The real incidence of sudden death: Fair estimations or futile speculations?

BACKGROUND: The true incidence of sudden death remains undetermined, with controversial results from various publications over time and countries. AIM: To investigate if different estimations would reach the values usually reported for France. METHODS: Three different kinds of estimations were used. First, the number of resuscitated sudden deaths and necropsies for sudden death in the Haute-Garonne French administrative department (i.e. county) over the last 10years was expanded to the national level. Second, sudden death coding of death certificates was collected at the national level. Third, the total number of out-of-hospital cardiac arrests leading to any emergency call (with/without intervention) in Haute-Garonne over the last 10years was expanded to the national level. RESULTS: There was a mean of 26 resuscitated sudden deaths and 145 necropsies for sudden death each year in Haute-Garonne, i.e. 12 to 14 sudden deaths for 100,000 inhabitants, and 7700 to 9400 sudden deaths yearly when related to the whole French population, according to the year of inclusion. Based on death certificates, a mean of 6584 sudden deaths was registered each year in France. Finally, there were about 600 yearly calls/interventions for out-of-hospital cardiac arrests in Haute-Garonne, i.e. 40 to 50 sudden deaths for 100,000 inhabitants, and 16,000 to 27,000 sudden deaths yearly for the whole French territory, according to the year of inclusion. CONCLUSIONS: The incidence of sudden death ranges from 6500 to 27,000 in France according to the calculation methods. This huge difference raises the question of the true current incidence of sudden death, which may have been overestimated previously or may be underestimated in France. More straight prospective surveys are needed to solve this question, because of relevant implications for priorities that should be given to sudden death.

Lack of temporal correlations between COVID pandemic waves and the occurrence of malignant ventricular arrhythmias.

AIMS: Correlations between malignant ventricular arrhythmias and the COVID waves have never been investigated. METHODS AND RESULTS: Prevalence of malignant ventricular arrhythmias/sudden cardiac death has been correlated to the four COVID waves between the onset of pandemic and end 2021. No significant correlation was present in the temporal evolution of both COVID patients/positive tests and incidence of malignant ventricular arrhythmias, which tended to decrease after vaccination onset. CONCLUSION: We present evidence of complex higher-order periodicities and the co-existence of such regions with stable non-chaotic areas in ex vivo human hearts. We infer that the oscillation of the calcium cycling machinery is the primary mechanism of higher-order dynamics. These higher-order regions may act as niduses of instability and may provide targets for substrate-based ablation of VF.

Immunohistologic Features of Cerebral Venous Thrombosis Due to Vaccine-Induced Immune Thrombotic Thrombocytopenia.

OBJECTIVES: Vaccine-induced immune thrombotic thrombocytopenia (VITT), a recently described entity characterized by thrombosis at unusual locations such as cerebral venous sinus and splanchnic vein, has been rarely described after adenoviral-encoded COVID-19 vaccines. In this study, we report the immunohistological correlates in 3 fatal cases of cerebral venous thrombosis related to VITT analyzed at an academic medical center. METHODS: Detailed neuropathologic studies were performed in 3 cases of cerebral venous thrombosis related to VITT after adenoviral COVID-19 vaccination. RESULTS: Autopsy revealed extensive cerebral vein thrombosis in all 3 cases. Polarized thrombi were observed with a high density of neutrophils in the core and a low density in the tail. Endothelial cells adjacent to the thrombus were largely destroyed. Markers of neutrophil extracellular trap and complement activation were present at the border and within the cerebral vein thrombi. SARS-CoV-2 spike protein was detected within the thrombus and in the adjacent vessel wall. DISCUSSION: Data indicate that neutrophils and complement activation associated with antispike immunity triggered by the vaccine is probably involved in the disease process.

Ephrin-B1 regulates the adult diastolic function through a late postnatal maturation of cardiomyocyte surface crests.

The rod-shaped adult cardiomyocyte (CM) harbors a unique architecture of its lateral surface with periodic crests, relying on the presence of subsarcolemmal mitochondria (SSM) with unknown role. Here, we investigated the development and functional role of CM crests during the postnatal period. We found in rodents that CM crest maturation occurs late between postnatal day 20 (P20) and P60 through both SSM biogenesis, swelling and crest-crest lateral interactions between adjacent CM, promoting tissue compaction. At the functional level, we showed that the P20-P60 period is dedicated to the improvement of relaxation. Interestingly, crest maturation specifically contributes to an atypical CM hypertrophy of its short axis, without myofibril addition, but relying on CM lateral stretching. Mechanistically, using constitutive and conditional CM-specific knock-out mice, we identified ephrin-B1, a lateral membrane stabilizer, as a molecular determinant of P20-P60 crest maturation, governing both the CM lateral stretch and the diastolic function, thus highly suggesting a link between crest maturity and diastole. Remarkably, while young adult CM-specific Efnb1 KO mice essentially exhibit an impairment of the ventricular diastole with preserved ejection fraction and exercise intolerance, they progressively switch toward systolic heart failure with 100% KO mice dying after 13 months, indicative of a critical role of CM-ephrin-B1 in the adult heart function. This study highlights the molecular determinants and the biological implication of a new late P20-P60 postnatal developmental stage of the heart in rodents during which, in part, ephrin-B1 specifically regulates the maturation of the CM surface crests and of the diastolic function.

Increased Capillary Permeability in Heart Induces Diastolic Dysfunction Independently of Inflammation, Fibrosis, or Cardiomyocyte Dysfunction.

BACKGROUND: While endothelial dysfunction is suggested to contribute to heart failure with preserved ejection fraction pathophysiology, understanding the importance of the endothelium alone, in the pathogenesis of diastolic abnormalities has not yet been fully elucidated. Here, we investigated the consequences of specific endothelial dysfunction on cardiac function, independently of any comorbidity or risk factor (diabetes or obesity) and their potential effect on cardiomyocyte. METHODS: The ubiquitine ligase Pdzrn3, expressed in endothelial cells (ECs), was shown to destabilize tight junction. A genetic mouse model in which Pdzrn3 is overexpressed in EC (iEC-Pdzrn3) in adults was developed. RESULTS: EC-specific Pdzrn3 expression increased cardiac leakage of IgG and fibrinogen blood-born molecules. The induced edema demonstrated features of diastolic dysfunction, with increased end-diastolic pressure, alteration of dP/dt min, increased natriuretic peptides, in addition to limited exercise capacity, without major signs of cardiac fibrosis and inflammation. Electron microscopic images showed edema with disrupted EC-cardiomyocyte interactions. RNA sequencing analysis of gene expression in cardiac EC demonstrated a decrease in genes coding for endothelial extracellular matrix proteins, which could be related to the fragile blood vessel phenotype. Irregularly shaped capillaries with hemorrhages were found in heart sections of iEC-Pdzrn3 mice. We also found that a high-fat diet was not sufficient to provoke diastolic dysfunction; high-fat diet aggravated cardiac inflammation, associated with an altered cardiac metabolic signature in EC-Pdzrn3 mice, reminiscent of heart failure with preserved ejection fraction features. CONCLUSIONS: An increase of endothelial permeability is responsible for mediating diastolic dysfunction pathophysiology and for aggravating detrimental effects of a high-fat diet on cardiac inflammation and metabolism.

Kidney Histopathology Can Predict Kidney Function in ANCA-Associated Vasculitides with Acute Kidney Injury Treated with Plasma Exchanges.

BACKGROUND: Data from the PEXIVAS trial challenged the role of plasma exchange (PLEX) in ANCA-associated vasculitides (AAV). We aimed to describe kidney biopsy from patients with AAV treated with PLEX, evaluate whether histopathologic findings could predict kidney function, and identify which patients would most benefit from PLEX. METHODS: We performed a multicenter, retrospective study on 188 patients with AAV and AKI treated with PLEX and 237 not treated with PLEX. The primary outcome was mortality or KRT at 12 months (M12). RESULTS: No significant benefit of PLEX for the primary outcome was found. To identify patients benefitting from PLEX, we developed a model predicting the average treatment effect of PLEX for an individual depending on covariables. Using the prediction model, 223 patients had a better predicted outcome with PLEX than without PLEX, and 177 of them had >5% increased predicted probability with PLEX compared with without PLEX of being alive and free from KRT at M12, which defined the PLEX-recommended group. Risk difference for death or KRT at M12 was significantly lower with PLEX in the PLEX-recommended group (-15.9%; 95% CI, -29.4 to -2.5) compared with the PLEX not recommended group (-4.8%; 95% CI, 14.9 to 5.3). Microscopic polyangiitis, MPO-ANCA, higher serum creatinine, crescentic and sclerotic classes, and higher Brix score were more frequent in the PLEX-recommended group. An easy to use score identified patients who would benefit from PLEX. The average treatment effect of PLEX for those with recommended treatment corresponded to an absolute risk reduction for death or KRT at M12 of 24.6%. CONCLUSIONS: PLEX was not associated with a better primary outcome in the whole study population, but we identified a subset of patients who could benefit from PLEX. However, these findings must be validated before utilized in clinical decision making.

Gunshot residue detection in stagnant water: SEM-EDX or ICP-MS? A preliminary study.

The identification of gunshot residue (GSR) on wounds enables the differentiation of entry and exit wounds. Unfortunately, studies analyzing GSR on degraded bodies have been poorly documented, and no data exist regarding GSR detection after stagnant water immersion. The aim of this preliminary experimental study was to detect GSR on wounds altered in stagnant water, using scanning electron microscopy coupled with energy-dispersive X (SEM-EDX) and inductively coupled plasma mass spectrometry (ICP-MS). Shots were performed on sheep limbs with a 22LR at a distance of 20 cm. The limbs were then submerged in stagnant water and analyzed on days 0, 6, and 14. SEM-EDX was performed on previously dehydrated wounds. For ICP-MS analysis, the wounds were rubbed with a cotton swab that was then analyzed. In the SEM studies, a higher number of particles were detected in entry wounds compared to exit wounds under every set of experimental conditions. Unfortunately, SEM-EDX failed to detect GSR particles, even on day 0. ICP-MS enabled the detection of Pb, Sb, and Ba at every stage with higher quantities on entry than in exit. These elements remained detectable following limb immersion. ICP-MS enabled differentiate entry from exit wounds, even after immersion in stagnant water. Nevertheless, when manually swabbing the wounds, quantities of matter collected is highly variable. ICP-MS is a more suitable technique than SEM-EDX for GSR identification of wounds after decomposition in stagnant water; however, standardization is needed.

The last battle of Anne of Brittany: Solving mass grave through an interdisciplinary approach (paleopathology, biological anthropology, history, multiple isotopes and radiocarbon dating).

Mass graves are usually key historical markers with strong incentive for archeological investigations. The identification of individuals buried in mass graves has long benefitted from traditional historical, archaeological, anthropological and paleopathological techniques. The addition of novel methods including genetic, genomic and isotopic geochemistry have renewed interest in solving unidentified mass graves. In this study, we demonstrate that the combined use of these techniques allows the identification of the individuals found in two Breton historical mass graves, where one method alone would not have revealed the importance of this discovery. The skeletons likely belong to soldiers from the two enemy armies who fought during a major event of Breton history: the siege of Rennes in 1491, which ended by the wedding of the Duchess of Brittany with the King of France and signaled the end of the independence of the region. Our study highlights the value of interdisciplinary approaches with a particular emphasis on increasingly accurate isotopic markers. The development of the sulfur isoscape and testing of the triple isotope geographic assignment are detailed in a companion paper [13].

Kinin B1 receptor: a potential therapeutic target in sepsis-induced vascular hyperpermeability.

BACKGROUND: In sepsis, the endothelial barrier becomes incompetent, with the leaking of plasma into interstitial tissues. VE-cadherin, an adherens junction protein, is the gatekeeper of endothelial cohesion. Kinins, released during sepsis, induce vascular leakage and vasodilation. They act via two G-protein coupled receptors: B1 (B1R) and B2 (B2R). B1R is inducible in the presence of pro-inflammatory cytokines, endotoxins or after tissue injury. It acts at a later stage of sepsis and elicits a sustained inflammatory response. The aim of our study was to investigate the relationships between B1R and VE-cadherin destabilization in vivo in a later phase of sepsis. METHODS: Experimental, prospective study in a university research laboratory. We used a polymicrobial model of septic shock by cecal ligation and puncture in C57BL6 male mice or C57BL6 male mice that received a specific B1R antagonist (R-954). We studied the influence of B1R on sepsis-induced vascular permeability 30 h after surgery for several organs, and VE-cadherin expression in the lung and kidneys by injecting R-954 just before surgery. The 96-h survival was determined in mice without treatment or in animals receiving R-954 as a "prophylactic" regimen (a subcutaneous injection of 200 µg/kg, prior to CLP and 24 h after CLP), or as a "curative" regimen (injection of 100 µg/kg at H6, H24 and H48 post-surgery). RESULTS: B1R inactivation helps to maintain MAP above 65 mmHg but induces different permeability profiles depending on whether or not organ perfusion is autoregulated. In our model, VE-cadherin was destabilized in vivo during septic shock. At a late stage of sepsis, the B1R blockade reduced the VE-cadherin disruption by limiting eNOS activation. The survival rate for mice that received R-954 after sepsis induction was higher than in animals that received an antagonist as a prophylactic treatment. CONCLUSIONS: B1R antagonizing reduced mortality in our model of murine septic shock by limiting the vascular permeability induced by VE-cadherin destabilization through maintenance of the macrohemodynamics, consequently limiting organ dysfunctions.

Finding of Hyperostosis Frontalis Interna During the Autopsy Procedure: Forensic Issues.

Hyperostosis frontalis interna is a common phenomenon, which may have been overrated in its significance in the past, and may, currently be underrated in its significance. We present three cases of hyperostosis frontalis interna found during medicolegal autopsies and discuss their forensic considerations. The patients were all middle-aged women with metabolic and endocrine manifestations and psychiatric ailments; thickening of the inner table of the frontal bone of the skull was found during each autopsy. We describe the relationship between hyperostosis frontalis interna, metabolic manifestations, and neuropsychiatric symptoms as part of Morgagni-Stewart-Morel syndrome. There is still considerable disagreement in the scientific community as to whether this syndrome is a clinical entity. Nonetheless, awareness of Morgagni-Stewart-Morel syndrome can be of help in understanding the circumstances surrounding death. In some other cases, hyperostosis frontalis interna could be used by forensic pathologists as criteria for sexing and aging a skeleton.

Structural evidence for a new elaborate 3D-organization of the cardiomyocyte lateral membrane in adult mammalian cardiac tissues.

AIMS: This study explored the lateral crest structures of adult cardiomyocytes (CMs) within healthy and diseased cardiac tissue. METHODS AND RESULTS: Using high-resolution electron and atomic force microscopy, we performed an exhaustive quantitative analysis of the three-dimensional (3D) structure of the CM lateral surface in different cardiac compartments from various mammalian species (mouse, rat, cow, and human) and determined the technical pitfalls that limit its observation. Although crests were observed in nearly all CMs from all heart compartments in all species, we showed that their heights, dictated by the subsarcolemmal mitochondria number, substantially differ between compartments from one species to another and tightly correlate with the sarcomere length. Differences in crest heights also exist between species; for example, the similar cardiac compartments in cows and humans exhibit higher crests than rodents. Unexpectedly, we found that lateral surface crests establish tight junctional contacts with crests from neighbouring CMs. Consistently, super-resolution SIM or STED-based immunofluorescence imaging of the cardiac tissue revealed intermittent claudin-5-claudin-5 interactions in trans via their extracellular part and crossing the basement membrane. Finally, we found a loss of crest structures and crest-crest contacts in diseased human CMs and in an experimental mouse model of left ventricle barometric overload. CONCLUSION: Overall, these results provide the first evidence for the existence of differential CM surface crests in the cardiac tissue as well as the existence of CM-CM direct physical contacts at their lateral face through crest-crest interactions. We propose a model in which this specific 3D organization of the CM lateral membrane ensures the myofibril/myofiber alignment and the overall cardiac tissue cohesion. A potential role in the control of sarcomere relaxation and of diastolic ventricular dysfunction is also discussed. Whether the loss of CM surface crests constitutes an initial and common event leading to the CM degeneration and the setting of heart failure will need further investigation.

Sudden Death Due to Coronary Arteritis.

We report the case of a middle-aged man, without medical history, who suddenly died at his workplace. The autopsy highlighted a pathological heart macroscopically, with multiple small white areas on the left myocardium. Coronary dissection revealed a pseudotumoural fibromyxoid aspect within the anterior interventricular artery (AIVA) and the left main coronary trunk, including reduction in their diameter with tight stenosis. Microscopic examination of these arteries showed fibroinflammatory wall destruction. In the left myocardium, there were multiple focal ischemic areas at different stages of recovery. Our case is an illustration of primary ischemic heart disease due to coronary arteritis, with a pseudotumoural presentation, which was revealed by sudden death. We discuss the cause of death and the etiological diagnosis preceding coronary arteritis.

Detection of glass particles on bone lesions using SEM-EDS.

The problem of identifying the wounding agent in forensic cases is recurrent. Moreover, when several tools are involved, distinguishing the origin of lesions can be difficult. Scanning electron microscopy (SEM)/energy dispersive X-ray analysis (EDS) equipment is increasingly available to the scientific and medical community, and some studies have reported its use in forensic anthropology. However, at our knowledge, no study has reported the use of SEM-EDS in forensic cases involving glass tools, whether in case reports or experiments. We performed an experimental study on human rib fragments, on which we manually created wounds using fragments of window and mirror glass. SEM-EDS was executed on samples without any further preparation on low vacuum mode, then on the same samples after defleshing them completely by boiling them. Window and mirror glass particles were detected on experimental wounds. Both had silica in their spectra, and the opaque side of the mirror contained titanium, allowing for their identification. Boiling and defleshing the bone samples involved a loss of information in terms of the number of wounds detected as positive for glass particles and in the number of glass particles detected, for both window and mirror glass. We suggest the analysis of wounds with suspected glass particles using low vacuum mode and with no defleshment by boiling.

Biophysical properties of cardiomyocyte surface explored by multiparametric AFM.

PeakForce Quantitative Nanomechanical Mapping (PeakForce QNM) multiparametric AFM mode was adapted to qualitative and quantitative study of the lateral membrane of cardiomyocytes (CMs), extending this powerful mode to the study of soft cells. On living CM, PeakForce QNM depicted the crests and hollows periodic alternation of cell surface architecture previously described using AFM Force Volume (FV) mode. PeakForce QNM analysis provided better resolution in terms of pixel number compared to FV mode and reduced acquisition time, thus limiting the consequences of spontaneous living adult CM dedifferentiation once isolated from the cardiac tissue. PeakForce QNM mode on fixed CMs clearly visualized subsarcolemmal mitochondria (SSM) and their loss following formamide treatment, concomitant with the interfibrillar mitochondria climbing up and forming heaps at the cell surface. Interestingly, formamide-promoted SSM loss allowed visualization of the sarcomeric apparatus ultrastructure below the plasma membrane. High PeakForce QNM resolution led to better contrasted mechanical maps than FV mode and provided correlation between adhesion, dissipation, mechanical and topographical maps. Modified hydrophobic AFM tip enhanced contrast on adhesion and dissipation maps and suggested that CM surface crests and hollows exhibit distinct chemical properties. Finally, two-dimensional Fast Fourier Transform to objectively quantify AFM maps allowed characterization of periodicity of both sarcomeric Z-line and M-band. Overall, this study validated PeakForce QNM as a valuable and innovative mode for the exploration of living and fixed CMs. In the future, it could be applied to depict cell membrane architectural, mechanical and chemical defects as well as sarcomeric abnormalities associated with cardiac diseases.

Asymptomatic circulating T-cell clone cause renal polymorphic inflammatory fibrosis.

BACKGROUND: Renal complications of non-Hodgkin lymphoma encompass a wide spectrum of monoclonal Ig-related pathologies. Clonal circulating T cells can also be associated with non-renal autoimmune disorders induced by overproduction of specific patterns of cytokines or unbalanced lymphocytes sub-populations. METHODS: Immunophenotyping of circulating T cells and TCR gene restriction analysis using Biomed-2 protocol. NF-κB staining and mRNA quantification of inflammatory genes in HK-2 epithelial renal cells exposed to supernatants of peripheral blood mononuclear cells with clonal T-cell population. RESULTS: Here, we could identify a persistent clonal T-cell population, only characterized by in-depth immunophenotyping of circulating lymphocytes and using multiplex PCR analysis of TCR gene rearrangements, in two patients with polymorphic inflammatory renal fibrosis of unknown origin. Using an in vitro approach, we could demonstrate that peripheral blood mononuclear cells including the clonal population can trigger a phenotype switch of epithelial renal cells from a quiescent state to a pro-inflammatory state characterized by NF-κB nuclear translocation and overexpression of inflammatory cytokine or chemokine. CONCLUSION: These preliminary data suggest that circulating T-cell clones may directly activate epithelial renal cells or promote a T-/B-cell population with autoimmune reactive properties against kidney cells, which, in the absence of overt renal lymphoma infiltration, lead to the subsequent inflammatory renal fibrotic phenotype.

High intake of dietary tyramine does not deteriorate glucose handling and does not cause adverse cardiovascular effects in mice

Tyramine is naturally occurring in food and induces pressor responses. Low-tyramine diets are recommended for patients treated with MAO inhibitors to avoid the fatal hypertensive crisis sadly known as "cheese effect". Hence, tyramine intake is suspected to have toxicological consequences in humans, while its administration to type 1 diabetic rodents has been reported to improve glucose tolerance. We investigated in mice whether prolonged tyramine ingestion could alter glucose homeostasis, insulin sensitivity, adipose tissue physiology or cardiovascular functions. Tyramine was added at 0.04 or 0.14 % in the drinking water since this was estimated to increase by 10- to 40-fold the spontaneous tyramine intake of control mice fed a standard diet. Ten to 12 weeks of such tyramine supplementation did not influence body weight gain, adiposity or food consumption. Both doses (reaching approx. 300 and 1100 μmol tyramine/kg bw/day) decreased nonfasting blood glucose but did not modify glucose tolerance or fasting levels of glucose, insulin or circulating lipids. Blood pressure was not increased in tyramine-drinking mice, while only the higher tested dose moderately increased heart rate without change in its variability. Markers of cardiac tissue injury or oxidative stress remained unaltered, except an increased hydrogen peroxide production in heart preparations. In isolated adipocytes, tyramine inhibited lipolysis similarly in treated and control groups, as did insulin. The lack of serious adverse cardiovascular effects of prolonged tyramine supplementation in normoglycemic mice together with the somewhat insulin-like effects found on adipose cells should lead to reconsider favourably the risk/benefit ratio of the intake of this dietary amine (AU)

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Chronic tubulointerstitial nephropathy induced by glucosamine: a case report and literature review.

Glucosamine is a glycosylated amine and a slow-acting symptomatic treatment for osteoarthritis. Some experimental animal studies have shown that glucosamine can cause apoptosis in kidney tubular and mesangial cells as well as overexpression of transforming growth factor ß1 (TGF-ß1) and connective-tissue growth factor (CTGF), which are potent inducers of mesangial and interstitial tubulointerstitial fibrosis. We report the case of a 67-year-old patient who presented with non-proteinuric renal insufficiency and a reduction of the glomerularfiltration rate (GFR) from 86 to 46 mL/min within 3 months. A kidney biopsy showed noninflammatory 40 - 50% fibrosis of the renal cortex associated with acute tubular necrosis. The etiological investigation was negative apart from taking 1,200 mg of glucosamine daily for 3 years to treat osteoarthritic knee pain. Three weeks after stopping glucosamine, GFR increased from 47.5 to 60 mL/min. Reintroduction of glucosamine resulted in loss of kidney function after 3 weeks, with GFR reduced from 60 to 53 mL/ min. Thus, glucosamine was shown to cause renal toxicity. Referring to other reported cases, we conclude that toxicity is rare but may also be underreported.

Successful Transplantation in ABO- and HLA-Incompatible Living Kidney Transplant Patients: A Report on 12 Cases.

Few studies have assessed the outcomes of ABOi/HLAi living-kidney transplantation. We report a single-center experience of 12 ABOi/HLAi living-kidney recipients. Twenty-seven donor-specific alloantibodies (DSAs) (1-6 per patient) were found with fluorescence intensities of 1500-15 000. Desensitization was based on IVIg, two doses of rituximab (375 mg/m2 ), tacrolimus-based (0.2 mg/kg) immunosuppression (started on day-10 pretransplant), and 11 (6-27) pretransplant apheresis sessions (plasmapheresis, specific or semi-specific immunoadsorption). By day 0, 17 of the 27 DSAs had become undetectable. After 19 (3-51) months, patient- and graft-survival rates were 100% and 91.6%, respectively. One patient had an acute humoral rejection whereas three had a chronic antibody-mediated rejection (CAMR). At the last follow-up, kidney biopsies were nearly normal in seven cases (58.3%) and renal function was excellent except for the three cases of CAMR. Four patients had a BK virus infection. We conclude that ABOi/HLAi living-kidney transplantation is a reasonable option for highly sensitized patients.

Oxidative Stress by Monoamine Oxidase-A Impairs Transcription Factor EB Activation and Autophagosome Clearance, Leading to Cardiomyocyte Necrosis and Heart Failure.

AIMS: In heart failure (HF), mitochondrial quality control and autophagy are progressively impaired, but the role of oxidative stress in this process and its underlying mechanism remain to be defined. By degrading norepinephrine and serotonin, the mitochondrial enzyme, monoamine oxidase-A (MAO-A), is a potent source of reactive oxygen species (ROS) in the heart and its activation leads to the persistence of mitochondrial damage. In this study, we analyzed the consequences of ROS generation by MAO-A on the autophagy-lysosome pathway in the heart. RESULTS: Cardiomyocyte-driven expression of MAO-A in mice led to mitochondrial fission and translocation of Drp1 and Parkin in the mitochondrial compartment. Ventricles from MAO-A transgenic mice displayed accumulation of LC3-positive autophagosomes, together with p62 and ubiquitylated proteins, indicating impairment of autophagy. In vitro adenoviral delivery of MAO-A in cardiomyocytes and the consequent generation of ROS blocked autophagic flux with accumulation of LC3II, p62, and ubiquitylated proteins, leading to mitochondrial fission and cell necrosis. In addition, MAO-A activation induced accumulation of lysosomal proteins, cathepsin D and Lamp1, reduced lysosomal acidification, and blocked the nuclear translocation of transcription factor-EB (TFEB), a master regulator of autophagy and lysosome biogenesis. Most interestingly, overexpression of TFEB attenuated autophagosome buildup, mitochondrial fission, cardiomyocyte death, and HF associated with MAO-A activation. INNOVATION AND CONCLUSION: This study unravels a new link between MAO-dependent H2O2 production and lysosomal dysfunction. Altogether, our findings demonstrate that the MAO-A/H2O2 axis has a negative impact on the elimination and recycling of mitochondria through the autophagy-lysosome pathway, which participates in cardiomyocyte death and HF. Antioxid. Redox Signal. 25, 10-27.