Introduction The empty pelvis syndrome is a significant source of morbidity following pelvic exenteration surgery. It remains poorly defined with research in this field being heterogeneous and of... Show moreIntroduction The empty pelvis syndrome is a significant source of morbidity following pelvic exenteration surgery. It remains poorly defined with research in this field being heterogeneous and of low quality. Furthermore, there has been minimal engagement with patient representatives following pelvic exenteration with respect to the empty pelvic syndrome. ‘PelvEx—Beating the empty pelvis syndrome’ aims to engage both patient representatives and healthcare professionals to achieve an international consensus on a core outcome set, pathophysiology and mitigation of the empty pelvis syndrome. Methods and analysis A modified-Delphi approach will be followed with a three-stage study design. First, statements will be longlisted using a recent systematic review, healthcare professional event, patient and public engagement, and Delphi piloting. Second, statements will be shortlisted using up to three rounds of online modified Delphi. Third, statements will be confirmed and instruments for measurable statements selected using a virtual patient-representative consensus meeting, and finally a face-to-face healthcare professional consensus meeting. Ethics and dissemination The University of Southampton Faculty of Medicine ethics committee has approved this protocol, which is registered as a study with the Core Outcome Measures in Effectiveness Trials Initiative. Publication of this study will increase the potential for comparative research to further understanding and prevent the empty pelvis syndrome.Trial registration number NCT05683795. Show less
Saeed, D.; Feldman, D.; Banayosy, A. el; Birks, E.; Blume, E.; Cowger, J.; ... ; D'Alessandro, D. 2023
Combination therapies targeting malignancies aim to increase treatment efficacy and reduce toxicity. Hypomethylating drug 5-Aza-2'-deoxycytidine (5-Aza-2') enhances transcription of tumor... Show moreCombination therapies targeting malignancies aim to increase treatment efficacy and reduce toxicity. Hypomethylating drug 5-Aza-2'-deoxycytidine (5-Aza-2') enhances transcription of tumor suppressor genes and induces replication errors via entrapment of DNMT1, yielding DNA-protein crosslinks. Post-translational modification by SUMO plays major roles in the DNA damage response and is required for degradation of entrapped DNMT1. Here, we combine SUMOylation inhibitor TAK981 and DNA-hypomethylating agent 5-Aza-2'-deoxycytidine to improve treatment of MYC driven hematopoietic malignancies, since MYC overexpressing tumors are sensitive to SUMOylation inhibition. We studied the classical MYC driven malignancy Burkitt lymphoma, as well as diffuse large B-cell lymphoma (DLBCL) with and without MYC translocation. SUMO inhibition prolonged the entrapment of DNMT1 to DNA, resulting in DNA damage. An increase in DNA damage was observed in cells co-treated with TAK981 and 5-Aza-2'. Both drugs synergized to reduce cell proliferation in vitro in a B cell lymphoma cell panel, including Burkitt lymphoma and DLBCL. In vivo experiments combining TAK981 (25 mg/kg) and 5-Aza-2' (2.5 mg/kg) showed a significant reduction in outgrowth of Burkitt lymphoma in an orthotopic xenograft model. Our results demonstrate the potential of tailored combination of drugs, based on insight in molecular mechanisms, to improve the efficacy of cancer therapies. Show less
Objective To determine the ability of the Internet-based Spaeth/Richman Contrast Sensitivity (SPARCS) in assessing the change in contrast sensitivity (both central and peripheral) post-treatment... Show moreObjective To determine the ability of the Internet-based Spaeth/Richman Contrast Sensitivity (SPARCS) in assessing the change in contrast sensitivity (both central and peripheral) post-treatment with travoprost 0.004%. Design This is a prospective observational study. Methods and participants. Data of 62 eyes (33 patients) undergoing treatment for naive POAG patients were analysed. Patients were followed up for a period of six months after starting topical travoprost (Travatan 0.004%, Alcon), and the change in central and peripheral CS was studied. Results Mean total SPARCS score at baseline was 69 +/- 10.99, improved to 74.62 +/- 9.50 after 6 months of therapy (p: 0.001) in all the glaucoma severity groups. Mean SPARCS score at baseline in mild glaucoma group was 72.05 +/- 9.87, in the moderate glaucoma group, it was 62.23 +/- 9.2, and in the severe glaucoma group, it was 59.36 +/- 11.65. After 6 months of treatment with travoprost, the CS improved to 76.05 +/- 8.36 in mild group, 76.69 +/- 8.82 in moderate group and 67.18 +/- 11.15 in severe group (p value: 0.014). The percentage change in the CS from baseline showed significant improvement in the superotemporal quadrant at 1 month (p value: 0.032), superonasal quadrant (p value: 0.049), inferotemporal quadrant at 3 months (p value: 0.003) and 6 months (p value: 0.039). Inferonasal quadrant was affected most by glaucoma. A statistically significant correlation was seen between total SPARCS score with MD and PSD. Correlation was also seen between the percentage change in CS and average RNFL thickness at 3 and 6 months. Conclusion Both central and peripheral CS improve following IOP reduction with travoprost. Change in the CS has a significant correlation with RNFL thickness and the perimetric indices. Show less
BACKGROUND: Recurrent ventricular tachycardia (VT) due to dilated cardiomyopathy (DCM) is difficult to treat, and long-term outcome data are limited. OBJECTIVES: The aim of this study was to... Show moreBACKGROUND: Recurrent ventricular tachycardia (VT) due to dilated cardiomyopathy (DCM) is difficult to treat, and long-term outcome data are limited. OBJECTIVES: The aim of this study was to identify predictors of mortality or heart transplantation (HTx) and VT recurrence. METHODS: Consecutive patients with DCM accepted for radiofrequency catheter ablation (RFCA) of VT at 9 centers were prospectively enrolled and followed. RESULTS: Of 281 consecutive patients (mean age 60 +/- 13 years, 85% men, mean left ventricular ejection fraction [LVEF] 36% +/- 12%), 35% had VT storm, 20% had incessant VT, and amiodarone was unsuccessful in 68%. During follow-up of 21 months (IQR: 6-30 months), 67 patients (24%) died or underwent HTx, and 138 (49%) had VT recurrence (45 within 30 days, defined as early); the 4-year rate of VT recurrence or mortality or HTx was 70%. Independent predictors of mortality or HTx were early VT recurrence (HR: 2.92; 95% CI: 1.37-6.21; P < 0.01), amiodarone at discharge (HR: 3.23; 95% CI: 1.43-7.33; P < 0.01), renal dysfunction (HR: 1.92; 95% CI: 1.01-3.64; P = 0.046), and LVEF (HR: 1.36; 95% CI: 1.0-1.84; P = 0.052). LVEF <= 32% identified patients at risk for mortality or HTx (area under the curve: 0.75). Mortality or HTx per 100 person-years was 40.4 events after early, compared with 14.2 events after later VT recurrence and 8.5 events with no VT recurrence after RFCA (P < 0.01 for both). Patients with early recurrence and LVEFs <= 32% had a 1 -year rate of mortality or HTx of 55%. VT recurrence was predicted by prior implantable cardioverter-defibrillator shocks, basal anteroseptal VT origin, and procedural failure but not LVEF. CONCLUSIONS: Patients with DCM needing RFCA for VT are a high-risk group. Following RFCA, approximately one-half remain free of VT recurrence. Early VT recurrence with LVEF <= 32% identifies those at very high risk for mortality or HTx, and screening for mechanical support or HTx should be considered. Late VT recurrence after RFCA does not predict worse outcome. (J Am Coll Cardiol 2022;80:1045 & ndash;1056) (c) 2022 by the American College of Cardiology Foundation. Show less
We herein present an overview of the upcoming 5(th) edition of the World Health Organization Classification of Haematolymphoid Tumours focussing on lymphoid neoplasms. Myeloid and histiocytic... Show moreWe herein present an overview of the upcoming 5(th) edition of the World Health Organization Classification of Haematolymphoid Tumours focussing on lymphoid neoplasms. Myeloid and histiocytic neoplasms will be presented in a separate accompanying article. Besides listing the entities of the classification, we highlight and explain changes from the revised 4(th) edition. These include reorganization of entities by a hierarchical system as is adopted throughout the 5(th) edition of the WHO classification of tumours of all organ systems, modification of nomenclature for some entities, revision of diagnostic criteria or subtypes, deletion of certain entities, and introduction of new entities, as well as inclusion of tumour-like lesions, mesenchymal lesions specific to lymph node and spleen, and germline predisposition syndromes associated with the lymphoid neoplasms. Show less
The standard Lambda Cold Dark Matter (Lambda CDM) cosmological model provides a good description of a wide range of astrophysical and cosmological data. However, there are a few big open questions... Show moreThe standard Lambda Cold Dark Matter (Lambda CDM) cosmological model provides a good description of a wide range of astrophysical and cosmological data. However, there are a few big open questions that make the standard model look like an approximation to a more realistic scenario yet to be found. In this paper, we list a few important goals that need to be addressed in the next decade, taking into account the current discordances between the different cosmological probes, such as the disagreement in the value of the Hubble constant H-0, the sigma(8)-S-8 tension, and other less statistically significant anomalies. While these discordances can still be in part the result of systematic errors, their persistence after several years of accurate analysis strongly hints at cracks in the standard cosmological scenario and the necessity for new physics or generalisations beyond the standard model. In this paper, we focus on the 5.0 sigma tension between the Planck CMB estimate of the Hubble constant H-0 and the SH0ES collaboration measurements. After showing the H-0 evaluations made from different teams using different methods and geometric calibrations, we list a few interesting new physics models that could alleviate this tension and discuss how the next decade's experiments will be crucial. Moreover, we focus on the tension of the Planck CMB data with weak lensing measurements and redshift surveys, about the value of the matter energy density Omega(m), and the amplitude or rate of the growth of structure (sigma(8), f sigma(8)). We list a few interesting models proposed for alleviating this tension, and we discuss the importance of trying to fit a full array of data with a single model and not just one parameter at a time. Additionally, we present a wide range of other less discussed anomalies at a statistical significance level lower than the H-0-S-8 tensions which may also constitute hints towards new physics, and we discuss possible generic theoretical approaches that can collectively explain the non-standard nature of these signals. Finally, we give an overview of upgraded experiments and next-generation space missions and facilities on Earth that will be of crucial importance to address all these open questions. (C) 2022 The Author(s). Published by Elsevier B.V. Show less
Objective Pancreatic ductal adenocarcinoma (PDAC) has the characteristics of high-density desmoplastic stroma, a distinctive immunosuppressive microenvironment and is profoundly resistant to all... Show moreObjective Pancreatic ductal adenocarcinoma (PDAC) has the characteristics of high-density desmoplastic stroma, a distinctive immunosuppressive microenvironment and is profoundly resistant to all forms of chemotherapy and immunotherapy, leading to a 5-year survival rate of 9%. Our study aims to add novel small molecule therapeutics for the treatment of PDAC. Design We have studied whether TAK-981, a novel highly selective and potent small molecule inhibitor of the small ubiquitin like modifier (SUMO) activating enzyme E1 could be used to treat a preclinical syngeneic PDAC mouse model and we have studied the mode of action of TAK-981. Results We found that SUMOylation, a reversible post-translational modification required for cell cycle progression, is increased in PDAC patient samples compared with normal pancreatic tissue. TAK-981 decreased SUMOylation in PDAC cells at the nanomolar range, thereby causing a G2/M cell cycle arrest, mitotic failure and chromosomal segregation defects. TAK-981 efficiently limited tumour burden in the KPC3 syngeneic mouse model without evidence of systemic toxicity. In vivo treatment with TAK-981 enhanced the proportions of activated CD8 T cells and natural killer (NK) cells but transiently decreased B cell numbers in tumour, peripheral blood, spleen and lymph nodes. Single cell RNA sequencing revealed activation of the interferon response on TAK-981 treatment in lymphocytes including T, B and NK cells. TAK-981 treatment of CD8 T cells ex vivo induced activation of STAT1 and interferon target genes. Conclusion Our findings indicate that pharmacological inhibition of the SUMO pathway represents a potential strategy to target PDAC via a dual mechanism: inhibiting cancer cell cycle progression and activating anti-tumour immunity by inducing interferon signalling. Show less
Objective Pancreatic ductal adenocarcinoma (PDAC) has the characteristics of high-density desmoplastic stroma, a distinctive immunosuppressive microenvironment and is profoundly resistant to all... Show moreObjective Pancreatic ductal adenocarcinoma (PDAC) has the characteristics of high-density desmoplastic stroma, a distinctive immunosuppressive microenvironment and is profoundly resistant to all forms of chemotherapy and immunotherapy, leading to a 5-year survival rate of 9%. Our study aims to add novel small molecule therapeutics for the treatment of PDAC.Design We have studied whether TAK-981, a novel highly selective and potent small molecule inhibitor of the small ubiquitin like modifier (SUMO) activating enzyme E1 could be used to treat a preclinical syngeneic PDAC mouse model and we have studied the mode of action of TAK-981.Results We found that SUMOylation, a reversible post-translational modification required for cell cycle progression, is increased in PDAC patient samples compared with normal pancreatic tissue. TAK-981 decreased SUMOylation in PDAC cells at the nanomolar range, thereby causing a G2/M cell cycle arrest, mitotic failure and chromosomal segregation defects. TAK-981 efficiently limited tumour burden in the KPC3 syngeneic mouse model without evidence of systemic toxicity. In vivo treatment with TAK-981 enhanced the proportions of activated CD8 T cells and natural killer (NK) cells but transiently decreased B cell numbers in tumour, peripheral blood, spleen and lymph nodes. Single cell RNA sequencing revealed activation of the interferon response on TAK-981 treatment in lymphocytes including T, B and NK cells. TAK-981 treatment of CD8 T cells ex vivo induced activation of STAT1 and interferon target genes.Conclusion Our findings indicate that pharmacological inhibition of the SUMO pathway represents a potential strategy to target PDAC via a dual mechanism: inhibiting cancer cell cycle progression and activating anti-tumour immunity by inducing interferon signalling. Show less
Hoogendoorn, J.C.; Venlet, J.; Out, Y.N.J.; Man, S.; Kumar, S.; Sramko, M.; ... ; Zeppenfeld, K. 2021
BACKGROUND Cardiac sarcoidosis (CS) with right ventricular (RV) involvement can mimic arrhythmogenic right ventricular cardiomyopathy (ARVC). Histopathological differences may result in disease... Show moreBACKGROUND Cardiac sarcoidosis (CS) with right ventricular (RV) involvement can mimic arrhythmogenic right ventricular cardiomyopathy (ARVC). Histopathological differences may result in disease-specific RV activation patterns detectable on the 12-lead electrocardiogram. Dominant subepicardial scar in ARVC leads to delayed activation of areas with reduced voltages, translating into terminal activation delay and occasionally (epsilon) waves with a small amplitude. Conversely, patchy transmural RV scar in CS may lead to conduction block and therefore late activated areas with preserved voltages reflected as preserved R' waves.OBJECTIVE The purpose of this study was to evaluate the distinct terminal activation patterns in precordial leads V-1 through V-3 as a discriminator between CS and ARVC.METHODS Thirteen patients with CS affecting the RV and 23 patients with gene-positive ARVC referred for ventricular tachycardia ablation were retrospectively included in a multicenter approach. A non-ventricular-paced 12-lead surface electrocardiogram was analyzed for the presence and the surface area of the R' wave (any positive deflection from baseline after an S wave) in leads V-1 through V-3.RESULTS An R' wave in leads V-1 through V-3 was present in all patients with CS compared to 11 (48%) patients with ARVC (P=.002). An algorithm including a PR interval of >= 220 ms, the presence of an R' wave, and the surface area of the maximum R' wave in leads V-1 through V-3 of similar to 1.65 mm(2) had 85% sensitivity and 96% specificity for diagnosing CS, validated in a second cohort (18 CS and 40 ARVC) with 83% sensitivity and 88% specificity.CONCLUSION An easily applicable algorithm including PR prolongation and the surface area of the maximum R' wave in leads V-1 through V-3 of similar to 1.65 mm(2) distinguishes CS from ARVC. This QRS terminal activation in precordial leads V-1 through V-3 may reflect disease-specific scar patterns. Show less
Purpose:To assess changes in the central and peripheral contrast sensitivity in severe primary open-angle glaucoma (POAG) patients using a computer-based Spaeth/Richman contrast sensitivity test ... Show morePurpose:To assess changes in the central and peripheral contrast sensitivity in severe primary open-angle glaucoma (POAG) patients using a computer-based Spaeth/Richman contrast sensitivity test (SPARCS) over a period of 24 months.Methods:Our pilot, observational study included 15 patients (30 eyes) with severe POAG. Visual acuity, intraocular pressure, number of anti-glaucoma drugs, visual fields, and SPARCS score were recorded at first visit and at 12 and 24 months.Results:We observed changes in mean deviation (MD) from -19.37 +/- 5.04 to -20.63 +/- 4.07, mean pattern standard deviation (PSD) from 11.49 +/- 2.61 to 11.35 +/- 2.01, and mean SPARCS score from 54.97 +/- 15.66 to 53.50 +/- 16.42. We found no statistically significant difference between visual field parameters and SPARCS scores associated with the number or type of prescribed anti-glaucoma drugs. Spearman's correlation coefficient of SPARCS at baseline (SPARCS1) versus MD at baseline (MD1) was 0.274 (p = 0.142) and SPARCS1 versus PSD at baseline (PSD1) was -0.163 (p = 0.389). The correlation coefficient between SPARCS at 12 months (SPARCS2) versus MD (MD2) at the same time point was computed to be 0.391 (p = 0.03), whereas SPARCS2 versus PSD at 12 months was -0.212 (p = 0.262). Similarly, we found the coefficient to be 0.336 (p = 0.069) for SPARCS3 (SPARCS at 24 months) versus MD3 (MD at 24 months) and -0.242 (p = 0.197) for SPARCS3 versus PSD3 (PSD at 24 months). Correlation coefficients between SPARCS1/2, SPARCS1/3, MD1/2, MD1/3 PSD1/2, and PSD1/3 were 0.856, 0.865, 0.748, 0.722, 0.497, and 0.562, respectively (p < 0.001). MD changed by 9.46% +/- 12.73%, PSD by 0.64% +/- 14.03%, and average SPARCS by 3.31% +/- 12.73% over 24 months.Conclusion:The data from our study indicate the utilitarian application of SPARCS, an inexpensive and readily available tool for monitoring functional deterioration in cases with advanced glaucomatous damage, especially in resource-poor settings. Furthermore, it is a useful and reliable alternative to the imaging modalities where retinal nerve fiber layer measurement can be erroneous in advanced cases secondary to the floor effect. Show less
Purpose The current grading systems used for bleb morphology assessment in patients post-trabeculectomy are based on standardized slit-lamp photographs and anterior segment imaging devices. The... Show morePurpose The current grading systems used for bleb morphology assessment in patients post-trabeculectomy are based on standardized slit-lamp photographs and anterior segment imaging devices. The lack of availability of these expensive and non-portable devices in resource-deficient settings is a significant deterrent in their widespread utilization for proper post-operative management. The rapidly evolving utilization of smartphone photography has significantly benefited diagnostics of posterior segment disorders and is now being increasingly utilized for monitoring anterior segment pathologies as well as post-surgical course. In this study, we study a novel use of smartphones for bleb photography for assessing the morphological characteristics as vascularity and microcysts. Methods In this pilot, observational study, we compared the trabeculectomy bleb images of five subjects, obtained by iPhone X (dual lens) and iPhone 6S (single lens). We captured two image sets with both smartphones first with a focussed torchlight and then with a built-in flash video light. Results The images resulting from the newer iPhone X were substantially superior than those from iPhone 6S. For the 12-megapixel dual-camera set-up on the iPhone X, the 1 x lens resulted in better images than the 2 x lens with contrast and overall clarity of the area of interest. While the macro-lens attachment had promising results at 1 x zoom, there is no added advantage of the macro-lens attachment as it resulted in considerable loss of image quality at twice the zoom. Using a 20 D lens helped attain higher magnification and better framing as it reduced the focussing distance needed to get sharp images. The images obtained from both smartphones were of higher quality when illuminated from an external source when compared to the native iPhone flash due to even exposure and fewer autofocus artefacts. Conclusion Analyses of all image sets showed that the current generation in-built camera app on IOS and newer iPhone camera optics resulted in high-quality images of the ocular surface with high magnification without any loss in clarity. Show less
Boon, B.D.C.; Bulk, M.; Jonker, A.J.; Morrema, T.H.J.; Berg, E. van den; Popovic, M.; ... ; Hoozemans, J.J.M. 2020
Alzheimer's disease (AD) is characterized by amyloid-beta (A beta) deposits, which come in myriad morphologies with varying clinical relevance. Previously, we observed an atypical A beta deposit,... Show moreAlzheimer's disease (AD) is characterized by amyloid-beta (A beta) deposits, which come in myriad morphologies with varying clinical relevance. Previously, we observed an atypical A beta deposit, referred to as the coarse-grained plaque. In this study, we evaluate the plaque's association with clinical disease and perform in-depth immunohistochemical and morphological characterization. The coarse-grained plaque, a relatively large (o approximate to 80 mu m) deposit, characterized as having multiple cores and A beta-devoid pores, was prominent in the neocortex. The plaque was semi-quantitatively scored in the middle frontal gyrus of A beta-positive cases (n = 74), including non-demented cases (n = 15), early-onset (EO)AD (n = 38), and late-onset (LO)AD cases (n = 21). The coarse-grained plaque was only observed in cases with clinical dementia and more frequently present in EOAD compared to LOAD. This plaque was associated with a homozygousAPOE epsilon 4 status and cerebral amyloid angiopathy (CAA). In-depth characterization was done by studying the coarse-grained plaque's neuritic component (pTau, APP, PrP (c)), A beta isoform composition (A beta(40), A beta(42), A beta(N3pE), pSer8A beta), its neuroinflammatory component (C4b, CD68, MHC-II, GFAP), and its vascular attribution (laminin, collagen IV, norrin). The plaque was compared to the classic cored plaque, cotton wool plaque, and CAA. Similar to CAA but different from classic cored plaques, the coarse-grained plaque was predominantly composed of A beta(40). Furthermore, the coarse-grained plaque was distinctly associated with both intense neuroinflammation and vascular (capillary) pathology. Confocal laser scanning microscopy (CLSM) and 3D analysis revealed for most coarse-grained plaques a particular A beta(40)shell structure and a direct relation with vessels. Based on its morphological and biochemical characteristics, we conclude that the coarse-grained plaque is a divergent A beta plaque-type associated with EOAD. Differences in A beta processing and aggregation, neuroinflammatory response, and vascular clearance may presumably underlie the difference between coarse-grained plaques and other A beta deposits. Disentangling specific A beta deposits between AD subgroups may be important in the search for disease-mechanistic-based therapies. Show less
BackgroundDeletions removing 100s-1000s kb of DNA, and variable numbers of poorly characterised genes, are often found in patients with a wide range of developmental abnormalities. In such cases,... Show moreBackgroundDeletions removing 100s-1000s kb of DNA, and variable numbers of poorly characterised genes, are often found in patients with a wide range of developmental abnormalities. In such cases, understanding the contribution of the deletion to an individual's clinical phenotype is challenging.MethodsHere, as an example of this common phenomenon, we analysed 41 patients with simple deletions of similar to 177 to similar to 2000 kb affecting one allele of the well-characterised, gene dense, distal region of chromosome 16 (16p13.3), referred to as ATR-16 syndrome. We characterised deletion extents and screened for genetic background effects, telomere position effect and compensatory upregulation of hemizygous genes.ResultsWe find the risk of developmental and neurological abnormalities arises from much smaller distal chromosome 16 deletions (similar to 400 kb) than previously reported. Beyond this, the severity of ATR-16 syndrome increases with deletion size, but there is no evidence that critical regions determine the developmental abnormalities associated with this disorder. Surprisingly, we find no evidence of telomere position effect or compensatory upregulation of hemizygous genes; however, genetic background effects substantially modify phenotypic abnormalities.ConclusionsUsing ATR-16 as a general model of disorders caused by CNVs, we show the degree to which individuals with contiguous gene syndromes are affected is not simply related to the number of genes deleted but depends on their genetic background. We also show there is no critical region defining the degree of phenotypic abnormalities in ATR-16 syndrome and this has important implications for genetic counselling. Show less
Hoogendoorn, J.C.; Sramko, M.; Venlet, J.; Siontis, K.C.; Kumar, S.; Singh, R.; ... ; Zeppenfeld, K. 2020
OBJECTIVES This study sought to investigate the value of electroanatomical voltage mapping (EAVM) to distinguish cardiac sarcoidosis (CS) from arrhythmogenic right ventricular cardiomyopathy (ARVC)... Show moreOBJECTIVES This study sought to investigate the value of electroanatomical voltage mapping (EAVM) to distinguish cardiac sarcoidosis (CS) from arrhythmogenic right ventricular cardiomyopathy (ARVC) in patients with ventriculartachycardia from the right ventricle (RV).BACKGROUND CS can mimic ARVC. Because scar in ARVC is predominantly subepicardial, this study hypothesized that the relative sizes of endocardial low bipolar voltage (BV) to low unipolar voltage (UV) areas may distinguish CS from ARVC.METHODS Patients with CS affecting the RV (n = 14), patients with gene-positive ARVC (n = 13), and a reference group of patients without structural heart disease (n = 9) who underwent RV endocardial EAVM were included. RV regionspecific BV and UV cutoffs were derived from control subjects. In CS and ARVC, segmental involvement was determined and low-voltage areas were measured, using <1.5 mV for BV and <3.9 mV, <4.4 mV, and <5.5 mV for UV. The ratio between low BV and low UV area was calculated generating 3 parameters: Ratio3.9, Ratio4.4 and Ratio5.5, respectively.RESULTS In control subjects, BV and UV varied significantly among RV regions. The basal septum was involved in 71% of CS patients and in none of ARVC patients. Ratio5.5 discriminated CS from ARVC the best. An algorithm including Ratio5.5≥0.45 and basal septal involvement identified CS with 93% sensitivity and 85% specificity. This was validated in a separate population (CS [n = 6], ARVC [n = 10]) with 100% sensitivity and 100% specificity.CONCLUSIONS EAVM provides detailed information about scar characteristics and scar distribution in the RV. An algorithm combining Ratio5.5 (area BV <1.5 mV/area UV <5.5 mV) and bipolar basal septal involvement allows accurate diagnosis of (isolated) CS in patients presenting with monomorphic ventricular tachycardia from the RV. Show less
Background: An accurate estimation of the risk of life-threatening (LT) ventricular tachyarrhythmia (VTA) in patients with LMNA mutations is crucial to select candidates for implantable... Show moreBackground: An accurate estimation of the risk of life-threatening (LT) ventricular tachyarrhythmia (VTA) in patients with LMNA mutations is crucial to select candidates for implantable cardioverter-defibrillator implantation. Methods: We included 839 adult patients with LMNA mutations, including 660 from a French nationwide registry in the development sample, and 179 from other countries, referred to 5 tertiary centers for cardiomyopathies, in the validation sample. LTVTA was defined as (1) sudden cardiac death or (2) implantable cardioverter defibrillator-treated or hemodynamically unstable VTA. The prognostic model was derived using the Fine-Gray regression model. The net reclassification was compared with current clinical practice guidelines. The results are presented as means (SD) or medians [interquartile range]. Results: We included 444 patients, 40.6 (14.1) years of age, in the derivation sample and 145 patients, 38.2 (15.0) years, in the validation sample, of whom 86 (19.3%) and 34 (23.4%) experienced LTVTA over 3.6 [1.0-7.2] and 5.1 [2.0-9.3] years of follow-up, respectively. Predictors of LTVTA in the derivation sample were: male sex, nonmissense LMNA mutation, first degree and higher atrioventricular block, nonsustained ventricular tachycardia, and left ventricular ejection fraction (https://lmna-risk-vta.fr). In the derivation sample, C-index (95% CI) of the model was 0.776 (0.711-0.842), and the calibration slope 0.827. In the external validation sample, the C-index was 0.800 (0.642-0.959), and the calibration slope was 1.082 (95% CI, 0.643-1.522). A 5-year estimated risk threshold >= 7% predicted 96.2% of LTVTA and net reclassified 28.8% of patients with LTVTA in comparison with the guidelines-based approach. Conclusions: In comparison with the current standard of care, this risk prediction model for LTVTA in laminopathies significantly facilitated the choice of candidates for implantable cardioverter defibrillators. Show less
BACKGROUND The comparative efficacy of antiarrhythmic drug (AAD) therapy vs ventricular tachycardia (VT) ablation in arrhythmogenic right ventricular cardiomyopathy (ARVC) is unknown.OBJECTIVE We... Show moreBACKGROUND The comparative efficacy of antiarrhythmic drug (AAD) therapy vs ventricular tachycardia (VT) ablation in arrhythmogenic right ventricular cardiomyopathy (ARVC) is unknown.OBJECTIVE We compared outcomes of AAD and/or beta-blocker (BB) therapy with those of VT ablation (with AAD/BB) in patients with ARVC who had recurrent VT.METHODS In a multicenter retrospective study, 110 patients with ARVC (mean age 38 +/- 17 years; 91[83%] men) with a minimum of 3 VT episodes were included; 77 (70%) were initially treated with AAD/BB and 32 (29%) underwent ablation. Subsequently, 43 of the 77 patients treated with AAD/BB alone also underwent ablation. Overall, 75 patients underwent ablation.RESULTS When comparing initial AAD/BB therapy (n = 77) and VT ablation (n = 32) after >= 3 VT episodes, a single ablation procedure rendered 35% of patients free of VT at 3 years compared with 28% of AAD/BB-only-treated patients (P =.46). Of the 77 AAD/BB-only-treated patients, 43 subsequently underwent ablation. For all 75 patients who underwent ablation, 56% were VT-free at 3 years after the last ablation procedure. Epicardial ablation was used in 40/75 (53%) and was associated with lower VT recurrence after the last ablation procedure (endocardial/epicardial vs endocardial-only; 71% vs 47% 3-year VT-free survival; P =.05). Importantly, there was no difference in survival free of death or transplantation between the ablation- and AAD/BB-only-treated patients (P =.61).CONCLUSION In patients with ARVC and a high VT burden, mortality and transplantation-free survival are not significantly different between drug- and ablation-treated patients. These patients have a high risk of recurrent VT despite drug therapy. Combined endocardial/epicardial ablation is associated with reduced VT recurrence as compared with endocardial-only ablation. Show less
