Blockchain Papers

Scott Seidenberger, Anindya Maiti

No abstract is available for this record.

Filippo Crea

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This Focus Issue opens with the first President’s page by Prof. Thomas Lüscher entitled ‘From a group of friends to an esteemed institution: past successes and future challenges for the European Society of Cardiology’ in which the new President of the European Society of Cardiology (ESC) summarizes the key steps that have made ESC one of the largest and most prestigious medical societies in the world.1 He also highlights the main exciting goals that he will pursue during his presidency over the next two years. Then the Editor’s page entitled ‘European Heart Journal: a call to action’ in which the Editors of the European Heart Journal (EHJ) highlight the mission of the Journal, which is not only the dissemination of innovative scientific knowledge but also the promotion of best clinical practice.2 The Editors invite population, clinical, and translational scientists to submit their best manuscripts to EHJ highlighting the opportunities offered by the Journal. The Issue continues with three innovative European Society of Cardiology (ESC) Guidelines: the ‘2024 ESC Guidelines for the management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS)’3, the ‘2024 ESC Guidelines for the management of chronic coronary syndromes’,3 and the ‘2024 ESC Guidelines for the management of peripheral arterial and aortic diseases’.4 The rest of the Issue focuses on arrhythmias and ischaemic heart disease. Ischaemic heart disease remains the number one killer in the world and major efforts are needed to reduce its devastating impact.5–9 In a State of the Art Review article entitled ‘Myocardial ischaemic syndromes: a new nomenclature to harmonize evolving international clinical practice guidelines’, William Boden from the Boston University School of Medicine in the United States, and colleagues note that since the 1960s for chronic stable manifestations of myocardial ischaemia, various classifications have emerged over time, often with conflicting terminology—e.g. ‘stable coronary artery disease’ (CAD), ‘stable ischaemic heart disease’, and ‘chronic coronary syndromes’ (CCS). While the 2019 European guidelines introduced CCS to impart symmetry with ‘acute coronary syndromes’ (ACS), the 2023 American guidelines endorsed the alternative term ‘chronic coronary disease’.10 An unintended consequence of these competing classifications is perpetuation of the restrictive terms ‘coronary’ and ‘disease’, often connoting only a singular obstructive CAD mechanism. It is now important to advance a more broadly inclusive terminology for both obstructive and non-obstructive causes of angina and myocardial ischaemia that fosters conceptual clarity and unifies dyssynchronous nomenclatures across guidelines. The authors therefore propose a new binary classification of ‘acute myocardial ischaemic syndromes’ and ‘non-acute myocardial ischaemic syndromes’, which comprises both obstructive epicardial and non-obstructive pathogenetic mechanisms, including microvascular dysfunction, vasospastic disorders, and non-coronary causes. They herein retain the accepted categories of acute coronary syndrome, ST-segment elevation myocardial infarction (MI), and non-ST-segment elevation MI, as important subsets for which revascularization is of proven clinical benefit, as well as new terms like ischaemia and MI with non-obstructive coronary arteries. Overall, such a more encompassing nomenclature better aligns, unifies, and harmonizes different pathophysiologic causes of myocardial ischaemia and should result in more refined diagnostic and therapeutic approaches targeted to the multiple pathobiological precipitants of angina pectoris, ischaemia, and infarction. Risk stratification and optimal management of atrial fibrillation (AF) remain major targets in cardiovascular medicine.11–18 In the Fast Track Clinical Research article entitled ‘Gender and contemporary risk of adverse events in atrial fibrillation’, Asgher Champsi from the University of Birmingham in the United Kingdom, and colleagues indicate that the role of gender in decision-making for oral anticoagulation in patients with AF remains controversial.19 The population cohort study used electronic healthcare records of more than 16 500 000 patients from UK primary care (2005–2020). Primary (composite of all-cause mortality, ischaemic stroke, or arterial thromboembolism) and secondary outcomes were analysed using Cox hazard ratios (HR), adjusted for age, socioeconomic status, and comorbidities. A total of about 79 000 patients with AF were included, aged 40–75 years, 36% women, no prior stroke, and no prescription of oral anticoagulants. During a total follow-up of 431 086 patient-years, women had a lower adjusted primary outcome rate with HR 0.89 vs. men (P < .001) and HR 0.87 after censoring for oral anticoagulation (P < .001). This was driven by lower mortality in women (HR 0.86; P < .001). No difference was identified between women and men for the secondary outcomes of ischaemic stroke or arterial thromboembolism, any stroke or any thromboembolism, and incident vascular dementia. Clinical risk scores were only modest predictors of outcomes, with CHA2DS2-VA (ignoring gender) superior to CHA2DS2-VASc for primary outcomes in this population (receiver operating characteristic curve area 0.651 vs. 0.639; P < .001) and no interaction with gender (P = .45) (Figure 1). The impact of gender on adverse events in patients with atrial fibrillation (AF) based on a population cohort study using electronic healthcare records from UK primary care (2005–20).19 The authors conclude that removal of gender from clinical risk scoring could simplify the approach to which patients with AF should be offered oral anticoagulation. The contribution is accompanied by an Editorial by Gregory YH Lip and Peter Brønnum Nielsen from the University of Liverpool and Konsta Teppo from the University of Turku in Finland.20 The authors highlight that when ischaemic stroke rates were higher in women compared with men one to two decades ago, and women were undertreated with OACs, the use of the CHA2DS2-VASc score made sense, performing better than a non-sex CHA2DS2-VASc (i.e. CHA2DS2-VA). In more contemporary years, when the sex difference in AF-related stroke risk is less evident, the use of CHA2DS2-VA may offer some degree of simplicity in initial decision-making for stroke prevention. However, rather than undue focus of risk stratification schemes for identifying the somewhat artificial high-, moderate-, or low-risk subgroups, we should promote the initial identification of ‘low-risk’ patients, given the limitations of all clinical risk scores. After all, patients do not fall into three ‘static’ stroke risk categories, especially since risk is dynamic in nature and many stroke risk factors (e.g. blood pressure) represent a continuum of risk. Given the limitations of clinical risk scores in predicting high-risk patients, more emphasis could perhaps be placed on initially identifying the low-risk patients, such that ‘the default is stroke prevention, unless they are low-risk’, with these ‘low-risk’ patients being those with a CHA2DS2-VA score of zero. Patients with high bleeding risk (HBR) undergoing percutaneous coronary intervention (PCI) are at increased risk of not only bleeding, but also ischaemic events.21,22 In a Clinical Research article entitled ‘Long-term outcomes of high bleeding risk patients undergoing percutaneous coronary intervention: a Korean nationwide registry’, Jeehoon Kang from the Seoul National University College of Medicine in the Republic of Korea, and colleagues aimed to determine the long-term relative risk of ischaemic and bleeding events in HBR patients.23 This study was a nationwide cohort study, based on the Korean National Health Insurance Review and Assessment Service database. Patients diagnosed with stable angina or acute coronary syndrome and those who underwent PCI in Korea between 2009 and 2018 were included in the analysis. According to the Academic Research Consortium HBR criteria, the total population was divided into HBR and non-HBR groups. The co-primary outcomes were major bleeding events and ischaemic (composite of cardiac death, myocardial infarction, and ischaemic stroke) events. Among a total of more than 325 000 patients who underwent PCI, 20% had HBR. During the follow-up period, HBR patients had a higher risk for major bleeding events (23.9% vs. 8.9%, P < .001) and ischaemic events (33.8% vs. 14.4%, P < .001). The HBR group also exhibited a greater risk of all-cause mortality (HR 3.73, P < .001). The authors conclude that among patients undergoing PCI, those with HBR are at increased long-term risk for both bleeding and ischaemic events, with a greater risk of mortality compared with non-HBR patients. This manuscript is accompanied by an Editorial by Marco Valgimigli and Antonio Landi from the Cardiocentro Ticino Institute, Ente Ospedaliero Cantonale (EOC) in Switzerland.24 The authors conclude that this study adds to the overarching body of literature emphasizing the long-term importance of bleeding risk assessment in patients undergoing PCI. Bleeding first rather than ischaemic risk assessment emerges as the new paradigm for maximizing the net benefit of antithrombotic treatments in HBR patients. The cardiological community used to value the ischaemic risk at the expense of the bleeding risk. Yet, the study by Kang et al. reinforces once more the concept that a Copernican revolution should occur and that the ischaemic risk evolves around the bleeding risk and not vice versa. In a Clinical Research article entitled ‘Atherosclerosis quantification and cardiovascular risk: the ISCHEMIA trial’, Nick Nurmohamed from Amsterdam UMC in the Netherlands, and colleagues sought to determine the prognostic value of coronary computed tomography angiography (CCTA)-derived atherosclerotic plaque analysis in ISCHEMIA.25 Atherosclerosis imaging quantitative computed tomography (AI-QCT) was performed on all available baseline CCTAs to quantify plaque volume, composition, and distribution. Multivariable Cox regression was used to examine the association between baseline risk factors (age, sex, smoking, diabetes, hypertension, ejection fraction, prior coronary disease, estimated glomerular filtration rate, and statin use), number of diseased vessels, atherosclerotic plaque characteristics determined by AI-QCT, and a composite primary outcome of cardiovascular death or MI over a median follow-up of 3.3 years. The predictive value of plaque quantification over risk factors was compared in an area under the curve (AUC) analysis. Analysable CCTA data were available from 3711 participants (79% with multivessel CAD). Amongst the AI-QCT variables, total plaque volume was most strongly associated with the primary outcome (adjusted HR 1.56; P = .001). The addition of AI-QCT plaque quantification and characterization to baseline risk factors improved the model’s predictive value for the primary outcome at 6 months (AUC 0.688 vs. 0.637; P = .006), at 2 years (AUC 0.660 vs. 0.617; P = .003), and at 4 years of follow-up (AUC 0.654 vs. 0.608; P = .002) (Figure 2). The findings were similar for the other reported outcomes. Study design and main outcomes of the current study. AI-QCT, atherosclerosis imaging quantitative computed tomography; AUC, area under the curve; CAD, coronary artery disease; CCTA, coronary computed tomography angiography; CV, cardiovascular; FU, follow-up; MI, myocardial infarction; NRI, net reclassification improvement.25 The authors conclude that in the ISCHEMIA trial, total plaque volume is associated with cardiovascular death or MI. In this highly diseased, high-risk population, enhanced assessment of the atherosclerotic burden using AI-QCT-derived measures of plaque volume and composition modestly improve event prediction. The contribution is accompanied by an Editorial by Noel Bairey Merz from the Cedars-Sinai Medical Center in Los Angeles, CA (USA).26 Bairey Merz notes that the ISCHEMIA trial’s Guidelines-directed medical treatment (GDMT) adherence protocol worked well and could be replicated in systems. What would these protocols cost? On average, investments in secondary prevention interventions can yield a return of $10 for every $1 invested. Utilization of AI might reduce the costs. As we look to the future of targeted secondary prevention of cardiovascular disease related to the development of deep learning image analysis platforms and novel therapeutics, let’s not forget to invest in what we already know and ensure we deploy GDMT and adherence enhancers first. Type 1 long QT syndrome (LQT1) is caused by pathogenic variants in the KCNQ1-encoded Kv7.1 potassium channels, which pathologically prolong ventricular action potential duration (APD). In a Translational Research article entitled ‘KCNQ1 suppression-replacement gene therapy in transgenic rabbits with type 1 long QT syndrome’, Sahej Bains from the Mayo Clinic in Rochester, MN (USA), and colleagues rescued the pathologic phenotype in transgenic LQT1 rabbits using a novel KCNQ1 suppression-replacement (SupRep) gene therapy.27KCNQ1-SupRep gene therapy was developed by combining into a single construct a KCNQ1 shRNA (suppression) and an shRNA-immune KCNQ1 cDNA (replacement), packaged into adeno-associated virus serotype 9, and delivered in vivo via an intra-aortic root injection. To ascertain the efficacy of SupRep, 12-lead electrocardiograms were assessed in adult LQT1 and wild-type (WT) rabbits and patch-clamp experiments were performed on isolated ventricular cardiomyocytes. KCNQ1-SupRep treatment of LQT1 rabbits resulted in significant shortening of the pathologically prolonged QT index (QTi) towards WT levels. Ventricular cardiomyocytes isolated from treated LQT1 rabbits demonstrated pronounced shortening of APD compared with LQT1 controls, leading to levels like WT. Under β-adrenergic stimulation with isoproterenol, SupRep-treated rabbits demonstrated a WT-like physiological QTi and APD90 behaviour. The authors conclude that this study provides the first animal model, proof-of-concept gene therapy for correction of LQT1. In LQT1 rabbits, treatment with KCNQ1-SupRep gene therapy normalizes the clinical QTi and cellular APD90 to near WT levels both at baseline and after isoproterenol. If similar QT/APD correction can be achieved with intravenous administration of KCNQ1-SupRep gene therapy in LQT1 rabbits, these encouraging data should compel continued development of this gene therapy for patients with LQT1. The editors hope that this issue of the European Heart Journal will be of interest to its readers. Dr. Crea reports speaker fees from Abbott, Amgen, Astra Zeneca, BMS, Chiesi, Daiichi Sankyo, Menarini outside the submitted work. With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article.

Giulio Conte, Jędrzej Kosiuk, Ștefan Bogdan, Paweł Balsam · 7 authors

Interventional cardiac electrophysiology (EP) includes conventional and complex catheter ablations of cardiac arrhythmias and management of cardiac implantable electronic devices. The Accreditation Committee of the European Heart Rhythm Association (EHRA) has previously provided cardiologists interested in becoming clinical electrophysiologists with specific curricula, defining requirements both for training centres and trainees.1 Indeed, the presence of a structured EP training programme is of utmost importance in order to ensure high-quality training and comply with the requirements. Nevertheless, so far, very little information is available on EP training status across European Society of Cardiology (ESC) member countries.2,3 Therefore, the purpose of this survey was to obtain detailed information on educational EP training in ESC member countries and to assess the need of certification after completing the EP training. The present survey was conducted by the EHRA Young EP Committee from November 2017 to May 2018. Thirty-seven EHRA Young EP National Ambassadors were contacted to complete the survey. They were contacted by e-mail and/or phone and asked to answer a questionnaire containing information on the status of EP training in their specific country. The following parameters were queried: age at the beginning of medical studies, duration of medical studies, age at the beginning of cardiology training, duration of internal medicine training (if any), duration of cardiology training, features of training (duration/type/level/location), research activities performed during training, proportion of subjects performing a training abroad, need for EP and/or cardiac pacing (CP) certification after completing the training, mean number of centres per country accredited for EP/CP training, institution responsible of the certification (EHRA/National Societies/others). A total of 31 EHRA Young EP National Ambassadors completed the survey (84% response rate). Of the respondents, seven were female (23%). They represented the following ESC member countries: Algeria, Austria, Belarus, Belgium, Bosnia and Herzegovina, Bulgaria, Croatia, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Israel, Italy, Latvia, Lebanon, Lithuania, Malta, Norway, Poland, Portugal, Republic of Ireland, Romania, Serbia, Slovenia, Spain, Sweden, Switzerland, and United Kingdom. The information provided was based on the National Ambassador’s personal experience or on the mean value of data provided by additional young electrophysiologists who recently completed their training in the country or abroad. Descriptive statistics were analysed using SPSS V.24.0 (SPSS Chicago, IL, USA). Specific features of Cardiology and EP training are listed in Table 1. Mean age at the time of the beginning of medical studies was 19 years, ranging from 17 to 21 years. Mean duration of medical studies was 6 years, typical for ESC member countries. Internal medicine training was required in 27 countries (87%), with a mean duration of 2.5 years (range 6 months to 6 years). The mean age at the end of the cardiology training was 31.6 years, ranging from 27 to 40 years. The mean duration of EP training was 2.5 ± 1.1 years. Structured EP and CP training programmes were offered only in half of countries (49%). The mean number of centres accredited for EP/CP training per country was 10 ± 31 (range 0–149) (Figure 1). A formal EP/CP subspecialization was required in nine countries (29%) and had a mean duration of 2 years. Research activities were requested in about half (48%) of the countries as part of the training. Finally, there was a considerable variability regarding trainees attending an EP training abroad: 55% of the EHRA Young EP Ambassadors declared a rate of less than 20, and 42% of them reported a rate of greater than 50%. Cardiology and EP training features CP, cardiac pacing; EP, electrophysiology. Cardiology and EP training features CP, cardiac pacing; EP, electrophysiology. Number of EP training accredited centres per country. Reported data refer to the number of centres per 10 000 000 inhabitants in each country. Blue colour refers to centres accredited by their national society; red colour refers to EHRA Recognized Training Centres. *Centres with unavailable information. Six ESC member countries (Bulgaria, Estonia, France, Israel, Portugal, Serbia) (19%) require trainees to obtain certification by the respective National Society after their EP/CP training. None of the National Ambassadors reported obligation for the EHRA certification. Nevertheless, most of the EP trainees (72%) voluntarily take the certification exam after finishing their training. The responsible institution covering the costs of the certification was EHRA in 15 countries (68%) and the respective national society in seven countries (32%). This report highlights several features of the status of EP training in the ESC member countries: (i) a relatively high age of trainees initiating an EP training, (ii) high heterogeneity in the type and duration of training offered by each country, (iii) lack of centres offering a structured EP training programme in many countries, and (iv) request of EP/CP certification after completing training only in a minority of centres. All these aspects are of particular relevance when considering the development of structured EP training programmes and the subsequent individual EP career building. In this survey, the mean age of a cardiologist starting an educational EP training programme was 32 years; therefore, the age cut-off for definition of a young electrophysiologist should be defined accordingly. EHRA can play an active and important role in ensuring the achievement of a proper and homogenous EP training level across all ESC countries. Indeed, recently, EHRA supported good educational practices provided by centres by offering training fellowships programmes in EHRA Recognised Training Centres (ERTC). EHRA strives to maintain the highest standards in education and career development. So far, a list of 21 ERTCs using advanced and uniform teaching techniques has been provided. Moreover, EHRA EP training fellowships and proctor programmes have played a crucial role especially in countries with EP under development with a limited access to structured EP training programmes. In addition, EHRA Young EP Committee and the National Ambassadors can have an important role by highlighting potential training obstacles and issues experienced by trainees in each ESC member country, as they are the most involved stake holders in this training process. Finally, obtaining an EHRA certification after completing the training is demanded being a proof of achievement of practical experience and knowledge in cardiac devices and cardiac electrophysiology, and could guarantee high-level competence, knowledge, and skills of the trainees, supporting improved quality arrhythmia healthcare throughout the European countries. Nevertheless, further efforts are needed to continuously improve and develop activities related to EP training and networking within the EHRA Young EP community that will likely contribute to the improvement of the quality of EP training and early career building of young electrophysiologists. Considerable heterogeneity is present across ESC member countries with respect to access and specific characteristics of EP training. EP/CP certification after completing EP training is requested only in a small proportion of countries. However, most of the trainees voluntarily take the certification exam by EHRA or their national societies. Nevertheless, further efforts to harmonize EP training, and certification requirements across ESC member countries are warranted to improve and homogenize EP quality of care. Conflict of interest: none declared.

Ashish Singal, Sheiphali A. Gandhi, Marc Pritzker, Thenappan Thenappan

The human body has two circulation systems: the systemic circulation and the pulmonary circulation. An elevation of blood pressure in either system is referred to as hypertension. PH is elevated blood pressure in the arteries of the lungs. Normal mean PA pressure is about 14 mm Hg at rest. If this pressure is greater than 25 mm Hg at rest, it is classified as PH. According to the World Health Organization, PH is classified in five groups (I–V), with each group characterized by its etiology and pathogenesis. It is important to accurately diagnose the type of PH for treatment planning and disease management. A right heart catheterization (RHC) procedure remains the gold standard that can definitively diagnose PH. Numerous other techniques are being developed that, in conjunction with RHC, can aid in diagnoses of type, severity, cause, treatment options, and functional classification of PH [1].In this study, we developed time-domain digital signal processing methodologies for assessing PA pressure waveforms. We hypothesize that a correlation between PA waveform parameters will allow determination of whether a patient suffers from PH, and potentially the type of PH. This information could prove to be an essential aid for physicians in treatment and management of patients suffering from PH.Minnesota PH repository (measure) is a prospective registry that collects information on all PH patients followed by the PH clinic at the University of Minnesota. All patients gave informed consent before enrolling in this registry. From the measure registry, we identified 66 patients with PH (mean PA pressure ≥25 mm Hg at rest).Patients underwent RHC using a fluid-filled Swan–Ganz catheter at the time of diagnosis of PH. PA tracings from the procedure were digitally acquired at a sampling rate of 240 Hz. Custom matlab programs/routines were developed to postprocess the data and analyze the PA tracings for PH and wave reflections.For every patient, typically ten individual waveforms segments were extracted from the PA waveform tracings (for 66 subjects a total of 842 individual waveforms). These individual waveforms were time sequenced from the initiation of PA pressure systolic upstroke and averaged to create an average waveform (Fig. 1). For every individual waveform and the time averaged waveform, 15 waveform parameters were calculated, which are: (1) pulmonary artery pulse pressure (mm Hg); (2) systolic pulmonary artery pressure (mm Hg); (3) diastolic pulmonary artery pressure (mm Hg); (4) mean pulmonary artery pressure (MPAP, mm Hg); (5) pulmonary artery fractional pulse pressure; (6) augmentation pressure (AP, mm Hg); (7) augmentation index (AI); (8) systolic time (TS, s); (9) diastolic time (TD, s); (10) total time (TT, s); (11) inflection time (TI, s); (12) systolic area under curve (AUCS, mm Hg s); (13) diastolic area under curve (AUCD, mm Hg s); (14) total area under curve (AUCT, mm Hg s); and (15) diastolic decay (mm Hg/s).The characteristics of wave reflections (timing, amplitude, and index) were quantified by performing pressure waveform analysis in time domain as described previously [2]. The human pulmonary pressure waveform may encounter a characteristic impedance change as it flows into the pulmonary vasculature, which manifests itself as wave reflections in the PA waveform. In normal subjects, little wave reflections are expected, however, with underlying pathology (e.g., pulmonary thromboembolism, reduced PA compliance, lung disease, and heart disease), the wave reflections can be significant. The temporal location where the wave reflection occurs is referred to as the inflection point (Fig. 2). The relative change in pressure amplitude above the inflection point is an estimate of the magnitude of the reflected pressure wave and defined as the AP. Measurement of these wave reflections in temporal and spatial domain may allow diagnoses of PH that can further aid in risk stratification and therapy planning.The first derivative of the PA pressure tracing (dP/dt) was calculated for every individual waveform and the time averaged waveform (Fig. 3). If the inflection point occurred before the peak pulse pressure (i.e., in the systolic phase), then the first local-minima or a zero-crossing of dP/dt was defined as the inflection point. If the inflection point occurred after the peak pulse pressure (i.e., in the diastolic phase), then the second local-minima or zero-crossing was defined as the inflection point. Note that one of the local-minima or zero-crossing would signify the peak pulse pressure and another one would signify the dicrotic notch.The correlation between AP, AI, and inflection time is shown in Figs. 4 and 5. AI was defined as the ratio of AP to the pulse pressure, and it could have either a positive or negative value based on the location of the inflection point relative to the peak pulse pressure. In normal subjects, since there are minimal to no wave reflections, both the AP and AI are expected to have a negative value as compared to subjects who have severe form of PH. In PH subjects, wave reflections occurring in the systolic phase make both the AP and AI positive. This correlation is illustrated in Fig. 4. Similarly, inflection times (duration to inflection point) are smaller in PH patients as illustrated in Fig. 5. These markers could be used as a screening tool to stratify patients who require further evaluation.We have developed an automated way of differentiating patients with different types of PH based on time-domain analysis of PA waveform and wave reflections. As a proof of concept, in this study, we identified a subset of patients suffering from PH to understand how PA waveform and wave reflections changes in various states of PH. The fact that we observed correlation between various pulse parameters must be viewed as one of the strengths of this study. These results coupled with further refinement of detection algorithms would allow us to make this process specific, sensitive, and automated.These findings are consistent with results from other studies suggesting that changes in pulmonary tree elasticity and pulse pressure are primarily due to an increase in MPAP in patients with PH. Wave reflections occurring in the systolic phase of the PA pressure tracing are considered abnormal and can be identified using the techniques developed in this investigation. A decrease in pulmonary elasticity or an obstructive pulmonary disease would exhibit greater wave reflections resulting in higher APs, higher AIs, and decreased inflection times as compared to normal subjects.These findings may provide novel insights into the etiology and pathophysiology of PH, which may allow further improvements in risk stratification of patients with PH and development of diagnostic tools for better delivery of care. Knowledge gained from these diagnostic tools may be used as aids in diagnoses, for treatment planning, medication optimization, and disease management. It is clear that a thorough understanding of PH will be important to the future of this evolving era of diagnostic tools.

Fred H.M. Wittkampf

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.3–5 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 Cartomerge® 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 electrode–tissue 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 Cartomerge®. 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.

NAHUM A. FREEDBERG

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 “burning” often serves as “proof” of the arrhythmia mechanism (Learning by Burning). In a series of papers by Callans et al.2–4 published in this Journal, the term “learning while burning” 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 “common,”“typical,”“slow-fast” 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., “slow” and “fast” pathways). In “slow-fast” 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 “fast pathway region” 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.24–26 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 “VA conduction should be expected during the junctional ectopy that accompanies slow pathway ablation, even when there is poor VA conduction during baseline ventricular pacing,” 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 “de novo” 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 AVNRT—in 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.