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In patients with diabetes, peripheral arterial disease, particularly below the knee, is associated with medial arterial calcification. This is a frequent and potentially serious complication, affecting all types of diabetes. In recent years, our understanding of the pathophysiology and clinical significance of medial arterial calcification has improved considerably. Here, we offer a short narrative review of the epidemiology, clinical consequences, and pathophysiology of this complication. Now that medial arterial calcification of the lower limbs is better understood, we also focus on the prospect of treatments targeting arterial calcification., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:, (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Cardiometabolic disorders contribute to the global burden of cardiovascular diseases. Emerging sphingolipid metabolites like sphingosine-1-phosphate (S1P) and its receptors, S1PRs, present a dynamic signalling axis significantly impacting cardiac homeostasis. S1P's intricate mechanisms extend to its transportation in the bloodstream by two specific carriers: high-density lipoprotein particles and albumin. This intricate transport system ensures the accessibility of S1P to distant target tissues, influencing several physiological processes critical for cardiovascular health. This review delves into the diverse functions of S1P and S1PRs in both physiological and pathophysiological conditions of the heart. Emphasis is placed on their diverse roles in modulating cardiac health, spanning from cardiac contractility, angiogenesis, inflammation, atherosclerosis and myocardial infarction. The intricate interplays involving S1P and its receptors are analysed concerning different cardiac cell types, shedding light on their respective roles in different heart diseases. We also review the therapeutic applications of targeting S1P/S1PRs in cardiac diseases, considering existing drugs like Fingolimod, as well as the prospects and challenges in developing novel therapies that selectively modulate S1PRs., (© 2024 The Author(s). FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Background: Paroxysmal atrial fibrillation (pAF) may progress through cardiac remodeling to persistent atrial fibrillation (psAF). However, some may present in psAF without a preceding history of pAF. A preceding history of pAF may affect recurrence after direct current cardioversion (DCCV)., Objective: The aim of this study was to determine whether a preceding history of pAF is associated with a difference in recurrence rates after DCCV compared with patients without a preceding history of pAF., Methods: A prospective procedural database at a Veterans Affairs center identified 565 patients who underwent their first DCCV for psAF. Initial rhythm history was separated by prior pAF, and those with none were considered primary psAF. Electrocardiography follow-up was standardized at 1 month and 3 months after cardioversion., Results: Patients who underwent their first DCCV for psAF were more likely to have presented with primary psAF (81.6%). Those with pAF had a similar left atrial size but were more likely to have chronic kidney disease, sleep apnea, previous stroke, and use of antiarrhythmic drugs at the time of cardioversion. Patients with pAF had earlier recurrence and shorter median AF survival time, 1.6 months compared with 5 months (Kaplan-Meier plot, P = .0101). This difference persisted in controlling for antiarrhythmic drug use. Recurrence type was mostly persistent AF, similar in both groups., Conclusion: Patients with primary psAF may have a more sustained response to DCCV compared with those with a preceding history of pAF. Thus, those patients with pAF may benefit from a more aggressive, early rhythm control strategy because of higher likelihood of recurrence with DCCV., Competing Interests: Disclosures The authors have no conflicts of interest to disclose., (Published by Elsevier Inc.)

Background: Lead dwell time is the single strongest predictor of failure and complications in transvenous lead extraction., Objectives: To report the success rate and complications of transvenous lead extractions with implant dwell time of at least 15 years., Methods: Procedural and patient data were prospectively collected into a database. The excimer laser was the primary method for lead extraction with the use of mechanical rotational sheaths and femoral snares at operator discretion., Results: A total of 442 patients between 2011 and 2020 underwent lead extraction (705 leads) primarily for infection or device failure at our high-volume center. Forty-one patients with 71 leads > 15 years old were included in this cohort. Mean patient age was 53.5 ± 18.5 years, 67.5% were male. Mean lead dwell time was 19.6 ± 4.4 years. Thirty-six of 41 (88%) patients had successful extraction of all leads compared to 96% in the remaining 401 patients, p value.004. Of the five patients without fully successful extractions two of these patients had abandoned leads (three total) that were clinically significant. There were two (4.9%) major complications in the very old lead group and six (1.5%) in the other group. In the very old lead group, one patient experienced right atrial appendage perforation requiring surgical repair and recovered well. One patient experienced new complete heart block requiring 2 min of CPR but did well thereafter. There was no procedure-related mortality., Conclusions: Despite challenges posed by older leads, very old leads can be safely and effectively extracted with low complication rates., (© 2024 Wiley Periodicals LLC.)

Background: Safe and effective management of venous vascular access is a key component of electrophysiology (EP) procedures. Recently, the Z-stitch method has been developed for effective venous hemostasis. However, the standard postprocedure protocol often includes prolonged bed rest, which may affect patient satisfaction. The ZEBRA (Z stitch Early Bed Rest Assessment) study aims to systematically investigate and quantify patient satisfaction metrics and safety parameters associated with the early mobilization after Z-stitch placement., Objective: This study primarily investigates whether early mobilization following Z-stitch placement in venous vascular access management during EP procedures enhances patient satisfaction without compromising safety., Methods: In this prospective, multicenter, randomized clinical trial, approximately 200 patients undergoing various EP procedures at Oregon Health and Science University and Veterans Affairs Portland Health Care System will be randomly assigned to either a 1- or 4-hour bed rest regimen post-Z stitch. Patient satisfaction will be assessed through survey, alongside monitoring for hematomas, bleeding complications, and other safety endpoints. The study includes stratification based on heparin administration and sheath size to ensure robust and nuanced data analysis., Results: We anticipate that early mobilization will lead to higher patient satisfaction scores. We also expect to closely monitor and report the incidence of hematomas, pain medication use, healthcare costs, patient outcomes at 30 days, time to ambulation, and hospital readmissions or emergency visits related to groin complications., Conclusion: The ZEBRA study is poised to fill a critical knowledge gap in postprocedure care in EP labs. By rigorously evaluating the impact of early mobilization on patient satisfaction and safety, this study could significantly influence future guidelines and improve patient experiences in EP procedures., (© 2024 Heart Rhythm Society. Published by Elsevier Inc.)

Background: Studies have demonstrated that coronary artery calcification on one hand and non-alcoholic fatty liver disease (NAFLD) on the other hand are strongly associated with cardiovascular events. However, it remains unclear whether NAFLD biomarkers could help estimate cardiovascular risk in individuals with type 2 diabetes (T2D). The primary objective of the present study was to investigate whether the biomarkers of NAFLD included in the FibroMax® panels are associated with the degree of coronary artery calcification in patients with T2D., Methods: A total of 157 and 460 patients with T2D were included from the DIACART and ACCoDiab cohorts, respectively. The coronary artery calcium score (CACS) was measured in both cohorts using computed tomography. FibroMax® panels (i.e., SteatoTest®, FibroTest®, NashTest®, and ActiTest®) were determined from blood samples as scores and stages in the DIACART cohort and as stages in the ACCoDiab cohort., Results: CACS significantly increased with the FibroTest® stages in both the DIACART and ACCoDiab cohorts (p-value for trend = 0.0009 and 0.0001, respectively). In DIACART, the FibroTest® score was positively correlated with CACS in univariate analysis (r = 0.293, p = 0.0002) and remained associated with CACS independently of the traditional cardiovascular risk factors included in the SCORE2-Diabetes model [β = 941 ± 425 (estimate ± standard error), p = 0.028]. In the ACCoDiab cohort, the FibroTest® F3-F4 stage was positively correlated with CACS in point-biserial analysis (r pbi  = 0.104, p = 0.024) and remained associated with CACS after adjustment for the traditional cardiovascular risk factors included in the SCORE2-Diabetes model (β = 234 ± 97, p = 0.016). Finally, the prediction of CACS was improved by adding FibroTest® to the traditional cardiovascular risk factors included in the SCORE2-Diabetes model (goodness-of-fit of prediction models multiplied by 4.1 and 6.7 in the DIACART and ACCoDiab cohorts, respectively). In contrast, no significant relationship was found between FibroMax® panels other than FibroTest® and CACS in either cohort., Conclusions: FibroTest® is independently and positively associated with the degree of coronary artery calcification in patients with T2D, suggesting that FibroTest® could be a relevant biomarker of coronary calcification and cardiovascular risk., Trial Registration: ClinicalTrials.gov identifiers NCT02431234 and NCT03920683., (© 2024. The Author(s).)

Background: The impact of lead fixation mechanism on extractability is poorly characterized., Objective: We aimed to compare the technical difficulty of transvenous lead extraction (TLE) of active vs passive fixation right ventricular (RV) leads., Methods: A total of 408 patients who underwent RV TLE by a single expert electrophysiologist at Oregon Health & Science University between October 2011 and June 2022 were identified and retrospectively analyzed; 331 (81%) had active fixation RV leads and 77 (19%) had passive fixation RV leads. The active fixation cohort was further stratified into those with successfully retracted helices (n = 181) and failed helix retraction (n = 109). A numerical system (0-9) devised using 6 procedural criteria quantified a technical extraction score (TES) for each RV TLE. The TES was compared between groups., Results: Helix retraction was successful in ≥55% of active fixation TLEs. The mean TES for active-helix retracted, active-helix non-retracted, and passive fixation groups was 1.8, 3.5, and 3.7, respectively. The TES of the active-helix retracted group was significantly lower than those of the active-helix non-retracted group (adjusted P < .01) and the passive fixation group (adjusted P < .01). There was no significant difference in TES between the passive fixation and active-helix non-retracted groups in multivariate analysis ( P = .18). The TLE success rate of the entire cohort was >97%, with a major complication rate of 0.5%., Conclusion: TLE of active fixation leads where helical retraction is achieved presents fewer technical challenges than does passive fixation RV lead extraction; however, if the helix cannot be retracted, active and passive TLE procedures present similar technical challenges., (© 2023 Heart Rhythm Society. Published by Elsevier Inc.)

Background: Patients with type 2-diabetes mellitus (T2D), are characterized by visceral and ectopic adipose tissue expansion, leading to systemic chronic low-grade inflammation. As visceral adiposity is associated with severe COVID-19 irrespective of obesity, we aimed to evaluate and compare the predictive value for early intensive care or death of three fat depots (cardiac, visceral and subcutaneous) using computed tomography (CT) at admission for COVID-19 in consecutive patients with and without T2D., Methods: Two hundred and two patients admitted for COVID-19 were retrospectively included between February and June 2020 and distributed in two groups: T2D or non-diabetic controls. Chest CT with cardiac (CATi), visceral (VATi) and subcutaneous adipose tissue (SATi) volume measurements were performed at admission. The primary endpoint was a composite outcome criteria including death or ICU admission at day 21 after admission. Threshold values of adipose tissue components predicting adverse outcome were determined., Results: One hundred and eight controls [median age: 76(IQR:59-83), 61% male, median BMI: 24(22-27)] and ninety-four T2D patients [median age: 70(IQR:61-77), 70% male, median BMI: 27(24-31)], were enrolled in this study. At day 21 after admission, 42 patients (21%) had died from COVID-19, 48 (24%) required intensive care and 112 (55%) were admitted to a conventional care unit (CMU). In T2D, CATi was associated with early death or ICU independently from age, sex, BMI, dyslipidemia, CRP and coronary calcium (CAC). (p = 0.005). Concerning T2D patients, the cut-point for CATi was  > 100 mL/m 2 with a sensitivity of 0.83 and a specificity of 0.50 (AUC = 0.67, p = 0.004) and an OR of 4.71 for early ICU admission or mortality (p = 0.002) in the fully adjusted model. Other adipose tissues SATi or VATi were not significantly associated with early adverse outcomes. In control patients, age and male sex (OR = 1.03, p = 0.04) were the only predictors of ICU or death., Conclusions: Cardiac adipose tissue volume measured in CT at admission was independently predictive of early intensive care or death in T2D patients with COVID-19 but not in non-diabetics. Such automated CT measurement could be used in routine in diabetic patients presenting with moderate to severe COVID-19 illness to optimize individual management and prevent critical evolution., (© 2022. The Author(s).)

Sterol Regulatory Element Binding Protein-1c is a transcription factor that controls the synthesis of lipids from glucose in the liver, a process which is of utmost importance for the storage of energy. Discovered in the early nineties by B. Spiegelman and by M. Brown and J. Goldstein, it has generated more than 5000 studies in order to elucidate its mechanism of activation and its role in physiology and pathology. Synthetized as a precursor found in the membranes of the endoplasmic reticulum, it has to be exported to the Golgi and cleaved by a mechanism called regulated intramembrane proteolysis. We reviewed in 2002 its main characteristics, its activation process and its role in the regulation of hepatic glycolytic and lipogenic genes. We particularly emphasized that Sterol Regulatory Element Binding Protein-1c is the mediator of insulin effects on these genes. In the present review, we would like to update these informations and focus on the response to insulin and to another actor in Sterol Regulatory Element Binding Protein-1c activation, the endoplasmic reticulum stress., (© 2021 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Diabetes, whether due to pancreatic beta cells insufficiency or peripheral resistance to insulin, has been suggested as a risk factor of developing severe acute respiratory disease coronavirus-2 (SARS-CoV-2) infections. Indeed, diabetes has been associated with a higher risk of infections and higher risk of developing severe forms of coronavirus disease 2019 (COVID-19) related pneumonia. Diabetic patients often present associated comorbidities such as obesity, hypertension and cardiovascular diseases, and complications of diabetes, including chronic kidney disease, vasculopathy and relative immune dysfunction, all of which make them more susceptible to infectious complications. Moreover, they often present low-grade inflammation with increased circulating interleukin levels, endothelial susceptibility to inflammation and dysfunction, and finally, hyperglycemia, which increases this risk. Additionally, corticosteroids, which count among the few medications which showed benefit on survival and mechanical ventilation requirement in COVID-19 pneumonia in large randomized controlled trials, are associated to new onsets of diabetes, and metabolic disorders in patients with previous history of diabetes. Finally, SARS-CoV-2 via the alternate effects of the renin-angiotensin system, mediated by the angiotensin-converting-enzyme 2, was also associated with insulin resistance in key tissues involved in glucose homeostasis, such as liver, skeletal muscles, and adipose tissue; and also, with impaired insulin secretion by pancreatic β-cells. In this work, we reviewed all elements which may help understand how diabetes affects patients with COVID-19, how treatments affect outcomes in patients with COVID-19, how they may cause new onsets of diabetes, and finally review how SARS-CoV-2 may inherently be a risk factor of developing diabetes, through immune-mediated diabetogenic mechanisms., Competing Interests: Conflict-of-interest statement: All other authors have nothing to disclose., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: COVID-19 diabetic adults are at increased risk of severe forms irrespective of obesity. In patients with type-II diabetes, fat distribution is characterized by visceral and ectopic adipose tissues expansion, resulting in systemic inflammation, which may play a role in driving the COVID-19 cytokine storm. Our aim was to determine if cardiac adipose tissue, combined to interleukin-6 levels, could predict adverse short-term outcomes, death and ICU requirement, in COVID-19 diabetic patients during the 21 days after admission., Methods: Eighty one consecutive patients with type-II diabetes admitted for COVID-19 were included. Interleukin-6 measurement and chest computed tomography with total cardiac adipose tissue index (CATi) measurement were performed at admission. The primary outcome was death during the 21 days following admission while intensive care requirement with or without early death (ICU-R) defined the secondary endpoint. Associations of CATi and IL-6 and threshold values to predict the primary and secondary endpoints were determined., Results: Of the enrolled patients (median age 66 years [IQR: 59-74]), 73% male, median body mass index (BMI) 27 kg/m 2 [IQR: 24-31]) 20 patients had died from COVID-19, 20 required intensive care and 41 were in conventional care at day 21 after admission. Increased CATi and IL-6 levels were both significantly related to increased early mortality (respectively OR = 6.15, p = 0.002; OR = 18.2, p < 0.0001) and ICU-R (respectively OR = 3.27, p = 0.01; OR = 4.86, p = 0.002). These associations remained significant independently of age, sex, BMI as well as troponin-T level and pulmonary lesion extension in CT. We combined CATi and IL-6 levels as a multiplicative interaction score (CATi*IL-6). The cut-point for this score was ≥ 6386 with a sensitivity of 0.90 and a specificity of 0.87 (AUC = 0.88) and an OR of 59.6 for early mortality (p < 0.0001)., Conclusions: Cardiac adipose tissue index and IL-6 determination at admission could help physicians to better identify diabetic patients with a potentially severe and lethal short term course irrespective of obesity. Diabetic patients with high CATi at admission, a fortiori associated with high IL-6 levels could be a relevant target population to promptly initiate anti-inflammatory therapies., (© 2021. The Author(s).)

Epoxide hydrolases (EHs) regulate cellular homeostasis through hydrolysis of epoxides to less-reactive diols. The first discovered EH was EPHX1, also known as mEH. EH functions remain partly unknown, and no pathogenic variants have been reported in humans. We identified two de novo variants located in EPHX1 catalytic site in patients with a lipoatrophic diabetes characterized by loss of adipose tissue, insulin resistance, and multiple organ dysfunction. Functional analyses revealed that these variants led to the protein aggregation within the endoplasmic reticulum and to a loss of its hydrolysis activity. CRISPR-Cas9-mediated EPHX1 knockout (KO) abolished adipocyte differentiation and decreased insulin response. This KO also promoted oxidative stress and cellular senescence, an observation confirmed in patient-derived fibroblasts. Metreleptin therapy had a beneficial effect in one patient. This translational study highlights the importance of epoxide regulation for adipocyte function and provides new insights into the physiological roles of EHs in humans., Competing Interests: JG, CM, WC, JZ, MA, GB, EC, CM, YW, JY, BH, BC, FP, BF, CV, FA, IJ No competing interests declared, (© 2021, Gautheron et al.)

Plasma dihydroceramides are predictors of type 2 diabetes and related to metabolic dysfunctions, but the underlying mechanisms are not characterized. We compare the relationships between plasma dihydroceramides and biochemical and hepatic parameters in two cohorts of diabetic patients. Hepatic steatosis, steatohepatitis, and fibrosis are assessed by their plasma biomarkers. Plasma lipoprotein sphingolipids are studied in a sub-group of diabetic patients. Liver biopsies from subjects with suspected non-alcoholic fatty liver disease are analyzed for sphingolipid synthesis enzyme expression. Dihydroceramides, contained in triglyceride-rich very-low-density lipoprotein (VLDL), are associated with steatosis and steatohepatitis. Expression of sphingolipid synthesis enzymes is correlated with histological steatosis and inflammation grades. In conclusion, association of plasma dihydroceramides with nonalcoholic fatty liver might explain their predictive character for type 2 diabetes. Our results suggest a relationship between hepatic sphingolipid metabolism and steatohepatitis and an involvement of dihydroceramides in the synthesis/secretion of triglyceride-rich VLDL, a hallmark of NAFLD and type 2 diabetes dyslipidemia., Competing Interests: The authors declare no competing interests., (© 2020 The Author(s).)

Background: Lower limb arterial calcification is a frequent, underestimated but serious complication of diabetes. The DIACART study is a prospective cohort study designed to evaluate the determinants of the progression of lower limb arterial calcification in 198 patients with type 2 diabetes., Methods: Lower limb arterial calcification scores were determined by computed tomography at baseline and after a mean follow up of 31.20 ± 3.86 months. Serum RANKL (Receptor Activator of Nuclear factor kB Ligand) and bone remodeling, inflammatory and metabolic parameters were measured at baseline. The predictive effect of these markers on calcification progression was analyzed by a multivariate linear regression model., Results: At baseline, mean ± SD and median lower limb arterial calcification scores were, 2364 ± 5613 and 527 respectively and at the end of the study, 3739 ± 6886 and 1355 respectively. Using multivariate analysis, the progression of lower limb arterial log calcification score was found to be associated with (β coefficient [slope], 95% CI, p-value) baseline log(calcification score) (1.02, 1.00-1.04, p < 0.001), triglycerides (0.11, 0.03-0.20, p = 0.007), log(RANKL) (0.07, 0.02-0.11, p = 0.016), previous ischemic cardiomyopathy (0.36, 0.15-0.57, p = 0.001), statin use (0.39, 0.06-0.72, p = 0.023) and duration of follow up (0.04, 0.01-0.06, p = 0.004)., Conclusion: In patients with type 2 diabetes, lower limb arterial calcification is frequent and can progress rapidly. Circulating RANKL and triglycerides are independently associated with this progression. These results open new therapeutic perspectives in peripheral diabetic calcifying arteriopathy. Trial registration NCT02431234.

Background—: Sex is a well-recognized risk factor for sudden cardiac death (SCD). We hypothesized that sex modifies the association of electrophysiological (EP) substrate with SCD., Methods—: Participants from the Atherosclerosis Risk in Communities study with analyzable ECGs (n=14,725; age, 54.2±5.8 yrs; 55% female, 74% white) were included. EP substrate was characterized by heart rate, QRS, QTc, Cornell voltage, spatial ventricular gradient (SVG), and sum absolute QRST integral (SAI QRST) ECG metrics. Two competing outcomes were adjudicated SCD and nonSCD. Interaction of ECG metrics with sex was studied in Cox proportional hazards and Fine-Gray competing risk models. Model 1 was adjusted for prevalent cardiovascular disease (CVD) and risk factors. Time-updated model 2 was additionally adjusted for incident non-fatal CVD. Relative hazard ratio (RHR) and relative sub-hazard ratio (RSHR) with a 95% confidence interval for SCD and nonSCD risk for women relative to men was calculated. Model 1 was adjusted for prevalent CVD and risk factors. Time-updated model 2 was additionally adjusted for incident non-fatal CVD., Results—: Over a median follow-up of 24.4 years, there were 530 SCDs (incidence 1.72 (1.58-1.88)/1000 person-years). Women as compared to men experienced a greater risk of SCD associated with Cornell voltage (RHR 1.18(1.06-1.32); P=0.003), SAI QRST (RHR 1.16(1.04-1.30); P=0.007), and SVG magnitude (RHR 1.24(1.05-1.45); P=0.009), independently from incident CVD., Conclusion—: In women, the global EP substrate is associated with up to 24% greater risk of SCD than in men, suggesting differences in underlying mechanisms and the need for sex-specific SCD risk stratification., Competing Interests: Conflict of interest: None.

Background: The objective was to determine whether high-flow nasal cannula (HFNC), a promising respiratory support in infant bronchiolitis, could reduce the proportion of treatment failure requiring escalation of care., Methods: In this randomised controlled trial, we assigned infants aged <6 months who had moderate bronchiolitis to receive either HFNC at 3 L·kg -1 ·min -1 or standard oxygen therapy. Crossover was not allowed. The primary outcome was the proportion of patients in treatment failure requiring escalation of care (mostly noninvasive ventilation) within 7 days following randomisation. Secondary outcomes included rates of transfer to the paediatric intensive care unit (PICU), oxygen, number of artificial nutritional support-free days and adverse events., Results: The analyses included 268 patients among the 2621 infants assessed for inclusion during two consecutive seasons in 17 French paediatric emergency departments. The percentage of infants in treatment failure was 14% (19 out of 133) in the study group, compared to 20% (27 out of 135) in the control group (OR 0.66, 95% CI 0.35-1.26; p=0.21). HFNC did not reduce the risk of admission to PICU (21 (15%) out of 133 in the study group versus 26 (19%) out of 135 in the control group) (OR 0.78, 95% CI 0.41-1.41; p=0.45). The main reason for treatment failure was the worsening of modified Wood clinical asthma score (m-WCAS). Short-term assessment of respiratory status showed a significant difference for m-WCAS and respiratory rate in favour of HFNC. Three pneumothoraces were reported in the study group., Conclusions: In patients with moderate bronchiolitis, there was no evidence of lower rate of escalating respiratory support among those receiving HFNC therapy., Competing Interests: Conflict of interest: P. Durand has nothing to disclose. Conflict of interest: T. Guiddir has nothing to disclose. Conflict of interest: C. Kyheng has nothing to disclose. Conflict of interest: F. Blanc has nothing to disclose. Conflict of interest: O. Vignaud has nothing to disclose. Conflict of interest: R. Epaud has nothing to disclose. Conflict of interest: F. Dugelay has nothing to disclose. Conflict of interest: I. Breant has nothing to disclose. Conflict of interest: I. Badier has nothing to disclose. Conflict of interest: V. Degas-Bussière has nothing to disclose. Conflict of interest: F. Phan has nothing to disclose. Conflict of interest: V. Soussan-Banini has nothing to disclose. Conflict of interest: A. Lehnert has nothing to disclose. Conflict of interest: C. Mbamba has nothing to disclose. Conflict of interest: C. Barrey has nothing to disclose. Conflict of interest: C. Tahiri has nothing to disclose. Conflict of interest: M. Decobert has nothing to disclose. Conflict of interest: M. Saunier-Pernaudet has nothing to disclose. Conflict of interest: I. Craiu has nothing to disclose. Conflict of interest: M. Taveira has nothing to disclose. Conflict of interest: V. Gajdos has nothing to disclose., (Copyright ©ERS 2020.)

Objective: Aggressive antidiabetic therapy and rapid glycemic control are associated with diabetic neuropathy. Here we investigated if this is also the case for Charcot neuroarthropathy., Research Design and Methods: HbA1c levels and other relevant data were extracted from medical databases of 44 cases of acute Charcot neuroarthropathy., Results: HbA1c levels significantly declined from 8.25% (67mmol/mol) [7.1%-9.4%](54-79mmol/mol), at -6 months (M-6), to 7.40%(54mmol/mol) [6.70%-8.03%] (50-64 mmol/mol) during the six months preceding the diagnosis of Charcot neuroarthropathy (P <0.001)., Conclusions: HbA1c levels significantly declined during the six months preceding the onset of Charcot neuroarthropathy. This decline seems to be a associated factor with the appearance of an active phase of Charcot neuroarthropathy in poorly controlled patients with diabetic sensitive neuropathy., Competing Interests: The authors have declared that no competing interests exist.

[This corrects the article DOI: 10.1371/journal.pone.0229145.].

Background: Mechanisms of arrhythmogenicity in hypertrophic cardiomyopathy (HCM) are not well understood., Objective: To characterize an electrophysiological substrate of HCM in comparison to ischemic cardiomyopathy (ICM), or healthy individuals., Methods: We conducted a prospective case-control study. The study enrolled HCM patients at high risk for ventricular tachyarrhythmia (VT) [ n = 10; age 61 ± 9 years; left ventricular ejection fraction (LVEF) 60 ± 9%], and three comparison groups: healthy individuals ( n = 10; age 28 ± 6 years; LVEF > 70%), ICM patients with LV hypertrophy (LVH) and known VT ( n = 10; age 64 ± 9 years; LVEF 31 ± 15%), and ICM patients with LVH and no known VT ( n = 10; age 70 ± 7 years; LVEF 46 ± 16%). All participants underwent 12-lead ECG, cardiac CT or MRI, and 128-electrode body surface mapping (BioSemi ActiveTwo, Netherlands). Non-invasive voltage and activation maps were reconstructed using the open-source SCIRun (University of Utah) inverse problem-solving environment., Results: In the epicardial basal anterior segment, HCM patients had the greatest ventricular activation dispersion [16.4 ± 5.5 vs. 13.1 ± 2.7 (ICM with VT) vs. 13.8 ± 4.3 (ICM no VT) vs. 8.1 ± 2.4 ms (Healthy); P = 0.0007], the largest unipolar voltage [1094 ± 211 vs. 934 ± 189 (ICM with VT) vs. 898 ± 358 (ICM no VT) vs. 842 ± 90 μV (Healthy); P = 0.023], and the greatest voltage dispersion [median (interquartile range) 215 (161-281) vs. 189 (143-208) (ICM with VT) vs. 158 (109-236) (ICM no VT) vs. 110 (106-168) μV (Healthy); P = 0.041]. Differences were also observed in other endo-and epicardial basal and apical segments., Conclusion: HCM is characterized by a greater activation dispersion in basal segments, a larger voltage, and a larger voltage dispersion through LV., Clinical Trial Registration: www.clinicaltrials.gov Unique identifier: NCT02806479., (Copyright © 2020 Perez-Alday, Haq, German, Hamilton, Johnson, Phan, Rogovoy, Yang, Wirth, Thomas, Dalouk, Fuss, Ferencik, Heitner and Tereshchenko.)

Aims/hypothesis: Diabetic peripheral neuropathy is a frequent and severe complication of diabetes. As Matrix-gla-protein (MGP) is expressed in several components of the nervous system and is involved in some neurological disease, MGP could play a role in peripheral nervous system homeostasis. The aim of this study was to evaluate factors associated with sensitive diabetic neuropathy in Type 2 Diabetes, and, in particular, dephospho-uncarboxylated MGP (dp-ucMGP), the inactive form of MGP., Methods: 198 patients with Type 2 Diabetes were included. Presence of sensitive diabetic neuropathy was defined by a neuropathy disability score (NDS) ≥6. Plasma levels of dp-ucMGP were measured by ELISA., Results: In this cohort, the mean age was 64+/-8.4 years old, and 80% of patients were men. Peripheral neuropathy was present in 15.7% of the patients and was significantly associated (r = 0.51, p<0.0001) with dp-ucMGP levels (β = -0.26, p = 0.045) after integrating effects of height (β = -0.38, p = 0.01), insulin treatment (β = 0.42, p = 0.002), retinopathy treated by laser (β = 0.26, p = 0.02), and total cholesterol levels (β = 0.3, p = 0.03) by multivariable analysis., Conclusions: The association between diabetic neuropathy and the inactive form of MGP suggests the existence of new pathophysiological pathways to explore. Further studies are needed to determine if dp-ucMGP may be used as a biomarker of sensitive neuropathy. Since dp-ucMGP is a marker of poor vitamin K status, clinical studies are warranted to explore the potential protective effect of high vitamin K intake on diabetic peripheral neuropathy., Competing Interests: A patent has been filed on a method using circulating Matrix Gla protein measurement for diagnosis and treating peripheral neuropathies by Assistance Publique Hôpitaux de Paris - APHP). Olivier Bourron, Joe-Elie Salem and Agnès Hartemann are the inventors. The application number is 18306503.6 – 1118. Status of application: recorded. The patent specific aspect of manuscript covered in patent application: use of circulating Matrix Gla protein measurement for diagnosis and treating peripheral neuropathies. This study was supported by a fund from Lilly Company. The company was involved neither in the design of the study nor in data collection. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background Race is an established risk factor for sudden cardiac death (SCD). We sought to determine whether the association of electrophysiological substrate with SCD varies between black and white individuals. Methods and Results Participants from the ARIC (Atherosclerosis Risk in Communities) study with analyzable ECGs (n=14 408; age, 54±6 years; 74% white) were included. Electrophysiological substrate was characterized by ECG metrics. Two competing outcomes were adjudicated: SCD and non-SCD. Interaction of ECG metrics with race was studied in Cox proportional hazards and Fine-Gray competing risk models, adjusted for prevalent cardiovascular disease, risk factors, and incident nonfatal cardiovascular disease. At the baseline visit, adjusted for age, sex, and study center, blacks had larger spatial ventricular gradient magnitude (0.30 mV; 95% CI, 0.25-0.34 mV), sum absolute QRST integral (18.4 mV*ms; 95% CI, 13.7-23.0 mV*ms), and Cornell voltage (0.30 mV; 95% CI, 0.25-0.35 mV) than whites. Over a median follow-up of 24.4 years, SCD incidence was higher in blacks (2.86 per 1000 person-years; 95% CI, 2.50-3.28 per 1000 person-years) than whites (1.37 per 1000 person-years; 95% CI, 1.22-1.53 per 1000 person-years). Blacks with hypertension had the highest rate of SCD: 4.26 (95% CI, 3.66-4.96) per 1000 person-years. Race did not modify an association of ECG variables with SCD, except QRS-T angle. Spatial QRS-T angle was associated with SCD in whites (hazard ratio, 1.38; 95% CI, 1.25-1.53) and hypertension-free blacks (hazard ratio, 1.52; 95% CI, 1.09-2.12), but not in blacks with hypertension (hazard ratio, 1.15; 95% CI, 0.99-1.32) ( P -interaction=0.004). Conclusions Race did not modify associations of electrophysiological substrate with SCD and non-SCD. Electrophysiological substrate does not explain racial disparities in SCD rate.

Objective: To report a case of neuroarthropathy in the tarsus and knee following rapid glycaemic normalisation in a female patient with type I diabetes., Methods: A retrospective review of case notes., Results: We describe the case of a female patient with type I diabetes who had developed a multifocal neuroarthropathy in only six months, probably due to a rapid glycaemic normalisation. The onset of this neuroarthropathy was not only fast but mostly multifocal affecting two levels of joints., Conclusion: The link between the onset of multifocal neuroarthropathy and the rapid correction of chronic hyperglycaemia is probably proven in our case. Patients with chronic hyperglycaemia with sensitive neuropathy should benefit from a gradual correction of their glycaemic imbalance in order to avoid the apparition of neuroarthropathy., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Medial calcification in diabetes contributes to the arterial occlusive process occurring below the knee level. Adiponectin is an adipokine with atheroprotective properties and possible protective role against arterial calcification. The aim of the study was to investigate, in type 2 diabetes, the link between vascular expression and serum concentration of adiponectin and (1) peripheral arterial calcification and (2) lower limb occlusive arterial disease., Methods: Scoring of peripheral vascular calcification and peripheral arterial occlusive disease, using CT-scan and color-duplex ultrasonography respectively, were conducted and explored in relation to serum adiponectin level in a cross sectional study of 197 patients with type 2 diabetes. Vascular adiponectin expression in the arterial wall of diabetic patients with and without medial calcification was evaluated by immunohistochemistry., Results: Peripheral arterial calcification score was higher in patients with the highest adiponectin concentration. In a multivariate logistic regression analysis, an increase of 1 µg/mL of adiponectin was associated with a 22% increase of arterial calcification (adjusted OR = 1.22; 95% CI 1.03-1.44; p = 0.02). Arterial occlusive score was also higher in patients with adiponectin concentration > median (2.8 ± 4.8 vs 4.2 ± 5.7, p = 0.034). Immunohistochemical analyses showed a strong and specific staining of adiponectin in smooth muscle cells in calcified arteries, with a more pronounced expression of adiponectin in early stages of medial calcification., Conclusions: Peripheral arterial calcification is positively associated with circulating adiponectin levels in patients with type 2 diabetes, but vascular adiponectin expression is already observed at early stages of calcification. Adiponectin secretion could be a compensatory mechanism against the calcification process. Trial registration DIACART NCT number: NCT02431234. Registered 30 April 2015., Competing Interests: A patent has been filed on a method using circulating Matrix Gla protein measurement for diagnosis and treating peripheral neuropathies by Assistance Publique Hôpitaux de Paris—APHP). Olivier Bourron, Joe-Elie Salem and Agnès Hartemann are the inventors. The application number is 18306503.6–1118. The other authors declare that they have no competing interests.