Arrhythmic mitral valve prolapse in 2023: Evidence-based update

Patients with mitral valve prolapse (MVP) may develop ventricular arrhythmias, ranging from premature ventricular contractions through more complex non-sustained ventricular tachycardia to sustained life-threatening ventricular arrhythmias. The prevalence of MVP in autopsy series of young adults who died suddenly has been estimated to be between 4% and 7%. Thus, “arrhythmic MVP” has been reported as an underappreciated cause of sudden cardiac death, leading to a renewed interest in the study of this association. The term “arrhythmic MVP” refers to a small subset of patients who have, in the absence of any other arrhythmic substrate, MVP, with or without mitral annular disjunction, and frequent or complex ventricular arrhythmias. Our understanding of their coexistence in terms of contemporary management and prognosis is still incomplete. While literature regarding the arrhythmic MVP may be contrasting despite recent consensus document, the present review summarizes the relevant evidence concerning the diagnostic approach, prognostic implications, and targeted therapies for MVP-related ventricular arrhythmias. We also summarize recent data supporting left ventricular remodeling, which complicates the coexistence of MVP with ventricular arrhythmias. As the evidence for a putative link between MVP-associated ventricular arrhythmias and sudden cardiac death is scarce and based on scant and retrospective data, risk prediction remains a challenge. Thus, we aimed at listing potential risk factors from available seminal reports for further use in a more reliable prediction model that requires additional prospective data. Finally, we summarize evidence and guidelines on targeted therapies of ventricular arrhythmias in the setting of MVP, including implantable cardioverter defibrillators and catheter ablation. Our review highlights current knowledge gaps and provides an action plan for structured research on the pathophysiological genesis, diagnosis, prognostic impact, and optimal management of patients with arrhythmic MVP

Loss of DPP4 activity is related to a prothrombogenic status of endothelial cells: implications for the coronary microvasculature of myocardial infarction patients

Pro-coagulant and pro-inflammatory intramyocardial (micro)vasculature plays an important role in acute myocardial infarction (AMI). Currently, inhibition of serine protease dipeptidyl peptidase 4 (DPP4) receives a lot of interest as an anti-hyperglycemic therapy in type 2 diabetes patients. However, DPP4 also possesses anti-thrombotic properties and may behave as an immobilized anti-coagulant on endothelial cells. Here, we studied the expression and activity of endothelial DPP4 in human myocardial infarction in relation to a prothrombogenic endothelial phenotype. Using (immuno)histochemistry, DPP4 expression and activity were found on the endothelium of intramyocardial blood vessels in autopsied control hearts (n = 9). Within the infarction area of AMI patients (n = 73), this DPP4 expression and activity were significantly decreased, coinciding with an increase in Tissue Factor expression. In primary human umbilical vein endothelial cells (HUVECs), Western blot analysis and digital imaging fluorescence microscopy revealed that DPP4 expression was strongly decreased after metabolic inhibition, also coinciding with Tissue Factor upregulation. Interestingly, inhibition of DPP4 activity with diprotin A also enhanced the amount of Tissue Factor encountered and induced the adherence of platelets under flow conditions. Ischemia induces loss of coronary microvascular endothelial DPP4 expression and increased Tissue Factor expression in AMI as well as in vitro in HUVECs. Our data suggest that the loss of DPP4 activity affects the anti-thrombogenic nature of the endothelium

O-Glycosylation Regulates Ubiquitination and Degradation of the Anti-Inflammatory Protein A20 to Accelerate Atherosclerosis in Diabetic ApoE-Null Mice

Background: Accelerated atherosclerosis is the leading cause of morbidity and mortality in diabetic patients. Hyperglycemia is a recognized independent risk factor for heightened atherogenesis in diabetes mellitus (DM). However, our understanding of the mechanisms underlying glucose damage to the vasculature remains incomplete. Methodology/Principal Findings: High glucose and hyperglycemia reduced upregulation of the NF-κB inhibitory and atheroprotective protein A20 in human coronary endothelial (EC) and smooth muscle cell (SMC) cultures challenged with Tumor Necrosis Factor alpha (TNF), aortae of diabetic mice following Lipopolysaccharide (LPS) injection used as an inflammatory insult and in failed vein-grafts of diabetic patients. Decreased vascular expression of A20 did not relate to defective transcription, as A20 mRNA levels were similar or even higher in EC/SMC cultured in high glucose, in vessels of diabetic C57BL/6 and FBV/N mice, and in failed vein grafts of diabetic patients, when compared to controls. Rather, decreased A20 expression correlated with post-translational O-Glucosamine-N-Acetylation (O-GlcNAcylation) and ubiquitination of A20, targeting it for proteasomal degradation. Restoring A20 levels by inhibiting O-GlcNAcylation, blocking proteasome activity, or overexpressing A20, blocked upregulation of the receptor for advanced glycation end-products (RAGE) and phosphorylation of PKCβII, two prime atherogenic signals triggered by high glucose in EC/SMC. A20 gene transfer to the aortic arch of diabetic ApoE null mice that develop accelerated atherosclerosis, attenuated vascular expression of RAGE and phospho-PKCβII, significantly reducing atherosclerosis. Conclusions: High glucose/hyperglycemia regulate vascular A20 expression via O-GlcNAcylation-dependent ubiquitination and proteasomal degradation. This could be key to the pathogenesis of accelerated atherosclerosis in diabetes

EHRA expert consensus statement on arrhythmic mitral valve prolapse and mitral annular disjunction complex in collaboration with the ESC Council on valvular heart disease and the European Association of Cardiovascular Imaging endorsed cby the Heart Rhythm Society, by the Asia Pacific Heart Rhythm Society, and by the Latin American Heart Rhythm Society.

peer reviewe

p75(NTR)-dependent activation of NF-κB regulates microRNA-503 transcription and pericyte-endothelial crosstalk in diabetes after limb ischaemia

The communication between vascular endothelial cells (ECs) and pericytes in the microvasculature is fundamental for vascular growth and homeostasis; however, these processes are disrupted by diabetes. Here we show that modulation of p75NTR expression in ECs exposed to high glucose activates transcription of miR-503, which negatively affects pericyte function. p75NTR activates NF-κB to bind the miR-503 promoter and upregulate miR-503 expression in ECs. NF-κB further induces activation of Rho kinase and shedding of endothelial microparticles carrying miR-503, which transfer miR-503 from ECs to vascular pericytes. The integrin-mediated uptake of miR-503 in the recipient pericytes reduces expression of EFNB2 and VEGFA, resulting in impaired migration and proliferation. We confirm operation of the above mechanisms in mouse models of diabetes, in which EC-derived miR-503 reduces pericyte coverage of capillaries, increased permeability and impaired post-ischaemic angiogenesis in limb muscles. Collectively, our data demonstrate that miR-503 regulates pericyte–endothelial crosstalk in microvascular diabetic complications

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Epidémiologie de l’infection chez les brûles hospitalises à l’unité des brûlés de l’hôpital Militaire d’instruction Mohamed V de Rabat

Objectif : déterminer le profil bactériologique des patients de l’unité des brûlés de l’hôpital Militaire de Rabat et décrire la sensibilité aux antibiotiques des bactéries prédominantes issues des plaies. Matériel et méthode : l’étude prospective comprise entre juillet 2009 et mars 2011 a été menée à l’hôpital militaire de Rabat, au sein du laboratoire de bactériologie en collaboration avec l’unité des brûlés. Un questionnaire récoltant les données relatives au patient a été rempli à l’admission du brûlé. Les prélèvements bactériologiques ont été réalisés à l’admission du patient et à chaque changement de pansement. L’identification des bactéries s’est faite en se basant sur les caractères culturo-morphologiques et biochimiques. La sensibilité aux antibiotiques a été déterminée par méthode de diffusion sur milieu gélosé en suivant les recommandations de la société française de microbiologie. L’étude statistique s’est faite à l’aide du logiciel SPSS version 13 (Statistical Package for the Social Sciences). Résultat : 58 patients ont été inclus dans l’étude. L’âge moyen de la population a été de 38,2 ± 15,5 ans avec un taux de létalité par brûlure de 13,8% et une prévalence d’infection de 43,1%. Sur les 112 prélèvements réalisés, 126 souches bactériennes non redondantes ont été identifiées avec la prédominance d’Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumoniae, Entérobacter cloacae et staphylocoque. Lorsque les résultats sont rapportés au nombre de semaines après la brûlure, les staphylocoques sont les germes les plus isolés durant la première semaine d’admission pour les prélèvements de pus superficiel alors que pour ceux d’hémocultures ce sont les A.baumannii qui dominent. Conclusion : une vigilance avec une application rigoureuse des mesures d’hygiène et une surveillance épidémiologique des bactéries sont nécessaires, à l’échelle de l’unité des brûlés et de l’hôpital, pour mieux guider l’antibiothérapie probabiliste

Prevalence of uncontrolled blood pressure in Meknes, Morocco, and its associated risk factors in 2017.

BackgroundUncontrolled high blood pressure (UBP) can lead to various cardiovascular complications causing an estimated nine million deaths per year worldwide. In Meknes, epidemiologic data on UBP are scarce, depriving programs from evidence-based information that would allow a better management of hypertension. Hence, we aimed to assess UBP prevalence in hypertensive patients treated in Meknes and identify UBP-associated risk factors.MethodsBetween November and December 2017, we conducted a cross-sectional study enrolling 922 hypertensive patients managed at Meknes's primary health care facilities using the multistage sampling method. We interviewed patients face to face to collect their socio-demographic-characteristics, lifestyle behaviours, clinical parameters and the triad care system-patient-physician. Another questionnaire was self-administered by physicians to characterize therapeutic inertia. A multivariate logistic regression analysis highlighted the risk factors associated with UBP.ResultsUBP prevalence was 73% with a mean age of 61±11 years (mean±standard deviation) and a male/female ratio of 1/3. Risk factors associated with UBP were: therapeutic inertia (adjusted odds ratio to other variables (AOR) = 18.2, 95% CI [8.35-39.84]), drug non-adherence (AOR = 1.8, 95% CI [1.07-3.04]), obesity/overweight (AOR = 1.6, 95% CI [1.03-2.58]), unemployment (AOR = 1.9, 95% CI [1.09-3.01]), low income (AOR = 2.6, 95% CI [1.01-6.86]), family history of hypertension (AOR = 1.5, 95% CI [1.07-2.08]) and male sex (AOR = 1.6, 95% CI [1.04-2.58]).ConclusionUBP prevalence is high in Meknes. Prevention should firstly focus on raised awareness of hypertensive patients' self-care management. Secondly, health professionals should better comply to the guidelines of anti-hypertensive treatments. Lastly, health professionals should frequently be reminded to reach therapeutic goals to overcome therapeutic inertia