Blockchain Papers

Froylan Cortés-Santacruz, Luis Antonio Carrillo-Martínez, Luciano García‐Bañuelos, Jesús Anselmo Fortoul-Diaz

Although distributed ledger technologies (DLTs) have transformed financial sectors, their manufacturing applications lack systematic maturity assessment frameworks. Previous reviews identified DLT benefits but show critical gaps, including a lack of quantitative maturity metrics, insufficient categorization of use cases, and limited platform-specific comparative analysis. This systematic literature review addresses these gaps through three key contributions: (i) a novel Distributed Ledger Technology Maturity Level (DLTML) framework, (ii) a four-category manufacturing taxonomy, and (iii) platform-specific implementation analysis. Analyzing 60 primary studies (2018–2025) using Kitchenham’s guidelines, Wohlin’s snowballing, and Treiblmaier’s assessment framework, we answer the following: (i) What are the categories of use of DLT in manufacturing? (ii) What features of DLT are key enablers and what specific challenges have been addressed in current manufacturing solutions? (iii) What is the level of technological maturity of DLT applications in manufacturing according to the existing literature? The category Process Execution Tracking dominates (80 % of the studies), followed by Provenance (65 %), Ownership Management (30 %) and Payment Management (25 %). Smart contracts are the main enablers (81. 67 %), followed by decentralization (48.33 %). Governance mechanisms remain unaddressed, and interoperability progress is limited. Hyperledger Fabric leads privacy-sensitive scenarios (55 %), while Ethereum dominates transparency-focused applications (38 %). DLTML assessment shows that 61.66 % achieve intermediate maturity (DLTML-3), 20 % achieve high-fidelity prototypes (DLTML-4), but none achieves verified operational deployment (DLTML-5). This study provides evidence-based guidance for researchers and decision makers pursuing the adoption of DLT in manufacturing.

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 on arrhythmias contains a Special Article contribution entitled ‘1970–2020: 50 years of research on the long QT syndrome—from almost zero knowledge to precision medicine’, authored by Peter Schwartz from the IRCCS in Milan, Italy.1 A lot has been written about the long QT syndrome (LQTS) and there is a wealth of traditional reviews summarizing the existing knowledge on epidemiology, pathogenesis, clinical presentation, and the state of genetic testing.2,3 However, this Special Article is very special indeed. Professor Schwartz notes that those involved in clinical research rarely begin working on a rather obscure disease, still largely unexplored, following its ripening into a medical entity of great interest to clinicians and basic scientists alike, and to do so for exactly 50 years. This is what has been Professor Schwartz’s privilege in the relentless pursuit of the intriguing disease known as LQTS. This essay begins with the encounter with his first patient affected by LQTS when just a handful of cardiologists had seen similar cases, and continues with the series of efforts which eventually led—together with many brilliant partners and associates—to the description and understanding of the natural history of the disease and the most effective therapies. It then touches on how the International Registry for LQTS, with its well-documented family trees, constituted the necessary springboard for the major genetic discoveries of the 1990s. From the explosion of genetic data, his own interest focused first on the intriguing genotype–phenotype correlation and then on ‘modifier genes’, in an attempt to understand why family members with the same disease-causing mutation may have an opposite clinical history; and from there on to induced pluripotent stem cell (iPS)-derived cardiomyocytes, used for unravelling the specific mechanisms of action of modifier genes and for exploring novel therapeutic strategies. This long, and highly rewarding, journey continues because the fascination with and the attraction of the unknown is irresistible. Brugada syndrome (BrS) was first described as a primary electrical disorder predisposing to sudden cardiac death (SCD) by the Brugada brothers, although its eponymous title was only bestowed 4 years later. Eight patients had demonstrated an electrocardiogram (ECG) pattern of ‘right bundle branch block, normal QT interval and persistent ST-segment elevation in precordial leads V1 to V2–V3 not explainable by electrolyte disturbances, ischaemia or structural heart disease’.4 In a State of the Art Review article entitled ‘Brugada syndrome and reduced right ventricular outflow tract conduction reserve: a final common pathway?’, Elijah Behr from St George’s University of London in the UK, and colleagues5 note that BrS was first described as a primary electrical disorder predisposing to the risk of SCD and characterized by right precordial lead ST elevation. Then, early descriptions of right ventricular structural abnormalities and of right ventricular outflow tract (RVOT) conduction delay in BrS patients set the stage for the current controversy over the pathophysiology underlying the syndrome: channelopathy or cardiomyopathy; repolarization or depolarization. This review examines the current understanding of the BrS substrate, its genetic and non-genetic basis, theories of pathophysiology, and the clinical implications thereof. The authors propose that the final common pathway for BrS could be viewed as a disease of ‘reduced RVOT conduction reserve’ (Figure 1). Brugada syndrome (BrS) as a disease of impaired right ventricular outflow tract (RVOT) conduction reserve. Normally, intrinsic RVOT conduction reserve may be affected by a patient’s age and gender. In BrS, cellular and tissue abnormalities cause a reduction in RVOT conduction reserve: genetic abnormalities, whether mediated by a pathogenic SCN5A variant, an increased BrS-PRS, and/or additional genetic insults, may have direct effects on Nav1.5, as well as tissue effects causing RVOT inflammation, fibrosis, and gap junction abnormalities. Decreased Nav1.5 current, together with electrical discontinuity caused by RVOT structural changes, converges to disrupt normal depolarization, with or without secondary repolarization effects, leading to impairment of the conduction reserve of the RVOT. In this framework, the marginal conduction reserve can be exposed by acute modulators such as fever, drugs, and altered vagal tone which further impair conduction and expose the Brugada phenotype (from Behr ER, Ben-Haim Y, Ackerman MJ, Krahn AD, Wilde AAM. Brugada syndrome and reduced right ventricular outflow tract conduction reserve: a final common pathway? See pages 1073–1081). Brugada syndrome (BrS) as a disease of impaired right ventricular outflow tract (RVOT) conduction reserve. Normally, intrinsic RVOT conduction reserve may be affected by a patient’s age and gender. In BrS, cellular and tissue abnormalities cause a reduction in RVOT conduction reserve: genetic abnormalities, whether mediated by a pathogenic SCN5A variant, an increased BrS-PRS, and/or additional genetic insults, may have direct effects on Nav1.5, as well as tissue effects causing RVOT inflammation, fibrosis, and gap junction abnormalities. Decreased Nav1.5 current, together with electrical discontinuity caused by RVOT structural changes, converges to disrupt normal depolarization, with or without secondary repolarization effects, leading to impairment of the conduction reserve of the RVOT. In this framework, the marginal conduction reserve can be exposed by acute modulators such as fever, drugs, and altered vagal tone which further impair conduction and expose the Brugada phenotype (from Behr ER, Ben-Haim Y, Ackerman MJ, Krahn AD, Wilde AAM. Brugada syndrome and reduced right ventricular outflow tract conduction reserve: a final common pathway? See pages 1073–1081). Since its description, BrS has been the subject of increased scientific interest as a cause of SCD due to ventricular tachycardia/fibrillation in young and otherwise healthy individuals. BrS is believed to be a genetic disease, although the majority of clinically confirmed cases lack molecular validation, due to our current shortfall of understanding of the genetics of this syndrome.6,7 Despite SCN5A being the most commonly known mutated gene to date, the genotype–phenotype relationship is poorly understood and remains uncertain. In a clinical research article entitled ‘Brugada syndrome genetics is associated with phenotype severity’, Giuseppe Ciconte from the IRCCS Policlinico San Donato in Italy, and colleagues aimed to elucidate the genotype–phenotype correlation in BrS.8 BrS probands deemed at high risk of future arrhythmic events underwent genetic testing and phenotype characterization by means of epicardial arrhythmogenic substrate mapping and were allocated to two groups according to the presence or absence of the SCN5A mutation. Two hundred probands (mean age 43 years) were included in this study. SCN5A-positive patients exhibited a larger epicardial arrhythmogenic substrate area, more prolonged ECGs, and more frequently late potentials at non-invasive testing (Figure 2). The presence of an SCN5A mutation explained >26% of the variation in the epicardial arrhythmogenic substrate area and was the strongest predictor of a larger epicardial arrhythmogenic area. Brugada syndrome phenotypic expression predictors. (A) Large Brugada syndrome epicardial substrate in a male patient with spontaneous type 1 electrocardiogram pattern experiencing appropriate implantable cardioverter-defibrillator therapy. (B) Specific contribution of each variable (SCN5A mutations, spontaneous type 1 electrocardiogram pattern, and gender), in explaining the variance of the arrhythmogenic substrate. (C) Receiver-operating characteristic curve analysis demonstrating the accuracy of the model for the prediction of a large arrhythmogenic substrate (≥6.3 cm2) (from Ciconte G, Monasky MM, Santinelli V, Micaglio E, Vicedomini G, Anastasia L, Negro G, Borrelli V, Giannelli L, Santini F, de Innocentiis C, Rondine R, Locati ET, Bernardini A, Mazza BC, Mecarocci V, Calović Ž, Ghiroldi A, D’Imperio S, Benedetti S, Di Resta C, Rivolta I, Casari G, Petretto E, Pappone C. Brugada syndrome genetics is associated with phenotype severity. See pages 1082–1090). Brugada syndrome phenotypic expression predictors. (A) Large Brugada syndrome epicardial substrate in a male patient with spontaneous type 1 electrocardiogram pattern experiencing appropriate implantable cardioverter-defibrillator therapy. (B) Specific contribution of each variable (SCN5A mutations, spontaneous type 1 electrocardiogram pattern, and gender), in explaining the variance of the arrhythmogenic substrate. (C) Receiver-operating characteristic curve analysis demonstrating the accuracy of the model for the prediction of a large arrhythmogenic substrate (≥6.3 cm2) (from Ciconte G, Monasky MM, Santinelli V, Micaglio E, Vicedomini G, Anastasia L, Negro G, Borrelli V, Giannelli L, Santini F, de Innocentiis C, Rondine R, Locati ET, Bernardini A, Mazza BC, Mecarocci V, Calović Ž, Ghiroldi A, D’Imperio S, Benedetti S, Di Resta C, Rivolta I, Casari G, Petretto E, Pappone C. Brugada syndrome genetics is associated with phenotype severity. See pages 1082–1090). The authors conclude that in BrS, the genetic background is the main determinant for the extent of the electrophysiological abnormalities. SCN5A mutation carriers exhibit more pronounced epicardial electrical abnormalities and a more aggressive clinical presentation. These results contribute to the understanding of the genetic determinants of the phenotypic expression of BrS and provide possible explanations for the varying degrees of disease expression. The manuscript is accompanied by an Editorial by Connie R. Bezzina from the AMC Heart Center in Amsterdam, the Netherlands, and colleagues.9 The authors note that while we are still at the early stages of being able to offer individualized prognosis for BrS patients, studies like that of Ciconte and colleagues are beginning to illuminate the path between genetic risk factors and clinical outcomes. Although COVID-19 manifests primarily as a severe respiratory infection, numerous studies demonstrate that cardiovascular complications are common, and pre-existing cardiovascular conditions are predictors of survival in COVID-19.10–12 The first cases of COVID-19 in Sweden were reported in early February 2020. The Swedish Public Health Authority declared community spread in Sweden on 16 March. As a consequence, updated guidelines from the European Resuscitation Council (ERC) and the Swedish Resuscitation Council recommended that bystanders should avoid ventilation and focus their resuscitation attempts on chest compressions only in the case of suspected COVID-19.13 In a clinical research article entitled ‘Cardiac arrest in COVID-19: characteristics and outcomes of in- and out-of-hospital cardiac arrest. A report from the Swedish Registry for Cardiopulmonary Resuscitation’, Pedram Sultanian from the University of Gothenburg in Sweden, and colleagues investigated characteristics and outcomes among cardiac arrest cases with COVID-19 and differences between the pre-pandemic and the pandemic period in out-of-hospital cardiac arrest (OHCA) and in-hospital cardiac arrest (IHCA).14 The authors included all patients reported to the Swedish Registry for Cardiopulmonary Resuscitation from anuary to July 2020. Sultanian et al. enrolled ∼2000 cases of OHCA and 1000 cases of IHCA. During the pandemic, 10.0% of OHCAs and 16.1% of IHCAs had ongoing COVID-19 with regards to OHCA. Adjusted 30-day survival was 4.7% for patients with COVID-19, 9.8% for patients without COVID-19, and 7.6% in the pre-pandemic period (P = 0.03) with regards to IHCA. Adjusted 30-day survival was 23.1% in COVID-19-positive cases, 39.5% in patients without COVID-19, and 36.4% in the pre-pandemic period (P = 0.04). The authors conclude that this is, to the best of their knowledge, the most detailed report on characteristics and outcome in COVID-19 patients suffering cardiac arrest within and beyond the hospital perimeter, and that they report a number of unexpected findings, many of which highlight the severity of COVID-19 and the potential shift in the epidemiology of cardiac arrest brought about by this pandemic. The manuscript is accompanied by an Editorial by Xavier Jouven from the Université de Paris in France, and colleagues.15 The authors note that these findings highlight the importance of anticipation and planning in the management of healthcare crises. The observations with respect to the COVID-19 pandemic and cardiac arrest should serve as an important wake-up call for healthcare systems worldwide to develop blueprints and contingency plans for preparedness in the case of such eventualities. With improvements in pharmacological and device therapy, earlier and more aggressive cardiovascular prevention, and prompt coronary intervention, there has been a gradual and substantial reduction in SCD risk over the last two decades in patients with heart failure. Thus, one may even reasonably speculate whether the results of randomized trials on implantable cardioverter-defibrillators (ICDs) would be the same if conducted in the current era of heart failure management,16,17 as the evidence supporting guideline recommendations for ICDs dates from the late 1990s and early 2000s.18 There is a particular need to revisit the current status of routine primary prevention ICD implantation in women. This issue contains a Viewpoint article entitled ‘Time to revisit implantable cardioverter-defibrillator implantation criteria in women’ by Sérgio Barra from the Hospital da Luz Arrábida in Portugal, and colleagues.19 The authors note that the low level of participation of female patients in ICD trials is a long-standing problem, but physicians and guidelines continue to extrapolate from results derived mainly from men to recommend routine ICD implantation in women despite lack of clear proof of a reduction in mortality. Conversely, the benefit of an ICD in men may have been relatively underestimated when looking at the data in total. It is evident that the data being used for decision-making are both outdated and also weak with respect to potential benefit in women. Hence it can be strongly argued that true equipoise exists for new, well-designed randomized trials assessing the efficacy of primary prevention ICDs, particularly in female patients, in conjunction with current heart failure therapies. The issue is also complemented by two Discussion Forum contributions. In an article entitled ‘Prognostication after out-of-hospital cardiac arrest: biases and caveats’, Andrew Williams from the King’s College Hospital in London, UK and colleagues comment on the recent publication entitled ‘A practical risk score for early prediction of neurological outcome after out-of-hospital cardiac arrest: MIRACLE2’ by Nilesh Pareek from the King’s College Hospital NHS Foundation Trust in the UK, and colleagues.20,21 Pareek and colleagues respond in a separate contribution.22 The editors hope that readers of this issue of the European Heart Journal will find it of interest. With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article.

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.