in the forgotten past. While the mechanisms of cardiac arrhythmias had been a focus of interest since the early 20th century, 1 Schmitt F.O. Erlanger J. Directional differences in the conduction of the impulse through heart muscle and their possible relation to extrasystolic and fibrillatory contractions. Am J Physiol. 1928; 87: 326-347 Crossref Google Scholar the elucidation of the cellular electrophysiology (EP) of arrhythmias began to take shape in the early 1960s. 2 Hoffman B.F. Cranefield P.F. Electrophysiology of the Heart. McGraw Hill Book Company, Inc, New York1960 Google Scholar The origin of clinical EP soon followed. To a septuagenarian such as myself who has been involved in both aspects, the 1960s feels like yesterday. “Ah yes, I remember it well.” 3 The song “I remember it well” by Alan Jay Lerner and Frederick Lowe in the musical Gigi. 1958 Google Scholar But as the song sung by Maurice Chevalier and Hermione Gingold in the musical Gigi points out, memory is often tricky (“We met at nine, we met at eight, I was on time, no you were late, Ah yes I remember it well” 3 The song “I remember it well” by Alan Jay Lerner and Frederick Lowe in the musical Gigi. 1958 Google Scholar ). Despite this shortcoming, I will rely on my memory to recount my viewpoint of the origin of cellular and clinical EP of arrhythmias in the United States; I was present at the creation. 4 Acheson D. Present at the Creation: My Years in the State Department. W.W. Norton, New York1969 Google Scholar

Afterdepolarizations cause triggered arrhythmias. One kind occurs after repolarization is complete, delayed afterdepolarizations (DADs). Another occurs as an interruption in repolarization, early afterdepolarizations (EADs). Afterdepolarizations initiate arrhythmias when they depolarize membrane potential to threshold potential for triggering action potentials. DADs usually occur mostly when Ca2+ in the sarcoplasmic reticulum (SR) is elevated. The SR leaks some of the Ca2+ into the myoplasm through Ca2+ release channels controlled by ryanodine receptors (RyR2) during diastole. The Na+-Ca2+ exchanger extrudes elevated diastolic Ca2+ from the cell in exchange for Na+ (1 Ca2+ for 3 Na+) generating inward current causing DADs. DAD amplitude increases with decreasing cycle length, causing triggered activity during an increase in heart rate or during programmed electrical stimulation (PES). Coupling interval of the first triggered impulse is directly related to initiating cycle length. EADs are associated with an increased action potential duration (APD) causing long QT (LQT). EADs are caused by net inward currents (I-CaL, I-NCX) as a consequence. Hundreds of mutations can cause congenital LQT by altering repolarizing ion channels. Acquired LQT results from drug interaction with repolarizing ion channels. EAD-triggered ventricular tachycardia is polymorphic and called torsade de pointes. Effects of PES on EAD-triggered activity is related to effects of cycle length on APD. Shortening cycle length prevents EADs by accelerating repolarization. Typical PES protocols inhibit formation of EADs which can be therapeutic.

Ventricular tachycardia (VT) caused by a re-entrant circuit is a life-threatening arrhythmia that at present cannot always be treated adequately. A realistic model of re-entry would be helpful to accurately guide catheter ablation for interruption of the circuit. In this review, models of electrical activation wavefront propagation during onset and maintenance of re-entrant VT are discussed. In particular, the relationship between activation mapping and maps of transition in infarct border zone thickness, which results in source-sink mismatch, is considered in detail and supplemented with additional data. Based on source-sink mismatch, the re-entry isthmus can be modeled from its boundary properties. Isthmus boundary segments with large transitions in infarct border zone thickness have large source-sink mismatch, and functional block forms there during VT. These alternate with segments having lesser thickness change and therefore lesser source-sink mismatch, which act as gaps, or entrance and exit points, to the isthmus during VT. Besides post-infarction substrates, the source-sink model is likely applicable to other types of volumetric changes in the myocardial conducting medium, such as when there is presence of fibrosis or dissociation of muscle fibers.

Sudden cardiac death caused by acute ischemia results from electrophysiologic changes in myocardium deprived of its blood supply. These changes include a reduction in resting potential and phase 0 depolarization and an increase in intercellular resistivity that slow conduction, cause conduction block, and lead to reentrant excitation and ventricular fibrillation. Reperfusion of a coronary artery after a short period of occlusion leads to similar changes.

Mark E, Josephson, MD, died on January 11, 2017, at the age of 73. His passing is an extraordinary loss to his family, friends, and colleagues and to medicine and cardiology. Mark’s life and career were inextricably intertwined with the development of clinical cardiac electrophysiology (EP). He was one of the pioneers of this relatively new medical discipline which was born in the 1960s and whose first generation that inaugurated and developed it are now reaching their seventh and eighth decades of life. He was a true innovator. Mark’s curriculum vitae lists more than 500 publications. A recently published book details his legacy and aptly identifies the “Josephson School” of electrophysiologists trained by him, who will carry on his legacy. 1 Wellens H.J. Buxton A.E. Marchlinski F.E. Zimetbaum P. The Josephson School: A Legacy of Important Contributions to Electrophysiology. Cardiotext Publishing, Minneapolis, MN2016 Google Scholar The book contains selected reprints of 59 of more than 500 publications that were considered to be the most influential, with comments by expert reviewers elucidating the seminal importance of each one. I can add little to this fitting tribute to his legacy, except my personal remembrances of my interactions with the person I first met when a medical student and who has been part of my life since that time.

Sympathetic tone is important in cardiac arrhythmogenesis; however, methods to estimate sympathetic tone are either invasive or require proper sinus node function that may be abnormal in disease states. Because of the direct and extensive connections among various nerve structures, it is possible for the sympathetic nerves in the various structures to activate simultaneously. Therefore, we hypothesized that nerve activity can be recorded from the skin and it can be used to estimate the cardiac sympathetic tone. Preclinical studies in canines demonstrated that nerve activity is detectable using conventional ECG electrodes and can be used to estimate cardiac sympathetic tone. Subsequent clinical studies further supported this concept. In addition to studying the autonomic mechanisms of cardiac arrhythmia, these new methods may have broad application in studying both cardiac and non-cardiac diseases.

Background: Paroxysmal atrioventricular (A-V) block is relatively rare, and due to its transient nature, it is often under recognized. It is often triggered by atrial, junctional, or ventricular premature beats, and occurs in the presence of a diseased His-Purkinje system (HPS). Here, we present a 45-year-old white male who was admitted for observation due to recurrent syncope and near-syncope, who had paroxysmal A-V block. The likely cellular electrophysiological mechanisms(s) of paroxysmal A-V block and its differential diagnosis and management are discussed. Methods: Continuous electrocardiographic monitoring was done while the patient was in the cardiac unit. Results: Multiple episodes of paroxysmal A-V block were documented in this case. All episodes were initiated and terminated with atrial/junctional premature beats. The patient underwent permanent pacemaker implantation and has remained asymptomatic since then. Conclusions: Paroxysmal A-V block is rare and often causes syncope or near-syncope. Permanent pacemaker implantation is indicated according to the current guidelines. Paroxysmal A-V block occurs in the setting of diseased HPS and is bradycardia-dependent. The detailed electrophysiological mechanisms, which involve phase 4 diastolic depolarization, and differential diagnosis are discussed.

Reentrant ventricular tachycardia is an important clinical problem. It is caused by an electric circuit traveling in 1 or more loops that are constrained to the ventricular myocardium.1,2 The arrhythmia often originates after myocardial infarction, in the region near the infarcted area. This proximate region or infarct border zone (IBZ) contains surviving strands of myocardial fibers that continue to conduct electrical activity.1,2 Electrical conduction there is constrained by the infarcted region, which does not activate, by the geometry of the remaining viable myocardial tissue, and by the contour of the heart surface in proximity to the IBZ. Several mechanisms have been suggested to explain the formation of functional block leading to and maintaining reentry, all of which likely have a contribution. One possibility is that disparate gap junctional connecting properties suppress activation from one myocyte to the next. If, for example, there are less gap junctions between connecting cells than normal, it can result in an insufficient current density during activation and may lead to conduction block.3 Another mechanism that has been proposed is the presence of disparities in ion channel properties in the IBZ.4 Such regions would have differences in the functioning of sodium, potassium, and calcium current ion channel gates between the postinfarction myocardial cells, when compared with their normal properties. This would alter the depolarization and repolarization phases of the action potential, possibly preventing activation between cells or causing it to be slowed or weak. Similar to the proposed gap junction mechanism, if the ion channel properties are disparate across a transition zone, it may result in a lack of electrical connectivity. On one side of the transition zone, when activation occurs, ions are not transferred with sufficient density or rapidity to cells on the other side of the …

Introduction: In this study, the mechanisms for onset and maintenance of mid-myocardial (intramural) reentrant circuits are considered, based upon anatomical structure.Method: A model of electrical activation wavefront curvature in the mid-myocardial postinfarction border zone is developed. Two arrhythmogenic structures are considered: 1. a constrained slab of viable tissue, and 2. a strand of surviving myocardial fibers with distal expansion. Equations are formulated to estimate activation coupling intervals, and ranges in taper and circuit dimensions, that will support functional conduction block during premature stimulation and reentrant ventricular tachycardia.Results: For onset and maintenance of reentry, the arrhythmogenic regions forming both slab and strand circuits are in the range of 50-600 mu m at their thinnest dimension. For constrained slabs, unidirectional block leading to reentry forms in the thin-to-thick direction during premature stimulation, and functional block at lateral boundaries enable formation of a double-loop circuit. The activation wavefront proceeds around the impediment and then curves in the opposite direction through the slab, reentering the previously excited tissue. For strands, unidirectional block forms at a distal expansion in response to premature stimulation. The strand reentrant circuit is bounded by infarcted tissue causing anatomical block, and can be single-loop or coaxial. For all architectures, circuit dimensions ranging from 1.6 x 1.6 mm to 3.5 x 3.5 mm support functional block when premature stimulus coupling intervals are 117-150 ms and ventricular tachycardia cycle lengths are 160-350 ms.Conclusions: For slab and strand mid-myocardial arrhythmogenic structures, taper and circuit dimensions govern ranges in premature excitation coupling intervals and tachycardia cycle lengths necessary to support functional block. (C) 2016 Elsevier Ltd. All rights reserved.

We describe the mechanism underlying paroxysmal AV block that follows a sudden long cycle length.The phases and characteristics of the Purkinje fiber action potential are reviewed.Phase 4 block occurs when an impulse conducts into regions of Purkinje cells that have undergone spontaneous (phase 4) depolarization causing a reduction in the level of the membrane potential during diastole.This results in a decrease in inward sodium current during the depolarization phase (0) of the action potential, slow conduction and conduction block.The mechanisms involved are discussed in detail and compared to phase 3 block.

BACKGROUND:When the infarct border zone is stimulated prematurely, a unidirectional block line (UBL) can form and lead to double-loop (figure-of-eight) reentrant ventricular tachycardia (VT) with a central isthmus. The isthmus is composed of an entrance, center, and exit. It was hypothesized that for certain stimulus site locations and coupling intervals, the UBL would coincide with the isthmus entrance boundary, where infarct border zone thickness changes from thin-to-thick in the travel direction of the premature stimulus wavefront. METHOD:A quantitative model was developed to describe how thin-to-thick changes in the border zone result in critically convex wavefront curvature leading to conduction block, which is dependent upon coupling interval. The model was tested in 12 retrospectively analyzed postinfarction canine experiments. Electrical activation was mapped for premature stimulation and for the first reentrant VT cycle. The relationship of functional conduction block forming during premature stimulation to functional block during reentrant VT was quantified. RESULTS:For an appropriately placed stimulus, in accord with model predictions: 1. The UBL and reentrant VT isthmus lateral boundaries overlapped (error: 4.8±5.7mm). 2. The UBL leading edge coincided with the distal isthmus where the center-entrance boundary would be expected to occur. 3. The mean coupling interval was 164.6±11.0ms during premature stimulation and 190.7±20.4ms during the first reentrant VT cycle, in accord with model calculations, which resulted in critically convex wavefront curvature and functional conduction block, respectively, at the location of the isthmus entrance boundary and at the lateral isthmus edges. DISCUSSION:Reentrant VT onset following premature stimulation can be explained by the presence of critically convex wavefront curvature and unidirectional block at the isthmus entrance boundary when the premature stimulation interval is sufficiently short. The double-loop reentrant circuit pattern is a consequence of wavefront bifurcation around this UBL followed by coalescence, and then impulse propagation through the isthmus. The wavefront is blocked from propagating laterally away from the isthmus by sharp increases in border zone thickness, which results in critically convex wavefront curvature at VT cycle lengths.