IntroductionOver the past decades, anticoagulant medication has changed dramatically. During the past century (1950 onwards) the use of heparins and vitamin K antagonists (VKA) became common practice for prevention and treatment of venous thromboembolism (VTE), prevention of stroke in atrial fibrillation (AF), and other indications (1). From the 80-ies onwards, the introduction of low molecular weight heparins (LMWH) led to rapid replacement of unfractionated heparin for prevention and (initial) treatment of VTE (2). Subcutaneous administration of LMWH allowed for ambulatory management of many patients (3). From the 90-ies onwards, the introduction of direct oral anticoagulants (DOAC, also known as âNOACâ) led to a similarly rapid replacement of VKA for the major indications involving prolonged oral anticoagulation, VTE and AF (4,5). The basis for this pharmaceutical transition was established by the immense gain in knowledge of structure and function of coagulation enzymes and their natural inhibitors. Many years of research by academics and pharmaceutical companies alike paved the way for the successful marketing of LMWH, danaparoid and the synthetic glycosaminoglycan molecule fondaparinux (6,7). The development of DOAC was led by company-based researchers that spent many years on identifying suitable small molecules with the desired specificity for their target (thrombin or factor Xa), but also with the appropriate characteristics to allow oral ingestion and adsorption from the gastrointestinal tract, and with pharmacological properties enabling once or twice daily dosing (8-10). The high quality of this research and the successful translation to clinical trials and subsequent implementation cannot be overestimated. Large clinical trials comparing DOAC with VKA showed non-inferior or superior efficacy as well as safety, vs VKA (warfarin), with a class effect of reduced intracranial bleeding for all DOAC (11,12). Due to these encouraging features, coupled with strong marketing publicity, DOAC flooded the âmarketsâ; the large volumes of patients with VTE and particularly AF, meant big business worldwide. The downside of this success story may have been that there was little time left for reflection on possible hurdles and caveats. Which caveats could have been foreseen? One of the key differences between the âoldâ (heparins, VKA) and ânewâ anticoagulants was moving from a laboratory guided therapy towards a fixed dose policy. For heparins, aPTT controlled therapy had been important (in case of iv dosing), for VKA determination of the prothrombin time (translated into International Normalized Ratio, INR) was and remains pivotal to titrate the optimal dose for the individual patient (13,14). Ideally, VKA management is supported by trained anticoagulation service personnel; in countries like the Netherlands there still is an efficient network of anticoagulation clinics (âTrombosedienstenâ). With the introduction of DOAC, these anticoagulation clinics did not play any role of importance, leaving DOAC management to the prescriber and general practitioner with support from the pharmacy. In practice, my impression is that this vulnerable system of follow up of patients on DOAC is suboptimal. My international colleagues have oftentimes done the suggestion to use the system of existing anticoagulation clinics for organizing annual checks for patients on DOAC and to serve as a helpdesk for questions from patients and caregivers. However, the Dutch insurance companies have consistently deferred any serious discussions on such initiatives, on basis of the added costs of these clinics to the already expensive DOAC; now that most of these drugs are or will be generic, the cost argument becomes less important. In fact, even today one insurer actively promotes to replace remaining VKA use as much as possible by DOAC and to scale down anticoagulation clinics into centralized âdesksâ for dosing, which is bizarre as remaining patients on VKA are even more complex than before. How to improve DOAC management? Patients on DOAC deserve proper drug management, like for drugs taken to treat diabetes, hypertension or hypercholesterolemia. So-called cardiovascular risk management for patients with AF, is a successful instrument in our country. DOAC control is only occasionally part of this system, while general knowledge on indications, mode of action, drug-drug interactions (DDI), pharmacology, and side effects, is poor among patients and caregivers (DUTCH-AF study, submitted). It is probably a combination of these factors that underlies the surprising outcomes of the Dutch FRAIL-AF study in frail elderly patients with AF, showing that the conversion from VKA to DOAC led to more bleeding complications as compared to continued VKA, without any reduction in thromboembolic complications (15). While there can be debate about several trial elements, including selection bias (only patients already on VKA enrolled), the outcomes should have triggered concern about the quality of DOAC care in this country, at this moment. Most likely, DOAC are suitable drugs also in frail patients, as shown by others (16), but the demonstrated inferior safety, even for hemorrhagic stroke, is alarming. A consequence must be to critically revise our follow up system for DOAC, focusing more on proper patient information and guidance, addressing avoidable problems like suboptimal dosing, based on inappropriate subjective arguments (frail patient, prone to fall and bleed), but also based on lack of insight in individual pharmacodynamics, especially in an aging population. A place for DOAC monitoring? There has been much debate about the need for laboratory monitoring of DOAC and it is a pity that this discussion wasnât more broadly held at the introduction of these agents (17). It could be foreseen, as is recognized in most current guidelines, that at least in acute settings like major bleeding or thromboembolism, while on DOAC therapy, or in peri-procedural settings like surgery, or thrombolysis, there would be a need for determination of a DOAC plasma level, preferably even by point-of-care (POC) device; the INR still is an undisputed biomarker for VKA in the emergency setting. Still, the adagio remained âno monitoring necessaryâ for a long time. The result is that even after > 15 years of DOAC use, a POC assay is still lacking, except for a rapid urine test (18). Another assumption at onset was that DOAC would be markedly safer, driven by the class effect of less intracranial bleeds. The implicit conclusion was that reversal agents would not be really needed, in absence of frequent life-threatening bleeding complications, an unfortunate misconception. The positive exception was the Boehringer company that rapidly after introducing dabigatran decided to also develop a specific reversal agent; the monoclonal antibody fragment idarucizumab is a rapidly acting reversal agent without intrinsic procoagulant properties (19). Factor Xa inhibitor producing companies decided not to invest in developing reversal agents, maybe understandable from their short-term financial outlook, but not from a societal perspective where thousands of patients take a daily dose of a potentially harmful Factor Xa inhibitor without proper antidote available. The idea that in case of major bleeding prothrombin concentrate would be sufficient has been essentially refuted by the recent Andexa-I study outcomes, showing superior hemostatic effect of the reversal agent Andexia for intracranial bleeding, as compared with prothrombin complex concentrate (20). The fact that there still is debate on the costs and adverse effects of Andexia is relevant and the need for refinement of this and other reversal agents is evident, but the fact that this discussion takes place while most DOACs are already getting out of patent illustrates the lack of careful thinking upfront when developing these potent factor Xa targeted DOAC. Anticoagulation in a frail elderly populationExcept for acute situations like major bleeding, there should be further discussion and study regarding application of DOAC in frail elderly patients, as this population is increasing among those with AF. Our recent work and that of others clearly show concerning deviations of plasma DOAC levels when compared with on-therapy ranges derived from the initial large trials (21-23). Importantly, excess plasma levels are associated with bleeding risk (24,25). Most concerning is that it is not immediately evident what the reasons are for deviating, especially too high, plasma concentrations; mostly it is not directly linked to wrong dosing or renal insufficiency. For the time being this may mean that in practice, a check of plasma level over the age of 75 years or so, may be worth to explore whether a specific DOAC is appropriate for a given subject, certainly in case of frailty and other potential factors like DDI and renal impairment. While this policy may raise criticism based on lack of proper pharmacokinetics when sampling single blood draws, inappropriate use of on-therapy ranges and so forth, common sense may suffice to at least estimate whether the used DOAC is reasonable to begin with, or should be replaced by another, or tailored in dose within registered ranges. Obviously, clinical trials need to address the potential utility of DOAC laboratory monitoring for establishing long term safety among frail DOAC users. Lastly, one should be aware of VKA as a more than reasonable alternative. VKA remains a proper alternative for DOACMany starting physicians will have hardly any experience with VKA, so this alternative to DOAC is hardly ever considered in practice, is my observation. Many think that VKA are old fashioned (correct), complex (partially correct) and dangerous (not correct, at least not much worse than DOAC). However, important indications for VKA remain in place, as DOAC were inferior in patients with mechanical heart valves, antiphospholipid antibody syndrome (at least in those with triple positive antibodies) and moderate to severe mitral valve stenosis associated AF (26). Moreover, the practical advantage of VKA is the managed care, which, when organized properly provides individual tailoring that considers all possible factors including DDI and renal impairment. For patients with anticipated poor drug adherence, this may also be an advantage of VKA over DOAC. VKA have the disadvantage of increased vascular calcification and perhaps negative impact on renal function in those with renal insufficiency (27,28). Surprising advantages of VKA may be increased survival in subjects with cancer (maybe due to inhibition of specific proteins like Gas-6) (29), as well as in patients with AF, at least while on phenprocoumon, the single VKA in Germany (partially explained) (30); as compared to Factor Xa inhibitors, patients on dabigatran had a comparable survival advantage. This possible survival benefit, while prone to bias, sheds new light on this old class of agents and may be reassuring for those who feared that VKA, when indicated, would cause more harm (eg vascular calcification) than benefit. Altogether, one should not discard VKA as a treatment alternative even in frail elderly with AF, provided that a good time in therapeutic range is achieved; the latter is best obtained with phenprocoumon, but this medication is not available in many countries, unfortunately. The German colleagues appropriately call for a randomized trial to assess the merits of phenprocoumon against DOAC (30). Place for new anticoagulants? Finally, following initial enthusiasm about DOAC, we are entering a period of greater realism regarding the limitations in safety of DOAC (and VKA), with remaining annual risk of major bleeding of at least 2-3% on average, and substantial variation among individuals that is hard to predict with current risk scores. The hope among pharmaceutical companies (and their investors) is that safety can be further enhanced by addressing other targets, including factor XIa (31). On the one hand, this wishful thinking stems from observational data from patients with congenital factor XI deficiency showing that it is associated with a low risk of spontaneous bleeding, in contrast to other hemophilias. On the other hand, epidemiological, genetic and experimental evidence indicates that FXI is associated with thrombus formation and is specifically linked to cardioembolic stroke and VTE. Data on atherothrombosis remain controversial (32-34). A proof of principle human study showed that FXI gene silencing with siRNA technology markedly reduced FX levels in blood and also achieved a substantial reduction in postoperative venous thrombosis in knee replacement surgery (35). A comparable efficacy was shown for other approaches, including monoclonal antibodies and the small oral molecule milvexian (36). Based on these studies phase 2 trials were designed in patients with VTE, but also with arterial vascular disease, including AF, acute stroke and acute coronary syndrome (ACS). Last year, the outcomes of several phase 2 trials were published. The data unequivocally show reduced bleeding risk as compared with apixaban, or rivaroxaban in the AF studies, and acceptable bleeding rates in patients with ACS or stroke (discussed in 37-39). However, none of these studies gave a clear signal about efficacy, which although not accounted for in phase 2, would have been of interest. Driven by optimism, phase 3 was initiated with studies in AF, the OCEANIC-AF and LIBREXIA-AF, with asundexian and milvexian, respectively (40,41). While the LIBREXIA-AF trial is still ongoing, the OCEANIC-AF trial was arrested after inclusion of close to 15,000 patients, due to excess ischemic strokes in the asundexian arm. The main paper was recently published, discussing potential reasons for failure (40). These included too low dosing (although in plasma samples there was well over 90% inhibition of FXIa), escape mechanisms that were not alluded to, but may include bypass activation of FIX by kallikrein (42); finally, the authors note that the background population may have markedly changed with less AF burden, explaining the overall low rate of embolic stroke. A final option, that FXI activation may not be so relevant in all subjects with AF, was not mentioned. All arguments shed doubt on the design of such large studies, where the contribution of FXI to thrombosis risk, the impact of the drug (dose) and possible escape mechanisms, including the kallikrein driven activation of FIX bypassing FXI, were apparently not sufficiently explored or considered. Unfortunately, the negative trial outcome may lead to scepsis regarding the concept of FXI inhibition, that may be preliminary and unjustified, in absence of mechanistic data. Conclusion and perspectiveAlthough anticoagulant treatment has improved markedly from a practical perspective, its safety remains at stake as the follow up of patients on DOAC is insufficient. This certainly concerns frail elderly with AF where VKA may even be better than DOAC, if VKA care is well managed. Attention must be on improving the quality of DOAC, including adherence to therapy, which may also require occasional assessment of DOAC plasma level in frail patients, to assess the suitability of drug and dose. When moving forward with novel anticoagulants, e.g factor XIa inhibitors, one should not only rely on wishful thinking but also carefully consider disease related thrombosis mechanisms in the very diverse patients, to be better prepared for and hopefully avoid, more large study failures.
Asma Jodeiri Akbarfam, Sina Barazandeh, Deepti Gupta, Hoda Maleki
Access control is a critical component of computer security, governing access to system resources. However, designing policies and roles in traditional access control can be challenging and difficult to maintain in dynamic and complex systems, which is particularly problematic for organizations with numerous resources. Furthermore, traditional methods suffer from issues such as third-party involvement, inefficiency, and privacy gaps, making transparent and dynamic access control an ongoing research problem. Moreover detecting malicious activities and identifying users who are not behaving appropriately can present notable difficulties. To address these challenges, we propose DLACB, a Deep Learning Based Access Control Using Blockchain, as a solution to decentralized access control. DLACB uses blockchain to provide transparency, traceability, and reliability in various domains such as medicine, finance, and government while taking advantage of deep learning to not rely on predefined policies and eventually automate access control. With the integration of blockchain and deep learning for access control, DLACB can provide a general framework applicable to various domains, enabling transparent and reliable logging of all transactions. As all data is recorded on the blockchain, we have the capability to identify malicious activities. We store a list of malicious activities in the storage system and employ a verification algorithm to cross-reference it with the blockchain. We conduct measurements and comparisons of the smart contract processing time for the deployed access control system in contrast to traditional access control methods, determining the time overhead involved. The processing time of DLBAC demonstrates remarkable stability when exposed to increased request volumes.
Pulmonary vein (PV) isolation can be performed at different levels in the ostium. Initially, segmental isolation, targeting individual strands of atrial myocardial tissue in PV ostia, was performed using the combination of a circular mapping catheter and a standard ablation catheter.1 In most centres, clinical success rates were moderate. Soon, however, it was recognized that wider encircling improved success and reduced complications.2 Additional ablation lines and substrate modification may further increase success, but may also create a substrate for left atrial flutters.3â5 The creation of a long continuous ablation line around a PV antrum using a single ablation electrode is technically challenging. Kistler et al. described a prospective randomized study to investigate the contribution of image integration to catheter ablation of atrial fibrillation.6 The value of CartomergeÂź was investigated on the basis of an incomplete Carto map. It is highly remarkable that even then, image integration did not affect the quality of the procedure. The study suggests that an anatomically correct geometry does not facilitate the creation of continuous transmural lesions. Such geometry definitively helps to outline the desired course of the ablation lines, but apparently it does not improve the continuity of that line. Use it if you like it, but don't expect any miracles. The ablation procedure was performed using an irrigated ablation electrode to create the long ablation lines around both pairs of PV ostia.6 Wall contact during ablation, precise catheter manipulation, and the delivery of sufficient radiofrequency (RF) power are the most important determinants of successful electrical isolation. While irrigated catheters are highly advisable to reduce the risk of blood clot formation during RF ablation, electrode cooling greatly eliminates the electrode temperature increase as feedback for tissue contact. This may have been the reason for the investigators using a remarkable irrigation protocol: the flow rate was maintained at 2 mL/min unless the 50°C target temperature was reached with <20 W. One should remember that a flow rate of 2 mL/min may only be sufficient to keep the irrigation holes open, not to prevent blood clot formation on the heated tissue surface.7 Even with standard non-irrigated electrodes, detection of wall contact and lesion formation on the basis of electrode temperature response remains difficult. A high electrode temperature increase at low power may be caused not only by intimate electrodeâtissue contact, but also by low blood flow. Local electrogram characteristics and amplitude, impedance drop during ablation, fluoroscopic imaging, and intracardiac echocardiography (ICE) are alternative ways to judge wall contact, but they all have important limitations or add significant complexity. A combination of these methods and 3D mapping systems are used in most labs, but even then, multiple acute gaps in the lines are more the rule than the exception. Moreover, a large number of patients experience a recurrence after a first procedure because of resumed conduction through the antrum lines despite the fact that the observation time after isolation often is lengthened by additional ablations.8 Persistent continuity of ablation lines should be our main goal for future developments. A 30 W/50°C setting was originally used for segmental PV isolation where myocardial sleeves may be relatively thin. To prevent collateral damage, one should always try to limit RF power, but with low power it may sometimes be very difficult to achieve complete electrical isolation of the PV antrum that includes sections with thicker myocardium and the appendix ridge where catheter stability is a major challenge.9 Kistler et al. used an electrogram amplitude <0.1 mV or amplitude reduction >80% as endpoint during ablation.10 Reduction of the local unipolar electrogram clearly is an indicator for lesion formation. Often, however, electrograms <0.1 mV still can be found inside the PV ostia and some of these can be proven to be true local activations. Conversely, an electrogram >0.1 mV within PVs can be a remote signal from the bulk of the left or right atrium, left atrial appendage, or superior caval vein. The latter signals, very misleadingly, sometimes also show decremental properties with atrial extrastimuli. Consequently, a simple amplitude criterion is not sufficient to declare PVs electrically silent. If the goal is complete electrical isolation then one should meticulously investigate the origin of all electrograms distal from the ablation line and continue the search for leaks until all local signals have disappeared. Adenosine may reveal latent leaks, but mapping of those leaks can be very difficult.11 Kistler et al. speculate that image fusion in NavX could result in more reduction in fluoroscopy time than with Carto. With NavX, an accurate geometry can be created in 15 min, with only a few minutes of fluoroscopy. With image fusion, only these few minutes are at stake and it is unlikely that image fusion will reduce fluoroscopy time more than CartomergeÂź. Reduction in radiation exposure, however, always remains a valid argument to investigate new technologies. Many electrophysiology (EP) labs are equipped with fluoroscopy systems that were originally designed to visualize tiny arteries and stents. EP procedures, however, do not require that image quality; we mainly have to see the contrasting catheters. Fluoroscopy systems in EP labs can therefore use extra primary beam filtration and lower pulse rates. In addition, one is obliged to use standard measures such as lower body-protecting lead flaps and an upper body-protecting glass screen. With a badge on the collar above the apron, the total annual dose of all operators performing catheter ablation procedures in a single EP lab can then stay below 5 mSv. Any team with a significantly higher total operator badge dose for catheter ablation procedures alone should seek advice from the fluoroscopy system manufacturer. Most modern systems have three different dose rate settings that are individually programmable by the manufacturer. Both electrophysiologists and interventional cardiologists can then be satisfied when they have to share the lab, and often operator and patient dose rates can be reduced by a factor of 5 or more without any impact on the quality of EP procedures. As a method for reducing fluoroscopy exposure, the application of advanced technologies, such as ICE, robotic or magnetic catheter navigation, image integration, and even 3D mapping systems alone, only makes sense when basic measures such as optimized fluoroscopy settings have been put in operation. Conflict of interest: F.H.M.W. is a consultant for St Jude Medical.
In the differential diagnosis of supraventricular tachycardia, pacing maneuvers or observation rarely provide a diagnosis when used individually.1 The introduction of transcatheter therapy for cardiac arrhythmia transforms electrophysiology from an exclusive, scholarly, almost Talmudic, field to an interventional goal-oriented field where successful elimination of the arrhythmia by âburningâ often serves as âproofâ of the arrhythmia mechanism (Learning by Burning). In a series of papers by Callans et al.2â4 published in this Journal, the term âlearning while burningâ was coined, emphasizing that in contrast to the goal oriented approach, ablation procedure is indeed a powerful tool for understanding the interplay between anatomical substrate and the pathophysiology of clinical arrhythmia. The authors in the present Journal article5 put a new twist on that concept by utilizing junctional beats induced during ablation procedure of AV nodal slow pathway modification to gain a new insight to the differential diagnosis of atrioventricular node reentry tachycardia (AVNRT) versus junctional tachycardia (JT). The authors should be applauded for a meticulous execution of the study protocol and a rigorous validation of their findings that showed convincingly that the mean H-A during JT is shorter than the mean H-A during AVNRT and that the mean delta H-A (defined as retrograde H-A during ventricular pacing minus H-A during tachycardia) is negative during AVNRT, as opposed to positive during JT. In the study design, both AVNRT and JT were induced in each patient. When these measurements were compared on an individual basis (meaning that every patient's measurements during AVNRT were compared with his or her own measurements during JT controlling for variability between patients), these findings hold true in most patients (see Figs. 2 and 3). How can we explain these finding based on our present knowledge about the electrophysiological properties of these arrhythmias? AVNRT is the most common cause of supraventricular tachycardia in patients referred for electrophysiological study (EPS).1 The âcommon,ââtypical,ââslow-fastâ type is present in over 80% of all cases of AVNRT.6 In a simplistic model, AVNRT results from reentry involving two anatomically distinct AV node structures7,8 (i.e., âslowâ and âfastâ pathways). In âslow-fastâ AVNRT, the reentry circuit consists of anterograde conduction through the slow pathway and retrograde conduction by the fast pathway with the earliest retrograde atrial activation in the âfast pathway regionâ at the apex of the triangle of Koch, recorded on the His-bundle electrogram from the right septum.9,10 Unfortunately, life is not that simple: the three-dimensional anatomy and cytoarchitecture of the AV junction is complex11,12 and the exact location of the atrionodal connections and slow and fast pathways are still controversial. Although several elegant models based on functional characteristics of different areas of the compact AV node and surrounding structures were proposed to explain dual-AV node physiology, the sheer bulk of the literature on the subject and the ongoing debate attest that none of them is proven.13,14 In as many as 40% of the patients with AVNRT, there are multiple AV nodal pathways.15 Even in patients with typical AVNRT, recording with close-spaced electrodes in the His, coronary sinus (CS), and the slow-pathway areas has shown that there is heterogeneity of the retrograde fast pathway conduction pattern.16 Recording of the His bundle potential from the right and left sides of the septum has shown that the earliest retrograde atrial activation during AVNRT is most often recorded on the left side of the septum.17 Thus, it is not surprising that there is a considerable variability in H-A intervals in patients with typical AVNRT, making it difficult at times to differentiate between typical AVNRT and other arrhythmias (including JT) based on H-A interval alone. According to the slow-fast pathway model, the retrograde atrial activation sequence during right ventricular pacing at the tachycardia cycle length, immediately after typical AVNRT, propagates retogradely from the His bundle through the lower common pathway to the fast pathway, and should be similar to the activation sequence during typical AVNRT. Retrograde H-A interval during ventricular pacing (H-Ap; measured from the end of the most proximal His potential to earliest A) is the sum of retrograde conduction time of the lower common pathway and the retrograde fast pathway. The H-A of typical AVNRT (H-At) according to this model is retrograde conduction time of the fast pathway minus anterograde conduction time of the lower common pathway. The difference between H-Ap and H-At (so called delta H-A) equals retrograde plus anterograde conduction time of the lower common pathway13 (assuming that the retrograde fast pathway conduction time is identical during pacing and AVNRT). A positive delta HA suggests that a lower common pathway is present. A negative delta HA, which, in fact, was found in the present study5 and by others,18 cannot be explained by this simple model. Although there are several explanations for this phenomenon, including difference in conduction velocity, activation path,19 and a combination thereof,13 a negative delta HA probably reflects a very short or an absent lower common pathway. Automatic JT as described by Coumel20 is a rare arrhythmia seen mainly in the pediatric population21 and postcardiac surgery21,22 and very rarely in adults.23 In the few cases studied, abnormal automaticity within or in close proximity to the His bundle was found.24â26 JT is frequently seen during radio frequency ablation using the AV node modification by slow pathway approach. In fact, the presence of JT is associated with successful slow pathway ablation.27,28 The pathophysiology of JT during ablation is thought to be enhanced automaticity due to heating of the tissue29,30 or local release of norepinephrine.31 Studies in pig and rabbit heart models have shown that heating in a discrete area located in the middle of the triangle of Koch that was located in close proximity to the compact AV node induced JT. In that area, no slow pathway potential was seen and it was distant from the site of earliest retrograde atrial activation. There was a large variation between individual animals regarding the location of these sites.30 In canine blood-perfused atrioventricular node preparations, JT was induced by heating anterior to the CS os with the earliest retrograde atrial activation site at the His-potential recording site or in the middle of Koch's triangle. After interruption of the posterior input to the AV node, atrial activation during JT spread from the low posterior to the high anterior septum.29 In humans, VA block during junctional ectopy is a harbinger of AV block in patients undergoing RF ablation of the slow pathway,27 suggesting that the retrograde atrial activation during JT may involve the His area or the common lower pathway. However, in that same paper, the authors observed that âVA conduction should be expected during the junctional ectopy that accompanies slow pathway ablation, even when there is poor VA conduction during baseline ventricular pacing,â and that the AV block was proximal to the His.27 These astute observations suggest that the site of VA conduction during JT is proximal to site of VA block during ventricular pacing. Wagshal et al.32 reported that higher temperature lesions simultaneously abolish all slow pathway activity as well as the focus of JT, which suggests that the JT source is located or triggered by slow pathway tissue. In a study by Lee et al.,33 atrial activation sequences were assessed by comparing H-A interval (measured at the high right atrium) during various forms of AVNRT and JT induced by ablation. In 27 patients with slow-fast AVNRT, H-A during JT was shorter than during AVNRT: 58 ± 24 msec compared with 68 ± 21 msec, respectively (P < 0.01). In the present study,5 a similar trend in mean H-A interval was observed: 35 msec versus 54 msec during JT and AVNRT, respectively. These findings call into question the concept that JT seen during RF ablation originates or has an exit point near the His area as described in the rare âde novoâ automatic JT.24 Obviously, if a junctional beat originates near the His, distally to a common pathway, the H-A interval during JT will be longer than H-A interval during AVNRT that has a more proximal turn-around point to the fast pathway. In that situation, one would expect near-zero delta H-A in JT and positive delta H-A in AVNRTâin contrast to the finding of present5 and other33 studies. Studies in animal models and high resolution mapping in humans have demonstrated several mechanisms that can account for the shorter H-A interval during JT compared with AVNRT: changes in activation sequences that may cause direct activation of the atria, compact AV node,29 anisotropic spread from one more AV nodal transitional zone,34 fibers connecting to the fast pathway,35 or fibers connecting the slow pathway ablation area directly to the fast pathway in a more proximal location.33 Local heating may cause an increase in conduction velocity due to a direct effect30 or adrenergic stimulation. A recent study in a canine complete AV block model has shown that the application of RF energy caused a shift from the distal portion of the AV junctional area to a more proximal one. This enhanced junctional automaticity was suppressed by esmolol but not affected by atropine.31 In conclusion, differential diagnosis of a short RP tachycardia can be challenging. The paper by Srivathsan et al.5 adds a valuable new technique regarding the diagnosis of JT versus AVNRT, as well as provides insight into the electrophysiological mechanism of this fascinating and elusive arrhythmia. Further research is needed to ascertain whether these findings can be extended to the clinical forms of JT. Acknowledgment: The author would like to thank Dr. Shaul Atar for critical review of the manuscript.