Bridging therapy-induced phenotypes and genetic immune dysregulation to study interleukin-2-induced immunotoxicology.

Interleukin-2 (IL-2) holds promise for the treatment of cancer and autoimmune diseases, but its high-dose usage is associated with systemic immunotoxicity. Differential IL-2 receptor (IL-2R) regulation might impact function of cells upon IL-2 stimulation, possibly inducing cellular changes similar to patients with hypomorphic IL2RB mutations, presenting with multiorgan autoimmunity. Here, we show that sustained high-dose IL-2 stimulation of human lymphocytes drastically reduces IL-2Rß surface expression especially on T cells, resulting in impaired IL-2R signaling which correlates with high IL-2Rα baseline expression. IL-2R signaling in NK cells is maintained. CD4+ T cells, especially regulatory T cells are more broadly affected than CD8+ T cells, consistent with lineage-specific differences in IL-2 responsiveness. Given the resemblance of cellular characteristics of high-dose IL-2-stimulated cells and cells from patients with IL-2Rß defects, impact of continuous IL-2 stimulation on IL-2R signaling should be considered in the onset of clinical adverse events during IL-2 therapy.

Outcomes after cryoballoon ablation of paroxysmal atrial fibrillation with the PolarX or the Arctic Front Advance Pro: a prospective multicentre experience.

AIMS: The aim of this study was to compare procedural efficacy and safety, including 1-year freedom from AF recurrence, between the novel cryoballoon system PolarX (Boston Scientific) and the Arctic Front Advance Pro (AFA-Pro) (Medtronic), in patients with paroxysmal AF undergoing PVI. METHODS AND RESULTS: This multicentre prospective observational study included 267 consecutive patients undergoing a first cryoablation procedure for paroxysmal AF (137 PolarX, 130 AFA-Pro). Kaplan-Meier curves with the log-rank test was used to compare the 1-year freedom from AF recurrence between both groups. Multivariate Cox model was performed to evaluate whether the type of procedure (PolarX vs. AFA-Pro) had an impact on the occurrence of AF recurrences after adjustment on potentially confounding factors. The PolarX reaches lower temperatures than the AFA-Pro (LSPV 52 ± 5, vs. 59 ± 6; LIPV 49 ± 6 vs. 56 ± 6; right superior pulmonary vein: 49 ± 6 vs. 57 ± 7; right inferior pulmonary vein: 52 ± 6 vs. 59 ± 6; P < 0.0001). A higher rate of transient phrenic nerve palsy was found in patients treated with the PolarX system (15% vs. 7%, P = 0.05). After a mean follow-up of 15 ± 5 months, 20 patients (15%) had recurrences in AFA-Pro group and 27 patients (19%) in PolarX group (P = 0.35). Based on survival analysis, no significant difference was observed between both groups with a 12-month free of recurrence survival of 91.2% (85.1-95.4%) vs. 83.7% (76.0%-89.1%) (log-rank test P = 0.11). In multivariate Cox model hazard ratio of recurrence for PolarX vs. AFA-Pro was not significant [HR = 1.6 (0.9-2.8), P = 0.12]. CONCLUSION: PolarX and AFA-Pro have comparable efficacy and safety profiles for pulmonary veins isolation in paroxysmal atrial fibrillation.

Dosimetric evaluation of the benefit of deep inspiration breath hold (DIBH) for locoregional irradiation of right breast cancer with volumetric modulated arctherapy (VMAT).

INTRODUCTION: Right-lateralized cardiac substructures can be substantially exposed during right breast cancer (R-BC) radiotherapy. The cardiac benefit of deep inspiration breath hold (DIBH) is established in combination with volumetric modulated arctherapy (VMAT) for left breast cancer with regional node irradiation but is unknown for R-BC. This study evaluated the dosimetric benefit of DIBH for locoregional irradiation of R-BC with VMAT. MATERIAL AND METHODS: All patients treated for R-BC with adjuvant locoregional DIBH-VMAT in the Department of Radiation Oncology of the Institut Curie (Paris, France) until December 2022 were included, corresponding to 15 patients. FB- and DIBH-VMAT plans were compared both for a normofractionated regimen (50 Gy/25fx) used for treatment and a replanned hypofractionated regimen (40 Gy/15fx). Dose to the heart, cardiac substructures (sinoatrial node (SAN), atrio-ventricular node (AVN), right coronary artery, left anterior descending coronary artery, left ventricle), ipsilateral lung and liver were retrieved and compared. RESULTS: Mean heart dose (MHD) was 3.33 Gy with FB vs. 3.10 Gy with DIBH on normofractionated plans (p = 0.489), and 2.58 Gy with FB vs. 2.41 Gy with DIBH on hypofractionated plan (p = 0.489). The benefit of DIBH was not significant for any cardiac substructure. The most exposed cardiac substructure were the SAN (mean dose of 6.62 Gy for FB- and 5.64 Gy for DIBH-VMAT on normofractionated plans) and the RCA (mean dose of 4.21 Gy for FB- and 4.06 Gy for DIBH-VMAT on normofractionated plans). The maximum benefit was observed for the RCA with a median individual dose reduction of 0.84 Gy on normofractionated plans (p = 0.599). No significant dosimetric difference were observed for right lung. Liver mean dose was significantly lower with DIBH with median values decreasing from 2.54 Gy to 0.87 Gy (p = 0.01). CONCLUSION: Adding DIBH to efficient cardiac-sparing radiotherapy techniques, such as VMAT, is not justified in the general case for locoregional R-BC irradiation. Specific R-BC patient subpopulations who could benefit from additional DIBH combination with locoregional VMAT are yet to be identified.

Past and present work practices of European interventional cardiologists in the context of radiation protection of the eye lens-results of the EURALOC study.

This paper investigates over five decades of work practices in interventional cardiology, with an emphasis on radiation protection. The analysis is based on data from more than 400 cardiologists from various European countries recruited for a EURALOC study and collected in the period from 2014 to 2016. Information on the types of procedures performed and their annual mean number, fluoroscopy time, access site choice, x-ray units and radiation protection means used was collected using an occupational questionnaire. Based on the specific European data, changes in each parameter have been analysed over decades, while country-specific data analysis has allowed us to determine the differences in local practices. In particular, based on the collected data, the typical workload of a European cardiologist working in a haemodynamic room and an electrophysiology room was specified for various types of procedures. The results showed that when working in a haemodynamic room, a transparent ceiling-suspended lead shield or lead glasses are necessary in order to remain below the recommended eye lens dose limit of 20 mSv. Moreover, the analysis revealed that new, more complex cardiac procedures such as chronic total occlusion, valvuloplasty and pulmonary vein isolation for atrial fibrillation ablation might contribute substantially to annual doses, although they are relatively rarely performed. The results revealed that considerable progress has been made in the use of radiation protection tools. While their use in electrophysiology procedures is not generic, the situation in haemodynamic procedures is rather encouraging, as ceiling-suspended shields are used in 90% of cases, while the combination of ceiling shield and lead glasses is noted in more than 40% of the procedures. However, we find that still 7% of haemodynamic procedures are performed without any radiation protection tools.

Temporal Trends Over a Decade of Defibrillator Therapy for Primary Prevention in Community Practice.

BACKGROUND: Technology and clinical practice surrounding the use of the primary prevention implantable cardioverter defibrillator (ICD) are in a state of constant evolution. The purpose of the study was to test the hypothesis of significant temporal trends in characteristics and outcomes over a decade of ICD therapy. METHODS: Between 2002 and 2012, 5,539 consecutive patients (age 62.5 ± 11 years, 84.9% male), with ischemic or nonischemic cardiomyopathy, implanted with a primary prevention ICD from 12 centers in France were included. Information on characteristics and outcomes (including causes of death) were evaluated over a median follow-up of 994 days (466-1,667). RESULTS: In addition to a shift in the type of devices implanted with a significant increase in cardiac resynchronization therapy-defibrillator (CRT-D) over time (43.6 to 60.4%, P = 0.0001), an increase in mean age (from 61.5 ± 11.6 to 63.2 ± 10.9 years, P = 0.0016), proportion of nonischemic cardiomyopathy (31.0 to 44.7%, P <0.0001) and women recipients (11.4 to 15.8%, P = 0.004) was observed. A total of 1,181 patients (22.3%) received ≥1 appropriate therapy, inappropriate therapies occurred in 355 patients (6.7%) and 826 patients (15.2%) died, mainly from cardiovascular causes (49.3%). Annual mortality incidence (5.4% to 4.3%, P = 0.05), as well as incidence of appropriate therapy (10.4% to 7.1%, P = 0.0004), significantly decreased over the decade. By contrast, incidence of ICD-related late (>30 days after implant) complications significantly increased (4.6 to 7.6%, P = 0.003). CONCLUSION: Our findings demonstrate significant changes in patterns of use and outcomes in primary prevention ICD over the last decade with reductions in mortality and appropriate therapies, counterbalanced by an increase in complications.

Causes-of-death analysis of patients with cardiac resynchronization therapy: an analysis of the CeRtiTuDe cohort study.

AIMS: The choice of resynchronization therapy between with (CRT-D) and without (CRT-P) a defibrillator remains a contentious issue. Cause-of-death analysis among CRT-P, compared with CRT-D, patients could help evaluate the extent to which CRT-P patients would have additionally benefited from a defibrillator in a daily clinical practice. METHODS AND RESULTS: A total of 1705 consecutive patients implanted with a CRT (CRT-P: 535 and CRT-D: 1170) between 2008 and 2010 were enrolled in CeRtiTuDe, a multicentric prospective follow-up cohort study, with specific adjudication for causes of death at 2 years. Patients with CRT-P compared with CRT-D were older (P < 0.0001), less often male (P < 0.0001), more symptomatic (P = 0.0005), with less coronary artery disease (P = 0.003), wider QRS (P = 0.002), more atrial fibrillation (P < 0.0001), and more co-morbidities (P = 0.04). At 2-year follow-up, the annual overall mortality rate was 83.80 [95% confidence interval (CI) 73.41-94.19] per 1000 person-years. The crude mortality rate among CRT-P patients was double compared with CRT-D (relative risk 2.01, 95% CI 1.56-2.58). In a Cox proportional hazards regression analysis, CRT-P remained associated with increased mortality (hazard ratio 1.54, 95% CI 1.07-2.21, P = 0.0209), although other potential confounders may persist. By cause-of-death analysis, 95% of the excess mortality among CRT-P subjects was related to an increase in non-sudden death. CONCLUSION: When compared with CRT-D patients, excess mortality in CRT-P recipients was mainly due to non-sudden death. Our findings suggest that CRT-P patients, as currently selected in routine clinical practice, would not potentially benefit with the addition of a defibrillator.

EpiBrainRad: an epidemiologic study of the neurotoxicity induced by radiotherapy in high grade glioma patients.

BACKGROUND: Radiotherapy is one of the most important treatments of primary and metastatic brain tumors. Unfortunately, it can involve moderate to severe complications among which leukoencephalopathy is very frequent and implies cognitive deficits such as memory, attention and executive dysfunctions. However, the incidence of this complication is not well established and the risk factors and process are poorly understood. The main objective of the study is to improve knowledge on radio-induced leukoencephalopathy based on pluridisciplinar approaches combining cognitive, biologic, imagery and dosimetric investigations. METHOD/DESIGN: The EpiBrainRad study is a prospective cohort study including newly diagnosed high grade gliomas patients treated by radiotherapy and concomitant-adjuvant temozolomide chemotherapy. Patients are included between their surgery and first day of radio-chemotherapy, and the follow-up lasts for 3 years after treatment. Cognitive functioning assessments, specific blood biomarkers measures and magnetic resonance imagery are performed at different moment during the follow-up, and a specific dosimetric assessment of organs involved in the beam fields is performed. Firstly, leukoencephalopathy incidence rate will be estimated in this population. Secondly, correlations between cognitive impairments and dosimetry, biomarkers ranges and anomalies on imagery will be analyzed in order to better understand the onset and evolution of cognitive decrement associated with radiotherapy. Furthermore, a new cognitive test, quickly and easily performed, will be studied to determine its sensibility to detect leukoencephalopathy decrement. DISCUSSION: With an original multidisciplinary approach, the EpiBrainRad study aims to improve knowledge on radio-induced leukoencephalopathy in order to improve its early diagnosis and prevention. The main challenge is to preserve quality-of-life after cancer treatments which imply to study the incidence of radiation-induced complications and their associated risk factors. TRIAL REGISTRATION: NCT02544178.

Barriers to accessing hepatitis B medication: a qualitative study from the USA and Canada.

OBJECTIVES: To collect and document the numerous barriers that people living with hepatitis B (PLHB) encounter when trying to access their hepatitis B virus (HBV) medications. DESIGN: Researchers collected qualitative data through 24 online interviews. The semistructured interview questions focused on the impact that HBV has on different aspects of daily life (physical, emotional and social), personal experiences managing their infection, HBV treatment experiences and interactions with healthcare providers. SETTING: All interviews occurred over Zoom. PARTICIPANTS: The participant cohort consisted of 12 males and 12 females. 63% of all participants represented communities of colour (37% white, 17% black/African/African American and 46% Asian/Asian American). Most of the participants were on antiviral treatment at the time of the study (62%). Participants were PLHB (self-reported), ≥18 years old, living in the USA or Canada and spoke English. RESULTS: Participants reported several barriers to accessing medicine among PLHB including financial barriers, health insurance and pharmacy preauthorisation process and other intangible barriers like lack of access to reliable patient-friendly information and stigma. The identified barriers to accessing HBV medication impacted patients' continuity of care. CONCLUSIONS: Access to medicine is essential to improving health outcomes. PLHB experience significant barriers to accessing HBV antivirals at different levels. Patient-related, physician-related and healthcare system barriers were identified as themes contributing to antiviral access challenges. More research is needed to identify strategies to improve access to HBV medications.

Determinants of substrate specificity and biochemical properties of the sn-glycerol-3-phosphate ATP binding cassette transporter (UgpB-AEC2 ) of Escherichia coli.

Under phosphate starvation conditions, Escherichia coli can utilize sn-glycerol-3-phosphate (G3P) and G3P diesters as phosphate source when transported by an ATP binding cassette importer composed of the periplasmic binding protein, UgpB, the transmembrane subunits, UgpA and UgpE, and a homodimer of the nucleotide binding subunit, UgpC. The current knowledge on the Ugp transporter is solely based on genetic evidence and transport assays using intact cells. Thus, we set out to characterize its properties at the level of purified protein components. UgpB was demonstrated to bind G3P and glycerophosphocholine with dissociation constants of 0.68 ± 0.02 µM and 5.1 ± 0.3 µM, respectively, while glycerol-2-phosphate (G2P) is not a substrate. The crystal structure of UgpB in complex with G3P was solved at 1.8 Å resolution and revealed the interaction with two tryptophan residues as key to the preferential binding of linear G3P in contrast to the branched G2P. Mutational analysis validated the crucial role of Trp-169 for G3P binding. The purified UgpAEC2 complex displayed UgpB/G3P-stimulated ATPase activity in proteoliposomes that was neither inhibited by phosphate nor by the signal transducing protein PhoU or the phosphodiesterase UgpQ. Furthermore, a hybrid transporter composed of MalFG-UgpC could be functionally reconstituted while a UgpAE-MalK complex was unstable.

Early Development of Atherosclerotic Plaques in the Coronary Arteries after Radiotherapy for Breast Cancer (BACCARAT Study).

Background-Radiotherapy (RT) for breast cancer (BC) can lead to an increased risk of coronary artery disease several years after RT. The aim of this study was to evaluate the development of overall, non-calcified and calcified atherosclerotic plaques over 2 years after BC for RT and associations with cardiac exposure. Methods-The study included 101 left- or right-sided BC patients treated with RT without chemotherapy. A coronary CT angiography was performed before and 2 years after RT. Plaque development thorough the entire coronary network was defined as an increased number of plaques. Cardiac exposure was quantified with mean doses to the heart, left ventricle, and coronary arteries. Logistic regression models were used to assess association with doses. Results-At inclusion, 37% of patients had plaques, increasing to 42% two years after RT. Overall plaque development was observed in seven patients: five with calcified plaque development and four with non-calcified plaque development. The risk of overall plaque development was significantly associated with doses to the Left Main and Circumflex coronary arteries (OR at 1 Gy = 2.32, p = 0.03 and OR at 1 Gy = 2.27, p = 0.03, respectively). Specific analyses for calcified and non-calcified plaque development showed similar results. Conclusion-Our study suggests an association between coronary arteries exposure and the risk of developing both calcified and non-calcified atherosclerotic plaques over 2 years after BC RT. Trial registration number: NCT02605512.

Temporal Trends in Pacemaker Implantations Over the Past Decade in France: Impact of Transcatheter Aortic Valve Implantations.

In this study, we assessed the temporal trends of permanent pacemaker implantations in France from 2008 to 2018 using data from the Échantillon Généraliste de Bénéficiaires (EGB) administrative database, a representative sample of the French population. Additionally, we evaluated the impact of transcatheter aortic valve implantations on the overall pacemaker implantation rate. Our data suggest that the incidence of permanent pacemaker implantations in France increased significantly only in patients ≥80 years old, with post-transcatheter aortic valve implantations accounting for at least 2/3 of this increase.

A novel stepwise approach incorporating ethanol infusion in the vein of Marshall for the ablation of persistent atrial fibrillation.

Introduction: Apart from pulmonary vein isolation (PVI), several step-by-step procedures that aim to modify left atrial substrate have been proposed for the ablation of persistent atrial fibrillation (AF), yet the optimal strategy remains elusive. There are cumulative data suggesting an incremental benefit of adding vein of Marshall (VOM) ethanol infusion to PVI in patients with persistent AF. We sought to evaluate the feasibility and efficacy of a novel stepwise ablation approach, incorporating a VOM alcoholization step, for persistent AF. Methods: In this single-center study, we prospectively enrolled 66 consecutive patients with symptomatic persistent AF and failure of at least one antiarrhythmic drug (ADD). The ablation procedure consisted of (i) PVI, (ii) left atrial segmentation with VOM ethanol infusion and the deployment of linear radiofrequency lesions across the roof and the mitral isthmus and (iii) electrogram-based ablation of dispersion zones. The first two steps were performed in all patients, whereas the third step was carried out only in those still in AF at the end of the second step. Atrial tachycardias during the procedure were mapped and ablated. At the end of the procedure, cavotricuspid isthmus ablation was additionally performed in all patients. The primary endpoint was 12-month freedom from AF and atrial tachycardia after a single procedure and an initial three-month blanking period. Results: Total procedure time was 153 ± 38.5 min. Fluoroscopy time was 16 ± 6.5 min and the radiofrequency ablation time was 26.14 ± 0.26 min. The primary endpoint occurred in 54 patients (82%). At 12 months, 65% of patients were off any AAD. In the univariate Cox regression analysis, left ventricular ejection fraction < 40% was the only predictor of arrhythmia recurrence (HR 3.56; 95% CI, 1.04-12.19; p = 0.04). One patient developed a pericardial tamponade and another a minor groin hematoma. Conclusion: A novel stepwise approach, including a step of ethanol infusion in the VOM, is feasible, safe and provides a high rate of sinus rhythm maintenance at 12 months in patients with persistent AF.

Does uranium induce circulatory diseases? First results from a French cohort of uranium workers.

OBJECTIVES: Increased risk of circulatory system diseases (CSDs) was observed in nuclear workers handling uranium and plutonium in Russia and the UK. This work examines the CSD mortality after chronic intake of uranium among 2897 workers (79,892 person-years) at a uranium processing plant (1960-2006) in France. METHODS: Cumulative exposure to different uranium compounds, classified by their isotopic composition and solubility type, was quantified on the basis of a plant-specific job-exposure matrix and individual job histories. HRs and associated 95% CI for CSD (n = 111) and specific CSD categories were estimated using Cox regression models, stratified on sex and birth cohort and adjusted for potential confounders. The effect of smoking was analysed among 260 smokers (42 CSD deaths). RESULTS: Compared to unexposed workers, CSD mortality was increased among workers exposed to slowly soluble reprocessed uranium (RPU) (HR = 2.13, 95% CI = 0.96 to 4.70) and natural uranium (HR = 1.73, 95% CI = 1.11 to 2.69). The risk increased with cumulative exposure and exposure duration. In the subgroup of smokers, the risk estimates were higher but with larger CIs: HR=1.91 (95% CI = 0.92 to 3.98) for natural uranium and HR = 4.78 (95% CI = 1.38 to 16.50) for RPU. CONCLUSIONS: The authors observed that exposure to slowly soluble uranium, namely RPU, may increase the risk of CSD mortality. However, these results are preliminary since the study is lacking statistical power and many other biological and lifestyle-related factors may cause CSD. More detailed investigations are necessary to confirm these findings and analyse in depth the effects of internal radiation exposure on the circulatory system.

Subclinical Left Ventricular Dysfunction Detected by Speckle-Tracking Echocardiography in Breast Cancer Patients Treated With Radiation Therapy: A Six-Month Follow-Up Analysis (MEDIRAD EARLY-HEART study).

Background: In the case of breast cancer (BC), radiotherapy (RT) helps reduce locoregional recurrence and BC-related deaths but can lead to cardiotoxicity, resulting in an increased risk of long-term major cardiovascular events. It is therefore of primary importance to early detect subclinical left ventricular (LV) dysfunction in BC patients after RT and to determine the dose-response relationships between cardiac doses and these events. Methods: Within the frame of the MEDIRAD European project (2017-2022), the prospective multicenter EARLY-HEART study (ClinicalTrials.gov Identifier: NCT03297346) included chemotherapy naïve BC women aged 40-75 years and treated with lumpectomy and adjuvant RT. Myocardial strain analysis was provided using speckle-tracking echocardiography performed at baseline and 6 months following RT. A global longitudinal strain (GLS) reduction >15% between baseline and follow-up was defined as a GLS-based subclinical LV dysfunction. Individual patient dose distributions were obtained using multi-atlas-based auto-segmentation of the heart. Dose-volume parameters were studied for the whole heart (WH) and left ventricle (LV). Results: The sample included 186 BC women (57.5 ± 7.9 years, 64% left-sided BC). GLS-based subclinical LV dysfunction was observed in 22 patients (14.4%). These patients had significantly higher cardiac exposure regarding WH and LV doses compared to patients without LV dysfunction (for mean WH dose: 2.66 ± 1.75 Gy versus 1.64 ± 0.96 Gy, p = 0.01). A significantly increased risk of subclinical LV dysfunction was observed with the increase in the dose received to the WH [ORs from 1.13 (V5) to 1.74 (Dmean); p <0.01] and to the LV [ORs from 1.10 (V5) to 1.46 (Dmean); p <0.01]. Based on ROC analysis, the LV-V5 parameter may be the best predictor of the short-term onset of subclinical LV dysfunction. Conclusion: These results highlighted that all cardiac doses were strongly associated with the occurrence of subclinical LV dysfunction arising 6 months after BC RT. Whether measurements of GLS at baseline and 6 months after RT combined with cardiac doses can early predict efficiently subclinical events occurring 24 months after RT remains to be investigated.

Association Between Cardiac Radiation Exposure and the Risk of Arrhythmia in Breast Cancer Patients Treated With Radiotherapy: A Case-Control Study.

Background: Previous studies suggested that radiation therapy (RT) for breast cancer (BC) can induce cardiac arrhythmias and conduction disorders. However, the association with mean heart dose and specific cardiac substructures doses was less studied. Materials and Methods: We conducted a nested case-control study based on French BC patients, enrolled in the European MEDIRAD-BRACE study (https://clinicaltrials.gov, Identifier: NCT03211442), who underwent three-dimensional conformal radiation therapy (3D-CRT) between 2009 and 2013 and were retrospectively followed until 2019. Cases were incident cases of cardiac arrhythmia. Controls without arrhythmia were selected with propensity-scored matching by age, duration of follow-up, chemotherapy, hypertension, and diabetes (ratio 1:4 or 5). Doses to the whole heart (WH), left and right atria (LA and RA), and left and right ventricles (LV and RV) were obtained after delineation with multi-atlas-based automatic segmentation. Results: The study included 116 patients (21 cases and 95 controls). Mean age at RT was 64 ± 10 years, mean follow-up was 7.0 ± 1.3 years, and mean interval from RT to arrhythmia was 4.3 ± 2.1 years. None of the results on association between arrhythmia and cardiac doses reached statistical significance. However, the proportion of right-sided BC was higher among patients with arrhythmia than among controls (57% vs. 51%, OR = 1.18, p = 0.73). Neither mean WH dose, nor LV, RV, and LA doses were associated with an increased risk of arrhythmia (OR = 1.00, p > 0.90). In contrast, the RA dose was slightly higher for cases compared to controls [interquartile range (0.61-1.46 Gy) vs. (0.49-1.31 Gy), p = 0.44], and a non-significant trend toward a potentially higher risk of arrhythmia with increasing RA dose was observed (OR = 1.19, p = 0.60). Subanalysis according to BC laterality showed that the association with RA dose was reinforced specifically for left-sided BC (OR = 1.76, p = 0.75), while for right-sided BC, the ratio of mean RA/WH doses may better predict arrhythmia (OR = 2.39, p = 0.35). Conclusion: Despite non-significant results, our exploratory investigation on BC patients treated with RT is the first study to suggest that right-sided BC patients and the right atrium irradiation may require special attention regarding the risk of cardiac arrhythmia and conduction disorders. Further studies are needed to expand on this topic.

Early Coronary Artery Calcification Progression over Two Years in Breast Cancer Patients Treated with Radiation Therapy: Association with Cardiac Exposure (BACCARAT Study).

Background: Radiotherapy (RT) for breast cancer (BC) can induce coronary artery disease many years after RT. At an earlier stage, during the first two years after RT, we aimed to evaluate the occurrence of increased coronary artery calcium (CAC) and its association with cardiac exposure. Methods: This prospective study included 101 BC patients treated with RT without chemotherapy. Based on CAC CT scans performed before and two years after RT, the event 'CAC progression' was defined by an increase in overall CAC score (CAC RT+ two years­CAC before RT > 0). Dosimetry was evaluated for whole heart, left ventricle (LV), and coronary arteries. Multivariable logistic regression models were used to assess association with doses. Results: Two years after RT, 28 patients presented the event 'CAC progression', explained in 93% of cases by a higher CAC score in the left anterior descending coronary (LAD). A dose−response relationship was observed with LV exposure (for Dmean LV: OR = 1.15, p = 0.04). LAD exposure marginally explained increased CAC in the LAD (for D2 LV: OR =1.03, p = 0.07). Conclusion: The risk of early CAC progression may be associated with LV exposure. This progression might primarily be a consequence of CAC increase in the LAD and its exposure.

Prevalence of rheumatic heart disease detected by echocardiographic screening.

BACKGROUND: Epidemiologic studies of the prevalence of rheumatic heart disease have used clinical screening with echocardiographic confirmation of suspected cases. We hypothesized that echocardiographic screening of all surveyed children would show a significantly higher prevalence of rheumatic heart disease. METHODS: Randomly selected schoolchildren from 6 through 17 years of age in Cambodia and Mozambique were screened for rheumatic heart disease according to standard clinical and echocardiographic criteria. RESULTS: Clinical examination detected rheumatic heart disease that was confirmed by echocardiography in 8 of 3677 children in Cambodia and 5 of 2170 children in Mozambique; the corresponding prevalence rates and 95% confidence intervals (CIs) were 2.2 cases per 1000 (95% CI, 0.7 to 3.7) for Cambodia and 2.3 cases per 1000 (95% CI, 0.3 to 4.3) for Mozambique. In contrast, echocardiographic screening detected 79 cases of rheumatic heart disease in Cambodia and 66 cases in Mozambique, corresponding to prevalence rates of 21.5 cases per 1000 (95% CI, 16.8 to 26.2) and 30.4 cases per 1000 (95% CI, 23.2 to 37.6), respectively. The mitral valve was involved in the great majority of cases (87.3% in Cambodia and 98.4% in Mozambique). CONCLUSIONS: Systematic screening with echocardiography, as compared with clinical screening, reveals a much higher prevalence of rheumatic heart disease (approximately 10 times as great). Since rheumatic heart disease frequently has devastating clinical consequences and secondary prevention may be effective after accurate identification of early cases, these results have important public health implications.

Safety of deferring the reimplantation of pacing systems after their removal for infectious complications in selected patients: a 1-year follow-up study.

INTRODUCTION: Recent expert consensus guidelines mention that one of the principles for infected device replacement following removal is to "reevaluate carefully if there is a continued need for a new cardiac device replacement." This is a Class I recommendation, which nevertheless suffers from a very low level of evidence (level of evidence C), since no study has revisited the systematic practice of reimplanting the same device based on a meticulous clinical reassessment. In the present paper, we examined the safety of withholding the implantation of pacing systems in selected patients. METHODS AND RESULTS: Between January 2005 and December 2007, 188 consecutive patients underwent extractions of infected pacing systems at 2 medical centers. "Low-risk" patients were identified by (1) a spontaneous heart rate >45 bpm, (2) no symptomatic asystole during monitoring, (3) QRS duration <120 ms when history of AV block was noted, (4) no high-degree AV block during continuous monitoring. They remained device-free, unless an adverse clinical event occurred mandating the reimplantation. The primary study endpoint was rate of sudden death and syncope after a 12-month follow-up. Among the 74 (39.4%) "low-risk" patients, a single patient suffered a bradycardia-related syncopal event corresponding to a 1.3% (95% CI, 0.0-3.9) rate of primary endpoint. Pacing systems were also reimplanted in 24 patients (32.4%) for syncope (n = 1), nonsevere bradycardia-reated symptoms (n = 17), cardiac resynchronization (n = 2), and for reassurance in 4 asymptomatic patients. CONCLUSION: After removal of infected pacing systems, these preliminary data demonstrated that a strategy of nonsystematic device reimplantation associated with close surveillance was safe in "low-risk" patients, allowing the administration of antimicrobials in a device-free state.

Occupational cataracts and lens opacities in interventional cardiology (O'CLOC study): are X-Rays involved? Radiation-induced cataracts and lens opacities.

BACKGROUND: The eye is well known to be sensitive to clearly high doses (>2 Gy) of ionizing radiation. In recent years, however, cataracts have been observed in populations exposed to lower doses. Interventional cardiologists are repeatedly and acutely exposed to scattered ionizing radiation (X-rays) during the diagnostic and therapeutic procedures they perform. These "low" exposures may cause damage to the lens of the eye and induce early cataracts, known as radiation-induced cataracts. The O'CLOC study (Occupational Cataracts and Lens Opacities in interventional Cardiology) was designed to test the hypothesis that interventional cardiologists, compared with an unexposed reference group of non-interventional cardiologists, have an increased risk of cataracts. METHOD/DESIGN: The O'CLOC study is a cross-sectional study that will include a total of 300 cardiologists aged at least 40 years: one group of exposed interventional cardiologists and another of non-interventional cardiologists. The groups will be matched for age and sex. Individual information, including risk factors for cataracts (age, diabetes, myopia, etc.), will be collected during a telephone interview. A specific section of the questionnaire for the exposed group focuses on occupational history, including a description of the procedures (type, frequency, radiation protection tool) used. These data will be used to classify subjects into "exposure level" groups according to cumulative dose estimates. Eye examinations for all participants will be performed to detect cataracts, even in the early stages (lens opacities, according to LOCS III, the international standard classification). The analysis will provide an estimation of the cataract risk in interventional cardiology compared with the unexposed reference group, while taking other risk factors into account. An analysis comparing the risks according to level of exposure is also planned. DISCUSSION: This epidemiological study will provide further evidence about the potential risk of radiation-induced cataracts at low doses and contribute to cardiologists' awareness of the importance of radiation protection. TRIAL REGISTRATION: NCT01061463.

Incidence and prognostic significance of sustained ventricular tachycardias in heart failure patients implanted with biventricular pacemakers without a back-up defibrillator: results from the prospective, multicentre, Mona Lisa cohort study.

AIMS: The aim of this study was to investigate the 12-month incidence, predictive factors, and prognosis of sustained ventricular tachycardia (VT) in chronic heart failure patients implanted with biventricular pacemakers without a back-up defibrillator (CRT-P), assessed by continuous intracardiac ventricular electrograms. METHODS AND RESULTS: The Mona Lisa study, a prospective, multicentre, cohort study, designed to determine the incidence of sustained VT and its prognostic impact in CRT-P recipients within the year after implant enrolled 198 patients with moderate or severe chronic heart failure, despite optimal pharmacological therapy. An independent committee reviewed the data from all arrhythmic episodes as well as causes of death according to predefined criteria. During a mean follow-up of 9.8 +/- 3.1 months after implantation, 8 patients experienced at least one episode of sustained VT [4.3%; 95% confidence interval (CI), 1.1-7.5] and 21 deaths occurred, giving a 12-month mortality rate of 11.7% (95% CI, 6.4-16.9). The presence of sustained VT was associated with a high risk of sudden cardiac death (SCD) and the lowest 12-month overall survival (P < 0.0001). CONCLUSION: The incidence of sustained VT remains relatively low in the first year after CRT-P implantation, but when present appears closely associated with short-term adverse outcomes, especially SCD. This emphasizes the possible value of remote monitoring to detect high-risk patients for urgent upgrading.