High Body Mass Index and Response to Anti-Tumor Necrosis Factor Therapy in Pediatric Crohn's Disease.

INTRODUCTION: Obesity is common among patients with pediatric Crohn's disease (PCD). Some adult studies suggest obese patients respond less well to anti-tumor necrosis factor (TNF) treatment. This study sought compares anti-TNF response and anti-TNF levels between pediatric patients with normal and high body mass index (BMI). METHODS: The COMBINE trial compared anti-TNF monotherapy with combination therapy with methotrexate in patients with PCD. In this secondary analysis, a comparison of time-to-treatment failure among patients with normal BMI vs BMI Z -score >1, adjusting for prescribed anti-TNF (infliximab [IFX] or adalimumab [ADA]), trial treatment assignment (combination vs monotherapy), and relevant covariates. Median anti-TNF levels across BMI category was also examined. RESULTS: Of 224 participants (162 IFX initiators and 62 ADA initiators), 111 (81%) had a normal BMI and 43 (19%) had a high BMI. High BMI was associated with treatment failure among ADA initiators (7/10 [70%] vs 12/52 [23%], hazard ratio 0.29, P = 0.007) but not IFX initiators. In addition, ADA-treated patients with a high BMI had lower ADA levels compared with those with normal BMI (median 5.8 vs 12.8 µg/mL, P = 0.02). IFX trough levels did not differ between BMI groups. DISCUSSION: Overweight and obese patients with PCD are more likely to experience ADA treatment failure than those with normal BMI. Higher BMI was associated with lower drug trough levels. Standard ADA dosing may be insufficient for overweight children with PCD. Among IFX initiators, there was no observed difference in clinical outcomes or drug levels, perhaps due to weight-based dosing and/or greater use of proactive drug monitoring.

vaRHC: an R package for semi-automation of variant classification in hereditary cancer genes according to ACMG/AMP and gene-specific ClinGen guidelines.

MOTIVATION: Germline variant classification allows accurate genetic diagnosis and risk assessment. However, it is a tedious iterative process integrating information from several sources and types of evidence. It should follow gene-specific (if available) or general updated international guidelines. Thus, it is the main burden of the incorporation of next-generation sequencing into the clinical setting. RESULTS: We created the vaRiants in HC (vaRHC) R package to assist the process of variant classification in hereditary cancer by: (i) collecting information from diverse databases; (ii) assigning or denying different types of evidence according to updated American College of Molecular Genetics and Genomics/Association of Molecular Pathologist gene-specific criteria for ATM, CDH1, CHEK2, MLH1, MSH2, MSH6, PMS2, PTEN, and TP53 and general criteria for other genes; (iii) providing an automated classification of variants using a Bayesian metastructure and considering CanVIG-UK recommendations; and (iv) optionally printing the output to an .xlsx file. A validation using 659 classified variants demonstrated the robustness of vaRHC, presenting a better criteria assignment than Cancer SIGVAR, an available similar tool. AVAILABILITY AND IMPLEMENTATION: The source code can be consulted in the GitHub repository (https://github.com/emunte/vaRHC) Additionally, it will be submitted to CRAN soon.

Predictive value of retinal atrophy for cognitive decline across disease duration in multiple sclerosis.

BACKGROUND: We investigated the association between changes in retinal thickness and cognition in people with MS (PwMS), exploring the predictive value of optical coherence tomography (OCT) markers of neuroaxonal damage for global cognitive decline at different periods of disease. METHOD: We quantified the peripapillary retinal nerve fibre (pRFNL) and ganglion cell-inner plexiform (GCIPL) layers thicknesses of 207 PwMS and performed neuropsychological evaluations. The cohort was divided based on disease duration (≤5 years or >5 years). We studied associations between changes in OCT and cognition over time, and assessed the risk of cognitive decline of a pRFNL≤88 µm or GCIPL≤77 µm and its predictive value. RESULTS: Changes in pRFNL and GCIPL thickness over 3.2 years were associated with evolution of cognitive scores, in the entire cohort and in patients with more than 5 years of disease (p<0.01). Changes in cognition were related to less use of disease-modifying drugs, but not OCT metrics in PwMS within 5 years of onset. A pRFNL≤88 µm was associated with earlier cognitive disability (3.7 vs 9.9 years) and higher risk of cognitive deterioration (HR=1.64, p=0.022). A GCIPL≤77 µm was not associated with a higher risk of cognitive decline, but a trend was observed at ≤91.5 µm in PwMS with longer disease (HR=1.81, p=0.061). CONCLUSIONS: The progressive retinal thinning is related to cognitive decline, indicating that cognitive dysfunction is a late manifestation of accumulated neuroaxonal damage. Quantifying the pRFNL aids in identifying individuals at risk of cognitive dysfunction.

Factors related to the development of high antibody titres against SARS-CoV-2 in convalescent plasma donors from the ConPlas-19 trial.

BACKGROUND AND OBJECTIVES: The efficacy of COVID-19 convalescent plasma (CP) associates with high titres of antibodies. ConPlas-19 clinical trial showed that CP reduces the risk of progression to severe COVID-19 at 28 days. Here, we aim to study ConPlas-19 donors and characteristics that associate with high anti-SARS-CoV-2 antibody levels. MATERIALS AND METHODS: Four-hundred donors were enrolled in ConPlas-19. The presence and titres of anti-SARS-CoV-2 antibodies were evaluated by EUROIMMUN anti-SARS-CoV-2 S1 IgG ELISA. RESULTS: A majority of 80.3% of ConPlas-19 donor candidates had positive EUROIMMUN test results (ratio ≥1.1), and of these, 51.4% had high antibody titres (ratio ≥3.5). Antibody levels decline over time, but nevertheless, out of 37 donors tested for an intended second CP donation, over 90% were still EUROIMMUN positive, and nearly 75% of those with high titres maintained high titres in the second sample. Donors with a greater probability of developing high titres of anti-SARS-CoV-2 antibodies include those older than 40 years of age (RR 2.06; 95% CI 1.24-3.42), with more than 7 days of COVID-19 symptoms (RR 1.89; 95% CI 1.05-3.43) and collected within 4 months from infection (RR 2.61; 95% CI 1.16-5.90). Male donors had a trend towards higher titres compared with women (RR 1.67; 95% CI 0.91-3.06). CONCLUSION: SARS-CoV-2 CP candidate donors' age, duration of COVID-19 symptoms and time from infection to donation associate with the collection of CP with high antibody levels. Beyond COVID-19, these data are relevant to inform decisions to optimize the CP donor selection process in potential future outbreaks.

The clinical anatomy of the atrioventricular conduction axis.

It is axiomatic that the chances of achieving accurate capture of the conduction axis and its fascicles will be optimized by equally accurate knowledge of the relationship of the components to the recognizable cardiac landmarks, and we find it surprising that acknowledged experts should continue to use drawings that fall short in terms of anatomical accuracy. The accuracy achieved by Sunao Tawara (1906) in showing the location of the atrioventricular conduction axis is little short of astounding. Our purpose in bringing this to current attention is to question the need of the experts to have produced such inaccurate representations, since the findings of Tawara have been extensively endorsed in very recent years. The recent studies do no more than point to the amazing accuracy of the initial account of Tawara. At the same time, we draw attention to the findings described in the middle of the 20th century by Ivan Mahaim (1947). These observations have tended to be ignored in recent accounts. They are, perhaps, of equal significance to those seeking specifically to pace the left fascicles of the branching atrioventricular bundle.

Cannon A wave validation as a diagnostic tool in paroxysmal supraventricular tachycardias.

OBJECTIVE: The presence of cannon A waves, the so called "frog sign", has traditionally been considered diagnostic of atrioventricular nodal re-entrant tachycardia (AVNRT). Nevertheless, it has never been systematically evaluated. The aim of this study is to assess the independent diagnostic utility of cannon A waves in the differential diagnosis of supraventricular tachycardias (SVTs). METHODS: We prospectively included 100 patients who underwent an electrophysiology (EP) study for SVT. The right jugular venous pulse was recorded during the study. In 61 patients, invasive central venous pressure (CVP) was registered as well. CVP increase is thought to be related with the timing between atria and ventricle depolarization; two groups were prespecified, the short VA interval tachycardias (including typical AVNRT and atrioventricular reciprocating tachycardia (AVRT) mediated by a septal accessory pathway) and the long VA interval tachycardias (including atypical AVNRT and AVRT mediated by a left free wall accessory pathway). RESULTS: The relationship between cannon A waves and AVNRT did not reach the statistical significance (OR: 3.01; p = .058); On the other hand, it was clearly associated with the final diagnosis of a short VA interval tachycardia (OR: 10.21; p < .001). CVP increase showed an inversely proportional relationship with the VA interval during tachycardia (b = -.020; p < .001). CVP increase was larger in cases of AVNRT (4.0 mmHg vs. 1.2 mmHg; p < .001) and short VA interval tachycardias (3.9 mmHg vs. 1.2 mmHg; p < .001). CONCLUSION: The presence of cannon A waves is associated with the final diagnosis of short VA interval tachycardias.

Evaluating the Accuracy of Self-Collected Swabs for the Diagnosis of Mpox.

We evaluated the accuracy of patient-collected skin lesions, oropharyngeal, and rectal swabs among 50 individuals enrolled in a study of mpox viral dynamics. We found that the performance of self-collected samples was similar to that of physician-collected samples, suggesting that self-sampling is a reliable strategy for diagnosing mpox.

Clinical presentation and virological assessment of confirmed human monkeypox virus cases in Spain: a prospective observational cohort study.

BACKGROUND: In May, 2022, several European countries reported autochthonous cases of monkeypox, which rapidly spread globally. Early reports suggest atypical presentations. We aimed to investigate clinical and virological characteristics of cases of human monkeypox in Spain. METHODS: This multicentre, prospective, observational cohort study was done in three sexual health clinics in Madrid and Barcelona, Spain. We enrolled all consecutive patients with laboratory-confirmed monkeypox from May 11 to June 29, 2022. Participants were offered lesion, anal, and oropharynx swabs for PCR testing. Participant data were collected by means of interviews conducted by dermatologists or specialists in sexually transmitted infections and were recorded using a standard case report form. Outcomes assessed in all participants with a confirmed diagnosis were demographics, smallpox vaccination, HIV status, exposure to someone with monkeypox, travel, mass gathering attendance, risk factors for sexually transmitted infections, sexual behaviour, signs and symptoms on first presentation, virological results at multiple body sites, co-infection with other sexually transmitted pathogens, and clinical outcomes 14 days after the initial presentation. Clinical outcomes were followed up until July 13, 2022. FINDINGS: 181 patients had a confirmed monkeypox diagnosis and were enrolled in the study. 166 (92%) identified as gay men, bisexual men, or other men who have sex with men (MSM) and 15 (8%) identified as heterosexual men or heterosexual women. Median age was 37·0 years (IQR 31·0-42·0). 32 (18%) patients reported previous smallpox vaccination, 72 (40%) were HIV-positive, eight (11%) had a CD4 cell count less than 500 cells per µL, and 31 (17%) were diagnosed with a concurrent sexually transmitted infection. Median incubation was 7·0 days (IQR 5·0-10·0). All participants presented with skin lesions; 141 (78%) participants had lesions in the anogenital region, and 78 (43%) in the oral and perioral region. 70 (39%) participants had complications requiring treatment: 45 (25%) had a proctitis, 19 (10%) had tonsillitis, 15 (8%) had penile oedema, six (3%) an abscess, and eight (4%) had an exanthem. Three (2%) patients required hospital admission. 178 (99%) of 180 swabs from skin lesions collected tested positive, as did 82 (70%) of 117 throat swabs. Viral load was higher in lesion swabs than in pharyngeal specimens (mean cycle threshold value 23 [SD 4] vs 32 [6], absolute difference 9 [95% CI 8-10]; p<0·0001). 108 (65%) of 166 MSM reported anal-receptive sex. MSM who engaged in anal-receptive sex presented with proctitis (41 [38%] of 108 vs four [7%] of 58, absolute difference 31% [95% CI 19-44]; p<0·0001) and systemic symptoms before the rash (67 [62%] vs 16 [28%], absolute difference 34% [28-62]; p<0·0001) more frequently than MSM who did not engage in anal-receptive sex. 18 (95%) of 19 participants with tonsillitis reported practising oral-receptive sex. The median time from onset of lesions to formation of a dry crust was 10 days (IQR 7-13). INTERPRETATION: In our cohort, monkeypox caused genital, perianal, and oral lesions and complications including proctitis and tonsillitis. Because of the variability of presentations, clinicians should have a low threshold for suspicion of monkeypox. Lesion swabs showed the highest viral loads, which, combined with the history of sexual exposure and the distribution of lesions, suggests close contact is probably the dominant transmission route in the current outbreak. FUNDING: None.

Neutrophil-to-lymphocyte ratio an inflammatory biomarker, and prognostic marker in heart failure, cardiovascular disease and chronic inflammatory diseases: New insights for a potential predictor of anti-cytokine therapy responsiveness.

In the 20th century, research focused on cholesterol and lipoproteins as the key mechanism in establishing atherosclerotic cardiovascular disease (ASCVD). Given that some studies demonstrated subclinical atherosclerosis in subjects without conventional cardiovascular risk factors, the elevated low-density lipoprotein (LDL) levels alone cannot account for the entire burden of atherosclerosis. Hence, large-scale clinical trials demonstrated the operation of immune and inflammatory pathways in ASCVD. In this regard, the evidence establishes that cells of the immune system, both the innate (neutrophils, macrophages) and adaptive (T cell and other lymphocytes) limbs, contribute to atherosclerosis and atherothrombosis. Besides, basic science studies have identified proatherogenic cytokines such as interleukin (IL)-1, IL-12, and IL-18. In this regard, some studies showed that antiinflammatory therapy targeting the immune system by modulating or blocking interleukins, also known as anti-cytokine therapy, can reduce the risk of major cardiovascular adverse events. The neutrophils play a key role in the innate immune system, representing the acute phase of an inflammatory response. In contrast, lymphocytes represent the adaptive immune system and promote the induction of autoimmune inflammation, especially in the chronic inflammatory response. Through the literature review, we will highlight the inflammatory pathway for the physiopathology of ASCVD, HF, and COVID-19. In this regard, the neutrophil-to-lymphocyte ratio (NLR) integrates the innate immune and adaptive immune systems, making the NLR a biomarker of inflammation. In addition, we provided an update on the evidence showing that high NLR is associated with worse prognosis in heart failure (HF), ASCVD, and COVID-19, as well as their clinical applications showing that the normalization of NLR after anti-cytokine therapy is a potential predictor of therapy responsiveness and is associated with reduction of major adverse cardiovascular events.

Deciphering the role of platelets in severe allergy by an integrative omics approach.

BACKGROUND: Mechanisms causing the onset and perpetuation of inflammation in severe allergic patients remain unknown. Our previous studies suggested that severe allergic inflammation is linked to platelet dysfunction. METHODS: Platelet-rich plasma (PRP) and platelet-poor plasma (PPP) samples were obtained by platelet-apheresis from severe (n = 7) and mild (n = 10) allergic patients and nonallergic subjects (n = 9) to perform platelet lipidomics by liquid chromatography coupled to mass spectrometry (LC-MS) and RNA-seq analysis. Significant metabolites and transcripts were used to identify compromised biological pathways in the severe phenotype. Platelet and inflammation-related proteins were quantified by Luminex. RESULTS: Platelets from severe allergic patients were characterized by high levels of ceramides, phosphoinositols, phosphocholines, and sphingomyelins. In contrast, they showed a decrease in eicosanoid precursor levels. Biological pathway analysis performed with the significant lipids revealed the alteration of phospholipases, calcium-dependent events, and linolenic metabolism. RNAseq confirmed mRNA overexpression of genes related to platelet activation and arachidonic acid metabolism in the severe phenotypes. Pathway analysis indicated the alteration of NOD, MAPK, TLR, TNF, and IL-17 pathways in the severe phenotype. P-Selectin and IL-17AF proteins were increased in the severe phenotype. CONCLUSIONS: This study demonstrates that platelet lipid, mRNA, and protein content is different according to allergy severity. These findings suggest that platelet load is a potential source of biomarkers and a new chance for therapeutic targets in severe inflammatory pathologies.

Pathogen reduction with methylene blue does not have an impact on the clinical effectiveness of COVID-19 convalescent plasma.

BACKGROUND AND OBJECTIVES: There is a concern about a possible deleterious effect of pathogen reduction (PR) with methylene blue (MB) on the function of immunoglobulins of COVID-19 convalescent plasma (CCP). We have evaluated whether MB-treated CCP is associated with a poorer clinical response compared to other inactivation systems at the ConPlas-19 clinical trial. MATERIALS AND METHODS: This was an ad hoc sub-study of the ConPlas-19 clinical trial comparing the proportion of patients transfused with MB-treated CCP who had a worsening of respiration versus those treated with amotosalen (AM) or riboflavin (RB). RESULTS: One-hundred and seventy-five inpatients with SARS-CoV-2 pneumonia were transfused with a single CCP unit. The inactivation system of the CCP units transfused was MB in 90 patients (51.4%), RB in 60 (34.3%) and AM in 25 (14.3%). Five out of 90 patients (5.6%) transfused with MB-treated CCP had worsening respiration compared to 9 out of 85 patients (10.6%) treated with alternative PR methods (p = 0.220). Of note, MB showed a trend towards a lower rate of respiratory progressions at 28 days (risk ratio, 0.52; 95% confidence interval, 0.18-1.50). CONCLUSION: Our data suggest that MB-treated CCP does not provide a worse clinical outcome compared to the other PR methods for the treatment of COVID-19.

Influence of non-osteoporotic treatments in patients on active anti-osteoporotic therapy: evidence from the OSTEOMED registry.

PURPOSE: To evaluate the effect of different non-osteoporotic drugs on the increase or decrease in the risk of incident fragility fractures (vertebral, humerus or hip) in a cohort of patients diagnosed with osteoporosis on active anti-osteoporotic therapy. METHODS: For this retrospective longitudinal study, baseline and follow-up data on prescribed non-osteoporotic treatments and the occurrence of vertebral, humerus or hip fractures in 993 patients from the OSTEOMED registry were analyzed using logistic regression models. The drugs evaluated with a possible beneficial effect were thiazides and statins, while the drugs evaluated with a possible harmful effect were antiandrogens, aromatase inhibitors, proton pump inhibitors, selective serotonin reuptake inhibitors, benzodiazepines, GnRH agonists, thyroid hormones, and oral and inhaled corticosteroids. RESULTS: Logistic regression analyses indicated that no treatment significantly improved fracture risk, with the only treatments that significantly worsened fracture risk being letrozole (OR = 0.18, p-value = 0.03) and oral corticosteroids at doses ≤ 5 mg/day (OR = 0.16, p-value = 0.03) and > 5 mg/day (OR = 0.27, p-value = 0.04). CONCLUSION: The potential beneficial or detrimental effects of the different drugs evaluated on fracture risk are masked by treatment with anabolic or antiresorptive drugs that have a more potent action on bone metabolism, with two exceptions: letrozole and oral corticosteroids. These findings may have important clinical implications, as patients receiving these treatments are not fully protected by bisphosphonates, which may imply the need for more potent anti-osteoporotic drugs such as denosumab or teriparatide.

Screening of CNVs using NGS data improves mutation detection yield and decreases costs in genetic testing for hereditary cancer.

INTRODUCTION: Germline CNVs are important contributors to hereditary cancer. In genetic diagnostics, multiplex ligation-dependent probe amplification (MLPA) is commonly used to identify them. However, MLPA is time-consuming and expensive if applied to many genes, hence many routine laboratories test only a subset of genes of interest. METHODS AND RESULTS: We evaluated a next-generation sequencing (NGS)-based CNV detection tool (DECoN) as first-tier screening to decrease costs and turnaround time and expand CNV analysis to all genes of clinical interest in our diagnostics routine. We used DECoN in a retrospective cohort of 1860 patients where a limited number of genes were previously analysed by MLPA, and in a prospective cohort of 2041 patients, without MLPA analysis. In the retrospective cohort, 6 new CNVs were identified and confirmed by MLPA. In the prospective cohort, 19 CNVs were identified and confirmed by MLPA, 8 of these would have been lost in our previous MLPA-restricted detection strategy. Also, the number of genes tested by MLPA across all samples decreased by 93.0% in the prospective cohort. CONCLUSION: Including an in silico germline NGS CNV detection tool improved our genetic diagnostics strategy in hereditary cancer, both increasing the number of CNVs detected and reducing turnaround time and costs.

Pacing of the specialized His-Purkinje conduction system: 'back to the future'.

The conduction system of the human heart is composed of specialized cardiomyocytes that initiate and propagate the electric impulse with consequent rhythmic and synchronized contraction of the atria and ventricles, resulting in the normal cardiac cycle. Although the His-Purkinje system (HPS) was already described more than a century ago, there has been a recent resurgence of conduction system pacing (CSP), where pacing leads are positioned in the His bundle region and left bundle branch area to provide physiological cardiac activation as alternatives to the unnatural myocardial stimulation obtained with conventional right ventricular and biventricular pacing. In this review, we describe the fundamental anatomical and pathophysiological aspects of the specialized HPS along with the CSP technique's nuts and bolts to highlight its potential benefits in everyday clinical practice.

Decrement Evoked Potential (DEEP) Mapping of the Atria: Unmasking Atrial Fibrillation Substrate.

BACKGROUND: Atrial myopathy may underlie the progression of atrial fibrillation (AF) from a treatable disease to an irreversible condition with poor ablation outcomes. Electrophysiological methods to unmask areas prone to re-entry initiation could be key to defining latent atrial myopathy. METHODS: Consecutive patients referred for AF ablation were prospectively included at four institutions. Decrement evoked potential mapping (DEEP) was performed in eight left atrial sites and five right atrial sites, from two different pacing locations (endocardially from the left atrial appendage, epicardially from the proximal coronary sinus). The electrograms (EGMs) during S1 600 ms drive and after an extra stimulus (S2 at +30 ms above atrial refractoriness) were studied at each location and assessed for decremental properties. Follow-up was 12 months. RESULTS: Seventy-four patients were included and 85% had persistent AF. A total of 17,614 EGMs were individually analysed and measured. Nine percent of the EGMs showed DEEP properties (local delay of >10 ms after S2) with a mean decrement of 33±26 ms. DEEPs were more frequent in the left atrium than the right atrium (9.4% vs 8.0%; p<0.001) and more prevalent in persistent AF patients than paroxysmal AF patients (9.8% vs 4.6% p=0.001). Atrial DEEPs were more frequently unmasked in normal bipolar voltage areas and by epicardial pacing than endocardial pacing (9.6% vs 8.4%, respectively; p=0.004). Within the left atrium, the roof had the highest prevalence of DEEP EGMs. CONCLUSIONS: DEEP mapping of both atria is useful for highlighting areas with a tendency for unidirectional block and re-entry initiation. Those areas are more easily unmasked by epicardial pacing from the coronary sinus and more prevalent in persistent AF patients than in paroxysmal AF patients.

CNVfilteR: an R/Bioconductor package to identify false positives produced by germline NGS CNV detection tools.

SUMMARY: Germline copy-number variants (CNVs) are relevant mutations for multiple genetics fields, such as the study of hereditary diseases. However, available benchmarks show that all next-generation sequencing (NGS) CNV calling tools produce false positives. We developed CNVfilteR, an R package that uses the single-nucleotide variant calls usually obtained in germline NGS pipelines to identify those false positives. The package can detect both false deletions and false duplications. We evaluated CNVfilteR performance on callsets generated by 13 CNV calling tools on three whole-genome sequencing and 541 panel samples, showing a decrease of up to 44.8% in false positives and consistent F1-score increase. Using CNVfilteR to detect false-positive calls can improve the overall performance of existing CNV calling pipelines. AVAILABILITY AND IMPLEMENTATION: CNVfilteR is released under Artistic-2.0 License. Source code and documentation are freely available at Bioconductor (http://www.bioconductor.org/packages/CNVfilteR). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Miniseries 2-Septal and paraseptal accessory pathways-Part IV: Inferior paraseptal accessory pathways-lessons from surgical and catheter ablation.

Surgeons and electrophysiologists performing accessory pathway ablation procedures have used the term 'posteroseptal' region. This area, however, is neither septal nor posterior, but paraseptal and inferior; paraseptal because it includes the fibro-adipose tissues filling the pyramidal space and not the muscular septum itself and inferior because it is part of the heart adjacent to the diaphragm. It should properly be described, therefore, as being inferior and paraseptal. Pathways in this region can be ablated at three areas, which we term right inferior, mid-inferior, and left inferior paraseptal. The right- and left inferior paraseptal pathways connect the right and left atrial vestibules with the right and left paraseptal segments of the parietal ventricular walls. The mid-inferior paraseptal pathways take a subepicardial course from the myocardial sleeves surrounding the coronary sinus and its tributaries. Our review addresses the evolution of the anatomical concept of the inferior paraseptal region derived from surgical and catheter ablation procedures. We also highlight the limitations of the 12-lead electrocardiogram in identifying, without catheter electrode mapping, which are the pathways that can be ablated without a coronary sinus, or left heart approach.

Miniseries 2-Septal and paraseptal accessory pathways-Part I: The anatomic basis for the understanding of para-Hisian accessory atrioventricular pathways.

AIMS: Although the anatomy of the atrioventricular conduction axis was well described over a century ago, the precise arrangement in the regions surrounding its transition from the atrioventricular node to the so-called bundle of His remain uncertain. We aimed to clarify these relationships. METHODS AND RESULTS: We have used our various datasets to examine the development and anatomical arrangement of the atrioventricular conduction axis, paying particular attention to the regions surrounding the point of penetration of the bundle of His. It is the areas directly adjacent to the transition of the atrioventricular conduction axis from the atrioventricular node to the non-branching atrioventricular bundle that constitute the para-Hisian areas. The atrioventricular conduction axis itself traverses the membranous part of the ventricular septum as it extends from the node to become the bundle, but the para-Hisian areas themselves are paraseptal. This is because they incorporate the fibrofatty tissues of the inferior pyramidal space and the superior atrioventricular groove. In this initial overarching review, we summarize the developmental and anatomical features of these areas along with the location and landmarks of the atrioventricular conduction axis. We emphasize the relationships between the inferior pyramidal space and the infero-septal recess of the subaortic outflow tract. The details are then explored in greater detail in the additional reviews provided within our miniseries. CONCLUSION: Our anatomical findings, described here, provide the basis for our concomitant clinical review of the so-called para-Hisian arrhythmias. The findings also provide the basis for understanding the other variants of ventricular pre-excitation.

Miniseries 2-Septal and paraseptal accessory pathways-Part III: Mid-paraseptal accessory pathways-revisiting bypass tracts crossing the pyramidal space.

The mid-paraseptal region corresponds to the portion of the pyramidal space whose right atrial aspect is known as the triangle of Koch. The superior area of this mid-paraseptal region is also para-Hisian, and is close to the compact atrioventricular node and the His bundle. The inferior sector of the mid-paraseptal area is unrelated to the normal atrioventricular conduction pathways. It is, therefore, a safe zone in which, if necessary, to perform catheter ablation. The middle part of the mid-paraseptal zone may, however, in some patients, house components of the compact atrioventricular node. This suggests the need for adopting a prudent attitude when considering catheter ablation in this area. The inferior extensions of the atrioventricular node, which may represent the substrate for the slow atrioventricular nodal pathway, take their course through the middle, and even the inferior, sectors of the mid-paraseptal region. In this review, we contend that the middle and inferior areas of the mid-paraseptal region correspond to what, in the past, was labelled by most groups as the 'midseptal' zone. We describe the electrocardiographic patterns observed during pre-excitation and orthodromic reciprocating tachycardia in patients with pathways ablated in the middle or inferior sectors of the region. We discuss the modification of the ventriculo-atrial conduction times during tachycardia after the development of bundle branch block aberrancy. We conclude that the so-called 'intermediate septal' pathways, as described in the era of surgical ablation, were insufficiently characterized. They should not be considered the surrogate of the 'midseptal' pathways defined using endocardial catheter electrode mapping.

Miniseries 2-Septal and paraseptal accessory pathways-Part II: Para-Hisian accessory pathways-so-called anteroseptal pathways revisited.

Surgeons, when dividing bypass tracts adjacent to the His bundle, considered them to be 'anteroseptal'. The area was subsequently recognized to be superior and paraseptal, although this description is not entirely accurate anatomically, and conveys little about the potential risk during catheter interventions. We now describe the area as being para-Hisian, and it harbours two types of accessory pathways. The first variant crosses the membranous septum to insert into the muscular ventricular septum without exiting the heart, and hence being truly septal. The second variant inserts distally in the paraseptal components of the supraventricular crest, and consequently is crestal. The site of ventricular insertion determines the electrocardiographic expression of pre-excitation during sinus rhythm, with the two types producing distinct patterns. In both instances, the QRS and the delta wave are positive in leads I, II, and aVF. In crestal pathways, however, the QRS is ≥ 140 ms, and exhibits an rS configuration in V1-2. The delta wave in V1-2 precedes by 20-50 ms the apparent onset of the QRS in I, II, III, and aVF. In the true septal pathways, the QRS complex occupies ∼120 ms, presenting a QS, W-shaped, morphology in V1-2. The delta wave has a simultaneous onset in all leads. Our proposed terminology facilitates the understanding of the electrocardiographic manifestations of both types of para-Hisian pathways during pre-excitation and orthodromic tachycardia, and informs on the level of risk during catheter ablation.