Decreasing microtubule detyrosination modulates Nav1.5 subcellular distribution and restores sodium current in mdx cardiomyocytes.

Aims: The microtubule (MT) network plays a major role in the transport of the cardiac sodium channel Nav1.5 to the membrane, where the latter associates with interacting proteins such as dystrophin. Alterations in MT dynamics are known to impact on ion channel trafficking.

Recent advances and current limitations of available technology to optically manipulate and observe cardiac electrophysiology.

Optogenetics, utilising light-reactive proteins to manipulate tissue activity, are a relatively novel approach in the field of cardiac electrophysiology. We here provide an overview of light-activated transmembrane channels (optogenetic actuators) currently applied in strategies to modulate cardiac activity, as well as newly developed variants yet to be implemented in the heart. In addition, we touch upon genetically encoded indicators (optogenetic sensors) and fluorescent dyes to monitor tissue activity, including cardiac transmembrane potential and ion homeostasis.

Optogenetic manipulation of cardiac repolarization gradients using sub-threshold illumination.

Mechanisms underlying cardiac arrhythmias are typically driven by abnormalities in cardiac conduction and/or heterogeneities in repolarization time (RT) across the heart. While conduction slowing can be caused by either electrophysiological defects or physical blockade in cardiac tissue, RT heterogeneities are mainly related to action potential (AP) prolongation or abbreviation in specific areas of the heart. Importantly, the size of the area with altered RT and the difference between the short RT and long RT (RT gradient) have been identified as critical determinators of arrhythmogenicity.

Microtubule plus-end tracking proteins: novel modulators of cardiac sodium channels and arrhythmogenesis.

The cardiac sodium channel NaV1.5 is an essential modulator of cardiac excitability, with decreased NaV1.5 levels at the plasma membrane and consequent reduction in sodium current (INa) leading to potentially lethal cardiac arrhythmias.

Desmosomal protein degradation as an underlying cause of arrhythmogenic cardiomyopathy.

Arrhythmogenic cardiomyopathy (ACM) is an inherited progressive cardiac disease. Many patients with ACM harbor mutations in desmosomal genes, predominantly in plakophilin-2 (). Although the genetic basis of ACM is well characterized, the underlying disease-driving mechanisms remain unresolved.

Subcellular diversity of Nav1.5 in cardiomyocytes: distinct functions, mechanisms and targets.

In cardiomyocytes, the rapid depolarisation of the membrane potential is mediated by the α-subunit of the cardiac voltage-gated Na channel (Na 1.5), encoded by the gene SCN5A. This ion channel allows positively charged Na ions to enter the cardiomyocyte, resulting in the fast upstroke of the action potential and is therefore crucial for cardiac excitability and electrical propagation.

Optogenetic manipulation of cardiac electrical dynamics using sub-threshold illumination: dissecting the role of cardiac alternans in terminating rapid rhythms.

Cardiac action potential (AP) shape and propagation are regulated by several key dynamic factors such as ion channel recovery and intracellular Ca cycling. Experimental methods for manipulating AP electrical dynamics commonly use ion channel inhibitors that lack spatial and temporal specificity. In this work, we propose an approach based on optogenetics to manipulate cardiac electrical activity employing a light-modulated depolarizing current with intensities that are too low to elicit APs (sub-threshold illumination), but are sufficient to fine-tune AP electrical dynamics.

Targeting the Microtubule EB1-CLASP2 Complex Modulates Na1.5 at Intercalated Discs.

[Figure: see text].

Low human dystrophin levels prevent cardiac electrophysiological and structural remodelling in a Duchenne mouse model.

Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disorder caused by loss of dystrophin. This lack also affects cardiac structure and function, and cardiovascular complications are a major cause of death in DMD. Newly developed therapies partially restore dystrophin expression.

Patch-Clamp Recordings of Action Potentials From Human Atrial Myocytes: Optimization Through Dynamic Clamp.

Atrial fibrillation (AF) is the most common cardiac arrhythmia. Consequently, novel therapies are being developed. Ultimately, the impact of compounds on the action potential (AP) needs to be tested in freshly isolated human atrial myocytes.

Oxidation of Protein Kinase A Regulatory Subunit PKARIα Protects Against Myocardial Ischemia-Reperfusion Injury by Inhibiting Lysosomal-Triggered Calcium Release.

Background: Kinase oxidation is a critical signaling mechanism through which changes in the intracellular redox state alter cardiac function. In the myocardium, PKARIα (type-1 protein kinase A) can be reversibly oxidized, forming interprotein disulfide bonds in the holoenzyme complex. However, the effect of PKARIα disulfide formation on downstream signaling in the heart, particularly under states of oxidative stress such as ischemia and reperfusion (I/R), remains unexplored.

Functional modulation of atrio-ventricular conduction by enhanced late sodium current and calcium-dependent mechanisms in Scn5a1798insD/+ mice.

Aims: SCN5A mutations are associated with arrhythmia syndromes, including Brugada syndrome, long QT syndrome type 3 (LQT3), and cardiac conduction disease. Long QT syndrome type 3 patients display atrio-ventricular (AV) conduction slowing which may contribute to arrhythmogenesis. We here investigated the as yet unknown underlying mechanisms.

Radiofrequency ablation with four electrodes as a building block for matrix radiofrequency ablation: Ex vivo liver experiments and finite element method modelling. Influence of electric and activation mode on coagulation size and geometry.

Purpose: Radiofrequency ablation (RFA) is increasingly being used to treat unresectable liver tumors. Complete ablation of the tumor and a safety margin is necessary to prevent local recurrence. With current electrodes, size and shape of the ablation zone are highly variable leading to unsatisfactory local recurrence rates, especially for tumors >3 cm.

Absence of Functional Na1.8 Channels in Non-diseased Atrial and Ventricular Cardiomyocytes.

Purpose: Several studies have indicated a potential role for SCN10A/Na1.8 in modulating cardiac electrophysiology and arrhythmia susceptibility. However, by which mechanism SCN10A/Na1.

Functional Consequences of the -p.Y1977N Mutation within the PY Ubiquitylation Motif: Discrepancy between HEK293 Cells and Transgenic Mice.

Dysfunction of the cardiac sodium channel Nav1.5 (encoded by the gene) is associated with arrhythmias and sudden cardiac death. mutations associated with long QT syndrome type 3 (LQT3) lead to enhanced late sodium current and consequent action potential (AP) prolongation.

A common co-morbidity modulates disease expression and treatment efficacy in inherited cardiac sodium channelopathy.

Aims: Management of patients with inherited cardiac ion channelopathy is hindered by variability in disease severity and sudden cardiac death (SCD) risk. Here, we investigated the modulatory role of hypertrophy on arrhythmia and SCD risk in sodium channelopathy.

Methods And Results: Follow-up data was collected from 164 individuals positive for the SCN5A-1795insD founder mutation and 247 mutation-negative relatives.

Prognostic features of breast cancer differ between women in the Democratic Republic of Congo and Belgium.

Objectives: Compared to European women, breast cancers in African women present at a younger age, with a higher tumor grade and are more often estrogen receptor (ER)/progesterone receptor (PR) negative. We here investigate the histopathological and immunohistochemical characteristics (ER, PR and human epidermal growth receptor 2 (HER2)) and the proportion of triple negative (Tneg) invasive breast cancers from an unselected series of patients diagnosed in Kinshasa, and compare them to a population of Caucasian women with a palpable breast cancer.

Materials And Methods: From 2010 till 2013, during the first breast cancer awareness campaign, organized in Kinshasa, 87 patients were diagnosed with invasive breast cancer.

Bipolar radiofrequency ablation with 2 × 2 electrodes as a building block for matrix radiofrequency ablation: Ex vivo liver experiments and finite element method modelling.

Purpose: Size and geometry of the ablation zone obtained by currently available radiofrequency (RF) electrodes is highly variable. Reliability might be improved by matrix radiofrequency ablation (MRFA), in which the whole tumour volume is contained within a cage of x × y parallel electrodes. The aim of this study was to optimise the smallest building block for matrix radiofrequency ablation: a recently developed bipolar 2 × 2 electrode system.

Requirement of MyD88 and Fas pathways for the efficacy of allergen-free immunotherapy.

Background: We have shown that mycobacterial antigens and CpG oligodeoxynucleotides downmodulate airway allergic inflammation by mechanisms dependent on T-cell activation. Here, we investigated the participation of the innate response, particularly the role of MyD88 adaptor, and Fas molecules in the effectiveness of DNA-HSP65 or CpG/culture filtrated proteins (CFP) immunotherapy.

Methods: Mice sensitized and challenged with Der p 1 allergen were treated with DNA-HSP65, CpG/CFP, or with adoptively transferred cells from immunized mice.

From the set-up of a screening program of breast cancer patients to the identification of the first BRCA mutation in the DR Congo.

Background: Breast cancer incidence in African population is low compared to western countries but the mortality rate is higher and the disease presents at a younger age and at a more advanced stage. The World Health Organisation and the Breast Health Global Initiative concluded that in low and middle income countries early breast cancer detection can be achieved by informing women on symptoms of breast cancer, on the practice of breast self-examination and clinical breast examination by trained health care workers. Based on these recommendations, we set up a breast cancer awareness campaign in Kinshasa, Democratic Republic of Congo (DRC).

Bacillus Calmette-Guérin strain differences have an impact on clinical outcome in bladder cancer immunotherapy.

Background: Whether the commonly used bacillus Calmette-Guérin (BCG) strains Connaught and Tice confer different treatment responses in non-muscle-invasive bladder cancer (NMIBC) is unknown.

Objectives: To compare clinical efficacy, immunogenicity, and genetics of BCG Connaught and Tice.

Design, Setting, And Participants: A prospective randomized single-institution trial with treatment of 142 high-risk NMIBC patients with BCG Connaught or Tice.